Management of nasopharyngeal carcinoma (NPC) remains elusive despite new developments and advancement that has been made in the current management approaches. A patient’s survival and prognosis remain dismal especially for a late-stage disease. This is highly attribute to the chemoradiation resistance. Arrays of genes and molecular mechanisms underlie the development of chemoradiation resistance in NPC. Imperatively, unravelling the true pathogenesis of chemoradiation resistance is crucial as these significant proteins and genes can be modulated to produce an effective therapeutic target. It is pivotal to identify the chemoradiation resistance at the very beginning in order to combat the chemoradiation resistance efficiently. Intense research in the genetic ecosphere is critical, as the discovery and development of novel therapeutic targets can be used for screening, diagnosis, and treating the chemoradiation resistance aggressively. This will escalate the management trajectory of NPC patients. This article highlights the significance of genetic and molecular factors that play critical roles in the chemoradiation resistance and how these factors may be modified for next-generation targeted therapy products. Nasopharyngeal carcinoma (NPC) is a solid tumor composed of phenotypically and genotypically heterogeneous populations of neoplastic cells. NPC affects both the young and the elderly patients and has caused a significant burden on cancer statistics. NPC is a prevalent tumor in Southeast Asia, China, Taiwan, Hong Kong, the Middle East, and North Africa ,2,3. TheChemoradiation is the mainstay treatment for NPC. Generally, early-stage disease is highly radiosensitive and stage III–IV disease is treated with concurrent chemoradiation ,10,11. ODrug resistance, either intrinsic or acquired, is one of the major significant challenges in the recent treatment armamentarium of NPC. In practice, the majority of NPC patients present with late-stage disease and are unresponsive to chemoradiation ,21. ThisAlthough NPC patients are sensitive to chemotherapy during the initial treatment, they develop acquired resistance shortly after, leading to treatment failure. Many crucial factors contribute to the development of radioresistance in NPC. The molecular mechanisms that have been proven to contribute to the chemoresistance include drug efflux, DNA damage and repair, epithelial-mesenchymal and autophagy, exosomes, and Epstein Barr virus (EBV) ,31. EvasSignificant recent literature highlights the roles of microRNAs (miRNAs) in the pathogenesis of drug resistance. NPC carcinogenesis and development of chemoradiation resistance have all been linked to dysregulated microRNAs . By alteRecent research focus has shifted to the development of new drugs that can enhance patient prognosis and survival with fewer related complications. By understanding the true mechanism of chemoradiation resistance, a potent therapeutic target can be developed for clinical application in the head and neck oncology management armamentarium. Thus, clarifying the molecular mechanisms of chemoradiation resistance in NPC is important for developing a personalized and precise therapeutic approach. In this review, we will discuss the key genes that are involved in chemoradiation resistance in NPC and their specific mechanisms. In addition, a brief description of the pathways of implicated genes or proteins and their potential applications in fighting against drug resistance and improving anticancer efficacy will be highlighted.There are multiple critical mechanisms that underlie the chemoradiation resistance in NPC. This involves arrays of genes, proteins, and peptide products, which interact in a delicate system that play critical roles in modulation of the chemoradiation effects . The comEpithelial–mesenchymal transition (EMT) is a process by which cells change their original epithelial morphology, i.e., the epithelial cells transform into mesenchymal cells. The EMT has significant roles in cancer progression and metastases . EMT allMany facets of critical tumor growth are aided by EMT functions. Some chemo-resistant NPC cells have EMT features, implying that EMT is a type of chemo-resistance maintenance mechanism in NPCs. In NPC, Zhang et al. discovered a link between EMT and cisplatin resistance. They discovered that cisplatin-resistant NPC cells had more EMT characteristics, such as decreased E-cadherin expression and increased vimentin, fibronectin, and matrix metalloproteinase expression .Carnitine Palmitoyl Transferase 1A is a rate-limiting enzyme for mitochondrial fatty acid transportation, which plays a critical role in increasing fatty acid oxidation required for the cellular fuel demands. High expression of CPT1A promotes radiation resistance in NPC cells and contributes to poor overall survival of NPC patients following radiation therapy . DisruptThe reprogramming of lipid metabolism is a relatively emerging characteristic of cancer. Increased lipid uptake, storage, and lipogenesis are all linked to fast tumor growth in a variety of malignancies. The sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors found in the endoplasmic reticulum that play a key role in lipid metabolic control . SREBPs RARS-MAD1L1, which can be found in primary NPC and induces cellular proliferation and stem cell properties in NPC [RARS-MAD1L1 and was associated with poor survival in esophageal carcinoma [FGFR3-TACC3 fusion gene, which promotes cell proliferation, colony formation, and transforming potential via activating the ERK and AKT signaling pathways.The chromosome translocations and relevant gene fusions may contribute to tumor progression, but also the fusion protein produced by a fusion gene can be oncogenic . An exams in NPC . The humarcinoma . Other eThe base excision repair (BER) pathway has been identified as a predictor of therapeutic response, prognostic factor, and therapeutic target in a variety of cancers. The BER pathway is made up of a variety of glycosylases, endonucleases, polymerases, and ligases that work together to repair damaged DNA bases. Cancer cells take advantage of BER’s ability to repair DNA damage in order to resist DNA-damaging chemotherapies and radiotherapy. BER proteins have thus been identified as potential therapeutic targets and chemoresistance factors in a variety of cancers .XRCC1, OGG1, and APEX1, in the BER pathway were studied in 174 NPC patients who were treated with chemoradiation with five potentially functional single nucleotide polymorphisms (SNPs). They reported that that XRCC1 and OGG1 had a significant impact on primary tumor efficacy at the end of radiotherapy [Base excision repair (BER) pathway is the main way to repair the radiation-induced DNA single-strand break, including the apurinic/apyrimidinic (AP) site break and DNA base injury. In a study by Wang et al., three genes, otherapy , which mBST2 was identified as a platinum-resistant factor in NPC patients. The upregulation of BST2 resulted in platinum resistance by activating the NF-κB pathway to promote the expression of anti-apoptotic proteins. It has been shown that BST2 upregulation was associated with poor survival in patients with locally advanced NPC . NF-κB dER stress may be activated by tumor microenvironment factors such as hypoxia, pH changes, and oxidative stress induced by chemoradiation, which results in cancer and metastases. Functional polymorphisms in ER stress pathway-related genes, especially SNPs in the coding regions, may affect the expression and activity of proteins, which might be predictive factors for chemoradiotherapy efficacy and may account for the inter-patient response heterogeneity and chemoradiation resistance .Activation of Wnt-β catenin pathway has been associated with tumorigenesis and cancer progression in various types of cancers. Wnt/β-catenin signaling pathway maintains the capability for self-renewal and differentiation and induces radioresistance in several human cancers including NPC ,49. Elucβ-catenin may play a role in the migration and proliferation of NPC cells. The SNPs were correlated with grade 3 radiation-induced toxic reactions in NPC patients . This shLong noncoding RNAs (lncRNAs) are generally primary non-protein-coding sequences greater than 200 nucleotides in length. They can interact with DNA, RNA, and proteins . They arThey also underlie the chemoradioresistance in NPC. Furthermore, multiple lncRNAs are abnormally expressed in cancer cells and have been linked to the establishment of cancer cells’ radioresistant character. Increasing evidence suggests that lncRNAs affect the transcription of genes involved in the DNA damage response via a variety of regulatory mechanisms . StudiesProtein Kinase (CK2) is an important kinase expressed in most eukaryotes. The CK2 complex is a tetramer composed of two catalytic subunits, which play a vital role in cell growth, proliferation, differentiation, and apoptosis and are considered to be potential targets for regulation of processes such as cell cycle distribution, apoptosis, and DNA damage repair. SHP-1 was highly expressed in NPC tissues in contrast to normal nasopharyngeal mucosa and was associated with local recurrence and metastasis after radiotherapy in NPC patients , which cC-Jun is a major constituent of activating protein transcription factor that transduces multiple mitogen growth signals . OverexpMicroRNAs are short non-coding RNAs, typically 21–23 nucleotides long, that function in post-transcriptional gene regulation typically through translation inhibition and mRNA degradation . SpecifiNPC has a high degree of expression of EBV-encoded microRNAs, particularly BART miRNAs, which are encoded from the viral genome’s BamHI-A region. According to growing data, ebv-mir-BARTs play a vital role in host cell survival, immunological evasion, cell proliferation, cell apoptosis, and cancer metabolism, boosting NPC formation. In NPC cell lines and primary tissues, ebv-mir-BART21 and ebv-mir-BART22 are substantially expressed . ImportaMTOR, and regulating the cell cycle. Another study reported that the metastasis suppressor miR-29c can also increase NPC cells’ sensitivity to both radiotherapy and cisplatin-based chemotherapy [The importance of miRNAs in chemotherapy response has been demonstrated in NPC. For instance, miR-3188 has been found to inhibit cell growth and resistance to fluorouracil by directly targeting the mechanistic target of rapamycin kinase gene, otherapy . Tian etotherapy .Cancer stem cells (CSCs) are elucidated as cells that can perpetuate themselves via autorestoration. These cells are highly resistant to current therapeutic approaches and are the main reason for cancer recurrence. CSCs have been observed to drive tumor initiation and tumor chemoradioresistance ,51,63,64Imperatively, CSCs’ subpopulations are able to express various markers that have different phenotypic and functional characteristics, even within the same tumor . The proManagement of NPC presents specific challenges because of the complexity of the anatomical structures, the need for a multidisciplinary team, and the lifelong follow-up required for the patients. It goes without saying that early treatment saves a life. The genetic abnormalities in NPC drive the cell towards unrestricted growth by two general classes of genes, proto-oncogenes and tumor suppressor genes.Livin gene that encodes anti-apoptotic protein was found to be involved in the overgrowth of cancer cells [livin gene can prevent the development of radioresistance in the NPC cells [The mechanisms of chemoradiation resistance in NPC cells are influenced by several factors, and many approaches on how to overcome the course of chemoradiation resistance have been investigated. Among the major challenges of chemoradiation resistance is the evasion of apoptosis; inhibition of associated genes and signaling pathways have been extensively studied. The er cells . InhibitPC cells . It has PC cells .HMGB1 gene, is involved in several cellular processes including transcriptional regulation and DNA repair, and plays a role in the efficiency of NHEJ pathway [HMBG1 promotes DNA ligation in vitro and repairs DSB with an incompatible end that is normally caused by ionizing radiation. Due to its role in NHEJ machinery, a study by Zhu et al. found that inhibiting HMGB1 can overcome chemoradiation resistance in NPC.Carcinogenesis may result from chromosomal aberrations caused by unrepaired DNA double-strand breaks (DSBs), and the NHEJ pathway was known as the main DSB repair pathway. DSBs are the most critical factor in stabilizing the genome maintenance systems as they can induce apoptosis if unrepaired and can cause chromosomal aberrations if mis-repaired, which will consequently contribute to cancer formation . One of  pathway . ThroughA previous study of the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family, which includes RIG-I, reported that RIG-I activation by its ligand could induce apoptosis in several tumor cells . The effOne reason for the failures of chemotherapy is multidrug resistance (MDR) . MultidrDrug resistance in tumor is acquired via cellular and non-cellular mechanisms. Overexpression of the plasma membrane P-glycoprotein (P-gp), responsible for the cellular mechanism, is capable of repelling drugs from the cell, causing decreased sensitivity and intracellular accumulation of drugs. P-glycoprotein binds to drugs, forming transmembrane channels, pumping the compounds out of the cells . This caCompounds that can reverse the chemo drug resistance is identified as chemosensitizers or drug resistance modulators. They are classified as first-, second-, and third-generation agents. First-generation modulators are drugs that were initially developed for other purposes but incidentally found to be useful for enhancing tumor response towards chemotherapy. Some of these are tamoxifen, erythromycin, calcium channel blockers, antimalarials, and immunosuppressant agents . The secStemona curtisii has improved the response of cervical cancer patients toward vinblastine, paclitaxel, and colchicines [The root extract of chicines . Anotherchicines , was fouchicines . Variouschicines . BiochanAn ideal drug delivery technology is an ability of a drug system to stay in the blood flow and allow a continuous drug release at a particular target site. To ensure this system will work efficiently as a cancer therapeutic, it must be able to control and sustain the release of a specific drug to allow sufficient accumulation in the tumor cells . There aNanotechnologically targeted cancer chemotherapy offers a solution to overcome drug resistance tumor phenotype. It can be used to deliver specific drugs to a targeted area without harmful effects to the surrounding organs or tissue ,102. AmoThe advantage of miRNA-based treatment approaches is that miRNAs can concurrently target multiple effectors of pathways involved in tumor cell differentiation and proliferation. Thus, miRNA-based cancer treatments, alone or combined with standard chemotherapy and/or radiotherapy, hold promise to improve treatment response and cure rates . Future In addition, radioresistance is caused by several signaling pathways that interact with many key associated genes. By discovering more details on the related signaling pathways and the associated key genes, including biomarkers, we may elucidate other factors that influence radioresistance and improve patient prognosis . DentifiA major proportion of NPC patients present with recurrent and metastatic diseases despite a combined treatment modality approach. These clinical treatment failure rates remain high due to either intrinsic or extrinsic drug resistance. The chemoradioresistance in NPC is influenced by multiple critical factors including numerous proteins and molecules such as aberrant miRNAs, fusion genes, CSCs, BER pathways, etc. Accumulating evidence demonstrates a close association between chemotherapy radioresistance and these dysregulated gene expressions. An important signature in tumor progression and therapy is the advancement in genomic and molecular profiling. Microarray technology, which was developed utilizing high-throughput platforms during the last few decades, has proven to be a promising and efficient technique for detecting multiple significant cancer phenotypic features. Multitudes of proteins and biomarkers have been studied and these can be a remarkable avenue for developing a versatile and potent therapeutic agent in the near future. It is exquisitely vital to negate the chemoradioresistance efficiently, early in the disease process, in order to gain improved therapeutic outcomes. Hence, patient prognosis and quality of life can be dramatically improved.


There have been few investigations of the role that adolescent cognitive ability might play in predicting physical resilience across the life course, including decreased risk of early mortality. Our limited knowledge of how multiple cognitive ability domains shape trajectories of longevity is due, in part, to a lack of aging cohorts with early life cognitive assessments, and family data that allow for examination of shared family and genetic characteristics that may play a role in cognitive ability-health links. We capitalized on data from the 1960 Project Talent high school cohort  and mortality data  collected as part of two recent follow-ups, the Project Talent Twin & Sibling Study and the Project Talent Aging Study, to examine these potential associations. In 1960, ability was assessed in multiple cognitive domains . Mortality status was ascertained through 2016. Binary logistic generalized estimating equations with race, age, sex, and adolescent family SES covariates, indicated that each 1 standard deviation higher ability in multiple cognitive domains in adolescence predicted lower odds of earlier mortality (ORs of 0.79 - 0.87). Co-sibling control models indicated a similar pattern, suggesting that benefits associated with higher cognitive performance do not simply reflect shared environmental and genetic background, but may represent a direct protective effect. These findings indicate that better performance in multiple cognitive domains in adolescence, above and beyond the influence of genetic and family environmental factors, may be or point to modifiable protective factors against risk of early mortality.


Chronic, heavy alcohol consumption disrupts normal organ function and causes structural damage in virtually every tissue of the body. Current diagnostic terminology states that a person who drinks alcohol excessively has alcohol use disorder. The liver is especially susceptible to alcohol-induced damage. This review summarizes and describes the effects of chronic alcohol use not only on the liver, but also on other selected organs and systems affected by continual heavy drinking—including the gastrointestinal tract, pancreas, heart, and bone. Most significantly, the recovery process after cessation of alcohol consumption (abstinence) is explored. Depending on the organ and whether there is relapse, functional recovery is possible. Even after years of heavy alcohol use, the liver has a remarkable regenerative capacity and, following alcohol removal, can recover a significant portion of its original mass and function. Other organs show recovery after abstinence as well. Data on studies of both heavy alcohol use among humans and animal models of chronic ethanol feeding are discussed. This review describes how (or whether) each organ/tissue metabolizes ethanol, as metabolism influences the organ’s degree of injury. Damage sustained by the organ/tissue is reviewed, and evidence for recovery during abstinence is presented. A vast body of evidence from human studies and animal research clearly indicates that chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body. In heavy consumers of alcohol, the liver is especially susceptible to alcohol-induced injury.3As the largest internal organ and the first to see blood-borne nutrients, toxins, and xenobiotics absorbed from the GI tract, the liver is especially vulnerable to alcohol-induced damage. The liver plays a key role in the body’s metabolic regulation and is a “frontline” organ that rapidly metabolizes  alcohol to less harmful substances. However, acetaldehyde, the first metabolite generated by alcohol oxidation is actually more toxic than alcohol, but acetaldehyde is rapidly converted to acetate for use in other biochemical reactions in the body.4After drinking stops, damaged organs may regain partial function or even heal completely, depending on the extent of organ damage and whether there is relapse . Organ damage due to heavy drinking is greatest in the liver, in part because the liver has higher levels of enzymes that catalyze the metabolism of acetaldehyde from alcohol. Acetaldehyde is more toxic than ethanol because it is highly reactive and binds to biomolecules  and disrupts their function.6This review examines injury to selected organs and tissues from chronic alcohol use and their “natural recovery” after drinking ceases. Data have been obtained from both human studies and studies with experimental animal models of alcohol administration. The main points of emphasis will be how ethanol, the active ingredient and principal component in alcoholic beverages, affects the liver, GI tract, pancreas, heart, and bone. This review describes how (or whether) each organ/tissue metabolizes ethanol, as this property is closely related to the organ’s degree of injury. The damage sustained by the organ/tissue is then described, and the evidence for natural recovery after drinking cessation is reviewed. It is important to emphasize that “natural recovery” is that which is unaided by external agents that directly enhance healing of the damaged organ or tissue. In the case of the liver, such agents include drugs or other compounds that suppress inflammation or dietary or medicinal compounds , which alleviate tissue damage by enhancing protective pathways, thereby preventing further damage. Throughout the article, “alcohol” and “ethanol” are used interchangeably, given that they have the same meaning.In humans , the liver is the primary site of alcohol metabolism. The same two enzymes catalyze ethanol oxidation in both species. The major, most catalytically efficient enzyme is alcohol dehydrogenase (ADH), which catalyzes the formation of acetaldehyde from alcohol. The other enzyme, cytochrome P450 2E1 (CYP2E1), is catalytically less efficient than ADH, but it increases in both content and activity severalfold after continual alcohol exposure.Fatty liver (steatosis), characterized by an accumulation of lipids in hepatocytes, is one of the earliest pathological changes in the progression of ALD. More than 90% of people who drink heavily consume up to 60 grams or more of ethyl alcohol per day. Most of these individuals develop fatty liver.6Excessive use of alcohol (≥ 60g/day) for more than 2 weeks results in development of fatty liver (steatosis), characterized by deposition of fat in more than 5% of hepatocytes resulting in mostly macrovesicular steatosis (large intrahepatocyte lipid droplets) with or without minimal inflammation. Steatosis is mostly asymptomatic, although some people feel weakness, nausea, and pain in the right upper quadrant. Mild elevations in serum alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transferase (GGT) are seen in patients with ALD. After abstinence from alcohol for 2 to 3 weeks, hepatic steatosis completely resolves and liver biopsies appear normal when examined by electron microscopy.14With continued excessive drinking, about 20% to 40% of heavy-alcohol consumers with steatosis develop alcoholic steatohepatitis (ASH), characterized by fatty liver, inflammation with accumulation of neutrophils, ballooning degeneration of hepatocytes with or without Mallory-Denk bodies, and pericentral and perisinusoidal fibrosis. The severity of ASH can range from mild to severe and is superimposed on chronic liver disease. Severity of ASH can be assessed by the model for end-stage liver disease (MELD). A MELD score greater than 20 has been proposed as defining severe ASH with approximately 20% mortality.10Repeated episodes of ASH are accompanied by hepatic fibrosis and characterized by ballooned and dying hepatocytes and abnormal deposition of extracellular matrix around these cells. The stage/intensity of fibrosis (F0–F4) can be evaluated histologically and, in some cases, on the basis of liver stiffness, which is determined by transient elastography (FibroScan).19Researchers have studied molecular mechanisms of ALD and recovery from ALD in several animal models, most notably in rats and mice, using a wide variety of experimental conditions and various genetic backgrounds. As noted previously, both rats and mice develop fatty liver after alcohol administration, but progression to fibrosis or cirrhosis occurs only with manipulation of the diet and/or injection of an agent such as endotoxin or low-dose carbon tetrachloride to enhance a fibrotic response. This review summarizes cellular mechanisms that contribute to resolution of liver injury in alcohol-fed rats subjected to alcohol cessation. All studies described here used a similar model to investigate effects of alcohol and its cessation: Rats fed control or alcohol-containing Lieber-DeCarli liquid diets for 1 to 6 weeks showed typical serum alcohol concentrations of 200 to 300 mg/dl.23Work from Casey and others has identified alcohol-induced defects in protein trafficking and organelle function, both of which recover upon alcohol cessation.Another study reported that alcohol cessation normalizes alcohol-induced Golgi apparatus disorganization in the liver.2+) in the extracellular compartment. Ten days after alcohol cessation, Mg2+ homeostasis was restored.23In another study, Torres et al. reported that 3 weeks of alcohol administration to rats impairs hepatocytes’ ability to increase the level of magnesium ion .It is well established that impaired liver function affects other organs, and vice versa. For example, high serum NEFA levels in alcohol-fed rats arise from alcohol-induced lipolysis in adipose tissue, generating serum NEFA levels that exacerbate hepatic fat accumulation. This occurs because hepatocytes rapidly take up circulating NEFA,Alcohol cessation also resolves impaired hepatic autophagy, a key intracellular catabolic pathway that breaks down lipid droplets and other obsolete organelles. Chronic feeding of alcohol reduces the nuclear localization of transcription factor EB,22Yin et al. (1988) examined recovery in rats subjected to intragastric alcohol feeding, during which rodents are given continual intragastric infusion of an alcohol diet through an inserted cannula.26The foregoing findings indicate that several cellular mechanisms collectively contribute to resolution of steatosis and liver injury following alcohol cessation. First, since alcohol cessation would terminate ethanol metabolism, oxidant generation would be greatly decreased. Second, cessation normalizes circulating NEFA, their uptake by liver cells, and their reesterification into triglycerides. Third, alcohol cessation reactivates hepatic autophagy by restoring nuclear transcription factor EB levels, allowing resumption of lipid droplet degradation and organelle turnover. Interestingly, although alcohol cessation alleviates fat accumulation, it does not completely reverse fatty liver, probably because the amount of residual fat in livers of alcohol-fed rats overwhelms the degradation/oxidative systems. The latter findings indicate a longer recovery period is necessary to reverse fatty liver completely in alcohol-withdrawn rats.As the principal site of alcohol absorption, the GI tract plays a particularly significant role in mediating the toxic effects of alcohol on the liver and other organs. GI metabolism of alcohol is significant as it affects the systemic availability of alcohol while it locally generates acetaldehyde. GI mucosal ADH catalyzes alcohol oxidation, especially in the oropharynx and esophagus where ADH class IV activity is relatively high, and it likely contributes to local toxicity because of the acetaldehyde it produces.27Before alcohol reaches the liver, the stomach lining is the principal site of “first pass” metabolism of the ingested alcohol.27Alcohol consumption interferes with the function of all parts of the GI tract. These malfunctions are due to the local production and systemic levels of acetaldehyde. Chronic alcohol use also damages and erodes the upper GI mucosa, which encounter undiluted alcoholic beverages, causing hemorrhagic lesions and increasing the risk of cancer development. Alcohol also impairs the muscles surrounding the stomach, small intestine, and large intestine. This affects motility, which, while delaying gastric emptying, shortens transit time in the small intestine, causing diarrhea. Essentially, alcohol inhibits absorption of a variety of nutrients by the small intestine and contributes to malnourishment commonly seen in patients with alcohol use disorder (AUD).29.Most relevant, chronic alcohol use disrupts the tightly regulated gut barrier function. This barrier consists of a system of highly specialized, intercellular, multiprotein junctional complexes known as tight junctions. These are located at the apical  ends of intestinal epithelial cells. Studies reveal that alcohol metabolism in the gut disrupts tight junction structural integrity. The consequent loss of the mucosal barrier allows paracellular translocation of pathogenic molecules—including cell wall components from gram-positive and gram-negative bacteria and fungi—into the general circulation, allowing direct access to the liver via the portal vein. Once inside the liver, these microbial components can activate resident macrophages (Kupffer cells) to initiate a necroinflammatory cascade. Alcohol compromises tight junction integrity by the following molecular mechanisms: generating reactive oxygen species, upregulating production of specific micro-RNAs, and disrupting both the epithelial cell methionine metabolic pathway and the intestinal circadian rhythm.A symbiotic balance between proinflammatory and commensal bacteria allows only trace amounts of luminal antigens to penetrate the intestinal barrier and enter the portal vein and systemic circulation. However, chronic alcohol administration alters the balance among intestinal microbiota. This is characterized by both quantitative and qualitative changes, including suppression of many commensal probiotic bacteria, vital for bile acid metabolism and for the generation of short- and long-chain fatty acids necessary for maintaining gut health and liver homeostasis.30Recent studies have shown that a 3-week abstinence following the removal of alcohol induces a complete recovery of gut barrier function in subjects with AUD who presented with high intestinal permeability.31Most studies conducted to date using animal models have examined whether external agents—such as antibiotics, probiotics, prebiotics, synbiotics, betaine, zinc, indole-3-acetic acid, and long- and short-chain fatty acids—prevent or reverse alcohol-induced changes in the gut and prevent liver damage. Only one animal study has shown that sobering for 24 hours after 4 weeks of alcohol feeding partially restored intestinal barrier function, but such cessation did not reduce the inflammatory response in the colon.33Although the pancreas expresses both ADH and CYP2E1, its capacity for oxidative alcohol metabolism is significantly lower than that of the liver.The association between alcohol consumption and pancreatic diseases has been recognized for more than 100 years. The pancreas contains two functionally distinct compartments: As an endocrine gland, the pancreas secretes insulin and glucagon, the hormones that govern glycemia. As an exocrine gland, the pancreas produces zymogen precursors of digestive enzymes used for food breakdown in the gut. Both compartments can suffer consequences of chronic alcohol use.Chronic alcohol use is commonly associated with pancreatitis, a necroinflammatory disease of the exocrine pancreas that is classified as either acute or chronic. Although the association between chronic alcohol use and pancreatitis has long been recognized, the mechanism or mechanisms by which chronic alcohol use predisposes the pancreas to disease are not entirely understood. Despite this association, chronic alcohol use alone is not sufficient to trigger a clinical event, such as development of acute pancreatitis.In developed countries, chronic alcohol use is the second most common factor associated with acute pancreatitis.37In contrast, in the Western world, chronic alcohol use is the major etiological factor in chronic pancreatitis, accounting for approximately 70% of reported cases. Alcohol-induced chronic pancreatitis is thought to have an early stage associated with recurrent attacks of alcohol-induced acute pancreatitis and a late stage characterized by steatorrhea, diabetes, fibrotic scarring, and pancreatic calcification. In many cases, it appears that alcohol-induced acute pancreatitis progresses to chronic pancreatitis. This progression is generally associated with frequent, severe, and acute attacks that are common among chronic alcohol users. Little is known regarding the effects of alcohol in humans after pancreatic damage. Because chronic pancreatitis is commonly associated with recurrent attacks of acute pancreatitis, it appears that continued alcohol consumption impairs proper pancreatic repair. In support of this, one study investigated pancreatic dysfunction associated with alcohol-induced chronic pancreatitis and demonstrated that pancreatic function deteriorated more slowly in patients who quit drinking compared with those who continued heavy drinking. These findings indicate that the functional deterioration of the pancreas associated with alcohol-induced chronic pancreatitis continues even after drinking ceases, although this occurs to a lesser degree than in those who continue to chronically use alcohol.The structural and functional regeneration of the pancreas after acute injury is supported by studies of experimentally induced pancreatitis in rodents.Cardiac tissue expresses both major alcohol-metabolizing enzymes: ADH and CYP2E1.2+ sensitivity, impaired protein synthesis, and altered fatty acid extraction and deposition, along with changes in protein catabolism.Alcohol-induced dilated cardiomyopathy is an important manifestation of chronic alcohol use. Chronic AUD is accompanied by a high incidence of cardiac morbidity and mortality due to development of alcoholic cardiomyopathy. Cardiomyopathy can be seen by ventricle dilation, along with a reduced ventricular wall thickness and some contractile dysfunction. Alcohol/acetaldehyde toxicity along with mitochondrial production of reactive oxygen species is one theory proposed for alcohol-induced cardiac injury. Indeed, acetaldehyde can directly impair cardiac contractile function, disrupt cardiac excitation-contraction coupling, and promote oxidative damage and lipid peroxidation. Some resulting effects are oxidative injury, apoptosis, impaired myofilament CaThe QTc interval (a measure of heart rate) is frequently prolonged during alcohol cessation syndrome and tends to become normal over time.52Alcoholic cardiomyopathy is a specific heart muscle disease caused by chronic alcohol intake and has been studied in animal models. Chronic alcohol intake tends to increase left ventricular mass and dilatation that leads to heart failure in a rat model of alcohol administration. In one study, the authors postulated that alcohol intake activates the pro-renin receptor and contributes to cardiac remodeling and damage.It is not clear whether bone tissue itself metabolizes alcohol by oxidative metabolism  or by esterification with fatty acids. Current evidence supports that alcohol alone is the causative agent that delays bone growth and repair.Continued heavy alcohol use decreases bone density. The pathogenesis of osteopenia in AUD remains unclear, and many alcohol-related abnormalities have been proposed to explain bone loss.56The biochemical markers for bone formation  and resorption  were studied in men who were heavy-alcohol users and in abstainers with more than 5 years of abstinence. The results were compared with male controls. The findings suggest that there is an imbalance between bone formation and bone resorption among heavy-alcohol users that results in rapid bone loss. Although most directions tended to normalize shortly following the removal of alcohol, biochemical data suggest that there may still be persistently high bone turnover after more than 5 years of abstinence.57Although most studies suggest that alcohol induces bone loss, epidemiological studies indicate that higher bone mass is associated with moderate alcohol consumption in postmenopausal women. Therefore, a study investigated the hypothesis that moderate alcohol intake attenuates bone turnover after menopause. This study showed that abstinence from alcohol results in increased markers of bone turnover, whereas resumption of drinking reduces bone turnover markers. These results suggest that the inhibitory effect of alcohol on bone turnover attenuates the detrimental skeletal consequences of excessive bone turnover associated with menopause.N-acetylcysteine.Animal (rodent) studies report that the adverse effects of alcohol on bones are limited not only to bone formation and resorption, but that chronic alcohol administration also impairs the healing capacity of fractured bone in rodents.Continual heavy alcohol consumption damages multiple organs/systems. This review focused on damage and recovery in five of those tissues in humans and experimental rodents. The greatest degree of alcohol-induced injury occurs in the liver and GI tract, as both these organs/systems are the first to encounter high concentrations of imbibed alcohol. The liver and GI tract are well equipped to oxidatively metabolize alcohol. However, alcohol oxidation comes at a cost, as it generates acetaldehyde, which is capable of forming toxic acetaldehyde-macromolecular adducts as well as free radicals that oxidize lipids and form reactive lipid peroxides. Thus, the continual metabolic generation of these intermediates eventually disrupts homeostasis, causing cell death, inflammation, and the eventual breakdown of organ integrity.In the pancreas and heart, alcohol is minimally oxidized. Instead, most of it is esterified with fatty acids, forming FAEE. These molecules bind to mitochondria and disrupt the generation of energy that is normally reserved for pancreatic secretion or myocardial contraction. Although it is not clear whether oxidative or nonoxidative alcohol metabolism actually occurs in bone tissue, it is clear that alcohol exposure to osteoblasts inhibits their proliferation by causing oxidant stress. Also, structural weakening of bone and delays in fracture healing are clearly evident after chronic alcohol consumption by rodents.Despite alcohol-induced damage to these tissues, abstinence, in its simplest form, brings about either complete or partial recovery, but the extent of such recovery depends on the extent of the damage, as shown in Finally, more basic research is needed to clearly evaluate whether abstinence that follows chronic alcohol consumption completely or partially restores the full integrity of the affected organs. To date, the results appear promising that cessation of alcohol consumption indeed allows partial or full recovery, depending on the parameter being measured. It is also worth noting that alcohol-induced pathology in animals  does not fully reflect the extent of injury incurred by human heavy drinkers. However, the use of other feeding models, such as intragastric feeding and the acute-on-chronic feeding model have yielded valuable information on liver damage in animals that consume similar amounts of alcohol and have similar drinking patterns as humans with AUD.The focus of this review has been on organ recovery after cessation of chronic alcohol use. Abstaining from alcohol by a person with AUD is not a trivial matter. A recent review by Asrani et al. gives important details on the scope of the global burden of alcohol-associated disease;


To synthesise evidence on the effectiveness, cost-effectiveness and barriers to responding to violence against women (VAW) in sexual and reproductive health (SRH) services in low/middle-income countries (LMICs).Mixed-methods systematic review.Medline, Embase, Psycinfo, Cochrane, Cinahl, IMEMR, Web of Science, Popline, Lilacs, WHO RHL, ClinicalTrials.gov, Google, Google Scholar, websites of key organisations through December 2019.Studies of any design that evaluated VAW interventions in SRH services in LMICs.Concurrent narrative quantitative and thematic qualitative syntheses, integration through line of argument and mapping onto a logic model. Two reviewers extracted data and appraised quality.26 studies of varied interventions using heterogeneous outcomes. Of ten interventions that strengthened health systems capacity to respond to VAW during routine SRH consultation, three reported no harm and reduction in some types of violence. Of nine interventions that strengthened health systems and communities’ capacity to respond to VAW, three reported conflicting effects on re-exposure to some types of VAW and mixed effect on SRH. The interventions increased identification of VAW but had no effect on the provision (75%–100%) and uptake (0.6%–53%) of referrals to VAW services. Of seven psychosocial interventions in addition to SRH consultation that strengthened women’s readiness to address VAW, four reduced re-exposure to some types of VAW and improved health. Factors that disrupted the pathway to better outcomes included accepting attitudes towards VAW, fear of consequences and limited readiness of the society, health systems and individuals. No study evaluated cost-effectiveness.Some VAW interventions in SRH services reduced re-exposure to some types of VAW and improved some health outcomes in single studies. Future interventions should strengthen capacity to address VAW across health systems, communities and individual women. First-line support should be better tailored to women’s needs and expectations.CRD42019137167. This review was carried out by a team of researchers from the UK and low-income and middle-income countries with expertise and experience in health system responses to violence against women and global health.Inclusion of peer-reviewed and grey reports of studies of any design resulted in selection of the most relevant studies.The logic model approach to the integration of synthesis findings produced evidence in a format understandable to the end-users of this review.Most included studies had methodological limitations and high risk of bias.We could not perform meta-analysis of quantitative findings because primary studies evaluated varied interventions and used different instruments to measure varied outcomes.Violence against women (VAW) is a violation of global health and human rights.5building blocks from the Health Systems Wheel: (i) leadership and governance, (ii) multi-sectoral coordination, (iii) workforce development, (iv) healthcare delivery, (v) infrastructure, (vi) financing, (vii) monitoring and evaluation (WHO 2010).building blocks.14The healthcare system has a key role in preventing VAW because most women attend sexual and reproductive health (SRH) services at some point.Systematic reviewsbuilding blocks. We looked at the capacity of the health systems at three levels: individual providers , services and organisations , community .21We conducted concurrent quantitative and qualitative evidence syntheses with integration into a line of argumentWe included primary intervention studies reported in any language with an English abstract published since 2005, the year of the first published evaluation of VAW interventions in SRH services (expert opinion from the study advisory group). We identified earlier studies through reference checking. We used terminology and definitions from WHO guidance on strengthening health systems to respond to VAW .1313An information specialist (AR) applied the search strategy to Medline, Embase, Psycinfo, Cochrane, Cinahl, IMEMR, Web of Science, Popline, Lilacs, WHO RHL, ClinicalTrials.gov (20 August 2018 and 3–4 December 2019) . AR sear10.1136/bmjopen-2021-051924.supp1Supplementary dataimprovement, mixed effect or null effect. We ascribed a mixed effect when one or more, but not all measures of the same outcome changed under the same intervention . NVL asked corresponding authors to check data extraction forms for their studies and provide missing information; nine responded.NVL adapted the Cochrane Effective Practice and Organisation of Care (EPOC) data extraction form.Reviewers assessed the quality of the primary studies as part of data extraction. For randomised controlled trials (RCTs), we used the Revised Cochrane risk-of-bias tool for randomised trials.We summarised interventions by mapping them onto the Health Systems WheelDirect effects result from intervention activities producing structural changes at service level and changes in health-related cognitive and emotional outcomes among HCPs and women indicating improvement in the health systems capacity and women readiness to respond to VAW.Intermediate effects result from direct effects producing changes in health-related behaviour and practices indicating improvement in the health systems capacity and women readiness to respond to VAW. HCPs identify women affected by VAW and provide first-line support; women disclose VAW, use offered support, develop adaptive coping strategies.Health outcomes result from intermediate effects producing changes in women health and safety indicating improvement in their readiness to cope with VAW. Women use adaptive coping strategies and safety behaviours; these lead to reduction in re-exposure to VAW and better health.No patients or members of the public were involved in this study.Searches identified 6082 records, we assessed 313 full text reports and included 3210.1136/bmjopen-2021-051924.supp2Supplementary dataOf the 26 studies, 18 were from sub-Saharan Africa,59Most interventions took place in antenatal care (ANC) services (n=11),31Most quantitative studies were at high risk of bias . Of 12 R10.1136/bmjopen-2021-051924.supp3Supplementary dataAll interventions were complex healthcare interventions,32 34 50 59Most VAW work was delivered by a single HCP (n=10) or by several HCPs within the same facility (n=9). Only six interventions were integrated at a systems-level with HCPs identifying VAW cases, providing clinical care and first-line support, and referring to external VAW services.These interventions aimed to strengthen health system capacity to respond to VAW through integrating identification and first-line support into routine SRH consultations.38 46These interventions aimed to strengthen health system capacity to respond to VAW across SRH service and surrounding communities.These interventions aimed to strengthen women’s readiness to respond to VAW.52The logic model displays all outcomes of interest in the three intervention categories . The arrNone of the primary studies reported outcomes at service level. Most studies that evaluated interventions that aimed to strengthen health system capacity to respond to VAW across SRH service and community measured direct and intermediate effects on HCP and women’s knowledge, attitudes and behaviour. In contrast, all studies that evaluated interventions that aimed to strengthen women’s readiness to cope with VAW reported their health outcomes, but only a few looked at preceding changes in women’s cognition, emotions and behaviour , table 3The routine SRH-VAW intervention category had overall positive direct effects on HCP and women’s knowledge, attitudes and readiness. Interventions with community engagement reported mixed and improved direct effects.Changes in professional behaviour were measured through the rates of VAW screening, provision of referrals to support services and post-rape care. Changes in women’s behaviour were measured through VAW disclosure, uptake of referrals and other services. The overall evidence was uncertain across all three intervention categories with RCTs and non-randomised evaluations reporting improved, mixed and null effects.routine SRH-VAW consultation category and in the additional response category. In contrast, most interventions in the plus community engagement category reported mixed or null effect on women’s health and re-exposure to VAW. We found that although some interventions did not reduce re-exposure to VAW, none reported violence escalation. Of ten studies that measured re-exposure to VAW, six found a reduction,38 60Only half the studies reported measures of health and re-exposure to VAW; two interventions reported no harm resulting from taking part in interventions,routine SRH-VAW consultation categoryplus community engagement category.additional response category reported changes across two domains - intermediate effects on behaviour and practices and women’s health outcomes.Of 26 studies, only two reported changes across all three domains of the logic model, one from the Of ten evaluations, two RCTs10.1136/bmjopen-2021-051924.supp4Supplementary dataAn RCT38Another RCT of a 7 min integrated HIV-IPV consultation over the phone reported that 62% of women used a safety plan and 80% employed at least one safety strategy, however their use of SRH services and perceived risk and safety did not change. Despite no effect on women’s behaviour, the trial reported a fourfold reduction in HIV-disclosure-related violence .32Other randomised and non-randomised evaluations of varied one-off training for HCPs reported conflicting findings on their knowledge, attitudes and readiness to address VAW. Non-randomised studies reported increased IPV screening rates,28 54Qualitative evaluations confirmed that training increased HCP ability to respond to VAW during routine SRH consultations.33 38 57Three cluster RCTs reported conflicting findings on women’s SRH and re-exposure to VAW. The overall effect was uncertain .34 59 605910.1136/bmjopen-2021-051924.supp5Supplementary dataNon-randomised studies reported more positive effects on HCP knowledge, attitudes, preparedness49 56Qualitative evaluations confirmed that VAW training transformed HCP attitudes towards patients and their own work and improved their diagnostic and counselling skills. HCPs appreciated the intervention and expressed a willingness to continue VAW work.56This intervention category had the most robust evidence from six RCTs29 40 4710.1136/bmjopen-2021-051924.supp6Supplementary dataThree RCTs of counselling sessions for pregnant women with experience of VAW reported conflicting results with no evidence for a dose–response.29Two RCTs with high risk of bias evaluated more intensive training interventions and found mixed effects on behaviour and mixed and null effects on VAW and health.44An Iranian RCT with high risk of bias of four 90 min sessions with pregnant women reported reduction in scores of IPV and psychological distress.40 41No studies evaluated cost-effectiveness of VAW interventions in SRH services. One study of an integrated HIV-IPV consultation paid HCPs $6 per day for identifying patients experiencing VAW and referring them to the on-site GBV clinic.30 38 47 50 53 56 5710.1136/bmjopen-2021-051924.supp7Supplementary dataresponse during routine SRH consultation and response with community engagement described attitudes accepting violence and patriarchal gender norms as major barrier to behaviour change.33 45 54 56Four evaluations of interventions on Eight studies across all three interventions categories identified fear of negative consequences as a barrier to identification, disclosure and engagement in VAW interventions.30 33 38 44 45 49 51 53response to VAW during routine SRH consultationresponse with community engagement,response to VAW during routine SRH consultation explored reasons for low uptake of referrals to specialist services. Some women had expectations that could not be met by the current services. Instead of referral, they wanted HCPs to talk to their partners about stopping the abuse.38 57Evaluations reported limited readiness for engaging in VAW interventions at system and individual levels. In evaluations of responses to VAW during routine SRH consultation found reduction in HIV-disclosure-related IPV and potential risk of becoming a victim of femicide, but no effect on IPV in the past month. Some of these effects could be attributed to improvement in HCPs’ readiness, screening and provision of first-line support for VAW. For women, these effects could be attributed to increased knowledge about VAW and disclosure of violence. Response to VAW during routine SRH consultation plus community engagement had uncertain evidence with single studies reporting improvement, mixed effect, and no effect on re-exposure to violence and SRH possibly through some improvement in provision and use of SRH services. More intensive psychosocial interventions delivered to women with experience of VAW in addition to routine SRH consultation had the most robust evidence for reduction in re-occurrence of violence and improvement in health outcomes possibly through an improvement in safety behaviours. We identified individual, community and system-level barriers that could disrupt the pathway from intervention activities to outcomes: (i) attitudes and social norms that accept and normalise violence, (ii) fear of negative consequences and (iii) limited readiness of individuals, health systems and society to address VAW. No studies reported cost-effectiveness analysis.We conducted a mixed-methods systematic review of studies from LMICs on the effectiveness and barriers to strengthening SRH services response to VAW. We grouped 26 heterogeneous complex interventions into three categories: (i) response to VAW during routine SRH consultation, (ii) response to VAW during routine SRH consultation plus community engagement and (iii) response to VAW in addition to routine SRH consultation. We mapped outcomes on a process-oriented logic model illustrating the hypothesised changes from intervention through direct and intermediate effects on health-related cognition, emotions and behaviour to health outcomes. We cannot conclude which intervention was the most effective in improving any of these effects and outcomes due to heterogeneity of the interventions and measures at varying time points. Overall, ten interventions did not escalate violence and two reported no harmful events. We found mixed effects on women’s health and re-occurrence of VAW across all three categories, with studies reporting conflicting findings. Evaluations of the varied This review is methodologically strong. It involved a multidisciplinary team of researchers from LMICs and the UK with content and methodological expertise in health systems response to VAW and global health. We followed the Cochrane method and included studies of any design reported in peer-reviewed and grey literature in any language with English abstract. This comprehensive approach ensured inclusion of the most relevant studies from the field and reduced the potential for bias/errors.The evidence for VAW interventions in SRH settings is weak because of the methodological limitations of the primary studies and uncertain effectiveness of the interventions. Each study used differing operational definitions and outcomes measures, relied on self-report, and evaluated a different complex intervention. No studies measured contextual and implementation factors nor adjusted their analysis for those factors which could mediate the effect of the intervention on outcomes of individual HCPs and women, although those were explored in some qualitative evaluations. Because of the diverse complex interventions and outcomes measures we could not perform a meta-analysis. Our findings should be interpreted with caution because two-thirds of trials and all 13 quasi-experimental studies had high risk of bias.The evidence we found is applicable to ANC and HIV services and depends on the intervention category. Interventions that strengthened capacity of HIV and ANC services to respond to VAW can increase identification and provision of first-line support to women experiencing violence which can lead to reduction in HIV-disclosure-related IPV, physical and sexual IPV, and the risk of becoming a victim of femicide. More intensive psychosocial interventions that strengthen women’s readiness to cope with VAW can increase use of SRH services and safety behaviours, reduce re-exposure to IPV and DV, and improve health and quality of life. The positive effect of additional psychosocial interventions can be explained by their theoretical underpinning, higher dose of provider–patient contact, delivery by study personnel specialised in counselling and VAW, and samples of self-selected women who could be more motivated and ready for change. The first two intervention categories might appear less effective because few studies examined women’s outcomes beyond the point of identification and first-line response. Our findings suggest that future VAW interventions should strengthen multi-level capacity across individual HCPs and women, SRH services, and communities.The uncertain evidence for the two SRH consultation-based intervention categories is consistent with other evidence for a healthcare response to VAW in LMICs65plus community engagement category, one reporting improvement in HCP attitudes and one partial shift in women’s attitudes and gender norms. These findings can be explained by the community and societal roots of gender norms and attitudes of HCPs and women which are best addressed at community and societal levels. Our findings suggest that a shift in individual’s attitudes potentially leading to behavioural change can be achieved through service-based plus community-based education. This finding is consistent with a review of evidence on what works to prevent VAW in LMICs. The review found good evidence for community activism approaches to shift harmful gender attitudes, roles and social norms.66An important finding on the direct effects of interventions is that increasing awareness about VAW and relevant procedures often did not lead to a shift in judgemental attitudes towards victims, the major barrier to changes in professional and patient behaviour and practices. An exception was studies in the An important finding is that routine integrated SRH-VAW consultations with referral or signposting to VAW/GBV specialist or other services did not increase women’s use of these services. This gap between availability and acceptability of referrals to other services has several explanations. Our themes of barriers to intervention impact suggested that HCP response may not have matched women’s needs and expectations, or the VAW services were not accessible, or contextual factors prevented women from accessing them. This finding suggests that integrated SRH-VAW consultation and VAW services require better tailoring to women’s needs and expectations. This should be based on understanding what women want and need and what is feasible. A recent qualitative meta-synthesis found that after disclosing IPV to HCPs, women wanted assistance with documentation of injuries, insurance issues and help with connecting to community services more than referrals to IPV services.Finally, most interventions in the first two categories targeted the behaviour of individual HCPs rather than the SRH service or health system. The expectation was that trained HCPs would integrate VAW work into their clinical practice without structural changes to the environment, support from leadership, supervision, monitoring and incentivisation. Most qualitative evaluations described passionate HCPs who were enthusiastic about helping patients experiencing violence. However, some studies reported HCPs concerns about unrealistic expectations and limited health system readiness for embedding VAW work in routine practice. This finding is in line with other studies on health systems readiness for responding to VAW.68This review’s results are relevant for practitioners and policy makers in LMICs. The logic model approach allowed us to: (i) illustrate the hypothesised cause-result pathway, (ii) map evidence from primary studies for the direct and intermediate effects and outcomes, (iii) identify barriers that can disrupt the trajectory of changes. It allowed us to present evidence in a format understandable to end users: people who develop, deliver, evaluate and fund VAW interventions in LMICs. We need more methodologically robust evaluations of interventions for strengthening the capacity of the health systems, communities and individual women to respond to VAW with measures throughout the pathway from intervention activities to women’s outcomes. Absence of evidence on the cost-effectiveness of VAW interventions in SRH services is another gap. Finally, very few interventions have been evaluated in LMICs outside Africa.We found that interventions to improve response to VAW in SRH services did not escalate violence. Some interventions that strengthened capacity of HIV and ANC services increased identification and reduced some types of IPV. Some interventions that strengthened capacity of HIV and ANC services and communities improved use of SRH services and reduced re-exposure to some types of VAW. Several studies identified a gap between provision and uptake of referrals to VAW services suggesting that first-line support should be better tailored to women’s needs and preferences. Most additional psychosocial interventions that strengthened women’s readiness to respond to VAW reduced re-exposure to violence and improved health. Our findings are relevant to people who develop, implement, evaluate and fund VAW interventions in healthcare. Future interventions should have better theoretical development and use a systemic approach to strengthen the capacity to respond to VAW across the healthcare systems, communities and women. Future evaluations of VAW interventions in SRH services in LMICs should have longer follow-up and use standardised measures of individual-level, organisation-level and system-level outcomes on the pathway from intervention to women’s health.


Chronic lung allograft rejection remains one of the major causes of morbi-mortality after lung transplantation. The term Chronic Lung Allograft Dysfunction (CLAD) has been proposed to describe the different processes that lead to a significant and persistent deterioration in lung function without identifiable causes. The two main phenotypes of CLAD are Bronchiolitis Obliterans Syndrome (BOS) and Restrictive Allograft Syndrome (RAS), each of them characterized by particular functional and imaging features. These entities can be associated (mixed phenotype) or switched from one to the other. If CLAD remains a clinical diagnosis based on spirometry, computed tomography (CT) scan plays an important role in the diagnosis and follow-up of CLAD patients, to exclude identifiable causes of functional decline when CLAD is first suspected, to detect early abnormalities that can precede the diagnosis of CLAD (particularly RAS), to differentiate between the obstructive and restrictive phenotypes, and to detect exacerbations and evolution from one phenotype to the other. Recognition of early signs of rejection is crucial for better understanding of physiopathologic pathways and optimal management of patients. More than 4500 lung transplantations (LTs) are performed every year worldwide. Despite global improvements in surgical techniques and post-operative management of patients, long-term outcomes after lung transplantation remain poor compared to those of other solid organ transplantation. According to the last International Society for Heart and Lung Transplantation (ISHLT) registry report, median survival in the most recent era of lung transplantation is 6.5 years . The firFor a long time, bronchiolitis obliterans syndrome (BOS) has been considered the hallmark of chronic allograft rejection. Different phenotypes have emerged in recent literature, and the division became more apparent when Sato et al. defined a restrictive phenotype affecting up to 30% of patients, with evidence of functional decline, named Restrictive Allograft Syndrome (RAS) . The terCLAD is defined as a persistent and irreversible decline in forced expiratory volume in 1 s (FEV1) of at least 20% compared to the mean of the two best post-operative values at least 3 weeks apart.CLAD can present either as a predominantly obstructive pattern, a restrictive pattern, or a mixed obstructive and restrictive pattern that is not explained by other conditions. Numerous processes and diseases may be responsible for acute or chronic functional deterioration and are not included in the current definition of CLAD . CT is vAccording to the last consensus report from the Pulmonary Council of the ISHLT, the critical level of ≥20% fall from baseline FEV1, with or without change in forced vital capacity (FVC), qualifies for “possible CLAD” and should prompt investigations to identify potentially treatable causes, such as infection, acute cellular/antibody-mediated rejection, or airway stenosis . If lungCLAD encompasses two main clinical entities, BOS and RAS, which can be differentiated on the basis of spirometry and imaging. RAS is characterized by persistent opacities on chest imaging (chest X-ray and/or CT) and a decline in total lung capacity (TLC) ≥ 10% compared to the best post-operative TLC  or a decCLAD will be “confirmed” if the physiologic abnormalities persist for 3 months after the first value has been obtained. Further investigation, including CT, to exclude any treatable causes or complications of therapy may be warranted at any stage.Azithromycin-Reversible Allograft Dysfunction (ARAD) is a form of functional decline that responds to neomacrolid azithromycin therapy ,11,12,13Pseudomonas aeruginosa, Aspergillus fumigatus), donor and recipients genetic factors, and the presence of HLA antibodies or antibodies to self-antigens [BOS is the most common form of CLAD, accounting for approximately 65–70% of cases and occurring in 48% of patients 5 years after lung transplantation . It is cantigens .The pathophysiologic mechanism involves diverse immune pathways, which ultimately converge to the development of fibroproliferative tissue obstructing the small airways. At histopathology, there is partial or complete obstruction of bronchiolar lumens by a dense infiltrate made of smooth-muscle cells, myofibroblasts, and mature collagen . Due to CT features of BOS include mosaicism of lung attenuation and expiratory air trapping, sometimes associated with large airway abnormalities. Mosaicism and air trapping are direct consequences of small airway fibrosis. Hypoventilation due to obliterans bronchiolitis is responsible for hypoxic vasoconstriction and manifests on a CT scan as low attenuation areas with small and rare vascular markings . These poorly perfused areas alternate with areas of relative hyperattenuation due to vascular redistribution in the spared lung . In equiLarge airway abnormalities, including bronchial wall thickening and mild cylindrical bronchiectasis, are often present . Small cRAS is the second most common form of allograft rejection, with a prevalence of approximately 25–35% in the CLAD population. The outcome in patients with RAS is worse than patients with BOS, with a median survival of 6–18 months after the diagnosis of RAS compared to 3–5 years after the diagnosis of BOS .RAS is defined by a restrictive pulmonary defect without evidence of obstruction and the presence of persistent opacities on chest imaging. Functional decline may be progressive and steady or marked by periodic stepwise exacerbations. Patients can also present with acute respiratory failure. The gradually progressive decline is associated with the best prognosis ,27,28. RAS has complex histopathologic features involving interstitial and small airway compartments. Fibrotic changes most often consist in intra-alveolar fibroelastosis (IAFE) adjacent to the bronchioles, the pleura, and the interlobular septa ,30. ThisFibrotic lesions can merge with areas of diffuse alveolar damage (DAD) and acute fibrinoid organizing pneumonia (AFOP). AFOP is characterized by intra-alveolar filling of ball-like fibrin exudates, without hyaline membranes, which would suggest a diagnosis of DAD, and without overt fibroblastic organization, which would suggest organizing pneumonia. It is considered a severe form of acute lung injury and is associated with a poor prognosis . WhetherParenchymal abnormalities can precede the diagnosis of CLAD. Peripheral consolidation and peripheral ground glass have been reported in approximately 40% and 20% of cases, respectively, before functional confirmation of RAS . InitialImaging features of late RAS often correlate with those of idiopathic PPFE . They inIn a study comparing CT scans obtained at different time points , CT scores demonstrated a significant increase in bronchiectasis, central, and peripheral consolidation, architectural distortion, volume loss, and hilus retraction over time  Figure . The absExtensive consolidation, ground glass opacities, and septal lines are suggestive of underlying DAD or AFOP lesions . Dubbeldp < 0.0001), and high SUV in RAS patients was associated with worse survival. In the same study, the authors examined the explanted lungs using microCT and showed extensive fibrosis in regions of high SUV, with an increased number of glucose transporter-1 positive cells.F-fluorodeoxyglucose positron emission tomography with computed tomography (F-FDG PET/CT) may help in differentiating BOS from RAS, as reported in a recent monocentric retrospective study . MaximumThe initial phenotype of CLAD should be re-assessed regularly as it can transition from one phenotype to another . The comAn initial CT scan is recommended for all patients 6 months after lung transplantation, when spirometry is expected to be optimal . It shouDettmer et al. demonstrated the utility of CT as a predictor of restrictive CLAD and predictor of survival . CT at CDuring follow-up and according to clinical and functional changes, CT may be used to exclude any treatable causes or complications of therapy or to detect possible evolution to a mixed phenotype. Is machine learning (ML) able to detect CLAD earlier and with higher sensitivity than the current methodologies? Volumetric quantitative CT analysis has shown that, in patients with BOS, a decline in lung function was associated with a statistically significant increase in airway lumen area and a decrease in vessel cross-sectional area . p < 0.5), whereas no spirometric parameter could. ML methods could identify BOS developers at baseline with an accuracy of 85%, using only three QCT parameters [In a retrospective study including 178 LT patients, Barbosa et al. established quantitative CT (QCT) scores, including lung volumes and air trapping volumes by lobe, and semi-quantitative scores  for features including mosaic attenuation and bronchiectasis on paired inspiratory and expiratory CT acquisitions . QCT metrameters .Using a biomechanical model-based platform to characterize changes in lung deformation, Horie et al. reported increasing lung deformation in patients with RAS compared to patients with BOS and no-CLAD patients . They alCLAD remains a major limiting factor for long term graft viability. CT in combination with spirometry plays a crucial role in the positive and differential diagnosis of CLAD. It helps identify the main phenotypes  of CLAD, their evolution, and the intercurrent complications. Accurate diagnosis of the different phenotypes of CLAD is important to better understand the underlying pathogenesis, identify homogeneous populations for clinical trials, and guide future therapeutic approaches. Furthermore, quantitative imaging and IA-based algorithms are promising tools for early detection of CLAD and prediction of disease.


Dechloromonas are often abundant in enhanced biological phosphorus removal (EBPR) systems and are recognized putative polyphosphate accumulating organisms (PAOs), but their role in phosphate removal is still unclear. Here, we used 16S rRNA gene sequencing and fluorescence in situ hybridization (FISH) to investigate the abundance and distribution of Dechloromonas spp. in Danish and global wastewater treatment plants. The two most abundant species worldwide revealed in situ dynamics of important intracellular storage polymers, measured by FISH-Raman in activated sludge from four full-scale EBPR plants and from a lab-scale reactor fed with different substrates. Moreover, seven distinct Dechloromonas species were determined from a set of ten high-quality metagenome-assembled genomes (MAGs) from Danish EBPR plants, each encoding the potential for polyphosphate (poly-P), glycogen, and polyhydroxyalkanoates (PHA) accumulation. The two species exhibited an in situ phenotype in complete accordance with the metabolic information retrieved by the MAGs, with dynamic levels of poly-P, glycogen, and PHA during feast-famine anaerobic–aerobic cycling, legitimately placing these microorganisms among the important PAOs. They are potentially involved in denitrification showing niche partitioning within the genus and with other important PAOs. As no isolates are available for the two species, we propose the names Candidatus Dechloromonas phosphoritropha and Candidatus Dechloromonas phosphorivorans.Members of the genus  Ca. Accumulibacter and Tetrasphaera, has been extensively investigated in lab-scale enrichments  and Candidatus Dechloromonas phosphorivorans  for the two species, based on the recommendations by Murray and Stackebrandt [As no axenic cultures representing the novel species are available, we propose the names kebrandt . The comDechloromonas spp. We have shown that these lineages are PAOs that are often abundant and actively involved in P removal in full-scale EBPR plants worldwide, and they should be regarded as important PAOs along with Ca. Accumulibacter and Tetrasphaera. They exhibit a physiology very similar to Ca. Accumulibacter, but seem more diverse in their substrate utilization profile and share some traits with Tetrasphaera too. They may also be important for nitrogen removal with most species possessing full denitrifying capabilities. The co-occurrence of these three genera in most EBPR plants suggests niche differentiation and functional redundancy, which may be even more pronounced by the presence of other PAOs. Some putative PAOs can occasionally be abundant in specific plants [Ca. Methylophosphatis [Here, we have provided the first experimental and genomic insights into the physiology of uncultivated c plants  and our osphatis , stronglSupplementary data file1Supplementary data file2Supplementary materialSupplementary Table S1


This poster aims to examine the impact of social cognitive deficits on psychosocial functioning in depressed patients, as well as summarise the utility of various evidence-based therapeutic interventions employed to target these deficits. The stated hypotheses were twofold: (1) that social cognitive impairment in major depressive disorder will correlate with poorer psychosocial functioning; and (2) that these deficits will respond to existing anti-depressant therapies.Social cognition is an important adaptive trait that incorporates the identification, perception and interpretation of socially relevant information from the external world. It is frequently affected in major depressive disorder such that depressed patienA review of the existing literature was performed in order to test the stated hypotheses. Pertinent sources were identified via the MEDLINE, EMBASE, PsycINFO, PubMed, Scopus and Google Scholar databases. A total of 107 studies met inclusion criteria for review.Impaired social cognitive performance in depressed patients correlated with poorer psychosocial functioning across the key domains of general cognitive functioning and quality of life. Many current anti-depressant therapies were found to have a normalising effect on the social cognitive abilities of depressed subjects, both at a neural and functional level. Anti-depressant medications, in particular citalopram and reboxetine, appeared to correct facial affect recognition deficits, while a psychotherapeutic approach demonstrated improvements in theory of mind and negative interpretive bias. Data relating to other common treatments, such as electroconvulsive therapy, are limited.The impact and treatment of social cognitive deficits in major depressive disorder is an important emerging field. The social cognitive deficits evident in depressed patients are sometimes subtle, but afford a significant functional impact. Additionally, it appears these impairments are at least partially reversible using anti-depressants or psychotherapy.


Among other functions, these gamma oscillations regulate plasticity associated with learning, decision making, attention, cognitive flexibility, and working memory. The detailed mechanisms by which PNN removal increases plasticity are only beginning to be understood. Here, we review the impact of PNN removal on several electrophysiological features of their underlying PV interneurons and nearby pyramidal neurons, including changes in intrinsic and synaptic membrane properties, brain oscillations, and how these changes may alter the integration of memory-related information. Additionally, we review how PNN removal affects plasticity-associated phenomena such as long-term potentiation (LTP), long-term depression (LTD), and paired-pulse ratio (PPR). The results are discussed in the context of the role of PV interneurons in circuit function and how PNN removal alters this function.Perineuronal nets (PNNs) are specialized extracellular matrix structures that surround specific neurons in the brain and spinal cord, appear during critical periods of development, and restrict plasticity during adulthood. Removal of PNNs can reinstate juvenile-like plasticity or, in cases of PNN removal during early developmental stages, PNN removal extends the critical plasticity period. PNNs surround mainly parvalbumin (PV)-containing, fast-spiking GABAergic interneurons in several brain regions. These inhibitory interneurons profoundly inhibit the network of surrounding neurons  Perineuronal nets (PNNs) are specialized extracellular matrix structures surrounding specific neurons in the brain and spinal cord that appear during development in an experience–dependent manner -containing GABAergic interneurons within many brain regions  enhances reversal learning in the auditory cortex  this plasticity takes. How PNN removal impacts Hebbian activity-dependent plasticity mechanisms such as excitatory and inhibitory forms of spike-timing-dependent long-term potentiation (LTP) and long-term depression (LTD) on different cell types has also received relatively little investigation. PNN removal may also alter the intrinsic activity of neurons in addition to these other mechanisms. Perineuronal nets (PNNs) play such a critical role in PV interneuron function that recent cell-type specific manipulations have focused on manipulating PV interneurons alone to alter cortical plasticity : A bacterial enzyme derived from Proteus vulgaris that degrades chondroitin sulfates A, B, C, chondroitin sulfate, and hyaluronic acid  so that the compound signal is a monosynaptic excitatory input and a disynaptic inhibitory input with a delay.Lateral inhibition: Condition in a neuronal circuit in which an excitatory cell recruits an inhibitory cell that inhibits other nearby excitatory cells that may compete with other neurons to be the active members of the circuit.Normalizing inhibition: In its simplest form, normalizing inhibition is an extension of blanket inhibition but moves a step further by suggesting a functional role for interneurons to be recruited in a manner that is scalable with increases in circuit drive. As the number of active neurons in a cortical region increases, so, too, will the level of inhibition being provided to the neurons within that population  without altering its selectivity to a particular stimulus. Common factors that impact modulation are movement, attention, neuromodulators, and other brain state changes  or a dense code (every cell is active to some degree and the stimulus is represented by the whole population). In a sparse code, some number of cells (more than one cell and less than 100% of the population) may be active during any given stimulus.Tuning : When a neuron shows a specific response to a narrow range of presented stimuli. It is typically investigated in sensory modalities such as vision or hearing in which neurons respond to sweeps of stimuli, such as when black-and-white bars of varying orientations are presented to the eyes or tones of different frequencies are presented.modulation, sparse encoding (or sparse coding), pattern separation, and interregional communication  inhibition, and lateral inhibition can greatly shape circuit responses to input. Parvalbumin neurons are involved in all of these types of inhibition, although the contribution of each of these types may be different depending on the region and/or cortical layer investigated . Thus, these neurons do not execute the complex computations as pyramidal cells do but instead sample cortical activity and linearly provide scalable blanket inhibition, termed in vivo calcium imaging to map pyramidal cell orientation responses and trace their proximal targets . In the rodent visual cortex, pyramidal neurons that show orientation tuning to different directions are scattered randomly across the cortex in what is described as a salt-and-pepper-like distribution  neurons to maintain high firing frequencies after PNN removal.An early observation was that a key function of PNNs was to maintain the high frequency of firing in PV interneurons  and delayed (7 days in vivo) effects of Ch-ABC on fast-spiking interneurons in the mouse hippocampal CA2 region. Although they found no effects of acute Ch-ABC treatment, longer-term treatment reduced the firing threshold, decreased the frequency of sEPSCs and mEPSCs, and increased the frequency of sIPSCs, suggesting increased excitability of fast-spiking interneurons in the CA2 region, but possibly compensatory increases in inhibitory transmission to these neurons. Although a decrease in glutamatergic transmission is similar to the findings by Favuzzi et al.  of fast-spiking neurons, with no change in other intrinsic properties . In a second study by the same group, and only the second study to examine in vivo putative inhibitory neurons following PNN removal, Christensen et al. . In addition, another study that used pharmacogenetics to suppress PV interneurons found similar network instability in the medial entorhinal cortex , Ch-ABC treatment in adults produced no changes in intrinsic properties of PV interneurons  decreased the resting membrane potential and input resistance but did not alter the threshold or firing frequency of fast-spiking interneurons  an increase in resting membrane potential; (2) a decrease in the firing threshold; (3) a decrease in firing rate; (4) an increase in action potential half-width; (5) a decrease in AHP amplitude; and (6) an increase in AHP duration . Howeverin vitro on cultured hippocampal neurons or neurons co-cultured with astrocytes , but the mechanisms mediating these opposing effects on CA1 pyramidal neurons remains unknown. Genetic knockout of BCAN did not alter sIPSCs, unlike the increases in sIPSC amplitude and frequency in mice given BCAN shRNA, suggesting that compensatory effects may have occurred during development in these KO mice. Genetic knockout of TN-R produced an increase in the frequency of mEPSCs and mIPSCs, and increased the amplitude of the periosomatic unitary current, suggesting that there was decreased inhibition of pyramidal neurons in TN-R KO mice. Hyaluronidase treatment did not affect intrinsic properties of CA1 neurons , a marker for PNNs. While many of the PNNs surround inhibitory neurons in the CA2 of mouse [and fewer in the rat  and longer-term (7 days), Ch-ABC treatment in the CA2 region of 3–5 week old mice  on pyramidal neurons. They found an increase in the firing frequency of pyramidal neurons, which is consistent with the reduced function of PNN-surrounded interneurons after Ch-ABC treatment.Degradation of PNNs nd Lodge  conductein vivo electrophysiology in the visual cortex (V1) of awake adult rats to examine how Ch-ABC given 3–14 days earlier affected putative excitatory neurons. They found no change in the firing rate of excitatory output neurons, but, similar to their findings in inhibitory neurons, there was increased spiking variability. This variability in both excitatory and inhibitory neurons suggested to the authors that Ch-ABC decreased the stability of the excitatory: inhibitory network, which they attributed to a decrease in inhibition by fast-spiking PV interneurons (see above).Faini et al.  conductein vivo recordings in BCAN KO mice and found decreases in the firing rate evoked by sound, with a broader presynaptic action potential and a broader post-synaptic EPSP. Together with reduced vGlut1 in calyx terminals in the MNTB, these findings suggested a decrease in glutamate release at the calyx of Held synapse in BCAN KO mice. Consistent with the decreased response to sound in BCAN KO mice, Balmer  medial nucleus of the trapezoid body (MNTB) neurons. Blosa et al.  used in , Balmer  delivereIn the cerebellum, Edamatsu et al.  reduced in vivo Ch-ABC treatment effects on excitatory output neurons in slices from the rat medial prefrontal cortex (mPFC) 9 days later. They found an increase in the firing rate of these neurons, with a decrease in mIPSC frequency and no changes in mIPSC amplitude. The mIPSC frequency trended toward a decrease when examined 3 days later (unpublished observations), indicating that the outcome on synaptic properties likely depended on the interval of time after Ch-ABC treatment. Overall, the findings in the mPFC are in accordance with others demonstrating a decrease in inhibitory input onto these neurons after Ch-ABC treatment. Tewari et al. . However, it must be kept in mind that the majority of studies have examined the influence of PNN removal after short intervals, whereas a reorganization of the network in addition to intrinsic and synaptic consequences may require days rather than hours  memory strength and memory generalization may change; and (2) that PNN removal could lead to failures in the separation of input, inducing memory interference. One intriguing new study by Christensen et al. , PNN removal now severely decreases cue recall the next day and for several days afterward. This suggests that exposure to a similar but new rule in the absence of PNNs degrades the original memory, akin to the grid cell findings  in response to physiological stimuli, such as stress, exercise, environmental enrichment, diet, circadian rhythms, and normal aging processes. Short term and chronic stress lead to brain region-dependent changes in PV cells and PNNs both in early life . PV interneurons coordinate long-range communication with other brain regions through the coupling of theta and gamma oscillations, which are altered when PNNs are removed. Thus, by virtue of PV properties and circuit connectivity, PNNs allow PV interneurons to play a vital role in synchronizing the output of pyramidal neurons into discrete groups of activated neurons  thought to represent the coding of separate events or memories. Inhibiting PV interneuronal firing by PNN removal would therefore degrade the usually precise spatiotemporal firing patterns, producing overlapping neuronal assemblies, leading to less specificity of which assemblies represent a particular stimulus or memory. Future studies need to determine the contribution of PNN removal to PV interneuron-mediated modulation and tuning properties in other brain areas and under different modulatory states, such as attention or movement, to understand how PNN removal impacts inhibitory drive in these systems. To better understand how PNN removal impacts theta and gamma activity, future studies should investigate how PNN removal impacts behavior known to be dependent on narrowband oscillatory activity. In addition, it is important to investigate the impact of PNN removal on coherence between brain regions, phase-locking of single units to ongoing oscillations, and characterization of oscillations beyond analyzing predefined frequency ranges, such as burst detection methods, analysis of individual gamma cycle amplitudes, cycle durations, and cycle shape. We expect future in vivo studies in awake, behaving animals to permit a much-needed, detailed understanding of the mechanisms by which PNNs regulate the ability of their underlying PV interneurons to shape circuit function. Such an understanding has vast implications for how PNNs could be modified to optimize normal physiological functions such as learning and memory and to alleviate excitatory: inhibitory imbalances in a wide range of developmental and neurological disorders.PNNs allow for the normal firing of PV interneurons, which tightly regulate pyramidal cell firing JW: writing original draft and editing. BS: writing original draft and editing, and funding acquistion. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ferroptosis, a new form of programmed necrosis characterized by iron-dependent lethal accumulation of lipid hydroperoxides, is associated with many human diseases. Targeting amino acid (AA) availability can selectively suppress tumor growth and has been a promising therapeutic strategy for cancer therapy. Compelling studies have indicated that AA metabolism is also involved in ferroptosis, closely regulating its initiation and execution. This manuscript systematically summarizes the latest advances of AA metabolism in regulating ferroptosis and discusses the potential combination of therapeutic strategies that simultaneously target AA metabolism and ferroptosis in cancer to eliminate tumors or limit their invasiveness. As the amino acid (AA) metabolic network is the most complex and highly interconnected with other pathways, AA metabolic reprogramming has garnered considerable attention As the basis of protein synthesis and the intermediate metabolites that ignite other biosynthetic pathways, cancer cells with AA metabolic addiction have received an increasing attention in recent years The trade of metabolites between ferroptosis and cancer cells is increasingly recognized as a critical aspect of tumor metabolism. Evidence has demonstrated that AA metabolism is critical for ferroptosis -2S) production, epigenetic regulation, and energy production Cys is a sulfur-containing proteinogenic AA whose free thiol group confers unique properties on protein functional sites Prior studies have indicated that Cystine/Cys depletion increases reactive oxygen species (ROS) production and induces ferroptosis, and certain cancers rely on Cystine/Cys metabolism to avoid ferroptosis In the second catabolic pathway, cysteine dioxygenase (CDO1) catalyzes Cys transformation into taurine - system-mediated absorption of cystine is a classical approach to induce cell ferroptosis in basic studies. The clinical development of drugs targeting Cystine/Cys metabolic pathways to treat ferroptosis-related diseases may provide an avenue for future translation of this concept. It is still unknown whether human cancer is also susceptible to Cystine/Cys depletion-induced ferroptosis in clinic practice. A recent study demonstrates that the trans-sulfuration pathway is a direct advantage for cancer cells in maintaining redox equilibrium and evading ferroptosis. The trans-sulfuration pathway can produce endogenous Cys to synthesize GSH when cystine import is inhibited Targeting the XcCysteine persulfide (CysSSH) and cysteine polysulfides , which are Cys derivatives, have been proposed as powerful antioxidants and cytoprotective agents based on their superior nucleophilicity and reducibility Moreover, mitochondrial cysteine desulfurase NFS1) can metabolize Cys and produce a sulfur carrier  can metaRecent research discovered that cystine/Cys can activate Rag-mTORC1-4EBPs signaling axis and promote GPX4 protein synthesis to prevent cell ferroptosis in a GSH-independent manner. This study elucidated a regulatory mechanism that linked cystine/Cys availability to GPX4 protein synthesis and provided a new idea for using combinatorial therapy of ferroptosis inducers and mTORC1 inhibitors in cancer therapy In conclusion, tumor resistance to ferroptosis caused by Cys deprivation can be reversed by concurrently targeting exogenous uptake and endogenous synthesis. It is necessary to explore additional and newer methods of targeting Cys metabolism to kill tumor cells more efficiently in the future. Cystine/Cys and Gln together form a metabolism network of AAs capable of providing the core metabolic pathways underlying key cancer processes. The production of Gln and its role in bioenergetics and signaling are addressed in the next section.Gln is the most abundant AA in the human body and the most critical non-toxic carrier in the ammonia cycle In vivo experiments in hepatomas and hepatic fibrosarcoma revealed that cancer cells consume Gln ten times faster than normal hepatocytes After entering cell via the SLC1A5 (ASCT2), Gln mainly undergoes three metabolic routes Gln metabolism is tightly linked to ferroptosis regulation - induced ferroptosis by depleting cellular GSH and accordingly increasing ROS, and concurrently accelerated the death process through Glu accumulation, the glutaminolysis product Consistent with previous research, deprivation of cystine or Cys or inhibition of the system XcThe function of glutaminolysis in ferroptosis could also be explained by the discovery that α-KG, a product of glutaminolysis, could substitute Gln to function in Cys deprivation-induced lipid ROS accumulation and ferroptosis At present, studies on Gln starvation therapy have confirmed that Gln transporter inhibitor GPNA Branched-chain amino acids (BCAAs), including leucine, valine, and isoleucine, are a subclass of EAAs whose metabolism has been linked to specific cancer phenotypes - inhibition and protect liver cancer and pancreatic cancer cells from ferroptosis. Therefore, BCAT2 could serve to predict the responsiveness of cancer cells to the ferroptosis-inducing therapy Both BCAT1 and BCAT2 are highly active and reversible enzymes that catalyze all three types of BCAAs and their corresponding branched-chain keto acids (BCKAs) As EAA, tryptophan (Trp) and its metabolites perform various nutritional and physiological roles and are intimately linked to regulating cancer, neurodegeneration, and other diseases Furthermore, recent research discovered that Trp metabolite, indole-3-pyruvate (I3P) can regulate ferroptosis Other AAs, such as Arg, Ser, Gly, lysine (Lys), etc., also play a critical role in cell metabolism and cancer development. Arg could serve as a precursor of many biomolecules, such as creatine, nitric oxide, polyamines, proteins, and other AAs de novo synthesis of Cys fails to perform without considering Ser and Gly in the one-carbon pathway de novo synthesis of serine-glycine has been established as an important factor in tumorigenesis. And the inhibition of serine-glycine biosynthesis could interfere with their redox state, leading to the ROS accumulation and cell death The A recent study showed that Lys was also involved in the regulation of ferroptosis, which found that L-lysine α-oxidase, a member of the L-amino acid oxidase family, activates ferroptotic signal by catalyzing the oxidative deamination of L-lysine and ROS production Since the concept of “ferroptosis” was defined, people have continuously explored its therapeutic potential in lipid peroxidation diseases. In fact, it has been confirmed in many cancers that they are more susceptible to this iron-catalyzed necrosis. However, working hard to develop tolerance and escape various forms of death seems to be the eternal hallmark of cancer cells, and ferroptosis is no exception. The sensitivity of cell to ferroptosis is correlated with numerous biological processes, including AA metabolism.As basic nutrients and energy sources, AAs contribute significantly to tumor proliferation and homeostasis by acting as intermediates in the metabolism of glucose, lipids and nucleotides. As new functions continue to be discovered, AA metabolism has exerted an increasing part in cancers. Numerous cancers exhibit a high requirement for specific AAs acquired exogenously or released endogenously. Thus, specific AA deprivation could shut down nutrient supply, resulting in AA starvation and cell death. Some AA starvation therapies designed according to the high demand of tumor cells for specific AAs have been introduced into clinical practice or are undergoing clinical evaluation, such as Arg, asparagine, Lys, methionine, phenylalanine, tyrosine and so on Targeting AA metabolism is currently moving towards combinatorial studies based on the synergistic drug interactions, such as the study of combining immunotherapy and metabolic inhibitors. Although the current research on the regulation of ferroptosis by AA metabolism is limited, the combinatorial targeting of AA metabolism and ferroptosis has shown great promise in cancer treatment. While there are still some thorny issues for this mode of therapy that urgently need to be further studied. For example, it is necessary to clarify the metabolic dependence in specific cancer type, so as to select an appropriate AA target. Attention should also be paid to the crosstalk of AA metabolism between cancer cells and immune cells as well as normal cells in the surrounding environment, as ferroptosis may affect cancer immune surveillance in a dual way. A full understanding of metabolic flexibility and diversity of ferroptosis in cancers will help better guide drugs usage and cancer treatment.