Head and neck squamous cell carcinomas (HNSCCs) are the eighth most common cancers worldwide. While promising new therapies are emerging, cisplatin-based chemotherapy remains the gold standard for advanced HNSCCs, although most of the patients relapse due to the development of resistance. This review aims to condense the different mechanisms involved in the development of cisplatin resistance in HNSCCs and highlight future perspectives intended to overcome its related complications. Classical resistance mechanisms include drug import and export, DNA repair and oxidative stress control. Emerging research identified the prevalence of these mechanisms in populations of cancer stem cells (CSC), which are the cells mainly contributing to cisplatin resistance. The use of old and new CSC markers has enabled the identification of the characteristics within HNSCC CSCs predisposing them to treatment resistance, such as cell quiescence, increased self-renewal capacity, low reactive oxygen species levels or the acquisition of epithelial to mesenchymal transcriptional programs. In the present review, we will discuss how cell intrinsic and extrinsic cues alter the phenotype of CSCs and how they influence resistance to cisplatin treatment. In addition, we will assess how the stromal composition and the tumor microenvironment affect drug resistance and the acquisition of CSCs’ characteristics through a complex interplay between extracellular matrix content as well as immune and non-immune cell characteristics. Finally, we will describe how alterations in epigenetic modifiers or other signaling pathways can alter tumor behavior and cell plasticity to induce chemotherapy resistance. The data generated in recent years open up a wide range of promising strategies to optimize cisplatin therapy, with the potential to personalize HNSCC patient treatment strategies. Head and neck squamous cell carcinomas (HNSCCs) were the eighth most frequent tumors worldwide in 2020, with 931,931 newly diagnosed cases and 467,125 deaths ,9467,94]SNAI2  did, but SNAI1 (SNAIL), ZEB1/2 and TWIST1/2 did not. This was the first time that partial EMT expressing cells were described in HNSCCs, and although the connection with the metastatic process was shown, the effects of the pEMT phenotype on CSC properties were not studied. The fact that pEMT cells were detected at the basal layer of the tumor, where adult SCs are usually localized, may suggest that pEMT could indeed be enriched in CSC properties, but further analysis would need to be conducted to prove it. Puram et al. characterized the tumor heterogeneity and transcriptional programs of tumor cells from primary and lymph node metastasis from HNSCCs at the single cell level, uncovering a population of cells expressing a transcriptional program of pEMT . The preERCC1 expression, and together they mediate cisplatin resistance . . 102]. Although much more detailed studies are needed, these publications exemplify the relevance of epigenetics in cisplatin resistance. Other mechanisms such as miRNA activity, or DNA methylation, are also important regulating therapy-resistance mechanisms. For example, MGMT promoter methylation can functionally predict temozolomide response in glioblastoma , while mSince the establishment of the first cell line in 1951, scientists have used 2D culture models to study the intrinsic properties of cancer cells, trying to unravel mechanisms of chemotherapy resistance. Nevertheless, tumor cells grow in a continuously changing ecosystem within 3D structures that contain nutrient and oxygen gradients, and constantly interact with biological factors such as other cell types in a physical space formed by the ECM. All these factors will change the cancer cell characteristics and add other players to the equation of chemotherapy resistance. These elements can be classified into physical and biological factors . PhysicaA growing body of evidence suggests that the ECM supporting the growing mass of tumoral cells can modulate therapeutic response. Research has shown that biophysical traits such as matrix density, stiffness and composition can alter drug delivery, reception, and efficacy. In fact, high ECM rigidity is often a poor prognostic factor and is associated with chemoresistance and higher metastatic potential in highly fibrotic tumors . ECM stiUpregulation and increased secretion of certain collagens by CAFs (particularly COL8A1 and COL11A1) seems to promote resistance to common chemotherapeutic agents such as cisplatin in HNSCC cell lines through collagen discoidin-domain receptor 1 (DDR1) upregulation, which controls cell differentiation and tissue homeostasis. Although its role in cancer is yet to be fully elucidated, growing evidence links this tyrosine-receptor kinase to metastatic and pro-survival mechanisms . Other cHigher cellular density from increased tumor proliferation creates a progressively hypoxic environment due to a shortage of oxygen and available nutrients. Hypoxia inducible factor (HIF1α) target genes feed the stiffening ECM with the induction of LOX, LOXL, collagens, and MMPs that are responsible for basal membrane protein cleavage , releasiA stiff ECM has also been linked to the activation of EMT-related signaling pathways, which play a role in treatment resistance , as seenOther ECM components such as small-size hyaluronan synthase-3 (HAS-3) have been linked to malignant processes in a variety of carcinomas, while isoform HAS-2 downregulation has shown cisplatin resensitization and tumor growth arrest in OSCCs. CSCs marker CD44 variant 3 (CD44v3) has been detected and linked to lymph node metastasis and cancer progression in HNSCC . This alThe cellular component of the tumor microenvironment can be divided into immune and non-immune cell types. The non-immune cell types are mainly fibroblasts and endothelial cells, and a minority of other important cell types of the neural lineage such as Schwann cells in tumor-associated innervation . Cancer-associated fibroblasts (CAFs) represent up to 70% of the stromal cells in the TME within HNSCCs , having TMEs enriched in CAFs are considered immunosuppressed and are also a predictor of bad prognosis . In HNSCChemotherapy administration and its effects are not tumor cell-exclusive, given that the agent penetrates within other proliferating cells in the TME. Compelling evidence strongly suggests CAFs respond to cisplatin, mainly through exosome, cytokine, and ECM component secretion, reducing therapeutic efficacy. Higher absorption and retention (and therefore decreased release) of cisplatin by CAFs have been linked to higher chemoresistance and recurrence of HNSCC, as well as greater clonogenic ability . A ratheOther understudied components of the TME in HNSCCs are the oral tissue-resident macrophages and tumor-associated macrophages C. Clinic− Foxp3high Tregs correlated with an advanced stage of HNSCC and a shorter relapse-free survival time after treatment with cisplatin or cetuximab [The presence of CAFs and TAMs usually correlates with the presence of regulatory T cells (Treg) and high expression levels of the inhibitory ligand PD-L1, which promotes T exhaustion . Tregs cetuximab . The preetuximab . OverallCisplatin can also alter the immune landscape of the tumors, facilitating the appearance of tumor relapses. It has been shown that HNSCC recurrences contain decreased levels of B and T cell infiltrates and increased levels of macrophages, neutrophils, and dendritic cells . This phYAP/TAZ proteins are downstream transcriptional coactivators within the Hippo pathway, which translocate from the cytoplasm to the nucleus and bind to DNA-binding TEAD factors . TranscrFAT1, showing deletions in approximately 30% of HNSCCs, contributing to unrestrained YAP activity [YAP/TAZ regulation is highly complex, integrating and responding to both cell-intrinsic and cell-extrinsic stimuli. Canonical Hippo pathway activation downregulates YAP/TAZ via LATS1/2 kinases and has traditionally been described as an antitumoral mechanism due to its interference between YAP/TAZ and their proliferative and prosurvival target genes . Aberranactivity . Other additional regulatory mechanisms regarding YAP/TAZ upregulation and escape from cytoplasm arrest are those related to mechanotransduction, cell–cell and cell–ECM interaction. YAP/TAZ are activated in the presence of mechanical stimuli such as high ECM stiffness, which is a hallmark of HNSCCs . IncreasYAP/TAZ pathway has been linked to multi-drug resistance among a variety of cancers, and is considered of interest in HNSCCs due to common genomic alterations affecting YAP/TAZ activity and regulation, as well as their characteristic fibrotic TME . YAP andCSCs or cells with EMT-induced CSC properties are the cornerstone of multidrug resistance. YAP/TAZ activation has been suggested as a possible mechanism through which CSC or CSC-like cell populations are maintained and enriched throughout various malignancies . StudiesAn interesting aspect to consider is that YAP/TAZ transcriptional co-activators may bind different TFs. This brings about the possibility of YAP and/or TAZ having specific roles, target genes, etc., depending on driver mutations, specific anatomic locations of HNSCCs or the composition of the TME. More detailed analysis will be required to answer these questions. This would explain contradictory results demonstrating that under AKT signaling, YAP acts as a tumor suppressor, inhibiting cell survival and decreasing cisplatin resistance .Secretion of IL-6 and other cytokines including IL-11 function by promoting stemness and survival cues to cancer cells and subsequent persistence after cisplatin treatment. For instance, IL-6 binds to its receptor IL-6R-alpha and co-receptor gp130, activating JAK/STAT signaling. Other GF receptors such as EGFR or VEGFR can also trigger this pathway. The signal transducers and activators of transcription (STAT) family is well known to mediate cell survival (stabilizing Bcl-2 and Survivin), proliferation (through c-MYC and CyclinD1), invasion (MMP-9 secretion and EMT induction) and angiogenesis (through VEGF), and its function in HNSCC has been extensively documented . Since fThe function of the NOTCH pathway in the initiation, progression, and therapy resistance in HNSCCs remains controversial . While tAutophagy is upregulated in various types of cancer, including HNSCC, and has sparked interest as a novel pro-survival mechanism. Canonically employed by the cell to maintain homeostasis, cell survival, and metabolism, intracellular components and organelles undergo degradation within a physiological context. Recent research has pointed towards autophagy as a key player in ECM secretion, mediating transport of well-known tumorigenic mediator molecules . CAFs showed higher levels of basal autophagy when compared to normal fibroblasts. Inhibition of autophagy with hydroxychloroquine mitigated HNSCC progression and invasive potential in vitro, having a synergistic effect in combination therapy with and RT ,198. HigOver the years, it has become clear that CSCs play a critical role in cancer resistance against multiple treatments, especially chemotherapy. HNSCCs are a group of heterogenous cancers that originate from epithelial tissues maintained by specific adult SC populations. Importantly, each adult SC population contain unique characteristics  that wilOn the other hand, cisplatin resistance mechanisms such as tumor heterogeneity, the presence of various tumor drivers, and cell plasticity have emerged as potential targets to design tailored combinatorial treatments (summarized in Deeper understanding of the cisplatin mechanisms of action, the identification of synergistic treatments, and the definition of novel biomarkers allowing the prediction of therapy response will be critical to developing alternative regimens and stratifying patients to optimize cisplatin treatment. In addition, the use of cisplatin as a neoadjuvant in combination with numerous immunotherapies targeting the TME is opening up a brand new field in the management of HNSCC patients, although their clinical benefit remains to be revealed.


The network of tunneling nanotubes (TNTs) represents the filamentous (F)-actin rich tubular structure which is connected to the cytoplasm of the adjacent and or distant cells to mediate efficient cell-to-cell communication. They are long cytoplasmic bridges with an extraordinary ability to perform diverse array of function ranging from maintaining cellular physiology and cell survival to promoting immune surveillance. Ironically, TNTs are now widely documented to promote the spread of various pathogens including viruses either during early or late phase of their lifecycle. In addition, TNTs have also been associated with multiple pathologies in a complex multicellular environment. While the recent work from multiple laboratories has elucidated the role of TNTs in cellular communication and maintenance of homeostasis, this review focuses on their exploitation by the diverse group of viruses such as retroviruses, herpesviruses, influenza A, human metapneumovirus and SARS CoV-2 to promote viral entry, virus trafficking and cell-to-cell spread. The later process may aggravate disease severity and the associated complications due to widespread dissemination of the viruses to multiple organ system as observed in current coronavirus disease 2019 (COVID-19) patients. In addition, the TNT-mediated intracellular spread can be protective to the viruses from the circulating immune surveillance and possible neutralization activity present in the extracellular matrix. This review further highlights the relevance of TNTs in ocular and cardiac tissues including neurodegenerative diseases, chemotherapeutic resistance, and cancer pathogenesis. Taken together, we suggest that effective therapies should consider precise targeting of TNTs in several diseases including virus infections. The ability of a cell to communicate with the distant neighboring cell is vital for its survival and efficient function. Many pharmaceuticals work by enhancing or inhibiting components of the cell communication mechanisms , 2. The TNTs exist as a cytoplasmic bridge between the two closely or distant cells. They form gap-like junctions between connected cells and mediate the exchange of cytoplasmic proteins, cellular organelles , lipids, nucleic acids, microRNA, ions, calcium, and several other components , 8–10. TWhile numerous processes are downregulated when cellular supplies are low and cells are under distress, TNT polymerization is enhanced . CellulaCells utilize numerous mechanisms for communication and sensing their environment such as filopodia. Filopodia, like TNTs, can form long range intercellular bridges . HoweverNumerous studies have attempted to elucidate the signaling cascade involved in the formation of TNTs. Delage et al., 2016 reported that CDC42, IRSp53, and VASP form a complex which inhibits TNT formation and vesicular transport . InteresAs TNTs form in response to cellular stress, the molecules involved in DNA repair and cell cycle arrest could be involved in the upregulation of TNTs. p53-activated pathways were reported to be essential for production of TNTs . Cells ivia the Wnt/Ca2+ pathway  in the formation of TNT in squamous cancer cells protease . While Mprotease .In general, the TNTs formation are preferentially driven by the activation of Rho GTPase signaling with the polymerization of the filamentous actin at the cellular tip , 38. Thevia TNTs  between MSCs and injured cardiomyoblasts functioned to facilitate organelle transfer, resulting in rescue of damaged cells  and herpes simplex virus, can evade host immunity and avoid pharmaceutical targeting by using TNTs to pass their genomes to naive cells , 52. In via TNTs provides critical protection from circulating immune cells and avoids virus-cell interactions that may alert host defenses. Furthermore, TNTs allow for infectious particles that initially attach to non-permissive cells to spread to vulnerable cells and promote infection , other members of the herpesvirus family, such as gamma herpesviruses exemplified by murine gamma herpesvirus 68 (MHV-68) and Epstein-Barr virus (EBV), have also been shown to induce and exploit TNT for viral spread using gp48 and ORF58 , a protein kinase that induces phosphorylation of cytoskeleton protein targets like α-catenin and motor protein myosin IIa  which has been found to induce F-actin polymerization, or protrusive growths from the cell surface, and SARS-CoV and murine hepatitis virus, which induce cell membrane interruptions and filopodia formation like the CK2 protrusions off SARS-CoV-2 infected cells , which together with human ACE-2 receptors enhance viral attachment and cell entry Figure 6en cells  and hepaen cells , a key epatients . Clearlyvia TNTs is beneficial for viruses. Mitochondrial transfer promotes viral survival, factory production, infection rate, and redistribution of mitochondria; overall, leading to an increase in infectious viral particles. For example, porcine reproductive and respiratory syndrome virus (PRRSV) can not only induce TNT formation in infected cells but also spread to uninfected cells via proteins that associate with mitochondria , and increased rescue of cells with dysfunctional mitochondria  mediated by TNTs, with drug-dependent increase in TNT formation , cell-to-cell communication structures have become a target of investigation in response to acquired drug resistance . Utilizichondria . Using iormation . Furtherormation .In addition to facilitating organelle transfer, studies have implicated nanotubular structures in potentiating angiogenesis and creating sustainable environments for tumor cell proliferation and metastasis. TNTs mediate pericyte vascularization and collateralization in fetal cerebral cortex and human glioblastoma samples . The resin vivo investigations are critical in adequately understanding the complex interplay of nanotubular connections in early pathogenesis and spread of human cancers.Taken together, TNTs present a novel mechanism of cell-to-cell communication in cancer. Further research clarifying the mechanisms of chemoresistance through mitochondrial transfer or macromolecular exchanges are necessary in developing targeted anti-cancer therapies. Additionally, supportive via TNTs and vice versa (It has been shown that cancer cells may develop resistance to chemotherapeutics even without prior exposure to them. One explanation for this phenomenon is that TNTs mediate communications between cancer cells exposed and not exposed to chemotherapeutics which selects for progeny that are resistant. This mechanism of resistance has been demonstrated in pancreatic cancer cells that were harvested from patients and then treated with the popular chemotherapeutic drug doxorubicin . Doxorubce versa . These rce versa . For resce versa . While d+)  . Thus, tIt may be possible to exploit TNT-mediated transport of molecules between cancer cells. Tumor cells expressing HSV thymidine kinase (TK) can be killed with ganciclovir treatment . HoweverThe significance of TNTs extends beyond viral infections and cancer as they play a role in the pathogenesis of numerous neurodegenerative diseases, many neurodegenerative diseases are the result of an accumulation of misfolded proteins. There exists evidence that disease such as Parkinson’s, Huntington’s, and Alzheimer’s diseases can be propagated through passage of defective proteins through TNTs. In a model of Parkinson’s disease., α-synuclein fibrils were transported through TNTs inside of lysosomes from defective cells to healthy cells, contributing to α-synuclein aggregation in the latter . Misfoldvia the culture medium. Instead, the huntingtin aggregates were transported through TNTs. Furthermore, mutant huntingtin stimulated TNT formation in a parallel mechanism to those in Parkinson’s and Alzheimer’s diseases  for initiating the local contacts between the migrating cells (<20 μm)  . Non-loc(<20 μm) –117.via TNTs- contribute directly to enhanced aggressiveness of various forms of cancers  cells in the corneal stroma has also been observed , individual viral proteins , capsid protein VP26, and tegument protein Us3), as well as the viral genomes  to the recipient cells  to DS is kindly acknowledged.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.


Heart failure (HF) is a major health care burden increasing in prevalence over time. Effective, evidence-based interventions for HF prevention and management are needed to improve patient longevity, symptom control, and quality of life. Dietary Approaches to Stop Hypertension (DASH) diet interventions can have a positive impact for HF patients. However, the absence of a consensus for comprehensive dietary guidelines and for pragmatic evidence limits the ability of health care providers to implement clinical recommendations. The refinement of medical nutrition therapy through precision nutrition approaches has the potential to reduce the burden of HF, improve clinical care, and meet the needs of diverse patients. The aim of this review is to summarize current evidence related to HF dietary recommendations including DASH diet nutritional interventions and to develop initial recommendations for DASH diet implementation in outpatient HF management. Articles involving human studies were obtained using the following search terms: Dietary Approaches to Stop Hypertension (DASH diet), diet pattern, diet, metabolism, and heart failure. Only full-text articles written in English were included in this review. As DASH nutritional interventions have been proposed, limitations of these studies are the small sample size and non-randomization of interventions, leading to less reliable evidence. Randomized controlled interventions are needed to offer definitive evidence related to the use of the DASH diet in HF management. Approximately 6.2 million adults in the United States have heart failure (HF) . The oveHF is the end stage manifestation of various pathophysiologic disruptions of cardiac function characterized by insufficient cardiac output to meet body tissue metabolic demands . HF doesChallenges to successfully managing HF include (1) diverse disease etiologies with varied responses to treatment regimens, (2) nutrition therapies inconsistent with patient preferences that reduce patient quality of life and adherence to dietary recommendations, and (3) metabolic heterogeneities affecting individual disease progression and management response. For instance, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are dissimilar in their responses to treatment. While HFrEF responds well to standard treatment, HFpEF is less responsive and new evidence-based care strategies are being tested.Despite these challenges, there are also opportunities to better understand HF and reevaluate long accepted but non-individualized HF standards of care. Interdisciplinary research and health care teams are best equipped to monitor and interpret clinically relevant metabolic pathways and biomarkers while prioritizing functional patient-centered outcomes along with engaging HF patients, caretakers, and the community to effectively manage HF.Improved outpatient disease management may slow disease progression and improve health outcomes such as re-hospitalization and death and are therefore important research objectives. Nutritionally, comprehensive diet approaches with individualized flexibility may meet the needs of HF patients better when compared to fluid and sodium restrictions. The Dietary Approaches to Stop Hypertension (DASH) diet is a promising combination diet that may be influential in HF management if it can be incorporated into the lives of HF outpatients. This comprehensive dietary approach allows more opportunities for individualization through precision nutrition and may be beneficial for successful HF management in free-living patients, rather than a reductionist focus on nutrient intake . CoupledThe purpose of this review is to summarize the literature related to the implementation and effectiveness of the DASH diet in outpatient HF management and to inform future precision nutrition research for cardiovascular health.Available literature related to the DASH diet were reviewed for human studies without a time restriction. Relevant and reviewed studies included randomized controlled trials, prospective and cross-sectional studies, systematic reviews, and meta-analyses. Online literature was searched using PubMed. Search terms included heart failure, Dietary Approaches to Stop Hypertension (DASH diet), diet, diet pattern, dietary behavior, implementation science, metabolism, metabolomics, and outcome. Search term combinations included but were not limited to diet pattern and metabolism and heart failure, DASH diet and metabolism and heart failure, diet pattern and heart failure, diet patterns and heart failure and outcome, DASH and heart failure, and diet and heart failure. A total of 85 articles were identified after the initial search, while additional search terms and criteria were included as reviewers became increasingly familiar with the literature. Articles were organized by themes of diet pattern and HF; DASH diet and HF; and diet, metabolism, and HF.HF is the end stage manifestation of heart diseases, characterized by insufficient cardiac output to meet the body’s metabolic demands . The impHF is a heterogeneous syndrome where each patient’s complex characteristics dictate the functional and structural biomarker changes during disease progression. HF is classified into four sequential stages where A (at risk) is at risk for HF due to pre-existing conditions; B (pre-HF) is asymptomatic structural heart disease; C (HF) is symptomatic structural heart disease; and D (advanced HF) is end stage HF with marked symptoms at rest despite therapeutic interventions . HF can With over 6 million Americans and over 26 million people worldwide diagnosed with HF, the prevalence continues to rise with survival improvements and population aging, while large increases in HF incidence are expected in older adults of all sex and racial/ethnic groups through the year 2030 ,10,11. IDiet patterns that support good health emphasize the consumption of fruits, vegetables, whole grains, lean protein sources, legumes, dairy, nuts, and healthy fats, while limiting intake of energy-dense sugars and processed foods. The DASH diet has been shown to be efficacious for CVD risk reduction and is a healthy diet pattern endorsed in the USDA Dietary Guidelines for Americans, 2020–2025 ,15. WhilNutrition care is integral to comprehensive HF management. The current primary dietary approaches for HF management are sodium and fluid restriction, but individualization to patient needs is essential as multiple variables need to be considered in advanced HF ,20. VariFactors to consider when personalizing sodium recommendations for HF patients include HF stage and symptoms, LVEF, diagnosis of HFpEF vs. HFrEF, concurrent medications affecting cardiac function and urinary output, comorbidities, patient body size, and baseline diet. While excessive sodium and fluid intake seen in the setting of non-compliance are common causes of HF exacerbation and hospitalizations, overly strict recommendations can have adverse nutritional and physiologic consequences. Excessive sodium and fluid restrictions increase the perception of thirst . Severe For fluid restriction, the ACC/AHA HF guidelines suggest fluid restriction of 1.5 to 2 L/day in patients with HF class D or severe hyponatremia ; the recExcess body weight results in metabolic and neurohormonal pathways that promote cardiac remodeling, risk of HF, and incidence of HF symptomology . Weight Chronic inadequate caloric intake in HF patients leads to sarcopenia and cachexia, ultimately increasing the risk of mortality and recurrent hospitalizations. Inadequate intake has been found to be an independent predictor of adverse events, even when confounding factors are controlled . MicronuDietary quality in the context of various healthy diet patterns is an important determinant of health outcomes. Various dietary quality scores have been used to evaluate eating patterns, such as the Healthy Eating Index-2015 (HEI-2015), Alternate Healthy Eating Index (AHEI), Healthful Plant-Based Diet Index (HPDI), and Alternate Mediterranean Diet Score (AMED). High adherence to each of these scores was consistently and inversely associated with CVD risk in large prospective study populations with long-term follow-up . This unThe Mediterranean diet and the DASH diet are well documented to be protective against the incidence of CVD . In effoThe DASH diet emphasizes the consumption of whole grains, fruits and vegetables, low-fat dairy, lean meat, fish, poultry, nuts, seeds, and legumes, and sparse use of fats and oils . This eaHypertension is a risk factor for HF incidence as well as a target for HF management, and BP reductions can be achieved with the DASH diet . The oriThe BP reductions that can be achieved with the DASH diet are important in HF pathophysiology, but the protective effects likely extend beyond BP control. The DASH diet is beneficial in preventing the incidence of HF in patients younger than 75 years as reported from the MESA (Multi-Ethnic Study of Atherosclerosis) . This coDietary supplements have been studied for their effects on HF management and have proven ineffective or not yet reproducible. Antioxidant vitamins (such as vitamin C and E) have been largely ineffective in clinical trials, while coenzyme Q10 (CoQ10) has been studied as a targeted approach to treat oxidative stress and mitochondrial dysfunction, with modest yet controversial results ,57. ResuThe DASH diet is effective in the prevention of CVD. However, the effects of the DASH diet on the routine medical management of free-living HF patients are less understood. Consistent observational evidence supports DASH diet eating patterns are associated with improved cardiac function, lower HF event rates, and reduced mortality . There iEvidence supports that the DASH diet may improve cardiac function, functional capacity, blood pressure, oxidative stress, and mortality . AdditioHF is a set of complex and heterogeneous diagnoses with underlying variability in etiology, pathophysiology, metabolic, and other individual factors. HFrEF is responsive to a standardized treatment approach despite heterogeneity of etiologies . ConversThe taxonomy or classification of HF recognizes the diverse etiologies and associated mechanistic disruptions of cardiac function. Biomarkers that predict progression or response to treatment will aid in the development of a new precision nutrition taxonomy that will identify those patients most likely to benefit from the DASH diet. The inverse association of DASH diet adherence with incident HF in the REGARDS cohort was not statistically different between HFrEF and HFpEF . A recenStudying specific metabolites with metabolomics techniques has been used to further understand HF and the DASH diet. The innovative use of metabolomics profiling in nutrition research is growing and can identify metabolites as biomarkers of dietary pattern and food exposure to advance the ability to evaluate dietary adherence and nutritional intake assessment in a quantitative manner . AdditioThe medical literature includes multiple studies associating metabolites with HF characteristics and outcomes. Examples include findings that metabolic profiling can discriminate and identify patients at risk of HF-related decompensation, and metabolomic profiles showing differentially expressed signaling pathways are associated with lower cyclic guanosine monophosphate/brain natriuretic peptide (cGMP/BNP) ratios in HF patients ,78. Of rSeveral observational and cross-sectional studies have identified dietary-derived serum metabolites characteristically associated with specific foods and healthy diet patterns, including the DASH diet ,82,83,84Two recent small, controlled feeding trials of the DASH pattern demonstrated metabolites specific to the DASH diet and food-specific components reflecting the intervention diet ,92. In aClinical trials are contributing to emerging evidence that the DASH diet is efficacious in HF management. A three-week diet intervention of DASH sodium-restricted meals provided to HFpEF patients was associated with significant reductions in BP and arterial stiffness, improved ventricular diastolic function, and reduced oxidative stress ,94. ThisExamples of successful DASH lifestyle interventions include the PREMIER study and ENCORE trial, which resulted in the intervention groups significantly increasing consumption of nutrient-rich DASH-specific foods and food categories as compared to the advice only control group ,97. ThesSustaining behavior change around diet and other lifestyle habits is challenging for free-living outpatients with chronic disease. Assessment of adherence to HF self-care recommendations that include diet, medications, exercise, and other self-reported behaviors have revealed typically low or selective adherence . Poor adPatient self-efficacy is a central precept in behavior and behavior modification. Interventions designed to improve self-efficacy should use validated tools to measure self-efficacy pre- and post-intervention, and the intervention should be targeted to improving self-efficacy to achieve dietary behavior change. Self-efficacy can be enhanced through a variety of evidence-based strategies utilized by registered dietitians and other healthcare providers, such as individualization to tailor recommendations, social support, goal setting, self-monitoring, and others . CognitiUtilization of telemedicine can help control diseases, manage clinical cases, and support caregivers . During Despite the importance of translating research findings into clinical care, it takes an estimated 17 years to incorporate evidence into practice . There aRecognizing the potential of implementation science in nutrition research, the Academy of Nutrition and Dietetics identified implementation science as one of four domains for the organization’s 2020 research priorities . An implAlong with efforts to focus on implementation of evidence-based strategies into clinical care through healthcare delivery science, clinicians and scientists must consider ways to reduce health inequities while implementing new care strategies. Recommendations to confront health inequities include developing networks of collaborations and stakeholders to launch transformative studies, optimizing new data sources, platforms, and natural experiments, developing transdisciplinary training programs to enhance research capacities, embracing inclusive research themes, and developing platforms for innovative transdisciplinary research promoting systems science approaches .A precision medicine taxonomy may enhance our understanding of the risk of HF and define interventions more likely to be effective or less toxic based upon the integration of many sources of data including phenotype, omics biomarkers, environmental, and behavioral domains. The variation is best understood by large data bases or cohorts that promote health equity by being inclusive and thus promote tailored therapies for all patients or persons at risk. Comprehensive molecular information, obtained by omic technologies, enables the conduction of precision medicine approaches. Precision nutrition, a form of precision medicine, promises a better understanding of variability in an individual’s response to dietary interventions. Specifically, precision nutrition is nutritional recommendation and guidance designed to maximize therapeutic benefit and health outcomes based on individual profiling or phenotyping. This in-depth metabolic and physiologic information is generated through genomic, metabolomics, proteomic, and metagenomics data. Examples include single nucleotide polymorphism genetic variations that impact nutritional needs or metabolic responses to diet, as well as the influence of gut microbiome composition as a determinant of glycemic and triglyceride responses ,124,125.As noted, HF is a complex and heterogeneous condition involving various etiologies and dysfunctions across multiple organs, yet current nutritional care and recommendations focus on sodium, fluid, and the caloric intake of heart-healthy choices applied in a broad manner. The new taxonomy of HF promotes a targeted and personalized approach to clinical care ,73,127. Implementation of evidence-based nutrition strategies that have shown benefit in carefully controlled clinical trials may positively impact HF outcomes in a cross section of the HF population. Use of the DASH diet in diagnosed HF patients has not yet become standard of care in HF management as it has not been evaluated in pragmatic clinical trials. There is a need for a revised taxonomy of HF that integrates the diverse causes of HF with the diverse demographics of patients with HF and the response or resistance to the DASH diet .Additionally, health care implementation science approaches may ensure that combining effective nutrition interventions with systems of care that integrate behavioral support and modification can be successfully incorporated into routine clinical care. The stratification of patients with pre-existing self-efficacy and systems that support or improve self-efficacy are important baseline measurements. The ability of HF patients to successfully adopt the DASH diet outside of controlled feeding studies has not been widely studied. Precision nutrition technologies should also be explored to understand patient responsiveness to dietary interventions based on patient and disease characteristics such as genotype, HF etiology, therapeutic medications, and other parameters, along with omic technologies that enable objective assessments of dietary intake and subtle metabolic changes. Research studies evaluating the effectiveness and implementation of the DASH diet for outpatient HF management are warranted and have the potential to influence the future health care approaches in CVD prevention, treatment, and management.


In this review we discuss the evidence that animal models of early adversity impinge on fundamental mechanisms of brain aging, setting up a substratum that can accelerate and compromise the time-line and nature of brain aging, and increase risk for aging-associated neuropathologies.Early adversity is an important risk factor that influences brain aging. Diverse animal models of early adversity, including gestational stress and postnatal paradigms disrupting dam-pup interactions evoke not only persistent neuroendocrine dysfunction and anxio-depressive behaviors, but also perturb the trajectory of healthy brain aging. The process of brain aging is thought to involve hallmark features such as mitochondrial dysfunction and oxidative stress, evoking impairments in neuronal bioenergetics. Furthermore, brain aging is associated with disrupted proteostasis, progressively defective epigenetic and DNA repair mechanisms, the build-up of neuroinflammatory states, thus cumulatively driving cellular senescence, neuronal and cognitive decline. Early adversity is hypothesized to evoke an “allostatic load”  Early adversity is a potent risk factor for adult psychopathology . Early sin utero, or during early postnatal time-windows, which can evoke persistent alterations in mood-related behavior, noted long after the cessation of stress  model, results in persistent changes in anxio-depressive behaviors in the progeny  and long-term (10–12 months) changes in mitochondrial function within limbic brain regions and the periphery . Adult pvia a cytokine-dependent mechanism , and drive impaired autophagy thus establishing a substrate for aging-associated neuropathology . Maintaiechanism . Early aechanism . Postnatechanism . Early aechanism ,a. LBN eechanism . Furtherechanism . Howeverechanism . Whilst Amongst the foremost candidates for mediating the persistent effects of early adversity is a perturbed epigenetic landscape, thus driving transcriptional changes that hasten aging-evoked changes . In animEarly stress triggers neuroimmune responses that drive prolonged, pathological and maladaptive neuroinflammation . NeuroinThe aging brain has several hallmark features, including atrophy of vulnerable neuronal populations and marked cognitive impairments . AmongstEarly adversity disrupts the functioning of key physiological processes that facilitate adaptive stress responses, setting in motion a cumulative “allostatic load” that alters the nature and time-line of healthy brain aging. Further, early adversity could also impact key neurodevelopmental milestones, which could alter the optimal functioning of neurocircuits thus setting up a substratum for a disruption of the trajectory for brain aging. The interim duration between exposure to early stressors and eventual brain aging outcomes provides a substantial temporal window for interventional approaches, including life-course factors such as exercise, diet, environmental enrichment, epigenetic and pharmacological interventions that may serve to reverse or ameliorate the negative impacts of early adversity on brain aging. Here we have provided an overview of the key brain aging-associated processes targeted by early adversity, and highlighted gaps in knowledge that require future investigation.PC, AS, and VV jointly wrote the manuscript. 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Small-scale fisheries are critically important for livelihoods around the world, particularly in tropical regions. However, climate variability and anthropogenic climate change may seriously impact small-scale fisheries by altering the abundance and distribution of target species. Social relationships between fishery users, such as fish traders, can determine how each individual responds and is affected by changes in fisheries. These informal cooperative and competitive relationships provide access, support, and incentives for fishing and affect the distribution of benefits. Yet, individuals’ actions and impacts on individuals are often the primary focus of the economic analyses informing small-scale fisheries’ formal management. This focus dismisses relevant social relationships. We argue that this leads to a disconnect between reality and its model representation used in formal management, which may reduce formal fisheries management’s efficiency and efficacy and potentially trigger adverse consequences. Here, we examine this argument by comparing the predictions of a simple bioeconomic fishery model with those of a social-ecological model that incorporates the dynamics of cooperative relationships between fish traders. We illustrate model outcomes using an empirical case study in the Mexican Humboldt squid fishery. We find that (1) the social-ecological model with relationship dynamics substantially improves accuracy in predicting observed fishery variables to the simple bioeconomic model. (2) Income inequality outcomes are associated with changes in cooperative trade relationships. When environmental temperature is included in the model as a driver of species production dynamics, we find that climate-driven temperature variability drives a decline in catch that, in turn, reduce fishers’ income. We observe an offset of this loss in income by including cooperative relationships between fish traders (oligopoly) in the model. These relationships break down following species distribution changes and result in an increase in prices fishers receive. Finally, (3) our social-ecological model simulations show that the current fishery development program, which seeks to increase fishers’ income through an increase in domestic market demand, is supported by predictions from the simple bioeconomic model, may increase income inequality between fishers and traders. Our findings highlight the real and urgent need to re-think fisheries management models in the context of small-scale fisheries and climate change worldwide to encompass social relationship dynamics.The online version contains supplementary material available at (10.1007/s10113-021-01747-5) Climate change and variability trigger changes in the abundance and distribution of target species, influencing fishers, fish traders, and their relationships  on the distribution of fishery benefits. We chose the Humboldt squid fishery because of its significant and well-documented response to recent changes in environmental and climate trajectories . We followed a semi-structured protocol but allowed for flexible responses through semi-directed and open-ended questions  of a type often used in real strategic fisheries management , although these numbers differ marginally with those predicted by the EDM . In contrast, the BEM predicts both variables poorly in the Monte Carlo simulations . The SEM and EDM capture qualitative dynamics of catches equally well. Both models also capture the general downward trend and several years of peak catches. Indeed, catch simulations are essentially the same in the second half of the simulated period. Despite large observed price differences, catch values are comparatively close with or without integrating trader cooperation. The form of the effort function causes this proximity. We used an optimization approach to test whether results were sensitive to the effort function