Polyglutamine disorders are chronic, progressive neurodegenerative diseases caused by expansion of a glutamine tract in widely expressed genes. Despite excellent models of disease, a well-documented clinical history and progression, and established genetic causes, there are no FDA approved, disease modifying treatments for these disorders. Downstream of the mutant protein, several divergent pathways of toxicity have been identified over the last several decades, supporting the idea that targeting only one of these pathways of toxicity is unlikely to robustly alleviate disease progression. As a result, a vast body of research has focused on eliminating the mutant protein to broadly prevent downstream toxicity, either by silencing mutant protein expression or leveraging the endogenous protein quality control machinery. In the latter approach, a focus has been placed on four critical components of mutant protein degradation that are active in the nucleus, a key site of toxicity: disaggregation, ubiquitination, deubiquitination, and proteasomal activity. These machineries have unique functional components, but work together as a cellular defense system that can be successfully leveraged to alleviate disease phenotypes in several models of polyglutamine toxicity. This review will highlight recent advances in understanding both the potential and role of these components of the protein quality control machinery in polyglutamine disease pathophysiology. Polyglutamine (polyQ) diseases encompass nine untreatable and invariably fatal neurodegenerative diseases associated with protein misfolding and aggregation. The cause of this family of disease is expansion of a glutamine tract within widely differing proteins, leading to gain of function effects and a shared phenotype of adult-onset progressive neurodegeneration. There are no FDA approved disease modifying treatments for any polyQ disease despite their well-established genetic causes, carefully documented clinical history, and the availability of excellent genetic models that recapitulate aspects of the disease phenotype . Over 90 DUBs have been identified within the human genome, each belonging to one of seven distinct families. These enzymes play diverse roles including altering protein function and impacting proteasomal degradation.Recently, DUBs have emerged as attractive therapeutic targets in polyglutamine disorders. By removing ubiquitin tags from substrates, DUBs can delay proteasomal degradation. In contrast, their inhibition enhances substrate degradation, demonstrating a pivotal role in diseases caused by misfolded protein accumulation . UBQLN2, also known as hPLIC2, is encoded by an intronless gene and contains both a ubiquitin-like domain and a ubiquitin-associated domain (Deng et al., The above evidence supports a model in which Hsp70/Hsp110 acts to recognize and solubilize protein aggregates. UBQLN2 associates with client-bound Hsp70 and assists in shuttling aggregated components to the proteasome. One key remaining question is whether disaggregation alleviates toxicity in organismal models of polyglutamine disease, which will identify the importance of the disaggregation system for therapeutic strategies. Understanding how to therapeutically manipulate the disaggregase machinery is a worthwhile endeavor likely to lead to a better understanding of pathophysiology.A wealth of evidence has linked the proteasome to several polyQ diseases, both as a therapeutic target and as a dysfunctional pathway downstream of mutant polyQ proteins. The 20S proteasome was first shown to colocalize with aggregates of polyQ ataxin-1 in both patients and transgenic mice. This same colocalization was later found in human SCA3 tissue, a mouse model expressing polyQ ataxin-7, HeLa cells expressing polyQ androgen receptor, and mice over-expressing truncated polyQ androgen receptor (Cummings et al., The proteasome also shows a preference for degrading misfolded polyQ proteins over their wild type counterparts, likely due to efficient targeting of mutant proteins for degradation. In MN1 cells expressing either 24Q or 65Q androgen receptor, the mutant protein demonstrates significantly reduced half-life, and this degradation is inhibited by the proteasome inhibitor lactacystin (Lieberman et al., While the proteasome has been implicated in polyQ protein degradation, studies have also shown impaired function in several disease models. In mice over-expressing N-terminal polyQ huntingtin, altered proteasome localization to aggregates was accompanied by an increase in half-life of the proteasome substrate p53 (Jana et al., in vivo studies have lacked consistent results (Bowman et al., Though cellular data has been very consistent in demonstrating proteasome dysregulation, Perhaps the most compelling evidence for proteasome dysfunction playing a key role in pathophysiology comes from successful attempts to modulate degradation through this pathway, resulting in reduced toxicity in disease models. Several excellent reviews have highlighted therapeutic strategies to promote degradation of mutant proteins through the proteasome, including Hsp90 inhibition (Waza et al., Recent advances in our understanding of polyQ disease pathophysiology have shed light on several divergent pathways of toxicity downstream of the mutant protein (Mhatre et al., SN and AL co-authored this manuscript. SN is a student in the M.D.-Ph.D. program at the University of Michigan Medical School and a thesis student in AL's laboratory.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.


Satish Gopal discusses the challenges of deliverable cancer care and cancer trials in sub-Saharan Africa as well as a potential framework for overcoming these challenges. There is an extreme scarcity of evidence to guide cancer treatment in sub-Saharan Africa (SSA), as well as major differences between SSA and resource-rich settings regarding cancer treatment infrastructure.A possible framework for conceptualizing cancer clinical trials in SSA is proposed, and key issues related to equipoise, innovation, and efficiency are addressed within the SSA context.Strongly aligned cancer care and research agendas can generate forward progress for cancer treatment in the region and globally impactful clinical science that can change treatment paradigms even in resource-rich settings.Cancer burden is increasing in sub-Saharan Africa (SSA), with more than 600,000 estimated new cancer cases in 2012 and age-standardized incidence increases of 10%–20% in most countries between 2005 and 2015 . HoweverOne difficulty is deciding which established treatments in resource-rich settings can be straightforwardly generalized to SSA and which require specific demonstrations of safety and efficacy in SSA. There is no established framework for such decisions, and there are significant differences of opinion regarding this issue. Uncertainty results from scarce regional data and important SSA differences from resource-rich settings where cancer treatments have been studied. These differences include host genetics and metabolism; tumor biology; endemic burden of infectious pathogens, including HIV; and profound differences in general healthcare infrastructure, any of which could dramatically alter how specific treatments perform relative to high-income countries.As a result, one might argue that SSA is sufficiently different from resource-rich settings where existing evidence for cancer treatment has been generated and that all studies should be redone in the region. Indeed, for an arguably much less intensive intervention, antiretroviral therapy (ART), the HIV community first undertook proof-of-principle studies as a foundation for larger scale-up, to mitigate concerns that poor adherence and rampant HIV resistance would result without intensive monitoring ,9. AdditTherefore, a nuanced middle approach is likely most sensible, with clearer articulation of evidentiary standards for including antineoplastic essential medicines in World Health Organization (WHO) lists . For insMYC oncogene, and modern principles of combination chemotherapy [Given uncertainties about clinical equipoise in SSA, a related question is what constitutes cancer innovation in SSA, as well as whether SSA cancer trials can have global rather than regional importance. Indeed, the global cancer research community was remarkably fortunate with its first SSA activities focused on endemic Burkitt lymphoma, which led to the discovery of Epstein-Barr virus (EBV), the otherapy . Similarotherapy –19.Moreover, in pursuit of innovation, the willingness to invest in incremental advances for cancer patients in high-income countries has often not translated to SSA. New “blockbuster” cancer therapies, like brentuximab vedotin for Hodgkin lymphoma or immune checkpoint inhibitors for many cancer types, are appropriately heralded with incremental efforts to define their utility across a range of clinical niches in high-income countries. In SSA, among all cancers, pediatric Burkitt lymphoma has benefitted from the strongest commitment to achieving rigorous incremental advances under local conditions, as in other international pediatric oncology groups –24. NeveWhatever the difficulties encountered in SSA, several lines of inquiry could lead to globally impactful and innovative clinical science. First, certain cancers occur with unique frequency in SSA and can only be studied in large numbers if patients are included from this region. Examples include endemic Burkitt lymphoma, Kaposi sarcoma, and conjunctival squamous cell carcinoma. Second, with the availability of highly effective noncytotoxic treatments for cancer and the identification of patient subgroups with particularly favorable prognoses like head and neck squamous cell carcinoma caused by human papillomavirus (HPV), there is increasing interest in treatment de-escalation in high-income countries. De-escalated treatment, however, may be difficult to accept in resource-rich settings, where there is a natural reluctance to deviate substantially from aggressive treatment protocols proven to result in excellent outcomes and where undertreatment is typically viewed as a graver error than overtreatment. Given real-world barriers to universally applying regimens from high-income countries as articulated above, de-escalated strategies may be highly appropriate and even necessary in SSA, presenting opportunities for “leapfrog” advances by evaluating regimens that could be applicable in high-income countries. Finally, development of noninvasive biomarkers for cancer diagnosis, prognosis, and response assessment would be particularly valuable in SSA where pathology and diagnostic imaging are limited, especially when these have realistic potential for implementation in SSA. As an example, we have pursued evaluation of quantitative plasma EBV DNA in endemic Burkitt lymphoma, using instruments already in place for HIV RNA monitoring, to guide risk-adapted and response-guided therapy analogous to fluorodeoxyglucose positron emission tomography (FDG-PET) in high-income countries –27.In addition to biologic heterogeneity, cancer trials in SSA will have to cope with marked heterogeneity in populations and health infrastructure across settings. Moreover, health infrastructure in SSA is changing constantly and at times quite rapidly. Trials predicated on absent radiotherapy or hematopoietic growth factors, for instance, might be undermined by the sudden introduction of these adjunctive treatments within relatively short periods and with this introduction typically not achieved in a uniform manner. Given these complicating factors, plus the enormous evidence deficit for cancer treatment in SSA, as well as the enormous need to build trust and prove to SSA stakeholders that cancer research unequivocally benefits public health, there is no region of the world in greater need of flexible, adaptive trial designs that appropriately respond to accumulating evidence or changing conditions on the ground, ensure maximum therapeutic benefit for trial participants, and minimize financial and time expenditures. Again, this is an opportunity for true leapfrog advances within nascent cancer trial networks in the region, which do not have to be unduly constrained by traditional protocol development approaches that may be too rigid and slow to drive oncology care forward in SSA.Taking these issues into consideration, a possible framework for conceptualizing cancer clinical trials in SSA is proposed in There is a growing recognition in high-income countries that care and research agendas for cancer must be brought closer together, for clinical, scientific, and economic reasons. In SSA, there are simply not sufficient resources to allow these agendas to diverge and/or compete, a luxury born of having excess resources in the first place. Care and research must be aligned and even considered the same—for example, as in international pediatric oncology groups, in which there has been a decades-long commitment to treating cancer on harmonized protocols across centers, to drive clinical science forward for specific diseases and individual children . A poten


Atrial fibrillation (AF) is the most common tachyarrhythmia which is associated with increased morbidity and mortality. AF usually progresses from a self-terminating paroxysmal to persistent disease. It has been recognized that AF progression is driven by structural remodeling of cardiomyocytes, which results in electrical and contractile dysfunction of the atria. We recently showed that structural remodeling is rooted in derailment of proteostasis, i.e., homeostasis of protein production, function, and degradation. Since heat shock proteins (HSPs) play an important role in maintaining a healthy proteostasis, the role of HSPs was investigated in AF. It was found that especially small heat shock protein (HSPB) levels get exhausted in atrial tissue of patients with persistent AF and that genetic or pharmacological induction of HSPB protects against cardiomyocyte remodeling in experimental models for AF. In this review, we provide an overview of HSPBs as a potential therapeutic target for normalizing proteostasis and suppressing the substrates for AF progression in experimental and clinical AF and discuss HSP activators as a promising therapy to prevent AF onset and progression. Atrial fibrillation (AF) is an age-related tachyarrhythmia in both left and right atria, which can be caused by underlying (heart) conditions, such as valvular heart disease, congestive heart disease, ischemic cardiomyopathy, obesity, diabetes mellitus, and hypertension  and therefore is called a DMPK-binding protein, indicating its importance in muscle maintenance  , thereby suppressing activation of the transcription factor NF-κB  induction of HSPB members provides prevention effect on tachycardia-induced structural remodeling and contractile dysfunction. A drug often used to boost HSP expression is geranylgeranylacetone (GGA) (Hoogstra-Berends et al. In addition to the pharmacological induction of HSPB, exercise is also found to induce HSPB levels and subsequently reveal cardioprotective effects. Various studies show that gene and protein levels of HSPB1 and HSPB6 are elevated after physical exercise in rat and mouse models. Interestingly, in these studies, HSPB1 and HSPB6 were phosphorylated, resulting in stabilization of myofilaments, restoration of disrupted contractile proteins, and consequently improved contractile function of the heart (Boluyt et al. Various HSPB members conserve a healthy proteostasis of cardiomyocytes and thereby prevent AF onset and progression. Their mode of action is via the stabilization of the cardiomyocyte structure, thus conserving the contractile and electrophysiological function of the atria. Since compounds, such as GGA, and exercise are found to induce HSPB expression, these may represent promising novel therapeutic strategies to prevent AF onset and progression.


Nutrition support is increasingly recognized as a clinically relevant aspect of the intensive care treatment of cardiac surgery patients. However, evidence from adequate large-scale studies evaluating its clinical significance for patients’ mid- to long-term outcome remains sparse. Considering nutrition support as a key component in the perioperative treatment of these critically ill patients led us to review and discuss our understanding of the metabolic response to the inflammatory burst induced by cardiac surgery. In addition, we discuss how to identify patients who may benefit from nutrition therapy, when to start nutritional interventions, present evidence about the use of enteral and parenteral nutrition and the potential role of pharmaconutrition in cardiac surgery patients. Although the clinical setting of cardiac surgery provides advantages due to its scheduled insult and predictable inflammatory response, researchers and clinicians face lack of evidence and several limitations in the clinical routine, which are critically considered and discussed in this paper. Patients undergoing cardiac surgery regularly experience a systemic inflammatory response, which contributes to acute and persistent organ injury. With an increasingly older population undergoing increasingly complex cardiosurgical procedures, the incidence of comorbidities and malnutrition rises. The nutritional status and adequate nutrition therapy are crucial factors contributing to the outcome of patients. The following sections will give a basic background on the inflammatory reaction expected after cardiac surgery, and will illustrate the pathomechanisms of organ dysfunctions and their influence on clinical outcome. In extension, we summarize current nutritional practice, which is thought to influence outcomes and we will illuminate opportunities for improvement in every day clinical practice.Patients undergoing cardiac surgery experience a complex systemic inflammatory response syndrome, which manifests as pyrexia, tachycardia, leukocytosis, hypotension, edema, and organ failure. Several stimuli lead to systemic inflammation reactions during and after cardiac surgery. The surgical trauma induces the activation of neutrophils, endothelial cells and platelets and the release of mediators of the inflammatory response, such as tumor necrosis factor α (TNFα) and diverse interleukins (IL) ,2. The fAfter an ischemic period during the cross-clamping of the aorta, the reoxygenation of the tissues further triggers the inflammatory response. This ischemia-and-reperfusion (I/R)-injury can also be divided into leukocyte-dependent-mechanisms—through the interaction of neutrophils and endothelial cells—and non-leukocyte-dependent pathways, such as the release of reactive oxygen species, arachidonic-acid metabolites and cytokines, as well as increased nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) activity ,9,12,13.The most frequent organ dysfunctions after cardiac surgery are pulmonary dysfunction (up to 79%) , ventricOrgan dysfunctions cause a prolonged need of life-sustaining therapies and consequently a longer stay on the intensive care unit (ICU). The influence of nutritional deficiencies on these pathomechanisms are described in the next section.Malnutrition is a subacute or chronic state of disordered nutrition in which a combination of varying degrees of over- or undernutrition and inflammatory activity have led to a change in body composition and diminished function ,23, or mMaintenance of metabolismAttenuation of catabolismMaintenance of gut-integrityReduction of postoperative complicationsImproved wound healingSecuring adequate hydration and euglycemia.Nutritional deficiencies contribute to the pathomechanisms of inflammation due to reduced defense mechanisms and depleted metabolic reserves in the patient. Malnourished patients are more susceptible to the surgical trauma, I/R-injury, anesthesia-related complications, hemodilution, as well as inflammation. Malnutrition promotes endothelial dysfunction of the gut mucosa, allowing for a possible bacterial translocation . A preexUntil today, evidence of well-designed, well-powered randomized controlled trials investigating the clinical significance of an early initiated nutrition therapy in high-risk cardiac patients after surgery remains sparse. Therefore, we conducted a systematic literature review focusing on nutritional protocols e.g., hypocaloric feeding or amount of macronutrients in critical illness with special focus on patients after cardiac surgery. The PICO-framework—an acronym for participants, intervention, comparison and outcome—addresses essential aspects of a well-built clinical research questions. It was used to define the focus of this systematic literature review. Studies were included if they met the following criteria:The low evidence received from rather small studies with from heterogeneous patient populations with different nutrition interventions and non-comparable outcome assessmentsThe resulting need for adequate studies andThe urgent need for specific guidelines for this cohort of critically ill patients, as current clinical practice may lead to malnutrition in these patients.(1) population: critically ill, adult patients after cardiac surgery; (2) intervention and comparison: any type of nutritional protocol, e.g., early intense versus early lower-dose enteral nutrition, early versus delayed enteral nutrition, enteral nutrition alone versus enteral nutrition plus supplemental parenteral nutrition; (3) any type of clinical outcome; (4) type of studies: prospective or retrospective observational studies, randomized or non-randomized clinical trials, systematic reviews of literature and meta-analyses. Medical Subject Headings (MeSH) was applied to identify most appropriate search terms. Consequently, the following search strategy (example given for MEDLINE) was developed to identify matching studies: ((Nutrition Therapy [MeSH Major Topic]) AND (cardiac [Title/Abstract] OR heart [Title/Abstract])) AND surg* [Title/Abstract]. To locate relevant articles, six bibliographic databases (Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARES), and the Medical Literature Analysis and Retrieval System Online (MEDLINE) were searched. Importantly, no sufficiently designed, adequately powered, randomized controlled trials investigating the effect of nutritional therapy in cardiac patients after surgery were available. Yet, several small studies have provided initial evidence on the feasibility and clinical significance of nutritional therapy in cardiac surgery patients. Based on the above-described findings, we proceed with a narrative review of the literature to illuminate current evidence about nutrition support in cardiac patients relevant for daily clinical practice to demonstrate:In clinical practice, often little attention is paid to nutrition support and various extrinsic risk factors hinder the adequate supplementation of nutrients as summarized in In a prospective observational study, Rahman et al. recently demonstrated as analysis of an international nutrition survey in critical care units around the world that nutritional adequacy was low with respect to both energy and protein supplementation in cardiac surgery patients . In addiNutrition adequacy was defined as the total amount of calories or protein received from EN and propofol, as well as PN, divided by the amount prescribed as per the baseline assessment and expressed as a percentage.Up to 8% loss of body weight and a consistently positive nutrition risk screening (NRS 2002) were reported in patients scheduled for cardiovascular rehabilitation for 1–6 months after treatment for ischemic, valvular, or combined causes of heart diseases .Given these findings, we can conclude that nutritional adequacy in cardiac surgery patients is low with respect to both energy and protein intake. However, in this observational study by Rahman et al., an improved nutritional adequacy was not associated with reduced overall mortality in all cardiac surgery patients per se. Given these findings, further research is needed to identify those cardiac surgery patients, who are most likely to benefit from an intense nutrition support.Detecting patients at high nutritional risk is essential for an adequate therapy. Nutritional status assessment scores are recommended by current international nutrition guidelines but are not validated for this population and rarely used in cardiac surgery. Using the well-established nutrition screening tools Short Nutritional Assessment Questionnaire (SNAQ), Malnutrition Universal Screening Tool (MUST), Malnutrition Screening Tool (MST) Nutrition Risk Screening 2002 (NRS-2002), Mini Nutritional Assessment Short-Form (MNA-SF) and Subjective Global Assessment (SGA), which are described in detail in As current findings indicate high malnourishment rates in cardiac patients ,53, it iIn clinical practice, metabolic control, maintenance of normoglycemia, substitution of electrolytes according to blood work remain the short-term goals for nutrition support. The nutrition support has to be adapted to the individual tolerance of each patient. Physical examination, evidence of gastrointestinal motility, absence of diarrhea, vomiting and abdominal complaints may serve as parameters to evaluate the tolerance of nutrition ,31,55.There are no valid biochemical or anthropometrical parameters recommended by current guidelines. Frequently used parameters, such as weight, nitrogen-balance, serum-albumin, handgrip-strength, CRP, transferrin and circumference of extremities did not show any influence on patient-outcome ,56,57. SAlthough the inflammatory response to cardiac surgery shares mechanisms with that observed in septic patients, the postsurgical inflammatory response is more predictable, mainly featuring the release of pro-inflammatory markers and reactive oxygen species. Therefore, the pre-operative period may represent an attractive time window in which to optimize nutritional status, correct deficiencies, and enhance immune defense mechanisms before surgery. This period is an especially effective time to act upon modifiable risk factors and potentially lower the risk of intra- and postoperative complications. The bulk of the literature on perioperative optimization in heart failure patients comes from anesthesiology and hence focuses on intra- and immediate postoperative management, when it may be too late to intervene and alter the outcome of a patient entering the operating room in a decompensated state . InteresIn cardiac surgery patients with progressive heart failure, preoperative fasting further (i) aggravates commonly observed symptoms such as dyspnea, with a resulting increase in work of breathing, and (ii) it may worsen gut edema as well as (iii) hepatic congestion, which may further result in early satiety and nausea . The chrAs it is generally accepted that preoperative medical and nutritional optimization is necessary and may provide beneficial effects if performed in patients scheduled for major surgery, multimodal approaches, such as enhanced recovery after surgery (ERAS) programs, may be useful in cardiac surgery patients to reduce surgical stress, maintain physiological functional capacity, and facilitate postoperative recovery by providing the best available evidence. However, while there several approaches available for other types of major surgery ,67,68, eWhile various large-scale randomized controlled studies evaluated different post-operative nutrition strategies in rather mixed cohorts of critically ill patients, only few small clinical studies specifically investigated its effects in cardiac surgery patients. In these studies, malnutrition has been reported to increase morbidity and mortality after cardiac surgery ,71, as wVisser et al. studied the effect of perioperative nutrition in cardiac surgery on the myocardial inflammatory response, supplementing either no nutrition, EN or PN from 2 days before to 2 days after CABG. While both forms of nutrition contained comparable macro- and micronutrients, myocardial atrial tissue samples before and after revascularization demonstrated no significant differences in the myocardial inflammatory response .p = 0.0056), and significantly less pneumoniae  in male intervention-group-patients receiving combined CABG and aortic valve surgery. In addition, survival was significantly higher in female patients receiving intense nutrition support than in the control group for both CABG  and aortic valve surgery  [The recent CoCoS trial evaluated the influence of nutrition therapy on possible alterations in caloric deficit, morbidity and mortality. No significant differences in patients, laboratory or mortality profile between the intervention group, which received intense nutrition support, and a retrospective control group were found. However, there were significantly less arrhythmias  .The data derived from this trial support the hypothesis, that patients with either high nutrition risk or at elevated risk for prolonged ICU stay are the patient groups which will most likely benefit the most from a nutrition intervention and to determine the effect of prolonged EN on patients’ clinical outcome. Despite well-established scoring systems for perioperative risk stratification, it is still challenging to identify patients at high nutrition risk early during their postoperative course, which may enable to start early an adequate nutrition support for these patients.The role of postoperative nutrition support is to maintain nutritional status and energy requirements in the catabolic period after surgery. An interruption of nutritional intake is frequently observed after surgery, although it is evident that early oral and/or enteral food intake is possible, diminishes the risk of infectious complications and favors shorter hospital stays ,78,79. TDespite the lack of evidence, EN is commonly considered to be contraindicated as it may negatively affect gut integrity during a state of severe circulatory compromise in patients requiring high levels of vasopressor support, resulting in (1) alteration of splanchnic perfusion and (2) an increased risk of GI complications, such as bowel ischemia. In addition, there are relevant practical hurdles such as the numerous interruptions of enteral feeding, pyloric dysfunction and intestinal atony, which are frequently seen in patients after major surgical procedures. In this context, there are several studies examining the GI response to enteral nutrition in the presence of compromised hemodynamics and evaluating intestinal intolerance in cardiac surgery patients .In the prospective study of Berger et al., a mean energy delivery of 70 ± 35% of the target could be achieved via EN, even though most patients were on vasoactive drugs for many days . DopaminA study by Flordelís Lasierra et al. including cardiac surgery patients with hemodynamic failure , EN was supplemented with a mean energy delivery 1228.4 kcal/day over a mean of 12.3 days. The mean energy target was achieved in 15 patients (40.4%). The most common EN-related complication was constipation, whereas no case of mesenteric ischemia was detected, further supporting the feasibility and safety of EN in these patients .Despite the small number of patients included in these studies and the differences among their inclusion and application strategies, it is important to note that enteral nutrition has repeatedly been demonstrated to be feasible and that the circulatory and metabolic response to EN is adequate during the early postoperative course after operation in patients with acute severe circulatory failure. Furthermore, these studies indicated a potential beneficial effect of enteral nutrition due to its ability to maintain the splanchnic perfusion, which is of particular importance for cardiac surgery patients with an increased risk for postoperative mesenteric ischemia. However, all the mentioned studies also concluded that it was not possible to meet the nutritional requirements with EN alone and suggested the addition of supplemental parenteral nutrition (sPN), which need to be systematically investigated in future studies.As intestinal ischemia is a rare, but highly lethal complication after cardiac surgery, occurring in 0.5% and being fatal in up to a quarter of patients ,87,88,89PN may be used as sole nutrition or as sPN, as demonstrated almost 3 decades ago by Paccagnella et al. in 1994 , who exaExisting guidelines recommend the initiation of PN in all critically ill patients within 3–7 days after admission if EN is contraindicated or cannot be tolerated in patients with low nutrition risk and within 24 h in patients with high nutrition risk ,31. PN sIntravenous fish oil (FO)-based lipid emulsions (LEs) are of increasing interest as part of the parenteral nutrition support. FO is rich in ω-3 polyunsaturated fatty acids (ω-3-PUFAs), such as eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA), which exhibit anti-inflammatory and immunomodulatory effects. Preliminary evidence received small phase II trials on FO-containing emulsions in cardiac surgery have provided preliminary evidence that preoperative FO infusion is a promising strategy to modulate the biological and clinical response to cardiac surgery with the use of CPB ,96,97,98One immune-active substance, the non-essential amino acid glutamine, is the most abundant amino acid in the human body and showed cardioprotective effects in several clinical trials. The perioperative administration of both parenteral (N(2)-L-alanyl-L-glutamine)  and enteHowever, in view of the insufficient evidence, recent guidelines state that routine supplementation with glutamine cannot be recommended due to the unproved clinical benefits in cardiac surgery patients and even a risk of harm, which has been demonstrated in critically ill patients .Selenium is a trace element that is important for many of the body’s regulatory and metabolic functions, especially during times of stress ,113. In Few data are available regarding vitamin supplementation in cardiac surgery patients. Among the most relevant vitamins, thiamine and vitamins D and C are the most promising candidates and have been studied in several trials. Thiamine, the essential co-factor for pyruvate dehydrogenase function, is responsible for adequate aerobic metabolism. Preliminary studies demonstrated that thiamine levels are decreased after cardiac surgery and that low serum levels are inversely associated with blood lactate level ,118, whiVitamin D is known to affect the bones, the muscles, the blood vessels, cell proliferation and differentiation, autoimmune processes and the immune system in parallel with the regulation of calcium homeostasis . TherefoVitamin C shows pleiotropic functions in the human biology and reduced oxidative damage and resulting organ injury in critically ill patients with sepsis or septic shock . In cardThe systematic review of the literature already demonstrated the need for well-designed and adequately powered studies to develop specific evidence-based recommendations and guidelines for this cohort of critically ill patients. As cardiac surgery itself is a scheduled insult, it offers opportunities for nutrition support through the preoperative, intraoperative and postoperative window. To comprehensively address the clinical relevance of nutrition support in cardiac surgery patients we have developed with cardiac surgeons, cardiologist dieticians and the following research strategies, which should be the base for future clinical studies in this field to improve the nutrition support for this group of critically ill patients, as outlined in In addition, more research is warranted to evaluate the effect of an intense nutrition support on functional outcomes in this cohort of critically ill patients and to focus on identification of patients, which may benefit from an intense nutrition support.Assessment of preoperative nutritional status may guide health care professionals to consider early preoperative nutrition interventions in patients at elevated risk of developing postoperative complicationsPostoperative oral/enteral nutrition intake should be resumed early in the hemodynamic stable cardiac surgery patientsCardiac surgery patients with brief ICU stays often recover within the first 1–2 days after surgery and are considered less likely to benefit from an intense nutrition supportIntense nutrition support with adequate caloric and protein intake is of special relevance for patients with prolonged ICU stay or patients at high nutritional riskClinical significance of pharmaconutrients, fish oil and vitamins need further clarification in adequately designed clinical studiesIn absence of specific guidelines for the nutrition support of cardiac surgery patients, actual guidelines for the postoperative nutrition support of surgical and critically ill patients ,31 shoulDespite substantial procedural advances, open-heart surgery continues to be associated with disconcerting complication rates, often necessitating a prolonged ICU stay until the organ functions recover, especially in high-risk cardiac surgery patients with significant comorbidities and complex cardiac surgical procedures. While cardiac surgery patients with brief ICU stay are considered less likely to benefit from an intense nutrition support, an early intense nutrition support should be considered in high-risk cardiac surgery with prolonged ICU. In general, an oral or enteral nutritional intake shall be continued after surgery to reduce surgical stress, maintain physiological functional capacity, and facilitate postoperative functional recovery. Yet, adequate strategies are still needed for an early identification of these cardiac surgery patients with prolonged ICU stay. In addition, more research is warranted, to evaluate the effect of an intense nutrition support on functional outcomes in this cohort of critically ill patients. Considering the patients` perioperative inflammatory response, adequately designed studies are supported by smaller pilot studies and currently under way to evaluate the clinical significance of different anti-inflammatory strategies. Given the high number of cardiac surgical ICU patients, future studies should aim to contribute to the development of specific nutrition guidelines for cardiac surgery patients.


Since Axl is expressed at different levels in most advanced tumors, the selection of the patients who would benefit of anti-Axl therapies remains the major challenge.The receptor tyrosine kinase (RTK) Axl has been shown to be involved in cancer progression . A systeWe have recently reported that Axl and Axl-co-regulated genes could stratify melanoma and epithelial ovarian cancer (EOC) subtypes -4. In meThus, data obtained from two independent laboratories converge on the notion that Axl together with 16 genes are highly expressed in the most aggressive EOCs. Although this core list of common co-regulated genes deserves validation and refinement in ‘mesenchymal’ subtype of HGEOCs, these findings support further investigation of these genes. Indeed, in a pathological context, Axl protein expression by immunohistochemistry resulted almost ubiquitous among HGEOCs ; thus thAltogether these data also reinforce the idea that Axl appears a fascinating candidate for targeted therapies in the mesenchymal subtype of HGEOC patients. However, we should be aware that Axl is also involved in the regulation of the immune system. Therefore, Axl inactivation could exert a dual effect: one direct, as anti-tumor agent, and the other indirect, as modulator of the immune response which can lead to either positive or negative effect on tumor cells. While further analysis will be required to investigate these particular aspects, the targeting of Axl downstream signalling networks would improve selectivity providing cancer patients with new therapeutic options for this aggressive form of EOC.As final note, a recent observation indicates that Axl expression and activation have a positive role in the homologous recombination (HR)-mediated DNA repair and its inhibition increases the efficacy of PARP inhibitor on carcinoma cells of different histotypes . Since P


The objective of this article is to review and summarize the extant literature on head and neck cancer (HNC) patients’ informational needs and to characterize emerging issues in this patient population in order to define priorities for future research. HNC patients may undergo challenging treatment regimens and experience treatment-related alterations in primary daily functions such as speech and eating. These changes often persist following treatment and may lead to significant deficits in quality of life and interpersonal relations. Despite empirical evidence demonstrating that receipt of adequate information and support is predictive of improved outcomes post-treatment, relatively limited attention has been paid to the informational and support needs of HNC patients. This review focuses primarily on three topic domains: (1) managing treatment-related side effects; (2) addressing alcohol and tobacco dependence; and (3) informational needs in the areas of human papillomavirus (HPV) and clinical trials. While there is increasing awareness of the rehabilitation and survivorship needs in this patient population, patients note that the impact of treatment on social activities and interactions is under-discussed and of key concern. In addition, there is a significant gap in addressing communication and informational needs of caregivers and family members who are integral for promoting healthy behaviors and self-care post-treatment. Greater integration of programs that address tobacco or alcohol dependency within a comprehensive treatment and support plan may increase patient motivation to seek help and enhance patient success in maintaining long-term abstinence. Finally, emerging patient-provider communication needs, particularly in the context of decision making about clinical trials or surrounding an HPV-related diagnosis, have been noted among both patients and healthcare providers. Future research on the development of novel programs that offer feasible and acceptable methods for addressing unmet informational and support needs is warranted and may yield benefit for improving patient-reported outcomes. Despite advances in diagnostic tools and treatment modalities, treatment for head and neck squamous cell carcinoma (HNC) can lead to considerable long-term functional impairment. Patients may experience difficulty swallowing, dry mouth, nutritional deficits, pain, and declines in social functioning, speech, and sexuality . PhysicaNotably, empirical data indicate that patients’ perceptions of having obtained adequate information and support are predictive of positive rehabilitation outcomes in the 2- to 6-year post-treatment period . HoweverHNC patients undergoing surgical treatment may experience physical alterations on a part of their body that is highly visible (i.e. face) and with significant implications for social interactions. As a result, several studies focused on issues of postoperative changes in appearance or speech –7. In a Among surgical patients, a desire for greater pre-operative education and preparation for post-operative changes has been reported , particuOf note, studies have revealed a potential disconnect between what doctors believe their patients are worried about and what patients say they are worried about. Healthcare professionals perceived that speech impairment and self-image were patients’ primary concerns after surgery; however, patients rated concerns about the physical consequences of treatment and its interference with social activities as key concerns post-surgery . AlteratIn addition to swallowing and speech issues, there is growing awareness that HNC patients experience sleep disturbance. Among 58 HNC patients who completed a cross-sectional survey on sleep and fatigue, greater sleep dysfunction was associated with younger age and higher symptom burden . MultiplSleep disruption may be due to not only pain or symptom burden, but also the physiologic alterations resulting from the tumor or cancer treatment. Both radiation and surgical treatments lead to changes in the upper airway that can contribute to the development of obstructive sleep apnea (OSA) . AlthougOther unmet informational and support needs that have been identified pertain to financial and psychosocial domains. In a prospective study of 82 newly diagnosed HNC patients, informational needs commonly reported at pre-treatment included issues involving financial support (78 %), access to support groups for patient or partner (52 %), treatment side effects (50 %), and how treatment may impact QOL and functioning over the next year (43 %) . PatientFamily caregivers often play an important role in supporting HNC patients and providing assistance during and after treatment , 25. SimThe extant literature has characterized patients’ unmet informational and support needs across multiple domains, but limitations of the existing research include small sample sizes in many studies, wide variability in the timing of study assessments relative to treatment and across studies, and a reliance on predominantly cross-sectional study designs. Most studies utilized a convenience sample comprised of predominantly non-Hispanic whites, and therefore informational and support needs of HNC patients from other racial/ethnic subgroups are not well-described. In addition, the studies conducted have tended to use varied measures to assess informational needs and satisfaction with information received, thereby making it difficult to compare across studies. However, a standardized measure of satisfaction with information has been developed and evaluated specifically among HNC patients . This meMultimedia interventions can offer a promising approach to addressing communication and information needs. In one study, partners of HNC patients received a multimedia-based program including a patient booklet, interactive computer booth and take-home DVD, which was delivered by a nurse practitioner . PartnerDue to the diversity of individual needs and preferences, tailored communication materials may represent the best strategy for addressing informational gaps , 30. As Following a cancer diagnosis and/or treatment, patients may seek to maintain or improve their health via alterations in lifestyle behaviors such as physical activity, diet, smoking, or alcohol use. Given that cancer treatment and subsequent side effects can adversely affect physical functioning and nutritional status, numerous studies have focused on the effects of physical activity or nutritional support interventions on patient outcomes   among paFew empirically-supported programs targeted for or tested specifically with HNC patients exist. The results of three randomized trials for HNC patients have been published. In the first study published in 1993, the intervention consisted of surgeon- or dentist-delivered advice to stop smoking, a contracted quit date, tailored written materials, and booster advice sessions compared to a usual care advice control condition . At randIn Duffy and colleagues’ study published in 2006, Veterans Affairs Medical Center (VAMC) patients with HNC and tobacco, alcohol, or depression disorders were randomized to a nurse-administered cognitive-behavioral and pharmacotherapy intervention for treatment of tobacco, alcohol, and depression . SignifiDespite the mixed results that have been reported to date, it is imperative that providers take advantage of the “teachable moment” of a diagnosis of HNC to advise smokers to quit, which can be quite effective . TobaccoA topic not commonly addressed is the impact of cancer and its treatment on sexual functioning , 58, 59.In addition, data suggest that the incidence of human papillomavirus (HPV)-associated head and neck cancers is increasing –62. AccuAmong HNC patients receiving an HPV-related diagnosis, informational and psychosocial needs are particularly apparent. In a qualitative study of 10 men with HPV-related HNC, the majority (8/10) sought additional HPV-specific information, mostly from the Internet . PatientThe sexually-transmitted nature of HPV may create challenges for healthcare professionals who have limited experience discussing sexual health with their patients. In a qualitative study of 15 healthcare professionals who treat patients with oropharyngeal cancers, providers described two primary challenges: (1) discomfort or lack of familiarity with talking about sexual health and behaviors; and (2) limitations of scientific knowledge about the virus . PatientAnother area of emerging need is the provision of informational support for clinical trials. While clinical trials are essential to the evaluation of new therapeutic regimens, a relatively small proportion of cancer patients participate in these trials . This isHence, the utilization of decision aids to assist with informed decision making about clinical trial participation has been explored as a potentially useful tool to help patients identify their values and goals, consistent with making an informed choice. To date, there have been no decision aids developed to specifically support HNC patients’ informational needs and decision making about clinical trials. But prospective, randomized studies involving mixed cancer patient populations have yielded promising results. For example, among 1255 cancer patients who were randomly assigned to receive either a web-based program that provided tailored, interactive educational content about clinical trials (intervention condition) or general written information about clinical trials (control condition), intervention participants reported significantly greater increases in knowledge and greater decreases in attitudinal barriers compared to control participants . Thus, tAcross studies, many patients desire additional information and support, particularly with respect to managing treatment-related side effects, maintaining one’s health and healthy lifestyle behaviors after treatment, and understanding an HPV-related diagnosis. Despite the growing body of research on rehabilitation and survivorship needs in this patient population, patients note that the impact of treatment on social activities and interactions is under-discussed and of key concern. Interventions focused on swallowing and improving jaw mobility (for a review see ) often nIn addition, there is a need for more fully integrated programs to provide support for managing substance dependency issues. For example, many HNC patients express interest in quitting smoking and attempt to quit, but fewer follow through with enrolling in evidence-based smoking cessation programs or are successful in maintaining long-term abstinence. Motivational interventions to facilitate enrollment into formal programs that address alcohol or tobacco dependence among cancer patients may be beneficial . StudiesFinally, two emerging areas of informational needs that warrant greater attention include: (1) communication about an HPV-related diagnosis and its impact on intimacy; and (2) support for decision making about clinical trials. Although patients with HPV-related disease desire more information regarding HPV and head and neck cancer, communication and practical barriers  reduce patient satisfaction with the information provided. With the increasing prevalence of HPV-related HNCs, corresponding programs that address patient and partner concerns regarding HPV-related issues are greatly needed. Similarly, multiple challenges exist in the enrollment of HNC patients to clinical trials, including limited time for conveying large amounts of complex information, addressing informational needs of patients and family members, and discussing patient preferences and values. Findings derived from other cancer patient populations suggest that novel web-based programs may not only be an effective and cost-efficient approach for delivering such information, but may also represent an acceptable and feasible format for communicating information about multiple topics that can be tailored to meet the unique needs of patients and family members.


The past decade has witnessed an upsurge in studies demonstrating mitochondrial transfer as one of the emerging mechanisms through which mesenchymal stem cells (MSCs) can regenerate and repair damaged cells or tissues. It has been found to play a critical role in healing several diseases related to brain injury, cardiac myopathies, muscle sepsis, lung disorders and acute respiratory disorders. Several studies have shown that various mechanisms are involved in mitochondrial transfer that includes tunnel tube formation, micro vesicle formation, gap junctions, cell fusion and others modes of transfer. Few studies have investigated the mechanisms that contribute to mitochondrial transfer, primarily comprising of signaling pathways involved in tunnel tube formation that facilitates tunnel tube formation for movement of mitochondria from one cell to another. Various stress signals such as release of damaged mitochondria, mtDNA and mitochondrial products along with elevated reactive oxygen species levels trigger the transfer of mitochondria from MSCs to recipient cells. However, extensive cell signaling pathways that lead to mitochondrial transfer from healthy cells are still under investigation and the changes that contribute to restoration of mitochondrial bioenergetics in recipient cells remain largely elusive. In this review, we have discussed the phenomenon of mitochondrial transfer from MSCs to neighboring stressed cells, and how this aids in cellular repair and regeneration of different organs such as lung, heart, eye, brain and kidney. The potential scope of mitochondrial transfer in providing novel therapeutic strategies for treatment of various pathophysiological conditions has also been discussed. Recent advancements in regenerative medicine have capitalized on using stem cells for cellular repair and regeneration. Mesenchymal stem cells (MSCs) have emerged as promising candidates to treat various diseases owing to their unique characteristic properties such as self-renewal, immuno-suppressive potential and ability to trans-differentiate. They are easily available from various tissue sources such as bone marrow, adipose tissue, dental, umbilical cord etc. with low risk of rejection and several clinical trials have provided evidences of their beneficial roles. Interestingly, apart from through engraftment, MSCs are also being shown to exert their actions through paracrine mechanisms, thus repairing cellular damage –3. These, had demonstrated de novo formation of multiple tunnel tubes leading to complex networks between cells and facilitating transfer of membrane vesicles and organelles between cells [The transfer of mitochondria, which is a DNA containing organelle, is quite an intriguing phenomenon. Initial discovery of this process was observed in a co-culture system when mitochondrial DNA from donor human MSCs was found in recipient cells devoid of mitochondria . Human een cells . These ten cells . These sen cells –18. The en cells . MSCs fren cells . Table 1Mitochondria play important roles in oxidative phosphorylation, ATP generation, and cellular apoptosis. At the mitochondrial inner membrane, electron transport chain is involved in the generation of energy, where oxygen acts as the electron acceptor. During oxidative phosphorylation, electron leak from mitochondrial complexes in electron transport chain results in partial reduction of oxygen and generation of reactive oxygen species (ROS). Antioxidant enzymes present in the cells metabolize toxic intermediates to maintain cellular homeostasis. However, these control mechanisms are not effective in dysfunctional mitochondria and accumulation of ROS results in oxidative damage in cell. In a bio-energetically active cells, increased ROS production triggers dynamic changes in mitochondria and mitochondrial fragmentation occurs through fission and autophagy. Under stress, these cellular mechanisms are unable to maintain mitochondrial homeostasis resulting in dysfunctional mitochondria. In contrast, MSCs maintain themselves in the glycolytic state, and switch from glycolysis to oxidative phosphorylation upon differentiation to meet energy needs of the cells. Mitochondria in MSC exist in dormant state and display low activity status due to lesser energy demands. However upon differentiation, an increase in mtDNA copy number, high levels of respiratory enzymes and mRNA levels, enhanced oxygen consumption rate and increased levels of intracellular ATP are observed , 21. Ext2+, AMP/ATP and NAD+/NADH ratio in cells under oxidative stress. This further stimulates transfer of mitochondria from MSCs to recipient cells. In another study it was shown that calcium dependent mechanism of CD38/cyclic ADP ribose signaling mediated transfer of mitochondria from neurons to astrocytes for recycling and disposal of damaged mitochondria. This was seen to contribute to neuroprotective and neuro-recovery mechanism after stroke [The signals that trigger transfer of mitochondria from MSCs have intrigued scientists for a long time. Researchers have postulated theories suggesting that oxidative stress of dysfunctional mitochondria of recipient cell sends environment cues to the MSCs , 34. Ther stroke . As CD38r stroke . Anotherr stroke .In addition, under stress, MSCs are programmed to secrete depolarized mitochondria for their own protection through transcellular mitophagy . In an iMitochondrial transfer has been found to be mediated by different modes that include tunnel tube formation, gap junctions, micro vesicles, cell fusion and transfer of isolated mitochondria , 53–56. In an interesting study by Zhang et al., iPSCs show superior efficiency than BM-MSCs in mitochondrial transfer in rescue of Anthracycline induced cardiomyopathy due to higher expression of Miro 1 . This waSimilar results have been observed in another study where MSCs transferred mitochondria to corneal epithelial cells through tunnel tube formation via NF-κB/TNFαip2 signaling. This was confirmed by western blot analysis of protein showing that enhanced levels of phosphorylated of NF-κB subunit p-IκB along with elevated levels of TNFα and TNFαip2 was markedly increased during tunnel tube formation. It was observed that NF-κB inhibitor SC-514 significantly attenuated tunnel tube formation thus; demonstrating the role of NF-κB mediated signaling mechanism in tunnel tube formation. Furthermore, the role of ROS signal in stimulating of tunnel tube formation was validated by using antioxidant scavenger, N-acetylcysteine (NAC) treatment that reduced ROS levels and concomitantly resulted in inhibition of tunnel tube formation and mitochondria transfer between MSCs and CECs .Majority of the studies have shown that mitochondrial transfer is mainly mediated through tunnel tube formation and micro vesicles rather than gap junctions. This could be because most of the studies are carried out in in vitro co-culture system wherein tunnel tube formation is easily observed. However, connexin 43 containing gap junctions channels have been particularly well observed in in vivo acute lung injury mouse model . SinclaiIn a study by Spees et al., BM-MSCs were shown to transfer functional mitochondria to rhoφ cells devoid of functional mitochondria. Careful examination of these rescued cells excluded cell fusion as one of the main mechanisms of mitochondrial transfer. It was also shown that active formation of TNTs or vesicular transfer of mitochondria, but not passive uptake of mitochondrial fragments, resulted in functional complementation. Islam et al showed that formation of connexin-43 gap junction channels is essential for mitochondrial transfer from BM-MSCs to alveolar epithelial cells, thus increasing epithelial ATP production. BM-MSCs expressing dysfunctional connexin 43 could not adhere to alveolar epithelium, and also could not transfer mitochondria. Cytosolic calcium ions and cellular bioenergetics levels of ATP and glucose are also considered as major players in regulating movement of mitochondria . FurtherMitochondria transfer from MSCs has been studied in various disease models that have not only provided evidence for its significance in regenerative medicine but also helped to gain insight on mitochondria transfer mechanisms. Different preferred mechanism and modes have been observed on the basis of concerned recipient cells and stress condition. In lung cells, renal cells, corneal epithelial cells and brain cortical cells, mitochondria transfer has occurred mostly through tunnel tube formation. However, cell fusion and reprogramming of progenitor cells have been observed in cardiac cells. Micro vesicle formation has been observed predominantly in studies where immune-mechanisms are involved as in the case of anti-microbial activity. Nonetheless, remarkable restoration of cellular bioenergetics and reduction in oxidative stress was observed in all the studies that demonstrates that mitochondria transfer from MSCs plays critical role in cellular repair and regeneration. Also, another therapeutic strategy that targets inhibition of tunnel tube formation and mitochondrial transfer in case of tumors has also been discussed.Interestingly, mitochondrial transfer has been studied mostly in lung diseases. One of the remarkable works includes study carried out by Islam et al., wherein they found that BM-MSCs transfer mitochondria to pulmonary alveoli contributing to protection from acute lung injury . This stMitochondrial transfer between endothelial progenitor cells were reported to regenerate and repair damaged myocardium , 61. ValMSCs were found to transfer functional mitochondria to human corneal epithelial cells, which improved mitochondrial bioenergetics in recipient cells, studied using extracellular flux analyzer. Comparison of ATP production, resting respiration and maximal respiration rates showed that rates of these bioenergetics parameters were found to be lower in rotenone-treated corneal epithelial cells (CECs) as compared to normal CECs. All these parameters were improved in CECs co-cultured with MSCs. It was demonstrated that mitochondria were transferred from MSCs to damaged CECs, which also protected them from rotenone-induced cell death and proliferation-inhibition . This stIntercellular communication and mitochondrial transfer from MSCs to rat cortical neurons has been observed in co-culture in in vitro system . A promiWJ-MSCs were co-cultured with mitochondrial DNA-depleted cells. Importantly, these cells regained the expression of mtDNA-encoded proteins and showed functional oxygen consumption and respiratory control, as well as the activity of electron transport chain complexes I, II, III and IV. In addition, metabolic shifting and ETC complex V-inhibitor-sensitive ATP production were also recovered. Furthermore, cellular behaviors like attachment-free proliferation, aerobic viability and OXPHOS-dependent cellular motility were also recovered after mitochondrial transfer by WJMSCs . This stE. coli infected model with animal model treated with intranasal Clodronate Lipososmes (CL) that completely abrogated alveolar macrophages (AM). It was found that administration of MSC treatment in AM depleted mice was not able to restore levels of several cytokines involved in anti-inflammatory affects. But, in contrast MSCs could restore levels of cytokines in normal mice suggesting that the anti-microbial activity of MSCs is mediated through macrophages. Interestingly, macrophage phagocytosis of MSCs or fusion of MSC and macrophage was not observed in monocytes or neutrophils. This suggests that mitochondria transfer as the only means for enhanced engulfment by macrophages by both confocal and flow cytometry analysis. It was also observed that non-contact transfer of mitochondria through microvesicles or exosomes significantly enhanced mitochondria transfer and phagocytosis index of macrophages suggesting it as another critical mechanism for mitochondrial transfer. Another study by Phinney et al., has also shown that mitochondria transfer through microvesicles to macrophages and support paracrine and immune reaction. However, further investigation to better understand the role of mitochondria in anti-microbial and immune-modulation can provide better insights of multi-level reparative contributions of mitochondria in maintenance of cellular health post transfer to recipient cells.MSCs are known to aid in regeneration through multiple ways that include anti-oxidant property, anti-inflammatory activities of MSCs and differentiation to regenerate damaged tissue. MSCs also demonstrate ability to combat infection by transferring mitochondria to macrophages. This leads to modulation of phagocytic ability of macrophages through tunnel tube by enhancing their bioenergetics evidenced by increased ATP activity. This facilitates more efficient clearing of bacterial cells, thereby influencing innate immune response of these cells serving as an important mechanism in pre-clinical models of acute respiratory distress syndrome (ARDS) and sepsis . To estaMitochondria are the key regulators of cellular bioenergetics and metabolism that greatly impacts cancer progression . Many re-β, IL-10 and PGE2 were unaffected by Miro1 overexpression, suggesting that mitochondrial transfer can work independent of paracrine effects [Mitochondrial dysfunction is usually linked to a variety of diseases and as discussed above, mitochondrial transfer from healthy MSCs can potentially serve as an effective remedy for alleviation of such diseases. Despite significant advancements in this field, mitochondrial transfer has yet not become a therapeutic strategy for treatment purposes. The optimization of MSC donor type, dose, and development of cell delivery techniques present unexplored challenges for medical intervention to treat pathological conditions with mitochondrial dysfunction. In addition, very few research groups have investigated if mitochondrial transfer is self-sufficient for repair or requires synergistic release of other paracrine effects such as immunomodulatory factors and exosomes. It is critical to analyze mitochondria transfer holistically by comparing roles of secretome, exosome and mitochondrial transfer acting together and in isolation to better understand the regenerative mechanisms. Ahmad et al., demonstrated that paracrine mediators such as NO, TGF effects . In anot effects . MSCs we effects . But, coMitochondrial transfer through MSCs has shown promising therapeutic results in varied disease conditions through various modes of action as discussed in this review. In addition, it is widely known that intercellular organelle communication aids in maintenance of cellular homeostasis, particularly in terms of energy metabolism and cellular bioenergetics regulation , 71, 80.


The exact location of origin for giant cell tumors of bone (GCTB) remains controversial, as lesions are not routinely imaged early but rather late when the tumor is large and clinically symptomatic. At the time of diagnosis, GCTB are classically described as lucent, eccentric lesions with nonsclerotic margins, located within the epiphysis to a greater extent than the metaphysis. Here we present a case of a biopsy proven GCTB initially incidentally seen on MRI as a small strictly metaphyseal lesion, which over the course of several years expanded across a closed physis to involve the epiphysis and abut the articular surface/subchondral bone plate.  Giant cell tumors of bone (GCTB) are relatively common tumors, accounting for 5% of all primary bone tumors . GCTB moA 25-year-old man initially presented to an outside institution in 2011 with a history of a right knee hyperextension injury while playing basketball. He was evaluated with a right knee MRI that showed an anterior cruciate ligament (ACL) tear and a small subcortical lesion at the posterior aspect of the medial metaphysis of the distal femur that was nonspecific and too small to characterize; however, enthesopathy and small cortical based lesions such as nonossifying fibroma, enchondroma, fibrous cortical defect, and fibrous dysplasia were included in the differential diagnosis . He undeThe radiographs obtained in 2013 and 2015, two and four years, respectively, after the metaphyseal lesion was seen on the initial MRI, showed a well-marginated, locally aggressive, eccentric lesion in the right medial femoral condyle extending from the metaphysis to the epiphysis . MRI demDifferential diagnosis at this time was more limited and suggestive of GCTB based on age, location, and radiological criteria; however, aneurysmal bone cyst (ABC) and malignant tumors such as telangiectatic osteosarcoma or clear cell chondrosarcoma remained as alternative diagnoses. A total body bone scan was performed, demonstrating intense uptake in the right medial femoral condyle without other lesions identified . The pat USP6 gene rearrangement, characteristic of primary ABC [Macroscopic examination of the curettage specimen showed multiple, irregular fragments of rubbery, red-tan soft tissue, and white-tan hard osteocartilaginous tissue. Microscopic examination revealed blood-filled spaces lined by fibrous septa without an endothelial lining or vascular smooth muscle. The fibrous septa contained scattered multinucleated giant cells, abundant hemosiderin, osteoid matrix or reactive bone, and spindled mononuclear cells with plump nuclei without hyperchromasia or significant increase in mitoses, consistent with an aneurysmal bone cyst (ABC) component . In addimary ABC , was negThe patient has had an uncomplicated postoperative course: at 6 months after surgery, he has returned to pain-free, full activity, and postoperative radiographs showed no evidence of local recurrence.GCTB is characterized by the most recent World Health Organization classification as a benign but locally aggressive tumor . HistoloIn our patient, initial incidental MRI characterization was nonspecific and showed a small T1 hypointense and T2 heterogeneous subcortical intraosseous metaphyseal lesion. Follow-up radiographs 3 years later displayed the more typical radiographic features described above . USP6 gene, or secondary, arising in association with other benign or malignant tumors, including GCTB. Primary and secondary ABCs have a similar appearance radiographically and pathologically, and the diagnosis of GCTB with secondary ABC formation is typically confirmed with microscopic evaluation. Radiographically, ABC is more commonly characterized by a sclerotic margin, typically occurs in younger patients compared to GCTB, and often manifests fluid-fluid levels without other soft tissue components [Differential diagnosis included ABC which can be a primary, de novo neoplasm characterized by rearrangements of themponents . Rare prTreatment for GCTB is traditionally surgical with curettage and cement packing. However, the local recurrence rate has been reported to be as high as 25% depending on anatomical location , 11. PosWhile GCTB is classically described as abutting an articular surface, its location of origin remains somewhat controversial in the literature. GCTB most often presents in a skeletally mature patient with pain and at the time of initial imaging primarily involves the epiphysis . HoweverIn summary, to the best of our knowledge, this is the first case to clearly demonstrate multiple modalities of the unique progression of a pathologically confirmed GCTB in a single patient over four years from its origin in the metaphysis to its final eccentric location abutting an articular surface.


An investigation in Panama found that Punta Toro virus species complex (PTVs) may contribute to febrile illnesses with symptoms mirroring those of dengue fever. However, further studies are needed to determine if PTV infection causes only a mild disease or if it can have more serious manifestations in some patients. Phlebovirus, family Bunyaviridae), a member of the sand fly fever group, was initially described in humans in 1966 after being isolated from a soldier in Panama who had fever, headache, myalgia, and leukopenia  based on the highly conserved L (large) gene that detects Toscana, Naples, Sicilian, Aguacate, Punta Toro, and Rift Valley fever viruses  of the samples were dengue-negative. We further analyzed 201 of these samples for phlebovirus  Table 1.https://blast.ncbi.nlm.nih.gov/Blast.cgi) nucleotide sequence comparison suggested all were PTVs; 1 was previously described as Cocle virus  were RT-PCR–positive for phlebovirus. BLAST  of the PTV-positive samples. After de-identifying the data, we entered it into a dataset. A control group consisted of 90 dengue virus–positive patients from 2009 who were frequency matched by age and randomly selected from available records. The PTV-positive case-patients were largely located in the Panama City metropolitan area . Case-paFebrile syndromes in the tropics are often treated empirically; clinical decisions are often made on the basis of epidemiologic information and concurrent outbreaks. In Central America, dengue fever and malaria are treated without confirmatory testing because testing is costly and time-consuming. However, an increasing number of agents responsible for causing febrile illnesses have been identified in recent years. The variety of clinical outcomes observed with hantavirus and dengue, chikungunya, and Zika virus infections underscores the need for more accurate diagnostics to differentiate between causative agents. Clinical decisions must rely on accurate diagnoses because symptomatology is not an accurate predictor of the true etiology of a febrile illness.Our findings suggest that, in Panama, PTVs may be a major contributor to febrile illnesses with symptoms mirroring those of dengue fever. However, the clinical course and range of disease caused by PTVs are unknown. Prospective studies are needed to determine if PTV infection causes only mild disease or if it can have serious manifestations in some patients. PTVs are assumed to be sand fly–borne, and sand flies are usually present in rural or forested areas (Phylogenetic tree of Punta Toro species complex (PTVs), location and number of dengue-negatives samples in Panama analyzed for PTVs in 2009, and demographic characteristics and symptoms of persons with PTV infection versus those with dengue.


Antihypertensive treatment mitigates the progression of chronic kidney disease. Here, we comparatively assessed the effects of antihypertensive agents in normotensive and hypertensive diabetic patients with microalbuminuric kidney disease.MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) comparing oral antihypertensive agents in adult diabetic patients with microalbuminuria. The primary efficacy outcome was reduction in albuminuria, and the primary safety outcomes were dry cough, presyncope, and edema. Random-effects pairwise and Bayesian network meta-analyses were performed to produce outcome estimates for all RCTs, only hypertensive RCTs, or only normotensive RCTs. Surface under the cumulative ranking (SUCRA) probability rankings were calculated for all outcomes. Sensitivity analyses on type 2 diabetes status, age, or follow-up duration were also performed.A total of 38 RCTs were included in the meta-analyses. The angiotensin-converting enzyme inhibitor-calcium channel blocker (ACEI-CCB) combination therapy of captopril+diltiazem was most efficacious in reducing albuminuria irrespective of blood pressure status. However, the ACEI-angiotensin receptor blocker (ACEI-ARB) combination therapy of trandolapril+candesartan was the most efficacious in reducing albuminuria for normotensive patients, while the ACEI-CCB combination therapy of fosinopril+amlodipine was the most efficacious in reducing albuminuria for hypertensive patients. The foregoing combination therapies displayed inferior safety profiles relative to ACEI monotherapy with respect to dry cough, presyncope, and edema. With respect to type 2 diabetic patients with microalbuminuria, the Chinese herbal medicine Tangshen formula followed by the ACEI ramipril were the most efficacious in reducing albuminuria.Trandolapril+candesartan appears to be the most efficacious intervention for reducing albuminuria for normotensive patients, while fosinopril+amlodipine appears to be the most efficacious intervention for reducing albuminuria for hypertensive patients. For practitioners opting for monotherapy, our SUCRA analysis supports the use of trandolapril and fosinopril in normotensive and hypertensive adult diabetic patients with microalbuminuria, respectively. Diabetes mellitus affects ~4% of the global adult population with an estimated 382 million affected individuals in 2013 expected to increase to an estimated 592 million affected individuals by the year 2035 ) for all comparisons. τ is the estimated SD of the underlying effects of treatment across the studies in a meta-analysis. RCTs with drugs that could not be connected to the network were excluded from the network meta-analysis and only drugs directly or indirectly connected to placebo were included in the downstream ranking analysis. Consistency of the RCTs included in the network was assessed through applying inconsistency and node-splitting models. The consistency results were considered insignificant when 95% CIs of inconsistency factors included zero or when the To rank the treatments, we calculated surface under the cumulative ranking (SUCRA) probabilities, which express as a percentage the efficacy or safety of each intervention relative to a hypothetical ideal intervention. Thus, a large SUCRA score indicates a more effective or safer intervention. Rankings were calculated for the primary efficacy outcome and the three primary safety outcomes.In order to assess the effects of hypertensive status, the foregoing meta-analyses were also re-performed by pooling only hypertensive studies and pooling only normotensive studies. In addition, we performed three separate sensitivity analyses on type 2 diabetes status, age, or follow-up duration by measuring the effects of including only trials with type 2 diabetes participants, trials with participants aged 40 and older, or trials with follow-up durations of 12 months and longer, respectively.The PRISMA flowchart detailing the study selection process is provided in First, standard pairwise meta-analysis  and netwNext, standard pairwise meta-analysis  and netwFinally, standard pairwise meta-analysis  and netwFinally, three separate sensitivity analyses were performed to account for any putative effects of type 2 diabetes status, age, or follow-up duration upon the SUCRA analysis for the primary efficacy outcome of UAER reduction. First, the network map diagramming the direct comparisons for the type 2 diabetes sensitivity analysis is provided in Here, employing a Bayesian network meta-analytical approach, we assessed the comparative effects of antihypertensive agents in reducing albuminuria in adult diabetic patients with microalbuminuric kidney disease and also specifically examined the comparative effects of antihypertensive agents in reducing albuminuria in normotensive versus hypertensive patients within this microalbuminuric cohort. We found that the ACEI-CCB combination therapy of captopril+diltiazem was the most efficacious intervention for reducing albuminuria irrespective of BP status. However, the ACEI-ARB combination therapy of trandolapril+candesartan was found to be the most efficacious intervention for reducing albuminuria for normotensive patients, while the ACEI-CCB combination therapy of fosinopril+amlodipine was found to be the most efficacious intervention for reducing albuminuria for hypertensive patients. However, the foregoing combination therapies displayed inferior safety profiles relative to ACEI monotherapy with respect to the key adverse side effects of dry cough, presyncope, and peripheral edema.Palmer et al.’s previous network meta-analysis on adult diabetic patients with CKD identified four classes of antihypertensive agents that are able to significantly regress albuminuria in this patient population  : (i) ACEAlthough the majority of the evidence primarily concerns adult diabetic patients with macroalbumuria , there has been some guidance regarding antihypertensive therapy in adult diabetic patients with microalbuminuria . The most recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for managing diabetic CKD recommends either ACEI or ARB monotherapy for patients with microalbuminuria unless one of the following factors is present: ACEI or ARB therapy is contraindicated, metastatic cancer, treatment of malignancy in the past six months, or admission to a skilled nursing facility in the past three months . The 201Interestingly, our current findings reveal that the ACEI-ARB combination therapy of trandolapril+candesartan appears the most efficacious for reducing albuminuria in normotensive adult diabetic patients with microalbuminuria, while the ACEI-CCB combination therapy of fosinopril+amlodipine appears to be the most efficacious intervention for reducing albuminuria for hypertensive adult diabetic patients with microalbuminuria. Therefore, our findings provide an important clarifying distinction to Palmer et al.’s network meta-analysis, which found that ACEI or ARB therapy combined with CCB therapy produces reductions in albuminuria in adult diabetic patients with kidney disease irrespective of BP or microalbuminuric status .Moreover, our safety findings concord with the foregoing KDIGO and KDOQI guidelines regarding combination therapy, as we found that ACEI monotherapy produces a lower likelihood of key adverse outcomes relative to ACEI-ARB or ACEI-CCB combination therapy. For practitioners opting for monotherapy, our SUCRA analysis supports the use of trandolapril in normotensive adult diabetic patients with microalbuminuria and fosinopril in hypertensive adult diabetic patients with microalbuminuria.With specific respect to type 2 diabetic patients with microalbuminuria, our sensitivity analysis revealed that the Chinese herbal medicine Tangshen formula followed by the ACEI ramipril were the most efficacious interventions for reducing albuminuria. Multiple clinical studies by Ping Li’s research group have demonstrated the efficacy of the Tangshen formula in attenuating diabetic kidney disease in rodent models and human patients . NotablyThere are several limitations to this study. First, the three separate sensitivity analyses on type 2 diabetes status, age, and follow-up duration revealed that each of these three factors had a significant impact upon the findings. That being said, across all sensitivity analyses, ACEI monotherapy was found to be superior to all other antihypertensive medication classes . Second, we could not assess the degree of albuminuria reduction attributable to a medication class effect beyond BP reduction. We considered including target/achieved BP as part of our analysis; however, the included RCTs did not report this data to a sufficient degree to enable such an analysis in the current study. Third, as the response to different medication classes may vary with excretory renal function, a subgroup analysis according to the presence or absence of reduced excretory renal function would provide valuable insights. Unfortunately, this analysis was not possible with the available data. Fourth, although we were able to assess the effects of various hypertensive agents upon regressing UAER, the available reported data in the included studies did not enable us to estimate the effects of antihypertensive agents on other clinically relevant renal outcomes. For example, we were unable to examine acute kidney injury as a safety endpoint due to the paucity of reported data on this outcome. Fifth, as most of the included RCTs were from developed Western countries and Japan, there is a scarcity of data from other countries, which may have biased our conclusions. Finally, drug dosing was not controlled for in the meta-analyses; most of the included RCTs allowed the clinical investigators to titrate drug dosing for participants.In conclusion, the ACEI-ARB combination therapy of trandolapril+candesartan appears the most efficacious for reducing albuminuria in normotensive diabetic patients with microalbuminuria, while the ACEI-CCB combination therapy of fosinopril+amlodipine appears to be the most efficacious intervention for reducing albuminuria for hypertensive diabetic patients with microalbuminuria. However, the foregoing combination therapies displayed inferior safety profiles to ACEI monotherapy with respect to the key adverse side effects of dry cough, presyncope, and peripheral edema. For practitioners opting for monotherapy, our SUCRA analysis supports the use of trandolapril in normotensive adult diabetic patients with microalbuminuria and fosinopril in hypertensive adult diabetic patients with microalbuminuria.S1 FigNetworked interventions are placed in green boxes, while non-networked interventions are placed in grey boxes. Blue lines between interventions indicate direct comparisons with the number of studies indicated.(TIF)Click here for additional data file.S2 FigNetworked interventions are placed in green boxes, while non-networked interventions are placed in grey boxes. Blue lines between interventions indicate direct comparisons with the number of studies indicated.(TIF)Click here for additional data file.S3 FigNetworked interventions are placed in green boxes, while non-networked interventions are placed in grey boxes. Blue lines between interventions indicate direct comparisons with the number of studies indicated.(TIF)Click here for additional data file.S4 FigNetworked interventions are placed in blue circles with the circle size reflecting the relative study size. Black lines between interventions indicate direct comparisons with thicker lines indicating a larger number of comparator studies.(TIF)Click here for additional data file.S5 FigNetworked interventions are placed in blue circles with the circle size reflecting the relative study size. Black lines between interventions indicate direct comparisons with thicker lines indicating a larger number of comparator studies.(TIF)Click here for additional data file.S6 FigNetworked interventions are placed in blue circles with the circle size reflecting the relative study size. Black lines between interventions indicate direct comparisons with thicker lines indicating a larger number of comparator studies.(TIF)Click here for additional data file.


The advent of high throughput sequencing technologies has helped to reveal the tremendous genetic heterogeneity that underlies acute myeloid leukemia (AML), including pediatric AML. This level of complexity had already been suspected given the variability in patient outcomes associated with standard chemotherapy regimens, composed essentially of a cytarabine and anthracycline backbone, irrespective of disease subgroup. Currently in children, cure rates can vary dramatically from above 90% for acute promyelocytic leukemia (PML-RARA fusion) to below 30% for high risk subgroups, such as selected MLL- (Mixed Lineage Leukemia) rearranged AML . The dramatic improvements in treatment outcomes obtained with the introduction of retinoic acid (ATRA) and arsenic trioxide (ATO) for the treatment of acute promyelocytic leukemia highlights the importance of tailoring therapies according to specific genetic AML subgroups. In the emerging era following the large scale sequencing of tumor genomes, engineered human models of high fatality pediatric AMLs will be seminal to identify disease subtype specific functional dependencies and develop novel therapeutic strategies. It is these models that will be required to overcome the paucity of primary human samples, the genetic heterogeneity of the disease, and the clonal evolution of commercially available cell lines.in vitro and in vivo. In addition, a panel of leukemia activated genes was identified [In pediatric AML, translocations that generate chimeric fusion genes are critical transforming events and present in a high proportion of cases, including the highest risk categories. We have exploited the oncogenic potential of MLL fusions, considered hallmarks of infant and therapy-related AML, to generate human models of MLL-AF9 driven AML , using oentified , a signa+CD117+ AML, but not to the CD34-CD41+CD61+ leukemic blasts typically seen in pediatric AMKL, possibly indicating distinct cells of origin. In addition, the anti-tumor activity of novel pharmacological compounds will need to be assessed in models that more accurately reflect human disease, as well as potential cross toxicity on the normal hematopoietic system. Clearly, the recent development of HSPC self-renewal agonists has shown considerable variability in responses between model organisms. As reported, the aryl hydrocarbon receptor inhibitor StemRegenin 1 (or SR1) can expand human, monkey and dog cells, but had no impact on mouse HSPC [Human leukemia models will unmistakably become an indispensable complement to the currently developed model organisms used to gain further insights into relevant disease biomarkers and drug targets. For example, differences across species have been reported, especially in the cytological subtype of leukemia that is induced by a given oncogene, depending on the cell type that is used. Overexpression of MLL-AF4 in HSPC, for instance, gives rise to AML in mouse, but to acute lymphoblastic leukemia (ALL) when using adoptive transfer of engineered human cells into immunocompromised recipient mouse strains , giving in vitro genetic or chemical based screens. More restricted screens involving the most promising lead compounds (as single agents or in combination) can then be carried using AML subtype specific xenografts, to streamline pre-clinical testing, and only bring the most promising treatment modalities to clinical trials. A current inherent limitation of xenograft models, of course, remains the study of immune responses and bone marrow niche interactions, but improvements in this direction are actively being pursued [While human cells initially proved difficult to transform, the optimisation of human HSPC culture conditions and viral transduction protocols were critical milestones that paved the way to AML modeling. It is now possible to maintain engineered human AML cell lines in culture long-term , setting the stage for large-scale  pursued , 8.Overall, engineered human AML models constitute yet another weapon in our quest to conquer leukemia, that will enable us to tackle the heterogeneity of the disease with the identification of subtype specific functional susceptibilities, as well as improved biomarkers to gauge treatment responses. These models will be particularly critical for the rare and highly lethal AML subgroups, as seen in children, for which cure rates are stagnating and remain unacceptably low.