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Mitochondrial adaptation during non-alcoholic fatty liver disease (NAFLD) include remodeling of ketogenic flux and sustained tricarboxylic acid (TCA) cycle activity, which are concurrent to onset of oxidative stress. Over 70% of obese humans have NAFLD and ketogenic diets are common weight loss strategies. However, the effectiveness of ketogenic diets toward alleviating NAFLD remains unclear. We hypothesized that chronic ketogenesis will worsen metabolic dysfunction and oxidative stress during NAFLD. Mice (C57BL/6) were kept (for 16-wks) on either a low-fat, high-fat, or high-fat diet supplemented with 1.5X branched chain amino acids (BCAAs) by replacing carbohydrate calories (ketogenic). The ketogenic diet induced hepatic lipid oxidation and ketogenesis, and produced multifaceted changes in flux through the individual steps of the TCA cycle. Higher rates of hepatic oxidative fluxes fueled by the ketogenic diet paralleled lower rates of de novo lipogenesis. Interestingly, this metabolic remodeling did not improve insulin resistance, but induced fibrogenic genes and inflammation in the liver. Under a chronic “ketogenic environment,” the hepatocyte diverted more acetyl-CoA away from lipogenesis toward ketogenesis and TCA cycle, a milieu which can hasten oxidative stress and inflammation. In summary, chronic exposure to ketogenic environment during obesity and NAFLD has the potential to aggravate hepatic mitochondrial dysfunction.

During the normal embryonic-to-neonatal development, the chicken liver is subjected to intense lipid burden from high rates of yolk-lipid oxidation and also from the accumulation of the yolk-derived and newly synthesized lipids from carbohydrates. High rates of hepatic lipid oxidation and lipogenesis are also central features of non-alcoholic fatty liver disease (NAFLD) in both rodents and humans, but is associated with impaired insulin signaling, dysfunctional mitochondrial energetics and oxidative stress. However, these adverse effects are not apparent in the liver of embryonic and neonatal chicken, despite lipid burden. Utilizing comprehensive metabolic profiling, we identify that steady induction of hepatic mitochondrial tricarboxylic acid (TCA) cycle and lipogenesis are central features of embryonic-to-neonatal transition. More importantly, the induction of TCA cycle and lipogenesis occurred together with the downregulation of hepatic β-oxidation and ketogenesis in the neonatal chicken. This synergistic remodeling of hepatic metabolic networks blunted inflammatory onset, prevented accumulation of lipotoxic intermediates (ceramides and diacylglycerols) and reduced reactive oxygen species production during embryonic-to-neonatal development. This dynamic remodeling of hepatic mitochondrial oxidative flux and lipogenesis aids in the healthy embryonic-to-neonatal transition in chicken. This natural physiological system could help identify mechanisms regulating mitochondrial function and lipogenesis, with potential implications towards treatment of NAFLD.

Diets rich in fats and carbohydrates aggravate non-alcoholic fatty liver disease (NAFLD), of which mitochondrial dysfunction is a central feature. It is not clear whether a high-carbohydrate driven ‘lipogenic’ diet differentially affects mitochondrial oxidative remodeling compared to a high-fat driven ‘oxidative’ environment. We hypothesized that the high-fat driven ‘oxidative’ environment will chronically sustain mitochondrial oxidative function, hastening metabolic dysfunction during NAFLD. Mice (C57BL/6NJ) were reared on a low-fat (LF, 10% fat calories), high-fat (HF, 60% fat calories), or high-fructose/high-fat (HFr/HF, 25% fat and 34.9% fructose calories) diet for 10 weeks. De novo lipogenesis was determined by measuring the incorporation of deuterium from D2O into newly synthesized liver lipids using nuclear magnetic resonance (NMR) spectroscopy. Hepatic mitochondrial metabolism was profiled under fed and fasted states by the incubation of isolated mitochondria with [13C3]pyruvate, targeted metabolomics of tricarboxylic acid (TCA) cycle intermediates, estimates of oxidative phosphorylation (OXPHOS), and hepatic gene and protein expression. De novo lipogenesis was higher in the HFr/HF mice compared to their HF counterparts. Contrary to our expectations, hepatic oxidative function after fasting was induced in the HFr/HF group. This differential induction of mitochondrial oxidative function by the high fructose-driven ‘lipogenic’ environment could influence the progressive severity of hepatic insulin resistance.

Follicular helper T cells (TFH) have specialized properties in promoting normal B cell activation but their role in chronic lymphocytic leukemia (CLL) is unknown. We find that TFH cells are elevated in CLL patients and are phenotypically abnormal, expressing higher levels of PD-1, TIGIT, CD40L, IFNγ and IL-21, and exhibiting abnormal composition of TFH1, TFH2 and TFH17 subsets. Frequencies of CD4-positive T cells expressing TFH1 markers and IL-21 were positively correlated with patient lymphocyte counts and RAI stage, suggesting that accumulation of abnormal TFH cells is concomitant with expansion of the leukemic B cell clone. Treatment with ibrutinib led to normalization of TFH frequencies and phenotype. TFH cells identified in CLL bone marrow display elevated expression of several functional markers compared to blood TFH cells. CLL T cell-B cell co-culture experiments revealed a correlation of patient TFH frequencies with functional ability of their CD4-positive T cells to promote CLL proliferation. Conversely, CLL cells can preferentially activate the TFH cell subset in co-culture. Together our results indicate that CLL development is associated with expansion of abnormal TFH populations that produce elevated levels of cytokines and costimulatory molecules which may help support CLL proliferation.

Background Anastomotic leakage (AL) in the upper gastrointestinal (GI) tract is associated with high morbidity and mortality rates. Especially intrathoracic anastomotic leakage leads to life-threatening complications. Endoscopic vacuum therapy (EVT) for anastomotic leakage after transthoracic esophageal resection represents a novel concept. However, sound clinical data are still scarce. This retrospective, single-center study aimed to evaluate the feasibility, effectiveness, and safety of EVT for intrathoracic anastomotic leakage following abdomino-thoracic esophageal resection. Methods From March 2014 to September 2019 259 consecutive patients underwent elective transthoracic esophageal resection. 72 patients (27.8%) suffered from AL. The overall collective in-hospital mortality rate was 3.9% (n = 10). Data from those who underwent treatment with EVT were included. Results Fifty-five patients were treated with EVT. Successful closure was achieved in 89.1% (n = 49) by EVT only. The EVT-associated complication rate was 5.4% (n = 3): bleeding occurred in one patient, while minor sedation-related complications were observed in two patients. The median number of EVT procedures per patient was 3. The procedures were performed at intervals of 3–5 days, with a 14-day median duration of therapy. The mortality rate of patients with AL was 7.2% (n = 4). Despite successfully terminated EVT, three patients died because of multiple organ failure, acute respiratory distress syndrome, and urosepsis (5.4%). One patient (1.8%) died during EVT due to cardiac arrest. Conclusions EVT is a safe and effective approach for intrathoracic anastomotic leakages following abdomino-thoracic esophageal resections. It offers a high leakage-closure rate and the potential to lower leakage-related mortalities. Trial registration: This trial was registered and approved by the Institutional Ethics Committee of the University of Heidelberg on 16.04.2014 (Registration Number: S-635/2013).

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (

During prolonged nutrient restriction, developing animals redistribute vital nutrients to favor brain growth at the expense of other organs. In Drosophila, such brain sparing relies on a glia-derived growth factor to sustain proliferation of neural stem cells. However, whether other aspects of neural development are also spared under nutrient restriction is unknown. Here we show that dynamically growing somatosensory neurons in the Drosophila peripheral nervous system exhibit organ sparing at the level of arbor growth: Under nutrient stress, sensory dendrites preferentially grow as compared to neighboring non-neural tissues, resulting in dendrite overgrowth. These neurons express lower levels of the stress sensor FoxO than neighboring epidermal cells, and hence exhibit no marked induction of autophagy and a milder suppression of Tor signaling under nutrient stress. Preferential dendrite growth allows for heightened animal responses to sensory stimuli, indicative of a potential survival advantage under environmental challenges., eLife digest The organs of a young animal develop in a carefully controlled way to reach the right size relative to each other. However, if the animal’s diet does not contain the right amount of nutrients — a condition known as malnutrition – the body prioritizes the needs of the brain and other vital organs. This means that certain organs keep on growing while others stop. The brain is at the center of the nervous system, which is formed of networks of nerve cells (or neurons) that rapidly carry messages around the body. In the larvae of malnourished fruit flies, a molecular signal allows the nervous system to continue making new neurons as other parts of the body slow down their growth. During development, neurons also connect to each other by growing tree-like structures known as dendrites. However, it remained unclear whether the growth of dendrites was also protected during episodes of malnutrition. To address this question, Poe, Xu et al. performed experiments in the larvae of fruit flies, focusing on a type of neuron whose dendrites extend into the skin. When nutrients were scarce, the neurons grew more rapidly than the surrounding skin cells, resulting in dendrite overgrowth. Compared to neurons, the skin cells had higher levels of a stress sensor known as FoxO, which stops cell growth when nutrients are scarce. Conversely, low quantities of FoxO in neurons allow these cells to keep on growing dendrites, which ultimately helps the starved animals to better react to their environment. These results suggest that the growth of neurons and their connecting structures is preserved during malnutrition. Ultimately, dissecting how organisms prioritize resources can help to develop new approaches to treat human conditions that emerge during malnutrition.

Different mutations in the copper transporter gene Atp7b are identified as the primary cause of Wilson's disease. These changes result in high copper concentrations especially in the liver and brain, and consequently lead to a dysfunction of these organs. The Atp7(-/-) mouse is an established animal model for Wilson's disease and characterized by an abnormal copper accumulation, a low serum oxidase activity and an increased copper excretion in urine. Metallothionein (MT) proteins are low molecular weight metal-binding proteins and essential for the zinc homeostasis but also play a role for the regulation of other metals, e.g. copper. However the molecular mechanisms of MT in regard to Atp7b remain still elusive. In this study we investigate the expression of MT in the liver and duodenum of Atp7b(-/-) mice and wildtype mice. Hepatic and duodenal expression of MT was measured by real-time reverse transcription-polymerase chain reaction and post-translational expression was analyzed by immunoblot and immunofluorescence. Expression of MT in liver und duodenum was significantly higher in Atp7b(-/-) mice than in controls. Hepatic and duodenal copper, iron and zinc content were also studied. Compared to control hepatic copper and iron content was significantly higher while hepatic zinc content was significantly lower in Atp7b(-/-) mice. In the duodenum copper and zinc content of Atp7b(-/-) mice was significantly lower than in controls. Duodenal iron content was also lower in Atp7b(-/-) mice, but did not reach statistical significance. The results of our study suggest that metallothionein is elevated in the liver and duodenum of Atp7b(-/-) mice.

Background: The ECOG-ACRIN randomized phase 3 clinical trial E1912 established ibrutinib-rituximab (IR) as the standard of care for CLL patients Methods: Patients enrolled on E1912 completed the Functional Assessment of Cancer Therapy-General (FACT-G) and Leukemia subscale at randomization (baseline), 3, 6, and 12 months post-randomization, and every 6 months for 2 years regardless of disease status. The primary outcome was the 31-item FACT-Leukemia Trial Outcome Index (FACT-Leu TOI), calculated by summing items from the FACT-G physical wellbeing (PWB), functional well-being (FWB), and leukemia subscales (score range: 0-124). The primary endpoint was defined as the difference in FACT-Leu TOI change scores from randomization to 12 months (at response evaluation) between patients treated with continuous therapy Arm A (IR) vs time-limited therapy Arm B (FCR). Mean change scores from baseline to each time point were calculated using all cases with data at baseline and the corresponding time point. Comparisons between treatment arms were performed using two-sample t tests. Linear mixed effects models were used to estimate the trajectories of PRO scores. Results: PRO data was extracted on 3/8/2021. PRO data was provided at baseline and 12 months for 233/354 (65.8%) patients on the IR arm and 118/175 (67.4%) patients on the FCR arm. At enrollment, there were no significant differences in the baseline FACT-Leu TOI scores (mean ± SE) between the two arms: IR (93.27 ± 1.03) vs FCR (92.68 ± 1.38; p=0.73). The FACT-Leu TOI score improved from baseline to 12 months in both arms (Table 1 and Figure 1). The change scores from baseline to 12 months, the primary outcome, were not significantly different between IR (7.59 ± 1.09) vs FCR (8.22 ± 1.44; p=0.73). Change in FACT-Leu TOI from baseline to 3 months was 5.77 ± 0.77 and 4.06 ± 1.18 (p=0.22); and from baseline to 6 months was 6.87 ± 0.87 and 8.01 ± 1.44 (p=0.50) in the IR and FCR arms, respectively. After the first 6 months of treatment, the improvement in FACT-Leu TOI scores was maintained in both treatment arms. There was no significant difference in total FACT-Leu TOI score in the continuous therapy (IR) vs time-limited therapy (FCR) arms over the first 36 months post registration. Analysis of FACT subscales showed PWB improved in the IR arm (0.37 ± 0.22) and declined in the FCR arm (-0.92 ± 0.39) from baseline to 3 months (p=0.004 for difference in PWB change between arms) but there was no significant difference between the two arms for change in PWB scores from baseline to 6 and 12 months. There were no significant differences between the two arms for change in FWB and FACT-Leu subscales from baseline to 3, 6 and 12 months. Conclusions: QOL improves in CLL patients age 70 and younger when treated in the frontline setting with IR or FCR. The improvement in QOL is maintained during continuous therapy with ibrutinib and there is no significant decline in QOL over time. Given the improvement in PFS and OS with IR over FCR seen in E1912, the results of this QOL analysis support the use of frontline ibrutinib in previously untreated younger CLL patients. Acknowledgement: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers: U10CA180794, U10CA180820, UG1CA189863, UG1CA190140, UG1CA232760, UG1CA233180, UG1CA233230, UG1CA233253, UG1CA233277, UG1CA233290, UG1CA233339, UG1CA189859, UG1CA233332. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Figure 1 Figure 1. Disclosures Kay: Oncotracker: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Sunesis: Research Funding; Genentech: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Coutre: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Other: Data Safety Monitoring Committee, Research Funding. Barr: AstraZeneca: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Beigene: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Abbvie/Pharmacyclics: Consultancy. Cashen: Secura Bio, ADC Therapeutics: Consultancy. Mato: Adaptive Biotechnologies: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; MSKCC: Current Employment; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; Janssen: Consultancy, Research Funding; Genmab: Research Funding. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee; AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau. Stone: Onconova: Consultancy; AbbVie: Consultancy; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Takeda: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Innate: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Celgene: Consultancy; Macrogenics: Consultancy. Litzow: Actinium: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Tallman: NYU Grand Rounds: Honoraria; Kura: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Shanafelt: Genentech, Pharmacyclics: Research Funding. Wagner: Eli Lilly, Johnson & Johnson: Other: Spouse, previously held individual stocks;; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Athenex Inc: Consultancy.

Alien Hand Syndrome (AHS) is characterized by intermittent and involuntary movements of a single limb that is not associated with motor dysfunction. AHS may be the initial presentation of serious underlying pathology, such as stroke localized to the non-dominant parietal lobe, corpus callosum damage, or neurodegenerative disease. AHS occurs at a low prevalence in the general population yet represents significant underlying disease burden, necessitating early identification. In this case report, we present an 88-year-old right-handed male with involuntary movement of his left forearm and hand three hours prior to presentation. His symptom corresponded to findings on MRI of the brain, which showed acute infarcts of the right temporal lobe, right parietal cortex, and right parietal subcortex. Infarction of the right parietal cortex accounted for his AHS. The multifocal nature of the infarcts elevated the index of suspicion for an embolic source.

Wilson disease is a rare inherited autosomal recessive disorder. As a consequence of genetic alterations in the ATP7B gene, copper begins to accumulate in the body, particularly in the liver and brain. Affected persons are prone to develop liver cancer and severe psychiatric and neurological symptoms. Clinically, the development of corneal Kayser-Fleischer rings and low ceruloplasmin concentrations (&lt, 20 mg/dL) are indicative of Wilson disease. However, the detection of elevated hepatic copper content (&gt, 250 &micro, g/g dry weight) alone is still considered as the best but not exclusive diagnostic test for Wilson disease. Presently, specific copper stains (e.g., rhodanine) or indirect staining for copper-associated proteins (e.g., orcein) are widely used to histochemically visualize hepatic copper deposits. However, these procedures only detect lysosomal copper, while cytosolic copper is not detectable. Similarly, elemental analysis in scanning electron microscope with energy dispersive X-ray analysis (EDX) often leads to false negative results and inconsistencies. Here, we tested the diagnostic potential of laser ablation inductively-coupled mass spectrometry (LA-ICP-MS) that allows quantitative analysis of multiple elements. Comparative studies were performed in wild type and the Atp7b null mouse model. We propose LA-ICP-MS as a versatile and powerful method for the accurate determination of hepatic copper in people with Wilson disease with high spatial resolution.

Background: Primary sclerosing cholangitis (PSC) is a progressive liver disease and characterized by chronic inflammation, sclerosis and strictures of bile ducts. Several genetic risk factors might contribute to pathogenesis. Functional single nucleotide polymorphisms (SNPs) in the CD24 gene have been associated with the development of autoimmune and autoinflammatory diseases and might contribute to the susceptibility for inflammatory bowel disease (IBD).Aim: This retrospective study aimed to evaluate the impact of two functional CD24 SNPs on clinical features and disease progression in patients with PSC.Methods: A C to T coding polymorphism (rs8734) and a TG deletion in the 3´- untranslated region (rs3838646) were genotyped. The study cohort comprises of 359 PSC patients for rs3838646 genotype and 335 PSC patients for rs8734 genotype. Clinical and laboratory parameters were collected by chart review.Results: For the rs8734 genotype, 175 patients (52.2%) were found to be homozygous wildtype ('Ala/Ala'), 127 (37.9%) patients were heterozygous ('Ala/Val') and 33 patients (9.9%) were homozygous mutant ('Val/Val'). The rs8734genotype was associated with a decreased risk for dominant strictures at first diagnosis of PSC (p = .04). For the rs3838646 genotype, 322 patients (89.7%) were found to be homozygous wildtype ('TG/TG'); 37 showed the 'TG/del' genotype (10.3%). The 'TG/del'genotype was associated with alower risk of IBD (p = .01).There was no influence of both CD24 SNPs with clinical end points or transplantation-free survival in our PSC cohort.Conclusion: Our results suggest a mild association of the rs8734 CD24 genotype with dominant strictures at first diagnosis of PSC. The rs3838646 CD24 genotype is associated with a lower rate of IBD. Both SNPs seem to modulate the clinical phenotype without major pathogenetic importance for disease progression in PSC.

During prolonged nutrient restriction, developing animals redistribute vital nutrients to favor brain growth at the expense of other organs. InDrosophila, such brain sparing relies on a glia-derived growth factor to sustain proliferation of neural stem cells. However, whether other aspects of neural development are also spared under nutrient restriction is unknown. Here we show that dynamically growing somatosensory neurons in theDrosophilaperipheral nervous system exhibit organ sparing at the level of arbor growth: Under nutrient stress, sensory dendrites preferentially grow as compared to neighboring non-neural tissues, resulting in dendrite overgrowth. Underlying this neuronal nutrient-insensitivity is the lower expression of the stress sensor FoxO in neurons. Consequently, nutrient restriction suppresses Tor signaling less and does not induce autophagy in neurons. Preferential dendrite growth is functional desirable because it results in heightened animal responses to sensory stimuli, indicative of a potential survival advantage under environmental challenges.

Background: Patients with hepatorenal syndrome carry a high short-term mortality. Early diagnosis and treatment are essential for patients’ outcome. Nevertheless diagnosis of HRS remains difficult....

Purpose Breast cancer is among the leading causes of death resulting from cancer in Caribbean women. Studies examining exogenous and genetically predetermined endogenous risk factors are critical to define breast cancer susceptibility in Caribbean women. The purpose of this systematic review is to assess the existing scientific literature in the last 42 years (1975 to 2017) to describe the body of research generated for the population of this region and determine future research directions. Methods We selected published research articles using a combination of definite keyword searches in PubMed. Only articles presenting the Caribbean population as the focus of their research objectives were included in this analysis. Results Studies on breast cancer in the Caribbean are limited. A majority of publications on Caribbean populations were descriptive, focusing on cancer trends and clinicopathologic factors. High incidence and mortality rates for breast cancer are reported for the region, and there seem to be some differences between countries in the frequency of cases according to age at presentation. A limited number of epidemiologic, behavioral, and genetic and molecular studies were conducted in more recent years. Conclusion A regional strategy for cancer registration is needed for the Caribbean to address possible underestimates of breast cancer incidence. Furthermore, behavioral, molecular, genetic, and epidemiologic investigations of breast cancer are critical to address the concerns related to currently described high incidence and mortality rates in the Caribbean.

The mode of action of nuclear factor-κB (NF-κB) has been extensively observed in different aspects of cell growth and proliferation. The transcription factor regulates various genes controlling inflammation and anti-inflammatory responses in different tissues. Thus, NF-κB signal gains a therapeutic prospect. The activation of NF-κB requires nuclear localization of its p65 subunit. Research also indicates an impact of phosphorylated p65 on the transcription of genes during cell growth and the immune response. Following the trends in investigations over decades, different observations suggest that NF-κB activation and phosphorylation of p65 regulate neuronal plasticity. Also, inhibition of NF-κB activation is a well-demonstrated way to attenuate inflammation. In addition to anti-inflammatory drugs, recent researches unwind a way to regulate regeneration and repair tissue damage. Thus, keeping a critical view on NF-κB signals, we propose the importance of natural or synthetic NF-κB activators for neurogenesis. © 2015 Wiley Periodicals, Inc.

The HMGB1 protein has multiple functions in tumor biology and can act both as a transcription factor and as a cytokine. HMGB1 is released during cell death, and in our previous studies we demonstrated that HMGB1 induces a distinct, necrosis-like cell death in glioblastoma. In epithelial malignant tumors such as colorectal cancer (CRC), the HMGB1-dependent effects show cross-talk with apoptotic signal transduction. Treatment of CRC cells with low concentrations of recombinant HMGB1 results in dose-dependent cytotoxicity which is morphologically characterized by the formation of giant mitochondria and does not share features of apoptosis. HMGB1-triggered cell death is associated with intracellular ROS release, and overexpression of Bcl-2 blocks both the increase of ROS as well as HMGB1-dependent cell death. Importantly, treatment with recombinant HMGB1 or overexpression of endogenous HMGB1 strongly sensitizes CRC cells to the cytotoxic activity of the pro-apoptotic death ligand TRAIL as well as the small molecule Bcl-2 family inhibitor ABT‑737. Moreover, treatment of CRC cells with TRAIL or ABT‑737 induces a release of endogenous HMGB1 into the extracellular space, and preincubation with glycyrrhizin, an HMGB1 inhibitor, significantly inhibits induction of cell death by TRAIL and ABT‑737, suggesting that HMGB1 functionally contributes to the execution of cell death triggered by pro-apoptotic agents. Finally, we investigated the expression of HMGB1 in human CRC tumor samples and found that loss of HMGB1 expression is associated with a more aggressive phenotype and a more advanced stage of disease in patients with CRC. Altogether, our findings demonstrate a functional link between cytotoxic signaling cascades triggered by HMGB1 and pro-apoptotic agents leading to an HMGB1-dependent sensitization to CRC cell death. Thus, a further evaluation of recombinant HMGB1 as part of an experimental combination treatment of CRC seems warranted.

OBJECTIVES: Elevated circulating branched chain amino acid (BCAA) levels are correlated with the development of insulin resistance and type 2 diabetes mellitus in humans. On the other hand, BCAA supplementation has been shown to be beneficial in improving insulin resistance during chronic liver disease. Furthermore, there is recent evidence of significant crosstalk between BCAA and mitochondrial lipid metabolism. Considering the central role of dysfunctional mitochondrial lipid metabolism in diet-induced obesity and non-alcoholic fatty liver disease (NAFLD), our objective was to determine the impact of dietary BCAA supplementation on hepatic mitochondrial function, in a diet-induced mouse model of NAFLD. We hypothesized that the dietary supplementation of BCAA, together with a high fat diet, will exacerbate hepatic mitochondrial dysfunction during NAFLD. METHODS: C57BL/6NJ mice were fed with a control (10% kcal fat), high fat (HF; 60% kcal fat), or HF diet supplemented with BCAA (BA; 60% kcal fat; 1.5X BCAA) diet for 16 weeks. Livers from these mice were used for mitochondrial isolation, total liver and mitochondrial protein estimation, determination of amino acids and Kreb's cycle intermediates by mass spectrometry, and gene expression profiles. RESULTS: While the liver weights (g ± SEM) of HF fed mice (2.6 ± 0.36) were significantly higher than the control mice (1.5 ± 0.19), BCAA supplemented mice had significantly lower liver weights than the HF fed mice (1.8 ± 0.28). Hepatic mitochondrial protein content (µg/g liver ± SEM) was enriched in BCAA supplemented mice compared to their HF diet fed counterparts (BA, 3858 ± 476; HF, 2635 ± 394; P ˂ 0.05). Many of the organic acid intermediates of the Kreb's cycle were significantly lower in the liver of HF fed mice. Interestingly, BCAA supplementation (BA) with HF feeding restored hepatic organic acid intermediates to similar levels observed in control mice. Further, HF and BA feeding, both downregulated lipogenic gene expression (e.g., Fasn, Scd1, Acly) in the liver. CONCLUSIONS: Our results suggest that BCAA supplementation enhanced hepatic mitochondrial biogenesis and oxidative metabolism in the liver of mice with NAFLD. High-fat diets which significantly suppressed the rates of de novo lipogenesis, could have provided the BCAAs, a metabolic milieu favorable for the induction of mitochondrial activity. FUNDING SOURCES: National Institutes of Health (R01).

Dendritic cells are specialized antigen-presenting cells that play a dual role in induction of both innate and adaptive immunity as well as T cell tolerance. Dendritic cell based vaccines for the treatment of cancer have shown promise in clinical trials but have yet to demonstrate consistent immunologic potency or clinical efficacy. To address these issues, our group is focusing on strategies to target and activate dendritic cells, in vivo, in tumor bearing hosts. Experiments in animal models suggest that these strategies can overcome tumor-induced immunosuppression, and generate potent T cell mediated antitumor immunity that results in regression of established tumors.