Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.

Bezlotoxumab (Zinplava) for Clostridium Difficile Infection: The First Monoclonal Antibody Approved to Prevent the Recurrence of a Bacterial Infection.

Bezlotoxumab (Zinplava) to prevent the recurrence of Clostridium difficile infection.

Daclatasvir (Daklinza): A Treatment Option for Chronic Hepatitis C Infection.

Daclatasvir (Daklinza) for chronic hepatitis C infection.

Ceftolozane/Tazobactam: a new option in the treatment of complicated gram-negative infections.

Ceftolozane/tazobactam: a new option in the treatment of complicated gram-negative infections.

Droplet-based forward genetic screening of astrocyte-microglia cross-talk.

Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. Here, we developed a forward genetic screening platform that combines CRISPR-Cas9 perturbations, cell coculture in picoliter droplets, and microfluidic-based fluorescence-activated droplet sorting to identify mechanisms of cell-cell communication. We used SPEAC-seq (systematic perturbation of encapsulated associated cells followed by sequencing), in combination with in vivo genetic perturbations, to identify microglia-produced amphiregulin as a suppressor of disease-promoting astrocyte responses in multiple sclerosis preclinical models and clinical samples. Thus, SPEAC-seq enables the high-throughput systematic identification of cell-cell communication mechanisms.

Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers.

BACKGROUND: Serum/glucocorticoid-regulated kinase 1 (SGK1), a known target of the androgen receptor (AR) and glucocorticoid receptor (GR), is reported to enhance cell survival. This study sought to better define the role of SGK1 and GR in prostate cancer. METHODS: Immunohistochemistry was performed for AR, GR, and SGK1 on primary prostate cancers (n = 138) and 18 prostate cancers from patients treated with androgen deprivation therapy. Relative staining intensity was compared utilizing a Fisher's exact test. Univariate analyses were performed using log-rank and chi-squared tests to evaluate prostate cancer recurrence with respect to SGK1 expression. RESULTS: SGK1 expression was strong (3+) in 79% of untreated cancers versus 44% in androgen-deprived cancers (P = 0.003). Conversely, GR expression was present in a higher proportion of androgen-deprived versus untreated cancers (78% vs. 38%, P = 0.002). High-grade cancers were nearly twice as likely to have relatively low (0 to 2+) SGK1 staining compared to low-grade cancers (13.8% vs. 26.5%, P = 0.08). Low SGK1 expression in untreated tumors was associated with increased risk of cancer recurrence (adjusted log-rank test P = 0.077), 5-year progression-free survival 47.8% versus 72.6% (P = 0.034). CONCLUSIONS: SGK1 expression is high in most untreated prostate cancers and declines with androgen deprivation. However, these data suggest that relatively low expression of SGK1 is associated with higher tumor grade and increased cancer recurrence, and is a potential indicator of aberrant AR signaling in these tumors. GR expression increased with androgen deprivation, potentially providing a mechanism for the maintenance of androgen pathway signaling in these tumors. Further study of the AR/GR/SGK1 network in castration resistance.

Phenotypic differences between people varying in muscularity.

BACKGROUND: Body mass is the primary metabolic compartment related to a vast number of clinical indices and predictions. The extent to which skeletal muscle (SM), a major body mass component, varies between people of the same sex, weight, height, and age is largely unknown. The current study aimed to explore the magnitude of muscularity variation present in adults and to examine if variation in muscularity associates with other body composition and metabolic measures. METHODS: Muscularity was defined as the difference (residual) between a person's actual and model-predicted SM mass after controlling for their weight, height, and age. SM prediction models were developed using data from a convenience sample of 492 healthy non-Hispanic (NH) White adults (ages 18-80 years) who had total body SM and SM surrogate, appendicular lean soft tissue (ALST), measured with magnetic resonance imaging and dual-energy X-ray absorptiometry, respectively; residual SM (SMR ) and ALST were expressed in kilograms and kilograms per square meter. ALST mass was also evaluated in a population sample of 8623 NH-White adults in the 1999-2006 National Health and Nutrition Examination Survey. Associations between muscularity and variation in the residual mass of other major organs and tissues and resting energy expenditure were evaluated in the convenience sample. RESULTS: The SM, on average, constituted the largest fraction of body weight in men and women up to respective BMIs of 35 and 25 kg/m2 . SM in the convenience sample varied widely with a median of 31.2 kg and an SMR inter-quartile range/min/max of 3.35 kg/-10.1 kg/9.0 kg in men and 21.1 kg and 2.59 kg/-7.2 kg/7.5 kg in women; per cent of body weight as SM at 25th and 75th percentiles for men were 33.1% and 39.6%; corresponding values in women were 24.2% and 30.8%; results were similar for SMR indices and for ALST measures in the convenience and population samples. Greater muscularity in the convenience sample was accompanied by a smaller waist circumference (men/women: P < 0.001/=0.085) and visceral adipose tissue (P = 0.014/0.599), larger liver (P = 0.065/<0.001), kidneys (P = 0.051/<0.009), and bone mineral (P < 0.001/<0.001), and larger magnitude resting energy expenditure (P < 0.001/<0.001) than predicted for the same sex, age, weight, and height. CONCLUSIONS: Muscle mass is the largest body compartment in most adults without obesity and is widely variable in mass across people of similar body size and age; and high muscularity is accompanied by distinct body composition and metabolic characteristics. This previously unrecognized heterogeneity in muscularity in the general population has important clinical and research implications.

Vascular endothelial growth factor pathway-targeted therapy as initial systemic treatment of patients with renal cancer.

Advanced renal cancer is known to be largely refractory to traditional DNA- and DNA repair-targeted chemotherapy. Until recently, immunotherapy had been the mainstay for the treatment; however, it is effective in only a small proportion of patients. Advances in the understanding of the association between the von Hippel-Lindau pathway and angiogenesis and their role in the development of renal cancer has led to the development of highly effective vascular endothelial growth factor (VEGF) pathway-targeted inhibitors. Several such novel agents have demonstrated increased clinical benefit, progression-free survival, and superior quality of life in large, randomized phase III clinical trials, and additional VEGF pathway inhibitors are currently being studied. This review will summarize the major clinical trials and practical recommendations for the most studied VEGF inhibitors, including sunitinib, sorafenib, and bevacizumab; introduce novel VEGF inhibitor agents; outline side effects and toxicities; and discuss sequential and combination therapy with these agents.

A phase II trial of gemcitabine, capecitabine, and bevacizumab in metastatic renal carcinoma.

OBJECTIVES: Renal cancer is resistant to most DNA and DNA repair targeted chemotherapy; although moderate response rates to nucleotide analog based therapy have been reported. Bevacizumab also has activity. We thus performed a phase II trial of gemcitabine, capecitabine, and bevacizumab in patients with metastatic renal cancer. METHODS: Following significant hematotoxicity, dosing was modified to gemcitabine 1000 mg/m (Days 1, 8), capecitabine 1000 mg twice daily (Days 1-14), and bevacizumab 15 mg/kg (Day 1) on a 21-day cycle with evaluation every 3 cycles. Primary end point was objective response rate. RESULTS: Twenty-nine patients were enrolled between March 2005 and May 2008. Most patients had been previously treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Seven patients (24%) had a partial response. Median overall and progression-free survival were 9.8 months (95% confidence interval: 6.2, 14.9) and 5.3 months (95% confidence interval: 3.9, 9.9), respectively. The regimen was well tolerated with hematologic toxicity, fatigue, and rash being most common. CONCLUSION: The trial was terminated early despite not meeting criteria for success or futility because of slow accrual and because the historical response rate became irrelevant with emerging data using sequential vascular endothelial growth factor therapies. Nevertheless, the observed progression-free and overall survival compare favorably to other phase II trials in this heavily pretreated population.