The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation

The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance

Consensus Recommendations for Sick Day Medication Guidance for People With Diabetes, Kidney, or Cardiovascular Disease:A Modified Delphi Process

Rationale &amp; Objective: Sick day medication guidance (SDMG) involves withholding or adjusting specific medications in the setting of acute illnesses that could contribute to complications such as hypotension, acute kidney injury (AKI), or hypoglycemia. We sought to achieve consensus among clinical experts on recommendations for SDMG that could be studied in future intervention studies. Study Design: A modified Delphi process following guidelines for conducting and reporting Delphi studies. Setting &amp; Participants: An international group of clinicians with expertise relevant to SDMG was recruited through purposive and snowball sampling. A scoping review of the literature was presented, followed by 3 sequential rounds of development, refinement, and voting on recommendations. Meetings were held virtually and structured to allow the participants to provide their input and rapidly prioritize and refine ideas.Outcome: Opinions of participants were measured as the percentage who agreed with each recommendation, whereas consensus was defined as &gt;75% agreement. Analytical Approach: Quantitative data were summarized using counts and percentages. A qualitative content analysis was performed to capture the context of the discussion around recommendations and any additional considerations brought forward by participants. Results: The final panel included 26 clinician participants from 4 countries and 10 clinical disciplines. Participants reached a consensus on 42 specific recommendations: 5 regarding the signs and symptoms accompanying volume depletion that should trigger SDMG; 6 regarding signs that should prompt urgent contact with a health care provider (including a reduced level of consciousness, severe vomiting, low blood pressure, presence of ketones, tachycardia, and fever); and 14 related to scenarios and strategies for patient self-management (including frequent glucose monitoring, checking ketones, fluid intake, and consumption of food to prevent hypoglycemia). There was consensus that renin-angiotensin system inhibitors, diuretics, nonsteroidal anti-inflammatory drugs, sodium/glucose cotransporter 2 inhibitors, and metformin should be temporarily stopped. Participants recommended that insulin, sulfonylureas, and meglitinides be held only if blood glucose was low and that basal and bolus insulin be increased by 10%-20% if blood glucose was elevated. There was consensus on 6 recommendations related to the resumption of medications within 24-48 hours of the resolution of symptoms and the presence of normal patterns of eating and drinking. Limitations: Participants were from high-income countries, predominantly Canada. Findings may not be generalizable to implementation in other settings. Conclusions: A multidisciplinary panel of clinicians reached a consensus on recommendations for SDMG in the presence of signs and symptoms of volume depletion, as well as self-management strategies and medication instructions in this setting. These recommendations may inform the design of future trials of SDMG strategies.</p

A rare case of an aldosterone secreting metastatic adrenocortical carcinoma and papillary thyroid carcinoma in a 31-year-old male

We report a rare synchronous presentation of adrenocortical carcinoma (ACC) and papillary thyroid carcinoma (PTC). A 31-year-old male first presented with a large left adrenal mass that was identified during the workup for refractory hypertension due to hyperaldosteronism. The mass was removed surgically with pathology showing ACC. The patient was then treated with adjuvant radiation therapy and mitotane chemotherapy. Four months post ACC resection, metastatic ACC to the right upper lung and PTC in the left lobe of the thyroid were found in surveillance imaging. He subsequently developed pulmonary, contralateral adrenal and brain metastases from his ACC. Li Fraumeni syndrome and Multiple Endocrine Neoplasia Type I (MEN I) were considered, but testing of both P53 and menin genes showed no mutation. We also performed a review of the literature and found three similar cases, however gene mutation analysis was not performed.

Pre-therapy mRNA expression of TNF is associated with regimen-related gastrointestinal toxicity in patients with esophageal cancer: a pilot study

Author version made available following 12 month embargo from date of publication (27 March 2015) in accordance with publisher copyright policy.Purpose Esophageal cancer has a high mortality rate, and its multimodality treatment is often associated with significant rates of severe toxicity. Effort is needed to uncover ways to maximize effectiveness of therapy through identification of predictive markers of response and toxicity. As such, the aim of this study was to identify genes predictive of chemoradiotherapy-induced gastrointestinal toxicity using an immune pathway-targeted approach. Methods Adults with esophageal cancer treated with chemotherapy consisting of 5-fluorouracil and cisplatin and 45–50 Gy radiation were recruited to the study. Pre-therapy-collected whole blood was analyzed for relative expression of immune genes using real-time polymerase chain reaction (RT-PCR). Gene expression was compared between patients who experienced severe regimen-related gastrointestinal toxicity vs. those experiencing mild to moderate toxicity. Results Blood from 31 patients were analyzed by RT-PCR. Out of 84 immune genes investigated, TNF was significantly elevated (2.05-fold, p = 0.025) in the toxic group (n = 12) compared to the non-toxic group (n = 19). Nausea and vomiting was the most commonly documented severe toxicity. No associations between toxicity and response, age, sex, histology, or treatment were evident. Conclusions This study supports evidence of TNF as a predictive biomarker in regimen-related gastrointestinal toxicity. Confirming these findings in a larger cohort is warranted

Consensus Recommendations for Sick Day Medication Guidance for People With Diabetes, Kidney, or Cardiovascular Disease : A Modified Delphi Process

Acknowledgements We would like to thank the clinical experts who participated in the modified Delphi panel and provided their knowledge and expertise. We also thank Sarah Gil and Terry Smith for technical assistance.Peer reviewedproo

Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer

Cultured cells convert glucose to lactate, and glutamine is the major source of tricarboxylic acid (TCA)-cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells.National Science Foundation (U.S.) (Grant T32GM007287

The allopurinol metabolite, oxypurinol, drives oligoclonal expansions of drug‐reactive T cells in resolved hypersensitivity cases and drug‐naïve healthy donors

Allopurinol (ALP) is a successful drug used in the treatment of gout. However, this drug has been implicated in hypersensitivity reactions that can cause severe to life‐threatening reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Individuals who carry the human leukocyte antigen (HLA)‐B*58:01 allotype are at higher risk of experiencing a hypersensitivity reaction (odds ratios ranging from 5.62 to 580.3 for mild to severe reactions, respectively). In addition to the parent drug, the metabolite oxypurinol (OXP) is implicated in triggering T cell‐mediated immunopathology via a labile interaction with HLA‐B*58:01. To date, there has been limited information regarding the T‐cell receptor (TCR) repertoire usage of reactive T cells in patients with ALP‐induced SJS or TEN and, in particular, there are no reports examining paired αβTCRs. Here, using in vitro drug‐treated PBMCs isolated from both resolved ALP‐induced SJS/TEN cases and drug‐naïve healthy donors, we show that OXP is the driver of CD8+ T cell‐mediated responses and that drug‐exposed memory T cells can exhibit a proinflammatory immunophenotype similar to T cells described during active disease. Furthermore, this response supported the pharmacological interaction with immune receptors (p‐i) concept by showcasing (i) the labile metabolite interaction with peptide/HLA complexes, (ii) immunogenic complex formation at the cell surface, and (iii) lack of requirement for antigen processing to elicit drug‐induced T cell responsiveness. Examination of paired OXP‐induced αβTCR repertoires highlighted an oligoclonal and private clonotypic profile in both resolved ALP‐induced SJS/TEN cases and drug‐naïve healthy donors

An Eclipsing 47 minute Double White Dwarf Binary at 400 pc

We present the discovery of the eclipsing double white dwarf (WD) binary WDJ 022558.21-692025.38 that has an orbital period of 47.19 min. Following identification with the Transiting Exoplanet Survey Satellite, we obtained time-series ground based spectroscopy and high-speed multi-band ULTRACAM photometry which indicate a primary DA WD of mass 0.40 +- 0.04 Msol and a 0.28 +- 0.02 Msol mass secondary WD, which is likely of type DA as well. The system becomes the third-closest eclipsing double WD binary discovered with a distance of approximately 400 pc and will be a detectable source for upcoming gravitational wave detectors in the mHz frequency range. Its orbital decay will be measurable photometrically within 10 yrs to a precision of better than 1%. The fate of the binary is to merge in approximately 41 Myr, likely forming a single, more massive WD.Comment: Accepted for publication in MNRAS, 8 pages + 2 appendix pages, 6 figure

TIC 378898110: A Bright, Short-Period AM CVn Binary in TESS

AM CVn-type systems are ultracompact, helium-accreting binary systems which are evolutionarily linked to the progenitors of thermonuclear supernovae and are expected to be strong Galactic sources of gravitational waves detectable to upcoming space-based interferometers. AM CVn binaries with orbital periods $\lesssim$ 20--23 min exist in a constant high state with a permanently ionised accretion disc. We present the discovery of TIC 378898110, a bright ($G=14.3$ mag), nearby ($309.3 \pm 1.8$ pc), high-state AM CVn binary discovered in TESS two-minute-cadence photometry. At optical wavelengths this is the third-brightest AM CVn binary known. The photometry of the system shows a 23.07172(6) min periodicity, which is likely to be the `superhump' period and implies an orbital period in the range 22--23 min. There is no detectable spectroscopic variability. The system underwent an unusual, year-long brightening event during which the dominant photometric period changed to a shorter period (constrained to $20.5 \pm 2.0$ min), which we suggest may be evidence for the onset of disc-edge eclipses. The estimated mass transfer rate, $\log (\dot{M} / \mathrm{M_\odot} \mathrm{yr}^{-1}) = -6.8 \pm 1.0$, is unusually high and may suggest a high-mass or thermally inflated donor. The binary is detected as an X-ray source, with a flux of $9.2 ^{+4.2}_{-1.8} \times 10^{-13}$ erg cm$^{-2}$ s$^{-1}$ in the 0.3--10 keV range. TIC 378898110 is the shortest-period binary system discovered with TESS, and its large predicted gravitational-wave amplitude makes it a compelling verification binary for future space-based gravitational wave detectors.Comment: 15 pages, 14 figures. Accepted to MNRA