Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition of H2S biosynthesis. H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasing H2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, an H2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of H2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.

https://pharmrev.aspetjournals.org/content/pharmrev/69/4/497.full.pdf

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors.

Significance: Hydrogen sulfide (H2S) has been recognized as the third gaseous transmitter alongside nitric oxide and carbon monoxide. In the past decade, numerous studies have demonstrated an active role of H2S in the context of cancer biology. Recent Advances: The three H2S-producing enzymes, namely cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3MST), have been found to be highly expressed in numerous types of cancer. Moreover, inhibition of CBS has shown anti-tumor activity, particularly in colon cancer, ovarian cancer, and breast cancer, whereas the consequence of CSE or 3MST inhibition remains largely unexplored in cancer cells. Intriguingly, H2S donation at high amounts or a long time duration has also been observed to induce cancer cell apoptosis in vitro and in vivo while sparing noncancerous fibroblast cells. Therefore, a bell-shaped model has been proposed to explain the role of H2S in cancer development. Specifically, endogenous H2S or a relatively low level of exogenous H2S may exhibit a pro-cancer effect, whereas exposure to H2S at a higher amount or for a long period may lead to cancer cell death. This indicates that inhibition of H2S biosynthesis and H2S supplementation serve as two distinct ways for cancer treatment. This paradoxical role of H2S has stimulated the enthusiasm for the development of novel CBS inhibitors, H2S donors, and H2S-releasing hybrids. Critical Issues: A clear relationship between H2S level and cancer progression remains lacking. The possibility that the altered levels of these byproducts have influenced the cell viability of cancer cells has not been excluded in previous studies when modulating H2S producing enzymes. Future Directions: The consequence of CSE or 3MST inhibition in cancer cells need to be examined in the future. Better portrayal of the crosstalk among these gaseous transmitters may not only lead to an in-depth understanding of cancer progression but also shed light on novel strategies for cancer therapy.

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A Review of Hydrogen Sulfide Synthesis, Metabolism, and Measurement: Is Modulation of Hydrogen Sulfide a Novel Therapeutic for Cancer?

Background Burnout is a psychological syndrome that is very common among medical residents. It consists of emotional exhaustion (EE), depersonalization (DP) and reduced personal accomplishment (PA). Objective To estimate burnout among different medical residency specialties. Methods A systematic review with meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search of bibliographic databases and grey literature was conducted, from inception to March 2018. The following databases were accessed: Embase, PubMed, Web of Science, Google Scholar and Scopus, and 3,575 studies were found. Methodological quality was evaluated by Agency for Healthcare Research and Quality Methodology Checklist for Cross-Sectional/Prevalence Study. In the final analysis, 26 papers were included. Their references were checked for additional studies, but none were included. Results 4,664 medical residents were included. High DP, EE and low PA proportions were compared. Specialties were distributed into three groups of different levels of burnout prevalence: general surgery, anesthesiology, obstetrics/gynecology and orthopedics (40.8%); internal medicine, plastic surgery and pediatrics (30.0%); and otolaryngology and neurology (15.4%). Overall burnout prevalence found for all specialties was 35.7%. Conclusion The prevalence of burnout syndrome was significantly higher among surgical/urgency residencies than in clinical specialties. Prospero registration CRD42018090270.

/pdf/burnout-syndrome-among-medical-residents-a-systematic-review-3zqsgfcw9z.pdf

Burnout syndrome among medical residents: A systematic review and meta-analysis.

Importance Physicians in procedural specialties are at high risk for work-related musculoskeletal disorders (MSDs). This has been called “an impending epidemic” in the context of the looming workforce shortage; however, prevalence estimates vary by study. Objectives To estimate the prevalence of work-related MSDs among at-risk physicians and to evaluate the scope of preventive efforts. Data Sources and Study Selection Systematic search in MEDLINE (Ovid), Embase (Elsevier), Web of Science, PubMed (National Center for Biotechnology Information), and 2 clinical trial registries, without language restriction, for studies reporting on the prevalence and prevention of work-related MSDs among at-risk physicians published until December 2016. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for meta-analyses and systematic reviews of observational studies were used. At-risk physicians were defined as surgeons and medical interventionalists. Studies reporting on specific disorders or pain assessed with validated instruments were included. Data Extraction and Synthesis Study characteristics; disease prevalence for the neck, shoulder, back, and upper extremity; and measures of resulting disability were recorded. Study estimates were pooled using random-effects meta-analytic models. Main Outcomes and Measures Career prevalence of injuries and 12-month prevalence of pain. Results Among 21 articles (5828 physicians [mean age, 46.0 years; 78.5% male; 12.8 years in practice; 14.4 hours performing procedures per week]) included in this systematic review and meta-analysis, pooled crude prevalence estimates of the most common work-related MSDs were degenerative cervical spine disease in 17% (457 of 2406 physicians) (95% CI, 12%-25%), rotator cuff pathology in 18% (300 of 1513 physicians) (95% CI, 13%-25%), degenerative lumbar spine disease in 19% (544 of 2449 physicians) (95% CI, 5%-16%), and carpal tunnel syndrome in 9% (256 of 2449 physicians) (95% CI, 5%-16%). From 1997 to 2015, the prevalence of degenerative cervical spine disease and degenerative lumbar spine disease increased by 18.3% and 27%, respectively. Pooled prevalence estimates for pain ranged from 35% to 60% and differed by assessment instrument. Of those with a work-related MSD, 12% (277 of 2319 physicians) (95% CI, 7%-18%) required a leave of absence, practice restriction or modification, or early retirement. Heterogeneity was considerable for all crude analyses (meanI2 = 93.5%) but was lower for sensitivity analyses (meanI2 = 72.3%). Interventions focused on products and behaviors. Twelve at-risk specialties described a gross lack of awareness and an unmet need for ergonomics education. Conclusions and Relevance Prevalence estimates of work-related MSDs among at-risk physicians appear to be high. Further research is needed to develop and validate an evidence-based applied ergonomics program aimed at preventing these disorders in this population.

Prevalence of Work-Related Musculoskeletal Disorders Among Surgeons and Interventionalists: A Systematic Review and Meta-analysis.

Ferroptosis is a new form of programmed cell death characterized by the accumulation of iron-dependent lethal lipid peroxides Recent discoveries have focused on alterations that occur in lipid metabolism during ferroptosis and have provided intriguing insights into the interplay between ferroptosis and lipid metabolism in cancer Their interaction regulates the initiation, development, metastasis, therapy resistance of cancer, as well as the tumor immunity, which offers several potential strategies for cancer treatment This review is a brief overview of the features characterizing the interaction between ferroptosis and lipid metabolism, and highlights the significance of this interaction in cancer

/pdf/the-interaction-between-ferroptosis-and-lipid-metabolism-in-2ubyhiyuv2.pdf

The interaction between ferroptosis and lipid metabolism in cancer.

Burnout is a syndrome characterized by emotional exhaustion, depersonalization, and a decreased sense of personal accomplishment caused by work-related stress.1,2 Physicians are at increased risk for burnout as a result of long work hours, delayed gratification, challenges with work and home balance, and challenges associated with patient care, especially in the changing healthcare environment.1,3-5

In a recent study, more than half of physicians met criteria for burnout. In addition, the prevalence of burnout increased 10% in U.S. physicians between 2011 and 2014.6 The prevalence of burnout was lower in a probability-based sample of the general U.S. working population, with no increase over the same time period. This increase was observed across specialties, with many specialties reporting well over 50% of physicians being burned out.6 This disturbing trend is likely multifactorial, with increasing demands in clinical productivity, difficulty in funding research endeavors, more patients to care for with fewer resources, changes in reimbursement, rising student debt, and difficulty balancing personal and work life.7-10

Burnout is especially prevalent in surgical specialties. In the 2015 Medscape Physician Lifestyle Report, burnout rates ranged from 37-53% across specialties, with general surgeons nearly topping the list at 50%.11 Burnout has severe adverse consequences, including substance abuse, disruptive behavior, absenteeism, attrition, strained personal relationships, divorce, depression, suicidal ideation, and suicide.12-14 Over the past decade, awareness has been raised and the ability to accurately assess and identify physicians suffering from burnout has improved. The aim of this systematic review was to provide a concise review and identify studies reporting on identification, prevention, or intervention for surgeons suffering from burnout.

https://www.journalacs.org/article/S1072-7515(16)00255-6/pdf

Surgeon Burnout: A Systematic Review

Colon cancer cells contain high levels of cystathlonlne-β-synthase (CBS). Its product, hydrogen sulfide (H2S), promotes the growth and proliferation of colorectal tumor cells. To improve the antitumor efficacy of the prototypical CBS inhibitor aminooxyacetic acid (AOAA), we have designed and synthesized YD0171, a methyl ester derivative of AOAA. The antiproliferative effect of YD0171 exceeded the antiproliferative potency of AOAA in HCT116 human colon cancer cells. The esterase inhibitor paraoxon prevented the cellular inhibition of CBS activity by YD0171. YD0171 suppressed mitochondrial respiration and glycolytic function and induced G0/G1 arrest, but did not induce tumor cell apoptosis or necrosis. Metabolomic analysis in HCT116 cells showed that YD0171 affects multiple pathways of cell metabolism. The efficacy of YD0171 as an inhibitor of tumor growth was also tested in nude mice bearing subcutaneous HCT116 cancer cell xenografts. Animals were treated via subcutaneous injection of vehicle or AOAA (0.1, 0.5 or 1 mg/kg/d) for 3 wks. Tumor growth was significantly reduced by 9 mg/kg/d AOAA, but not at the lower doses. YD0171 was more potent: tumor volume was significantly inhibited at 0.5 and 1 mg/kg/d. Thus, the in vivo efficacy of YD0171 is nine times higher than that of AOAA. YD0171 (1 mg/kg/d) attenuated tumor growth and metastasis formation in the intracecal HCT116 tumor model. YD0171 (3 mg/kg/d) also reduced tumor growth in patient-derived tumor xenograft bearing athymic mice. YD0171 (3 mg/kg/d) induced the regression of established HCT116 tumors in vivo. A 5-d safety study in mice demonstrated that YD0171 at 20 mg/kg/d (given in two divided doses) does not increase plasma markers of organ injury, nor does it induce histological alterations in the liver or kidney. YD0171 caused a slight elevation in plasma homocysteine levels. In conclusion, the prodrug approach improves the pharmacological profile of AOAA; YD0171 represents a prototype for CBS inhibitory anticancer prodrugs. By targeting colorectal cancer bioenergetics, an emerging important hallmark of cancer, the approach exemplified herein may offer direct translational opportunities.

/pdf/cystathionine-b-synthase-inhibition-for-colon-cancer-4asc3t1up5.pdf

David Eckelbarger

Papers

Surgeon Burnout: A Systematic Review

Cystathionine-β-Synthase Inhibition for Colon Cancer: Enhancement of the Efficacy of Aminooxyacetic Acid via the Prodrug Approach