tbuckley/cabot-search huggingface dataset:
Peptide Hormone Regulation of DNA Damage Responses
Authors: Vera Chesnokova, Shlomo Melmed
Journal: Endocrine Reviews (2020)

DNA damage response (DDR) and DNA repair pathways determine neoplastic cell transformation and therapeutic responses, as well as the aging process. Altered DDR functioning results in accumulation of unrepaired DNA damage, increased frequency of tumorigenic mutations, and premature aging. Recent evidence suggests that polypeptide hormones play a role in modulating DDR and DNA damage repair, while DNA damage accumulation may also affect hormonal status. We review the available reports elucidating involvement of insulin-like growth factor 1 (IGF1), growth hormone (GH), α-melanocyte stimulating hormone (αMSH), and gonadotropin-releasing hormone (GnRH)/gonadotropins in DDR and DNA repair as well as the current understanding of pathways enabling these actions. We discuss effects of DNA damage pathway mutations, including Fanconi anemia, on endocrine function and consider mechanisms underlying these phenotypes. (Endocrine Reviews 41: 1 - 19, 2020).
Tumor circulome in the liquid biopsies for cancer diagnosis and prognosis
Authors: Jicheng Wu, Shen Hu, Lihong Zhang, Jinxia Xin, Chongran Sun, Liquan Wang, Kefeng Ding, Ben Wang
Journal: Theranostics (2020)

Liquid biopsy is a convenient, fast, non-invasive and reproducible sampling method that can dynamically reflect the changes in tumor gene expression profile, and provide a robust basis for individualized therapy and early diagnosis of cancer. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are the currently approved diagnostic biomarkers for screening cancer patients. In addition, tumor-derived extracellular vesicles (tdEVs), circulating tumor-derived proteins, circulating tumor RNA (ctRNA) and tumor-bearing platelets (TEPs) are other components of liquid biopsies with diagnostic potential. In this review, we have discussed the clinical applications of these biomarkers, and the factors that limit their implementation in routine clinical practice. In addition, the most recent developments in the isolation and analysis of circulating tumor biomarkers have been summarized, and the potential of non-blood liquid biopsies in tumor diagnostics has also been discussed.
Mark Erik Victor Petersen
Authors: Richard Sutton
Journal: BMJ (2020)

Mark Erik Victor Petersen, a brilliant scientist and compassionate physician, was appointed as consultant cardiologist for Gloucestershire NHS Healthcare Trust in 1996. He died, in post, sadly early, 23 years later.

He was born at St George's Hospital, Hyde Park Corner, to a physician father and nurse mother. Education at City of London School and St Mary’s Hospital Medical School gave a very bright student a foundation for an outstanding career. He secured …
Lack of protective gear disrupts oncology care
Authors: Roxanne Nelson
Journal: The Lancet Oncology (2020)

A recent crowdfunding campaign caught the attention of Scottish actor James McAvoy, who was inspired to donate £275 000 to the campaign. Coined Masks for NHS Heroes, the physician-led initiative is raising money to increase the amount of certified one face masks, visors, surgical gowns, and gloves that are available to health-care workers caring for patients with coronavirus disease 2019 (COVID-19).
Potential for Life Course Health Benefits From Improved Household Environments
Authors: Otavio T. Ranzani, Cathryn Tonne, Mauricio L. Barreto
Journal: JAMA Network Open (2020)

Lack of access to safe water, sanitation, and handwashing facilities has important consequences for human health and sustainable development (Sustainable Development Goal 6, as set by the United Nations). 1 Children are particularly affected by poor water, sanitation, and hygiene (WaSH), which are responsible for a large proportion of diarrheal-associated deaths among children and have a major effect on disability-adjusted life-years. 1 Inadequate WaSH has negative consequences for children's linear growth because of recurrent diarrheal episodes and undernutrition.The resulting
Hepatosplenic phagocytic cells indirectly contribute to anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes: Appearance of an unexplained mechanism in the ABC phenomenon
Authors: Marwa Mohamed El Sayed, Haruka Takata, Taro Shimizu, Yoshino Kawaguchi, Amr S. Abu Lila, Nehal E. Elsadek, Eman Alaaeldin, Yu Ishima, Hidenori Ando, Amal Kamal, Hatem A. Sarhan, Tatsuhiro Ishida
Journal: Journal of Controlled Release (2020)
Proteogenomic Characterization of Ovarian HGSC Implicates Mitotic Kinases, Replication Stress in Observed Chromosomal Instability
Authors: Jason E. McDermott, Osama A. Arshad, Vladislav A. Petyuk, Yi Fu, Marina A. Gritsenko, Therese R. Clauss, Ronald J. Moore, Athena A. Schepmoes, Rui Zhao, Matthew E. Monroe, Michael Schnaubelt, Chia-Feng Tsai, Samuel H. Payne, Chen Huang, Liang-Bo Wang, Steven Foltz, Matthew Wyczalkowski, Yige Wu, Ehwang Song, Molly A. Brewer, Mathangi Thiagarajan, Christopher R. Kinsinger, Ana I. Robles, Emily S. Boja, Henry Rodriguez, Daniel W. Chan, Bing Zhang, Zhen Zhang, Li Ding, Richard D. Smith, Tao Liu, Karin D. Rodland
Journal: Cell Reports Medicine (2020)

In the absence of a dominant driving mutation other than uniformly present TP53 mutations, deeper understanding of the biology driving ovarian high-grade serous cancer (HGSC) requires analysis at a functional level, including post-translational modifications. Comprehensive proteogenomic and phosphoproteomic characterization of 83 prospectively collected ovarian HGSC and appropriate normal precursor tissue samples (fallopian tube) under strict control of ischemia time reveals pathways that significantly differentiate between HGSC and relevant normal tissues in the context of homologous repair deficiency (HRD) status. In addition to confirming key features of HGSC from previous studies, including a potential survival-associated signature and histone acetylation as a marker of HRD, deep phosphoproteomics provides insights regarding the potential role of proliferation-induced replication stress in promoting the characteristic chromosomal instability of HGSC and suggests potential therapeutic targets for use in precision medicine trials.
Transplant Center Variability in Organ Offer Acceptance and Mortality Among US Patients on the Heart Transplant Waitlist
Authors: Ashley Y. Choi, Michael S. Mulvihill, Hui-Jie Lee, Congwen Zhao, Maragatha Kuchibhatla, Jacob N. Schroder, Chetan B. Patel, Christopher B. Granger, Matthew G. Hartwig
Journal: JAMA Cardiology (2020)

Under the current Centers for Medicare & Medicaid Services guidelines, there is incentivization to optimize posttransplant outcomes regardless of mortality among patients on the waitlist and transplant rates; few data exist with regard to transplant center acceptance practices and survival to heart transplant.To evaluate the extent of variability in organ acceptance practices in the US and whether this center-level behavior is associated with heart transplant candidate survival.In this retrospective cohort study, the US National Transplant Registry was queried for all match runs of adult candidates listed for isolated heart transplant between May 1, 2007, and March 31, 2017. Data analysis was conducted from October 30, 2018, to May 1, 2019. The final cohort included 93 transplant centers, 19 703 donors, and 9628 candidates.Center acceptance rates for heart allografts offered to the highest-priority candidates, association between center acceptance rate and mortality among patients on the waitlist, and posttransplant outcomes between candidates who accepted their first-rank offers vs those who accepted previously declined offers.Among 19 703 unique organ offers, 6302 hearts (32.0%) were accepted for first-rank candidates. After adjustment for donor, candidate, and geographic covariates, transplant centers varied in acceptance rates (12.3%-61.5%) of offers made to first-rank candidates. Higher acceptance rates were associated with lower cumulative incidence of 1-year mortality among patients on the waitlist. For every 10% increase in adjusted center acceptance rate, the risk of mortality decreased by 27% (subdistribution hazard ratio, 0.73; 95% CI, 0.67-0.80). No statistically significant difference was observed in 5-year adjusted posttransplant patient survival (adjusted hazard ratio, 1.02; 95% CI, 0.94-1.11) and graft failure (subdistribution hazard ratio; 0.95; 95% CI, 0.83-1.09) between hearts accepted at the first-rank compared with lower-rank positions.Variability in heart allograft acceptance rates appears to exist among transplant centers, with candidates listed at lower acceptance rate centers being more likely to experience mortality while on the waitlist. Comparable posttransplant survival suggests that allografts that were declined as a first offer perform as well as those that were accepted at their first offer. These findings suggest that organ acceptance rate or time to transplant from being added to the waitlist may be an additional measure of heart transplant program performance.
miR-1293, a Candidate for miRNA-Based Cancer Therapeutics, Simultaneously Targets BRD4 and the DNA Repair Pathway
Authors: Yuki Takagawa, Yasuyuki Gen, Tomoki Muramatsu, Kousuke Tanimoto, Jun Inoue, Hiroyuki Harada, Johji Inazawa
Journal: Molecular Therapy (2020)

BRD4, a member of the bromodomain and extra-terminal domain (BET) protein family, plays a role in the organization of super-enhancers and transcriptional activation of oncogenes in cancer and is recognized as a promising target for cancer therapy. microRNAs (miRNAs), endogenous small noncoding RNAs, cause mRNA degradation or inhibit protein translation of their target genes by binding to complementary sequences. miRNA mimics simultaneously targeting several tumor-promoting genes and BRD4 may be useful as therapeutic agents of tumor-suppressive miRNAs (TS-miRs) for cancer therapy. To investigate TS-miRs for the development of miRNA-based cancer therapeutics, we performed function-based screening in 10 cancer cell lines with a library containing 2,565 human miRNA mimics. Consequently, miR-1293, miR-876-3p, and miR-6571-5p were identified as TS-miRs targeting BRD4 in this screening. Notably, miR-1293 also suppressed DNA repair pathways by directly suppressing the DNA repair genes APEX1 (apurinic-apyrimidinic endonuclease 1), RPA1 (replication protein A1), and POLD4 (DNA polymerase delta 4, accessory subunit). Concurrent suppression of BRD4 and these DNA repair genes synergistically inhibited tumor cell growth in vitro. Furthermore, administration of miR-1293 suppressed in vivo tumor growth in a xenograft mouse model. These results suggest that miR-1293 is a candidate for the development of miRNA-based cancer therapeutics.
Anticipating a New Era in Heart Transplantation
Authors: Clyde W. Yancy, Gregg C. Fonarow
Journal: JAMA Cardiology (2020)

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Renal Recovery After Acute Kidney Injury and Long-term Outcomes
Authors: Ravindra L. Mehta
Journal: JAMA Network Open (2020)

Pavan K. Bhatraju, MD, MSc; Leila R. Zelnick, PhD; Vernon M. Chinchilli, PhD; Dennis G. Moledina, MD, PhD; Steve G. Coca, DO, MS; Chirag R. Parikh, MD, PhD; Amit X. Garg, MD; Chi-yuan Hsu, MD, MSc; Alan S. Go, MD; Kathleen D. Liu, MD, PhD; T. Alp Ikizler, MD; Edward D. Siew, MD, MS; James S. Kaufman, MD; Paul L. Kimmel, MD; Jonathan Himmelfarb, MD; Mark M. Wurfel, MD, PhD
Response by Petzold et al to Letter Regarding Article, “Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1”
Authors: Tobias Petzold, Manuela Thienel, Lisa Dannenberg, Philipp Mourikis, Carolin Helten, Aysel Ayhan, René M’Pembele, Alina Achilles, Kajetan Trojovky, Zhe Zhang, Ron Regenauer, Joachim Pircher, Andreas Ehrlich, Enzo Lüsebrink, Leo Nicolai, Thomas J. Stocker, Richard Brandl, Franz Röschenthaler, Jan Strecker, Inas Saleh, Michael Spannagl, Christoph H. Mayr, Herbert B. Schiller, Christian Jung, Norbert Gerdes, Till Hoffmann, Bodo Levkau, Thomas Hohlfeld, Tobias Zeus, Christian Schulz, Malte Kelm, Amin Polzin
Journal: Circulation Research (2020)
Lung Function Trajectories Leading to Chronic Obstructive Pulmonary Disease as Predictors of Exacerbations and Mortality
Authors: Jacob Louis Marott, Truls Sylvan Ingebrigtsen, Yunus Çolak, Jørgen Vestbo, Peter Lange
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Chronic obstructive pulmonary disease (COPD) can develop not only through a lung function trajectory dominated by an accelerated decline of FEV1 from normal maximally attained FEV1 in early adulthood (normal maximally attained FEV1 trajectory) but also through a trajectory with FEV1 below normal in early adulthood (low maximally attained FEV1 trajectory).Objectives: To test whether the long-term risk of exacerbations and mortality differs between these two subtypes of COPD.Methods: The cohort included 1,170 young adults enrolled in the Copenhagen City Heart Study during the 1970s and 1980s. In 2001–2003, which served as the baseline for the present analyses, 79 participants had developed COPD through normal maximally attained FEV1 trajectory, 65 had developed COPD through low maximally attained FEV1 trajectory, and 1,026 did not have COPD.Measurements and Main Results: From 2001 until 2018, we observed 139 severe exacerbations of COPD and 215 deaths, of which 55 were due to nonmalignant respiratory disease. In Cox models, there was no difference with regard to risk of severe exacerbations between the two trajectories, but individuals with normal maximally attained FEV1 had an increased risk of nonmalignant respiratory disease mortality (using inverse probability of censoring weighting with adjusted hazard ratio [HR], 6.20; 95% confidence interval [CI], 2.09–18.37; P = 0.001) and all-cause mortality (adjusted HR, 1.93; 95% CI, 1.14–3.26; P = 0.01) compared with individuals with low maximally attained FEV1.Conclusions: COPD developed through normal maximally attained FEV1 trajectory is associated with an increased risk of respiratory and all-cause mortality compared with COPD developed through low maximally attained FEV1 trajectory.
Association of Premorbid Blood Pressure with Vasopressor Infusion Duration in Patients with Shock
Authors: Hayley B. Gershengorn, Henry T. Stelfox, Daniel J. Niven, Hannah Wunsch
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Guidelines for vasopressor titration suggest a universal target-mean arterial pressure (MAP) >65 mm Hg. The implications for patients with premorbid low/high blood pressure are unknown.Objectives: To investigate the relationship between premorbid blood pressure and vasopressor duration for patients with shock.Methods: We performed a retrospective cohort study of adults admitted with shock to Calgary ICUs (June 2012-December 2018). The primary exposure was premorbid blood pressure: low (systolic <100); normal (systolic 100-139 and diastolic <90); and high (systolic ≥140 or diastolic ≥90). The primary outcome was vasopressor duration; secondary outcomes included ICU/hospital length of stay and ICU/hospital mortality. We examined associations of premorbid blood pressure with vasopressor duration and length of stay using multivariable competing risk models and mortality using multivariable mixed-effects logistic regression.Measurements and Main Results: Of 3,542 admissions with shock, 177 (5.0%) had premorbid low, 2,887 (81.5%) normal, and 478 (13.5%) high blood pressure. Premorbid low admissions had lower MAPs (vs. normal or high premorbid admissions) over the duration of vasopressor use (P = 0.003) and were maintained nearest premorbid MAPs while receiving vasopressors (P < 0.001). After adjustment, premorbid low admissions had longer vasopressor use (median, 1.35 d vs. 1.04 d for normal; hazard ratio for discontinuation vs. normal, 0.78 [0.73-0.85]; P < 0.001) and premorbid high admissions had shorter use (median, 0.84 d; hazard ratio, 1.22 [1.12-1.33]; P < 0.001). Premorbid low admissions had longer adjusted length of stay and higher adjusted mortality than premorbid normal admissions.Conclusions: Premorbid blood pressure was inversely associated with vasopressor duration.
SR9009 induces a REV-ERB dependent anti-small-cell lung cancer effect through inhibition of autophagy
Authors: Weitao Shen, Wei Zhang, Weilin Ye, Haihong Wang, Qingxi Zhang, Jie Shen, Qingsha Hong, Xiang Li, Ge Wen, Ting Wei, Jian Zhang
Journal: Theranostics (2020)

Rationale: The circadian clock coordinates cell proliferation and metabolism and impacts the progression of some diseases, particularly cancer. Pharmacological modulation of the circadian machinery may be an effective therapeutic approach for treating cancer. SR9009 is a specific synthetic agonist of the REV-ERBs, essential circadian clock components. However, the potential efficacy and antitumor mechanism of this drug in small-cell lung cancer (SCLC) remains poorly understood. Methods: Here, we used chemosensitive cells (H69 and H446) and the corresponding chemoresistant cells (H69AR and H446DDP) to assess the efficacy of the REV-ERB agonist SR9009 for the treatment of SCLC in vitro and further validated the antitumor effect in subcutaneous tumor models of SCLC. Then, we determined whether REV-ERBα was correlated with the anti-SCLC effect of SR9009. Chromatin immunoprecipitation (ChIP) sequencing assays were conducted to identify potential DNA sequences directly regulated by REV-ERBα. Autophagy regulation by REV-ERBα and its possible mechanism in SR9009-based SCLC therapy were analyzed. Results: Here, we showed that the REV-ERB agonist SR9009 is specifically lethal to both chemosensitive and chemoresistant SCLC cells. REV-ERBα was involved in the antitumor effect of SR9009 in SCLC. The core autophagy gene Atg5 was identified as a direct downstream target of REV-ERBα and was suppressed by the REV-ERB agonist SR9009 in SCLC. Furthermore, the interaction of REV-ERBα with this autophagy gene impaired autophagy activity, leading to SR9009 cytotoxicity in SCLC cells. Principal conclusions: Our study provided a novel viewpoint indicating that the REV-ERB agonist SR9009 could be a novel and promising therapeutic strategy in first- or second-line SCLC treatment. The anti-SCLC effect of SR9009 is mediated by REV-ERB dependent suppression of autophagy via direct repression of the autophagy gene Atg5.
Cardiopulmonary Resuscitation During the COVID-19 Pandemic
Authors: Ersilia M. DeFilippis, Lauren S. Ranard, David D. Berg
Journal: Circulation (2020)

hen we entered cardiology training, we never expected to think of our own safety before initiating chest compressions on a pulseless patient.Yet, the novel coronavirus disease 2019 (COVID-19) pandemic has raised new questions, including issues of clinician safety during cardiopulmonary resuscitation (CPR).CPR and endotracheal intubation are aerosol-generating procedures.According to the Centers for Disease Control and Prevention, aerosolizing procedures should be performed with personal protective equipment (PPE) consisting of eye protection, N95 respirators, gloves, and gowns in airborne infection isolation rooms given the higher risk of viral transmission. 1In New York City, the need for intensive care unit capacity has surpassed the number of negative-pressure rooms.Most intubated patients are placed in non-negative-pressure rooms where CPR should, in theory, be avoided given the risks of dislodgement of the endotracheal tube and aerosolization of secretions.Furthermore, there are already dramatic PPE shortages.These resource constraints challenge our ability to comply with Centers for Disease Control and Prevention recommendations.Because of the complex realities of resuscitation in the COVID-19 era, we encourage a national conversation on the following 4 points.First, how can we better identify patients who would not want CPR?As clinicians, one of our priorities has been, and continues to be, to provide patients with care aligned with their values and preferences in the event that they become critically ill.Advanced care planning is more imperative now than ever, particularly among older adults with chronic, life-limiting illnesses who are at higher risk for severe infection.Ideally, these conversations should occur before patients become infected and present to the hospital.Primary care clinicians or specialists who have longitudinal relationships with patients can address advanced care planning during outpatient visits scheduled for other reasons or during dedicated telemedicine visits. 2 In addition, patients and families can be directed to online resources to guide these conversations and to facilitate completion of physician order for life-sustaining treatments forms. 2 At the time of hospital admission, all patients should have conversations with their clinicians about goals of care and preferences for resuscitation, regardless of their CO-VID-19 status; however, these conversations should be prioritized in older patients with multiple comorbidities who test positive.Some institutions have also created palliative care telehealth services to assist frontline clinicians with reaching out to family members beginning in the emergency room.These services can dedicate time to having these important family discussions via phone or video conference because most hospitals now restrict inpatient visitation.Whenever feasible, primary team members should also partake in these conversations and revisit goals of care as a patient's clinical status changes.