tbuckley/cabot-search huggingface dataset:
“Should we be generous in peritonectomy?”: First prospective comparative analysis of total versus involved field parietal peritonectomy in CRS-HIPEC for peritoneal surface malignancies from COLO-rectal cancer—ISPSM collaboration study.
Authors: S.P. Somashekhar, Rohit Kumar C, Shabber Zaveri, Ashwin K Rajgopal, Amit Rauthan, Vijay Ahuja, Ramya Yethadka
Journal: Journal of Clinical Oncology (2019)

633 Background: Peritonectomy is the important components in management of peritoneal surface malignancies (PSM). Immunofluoresecne study done after involved field peritonectomy (IFP) has showed diease in areas not suspected on gross examination stressing the need for total parietal peritonectomy (TPP) for complete cytoreduction. The aim of this study was to assess the morbidity &amp; mortality, recurrence pattern &amp; oncological outcomes of extent of parietal peritonectomy with CRS &amp; HIPEC for colorectal carcinoma. Methods: Patients with PSM from CRC underwent TPP or IFP with CRS- HIPEC. Pre &amp; intraoperative data were analyzed with main focus on postoperative morbidity, mortality, recurrence pattern and oncological outcomes. Results: 40 cases of CRC of which four upfront, 17 interval and 19 recurrent cases. 19 &amp; 21 patients underwent TPP &amp; IFP respectively. Base line characteristics were comparable except median PCI (17 versus 12). TPP group had longer duration of surgery (11 vs 9), more blood loss (1300 vs 700 ml) increased diaphragmatic resections ( 46.2% vs 14.2%), multivisceral resection ( 46.2% vs 28.5%). Number of bowel resections, anastomosis and stoma were comparable. Overall TPP group had more G3-G5 morbidity (46.1% vs 35.7%) &amp; surgical morbidity (30.7% vs 21.5%) . TPP group had increased pleural &amp; intra-abdominal collections which needed intervention. With a median follow up of 30 months, DFS was significantly higher in TPP group (12months vs 8months, p &lt; 0.01) and median overall survival was 21 months in IFP group (yet to be achieved in TPP group). TPP group had most of the recurrences in visceral liver &amp; lung (50.0%) followed by peritoneal (37.5%) &amp; nodal (12.5%) whereas in IFP it was peritoneum (42.8%), visceral ( 38.4%) &amp; nodal (15.3%). Conclusions: It is the first prospective comparative study done on total parietal peritonectomy in PSM of colorectal cancer origin. TPP group had significantly higher DFS, with comparable postoperative morbidity. However, longer follow up and a prospective multi-institutional randomized study needs to be designed for more evidence of the same.
Abstract 15057: High Level of Adherence to Alirocumab and Concomitant Background Treatments for Patients With Heterozygous Familial Hypercholesterolemia in the ODYSSEY Open-Label Extension Study
Authors: Michel A Farnier, G. Kees Hovingh, Gisle Langslet, Robert Dufour, Marie T Baccara-Dinet, Chantal Din-Bell, Garen Manvelian, John R Guyton
Journal: Circulation (2017)

Introduction: Non-adherence to lipid-lowering therapies (LLTs) is associated with adverse outcomes in patients with cardiovascular disease. The ongoing ODYSSEY open-label extension (OLE) study (NCT...
Cholesteryl Ester Transfer Protein Inhibition for Preventing Cardiovascular Events
Authors: Jane Armitage, Michael V. Holmes, David Preiss
Journal: Journal of the American College of Cardiology (2019)

Cholesteryl ester transfer protein (CETP) facilitates exchange of triglycerides and cholesteryl ester between high-density lipoprotein (HDL) and apolipoprotein B100-containing lipoproteins. Evidence from genetic studies that variants in the CETP gene were associated with higher blood HDL cholesterol, lower low-density lipoprotein cholesterol, and lower risk of coronary heart disease suggested that pharmacological inhibition of CETP may be beneficial. To date, 4 CETP inhibitors have entered phase 3 cardiovascular outcome trials. Torcetrapib was withdrawn due to unanticipated off-target effects that increased risk of death, and major trials of dalcetrapib and evacetrapib were terminated early for futility. In the 30,000-patient REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, anacetrapib doubled HDL cholesterol, reduced non-HDL cholesterol by 17 mg/dl (0.44 mmol/l), and reduced major vascular events by 9% over 4 years, but anaceptrapib was found to accumulate in adipose tissue, and regulatory approval is not being sought. Therefore, despite considerable initial promise, CETP inhibition provides insufficient cardiovascular benefit for routine use.
Characteristics of Deceased Solid Organ Donors and Screening Results for Hepatitis B, C, and Human Immunodeficiency Viruses — United States, 2010–2017
Authors: Winston E. Abara, Melissa G. Collier, Anne Moorman, Danae Bixler, Jefferson Jones, Pallavi Annambhotla, James Bowman, Marilyn E. Levi, John T. Brooks, Sridhar V. Basavaraju
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

The ongoing U.S. opioid crisis has resulted in an increase in drug overdose deaths and acute hepatitis C virus (HCV) infections, with young persons (who might be eligible organ donors) most affected.*,† In 2013, the Public Health Service released a revised guideline to reduce the risk for unintended organ transplantation-associated hepatitis B virus (HBV), HCV, and human immunodeficiency virus (HIV) transmission (1). The guideline describes criteria to categorize donors at increased risk (increased risk donors [IRDs]) for transmitting these viruses to recipients (1). It also recommends universal donor testing for HBV, HCV, and HIV.§ CDC analyzed deceased donor data for the period 2010-2017 reported to the Organ Procurement and Transplantation Network for IRDs and standard risk donors (SRDs) (i.e., donors who do not meet any of the criteria for increased risk designation). During this period, the proportion of IRDs increased approximately 200%, from 8.9% to 26.3%; the percentage with drug intoxication reported as the mechanism of death also increased approximately 200%, from 4.3% to 13.4%; and the proportion of these donors with reported injection drug use (IDU) increased approximately 500%, from 1.3% to 8.0%. Compared with SRDs, IRDs were significantly more likely to have positive HBV and HCV screening results. These findings demonstrate the continuing need for identifying viral bloodborne pathogen infection risk factors among deceased donors to reduce the risk for transmission, monitor posttransplant infection in recipients, and offer treatment if infection occurs.
Biospecimens, Research Consent, and Distinguishing Cell Line Research
Authors: Kayte Spector-Bagdady, Holly Fernandez Lynch, J. Chad Brenner, Andrew G. Shuman
Journal: JAMA Oncology (2019)

Newly revised regulations for human research affecting translational oncology will become effective in January 2019. A substantial component of the debate leading to this revision was how to regulate biospecimen research; specifically, whether all biospecimens should be considered inherently "identifiable," thereby necessitating informed consent for use in research. The famous cases seminal to this discussion involve cancer cell lines, but the unique features of this kind of biospecimen research were largely missing from the regulatory deliberation. However, special aspects of cell line research-at the stages of procurement, generation, evolution, and sharing-alter how society should balance participant interests against the goals of research. Recommendations are offered to cancer researchers and policymakers going forward to enable ethically appropriate regulation of biospecimen research across its diverse spectrum.
Phase I/II trial of perioperative avelumab in combination with chemoradiation in the treatment of stage II/III resectable esophageal cancer.
Authors: Nataliya Volodymyrivna Uboha, James D. Maloney, Daniel McCarthy, Dustin A. Deming, Noelle K. LoConte, Kristina Matkowskyj, Jens C. Eickhoff, Daniel Mulkerin, Malcolm M. DeCamp, Sam Joseph Lubner, Anita Ahmed Turk, Michael Frederick Bassetti
Journal: Journal of Clinical Oncology (2019)

TPS181 Background: Neoadjuvant chemoradiation (CRT) followed by resection is the standard treatment for patients with stage II and III esophageal cancer. However, about 50% of patients develop recurrent disease after treatment completion. Patients with residual disease at the time of resection (~ 75%) and especially those with persistent lymph node involvement have the worst prognosis. Hence, novel strategies are needed to improve outcomes. A number of preclinical and clinical studies demonstrated synergism between radiation and immunotherapy. In esophageal cancers, CRT has been shown to alter tumor microenvironment with upregulation of PD-L1 expression and increase in CD8+ T lymphocyte infiltration. Immune checkpoint inhibitors have demonstrated promising activity in metastatic gastroesophageal cancer. Utilizing these agents in earlier disease stages and combining with chemoradiation may increase their efficacy by taking advantage of potential synergism with radiation. This trial will evaluate safety and efficacy of avelumab in combination with CRT in resectable esophageal cancer. Methods: This is a two-part phase I/II clinical trial evaluating safety and efficacy of perioperative avelumab plus CRT in patients with resectable esophageal cancer. This trial will enroll a total of 24 subjects with untreated resectable esophageal cancer (including gastroesophageal junction). Part 1 will be a run-in phase that enrolls 6 patients for safety evaluation. Part 2 will enroll 18 additional patients for efficacy and additional safety evaluation. The primary endpoint for the phase II component is the pathological complete response rate. Subjects will receive neoadjuvant radiation (41.4 Gy in 23 fractions) with weekly carboplatin (AUC 2) and paclitaxel (50 mg/mg2). Three doses of avelumab (10 mg/kg, every 14 days) will be administered starting on day 29 of treatment, to coincide with the last chemotherapy dose. Esophagectomy will be performed ~ 8 weeks after CRT completion. Subjects will receive 8 doses of avelumab after resection. This study is actively enrolling patients at University of Wisconsin. Clinical trial information: NCT03490292.
Intralesional sodium stibogluconate under inhaled anesthesia for the treatment of cutaneous leishmaniasis in children: A retrospective cohort
Authors: Yael Renert-Yuval, Claes D. Enk, Sari Murad, Valerie Yofe, David Gozal, Vered Molho-Pessach
Journal: Journal of the American Academy of Dermatology (2019)
Abstract 135: Effectiveness Of Live Vaccines Following Intravenous Immune Globulin Therapy During The Convalescent Phase Of Kawasaki Disease Using The Schedule Recommended In Japan
Authors: Yoshihiko Morikawa, Masaru Miura, Hiroshi Sakakibara
Journal: Circulation (2015)

Background: There are differences between Japan and the United States regarding recommended timing of live virus vaccinations after treatment of Kawasaki disease patients with intravenous immune globulin (IVIG): 6 months in Japan and 11 months in the U.S. The prevalence of antibodies to these vaccines using either vaccination schedule remains undetermined. Objective: The present study aimed to evaluate the effectiveness of the live virus vaccination schedule for Kawasaki disease recommended in Japan. Methods: This was a prospective observational study. Kawasaki disease patients aged 6 months and older without past history of or vaccination against measles, rubella, varicella-zoster (VZ), or mumps were enrolled. The children were vaccinated against measles, rubella, VZ, and mumps 6 months after IVIG. Serologic tests for IgG-class specific antibodies to each vaccine virus were performed prior to IVIG; 2 days, 3 months, and 6 months after IVIG, and 3 months after vaccination. The primary outcome was seroprevalence of positive antibodies, which was defined as serum concentration more than 4 IU/mL. Results: A total of 24 children (mean month age 16.8 ± 2.7 at vaccinations, 70.8% male) were enrolled. The rate of measles, rubella, VZ, and mumps seropositivity was 12.5% (3/24), 0% (0/24), 12.5% (3/24), and 0% (0/24), respectively, just before vaccination. The rate increased to 91.7% (22/24), 87.5% (21/24), 20.8% (5/24), and 8.3% (2/24), respectively, 3 months after vaccination. There were no serious adverse events. Conclusions: Use of the Japanese vaccination schedule led to extremely low seroprevalence of VZ and mumps antibodies but acceptable seroprevalence of measles and rubella antibodies. This study is ongoing and more cases (up to 30, the target sample size) are needed before the appropriateness of the timing of vaccination in Japan can be discussed.
Variant <i>PADI3</i> in Central Centrifugal Cicatricial Alopecia
Authors: Liron Malki, Ofer Sarig, Maria-Teresa Romano, Marie-Claire Mechin, Alon Peled, Mor Pavlovsky, Emily Warshauer, Liat Samuelov, Laura Uwakwe, Valeria Briskin, Janan Mohamad, Andrea Gat, Ofer Isakov, Tom Rabinowitz, Noam Shomron, Noam Adir, Michel Simon, Amy Mcmichael, Ncoza C Dlova, Regina C Betz, Eli Sprecher
Journal: New England Journal of Medicine (2019)

Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring alopecia among women of African ancestry. The disease is occasionally observed to affect women in families in a manner that suggests an autosomal dominant trait and usually manifests clinically after intense hair grooming. We sought to determine whether there exists a genetic basis of CCCA and, if so, what it is.
Updated Report on Identification of Molecular Predictors of Tazemetostat Response in an Ongoing NHL Phase 2 Study
Authors: Alice McDonald, Elizabeth Thomas, Scott Daigle, Franck Morschhauser, Gilles Salles, Vincent Ribrag, Pamela McKay, Herve Tilly, Anna Schmitt, Connie Lee Batlevi, Christophe Fruchart, Peter Johnson, Michael Dickinson, Stephen Opat, Wojciech Jurczak, Guillaume Cartron, Thierry Lamy, Pier Luigi Zinzani, Sarit Assouline, John Radford, John G. Gribben, Corinne Haioun, Aristeidis Chaidos, Steven Le Gouill, Alicia Clawson, John Larus, Stephen J Blakemore
Journal: Blood (2018)
Association of L-plastin Expression With Recalcitrant Nasal Polyps In The Patients With Aspirin-Exacerbated Respiratory Disease
Authors: Tetsuji Takabayashi, Yukie Tanaka, Masafumi Sakashita, Yoshimasa Imoto, Kanako Yoshida, Yukinori Kato, Robert P. Schleimer, Shigeharu Fujieda
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 24059: Optogenetic-induced Mitochondrial Membrane Potential Depolarization and Targeting Cell Death
Authors: Patrick Ernst, Ningning Xu, KahYong Goh, Brian O'Rourke, Jianyi J Zhang, Margaret X Liu, Lufang Zhou
Journal: Circulation (2017)

Introduction: There is growing evidence that mitochondrial dysfunction is closely associated with the development of cardiovascular diseases, although the precise mechanism is not well defined. Normal functioning of mitochondria relies on maintaining the inner membrane potential ( a.k.a. ΔΨ m ) to drive oxidative phosphorylation and redox balance. Thus, developing a tool to induce controlled mitochondrial depolarization and examine the effects on downstream intracellular processes will lead to critical information that helps to reveal the mechanisms underlying mitochondria-induced cellular dysfunction. Methods and Results: In this study, we developed a new generation optogenetic-based technique for targeting mitochondrial depolarization with light. Particularly, a heterologous light-gated channelrhodopsin protein, named ChR2, was targeted to and expressed on the inner mitochondrial membrane (IMM). We showed that ChR2 formed functional cationic channels on IMM with properties similar to that on the plasma membrane, allowing light-induced targeting ΔΨ m depolarization. We also showed that sustained moderate light illumination caused significant cell death in mitochondrial ChR2-expressing cells but not in the mock transfected or mitochondrial YFP-expressing cells. Finally, we provided evidence that the mitochondrial optogenetic-induced cell death is via apoptosis and is independent of the opening of the permeability transition pore. Conclusion: This new generation optogenetic tool can be used to study the mechanisms how a change of mitochondrial membrane permeability influences cell and organ functions.
Transcription factor mutations as a cause of familial myeloid neoplasms
Authors: Jane E. Churpek, Emery H. Bresnick
Journal: Journal of Clinical Investigation (2019)

The initiation and evolution of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are driven by genomic events that disrupt multiple genes controlling hematopoiesis. Human genetic studies have discovered germline mutations in single genes that instigate familial MDS/AML. The best understood of these genes encode transcription factors, such as GATA-2, RUNX1, ETV6, and C/EBPα, which establish and maintain genetic networks governing the genesis and function of blood stem and progenitor cells. Many questions remain unanswered regarding how genes and circuits within these networks function in physiology and disease and whether network integrity is exquisitely sensitive to or efficiently buffered from perturbations. In familial MDS/AML, mutations change the coding sequence of a gene to generate a mutant protein with altered activity or introduce frameshifts or stop codons or disrupt regulatory elements to alter protein expression. Each mutation has the potential to exert quantitatively and qualitatively distinct influences on networks. Consistent with this mechanistic diversity, disease onset is unpredictable and phenotypic variability can be considerable. Efforts to elucidate mechanisms and forge prognostic and therapeutic strategies must therefore contend with a spectrum of patient-specific leukemogenic scenarios. Here we illustrate mechanistic advances in our understanding of familial MDS/AML syndromes caused by germline mutations of hematopoietic transcription factors.
Abstract 20310: Excess All-Cause and Cardiovascular Morbidity Associated With Overweight and Obesity: Findings From the Chicago Heart Detection Project in Industry Study
Authors: Sadiya S Khan, Donald M Lloyd-Jones, Lihui Zhao, Lei Liu, Martha Daviglus, Kiang Liu, James F Fries, Tina Shih, Daniel Garside, Thanh Huyen Vu, Jeremiah Stamler, Norrina B Allen
Journal: Circulation (2016)

Background: We sought to determine the association of body-mass index (BMI) in younger adulthood with life lived free of morbidity and cumulative burden of all-cause and cardiovascular (CV) morbidity through older adulthood. Methods: Participants (N=25,930) from the Chicago Heart Association (CHA) study, a longitudinal cohort of employed men and women recruited from 1967-1973, ages 18-59 years at baseline were included. Linked CMS/NDI data from 1984-2010 were used to determine morbidity after age 65 from all participants enrolled in Medicare. Individuals were classified by BMI at baseline and analyses were adjusted for age, sex, race, education, smoking, hypertension, hyperlipidemia, and diabetes. All-cause morbidity was defined using the Gagne score. A CV morbidity score was defined as the sum of coronary heart disease, peripheral vascular disease, stroke, and heart failure diagnoses. Results: Participants were 41% female and 8% African American; mean age was 43±11 years. Two percent were underweight, 43...
Abstract 15: Glucose-Mediated Remodeling of Cardiac DNA Methylation
Authors: Mark E Pepin, David K Crossman, Joseph P Barchue, Salpy V Pamboukian, Steven M Pogwizd, Adam R Wende
Journal: Circulation Research (2017)

To identify the role of glucose in the development of diabetic cardiomyopathy, we had directly assessed glucose delivery to the intact heart on alterations of DNA methylation and gene expression using both an inducible heart-specific transgene (glucose transporter 4; mG4H) and streptozotocin-induced diabetes (STZ) mouse models. We aimed to determine whether long-lasting diabetic complications arise from prior transient exposure to hyperglycemia via a process termed “glycemic memory.” We had identified DNA methylation changes associated with significant gene expression regulation. Comparing our results from STZ, mG4H, and the modifications which persist following transgene silencing, we now provide evidence for cardiac DNA methylation as a persistent epigenetic mark contributing to glycemic memory. To begin to determine which changes contribute to human heart failure, we measured both RNA transcript levels and whole-genome DNA methylation in heart failure biopsy samples (n = 12) from male patients collected at left ventricular assist device placement using RNA-sequencing and Methylation450 assay, respectively. We hypothesized that epigenetic changes such as DNA methylation distinguish between heart failure etiologies. Our findings demonstrated that type 2 diabetic heart failure patients (n = 6) had an overall signature of hypomethylation, whereas patients listed as ischemic (n = 5) had a distinct hypermethylation signature for regulated transcripts. The focus of this initial analysis was on promoter-associated CpG islands with inverse changes in gene transcript levels, from which diabetes (14 genes; e.g. IGFBP4) and ischemic (12 genes; e.g. PFKFB3) specific targets emerged with significant regulation of both measures. By combining our mouse and human molecular analyses, we provide evidence that diabetes mellitus governs direct regulation of cellular function by DNA methylation and the corresponding gene expression in diabetic mouse and human hearts. Importantly, many of the changes seen in either mouse type 1 diabetes or human type 2 diabetes were similar supporting a consistent mechanism of regulation. These studies are some of the first steps at defining mechanisms of epigenetic regulation in diabetic cardiomyopathy.
The Deubiquitylase OTUB1 Mediates Ferroptosis via Stabilization of SLC7A11
Authors: Tong Liu, Le Jiang, Omid Tavana, Wei Gu
Journal: Cancer Research (2019)

Although cell-cycle arrest, senescence, and apoptosis are established mechanisms of tumor suppression, accumulating evidence reveals that ferroptosis, an iron-dependent, nonapoptotic form of cell death, represents a new regulatory pathway in suppressing tumor development. Ferroptosis is triggered by lipid peroxidation and is tightly regulated by SLC7A11, a key component of the cystine-glutamate antiporter. Although many studies demonstrate the importance of transcriptional regulation of SLC7A11 in ferroptotic responses, it remains largely unknown how the stability of SLC7A11 is controlled in human cancers. In this study, we utilized biochemial purification to identify the ubiquitin hydrolase OTUB1 as a key factor in modulating SLC7A11 stability. OTUB1 directly interacted with and stabilized SLC7A11; conversely, OTUB1 knockdown diminished SLC7A11 levels in cancer cells. OTUB1 was overexpressed in human cancers, and inactivation of OTUB1 destabilized SLC7A11 and led to growth suppression of tumor xenografts in mice, which was associated with reduced activation of ferroptosis. Notably, overexpression of the cancer stem cell marker CD44 enhanced the stability of SLC7A11 by promoting the interaction between SLC7A11 and OTUB1; depletion of CD44 partially abrogated this interaction. CD44 expression suppressed ferroptosis in cancer cells in an OTUB1-dependent manner. Together, these results show that OTUB1 plays an essential role in controlling the stability of SLC7A11 and the CD44-mediated effects on ferroptosis in human cancers. SIGNIFICANCE: This study identifies OTUB1 as a key regulator of ferroptosis and implicates it as a potential target in cancer therapy.See related commentary by Gan, p. 1749.