tbuckley/cabot-search huggingface dataset:
Druggable Transcriptional Networks in the Human Neurogenic Epigenome
Authors: Gerald A. Higgins, Aaron M. Williams, Alex S. Ade, Hasan B. Alam, Brian D. Athey
Journal: Pharmacological Reviews (2019)

Chromosome conformation capture methods have revealed the dynamics of genome architecture which is spatially organized into topologically associated domains, with gene regulation mediated by enhancer-promoter pairs in chromatin space. New evidence shows that endogenous hormones and several xenobiotics act within circumscribed topological domains of the spatial genome, impacting subsets of the chromatin contacts of enhancer-gene promoter pairs in <i>cis</i> and <i>trans</i>. Results from the National Institutes of Health-funded PsychENCODE project and the study of chromatin remodeling complexes have converged to provide a clearer understanding of the organization of the neurogenic epigenome in humans. Neuropsychiatric diseases, including schizophrenia, bipolar spectrum disorder, autism spectrum disorder, attention deficit hyperactivity disorder, and other neuropsychiatric disorders are significantly associated with mutations in neurogenic transcriptional networks. In this review, we have reanalyzed the results from publications of the PsychENCODE Consortium using pharmacoinformatics network analysis to better understand druggable targets that control neurogenic transcriptional networks. We found that valproic acid and other psychotropic drugs directly alter these networks, including chromatin remodeling complexes, transcription factors, and other epigenetic modifiers. We envision a new generation of CNS therapeutics targeted at neurogenic transcriptional control networks, including druggable parts of chromatin remodeling complexes and master transcription factor-controlled pharmacogenomic networks. This may provide a route to the modification of interconnected gene pathways impacted by disease in patients with neuropsychiatric and neurodegenerative disorders. Direct and indirect therapeutic strategies to modify the master regulators of neurogenic transcriptional control networks may ultimately help extend the life span of CNS neurons impacted by disease.
Reducing Suicidal Ideation Through Insomnia Treatment (REST-IT): A Randomized Clinical Trial
Authors: William V. McCall, Ruth M. Benca, Peter B. Rosenquist, Nagy A. Youssef, Laryssa McCloud, Jill C. Newman, Doug Case, Meredith E. Rumble, Steven T. Szabo, Marjorie Phillips, Andrew D. Krystal
Journal: American Journal of Psychiatry (2019)

The authors sought to determine whether targeted treatment of insomnia with controlled-release zolpidem (zolpidem-CR) in suicidal adults with insomnia would provide a reduction in suicidal ideation superior to placebo.Reducing Suicidal Ideation Through Insomnia Treatment was an 8-week three-site double-blind placebo-controlled parallel-group randomized controlled trial of zolpidem-CR hypnotic therapy compared with placebo, in conjunction with an open-label selective serotonin reuptake inhibitor. Participants were medication-free 18- to 65-year-olds with major depressive disorder, insomnia, and suicidal ideation. Suicidal ideation was the main outcome, measured first by the Scale for Suicide Ideation and second by the Columbia-Suicide Severity Rating Scale (C-SSRS).A total of 103 participants were randomly assigned to receive zolpidem-CR (N=51) or placebo (N=52) (64 women and 39 men; mean age=40.5 years). Zolpidem-CR had a robust anti-insomnia effect, especially in patients with the most severe insomnia symptoms. No significant treatment effect was observed on the Scale for Suicide Ideation (least squares mean estimate=-0.56, SE=0.83, 95% CI=-2.19, 1.08), but the reduction in scores was significantly positively related to improvement in insomnia after accounting for the effect of other depression symptoms. The C-SSRS indicated that zolpidem-CR had a significant treatment effect (least squares mean estimate=-0.26, SE=0.12, 95% CI=-0.50, -0.02). The advantage for zolpidem-CR in reducing suicidal ideation on the C-SSRS was greater in patients with more severe insomnia. No deaths or suicide attempts occurred.Although the results do not support the routine prescription of hypnotic medication for mitigating suicidal ideation in all depressed outpatients with insomnia, they suggest that coprescription of a hypnotic during initiation of an antidepressant may be beneficial in suicidal outpatients, especially in patients with severe insomnia.
Endoscopic ultrasound-guided pancreatic duct stent placement for symptomatic pancreaticojejunostomy stricture
Authors: Joel Fernandez de Oliveira, Karen Costa Carvalho Gon, Fauze Maluf-Filho
Journal: Endoscopy (2019)

A 57-year-old woman underwent a pancreaticoduodenectomy for a duct-type intraductal papillary mucinous neoplasm in the pancreatic head. She presented 3 years later with recurrent episodes of acute pancreatitis, with computed tomography (CT) revealing swelling of the pancreas remnant and dilation of the pancreatic duct, suggesting pancreaticojejunostomy (PJS) stricture. Endoscopic ultrasound (EUS)-guided pancreatic duct drainage was considered as a viable option for patient management ([Video 1]).
Predictors and early survival outcomes of maximal resection in WHO grade II 1p/19q-codeleted oligodendrogliomas
Authors: Maya Harary, Vasileios K Kavouridis, Matthew Torre, Hasan A Zaidi, Ugonma N Chukwueke, David A Reardon, Timothy R Smith, J Bryan Iorgulescu
Journal: Neuro-Oncology (2019)

Abstract Background Although surgery plays a crucial diagnostic role in World Health Organization (WHO) grade II 1p/19q-codeleted oligodendrogliomas, the role of maximal tumor surgical resection remains unclear, with early retrospective series limited by lack of molecular classification or appropriate control groups. Methods The characteristics, management, and overall survival (OS) of patients ≥20 years old presenting with histology-proven WHO grade II 1p/19q-codeleted oligodendrogliomas during 2010–2016 were evaluated using the National Cancer Database and validated using multi-institutional data. Patients were stratified by watchful waiting (biopsy only) versus surgical resection. OS was analyzed using Kaplan–Meier methods and risk-adjusted proportional hazards. Results Five hundred ninety adults met inclusion criteria, of whom 79.0% (n = 466) underwent surgical resection. Of patient and tumor characteristics, younger patients were more likely to be resected. Achieving gross total resection (GTR; n = 320) was significantly associated with smaller tumors, management at integrated network cancer programs (vs community cancer programs), and Medicare insurance (as compared with no, private, or Medicaid/other government insurance) and independent of other patient or tumor characteristics. In risk-adjusted analyses, GTR, but not subtotal resection (STR), demonstrated improved OS (vs biopsy only: hazard ratio 0.28, 95% CI: 0.09–0.85, P = 0.02). Conclusions WHO grade II 1p/19q-codeleted oligodendrogliomas amenable to resection demonstrated improved OS with GTR, but not STR, compared with biopsy-only watchful waiting. The OS benefits of GTR were independent of age, tumor size, or tumor location. Medicare-insured and integrated network cancer program patients were significantly more likely to have GTR than other patients, suggesting that insurance status and care setting may play important roles in access to timely diagnosis or innovations that improve maximal resection.
Sequentially-accumulated genetic alterations at chromosome 9p21 play a role in melanoma progression
Authors: G. Palmieri, C. Rozzo, A. Manca, A. Cossu, A. Lissia, M. Budroni, G. Botti, S. D'Atri, D. Castiglia, M. C. Sini
Journal: Journal of Clinical Oncology (2007)

8522 Background: Cytogenetic and molecular studies indicated the chromosome 9p21 and its CDKN locus, with the p16/CDKN2A tumor suppressor genes, as the genomic regions involved into the pathogenesis of malignant melanoma (MM). To further elucidate the role of such regions in melanoma, we evaluated the 9p21-linked molecular alterations during the different phases of melanocytic tumorigenesis. Methods: Paraffin-embedded tissue sections from common nevi, dysplastic nevi, and melanomas, including primary and metastatic MM lesion, as well as melanoma cell lines were evaluated by both fluorescence in situ hybridization (FISH) using probes spanning the entire 9p21 region and immunohistochemistry (IHC) for p16/CDKN2A expression. Results: Allelic deletion at the CDKN locus and p16/CDKN2A gene silencing were both observed at increased rates moving from nevi to early or advanced primary melanomas and to correspondent metastases. Dysplastic nevi, primary and secondary melanomas were instead found to be heterozygously deleted at one or more loci within the 9p21 chromosome in a quite similar fraction (55–62%) of cases. Inactivation of the p16/CDKN2A gene was found at rates higher in melanoma cell lines (67%) than in vivo melanomas (62% secondary and 12.5% primary melanomas), with a normal p16/CDKN2A IHC staining in all analyzed nevi. Conclusions: Our findings indicate a model of sequential accumulation of genetic alterations from normal melanocytes to metastatic melanoma, with a) 9p21 allelic loss playing a role in melanocytic transformation and tumor initiation; b) deletions at CDKN locus and p16/ CDKN2A gene inactivation participating to tumor dissemination. Presence of such alterations could be further evaluated as markers of the different phases of melanoma progression. No significant financial relationships to disclose.
Deep learning algorithm predicts diabetic retinopathy progression in individual patients
Authors: Filippo Arcadu, Fethallah Benmansour, Andreas Maunz, Jeff Willis, Zdenka Haskova, Marco Prunotto
Journal: npj Digital Medicine (2019)

Abstract The global burden of diabetic retinopathy (DR) continues to worsen and DR remains a leading cause of vision loss worldwide. Here, we describe an algorithm to predict DR progression by means of deep learning (DL), using as input color fundus photographs (CFPs) acquired at a single visit from a patient with DR. The proposed DL models were designed to predict future DR progression, defined as 2-step worsening on the Early Treatment Diabetic Retinopathy Diabetic Retinopathy Severity Scale, and were trained against DR severity scores assessed after 6, 12, and 24 months from the baseline visit by masked, well-trained, human reading center graders. The performance of one of these models (prediction at month 12) resulted in an area under the curve equal to 0.79. Interestingly, our results highlight the importance of the predictive signal located in the peripheral retinal fields, not routinely collected for DR assessments, and the importance of microvascular abnormalities. Our findings show the feasibility of predicting future DR progression by leveraging CFPs of a patient acquired at a single visit. Upon further development on larger and more diverse datasets, such an algorithm could enable early diagnosis and referral to a retina specialist for more frequent monitoring and even consideration of early intervention. Moreover, it could also improve patient recruitment for clinical trials targeting DR.
Sexual Dimorphism and Sex Steroids Influence Cardiovascular Autonomic Neuropathy in Patients With Type 1 Diabetes
Authors: Lía Nattero-Chávez, Sara Alonso Díaz, Lucía Jiménez-Mendiguchia, Ana García-Cano, Elena Fernández-Durán, Beatriz Dorado Avendaño, Héctor F. Escobar-Morreale, Manuel Luque-Ramírez
Journal: Diabetes Care (2019)

The male predominance of cardiovascular disease is overridden by the presence of diabetes, as the sex-related burden of cardiovascular disease increases in postmenopausal women with diabetes (1). Sexual dimorphism in cardiovascular autonomic neuropathy (CAN) might contribute to these findings (1).

We conducted a cross-sectional study hypothesizing that 1 ) the prevalence of CAN is different among women and men with type 1 diabetes, 2 ) such a difference is dependent on the pre- or postmenopausal status of women, and 3 ) sex steroids show opposite associations with CAN depending on sex.

In this study, we recruited 279 consecutive patients with type 1 diabetes attending our clinic (ClinicalTrials.gov identifier NCT02910271) (2,3). Inclusion and exclusion criteria are detailed elsewhere (2,3). Assuming a global prevalence of CAN of ∼30% in our population of patients with type 1 diabetes (2) and setting α at 0.05 and β at 0.20 for a two-sided test, the inclusion of at least 160 men and 120 women was enough to identify a difference in prevalence among them above 15% (www.imim.cat/ofertadeserveis/software-public/granmo/).

The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the local ethics committee of Hospital Universitario Ramon y Cajal (approval date 22 January 2016, protocol ID 464/15). Informed consent was obtained from all participants included in the study. Patients did not receive any economic compensation for their participation.

For …
Universal norm psychology leads to societal diversity in prosocial behaviour and development
Authors: Bailey R. House, Patricia Kanngiesser, H. Clark Barrett, Tanya Broesch, Senay Cebioglu, Alyssa N. Crittenden, Alejandro Erut, Sheina Lew-Levy, Carla Sebastian-Enesco, Andrew Marcus Smith, Süheyla Yilmaz, Joan B. Silk
Journal: Nature Human Behaviour (2019)
Hypoxia‐Inducible Factor‐2α Reprograms Liver Macrophages to Protect Against Acute Liver Injury Through the Production of Interleukin‐6
Authors: Rachel Y. Gao, Meng Wang, Qihui Liu, Dechun Feng, Yankai Wen, Yang Xia, Sean P. Colgan, Holger K. Eltzschig, Cynthia Ju
Journal: Hepatology (2019)

Background and Aims Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one third of patients in the United States. The effectiveness of the only antidote, N ‐acetylcysteine, declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover targets for therapeutic interventions. Approach and Results We observed that APAP challenge caused stabilization of hypoxia‐inducible factors (HIFs) in the liver and hepatic macrophages (MΦs), particularly HIF‐2α. Genetic deletion of the HIF‐2α gene in myeloid cells (HIF‐2α mye/− ) markedly exacerbated APAP‐induced liver injury (AILI) without affecting APAP bioactivation and detoxification. In contrast, hepatic and serum levels of the hepatoprotective cytokine interleukin 6 (IL‐6), its downstream signal transducer and transcription factor 3 activation in hepatocytes, as well as hepatic MΦ IL‐6 expression were markedly reduced in HIF‐2α mye/− mice compared to wild‐type mice post‐APAP challenge. In vitro experiments revealed that hypoxia induced IL‐6 production in hepatic MΦs and that such induction was abolished in HIF‐2α‐deleted hepatic MΦs. Restoration of IL‐6 by administration of exogenous IL‐6 ameliorated AILI in HIF‐2α mye/− mice. Finally, IL‐6‐mediated hepatoprotection against AILI was abolished in hepatocyte‐specific IL‐6 receptor knockout mice. Conclusions The data demonstrate that APAP treatment leads to HIF‐2α stabilization in hepatic MΦs and that HIF‐2α subsequently reprograms hepatic MΦs to produce the hepatoprotective cytokine IL‐6, thereby ameliorating AILI.
Public Knowledge of Human Papillomavirus and Receipt of Vaccination Recommendations
Authors: Ryan Suk, Jane R. Montealegre, Gizem S. Nemutlu, Alan G. Nyitray, Kathleen M. Schmeler, Kalyani Sonawane, Ashish A. Deshmukh
Journal: JAMA Pediatrics (2019)

This cross-sectional survey study assesses knowledge of human papillomavirus by age and sex.
Huge increase in hospital activity should be “wake-up call,” says acute medicine leader
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Adult critical care admissions to English hospitals have increased by 22% since 2011-12, new figures show.1

A report from NHS Digital details the volume of inpatient, day case, and adult critical care activity in England in 2018-19, based on hospital episode statistics. It reveals the scale of the increase in hospital activity in England over the past decade.

The figures show 291 679 usable critical care records in …
Are Patients With End-Stage Liver Disease Maximally Vasodilated?
Authors: Ahmed Aljizeeri, Mousa Alali Alfaris, Dalia Ahmed, Jabir Farea, Awadelkarim Elneama, Ihab Suliman, Mohsen Alharthi, Amjad Ahmed, Ahmed Alsaileek, Mouaz Al-Mallah
Journal: JACC. Cardiovascular imaging (2019)
Phase I/II Study of Palliative Triple Metronomic Chemotherapy in Platinum-Refractory/Early-Failure Oral Cancer
Authors: Vijay M. Patil, Vanita Noronha, Amit Joshi, Sachin Dhumal, Manoj Mahimkar, Atanu Bhattacharjee, Vikram Gota, Manish Pandey, Nandini Menon, Abhishek Mahajan, Nilesh Sable, Suman Kumar, Kavita Nawale, Sadaf Mukadam, Bhavin Solanki, Sudeep Das, Vijai Simha, George Abraham, Arun Chandrasekharan, Vikas Talreja, Hollis DSouza, Sujay Srinivas, Lakhan Kashyap, Shripad Banavali, Kumar Prabhash
Journal: Journal of Clinical Oncology (2019)

PURPOSE Platinum-resistant oral cancer has a dismal outcome with limited treatment options. We conducted a phase I/II study to identify the optimal biologic dose (OBD) of methotrexate when given along with erlotinib and celecoxib and to assess the efficacy of this three-drug regimen in advanced oral cancer. METHODS Patients with platinum-resistant or early-failure squamous cell carcinoma of the oral cavity were eligible for this study. They were orally administered erlotinib 150 mg once per day, celecoxib 200 mg twice per day, and methotrexate per week. The primary end point of phase I was to determine the OBD of methotrexate, and that of phase II was to determine the 3-month progression-free survival. The OBD of methotrexate was determined on the basis of the clinical benefit rate at 2 months and circulating endothelial cell level at day 8, using a de-escalation model. Pharmacokinetic evaluation was performed during phase I. Phase II consisted of an expansion cohort of 76 patients. RESULTS Fifteen patients were recruited in phase I, and 9 mg/m 2 methotrexate was identified as the OBD. A total of 91 patients were recruited, and the median follow-up was 6.8 months (range, 0 to 16.8 months). The 3-month progression-free survival rate was 71.1% (95% CI, 60.5% to 79.3%), the 6-month overall survival rate was 61.2% (95% CI, 49.2% to 67.8%), and the response rate was 42.9% (95% CI, 33.2% to 53.1%; n = 39). The mean Functional Assessment of Cancer Therapy-Head and Neck Trial Outcome Index score at day 8 was improved by 6.1 units (standard deviation, 13.6 units) and was maintained around this magnitude ( P = .001). CONCLUSION Triple oral metronomic chemotherapy with erlotinib, methotrexate, and celecoxib is efficacious in platinum-refractory oral cavity cancers and represents a new therapeutic option in patients with poor prognosis.
PCC0208017, a novel small-molecule inhibitor of MARK3/MARK4, suppresses glioma progression in vitro and in vivo
Authors: Fangfang Li, Zongliang Liu, Heyuan Sun, Chunmei Li, Wenyan Wang, Liang Ye, Chunhong Yan, Jingwei Tian, Hongbo Wang
Journal: Acta Pharmaceutica Sinica B (2019)

Gliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. In vitro, PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an in vivo glioma model, PCC0208017 showed robust anti-tumor activity, blood–brain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.
Duodenal and liver lesions in an adult with generalised weakness
Authors: David Szafron, Hyun-seok Kim, Christie G Turin, Eduardo Benzi, Natalia Khalaf, Ruben Hernaez
Journal: Gut (2019)

A 73-year-old man with a history of heart failure and hypertension presented with a several-week history of generalised weakness, anorexia, 5 kg weight loss, intermittent small volume hematochezia and right upper quadrant abdominal pain. He denied fever, chills, dysphagia, nausea, vomiting, diarrhoea and constipation. He had no previous endoscopy or colorectal cancer screening.

His admission vital signs were normal. He was anaemic (haemoglobin 8.6 g/dL reference 12–18 g/dL), with mean corpuscular volume 83 (81–100 fL/cell), ferritin 321.9 (11–336 ng/mL), alkaline phosphatase 174 (38–127 IU/L), albumin 2.4 (3.5–4.9 g/dL), total bilirubin 0.8 (0.2–1.2 mg/dL) and aspartate aminotransferase/alanine aminotransferase 28/21 (10–40 U/L, 7–56 U/L). Serological tests for hepatitis and HIV were negative. RPR was negative 1 month previously. CT imaging with intravenous contrast (figure 1) revealed six target-like liver lesions (0.7 to 1 cm) with peripheral arterial enhancement and several enlarged coeliac lymph nodes (largest 0.8 cm). Due to anaemia/hematochezia, upper and lower endoscopy were performed. His oesophagogastroduodenoscopy showed …
Preclinical development of a new leukaemia drug, PENAO
Authors: Pierre Dilda, Wimali Weerakoon, Amanda Philp, John Allen, Richard Lock, Philip Hogg
Journal: Cancer Research (2007)

5593  Arsenic trioxide is a trivalent arsenical that selectively kills acute promyelocytic leukaemia (APL) cells. It is also showing promise for the treatment of myelodysplastic syndrome, a disease for which no standard treatment currently exists. Side effects of arsenic trioxide include QTc prolongation, APL differentiation syndrome, peripheral neuropathies, hepatic dysfunction and gastrointestinal reactions. We have made a water-soluble derivative of arsenic trioxide in an attempt to blunt its side-effects. Eliminating the lipid solubility of arsenic trioxide should reduce its penetration into tissues and help restrict the drug mostly to the intravascular compartment where it acts. Phenylarsenoxide was conjugated to penicillamine to produce PENAO (4-(N-(S-penicillamine acetyl)amino)-phenylarsenoxide). PENAO is a mitochondrial poison. It cross-links closely spaced cysteine thiols on the matrix face of the inner-membrane transporter, adenine nucleotide translocase (ANT). ANT exchanges matrix ATP for cytosolic ADP across the inner-mitochondrial membrane and is the key component of the mitochondrial permeability transition pore. Inactivation of ANT by PENAO triggers mitochondrial permeability transition which results in proliferation arrest and apoptosis of cultured cells. PENAO cellular levels are controlled by export via the ATP- and glutathione-dependent multidrug resistance-associated proteins 1 and 2. PENAO was tested for anti-proliferative and cytotoxic activity on numerous carcinoma and primary cell lines and was found to be selective for APL cells and for some acute lymphoblastic leukaemia (ALL) cells derived from patients. PENAO is equivalent to arsenic trioxide in its effects on APL cells (NB4) and more efficacious than dexamethasone on some ALL cells. PENAO is reasonably well tolerated in mice with a MTD of ≈1mg/kg/day. Plasma PENAO levels peak at ≈15 μM following a single intraperitoneal administration of 1.5 mg/kg PENAO. Studies of the efficacy of PENAO in mouse models of human leukaemia are underway.