tbuckley/cabot-search huggingface dataset:
Colesevelam attenuates cholestatic liver and bile duct injury in <i>Mdr2<sup>−/−</sup></i> mice by modulating composition, signalling and excretion of faecal bile acids
Authors: Claudia Daniela Fuchs, Gustav Paumgartner, Veronika Mlitz, Victoria Kunczer, Emina Halilbasic, Nadja Leditznig, Annika Wahlström, Marcus Ståhlman, Andrea Thüringer, Karl Kashofer, Tatjana Stojakovic, Hanns-Ulrich Marschall, Michael Trauner
Journal: Gut (2018)

Background and aims Interruption of the enterohepatic circulation of bile acids (BAs) may protect against BA-mediated cholestatic liver and bile duct injury. BA sequestrants are established to treat cholestatic pruritus, but their impact on the underlying cholestasis is still unclear. We aimed to explore the therapeutic effects and mechanisms of the BA sequestrant colesevelam in a mouse model of sclerosing cholangitis. Methods Mdr2 −/− mice received colesevelam for 8 weeks. Gene expression profiles of BA homeostasis, inflammation and fibrosis were explored in liver, intestine and colon. Hepatic and faecal BA profiles and gut microbiome were analysed. Glucagon-like peptide 1 (GLP-1) levels in portal blood were measured by ELISA. Furthermore, Mdr2 −/− mice as well as wild-type 3,5-diethoxy-carbonyl-1,4-dihydrocollidine-fed mice were treated with GLP-1-receptor agonist exendin-4 for 2 weeks prior to analysis. Results Colesevelam reduced serum liver enzymes, BAs and expression of proinflammatory and profibrogenic markers. Faecal BA profiling revealed increased levels of secondary BAs after resin treatment, while hepatic and biliary BA composition showed a shift towards more hydrophilic BAs. Colonic GLP-1 secretion, portal venous GLP-1 levels and intestinal messenger RNA expression of gut hormone Proglucagon were increased, while ileal Fgf15 expression was abolished by colesevelam. Exendin-4 treatment increased bile duct mass without promoting a reactive cholangiocyte phenotype in mouse models of sclerosing cholangitis. Microbiota analysis showed an increase of the phylum δ-Proteobacteria after colesevelam treatment and a shift within the phyla Firmicutes from Clostridiales to Lactobacillus . Conclusion Colesevelam increases faecal BA excretion and enhances BA conversion towards secondary BAs, thereby stimulating secretion of GLP-1 from enteroendocrine L-cells and attenuates liver and bile duct injury in Mdr2 −/− mice.
Regulation of Water Intake
Authors: B. Andersson, L. G. Leksell, M. Rundgren
Journal: Annual Review of Nutrition (1982)

Here we have reviewed mainly the cerebral regulation of water intake and its relationship with the regulation of the water-retaining antidiuretic hormone (ADH). Much new information of obvious interest has been gained by experiments in conscious animals, by studies in healthy humans, and by clinical investigations. Of particularly great value has been the development of a sensitive radioimmunoassay for determination of plasma ADH (59). The sketchy picture that emerges in light of this new information is as follows. The osmotic regulation of water intake and ADH secretion is exerted by juxtacerebroventricular sensors apparently mainly located on the anterior border of the third ventricle. These sensors may be accessible both to CSF-borne and blood-borne stimuli and inhibitors, and their activity seems to be correlated to the Na concentration of the ECF rather than to its tonicity. A less sensitive volume regulation of water intake and ADH secretion is effectuated by cardiovascular distention and pressure receptors monitoring the effective circulating blood volume, and in severe volume depletion states also by the renin-angiotensin system (RAS). Afferent impulses from the cardiovascular receptors exert a tonic inhibition of the ADH release by acting upon its final neuronal link (the cells of the supraoptic and paraventricular nuclei). Afferent inflow from these receptors also inhibits thirst to some extent, perhaps by preventing at some synaptic level information from cerebral "thirst" sensors from reaching other parts of the brain where the information is converted into a conscious urge to drink. Therefore, increased cardiovascular receptor activity becomes manifested as elevated osmotic thresholds for ADH liberation and thirst. Severe volume depletion may induce RAS hyperactivity to such an extent that generated angiotensin II stimulates the ADH release and water intake. Demonstrated cerebral Na/angiotensin interaction suggests that this may occur via an angiotensin-induced lowering of the stimulus threshold for the sensors involved in the osmotic control of water balance. Cerebral damage affecting the sensors responsible for the osmotic regulation of water intake and ADH release may result in hypo- or adipsia associated with latent diabetes insipidus, and is apparently the ultimate cause of "essential" hypernatremia. This fragmentary outline of the cerebral control of water intake is based to a considerable extent upon circumstantial evidence, and is for that reason speculative on many points.
Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy
Authors: Claudia Lugo-Candelas, Jiook Cha, Susie Hong, Vanessa Bastidas, Myrna Weissman, William P. Fifer, Michael Myers, Ardesheer Talati, Ravi Bansal, Bradley S. Peterson, Catherine Monk, Jay A. Gingrich, Jonathan Posner
Journal: JAMA Pediatrics (2018)

<h3>Importance</h3> Selective serotonin reuptake inhibitor (SSRI) use among pregnant women is increasing, yet the association between prenatal SSRI exposure and fetal neurodevelopment is poorly understood. Animal studies show that perinatal SSRI exposure alters limbic circuitry and produces anxiety and depressive-like behaviors after adolescence, but literature on prenatal SSRI exposure in humans is limited and mixed. <h3>Objective</h3> To examine associations between prenatal SSRI exposure and brain development using structural and diffusion magnetic resonance imaging (MRI). <h3>Design, Setting, and Participants</h3> A cohort study conducted at Columbia University Medical Center and New York State Psychiatric Institute included 98 infants: 16 with in utero SSRI exposure, 21 with in utero untreated maternal depression exposure, and 61 healthy controls. Data were collected between January 6, 2011, and October 25, 2016. <h3>Exposures</h3> Selective serotonin reuptake inhibitors and untreated maternal depression. <h3>Main Outcomes and Measures</h3> Gray matter volume estimates using structural MRI with voxel-based morphometry and white matter structural connectivity (connectome) using diffusion MRI with probabilistic tractography. <h3>Results</h3> The sample included 98 mother (31 [32%] white, 26 [27%] Hispanic/Latina, 26 [27%] black/African American, 15 [15%] other) and infant (46 [47%] boys, 52 [53%] girls) dyads. Mean (SD) age of the infants at the time of the scan was 3.43 (1.50) weeks. Voxel-based morphometry showed significant gray matter volume expansion in the right amygdala (Cohen<i>d</i> = 0.65; 95% CI, 0.06-1.23) and right insula (Cohen<i>d</i> = 0.86; 95% CI, 0.26-1.14) in SSRI-exposed infants compared with both healthy controls and infants exposed to untreated maternal depression (<i>P</i> &lt; .05; whole-brain correction). In connectome-level analysis of white matter structural connectivity, the SSRI group showed a significant increase in connectivity between the right amygdala and the right insula with a large effect size (Cohen<i>d</i> = 0.99; 95% CI, 0.40-1.57) compared with healthy controls and untreated depression (<i>P</i> &lt; .05; whole connectome correction). <h3>Conclusions and Relevance</h3> Our findings suggest that prenatal SSRI exposure has an association with fetal brain development, particularly in brain regions critical to emotional processing. The study highlights the need for further research on the potential long-term behavioral and psychological outcomes of these neurodevelopmental changes.
Endocrine Therapy–Induced Alopecia in Patients With Breast Cancer
Authors: Azael Freites-Martinez, Jerry Shapiro, Donald Chan, Monica Fornier, Shanu Modi, Devika Gajria, Stephen Dusza, Shari Goldfarb, Mario E. Lacouture
Journal: JAMA Dermatology (2018)

Endocrine therapy-induced alopecia (EIA) has been anecdotally reported but not systematically described.To characterize EIA in patients with breast cancer.Retrospective cohort study of 112 patients with breast cancer, diagnosed with EIA from January 1, 2009, to December 31, 2016, the patients were examined at the dermatology service in a large tertiary care hospital and comprehensive cancer center.The clinical features, alopecia-related quality of life (QoL), and response to minoxidil of EIA in patients with breast cancer were assessed. Data from the Hairdex Questionnaire was used to assess the impact of the alopecia on patients QoL. Higher score indicates lower QoL (0-100 score). Efficacy of minoxidil was measured at 3 or 6 months by a single-blinded investigator through standardized clinical photographs of the scalp.A total of 112 female patients with breast cancer were included (median [range] age, 60 [34-90] years). A total of 104 patients (93%) had standardized clinical photographs; of these, 59 patients (53%) had trichoscopy images available at baseline, and 46 patients (41%) were assessed for response to minoxidil. Alopecia was attributed to aromatase inhibitors in 75 patients (67%) and tamoxifen in 37 (33%). Severity was grade 1 in 96 of 104 patients (92%), and the pattern was similar to androgenetic alopecia. The predominant trichoscopic feature at baseline was the presence of vellus hairs and intermediate- and thick-diameter terminal hair shafts. A negative impact on QoL was reported, with a higher effect in the emotion domain according to the Hairdex score (mean [SD], 41.8 [21.3]; P < .001). After treatment with topical minoxidil, moderate or significant improvement in alopecia was observed in 37 of 46 patients (80%).Endocrine therapies are associated with a pattern alopecia similar to androgenetic-type, consistent with the mechanism of action of causal agents. A significant negative impact on QoL was reported by patients, despite mostly mild alopecia severity.
Using Heart Pump Data to Manage Cardiogenic Shock
Authors: Jennifer Abbasi
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to <i>SDHB</i>-Mutated Cluster I Pheochromocytoma and Paraganglioma
Authors: Ying Pang, Yanxin Lu, Veronika Caisova, Yang Liu, Petra Bullova, Thanh-Truc Huynh, Yiqiang Zhou, Di Yu, Zdenek Frysak, Igor Hartmann, David Taïeb, Karel Pacak, Chunzhang Yang
Journal: Clinical Cancer Research (2018)

Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways.Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors.Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD+ metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B (SDHB)-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft.Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423-32. ©2018 AACR.
Pulmonary Metastases from Chondroblastic Osteosarcoma
Authors: Hirva Mamdani, Sara J Grethlein
Journal: New England Journal of Medicine (2018)

A 21-year-old woman presented to the emergency department with an 8-month history of progressive swelling and pain in the right thigh.Magnetic resonance imaging of the right leg revealed a large, enhancing, circumferential periosteal femoral mass that measured 30 cm in the craniocaudal dimension, as well as a nonocclusive thrombus in the right femoral vein, for which the patient received anticoagulation.Biopsy of the femoral mass confirmed a diagnosis of chondroblastic osteosarcoma.One week later, the patient had shortness of breath and left pleuritic chest pain.The oxygen saturation was 94% while the patient was breathing ambient air.Chest radiography revealed innumerable lesions in both lungs (Panel A).Computed tomography of the chest confirmed the presence of extensive, lobulated, and partially calcified nodules and masses throughout both lungs, a finding suggestive of pulmonary metastases (Panel B).Despite the initiation of chemotherapy, the disease progressed.A second chemotherapy regimen was started; five cycles have been completed, and the disease is currently stable.
Review: In adults with normal cognition or MCI, drugs do not prevent or delay cognitive decline
Authors: Calvin Hirsch
Journal: Annals of Internal Medicine (2018)

Source Citation Fink HA, Jutkowitz E, McCarten JR, et al. Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review. Ann Intern Med. 2018;168:39-51. 29255847
Hypoxia-inducible factor 1α in regulation of programmed death: Ligand 1 in glioma under hypoxia microenvironment.
Authors: Man Hu, Song Xue, Jinming Yu, Bingjie Fan, Ji Ma, Li Xie
Journal: Journal of Clinical Oncology (2017)

103 Background: Glioma is a highly lethal tumor that is known for its immune inhibitory capabilities. Despite great progress in treatment modalities, the median survival time of high-grade gliomas patients is only about 11.1 months. Gliomas are aberrantly expressed programmed death–ligand 1 (PD-L1) which results in tumor-induced immune suppression. Hypoxia is well known to induce aggressiveness, promotes tumor progression and resistance to chemotherapy and radiotherapy. Recently, studies have indicated that hypoxia play a prominent role in tumor immune escape. The aim of the study was to explore the relationship between PD-L1 and hypoxia inducible factor 1α (HIF-1α) and the role in the progression of gliomas. Methods: We adopted immunohistochemistry methods to detect expressions of PD-L1 and HIF-1α in 64 surgical specimens (23 cases for low-grade and 41 cases for high-grade gliomas, respectively). Immunoreactivity was analyzed in association with patients’ clinical characteristics or survival time. Expression of the PD-L1 and HIF-1α was analyzed in three GBM cell lines, U343, U373, and U251, under in vitro hypoxia (12, 24 or 72 h at 0.1% O2). Reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out to detect the mRNA expression of PD-L1 and HIF-1α. Results: PD-L1 and HIF-1α protein expression was detected in 81.25% and 84.73% of glioma specimens, respectively. The expression of PD-L1 protein is positively correlated with HIF-1α (r = 0.52; p= 0.013). Kaplan–Meier analysis revealed a significant effect of PD-L1 grade on cumulative overall survival. Patients with negative PD-L1 expression survive longer than those with positive expression ( p= 0.007). PD-L1 and HIF-1α mRNA was most consistently upregulated in relation to duration of in-vitro hypoxia (72h, p= 0.007). There was a significant and positive relationship between the PD-L1 and HIF-1α mRNA expression (r = 0.45; p= 0.01). Conclusions: The present study showed a role for hypoxia/HIF-1α in driving immune escape and provided a potential novel cancer immunotherapy targeting hypoxia to block PD-L1 expression, which may boost the immune system in cancer patients.
Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates
Authors: Marnix Lameijer, Tina Binderup, Mandy M. T. van Leent, Max L. Senders, Francois Fay, Joost Malkus, Brenda L. Sanchez-Gaytan, Abraham J. P. Teunissen, Nicolas Karakatsanis, Philip Robson, Xianxiao Zhou, Yuxiang Ye, Gregory Wojtkiewicz, Jun Tang, Tom T. P. Seijkens, Jeffrey Kroon, Erik S. G. Stroes, Andreas Kjaer, Jordi Ochando, Thomas Reiner, Carlos Pérez-Medina, Claudia Calcagno, Edward A. Fisher, Bin Zhang, Ryan E. Temel, Filip K. Swirski, Matthias Nahrendorf, Zahi A. Fayad, Esther Lutgens, Willem J. M. Mulder, Raphaël Duivenvoorden
Journal: Nature Biomedical Engineering (2018)
Safety, efficacy, and immunogenicity of autologous tumor lysate-pulsed dendritic cell vaccination therapy after resection of stage IIA (T2N0, T3N0) esophageal cancer: A phase I trial.
Authors: Yasuyoshi Sato, Hirokazu Matsushita, Kazuhiko Mori, Kazuhiro Kakimi, Yasuyuki Seto
Journal: Journal of Clinical Oncology (2017)

153 Background: Immunotherapy using active immunization of tumor associated antigens has been expected to improve the prognosis of malignant tumor patients. We conducted a phase I trial to investigate safety and efficacy of autologous tumor lysate-pulsed dendritic cell (DC) vaccination therapy after resection for esophageal cancer. Methods: Patients (pts) with stage IIA (T2N0 or T3N0, UICC TNM classification 6 th edition) esophageal cancer after curative (R0) resection, ECOG PS 0-2, 20 years or more and adequate organ function were eligible. We used tumor lysate for DC vaccines; the lysates potentially contain mutated proteins or neoantigens derived from somatic mutations in each patient's tumor. Patients received DC vaccines (more than 5.0×10 6 cells) 6 times every 2 weeks. Primary endpoint was safety and secondary endpoint were efficacy including recurrence rate and immunological responses. Results: A total of 11 pts (median age: 71 years) were enrolled until the trial stopped on March 31, 2016, because standard of therapy for objective patients had changed. No treatment related adverse events of grade 3 or 4 were reported. Recurrence rate within 2 years were 18% (n=2). We performed whole-exome sequence of tumors and adjacent normal tissues with 5 pts, and identified mutated peptide derived from their tumor specific missense mutations. To examine immune responses against those predicted candidate neoepitopes, we immunized HLA-A2 transgenic mice (HHD-II mice) with the synthesized peptides from the 2 pts harboring HLA-A2. Conclusions: This study showed that autologous tumor lysate-pulsed DC vaccination therapy is safe and have expectation of recurrence risk reduction after resection of T2N0 or T3N0 esophageal cancer. Clinical trial information: UMIN000002837.
Neurological adverse events from checkpoint inhibition: A comprehensive review of literature.
Authors: Ahmad Daher, Tummala Sudhakar
Journal: Journal of Clinical Oncology (2017)

62 Background: Checkpoint (CTLA-4 &amp; PD-1) inhibitors are the most commonly used anti-cancer immunotherapeutics. Their use is associated with well-documented immune-related adverse events (iAEs), but among those, neurological adverse events (nAEs) are rare. They have been described in multiple reports but detailed analysis of the spectrum of neurotoxicities, their relationship to the drug dose, and their time course is lacking. We provide a comprehensive review of all published checkpoint inhibitors-induced nAEs. Methods: PubMed and Ovid-MEDLINE databases were queried for all nAEs from checkpoint inhibition published cases. Three additional cases from our institution were included. Clinical, radiologic, and laboratory data was reviewed and analyzed. Results: 63 cases were identified, 57 of which were analyzed in Table 1. The remaining 6 cases included nAEs occurring &gt; 6 months after initiation of therapy and were analyzed separately. Neurotoxicity occurred after a median of 3 doses with a range of 1 to 6. Neuropathy was the most common nAE from overall checkpoint inhibition (32%) or CTLA-4 inhibition (43%) but in PD-1 blockade cases, Myasthenia Gravis (44%) was more common than neuropathy (11%). CNS demyelination (11%), encephalopathy (10%), and meningitis (6%) were also reported. Peripheral nAEs outweighed central ones by about 2:1. Improvement was seen in 77% of the cases while systemic iAEs were seen in 25% only. The 6 cases with delayed nAEs analyzed occurred 31-76 weeks after therapy initiation. Conclusions: nAEs from checkpoint inhibition typically affect PNS &gt; CNS, occur after a few doses of therapy, and are not commonly associated with systemic iAEs. Their profile varies by type of blockade (PD-1 vs. CTLA-4). Immunotherapy may unmask a subclinical previously undiagnosed neuromuscular disorder (ex: MG). Prompt recognition and relevant testing before and during therapy is of utmost importance as a majority of cases improve with discontinuation of the drug +/- immunosuppressive therapy. [Table: see text]
Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress
Authors: Jennifer Tsoi, Lidia Robert, Kim Paraiso, Carlos Galvan, Katherine M. Sheu, Johnson Lay, Deborah J.L. Wong, Mohammad Atefi, Roksana Shirazi, Xiaoyan Wang, Daniel Braas, Catherine S. Grasso, Nicolaos Palaskas, Antoni Ribas, Thomas G. Graeber
Journal: Cancer Cell (2018)