tbuckley/cabot-search huggingface dataset:
Direct Evidence for Microdomain-Specific Localization and Remodeling of Functional L-Type Calcium Channels in Rat and Human Atrial Myocytes
Authors: Alexey V. Glukhov, Marina Balycheva, Jose L. Sanchez-Alonso, Zeki Ilkan, Anita Alvarez-Laviada, Navneet Bhogal, Ivan Diakonov, Sophie Schobesberger, Markus B. Sikkel, Anamika Bhargava, Giuseppe Faggian, Prakash P. Punjabi, Steven R. Houser, Julia Gorelik
Journal: Circulation (2015)

Distinct subpopulations of L-type calcium channels (LTCCs) with different functional properties exist in cardiomyocytes. Disruption of cellular structure may affect LTCC in a microdomain-specific manner and contribute to the pathophysiology of cardiac diseases, especially in cells lacking organized transverse tubules (T-tubules) such as atrial myocytes (AMs).Isolated rat and human AMs were characterized by scanning ion conductance, confocal, and electron microscopy. Half of AMs possessed T-tubules and structured topography, proportional to cell width. A bigger proportion of myocytes in the left atrium had organized T-tubules and topography than in the right atrium. Super-resolution scanning patch clamp showed that LTCCs distribute equally in T-tubules and crest areas of the sarcolemma, whereas, in ventricular myocytes, LTCCs primarily cluster in T-tubules. Rat, but not human, T-tubule LTCCs had open probability similar to crest LTCCs, but exhibited ≈ 40% greater current. Optical mapping of Ca(2+) transients revealed that rat AMs presented ≈ 3-fold as many spontaneous Ca(2+) release events as ventricular myocytes. Occurrence of crest LTCCs and spontaneous Ca(2+) transients were eliminated by either a caveolae-targeted LTCC antagonist or disrupting caveolae with methyl-β-cyclodextrin, with an associated ≈ 30% whole-cell ICa,L reduction. Heart failure (16 weeks post-myocardial infarction) in rats resulted in a T-tubule degradation (by ≈ 40%) and significant elevation of spontaneous Ca(2+) release events. Although heart failure did not affect LTCC occurrence, it led to ≈ 25% decrease in T-tubule LTCC amplitude.We provide the first direct evidence for the existence of 2 distinct subpopulations of functional LTCCs in rat and human AMs, with their biophysical properties modulated in heart failure in a microdomain-specific manner.
Emergency Reversal of Novel Oral Anticoagulants
Authors: Stephan A. Mayer
Journal: JAMA Neurology (2015)

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 Neurology HomeNew OnlineCurrent IssueFor Authors Podcast 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 Neurology journal
Marijuana Use Has Doubled Among US Adults
Authors: Julie A. Jacob
Journal: JAMA (2015)

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
Fecal Calprotectin Levels Could Be Used as a Predictor of Endoscopic Remission for Inflammatory Bowel Disease Patients: Taiwan Society of Inflammatory Bowel Disease Multicenter Study
Authors: Wei-Chen Lin, Jau-Min Wong, Ching-Pin Lin, Jen-Wei Chou, Horng-Yuan Wang, Ming-Jium Shieh, Chin-Hao Chang, Heng-Hsiu Liu, Shu-Chen Wei
Journal: Clinical Gastroenterology and Hepatology (2015)
A single institution experience with neoadjuvant chemoradiation (CRT) with irinotecan (I) and cisplatin (C) in locally advanced esophageal carcinoma (LAEC)
Authors: R. Sharma, G. Y. Yang, H. R. Nava, T. L. Demmy, C. E. Nwogu, S. S. Yendamuri, D. Lamonica, W. Tan, R. V. Iyer, N. I. Khushalani
Journal: Journal of Clinical Oncology (2009)

e15619 Background: Multimodal therapy is considered standard for LAEC with cisplatin and 5FU-based CRT being commonly used, though with significant toxicity. Novel agents are needed to improve pathologic response (pCR) which predicts for better prognosis. We analyzed our experience with CRT using I + C in LAEC. Methods: LAEC patients (PTS) who underwent surgery preceded by CRT with I + C were identified from the Roswell Park tumor registry. Treatment consisted of Day 1,8 of C 30mg/m 2 and I 65mg/m 2 in a 21 day cycle. PTS concurrently received 45–50.4 Gy radiation in1.8Gy fractions. Data retrieved included toxicity, pCR rate and survival. Results: 44 eligible PTS, median age 61 yr, 43 males and 1 female. Histology included adenocarcinoma (n=38), squamous cell (n=4), mixed (n=2); 12 PTS had signet-ring cell features. 29 PTS had poorly differentiated tumors. Clinical stage was II (n=5), III (n=24), IVa(n=6), IVb(n=1), not available (n=8). ECOG PS was 0 (n=34) and 1 (n=10). Most common toxicities observed were fatigue (n=24), diarrhea (n=19), vomiting (n=15), hematologic (n=11), constipation (n=11) and neurologic (n=7). Dose delay or reduction was required in 10 PTS, usually from hematologic toxicity. Of these,1 week delay in 45% and 2 weeks in 36%; 1 PT discontinued treatment due to toxicity. There was no CRT-related mortality. 2 PTS died post-operatively (anastamotic leak and sepsis). Dyphagia improved in 33/35 (94%) PTS following CRT. All PTS underwent R0 resection and pCR rate was 25% (11/44). 15 PTS have experienced recurrence. The median disease-free and overall survival is 24 months and 34 months, respectively; 3-yr overall survival is 46%. Available pre- and post-CRT FDG uptake on PET imaging in 28 PTS did not correlate with pCR status (p=0.77). Conclusions: Neo-adjuvant CRT with I + C has modest efficacy in the treatment of LAEC and can be given safely in the out-patient setting. PTS should be monitored closely for toxicity, specifically diarrhea that requires prompt intervention. Efficacy results appear better than those reported in ECOG 1201. This regimen is being evaluated in CALGB 80302 and results are awaited. No significant financial relationships to disclose.
Seaweed as an anticarcinogenic agent in breast cancer
Authors: Jane Teas, Qixia Zhang, Valerie Kennedy
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4988 

Seaweed has been used to treat breast cancer for at least 3,000 years. First mentioned in the Smith Papyrus, seaweed is also part of the antitumor pharmacopoeia of Ayurvedic Medicine in India, Traditional Chinese Medicine, and numerous folk healing traditions. Epidemiologic evidence supports an association between seaweed consuming cultures and low breast cancer rates. In addition to low breast cancer incidence rates, women who develop breast cancer in Japan live longer with breast cancer. Various in vivo studies have demonstrated that seaweed and seaweed extracts are remarkably effective at preventing carcinogen-induced mammary tumors. In our study of seaweed extracts in vitro we have identified several pathways. First, Undaria pinnatifida seaweed extracts appeared to inhibit cell proliferation, significantly reducing BrdU DNA synthesis, and caused G1 phase cell cycle arrest.As seaweeds have been shown to act as pathogen associated molecular patterns that block Toll Like Receptor 2, we used immunohistochemistry stains for TLR-2 on MDA-231 breast cancer cells. Although TLR-2 receptors have not previously been identified on MDA-231 cells, we identified TLR-2 specific staining on the MDA-231 cells. Seaweed extracts at 0.1% concentration almost completely blocked TLR-2 staining. Using Western Blot analysis, we identified a persistent down regulation of ERK in MDA-231 cells treated with seaweed, suggesting that seaweed may act via regulation of the MAP kinase pathway. To answer the question of whether this might be relevant to breast cancer patients, we are recruiting women with newly diagnosed breast cancer, providing 5 g/d seaweed supplements until 24 hours before surgery, and comparing histology of stereotactic biopsy tissue samples with tumor tissue removed during surgery. Our preliminary results suggest that estrogen receptor positivity increases with seaweed supplementation, and CXCR4 and CCR5, two well known breast cancer tumor cell surface receptor sites involved in metastases were internalized after seaweed supplementation. These lines of evidence, although preliminary, all support the use of seaweed in future breast cancer clinical trials. As seaweed is safely eaten everyday by millions of people in Japan and Korea, and is on the Generally Regarded as Safe list of the USDA, the incorporation of seaweed into the American diet would be possible.
The Activity of the CCAAT-box Binding Factor NF-Y Is Modulated Through the Regulated Expression of Its A Subunit During Monocyte to Macrophage Differentiation: Regulation of Tissue-Specific Genes Through a Ubiquitous Transcription Factor
Authors: Giovanna Marziali, Edvige Perrotti, Ramona Ilari, Eliana M. Coccia, Roberto Mantovani, Ugo Testa, Angela Battistini
Journal: Blood (1999)
Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).
Authors: David R. Spigel, Scott N. Gettinger, Leora Horn, Roy S. Herbst, Leena Gandhi, Michael S. Gordon, Cristina Cruz, Paul Conkling, Philippe Alexandre Cassier, Scott J. Antonia, Howard A. Burris, Gregg Daniel Fine, Ahmad Mokatrin, Marcin Kowanetz, Xiaodong Shen, Daniel S. Chen, Jean-Charles Soria
Journal: Journal of Clinical Oncology (2013)

8008 Background: Human lung cancer expresses high levels of PD-L1, which may inhibit anti-cancer immune responses. MPDL3280A, a human monoclonal Ab containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: Pts with squamous or nonsquamous NSCLC received MPDL3280A IV q3w at doses between 1-20 mg/kg in a Ph I expansion study. Pts were treated for up to 1 y. Objective response rate (ORR) was assessed by RECIST v1.1. Reported ORR includes u/cCR and u/cPR. Results: As of Jan 10, 2013, 53 NSCLC pts were evaluable for safety and treated at doses of ≤1 (n=2), 10 (n=10), 15 (n=19) and 20 mg/kg (n=22). Pts had a median age of 61 y (range 24-83 y), 98% were PS 0-1, 89% had prior surgery and 55% had prior radiotherapy. 98% of pts received prior systemic therapy. Pts received treatment for a median duration of 106 days (range 1-324) of MPDL3280A. The incidence of all G3/4 AEs, regardless of attribution, was 34%, including pericardial effusion (6%), dehydration (4%), dyspnea (4%) and fatigue (4%). No G3-5 pneumonitis or diarrhea was reported. 37 NSCLC pts enrolled prior to Jul 1, 2012, were evaluable for efficacy. RECIST responses were observed at dose levels between 1 and 20 mg/kg, with all responses ongoing or improving. An ORR of 24% (9/37) was observed in pts with squamous and nonsquamous histologies, including several with rapid tumor shrinkage. Additional pts had delayed responses after apparent radiographic progression (not included in the ORR). The 24-week PFS was 48%. Analysis of biomarker data from archival tumor samples demonstrated a correlation between PD-L1 status and efficacy. Pts who were PD-L1 tumor status–positive showed an ORR of 100% (4/4) and a PD rate of 0% (0/4), while pts who were PD-L1 tumor status–negative showed an ORR of 15% (4/26) and a PD rate of 58% (15/26). Updated data will be presented. Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid and durable responses were observed. PD-L1 tumor status correlated with response to MPDL3280A. Clinical trial information: NCT01375842.
Companies to pay $39.5m in OxyContin and Risperdal cases
Authors: Michael McCarthy
Journal: BMJ (2015)

Purdue Pharma and Johnson & Johnson will pay a total of $39.5m (£27m; €36m) to the state of Kentucky to settle lawsuits alleging that the companies had engaged in false marketing practices and hid side effects of their drugs from clinicians and consumers.

In a settlement reached on 22 December, Purdue Pharma, maker of OxyContin, a time released formulation of oxycodone, agreed to pay $24m to settle a lawsuit by the state that alleged that the Connecticut based company had concealed the highly addictive nature of the opioid and encouraged doctors who were not trained in pain management to prescribe its formulation.

Kentucky officials had charged that soon after OxyContin was approved by the US Food …
Dynamic Patterns of Clonal Evolution in Tumor Vasculature Underlie Alterations in Lymphocyte–Endothelial Recognition to Foster Tumor Immune Escape
Authors: Daniel M. Corey, Yuval Rinkevich, Irving L. Weissman
Journal: Cancer Research (2016)

Abstract Although tumor blood vessels have been a major therapeutic target for cancer chemotherapy, little is known regarding the stepwise development of the tumor microenvironment. Here, we use a multicolor Cre-dependent marker system to trace clonality within the tumor microenvironment to show that tumor blood vessels follow a pattern of dynamic clonal evolution. In an advanced melanoma tumor microenvironment, the vast majority of tumor vasculature clones are derived from a common precursor. Quantitative lineage analysis reveals founder clones diminish in frequency and are replaced by subclones as tumors evolve. These tumor-specific blood vessels are characterized by a developmental switch to a more invasive and immunologically silent phenotype. Gene expression profiling and pathway analysis reveals selection for traits promoting upregulation of alternative angiogenic programs such as unregulated HGF-MET signaling and enhanced autocrine signaling through VEGF and PDGF. Furthermore, we show a developmental switch in the expression of functionally significant primary lymphocyte adhesion molecules on tumor endothelium, such as the loss in expression of the mucosal addressin MAdCAM-1, whose counter receptor a4β7 on lymphocytes controls lymphocyte homing. Changes in adhesive properties on tumor endothelial subclones are accompanied by decreases in expression of lymphocyte chemokines CXCL16, CXCL13, CXCL12, CXCL9, CXCL10, and CCL19. These evolutionary patterns in the expressed genetic program within tumor endothelium will have both a quantitative and functional impact on lymphocyte distribution that may well influence tumor immune function and underlie escape mechanisms from current antiangiogenic pharmacotherapies. Cancer Res; 76(6); 1348–53. ©2015 AACR.
Pre-morbid function and co-morbidity predict short and mid-term outcomes following ruptured abdominal aortic aneurysm (RAAA) repair
Authors: A. Srinivasan, G. Ambler, M.S. Gohel, K. Varty, P.D. Hayes, J.R. Boyle, P. Coughlin
Journal: International Journal of Surgery (2015)
Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII
Authors: Oscar A. Marcos-Contreras, Shannon M. Smith, Dwight A. Bellinger, Robin A. Raymer, Elizabeth Merricks, Armida Faella, Giulia Pavani, Shangzhen Zhou, Timothy C. Nichols, Katherine A. High, Paris Margaritis
Journal: Blood (2015)
Hospice Use Among Patients With Lymphoma: Impact of Disease Aggressiveness and Curability
Authors: Oreofe O. Odejide, Angel M. Cronin, Craig C. Earle, Ann S. LaCasce, Gregory A. Abel
Journal: JNCI Journal of the National Cancer Institute (2015)

Little is known about factors that influence hospice use for patients with blood cancers. We aimed to characterize hospice enrollment in a large population of patients with B-cell non-Hodgkin lymphoma (NHL) and assess the impact of disease characteristics such as aggressiveness and curability. Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients age 65 years and older who were diagnosed with indolent NHL, aggressive NHL, or mantle cell lymphoma (MCL, which is aggressive and incurable) and died between 1999 and 2009. We determined the prevalence of hospice use and predictors thereof, using multivariable logistic regression. All statistical tests were two-sided. Of 18 777 patients, 9645 had indolent NHL, 8226 had aggressive NHL, and 906 had MCL. Of the total cohort, 41.6% enrolled in hospice, and 34.3% enrolled three or more days before death. Compared with patients with indolent NHL, those with MCL were more likely to enroll (adjusted odds ratio [AOR] = 1.72, 95% confidence interval [CI] = 1.49 to 1.98), followed by patients with aggressive NHL (AOR = 1.41, 95% CI = 1.32 to 1.50). Other factors statistically significantly associated with hospice use included older age, female sex, white race, high socioeconomic status, and later year of death. In this large cohort of patients with lymphoma, hospice use was substantially lower than the national average for all cancers, suggesting either the need for improvement in enrollment or that the current hospice model is not meeting this population's end-of-life needs. Moreover, the fact that patients with MCL were most likely to enroll suggests that the end-of-life phase may be more easily determined in the context of cancers that are both aggressive and incurable.
Reply
Authors: Lesley De Pietri, Marcello Bianchini, Guadalupe Garcia‐Tsao, Erica Villa
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. We thank Dr. Intagliata and colleagues for their comments. We agree with many of them. The characterization of the coagulation status in cirrhosis has recently undergone profound changes, and it is now clear that patients with cirrhosis, especially those with advanced disease, are more prone to thrombotic, rather than hemorrhagic, complications. Furthermore, routine coagulation tests, such as the international normalized ratio (INR) and platelet (PLT) count, were shown to be quite unsatisfactory in defining bleeding or thrombotic risk.1 Despite this, in everyday practice, physicians, surgeons, interventional radiologists or endoscopists request that clotting abnormalities be corrected before performing invasive procedures,2 even given the low likelihood that fresh frozen plasma (FFP) and/or PLT transfusions will actually correct the abnormalities.3 This was the starting point of our study.4 We wanted to investigate whether a more comprehensive test such as thromboelastography (TEG) could better drive the decision‐making process in this context and, additionally, help in identifying the required amount of FFP and PLTs required to correct abnormalities. First of all, we showed that TEG would be useful to reduce transfusions. Our TEG‐guided transfusion scheme led to a striking decrease of FFP or PLT transfusions without increased bleeding. However, the most relevant result is another. We showed that patients with cirrhosis with abnormal coagulation tests at thresholds that are considered "dangerous" for the performance of invasive procedures (INR >1.8 and/or PLT count <50 × 103/µL) are not associated with an increased bleeding risk, and therefore these abnormalities do not require correction. In these patients, procedure‐related bleeding was exceptional and depended on variables other than coagulation status, including technical aspects of the procedure itself and the degree of portal hypertension. Bleeding occurred only after a traumatic event, such as mechanical damage to a vessel. This indicates that patients with cirrhosis with the characteristics of enrollment in the study do react as patients without cirrhosis. Therefore, we think that there is no need to replicate this study with a third cohort in which no prophylactic transfusions of PLTs or FFP will be given before invasive procedures. Indeed, in the TEG group as a whole, only 5 of 30 patients received PLTs or FFP and, in the high‐risk procedures, only 1 patient of 17 was transfused without any postprocedural bleeding complication. We think instead that additional effort should be put in identifying related conditions, which could alter this overall favorable situation. Decompensated patients with overt infection or with markers of systemic inflammation could be a much more challenging group in whom the performance of different clotting tests to predict risk of bleeding could be tested and in whom the value of correcting coagulopathy could be investigated.
Synergistic effect of targeting PI3k/PTEN and MDM2/p53 pathways in inducing apoptosis in acute lymphoblastic leukemia cells
Authors: Ningxi Zhu, Lubing Gu, Fengzhi Li, Muxiang Zhou
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

1345 

PI3k/Akt and p53 pathways are known to play anti-apoptotic and pro-apoptotic roles in cell death, respectively. High level of PI3k/Akt activation by loss of PTEN expression and inactivation of p53 by overexpression of MDM2 are associated with cancer cell growth and progression. Here, we report that inhibition of PI3k/Akt either by PI3k inhibitor Ly294002 or by expression of PTEN synergizes the MDM2 antagonist nutlin-3 in inducing apoptosis in acute lymphoblastic leukemia (ALL). First, we tested the effect of nutlin-3 on induction of p53 and apoptosis in a set of ALL cell lines with wild-type (wt) p53 and MDM2 overexpression. The p53 was induced by nutlin-3 in all cell lines tested, while induction of apoptosis was different in cells with distinct PTEN status. Nutlin-3 induced potent apoptosis in cell lines with PTEN expression but not in cell lines without PTEN expression. Consistent with the apoptotic effects, nutlin-3 significantly downregulated expression of survivin in PTEN-positive cells but not in PTEN-negative cells. When these nutlin-3 resistant cells were simultaneously treated with the PI3K inhibitor Ly294002 or pre-transfected with PTEN gene, their sensitivity to nutlin-3 was increased with a concomitant downregulation of survivin. Furthermore, direct silencing of survivin by siRNA increased the apoptotic effect of nutlin-3 on PTEN-negative ALL cells. Taken together, our results suggest that Akt-mediated survivin upregulation in PTEN-negative ALL cells attenuate nutlin-3 induced apoptosis, and combination of MDM2 antagonist and PI3K/Akt inhibitor may be a promising approach in the treatment of refractory ALL.