tbuckley/cabot-search huggingface dataset:
Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion
Authors: Lama Al-Qusairi, Denis Basquin, Ankita Roy, Renuga Devi Rajaram, Marc P. Maillard, Arohan R. Subramanya, Olivier Staub
Journal: Journal of the American Society of Nephrology (2017)

Adaptation of the organism to potassium (K+) deficiency requires precise coordination among organs involved in K+ homeostasis, including muscle, liver, and kidney. How the latter performs functional and molecular changes to ensure K+ retention is not well understood. Here, we investigated the role of ubiquitin-protein ligase NEDD4-2, which negatively regulates the epithelial sodium channel (ENaC), Na+/Cl- cotransporter (NCC), and with no-lysine-kinase 1 (WNK1). After dietary K+ restriction for 2 weeks, compared with control littermates, inducible renal tubular NEDD4-2 knockout (Nedd4LPax8/LC1 ) mice exhibited severe hypokalemia and urinary K+ wasting. Notably, expression of the ROMK K+ channel did not change in the distal convoluted tubule and decreased slightly in the cortical/medullary collecting duct, whereas BK channel abundance increased in principal cells of the connecting tubule/collecting ducts. However, K+ restriction also enhanced ENaC expression in Nedd4LPax8/LC1 mice, and treatment with the ENaC inhibitor, benzamil, reversed excessive K+ wasting. Moreover, K+ restriction increased WNK1 and WNK4 expression and enhanced SPAK-mediated NCC phosphorylation in Nedd4LPax8/LC1 mice, with no change in total NCC. We propose a mechanism in which NEDD4-2 deficiency exacerbates hypokalemia during dietary K+ restriction primarily through direct upregulation of ENaC, whereas increased BK channel expression has a less significant role. These changes outweigh the compensatory antikaliuretic effects of diminished ROMK expression, increased NCC phosphorylation, and enhanced WNK pathway activity in the distal convoluted tubule. Thus, NEDD4-2 has a crucial role in K+ conservation through direct and indirect effects on ENaC, distal nephron K+ channels, and WNK signaling.
COEXISTING CO-MORBIDITIES EXACERBATE LEFT VENTRICULAR DIASTOLIC DYSFUNCTION AND PROGNOSIS IN PATIENTS WITH SEVERE AORTIC STENOSIS
Authors: Saki Ito, William Miranda, Vuyisile Nkomo, Sorin Pislaru, Joseph Malouf, Patricia Pellikka, Jae Oh
Journal: Journal of the American College of Cardiology (2017)
ULTRASOUND ASSISTED CATHETER DIRECTED THROMBOLYSIS AND PERCUTANEOUS RIGHT VENTRICULAR MECHANICAL ASSIST DEVICE FOR THE MANAGEMENT OF MASSIVE PULMONARY EMBOLISM WITH REFRACTORY RIGHT VENTRICULAR FAILURE: PLAYING CHESS WITH PULMONARY EMBOLISM
Authors: Mohamed Shokr, Ahmed Rashed, Ashraf Mostafa, Ahmed Yasser Nagy, Emmanuel Akintoye, Mahir Elder, Amir Kaki, Theodore Schreiber
Journal: Journal of the American College of Cardiology (2017)
Differential genomic profiles of tumor-involved and tumor-free sentinel lymph nodes in patients with melanoma.
Authors: Ahmad A. Tarhini, William A LaFramboise, Uma N. M. Rao, Howard Edington, James F. Pingpank, Matthew Peter Holtzman, Hussein Abdul-Hassan Tawbi, Albert Geskin, Amy Rose, Christy Milburn, Michelle Merriman, Cindy Sander, Christin Sciulli, Yan Lin, John M. Kirkwood
Journal: Journal of Clinical Oncology (2013)

9043 Background: For clinical stage I and II node negative melanoma the histologic status of the sentinel lymph node (SLN) is the most significant predictor of survival. Molecular characterization of node positive and node negative SLNs through gene expression profiling may improve the understanding of the molecular mechanisms of metastasis and identify specific gene signatures for SLN+/SLN- that correlate with clinical outcome. Methods: We characterized 15 SLN+ and 15 SLN- melanoma patients (T3a/b, T4a/b) who underwent SLN dissection for routine staging using transcriptome profiling analysis on 5μ sections of fresh LN samples. The primary endpoint was mRNA expression profiling using the U133A 2.0 Affymetrix gene chips. Significance Analysis of Microarrays v.4 was used to perform non-parametric analysis and statistical comparison for each transcript corrected for false discovery rate (q value) to control for type 1 errors arising from multiple tests. Pathway analysis was performed using Ingenuity Pathway Analysis software. Results: Tumor size ranged from 1-2mm in size. Twenty-one genes were expressed at significantly (q value &lt;0.056) higher levels in SLN+ vs SLN-. These included CCNA2, CEP55, DCT, FEN1, HMMR, MLANA, PAICS, PBK, POSTN, RAB27A, RRM2, SHCBP1, SILV, TYR, CENPE, CCL20, CHEK1, LINS, TPX2, TTK, TYRP1. Pathway analysis (39 genes &gt;1.4 fold; q &lt; 0.12) identified the top disease categories as “Cancer” (26 genes, p = 5.7x10-9) and “Dermatological” (14 genes, p = 3.9x10-6). The top functional categories included “Cell Cycle” (21 genes p= 2.3x10-12) and “Cell Growth and Proliferation” (26 genes p=9x10-9). The relevant canonical pathways were “Eumelanin Biosynthesis” (p=3x10-5) and “Cell Cycle: G2/M DNA Damage Checkpoint Regulation” (p=1.2x10-4). Conclusions: We identified a 21 gene signature that is consistent with metastatic melanoma and its microenvironment and is differentially expressed in SLNs that are tumor involved. These gene families provide a signature of nodal involvement that may assist in diagnosis, and may be further explored towards prediction of outcome and development of therapy. A validation study is ongoing with clinical outcome association analyses as follow up is mature.
IS CABG THE BEST REVASCULARIZATION STRATEGY AMONG ALL DIABETICS SUBGROUPS WITH MULTI-VESSEL DISEASE IN THE MODERN ERA? A MULTI-CENTER ANALYSIS
Authors: Alexander Iribarne, Anthony DiScipio, Michael Robich, Andrew Eisenhauer, Bruce Leavitt, Yvon Baribeau, Peter Ver Lee, James Flynn, Yi-Ling Huang, David Malenka
Journal: Journal of the American College of Cardiology (2017)
Is nipple aspirate fluid (NAF) a reliable source to identify biomarkers in breast cancer? A feasibility study.
Authors: Atilla Soran, Ebru Menekse, John McKolanis, Priscilla F. McAuliffe, Kandace P. McGuire, Emilia Diego, Marguerite Bonaventura, Ronald Johnson, Gretchen M. Ahrendt, Olivera J. Finn
Journal: Journal of Clinical Oncology (2015)

e22101 Background: Elevated expression of MUC1 and Cyclin B1 has been reported in malignant breast tissue and is associated with more aggressive tumor characteristics. We hypothesized that in NAF, antibodies against these proteins would be present in higher concentrations in women with breast cancer (BC) compared to non-malignant lesion, and that anti-cyclin B1 and anti-MUC 1 antibodies elicited in patients in response to overexpression of these two markers could predict the aggressiveness of BC. Methods: NAF samples were collected after anesthesia was induced, but before the operation commenced in women with newly diagnosed BC, and high risk lesions (HRL). NAF was obtained from contralateral breast s of patients with carcinoma and HRL, those undergoing prophylactic surgery and those whose final pathology was reported as nonproliferative breast lesions. Pre-surgery serum samples were also collected. ELISA (OD of 405nm) was used to measure IgG, IgM and IgA antibodies against MUC1 and Cyclin B1. Characteristics such as tumor size, lymph node status (pN), estrogen receptor (ER), progesterone receptor (PR), Her2 neu, nuclear grade, lymphovascular invasion (LVI), extracapsular extension (ECE), and overall recurrence were recorded prospectively. Correlation of tumor characteristics with NAF and serum antibody levels was assessed using two-way ANOVA with α level of 0.05. Results: NAF samples were collected from 123 breasts with 45 carcinoma, 7 insitu lesions, 19 atypical hyperplasia, and 52 normal breast tissue from 77 women. Mean follow up was 73 months (range 51-187). There were 4 overall recurrences. There was no significant difference in levels of NAF and serum MUC1 and Cyclin B1 antibodies between BC, HRL and normal breast tissue. However, in the NAF of women diagnosed with BC, a high level of anti-cyclin B1 IgG was significantly associated with axillary node metastasis, ECE and recurrence (p < 0.05). Conclusions: We showed that cyclin B1 and MUC 1 antibody levels in NAF could not discriminate BC from other lesions, but they were associated with tumor aggressiveness. Future directions involve correlation of these markers in NAF and serum with response to neoadjuvant systemic therapy, recurrence and survival.
LNK Mutation Studies In Chronic- and Blast-Phase Myeloproliferative Neoplasms and JAK2 Mutation-Negative Erythrocytosis
Authors: Terra Lasho, Ayalew Tefferi, Alessandro M. Vannucchi, Christy Finke, Paola Guglielmelli, Lisa Pieri, Animesh Pardanani
Journal: Blood (2010)
HER2 POSITIVE BREAST CANCER AND SUBCLINICAL CARDIOTOXICITY BY ECHOCARDIOGRAM 2D STRAIN: DOES CHEMOTHERAPY SEQUENCE MATTER?
Authors: Viridiana Perez-Montessoro, Itzel Poblano-Aguilar, Zuilma Vasquez-Ortiz, Jaime Galindo-Uribe, Alejandra Armengol-Alonso
Journal: Journal of the American College of Cardiology (2017)
Updated results of a phase III trial comparing standard thoracic radiotherapy (RT) with or without concurrent daily low-dose carboplatin in elderly patients (pts) with locally advanced non-small cell lung cancer (NSCLC): JCOG0301.
Authors: Hiroaki Okamoto, Shinji Atagi, Masaaki Kawahara, Akira Yokoyama, Nobuyuki Yamamoto, Yuichiro Ohe, Toshiyuki Sawa, Tetsu Shinkai, Kiyoshi Mori, Koji Takeda, Masao Harada, Kazuhiko Nakagawa, Naruo Yoshimura, Yoshio Tomizawa, Yuichiro Takeda, Haruhiko Fukuda, Taro Shibata, Satoshi Ishikura, Nagahiro Saijo, Tomohide Tamura
Journal: Journal of Clinical Oncology (2012)

7017 Background: We previously reported the superiority of combined chemo-radiotherapy (CRT) over RT alone in elderly pts with locally advanced NSCLC (Atagi et al. ECCO2011). One and a half years follow-up data from last accrual are presented. Methods: Pts older than 70 years with unresectable stage III NSCLC were randomized to either RT alone (RT arm), a total dose of 60 Gy, or CRT arm including the same RT plus concurrent chemotherapy with carboplatin 30 mg/m 2 /day, 5 days/week × 20 days. The primary endpoint was overall survival (OS). The planned sample size was 100 pts in each arm with one-sided alpha of 5% and 80% power to detect a difference in median survival time (MST) from 10 months in RT arm to 15 months in CRT arm. Results: Between Sep 2003 and May 2010, 200 pts were randomized. Baseline characteristics were similar in the RT (n=100) vs CRT (n=100) arms: median age, 77 vs 77 years; stage IIIB (n), 46 vs 49; PS 0/1/2 (n), 41/55/4 vs 41/56/3. The second planned interim analysis was performed 10 months after the completion of accrual. In accordance with the pre-specified stopping rule, the JCOG Data and Safety Monitoring Committee recommended early publication of this trial because of the difference in OS favoring the CRT arm. In the updated analysis, OS was better in the CRT arm than the RT arm (HR = .64, 95% CI = .46-.89, one-sided p = .0033 by stratified log-rank test). In each arm (RT/CRT), MST was 16.5 mo/22.4 mo with 3-year OS of 14.3%/34.6%, response rate of 44.9%/54.6% (p=.201) and median progression-free survival of 6.9 mo/8.9 mo (p=.003). Gr 3/4 toxicities were (RT/CRT): neutropenia 0%/57.3%, infection 4.1%/12.5%, dysphagia 0%/1.0%, late RT toxicities 7.4%/7.5%. The pattern of relapse site and post-protocol treatment were almost similar between the arms. Even after an adjustment by the Cox regression analysis with six variables [stage, PS, sex, age, histology, smoking status], CRT arm showed better survival (HR=.71, p=.038). Conclusions: The CRT using daily carboplatin is considered to be the standard treatment for elderly pts with locally advanced NSCLC.
Abnormality of growth hormone and insulin-like growth factor I axis in advanced cancer patients
Authors: T. Takahata, M. Munakata, Y. Sakata, K. Nakagawa, T. Mukaiyama, K. Ishitani, K. Tamura
Journal: Journal of Clinical Oncology (2007)

19671 Background: Pituitary and thyroid hormones are known to be altered in anorexia nervosa, but few hormonal studies have been performed in cancer anorexia-cachexia syndrome. This study focused on growth hormone (GH) and Insulin-like Growth Factor (IGF)-I axis in cancer patients. Methods: To investigate the relationship among performance status (PS), nutritional and hormonal status, blood sampling was performed to measure GH, IGF-I, IGF-binding protein 3(IGFBP-3), T3, T4, complete blood counts and blood chemistry profiles for 15 cancer patients in each of PS0–1, PS2, PS3 and PS4 after the informed consent was obtained. Results: A total of 58 patients were evaluated including 15 patients in PS0–1, PS2 and PS3 and 13 in PS4. Hemoglobin and albumin levels went down along with progression of PS. GH level was high and T3 was low in poor PS. T4 and IGFBP-3 were lower in PS4 than those of other PS. There is a tendency of low IGF-I and thyroid hormones and high GH levels in poor PS as compared with those of good PS (p=0.0064 for IGF-I, p&lt;0.001 for T3, and T4, not significant for GH analyzed by ANOVA). Conclusions: Abnormal GH - IGF-I axis was more pronounced in poor PS. It is conceivable that normalization of this abnormality can improve cancer anorexia-cachexia syndrome and new drug development for such normalizing agents is warranted. No significant financial relationships to disclose.
General Internal Medicine and General Internists: Recognizing a National Need
Journal: Annals of Internal Medicine (1992)

The Federated Council for Internal Medicine (FCIM) comprises the American Board of Internal Medicine, American College of Physicians, American Society of Internal Medicine, Association of Professors of Medicine, Association of Program Directors in Internal Medicine, and the Society of General Internal Medicine. The Council was established in 1975 to speak with a collective voice for the specialty of internal medicine. In 1992, the Council developed the following statement in conjunction with its endorsement of a target of 50% of internal medicine residency graduates entering the practice of general internal medicine.
RIVAROXABAN ATTENUATES CARDIAC REMODELING DUE TO INTERMITTENT HYPOXIA BY SUPPRESSING THE SYNERGISTIC EFFECTS OF PAR-1 AND PAR-2
Authors: Rintaro Mitsuishi, Hideki Imano, Ryuji Kato, Yoshio Ijiri, Takehiro Yamaguchi, Minoru Yoshiyama, Tetsuya Hayashi
Journal: Journal of the American College of Cardiology (2017)
Phase II study with preoperative oxaliplatin (O), cisplatin (P), 5-fluorouracil (F) (OPF) and radiation (XRT) in patients with esophageal (ES), gastroesophageal (GE), and gastric (G) cancer
Authors: M. Pera, R. Gallego, M. Martin-Richard, C. Montagut, M. Iglesias, C. Conill, C. Balaguer, L. Petriz, D. Momblan, J. Maurel
Journal: Journal of Clinical Oncology (2009)

e15612 Background: A phase I study showed the feasibility of the triplet combination (OPF) with XRT in ES and GE cancer (Maurel et al, IJRBOP, 2005). We conducted a phase II study to evaluate the efficacy of the regimen. Methods: Enrolled pts had resectable, high-risk (HR) based on endoscopic ultrasonography (EUS) (uT3, uN1 or uT4 if deemed resectable) ES, GE and G cancer. The primary objective was to determine the pathologic complete response (pCR). If 2 or more pCR were reported in the first 18 pts treated, enrollment continues with 23 additional pts. Eligibility criteria: squamous cell or adenocarcinoma of the ES, GE or G cancer and ECOG Performance status (PS) 0–1. Staging was done with EUS and computed spiral tomography. Laparoscopic staging was mandatory for pts with ES, GE and G adenocarcinoma. Pts received 2 cycles of O 85 mg/m2, P 55 mg/m2, F (3 g/m2 in 96h CI) q4w, with concomitant 45 Gy XRT in 25 fractions; surgery was planned 5–8 weeks after XRT. All pathological specimens were reviewed by a unique pathologist and regression analysis was recorded using Cologne (C) and M.D.Anderson (MDA) classification for ES and European Journal of Surgical Oncology (EJSO) for GE and G. Results: Between 5/04 to 12/07, 41 pts were enrolled in 5 Spanish Institutions. Median age 62 yrs (39–75 yrs); Male/female 83%/17%; PS 0/1 27%/73%; ES/GE/G 39%/32%/29%; EUS stageT3N0 (20%), T2–3N1 (65%) and T4 (10%). G3/4 adverse events included asthenia (27%), infection (7%), diarrhea (7%) and stomatitis (5%). There were 2 toxic deaths. Of the 31 pts who underwent surgery, there were R0=94%/R1=3%/R2= 3%. 7/41 pts (17%) achieved pCR. Using C and MDA classification, 9/14 (61%) and 12/14 (85%) ES achieved grade IV/III and P0/P1 regression, respectively. With EJSO classification 3/17 (18%) GE and G tumors achieved pCR. Median time to progression or death (PFS) was 16.2 (CI:12.2-NR) months (mo). Median overall survival (OS) was 28.9 mo. (CI: 22.5-NR). Conclusions: Although in the whole group pCR, PFS and OS does not appear superior to results achieved in other trials with preoperative P/F/XRT in HR pts, the OPF regimen seems specially active in ES cancer. No significant financial relationships to disclose.
Breast cancer surveillance in high-risk women with magnetic resonance imaging every 6 months.
Authors: Rodrigo Santa Cruz Guindalini, Yi-Ching Huang, Elias Obeid, Linda Patrick-Miller, Angela R. Bradbury, Marion S. Verp, Susan Hong, Kristen Wroblewski, Hiroyuki Abe, Greg S. Karczmar, Gillian Newstead, Olufunmilayo I. Olopade
Journal: Journal of Clinical Oncology (2013)

1506 Background: Surveillance with mammography (MMG) and magnetic resonance imaging (MRI) is recommended for women at high-risk for breast cancer, but there is no consensus on screening strategy. Aim of this study was to evaluate the efficacy of semi-annual MRI in high-risk women. Methods: A multi-modality surveillance program was initiated in 2004. Yearly MMG was supplemented with semi-annual MRI. After 5 years, an additional 5 years of follow-up with yearly MMG and MRI was offered to mutation carriers. Defining positive screening as BIRADS 0, 4 and 5, sensitivity, specificity, NPV, and PPV of semi-annual MRI were analyzed. Results: From 2004 to 2012, 226 patients underwent 1467 MRI and 851 MMG with a mean follow-up of 3.6 yrs. Median age at entry was 43 yrs (range 21-73), 48% were mutation carriers (105 BRCA1/2, 2 CDH1, 1 P53) and 19% had personal history of breast cancer. Eleven cancers were screen-detected, of which 6 (55%) were detected only by MRI, 1 (9%) only by MMG, and 4 (36%) by both. Of these tumors, 4 were detected in the first round of MMG/MRI screening and 7 (64%) in mutation carriers (5 BRCA1, 1 BRCA2, 1 CDH1), and 3 tumors (27%) were detected due to the additional MRI during semi-annual screening. No interval cancers occurred. Sensitivity, specificity, PPV and NPV of MRI were 91%, 97%, 18%, 99%, respectively. Of the incident cancers, 3 (27%) were stage 0 (ductal) and 8 (73%) were stage 1 (7 ductal and 1 lobular). Mean size of the invasive cancers was 0.78 cm (range 0.1-1.6; only 2 tumors &gt; 1.0 cm), none had lymph node metastasis, and 75% were high grade and hormone receptor positive. The largest tumor detected was invasive lobular in a 73 year old CDH1mutation carrier. Conclusions: To our knowledge, this is the first surveillance protocol with repeated screening rounds that detected mean size of invasive tumors less than 1 cm. Absence of interval cancers, high sensitivity/specificity, and detection of all tumors in early stages (stages 0 or 1) support this screening strategy as a viable alternative to prophylactic mastectomy. Ongoing work will examine quality of life, cost effectiveness and impact on overall survival of this screening approach. Clinical trial information: NCT00989638.
Preliminary antitumor activity of BAY 43–9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT)
Authors: M. J. Ratain, K. T. Flaherty, W. M. Stadler, P. O'Dwyer, S. Kaye, H. Xiong, A. Patnaik, M. Gore, R. J. Lee, T. Eisen
Journal: Journal of Clinical Oncology (2004)

4501 Background: BAY 43–9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. The phase II RDT study was undertaken to determine the antitumor activity (either regression or disease stabilization) of BAY in patients (pts) with a variety of advanced refractory solid tumors. Methods: Pts were enrolled in a placebo-controlled, RDT consisting of a 12-week induction phase, in which pts received 400 mg bid oral BAY, followed by a randomization phase. At the end of the 12-week phase pts whose target lesion tumor burden showed growth >25% (progressive disease PD) were discontinued. Pts whose target lesion tumor burden showed shrinkage ≥25% (responders) continued open label BAY until PD or toxicity. Pts whose target tumor lesion remained within 25% of baseline (stable disease SD) were randomized to receive 400 mg bid oral BAY or placebo. Results: In 14 months, 397 pts were enrolled. The most common tumor types were colorectal (CRC), renal cell carcinoma (RCC) and melanoma. Typical drug-related toxicities were hand-foot skin reaction, rash, fatigue, diarrhea, anorexia and hypertension. Tumor regressions were observed in multiple tumor types including RCC, CRC, melanoma, thyroid, sarcoma and pancreas. Of the 112 pts with RCC, 65 pts have reached the initial 12-week assessment (63 evaluable for response). Response evaluation by investigator demonstrated 25 responders, 18 SD and 15 PD. Five pts discontinued due to other reasons (e.g. adverse event or withdrawal of consent). Conclusions: BAY has activity (as measured by disease regressions) in multiple tumor types, particularly RCC, and is well tolerated in pts with advanced cancers. The randomized portion will provide information about BAY's disease-stabilizing effect and long-term safety, in particular in pts with RCC. An ongoing phase III study in RCC will assess BAY's effect on time to progression and survival. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Pharmaceutical Corp. Bayer Bayer Pharmaceuticals Bayer
AUTOMATIC SPECT ANALYSIS COMPARED TO EXPERT VISUAL SCORING FOR THE DETECTION OF CORONARY ARTERY DISEASE
Authors: Roel Driessen, Pieter Raijmakers, Ibrahim Danad, Wijnand Stuijfzand, Stefan Schumacher, Adriaan Lammertsma, Albert van Rossum, Niels Van Royen, Stephen Underwood, Paul Knaapen
Journal: Journal of the American College of Cardiology (2017)
Diffuse large B-cell lymphoma developing in erythrodermic cutaneous T-cell lymphoma: a case series
Authors: B.C.Y. Chan, C.M. Stefanato, M.T. Moonim, S.L. Morris, P. Fields, D. Dasgupta, A. Therianou, S.J. Whittaker
Journal: British Journal of Dermatology (2017)