tbuckley/cabot-search huggingface dataset:
Correlation between low-dose cyclophosphamide-induced hyponatraemia and the use of aprepitant.
Authors: Yasutaka Tono, Toshiro Mizuno, Kanako Saito, Satoshi Tamaru, Yoshiki Yamashita, Hiroyasu Oda, Shinichi Kageyama, Naoyuki Katayama
Journal: Journal of Clinical Oncology (2012)

e19546 Background: For prevention of nausea/vomiting during anthracyline/cyclophosphamide (CPA) therapy for breast cancer, use of aprepitant (AP) combined with serotonin antagonist and dexamethasone is recommended. It has been reported that AP does not influence AUC’s of 4-hydro-cyclophosphamide, an active metabolite of CPA, and DCE, a CPA-metabolite causing nephrotoxicity. Although, in the previous clinical reports for anthracyline/CPA, the toxicities were not significant in patients who were given AP, compared to those without AP, we have experienced several cases of severe hyponatremia probably caused by AP. Occurrence of hyponatremia during chemotherapy might be an issue to be cautious. Methods: We investigated serum levels of Na in 67 breast cancer patients who received CPA-combined therapy with the use of AP, or not. They all received 600mg/m 2 of CPA combined with either of doxorubicine, epirubicin, or docetaxel. Their prior electrolytes were to be within normal range. In the first cycle, we evaluated serum Na levels before the CPA start and those of 24 hours after. We defined a serum Na level lower than 135 mEq/L as “hyponatremia”. Results: The background between the two groups, with AP and without AP, were comparable, in whom the prior Na levels were 140.0 ±1.97 mEq/L, and 140.1 ±1.88 mEq/L, in the AP- and in non-AP-group, respectively. The chemotherapies including CPA, the clinical stages, the uses of serotonin-receptor antagonist and dexamethasone were comparable between the two groups. Hyponatremia occurred in 11 patients out of 42 (26.2%) in AP-group, whereas 2 patients in 25 (8.0%) in non-AP-group. Since the rate in non-AP-group was comparable to the previous reports, hyponetremia seemed to occur frequently in AP-group. The average Na level at 24 hours after chemotherapy was 136.429 ±3.94 mEq/L in AP-group, and 138.68 ±3.05 mEq/L in non-AP-group, respectively. Among 11 patients who developed hyponateremia, they were resolved within 48 hours without any treatments in 10 patients, and only one needed Na replacement. The patient did not develop hyponatremia without using AP in the third cycle. Conclusions: According to our cohort study, AP might frequently cause hyponatremia in the CPA-combined chemotherapy.
PDLIM1 Inhibits Tumor Metastasis Through Activating Hippo Signaling in Hepatocellular Carcinoma
Authors: Zhao Huang, Jian‐Kang Zhou, Kui Wang, Haining Chen, Siyuan Qin, Jiayang Liu, Maochao Luo, Yan Chen, Jingwen Jiang, Li Zhou, Lei Zhu, Juan He, Jiao Li, Wenchen Pu, Yanqiu Gong, Jianbo Li, Qin Ye, Dandan Dong, Hongbo Hu, Zongguang Zhou, Lunzhi Dai, Canhua Huang, Xiawei Wei, Yong Peng
Journal: Hepatology (2019)

Background and Aims Tumor metastasis is a major factor of high recurrence and mortality in hepatocellular carcinoma (HCC), but its underlying mechanism remains elusive. We report that PDZ and LIM domain protein 1 (PDLIM1) is significantly down‐regulated in metastatic human HCC tissues, which predicts unfavorable prognosis, suggesting that PDLIM1 may play an important inhibitory role during HCC metastasis. Approach and Results Functional studies indicate that PDLIM1 knockdown induces epithelial‐to‐mesenchymal transition (EMT) of HCC cells, elevates their invasive capacity, and promotes metastasis in vitro and in vivo , whereas overexpression of PDLIM1 exhibits opposite phenotypes. Mechanistically, PDLIM1 competitively binds to the cytoskeleton cross‐linking protein alpha‐actinin 4 (ACTN4), leading to the disassociation of ACTN4 from F‐actin, thus preventing F‐actin overgrowth. In contrast, loss of PDLIM1 induces excessive F‐actin formation, resulting in dephosphorylation of large tumor suppressor kinase 1 and activation of Yes‐associated protein, thereby promoting HCC metastasis. Moreover, Asn145 (N145) of PDLIM1 is critical for its interaction with ACTN4, and N145A mutation abolishes its regulatory function in Hippo signaling and HCC metastasis. Conclusions Our findings indicate that PDLIM1 suppresses HCC metastasis by modulating Hippo signaling, suggesting that PDLIM1 may be a potential prognostic marker for metastatic HCC.
Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases
Authors: Rong Cai, Yu Zhang, Jacob E. Simmering, Jordan L. Schultz, Yuhong Li, Irene Fernandez-Carasa, Antonella Consiglio, Angel Raya, Philip M. Polgreen, Nandakumar S. Narayanan, Yanpeng Yuan, Zhiguo Chen, Wenting Su, Yanping Han, Chunyue Zhao, Lifang Gao, Xunming Ji, Michael J. Welsh, Lei Liu
Journal: Journal of Clinical Investigation (2019)

Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.
Multitrial evaluation of longitudinal tumor measurement (TM)-based metrics for predicting overall survival (OS) using the RECIST 1.1 data warehouse.
Authors: Sumithra J. Mandrekar, Ming-Wen An, XinXin Dong, Axel Grothey, Jan Bogaerts, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2013)

6520 Background: We previously reported that alternative cutpoints and alternate categorical metrics to RECIST standards provided no meaningful improvement in OS prediction. Here, we sought to identify and validate continuous, longitudinal TM-based metrics for predicting OS. Methods: Data from 13 trials (1739 patients with sufficient imaging-based measurements from breast, lung or colon cancer) were randomly split (60:40) into training and validation datasets and landmarked at 12-weeks (w). Multiple candidate metrics that capture tumor curve trajectory were considered: first slope (or % change) from baseline to 6 w, last slope (or % change) from 6 w to 12 w, and indicator of increase (&lt;5% (includes no increase or a decrease) vs. ≥5%) from the prior assessment (baseline to 6 w, 6 w to 12 w). Multivariable Cox models stratified by study and number of baseline target lesions (&lt;3 vs. &gt;3) and adjusted for baseline tumor burden (ratio of the sum of lesions/number of lesions) were fit for each tumor type. Predictive ability was assessed via concordance (c)-index (0.5: no association to 1.0: perfect association), and hazard ratios/p-values (HR/p). Results: Patients whose tumor size increased by at least 5% from the prior assessment, as well as whose tumors showed a positive slope (or % change) from 6 to 12 w (indicating tumor growth) had worse OS. The first slope (or % change) metric was less consistent, with an initial decrease in slope suggesting worse OS in some cases. Predictive ability of these metrics varied across tumor type with poorest prediction in Breast (Table). Conclusions: Continuous TM-based metrics performed no better than categorical RECIST metrics for OS prediction. [Table: see text]
Metastatic Hormone-Sensitive Prostate Cancer: Clinical Decision Making in a Rapidly Evolving Landscape of Life-Prolonging Therapy
Authors: David J. VanderWeele, Emmanuel S. Antonarakis, Michael A. Carducci, Robert Dreicer, Karim Fizazi, Silke Gillessen, Celeste S. Higano, Alicia K. Morgans, Daniel P. Petrylak, Christopher J. Sweeney, Maha Hussain
Journal: Journal of Clinical Oncology (2019)
Defining High Bleeding Risk in Patients Undergoing Percutaneous Coronary Intervention
Authors: Philip Urban, Roxana Mehran, Roisin Colleran, Dominick J. Angiolillo, Robert A. Byrne, Davide Capodanno, Thomas Cuisset, Donald Cutlip, Pedro Eerdmans, John Eikelboom, Andrew Farb, C. Michael Gibson, John Gregson, Michael Haude, Stefan K. James, Hyo-Soo Kim, Takeshi Kimura, Akihide Konishi, John Laschinger, Martin B. Leon, P.F. Adrian Magee, Yoshiaki Mitsutake, Darren Mylotte, Stuart Pocock, Matthew J. Price, Sunil V. Rao, Ernest Spitzer, Norman Stockbridge, Marco Valgimigli, Olivier Varenne, Ute Windhoevel, Robert W. Yeh, Mitchell W. Krucoff, Marie-Claude Morice
Journal: Circulation (2019)

Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limits trial design, data interpretation, and clinical decision-making. The Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a collaboration among leading research organizations, regulatory authorities, and physician-scientists from the United States, Asia, and Europe focusing on percutaneous coronary intervention–related bleeding. Two meetings of the 31-member consortium were held in Washington, DC, in April 2018 and in Paris, France, in October 2018. These meetings were organized by the Cardiovascular European Research Center on behalf of the ARC-HBR group and included representatives of the US Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, as well as observers from the pharmaceutical and medical device industries. A consensus definition of patients at high bleeding risk was developed that was based on review of the available evidence. The definition is intended to provide consistency in defining this population for clinical trials and to complement clinical decision-making and regulatory review. The proposed ARC-HBR consensus document represents the first pragmatic approach to a consistent definition of high bleeding risk in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing percutaneous coronary intervention.
Successful closure of a complicated endoscopic ultrasound-related duodenal perforation
Authors: José Celso Ardengh, Roberto Mundim Porto Filho, Vitor Ottoboni Brunaldi, José Eduardo Brunaldi, João Almiro Ferreira Filho, Rafael Kemp, José Sebastião dos Santos
Journal: Endoscopy (2019)

The incidence of duodenal perforation during endosonography (EUS) ranges from 0 % to 0.04 % [1]. The tip of the linear endoscope may perforate the duodenum as a consequence of angulation and the presence of stenosis or diverticula [1] [2]. Unfortunately, in general, surgical repair is needed [3].
New Frontiers in Osteoporosis Therapy
Authors: Cheng Cheng, Kelly Wentworth, Dolores M. Shoback
Journal: Annual Review of Medicine (2019)

Current osteoporosis medications reduce fractures significantly but have rare and serious adverse effects (osteonecrosis of the jaw, atypical femoral fractures) that may limit their safety for long-term use. Insights from basic bone biology and genetic disorders have led to recent advances in therapeutics for osteoporosis. New approaches now in clinical use include the antisclerostin monoclonal antibody romosozumab, as well as the parathyroid hormone-related peptide analog abaloparatide. Clinical trial data show significant antifracture benefits with recently approved romosozumab. Studies using abaloparatide build on our longstanding experience with teriparatide and the importance of consolidating the bone mineral density gains achieved from an anabolic agent by following it with an antiresorptive. Combination and sequential treatments using osteoporosis medications with different mechanisms of action have also been tested with promising results. On the horizon is the potential for cell-based therapies (e.g., mesenchymal stem cells) and drugs that target the elimination of senescent cells in the bone microenvironment.
Model Informed Drug Development: Novel Oncology Agents are Lost in Translation
Authors: Kapil Mayawala, Dinesh P. de Alwis, Jeffrey R. Sachs
Journal: Clinical Cancer Research (2019)

Excitement around and investment in oncology drug development are at unprecedented levels. To maximize the health impact and productivity of this research and development investment, quantitative modeling should impact key decisions in early clinical oncology including Go/No-Go decisions based on early clinical data, and dose selection for late stage studies.See related article by Bottino et al., p. 6633.
2019 Update on Medical Overuse
Authors: Daniel J. Morgan, Sanket S. Dhruva, Eric R. Coon, Scott M. Wright, Deborah Korenstein
Journal: JAMA Internal Medicine (2019)

Medical overuse is an important cause of patient harm and medical waste.This structured literature review of English-language articles supplemented by examination of tables of contents of high-impact journals published in 2018 identified articles related to medical overuse. Articles were appraised for their methodologic quality, clinical relevance, and influence on patients. Of 1499 candidate articles, 839 addressed medical overuse. Of these, 117 were deemed to be most significant, with the 10 highest-ranking articles selected by author consensus. The most important articles on medical overuse identified issues with testing, including that procalcitonin does not affect antibiotic duration in patients with lower respiratory tract infection (4.2 vs 4.3 days); incidentalomas are present in 22% to 38% of common magnetic resonance imaging or computed tomography studies; 9% of women dying of stage IV cancer are still screened with mammography; and computed tomography lung cancer screening offers stable benefit and higher rates of harm for patients at lower risk. Articles related to overtreatment reported that urgent care clinics commonly overprescribe antibiotics (in 39% of all visits, patients received antibiotics) and that treatment of subclinical hypothyroidism had no effect on clinical outcomes. Three studies highlighted services that should be questioned, including using opioids for chronic noncancer pain (meta-analysis found no clinically significant benefit), stress ulcer prophylaxis for intensive care unit patients (mortality, 31.1% with pantoprazole vs 30.4% with placebo), and supplemental oxygen for patients with normal oxygen levels (mortality relative risk, 1.21; 95% CI, 1.03-1.43). A policy article found that state medical liability reform was associated with reduced invasive testing for coronary artery disease, including 24% fewer angiograms.The findings suggest that many tests are overused, overtreatment is common, and unnecessary care can lead to patient harm. This review of these 2018 findings aims to inform practitioners who wish to reduce overuse and improve patient care.
Effect of increased body mass index on time to tumor progression in metastatic unresectable colorectal cancer patients treated with bevacizumab-based therapy.
Authors: Ibrahim Yildiz, Fatma Sen, Leyla Kilic, Serkan Keskin, Rumeysa Ciftci, Meltem Ekenel, Nuri Faruk Aykan
Journal: Journal of Clinical Oncology (2013)

e14594 Background: High body mass index (BMI) is a well known risk factor in the development and recurrence of several solid tumors including colorectal cancer (CRC). Obesity is associated with increased serum levels of vascular endothelial growth factor (VEGF). Bevacizumab is the main targeted therapy inhibiting tumor angiogenesis by blocking VEGF receptor. We evaluated the effect of BMI on time to tumor progression (TTP) in patients who received bevacizumab based therapy due to advanced colorectal cancer in our institution. Methods: Patients with metastatic colorectal cancer who have been treated with fluoropyrimidine-based combination chemotherapy with bevacizumab were included in the study. Data of patients’ clinical treatment characteristics were obtained from the medical records. The height and weight measured during the initiation of bevacizumab were used to assign the patients to group A (BMI&lt;25 kg/m2) and group B (BMI≥25 kg/m2). The time to tumor progression was defined as the day of initiation of bevacizumab based threpay to the date of first documented progressive disease, the date of death regardless of its course or the date of last follow up if no disease progression or no death occured at this time. Results: 236 patients (median age 57, range 27-79 years) were treated withfluoropyrimidine-based combination chemotherapy with bevacizumab between April 2007 and June 2011. 127 (51.3%) patients had a BMI &lt;25 kg/m2 and 115 (48.7%) patients were found to have a BMI ≥25 kg/m2. One hundred ninety-three patients (82.1%) had first line bevacizumab therapy, and 44 patients (22.8%) had second-line bevacizumab therapy. Tumors of 68.4% of patients in group A and 69,1% of patients in group B progressed during a median 10 months (3-57 months) follow up. The median TTP was 9.5 months in the BMI &lt;25 group and 8.2 months in the BMI &gt;25 group.In multivariate analysis, high BMI (≥25 kg/m2) was associated with significantly shorter TTP (p: 0.002; HR, 1.91; 95% CI, 1.26–2.88). Conclusions: High BMI is a relevant prognostic factor in predicting the time to tumor progression in metastatic colon cancer patients treated with bevacizumab.
Airway and alveolar epithelial cells in culture
Authors: Pieter S. Hiemstra, Teresa D. Tetley, Sam M. Janes
Journal: European Respiratory Journal (2019)

<b>Airway and alveolar epithelial cells play a key role in health and disease. This review provides an introduction into the principles of epithelial cell culture, emerging developments and foreseeable future applications.</b>http://bit.ly/33NxojQ
Cooperativity of co-factor NR2F2 with Pioneer Factors GATA3, FOXA1 in promoting ERα function
Authors: Guojuan Jiang, Xinrui Wang, Dandan Sheng, Lei Zhou, Yang Liu, Congling Xu, Suling Liu, Ji Zhang
Journal: Theranostics (2019)

Estrogen receptor α (ERα) drives growth in the majority of human breast cancers by binding to regulatory elements and inducing transcriptional events that promote tumor growth. ERα binding activity largely depends on access to binding sites on chromatin, which is facilitated in part by Pioneer Factors (PFs). Transcription factors operate in complexes through thousands of genomic binding sites in a combinatorial fashion to control the expression of genes. However, the extent of crosstalk and cooperation between ERα pioneer factors and more collaborative transcription factors in breast cancer still remains to be elucidated systematically.
Progesterone and Breast Cancer
Authors: Britton Trabert, Mark E Sherman, Nagarajan Kannan, Frank Z Stanczyk
Journal: Endocrine Reviews (2019)

Abstract Synthetic progestogens (progestins) have been linked to increased breast cancer risk; however, the role of endogenous progesterone in breast physiology and carcinogenesis is less clearly defined. Mechanistic studies using cell culture, tissue culture, and preclinical models implicate progesterone in breast carcinogenesis. In contrast, limited epidemiologic data generally do not show an association of circulating progesterone levels with risk, and it is unclear whether this reflects methodologic limitations or a truly null relationship. Challenges related to defining the role of progesterone in breast physiology and neoplasia include: complex interactions with estrogens and other hormones (eg, androgens, prolactin, etc.), accounting for timing of blood collections for hormone measurements among cycling women, and limitations of assays to measure progesterone metabolites in blood and progesterone receptor isotypes (PRs) in tissues. Separating the individual effects of estrogens and progesterone is further complicated by the partial dependence of PR transcription on estrogen receptor (ER)α-mediated transcriptional events; indeed, interpreting the integrated interaction of the hormones may be more essential than isolating independent effects. Further, many of the actions of both estrogens and progesterone, particularly in “normal” breast tissues, are driven by paracrine mechanisms in which ligand binding to receptor-positive cells evokes secretion of factors that influence cell division of neighboring receptor-negative cells. Accordingly, blood and tissue levels may differ, and the latter are challenging to measure. Given conflicting data related to the potential role of progesterone in breast cancer etiology and interest in blocking progesterone action to prevent or treat breast cancer, we provide a review of the evidence that links progesterone to breast cancer risk and suggest future directions for filling current gaps in our knowledge.
Obesity is a public health emergency
Authors: Agnes Ayton, Ali Ibrahim
Journal: BMJ (2019)

The obesity epidemic started in the 1970s, initially in the United States and subsequently spreading worldwide.1 Approximately 60-80% of adults and 20-30% of children in most Western countries are now overweight or obese, which is unprecedented in human history.23 The BMJ asks whether this change should be regarded a consequence of individual choices or a disease affecting the population.4 …
CORT-AHF Study
Authors: Òscar Miró, Koji Takagi, Etienne Gayat, Pere Llorens, Francisco J Martín-Sánchez, Javier Jacob, Pablo Herrero-Puente, Víctor Gil, Desiree N Wussler, Fernando Richard, María L López-Grima, Cristina Gil, José M Garrido, María J Pérez-Durá, Aitor Alquézar, Héctor Alonso, Josep Tost, Francisco J Lucas Invernón, Christian Mueller, Alexandre Mebazaa
Journal: JACC Heart Failure (2019)