tbuckley/cabot-search huggingface dataset:
Phase II study of biweekly irinotecan and cisplatin as second-line chemotherapy in pretreated patients with advanced gastric cancer
Authors: J. H. Baek, J. G. Kim, S. K. Sohn, H. S. Song, K. Y. Kwon, Y. R. Do, H. M. Ryu, S. H. Bae, G. W. Park, K. H. Lee
Journal: Journal of Clinical Oncology (2005)

4072 Background: The objectives of the present study were to evaluate the efficacy and safety of a combination regimen of biweekly irinotecan plus cisplatin in pretreated patients with advanced gastric cancer. Methods: Thirty-two patients with previously treated metastatic or recurrent gastric cancer were enrolled into the study. Chemotherapy consisted of intravenous irinotecan 70 mg/m2 and cisplatin 30 mg/m2 on day 1 and 15 every 4-week cycle. Treatment was continued until disease progression, patient refusal, or an unacceptable toxicity up to 6 cycles. Results: The median age of patients was 54.0 years (range, 27–69 years), and 27 (84.4%) patients were male. Sixteen patients had previously undergone surgery, one patient had received palliative radiation, and four patients had received 5-FU-based adjuvant chemotherapy. The prior palliative chemotherapies were paclitaxel/cisplatin (40.6%), paclitaxel/cisplatin/5-FU (21.9%), docetaxel/cisplatin (18.8%), and docetaxel/capecitabine (18.8%) and the responses included 1 CR (3.1%), 10 PR (31.3%), 7 SD (21.9%), and 14 PD (43.8%). Thirty one patients were assessable for efficacy and all for toxicity. No complete response and 5 partial responses were confirmed, giving an overall response rate of 15.6% (95% CI; 2.3%–28.9%). Grade 3/4 neutropenia occurred in 6 patients (18.8%), yet no febrile neutropenia was observed. Plus, grade 3 anorexia was observed in 4 patients (12.5%) and grade 3 diarrhea occurred in 2 patients (6.2%). There was no treatment-related death. At a median follow-up duration of 117 days (range, 14–462 days), the median time to progression and median overall survival for all patients was 113 days and 184 days, respectively. Conclusions: The combination chemotherapy of biweekly irinotecan and cisplatin was found to be moderately effective and well tolerated in pretreated patients with advanced gastric cancer. Accordingly, this regimen can be regarded as an important second-line treatment option for advanced gastric cancer. No significant financial relationships to disclose.
EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape
Authors: Seung-Oe Lim, Chia-Wei Li, Weiya Xia, Heng-Huan Lee, Shih-Shin Chang, Jia Shen, Jennifer L. Hsu, Daniel Raftery, Danijel Djukovic, Haiwei Gu, Wei-Chao Chang, Hung-Ling Wang, Mong-Liang Chen, Longfei Huo, Chung-Hsuan Chen, Yun Wu, Aysegul Sahin, Samir M. Hanash, Gabriel N. Hortobagyi, Mien-Chie Hung
Journal: Cancer Research (2016)

Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. EGF signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGFR, thereby increasing lactate excretion, which leads to inhibition of local cytotoxic T-cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-d-glucose with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC.
The Role of Nicotine in the Effects of Maternal Smoking during Pregnancy on Lung Development and Childhood Respiratory Disease. Implications for Dangers of E-Cigarettes
Authors: Eliot R. Spindel, Cindy T. McEvoy
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Use of e-cigarettes, especially among the young, is increasing at near-exponential rates. This is coupled with a perception that e-cigarettes are safe and with unlimited advertising geared toward vulnerable populations, the groups most likely to smoke or vape during pregnancy. There is now wide appreciation of the dangers of maternal smoking during pregnancy and the lifelong consequences this has on offspring lung function, including the increased risk of childhood wheezing and subsequent asthma. Recent evidence strongly supports that much of the effect of smoking during pregnancy on offspring lung function is mediated by nicotine, making it highly likely that e-cigarette use during pregnancy will have the same harmful effects on offspring lung function and health as do conventional cigarettes. In fact, the evidence for nicotine being the mediator of harm of conventional cigarettes may be most compelling for its effects on lung development. This raises concerns about both the combined use of e-cigarettes plus conventional cigarettes by smokers during pregnancy as well as the use of e-cigarettes by e-cigarette-only users who think them safe or by those sufficiently addicted to nicotine to not be able to quit e-cigarette usage during pregnancy. Thus, it is important for health professionals to be aware of the risks of e-cigarette usage during pregnancy, particularly as it pertains to offspring respiratory health.
Clinical advances in pediatric nonalcoholic fatty liver disease
Authors: Jeffrey B. Schwimmer
Journal: Hepatology (2016)

1Division of Gastroenterology, Hepatology, and Nutrition, Department of PediatricsUniversity of California, San Diego School of MedicineLa JollaCA 2Department of GastroenterologyRady Children's Hospital San DiegoSan DiegoCA 3Liver Imaging Group, Department of RadiologyUniversity of California, San Diego School of MedicineSan DiegoCA *ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:Jeffrey B. Schwimmer, M.D.Division of Gastroenterology, Hepatology, and NutritionDepartment of PediatricsUniversity of California, San Diego3020 Children's Way, MC 5030San Diego, CA 92123E‐mail: [email protected]fax: 858‐560‐6798
Safety and Efficacy of Bivalirudin Monotherapy in Patients With Diabetes Mellitus and Acute Coronary Syndromes
Authors: Frederick Feit, Steven V. Manoukian, Ramin Ebrahimi, Charles V. Pollack, E. Magnus Ohman, Michael J. Attubato, Roxana Mehran, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2008)
Abstract 18723: Genetic Variants Associated with QT Prolongation in Patients Exposed to Sotalol: A Genome Wide Association Study
Authors: Peter E Weeke, Jessica T Delaney, Jonathan D Mosley, Prince J Kannankeril, Quinn Wells, Sara Van Driest, Kris Norris, Gayle Kucera, Tanya Stubblefield, Toshio Tanaka, Yusuke Nakamura, Dan M Roden
Journal: Circulation (2012)

Introduction Sotalol is a frequently used antiarrhythmic drug known to cause QT-prolongation and increase the risk of the malignant arrhythmia Torsades de Pointes. We performed a genome wide association study (GWAS) to identify genetic markers associated with QT prolongation in sotalol exposed patients who were followed in an electronic medical record (EMR) system. Methods We identified 404 consented European American patients who initiated sotalol treatment via an EMR system through 2001-2011. Genotpying was performed on the Illumina 610-Quad BeadChip or the Illumina Human OMNI-express BeadChip, and the set of single nucleotide polymorphisms (SNPs) common to the two were analyzed initially. Maximum QT intervals were evaluated before and ≥48 hours after the start of therapy. Tests of association using linear regression were performed for change in the QTc interval assuming an additive genetic model adjusted for age and sex. Results After quality control, we analyzed a total of 314,618 SNP’s with a minor allele frequency of &gt;1% and a call rate of ≥98%. The strongest associations were found for SNPs harbored in genes FAM107B (p= 2.09E-07), NRG-3 (p=1.94E-06), and SVEP (p=6.44E-06). NRG-3 is involved in cardiac development and has previously been associated with QT prolongation. The estimated effect size of the top SNP in NRG-3 (rs7073972) is 12.3ms with a MAF=27%. FAM107B encode proteins of unknown function and SVEP encodes membrane proteins involved in cell adhesion processes. Both are expressed in cardiac tissue although neither has previously been associated with cardiac electrophysiology. Conclusion This GWAS identified genetic markers associated with change in the QTc interval during sotalol treatment. Notably, NRG-3 has previously been linked to drug induced QT interval prolongation. The results of this pharmacogenomics study provide novel insight into the clinical response to sotalol with the ultimate goal of directing therapy of future patients.
Rho Kinase as an Important Mediator of Aortic Stiffness
Authors: YX Li, PY Liu, HC Tai, YS Tsai, GF Mitchell, JK Liao
Journal: Circulation (2011)

Background: Rho kinases (ROCK1 and ROCK2) are important regulators of the actin cytockeleton and cellular contraction. Because advancing age is associated with increased vascular stiffening, we investigated whether aortic ROCK activity is increased with age and whether aortic stiffness could be attenuated by ROCK deletion.
Methods and Results: Compared to 4-month-old mice, 11- and 20-month-old mice exhibited increased aortic ROCK activity but not systemic blood pressure (BP). This correlated with increased aortic stiffness as determined by pulse wave velocity (PWV at 4, 11, and 20 months: 4.43 � 0.42, 6.66 � 0.53, and 7.22 � 0.56 m/sec; P<0.05 compared to 4 month). Compared to WT male mice at 4 months of age, aortic stiffness was slightly less in ROCK1+/- and ROCK2+/- mice (PWV: 3.55 � 0.25 and 3.33 � 0.20 m/sec, P<0.05). With increasing age (11 and 20 months), there was substantially less increase in aortic stiffening in ROCK1+/- and ROCK2+/- mice compared to WT mice, with the greatest attenuation observed in ROCK2+/- mice. Indeed, PWV in 4-month-old male WT mice was comparable to that of 11-month-old male ROCK1+/- mice and 20-month-old male ROCK2+/- mice. Aortic stiffness was also induced in WT, ROCK1+/- and ROCK2+/- mice with angiotensin (Ang) II (500 ng/kg/min by osmotic mini-pump) and the endothelial nitric oxide synthase inhibitor, L-NAME (0.5 g/L, po in drinking water), for 4 weeks. Compared to saline, treatment with Ang II/L-NAME increased systolic BP, pulse and augmented pressures, peripheral resistance (Z0), characteristic impedance (Zc), intrinsic stiffness (E), wall thickness, and PWV in WT mice, but to a lesser extent, in ROCK1+/- and ROCK2+/- mice. This correlated with greater differences between systolic and diastolic internal aortic root diameters suggesting greater vascular compliance or less stiffness. Indeed, decreased aortic stiffness in ROCK1+/- and ROCK2+/- mice was associated with preservation of elastic fibers and less deposition of mature collagen fibers. 
Conclusion: These findings indicate that ROCK2, and to a lesser extent, ROCK1, play an important role in the thickening and stiffening of the aorta. These results suggest that inhibition of ROCKs could attenuate age- and risk factor-associated increase in aortic stiffness.
Reevaluating the Need for Laboratory Testing in the Treatment of Onychomycosis
Authors: Matthew H. Kanzler
Journal: JAMA Dermatology (2015)

In this issue of JAMA Dermatology, Mikailov et al1 challenge our propensity to automatically order costly confirmatory diagnostic testing before initiating systemic therapy with terbinafine hydrochloride for onychomycosis. There are 2 issues of importance here: safety and cost-effectiveness.
Abstract 12206: P-Wave Morphologic Characteristics of 12-Lead Surface Electrocardiography Were Associated With Left Ventricular Diastolic Dysfunction
Authors: Tomoyuki Kabutoya, Satoshi Hoshide, Kazuo Eguchi, Kazuomi Kario
Journal: Circulation (2014)

Introduction:  Left ventricular diastolic dysfunction was demonstrated to be an early stage of heart failure, but the association between diastolic dysfunction and the P-wave morphology of 12-lead surface electrocardiography (ECG) has been unclear.   Hypothesis:  We assessed the hypothesis that the P-wave morphologic characteristics of 12-lead surface ECG were associated with diastolic dysfunction.   Methods:  We enrolled 1,256 patients who had at least one cardiovascular risk factor (hypertension, dyslipidemia, diabetes, or smoking). Their P-wave morphology on ECG was classified as normal (n=731), deflected (n=299), and notched type (n=226) in limb leads. P-wave morphology was defined as “deflected” if the ECG presented a deviation from a smooth fluent wave without showing a clear bifid pattern, and as “notched” if the peak-to-peak distance in the M-shape was more than 40 msec. We examined echocardiography and brain natriuretic peptide (BNP), and obtained an ECG in all patients.   Results:  Patients with notched P had significantly lower amplitudes of E-wave (60.5±17.0 vs. 66.8±16.9 cm/s, p   Conclusions:  Notched P-wave was associated with diastolic dysfunction, but not with left atrial diameter. P-wave morphologic characteristics might be a reflection of diastolic dysfunction.
Abstract 17099: Mineralocorticoid Receptors (MR)/Epithelial Na Channels (ENaCs) Pathway Activation in Choroid Plexus Exaggerates Salt-Induced Hypertension with Sympathoexcitation in Stoke-Prone Spontaneously Hypertensive Rats
Authors: Masatsugu Nakano, Yoshitaka Hirooka, Koji Ito, Kenji Sunagawa
Journal: Circulation (2012)

Background: High salt intake increases blood pressure via sympathoexcitation in salt-sensitive rats. An increase in cerebrospinal fluid Na+ concentration (CSF[Na+]) is suggested to be responsible f...
Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis
Authors: Li Wang, Na Liu, Chongxiang Xiong, Liuqing Xu, Yingfeng Shi, Andong Qiu, Xiujuan Zang, Haiping Mao, Shougang Zhuang
Journal: Journal of the American Society of Nephrology (2015)

Inhibitors of EGF receptor (EGFR) have antifibrotic effects in several organs, but the effect of these inhibitors on the development of peritoneal fibrosis is unknown. Here, we explored the therapeutic effect of gefitinib, a specific inhibitor of EGFR, on the development and progression of peritoneal fibrosis in a rat model. Daily intraperitoneal injections of chlorhexidine gluconate induced peritoneal fibrosis, indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts, accompanied by time-dependent phosphorylation of EGFR. Administration of gefitinib immediately after injury prevented the onset of peritoneal fibrosis and delayed administration after the onset of peritoneal fibrosis halted fibrosis progression. Gefitinib treatment abrogated the increased phosphorylation of EGFR, Smad3, signal transducer and activator of transcription 3, and NF-κB during peritoneal fibrosis; it also inhibited the accompanying overproduction of TGF-β1 and proinflammatory cytokines and the infiltration of macrophages to the injured peritoneum. Moreover, gefitinib significantly reduced the peritoneal increase of CD31-positive blood vessels and vascular EGF-positive cells after injury. Finally, gefitinib also attenuated high glucose-induced peritoneal fibrosis in rats and abrogated TGF-β1-induced phosphorylation of Smad3 and the epithelial-to-mesenchymal transition of cultured human peritoneal mesothelial cells. These results demonstrate that EGFR contributes to peritoneal fibrosis, inflammation, and angiogenesis, suggesting that EGFR inhibitors may have therapeutic potential in attenuating peritoneal fibrosis.
Prospective assessment of chemotherapy-induced neurotoxicity in breast cancer (HOR 02) and questionnaire survey of physicians’ perspectives
Authors: K. Kuroi, K. Shimozuma, Y. Ohashi, A. Takeuchi, T. Aranishi, S. Morita, S. Ohsumi, H. Makino, T. Watanabe, F. H. Hausheer
Journal: Journal of Clinical Oncology (2007)

6619 Background: Physician-based instruments (e.g., NCI-CTC) are widely used to assess chemotherapy-induced peripheral neuropathy (CIPN). However, current evidence suggests that physician-based assessments under-report the incidence and severity of CIPN. To overcome this limitation, a patient-based questionnaire, patient neurotoxicity questionnaire (PNQ) was developed, and a phase III randomized adjuvant trial of breast cancer (N-SAS BC 02; AC followed by PAC/DOC vs. PAC/DOC alone) has demonstrated that PNQ is reliable and sensitive and responsive instrument to assess CIPN (Shimozuma et al., SABCS 2004; #6037). We prospectively evaluated the reliability and sensitivity of PNQ in advanced or metastatic breast cancer treated by weekly administration of paclitaxel. Moreover, a questionnaire survey was conducted on physician perspectives regarding the assessment of CPIN in Japan. Methods: CIPN and QOL were prospectively assessed in thirty-five patients with advanced or metastatic breast cancer who received weekly paclitaxel (80–100 mg/m 2 /w). PNQ and FACT-Ntx subscale were compared to NCI-CTC. Assessments were conducted at baseline, 8 wk, 16 wk after starting treatments. A questionnaire was sent to physician who participated in N-SAS BC 02 to clarify their perspectives regarding the CPIN. Results: Average response rate of the instruments was 89%. Sensory PNQ scores correlated with sensory FACT-Ntx scores (r=0.51), and NCI-CTC scores (r=0.58). NCI-CTC scores mainly distributed between 0 and 1, while PNQ scores widely distributed. Follow-up study revealed that sensory CIPN assessed by PNQ appeared to be sensitive as compared to NCI-CTC. In clinician survey, 47 out of 61 physicians (77%) responded, and majority of them considered neurosensory symptoms as diagnostic hallmark for CIPN. However, for the justification for treatment delay, dose modification, or treatment cessation, most laid weight on functional impairment in patients with CIPN. Most (80%) rated PNQ is helpful in management of patients at risk for CIPN. Conclusions: This study confirmed that physicians tended to underestimate CIPN, and PNQ was a more reliable and valid instrument to assess CIPN with high acceptability in physicians. [Table: see text]
Abstract P1-05-02: Epithelial-to-epithelial transition precedes collective breast cancer invasion
Authors: KJ Cheung, AJ Ewald
Journal: Cancer Research (2012)

Abstract BACKGROUND: Invasion represents a fundamental step in tumor progression and is a driving force for metastasis and cancer-related mortality. Invasion has been studied largely in the context of single cells, but in vivo, most tumor cells are not found in isolation, but rather are found as ensembles of cells with substantial molecular heterogeneity. It remains poorly understood in this context which cells are invasive, how these cells arise or how these cells interact collectively to accomplish invasion. RESULTS: We developed an ex-vivo 3D culture assay enabling us to distinguish invasive from non-invasive cells and to interrogate their molecular phenotype. In two mouse models of luminal breast cancer, we find that invasive cells express markers of basal epithelium including cytokeratin K14, p63 and P-cadherin. Invasive K14+ cells were also molecularly and functionally distinct from normal myoepithelial cells and co-expressed luminal K8 and E-cadherin. In vivo, K14+ cells were localized to tumor-stromal interfaces in the primary tumor and in lung micro and macro-metastases. Using a molecular biosensor and time-lapse microscopy, we observed that K14+ invasive cells were derived from K14-negative luminal tumor cells by direct phenotypic conversion. Interestingly, the capacity of luminal tumor cells to acquire basal markers varied by model, with few K14+ cells in MMTV-Her2 and many K14+ cells in MMTV-PyMT mice, correlating with the known in vivo kinetics of tumor progression in these models. To block this epithelial to epithelial transition, we tested the activity of an inhibitor of ribosome S6 kinase (RSK), which has been shown previously to inhibit myoepithelial differentiation in normal mammary epithelium. RSK inhibition caused relative depletion of K14+ tumor cells in 3D culture and abrogation of invasion. Finally, our assay revealed that in fresh primary tissue from human ER+ luminal breast cancers, invasive cells also expressed basal epithelial markers. CONCLUSIONS: Taken together, these data suggest that an epithelial-to-epithelial transition precedes collective invasion in luminal breast cancers. Because we observe K14+ leader cells independent of tumor estrogen receptor status, these data may be generally applicable to breast cancer invasion across subtypes. Because many epithelial tissues have basal populations, K14+ tumor cells may also lead invasion in other cancers. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-02.
Autoantibodies Targeting a Collecting Duct–Specific Water Channel in Tubulointerstitial Nephritis
Authors: Nils Landegren, Mina Pourmousa Lindberg, Jakob Skov, Åsa Hallgren, Daniel Eriksson, Trine Lisberg Toft-Bertelsen, Nanna MacAulay, Eva Hagforsen, Anne Räisänen-Sokolowski, Heikki Saha, Thomas Nilsson, Gunnel Nordmark, Sophie Ohlsson, Jan Gustafsson, Eystein S. Husebye, Erik Larsson, Mark S. Anderson, Jaakko Perheentupa, Fredrik Rorsman, Robert A. Fenton, Olle Kämpe
Journal: Journal of the American Society of Nephrology (2016)

Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct–specific water channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells.
Global Use of Peripheral Blood vs Bone Marrow as Source of Stem Cells for Allogeneic Transplantation in Patients With Bone Marrow Failure
Authors: Ayami Yoshimi, Helen Baldomero, Mary Horowitz, Jeff Szer, Dietger Niederwieser, Alois Gratwohl, Yoshihisa Kodera
Journal: JAMA (2016)

This study uses international survey and transplant registry data to compare use of bone marrow with use of peripheral blood stem cells for hematopoietic stem cell transplantation in World Health Organization member countries.
Cell-of-Origin Assignment in Diffuse Large B-Cell Lymphoma Determined By Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Has Prognostic Significance Independent of IPI and MYC/BCL2 Immunohistochemistry
Authors: David W. Scott, Anja Mottok, Daisuke Ennishi, George W. Wright, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S Barry, Christoffer E Hother, Kerry J. Savage, Laurie H. Sehn, Louis M. Staudt, Joseph M. Connors, Lisa M. Rimsza, Randy D. Gascoyne
Journal: Blood (2014)
Semaphorin 4D produced by human head and neck squamous cell carcinoma induces myeloid derived suppressor cells expansion from peripheral blood monocytes
Authors: Rania H Younis, Kyu Han, Tonya Webb
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immune suppression is one of the hallmarks by which head and neck squamous cell carcinoma (HNSCC) develops a tumor permissible environment[[1][1]]. Semaphorin 4D (Sema4D), known for its various developmental, physiological and pathological effects, was recently shown to play a