tbuckley/cabot-search huggingface dataset:
The safety and efficacy of bevacizumab therapy in recurrent ovarian carcinoma
Authors: J. P. Diaz, M. M. Leitao, J. A. Konner, P. Sabbatini, M. L. Hensley, D. S. Chi, D. R. Spriggs, R. R. Barakat, C. A. Aghajanian, W. P. Tew
Journal: Journal of Clinical Oncology (2008)

16528 Background: To evaluate the safety and efficacy of bevacizumab alone or in combination therapy in heavily pretreated patients with ovarian cancer. Methods: We identified patients not participating in an ongoing clinical trial who received bevacizumab. Response was retrospectively assessed by CA125 criteria. Complete response (CR) was defined as normalization of serum levels to ≤ 35 U/mL. Partial response (PR) was defined as a ≥50% decrease after initiation of treatment confirmed 28 days apart. Adverse events were prospectively categorized using the common terminology criteria version 3.0. Progression-free and overall survival (PFS and OS) was estimated using Kaplan-Meier method with log-rank test where indicated. Results: Forty-nine patients were identified. The patients were pretreated with a median of 6 (range 1–15) prior chemotherapy regimens including a median of 2 (range 1–6) platinum based regimens. Twenty-two (45%) patients received bevacizumab alone and 27 (55%) received varied combination cytotoxic chemotherapy. Patients received bevacizumab therapy for a median 4.6 months (range 0–27 months). Twenty-two (45%) patients received 10 mg/kg every 2 weeks, while 16 (33%) patients received 15 mg/kg every 3 weeks. Eleven (22%) received both dosing schedules. CTC grade 3 and 4 toxicities occurred in 7 (14.3%) different patients. Toxicities included: 2 (4%) gastrointestinal (GI) perforation, 3 (6%) grade 3 HTN, 1 (2%) transient ischemic attack, and 1 (2%) subarachnoid hemorrhage, Thirty-four patients were evaluable for overall CA-125 response rate (ORR), which included both CR and PR. The ORR for this cohort was 47.1%. The ORR for those who received bevacizumab alone was 30% compared to 65% for those treated with bevacizumab in combination with cytotoxic chemotherapy (P = 0.04). The median PFS for the entire group was 4.6 months (95% CI: 1.1, 8.2 months). The median OS was 11.0 months (95% CI: 3.9, 18.0 months). Conclusions: Bevacizumab alone or in combination therapy is well tolerated and demonstrates activity in heavily pretreated patients with recurrent ovarian cancer. The GI perforation rate in our study is similar to previously reported. Further study of bev alone or in combination therapy is warranted. No significant financial relationships to disclose.
A multi-institutional feasibility study of induction pemetrexed (Pem) plus cisplatin (Cis) followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation (RT) for malignant pleural mesothelioma (MPM): Japan Mesothelioma Research Center (JMRC) 001001 trial.
Authors: F. Tanaka, S. Hasegawa, T. Yamanaka, M. Okada, T. Soejima, N. Kamikonya, K. Yokoi, K. Fukuoka, T. Nakano
Journal: Journal of Clinical Oncology (2010)

TPS285 Background: Trimodality treatment consisting of preoperative induction chemotherapy with Pem plus Cis (PC), EPP, and postoperative RT might be a promising treatment option for potentially resectable MMP, but its safety as well as efficacy remains unclear, especially in Asian population, as only limited information is currently available from a few Western studies. Methods: The Japan Mesothelioma Research Center (JMRC), supported by the Special Coordination Funds for Promoting Science and Technology from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, has planned a nationwide prospective study to assess the feasibility of trimodality treatment for potentially resectable clinical stage I-III MPM patients. Based on the results of a phase I/II study of PC for unresectable MPM conducted in Japan and a single-institution pilot study of induction PC for resectable MPM, we adopted Cis at the dose of 60 mg/m2 in combination with Pem (500 mg/m2). After 3 cycles of PC, patients received EPP followed by RT (54 Gy in 30 fractions of 1.8 Gy per day). The primary endpoints are macroscopic complete resection rate and treatment-related mortality, and secondary endpoints included completion rate of trimodality treatment, adverse events, radiographic response rate of induction chemotherapy, and 2-year disease-free survival and overall survival. A total of 40 patients will be accrued over 3 years. Patient accrual rate continues as planned after activation of this trial on May 15, 2008, with registration at the UMIN Clinical Trials Registry (No. 000001154). 19 eligible patients have been enrolled as of December 31, 2009. We expect that patient registration will be completed in 2011, and this nationwide multi-institutional study will provide a variety of information on trimodality treatment in the Japanese population, which contributes to planning future prospective studies for resectable MPM. No significant financial relationships to disclose.
Effect of 21-gene recurrence score results on treatment recommendations in patients age 65 and older with lymph node-positive, estrogen receptor-positive breast cancer.
Authors: R. Oratz, C. Chao, S. Skrzypczak, C. Ory, M. Broder
Journal: Journal of Clinical Oncology (2010)

e11077 Background: Results of recent Oncotype DX studies indicate that the recurrence score (RS) can identify patients with node-positive, estrogen receptor-positive (N+/ER+) breast cancer who may not benefit from chemotherapy. We performed a survey to characterize the effect of the Oncotype DX assay on adjuvant treatment recommendations in N+/ER+ breast cancer. Methods: U.S. medical oncologists who ordered Oncotype DX for at least one patient with N+/ER+ breast cancer were asked to complete a web-based survey regarding the most recent N+/ER+ patient for whom the Oncotype DX assay was ordered. The survey was developed through cognitive interviews with medical oncologists, and an institutional review board approved the protocol. Results: There were 160 completed surveys; this analysis focuses on the 59 surveys in which the patient was ≥ 65 years old. Most physician respondents were in community practices (76%), and they had a median of 9 years (range: 3–45) of practice experience. The median patient age was 71 years (range: 65–82). T1, T2, or T3 disease was reported in 58%, 39%, and 3% of patients, respectively. One, two, three, or 4+ nodes were reported in 58%, 31%, 7%, and 3%, respectively (unknown in 1 patient). Sixty-three percent of N+/ER+ patients had an RS < 18; 31% had an RS of 18–30; and 7% had an RS ≥ 31. Before obtaining the RS, oncologists had a treatment recommendation for 51 of the 59 patients: chemotherapy was planned in 27/59 (46%), endocrine therapy in 23/59 (39%), and other treatment for 1/59 (2%). After obtaining the RS, chemotherapy was eliminated in 23/51 patients (45%) and added in 7/51 (14%), for a 31% net reduction in chemotherapy. Conclusions: For patients aged 65 and older with N+/ER+ breast cancer, the RS is used more often (but not exclusively) in patients with 1–2 positive nodes and T1 or T2 stage disease. Treatment recommendations for these patients were frequently changed by the RS, with an overall reduction in the recommendation for chemotherapy, a change that may result in more cost-effective care. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genomic Health Genomic Health, Partnership for Health Analytic Research, The Women's Oncology & Wellness Practice Genomic Health The Women's Oncology & Wellness Practice Genomic Health
SH2B1 is critical for the regulation of cardiac remodelling in response to pressure overload
Authors: Gang Wu, Yu Liu, He Huang, Yanhong Tang, Wanli Liu, Yang Mei, Nian Wan, Xiaoxiong Liu, Congxin Huang
Journal: Cardiovascular Research (2015)

Src homology 2 (SH2) B adaptor protein 1 (SH2B1) is expressed in various tissues, including the heart. Previous studies have demonstrated that SH2B1 is involved in a variety of biological process, such as maintaining neuronal differentiation, regulating energy and glucose homeostasis, and promoting cell proliferation and motility. However, the role of SH2B1 in cardiac hypertrophy remains unclear. This study aimed at identifying the effects and the underlying mechanisms of SH2B1 in cardiac hypertrophy. We performed gain- and loss-of-function studies using genetic approaches, and cardiac hypertrophy was evaluated through pathological, echocardiographic, haemodynamic, and molecular analyses. We found that SH2B1 expression was significantly increased in both failing human hearts and hypertrophic murine hearts. Mice overexpressing SH2B1 specifically in the heart displayed increased aortic banding (AB)-induced cardiac hypertrophy, fibrosis, ventricular dilation, and dysfunction compared with controls, whereas loss of SH2B1 produced the opposite phenotype. Consistently, similar results were observed in a global SH2B1-knockout rat model. Mechanistically, the pro-hypertrophic effects elicited by SH2B1 were associated with activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signalling cascade. Furthermore, rescue experiments revealed that pharmacological inactivation of JAK2 rescued pressure overload-induced cardiac abnormalities in transgenic mice with cardiac-specific SH2B1 overexpression. Taken together, our data demonstrate, for the first time, that SH2B1 is a key positive mediator of pathological cardiac hypertrophy, and that it primarily acts by regulating JAK2/STAT3 signalling.
Abstract 16579: Readmission Rates for Acute Coronary Syndrome and Mortality after PCI for STEMI: The Influence of Socioeconomic Status
Authors: Abel E Moreyra, Yingzi Deng, Nora M Cogrove, John S Pantazopoulos, John B Kostis
Journal: Circulation (2012)

Objectives Primary percutaneous coronary intervention (PCI) is a preferred treatment ST-segment elevation myocardial infarction (STEMI).We studied the influence of income on the stent used, readmis...
Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial
Authors: N Raje, S Vadhan-Raj, W Willenbacher, E Terpos, V Hungria, A Spencer, Y Alexeeva, T Facon, A K Stewart, A Feng, A Braun, A Balakumaran, G D Roodman
Journal: Blood Cancer Journal (2016)

In a phase 3 trial of denosumab vs zoledronic acid in patients (n=1776) with bone metastases and solid tumors or multiple myeloma, denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events. There was no difference in overall survival between the two groups; however, an ad hoc overall survival analysis in the multiple myeloma subset of patients (n=180) favored zoledronic acid (hazard ratio (HR) 2.26; 95% confidence interval (CI) 1.13–4.50; P=0.014). In the present analysis, we found imbalances between the groups with respect to baseline risk characteristics. HRs with two-sided 95% CIs were estimated using the Cox model. After adjustment in a covariate analysis, the CI crossed unity (HR 1.86; 95% CI 0.90–3.84; P=0.0954). Furthermore, we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group; after accounting for these, the HR was 1.31 (95% CI 0.80–2.15; P=0.278). In conclusion, the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial.
Colorectal cancer: role of commensal bacteria and bystander effects
Authors: Xingmin Wang, Mark M Huycke
Journal: Gut Microbes (2015)

For years the human microbiota has been implicated in the etiology of colorectal cancer (CRC). However, identifying the molecular mechanisms for how aneuploidy and chromosomal instability (CIN) arise in sporadic and colitis-associated CRC has been difficult. In this Addendum we review recent work from our laboratory that explore mechanisms by which intestinal commensals polarize colon macrophages to an M1 phenotype to generate a bystander effect (BSE) that leads to mutations, spindle malfunction, cell cycle arrest, tetraploidy, and aneuploidy in epithelial cells. BSE represents the application of a phenomenon initially described in the radiation biology field. The result of commensal-driven BSE on colon epithelial cells is aneuploidy, chromosomal instability (CIN), expression of stem cell and tumor stem cell markers and, ultimately, malignant transformation. Our findings provide a conceptual framework for integrating the microbiota with aging, cyclooxygenase (COX)-2, and inflammation as risk factors for CRC.
Genome Editing and Its Applications in Model Organisms
Authors: Dongyuan Ma, Feng Liu
Journal: Genomics Proteomics & Bioinformatics (2015)

Technological advances are important for innovative biological research. Development of molecular tools for DNA manipulation, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regularly-interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas), has revolutionized genome editing. These approaches can be used to develop potential therapeutic strategies to effectively treat heritable diseases. In the last few years, substantial progress has been made in CRISPR/Cas technology, including technical improvements and wide application in many model systems. This review describes recent advancements in genome editing with a particular focus on CRISPR/Cas, covering the underlying principles, technological optimization, and its application in zebrafish and other model organisms, disease modeling, and gene therapy used for personalized medicine.
In vitro chemoresponse assay results and population chemotherapy response rates in endometrial cancer
Authors: W. K. Huh, J. M. Straughn, D. E. Cohn
Journal: Journal of Clinical Oncology (2009)

5503 Background: While a number of potentially active chemotherapeutic agents are available for the treatment of endometrial cancer, some therapies may not be effective in all women. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. The primary objective of this study was to determine whether the results from an in vitro chemoresponse assay are similar to the published population response rates for endometrial cancer. Methods: Tumor specimens were collected from Dec 1, 2007 to July 15, 2008 from 405 consecutive patients with endometrial carcinoma and were tested in vitro for a response by using the ChemoFx assay. Tumors were categorized prospectively as responsive (R), intermediately responsive (IR) or nonresponsive (NR) to each drug or combination tested. The in vitro response rates were compared to reported response rates from clinical trials. Results: FIGO stage distribution was 171 stage I patients, 32 stage II patients, 106 stage III patients, 57 stage IV patients, 37 recurrent patients, and 2 unknown patients. The assay was successfully completed for 360 (89%) cases. The majority of tumors (73%) exhibited varying degrees of responsiveness to different drug(s). No significant difference in response rate was observed between primary and recurrent tumors or between stage I/II and III/IV tumors. Conclusions: In vitro tumor response rates were similar to reported treatment response rates for all treatments except single-agent carboplatin. A drug response marker can provide clinically useful information to optimize individual chemotherapy regimens for women with endometrial cancer. [Table: see text] [Table: see text]
Valvular Heart Disease: From Bedside to Bench and Back Again
Authors: Linda Gillam
Journal: Circulation (2011)

The discipline of valvular heart disease owes much to Rene Laennec since the stethoscope he invented remains the primary tool with which valve disease is clinically recognized. The ability to diagnose stenotic and regurgitant lesions on the basis of their characteristic murmurs is a core element of the bedside examination. For many years, valvular heart disease remained an understudied family of conditions. However, in recent years we have gained a better understanding of the pathophysiology of valve disease through research that has included sophisticated analyses of the beating human heart, studies of animal and in vitro models of valve dysfunction as well as biochemical and microscopic examination of diseased valves. There has also been preliminary study of the feasibility of growing valves in vitro. Indeed, the study of valve disease has transitioned from the bedside to the bench. Investigation of two of the most common and clinically important conditions, aortic stenosis and functional mitral regurgitation, has led the way aided by advances in imaging methods for quantitating the progression of disease. For example we now appreciate the similarities and differences between calcific aortic valvular disease and atherosclerosis and know that functional mitral regurgitation, long defined by the absence of structural leaflet changes is, in fact associated with leaflet enlargement. With this new understanding that these studies have provided, has come the potential for new forms of treatment such as pharmacologic and non-surgical mechanical intervention for valve disorders, the treatment of which has heretofore been limited to surgical intervention for end-stage disease. Using the information we have gained at the bench to inform new bedside treatments will define future management of valve disease.
Precursor B cell all induces irreversible T cell dysfunction not solely dependent on TCR signaling
Authors: Haiying Qin, Paul Su, Chad R Burk, Terry Fry
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. With modern risk adapted multimodality therapy, the cure rates for pediatric ALL have reached approximately 90%, but leukemia remains the leading cause of cancer-related death in children and outcomes for
Former Chelsea team doctor alleges victimisation against Mourinho
Authors: Nigel Hawkes
Journal: BMJ (2015)

The former Chelsea football club doctor, Eva Carneiro, is to file a legal claim against the club’s manager, Jose Mourinho, alleging victimisation and discrimination.

The escalating dispute—Carneiro is already pursuing action against the club for constructive dismissal—arises from an incident on 8 August when she went to the aid of an injured player in the final minutes of a game against Swansea City. Mourinho criticised her as “impulsive and naive,” as he feared that Chelsea, already down to 10 men, could not afford to lose any more at a critical …
LBH589 (LBH) and bicalutamide (Bic) in castration-resistant prostate cancer (CRPC) patients (pts) progressing on second line anti-androgen (AA): NYU-08479/PCCTC.
Authors: Anna C. Ferrari, Joshi J. Alumkal, Mark N. Stein, Tina M. Mayer, Sarah Torneten, James Babb, Mary-Ellen Taplin, Robert S. DiPaola, Tomasz M. Beer
Journal: Journal of Clinical Oncology (2015)

5050 Background: Retrospective studies of CRPC pts resistant to 2nd-line AA indicate that progression develops within ~4 months (mo) of a 3rd-line AA treatment (tx). The histone-deacetylase inhibitor LBH decreases expression of androgen receptor (AR) mRNA, splice variants, protein and its targets in CRPC models. Combined with Bic, LBH induces a synergistic anti-proliferative response in Bic-resistant cells. Thus, by epigenetic modulation of AR alterations and restoration of AA sensitivity, LBH may delay AA-resistant CRPC progression. Methods: AA-resistant CRPC pts were randomized 1:1 to 3-week (wk) cycles of Bic 50 mg daily and LBH 40 mg (arm A) or 20 mg (arm B) tri-weekly 2 wks/cy. Endpoints (EPs): Primary (1o), radiographic progression (rP)-free survival (rPFS) at 6 & 9 mo with activity declared if >15% by Fisher Exact Test; Secondary (2o), PSA response, safety and tolerability. Pts receiving ≥ 2 tx cycles evaluated for 1oEP; all pts evaluated for 2oEP. Results: 52 pts (28/24, arms A/B) treated. Median (range): age 69 (48-84) years, PSA 14 ng/mL (2-543), previous AA tx, 2 (1-4); 50 pts had mets (mCRPC), 33 each bone/LN. Arm A: Tx cycles before stop (cycles,pts): < 2, 7; 2-7, 12 (+1 ongoing); 8-12 ( ≥ 6 mo), 8, of which 5 completed 13-25 cycles ( > 9 mo).13/28 (46%) pts had LBH dose reduction to 30-25 mg. rPFS was 40% (8/20 pts) at 6 mo (p = 0.006), 25% (5/20 pts) at 9 mo (p = 0.35); 5 pts (25%) had rP. PSA declines were: > 30%, 6 pts; > 50%,1 pt. Toxicities: Grade(G) G4 thrombocytopenia 8; G3 fatigue 2, diarrhea 2; G2 diarrhea 9, fatigue 5. Arm B: Tx cycles before stop (cycles, pts): < 2, 4; 2-7, 16; 8-12, 4; > 12, 2. Only 1/24 reduced LBH to15 mg. rPFS was 20% (4/20 pts) at 6 mo,10% (2/20pts) at 9 mo (p > 0.3); rP occurred in 7/20 pts (35%). PSA declines were: > 30%, 2 pts; > 50%,1 pt. Toxicities: G4 thrombocytopenia 1, Kaposi’s 1, G3 fatigue 1, diarrhea 1; G2 diarrhea1, fatigue 6. Conclusions: The proportion of mCRPC pts resistant to 2nd-line AA that achieved rPFS at 6 mo was significant after tx with Bic combined with LBH 40 mg and frequent dose reductions to 30-25 mg for tolerance. LBH 20 mg was not effective. Studies combining LBH with new 2nd-line AA are planned to prevent/delay resistance. Clinical trial information: NCT00878436.
Reply to Garner et al.
Authors: Aaron B.A. Shafer, Jochen B.W. Wolf, Paulo C. Alves, Linnea Bergström, Guy Colling, Love Dalén, Luc De Meester, Robert Ekblom, Simone Fior, Mehrdad Hajibabaei, A. Rus Hoezel, Jacob Hoglund, Evelyn L. Jensen, Michael Krützen, Anita J. Norman, E. Martin Österling, N. Joop Ouborg, John Piccolo, Craig R. Primmer, Floyd A. Reed, Marie Roumet, Jordi Salmona, Michael K. Schwartz, Gernot Segelbacher, Jens Thaulow, Mia Valtonen, Philippine Vergeer, Matthias Weissensteiner, Christopher W. Wheat, Carlese Vilà, Piotr Zieliński
Journal: Trends in Ecology & Evolution (2015)