tbuckley/cabot-search huggingface dataset:
Hospital Networks and Value-Based Payment
Authors: Karan R. Chhabra, Justin B. Dimick
Journal: JAMA (2015)

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Expression of Apoptosis-Related Proteins Is an Independent Determinant of Patient Prognosis in Advanced Ovarian Cancer
Authors: M. Baekelandt, R. Holm, J.M. Nesland, C.G. Tropé, G.B. Kristensen
Journal: Journal of Clinical Oncology (2000)

PURPOSE: The present study was undertaken to investigate the prognostic and predictive relevance of the expression of apoptosis-related proteins Bax, Bcl-X L , and Mcl-1 in advanced ovarian cancer. PATIENTS AND METHODS: Tumor biopsies from 185 consecutive and homogeneously treated patients with stage III ovarian cancer were examined immunohistochemically for the expression of Bax, Bcl-X L and Mcl-1 proteins. Their prognostic relevance was examined in a uni- and multivariate survival analysis. RESULTS: Sixty-six percent of cancer cases expressed Bax, 62% Bcl-X L , and 53% Mcl-1. The expression of Bax correlated with tumor differentiation (P = .016) and less residual disease after surgery (P &lt; .0001). In univariate analysis, Bax expression was associated with improved (P = .0004) prognosis and Mcl-1 expression with poorer (P = .011) prognosis. None of the factors studied was of independent prognostic significance by itself, but when Bax and Bcl-2 expression data were considered together, this combined variable was of independent prognostic significance (P = .0115), together with residual disease status (P = .0016), differentiation grade (P = .0014), and the presence of ascites (P = .0122). Patients with a long median survival (104 months) could be discriminated from those with a short one (16 months) by combining the individual patients’ expression data for p53, Bax, and Bcl-2 with their residual disease status (P &lt; .00001). None of the factors studied was able to predict response to chemotherapy. CONCLUSION: The expression of selected apoptosis-related proteins is of independent prognostic significance and may be helpful in a molecular substaging of patients with stage III ovarian cancer.
Abstract 72: Pka Is A Master Regulator Of Pathological Cardiac Hypertrophy
Authors: Xiaoying Zhang, Ying LI, Mingxin Tang, Xiaojie Ai, Christopher Szeto, Xiang Hua, Xiongwen Chen
Journal: Circulation Research (2014)

Aims: The role of PKA in pathological cardiac hypertrophy (PCH) is not clear. The literature suggests both prohypertrophic and antihypertrophic effects of PKA. Furthermore, there are endogenous PKA inhibitors, PKI, highly expressed in the heart to regulate PKA activity but their roles in PCH have not been studied. We aim to explore the role of PKI/PKA in PCH induced by isoproterenol, phenylephrine, angiotensin II and pressure overload. Methods and Results: 1. PKIα and PKIγ were highly expressed in the heart but only PKIα was reduced by transaortic banding (TAB); TAB induced a significant increase in cardiac PKA activity at 1 week post TAB. 2. Four transgenic mouse lines with high (HE), medium (ME), low (LE) and very low (VLE) expression of PKI-GFP were obtained with the inhibition of maximum PKA activity induced by 1μM cAMP by 95%, 57%, 20% and 10% in the cardiac homogenates; 3. In the VLE hearts, some myocytes were PKI-GFP+ and some were PKI-GFP-, GFP- LVMs had significantly larger surface area than GFP+ LVMs; 4. PKA inhibition by PKI-GFP abolished PCH induced by isoproterenol, phenylephrine, angiotensin II in HE mice; 5. TAB for 8 weeks did not change HW/BW, myocyte cross-sectional area and myocardial fibrosis in HE mice but induced significant increases in HW/BW, myocyte cross-sectional area, myocardial fibrosis and depressed cardiac fractional shortening in control mice. 6. In cultured neonatal rat ventricular myocytes, PKI-GFP prevented myocyte hypertrophy induced by isoproterenol (ISO), phenylephrine (PE) and angiotensin II, as evidenced by no significant increases in protein synthesis (protein/DNA ratio), myocyte surface area, sarcomere organization. 7. PKI-GFP in NRVMs prevented the translocation of NFAT3 and HDAC5 induced by ISO and PE and increased the secretion of antihypertrophic ANF at baseline; 8. TAB induced PKA-dependent phosphorylation of GSK-3α and GSK-3β, inactivating them to relieve their antihypertrophic effect and promote protein synthesis (increased phosphorylation of mTORC1, eIF-4EBP1, p70 S6K); PKA inhibition abolished these effects. Conclusions: PKA is regulated by PKI and is a master regulator of PCH induced by pressure overload.
Risk factors for high-dose cytarabine neurotoxicity: an analysis of a cancer and leukemia group B trial in patients with acute myeloid leukemia.
Authors: E H Rubin, J W Andersen, D T Berg, C A Schiffer, R J Mayer, R M Stone
Journal: Journal of Clinical Oncology (1992)

PURPOSE We analyzed pretreatment characteristics of patients with postremission acute myeloid leukemia (AML) treated with high-dose cytarabine (HIDAC) during a recent Cancer and Leukemia Group B (CALGB) trial to determine risk factors associated with HIDAC neurotoxicity. PATIENTS AND METHODS One hundred seventy-six patients received at least one course of HIDAC as part of a CALGB protocol designed to determine the optimal dose of cytarabine (ara-C) for postremission treatment of AML. HIDAC consisted of 3 g/m2 ara-C infused over 3 hours at 12-hour intervals on days 1, 3, and 5. The pretreatment characteristics of 170 patients were available for risk analyses. RESULTS Eighteen patients (10%) experienced neurotoxicity. Univariate analyses demonstrated associations between the occurrence of neurotoxicity and elevated serum creatinine, age, and alkaline phosphatase (AP). Multivariate analysis showed that these variables were independent risk factors. These findings were used to construct a risk model with the following parameters: creatinine greater than or equal to 1.2 mg/dL, age greater than or equal to 40 years, and AP greater than or equal to 3 x normal. Seventeen of 46 (37%) patients with two or more of these criteria developed neurotoxicity compared with one of 124 (1%) patients with one or none. The sensitivity and specificity of this model were 94% and 81%, respectively. CONCLUSION We conclude that patients with two or more of the following parameters may be at increased risk for HIDAC neurotoxicity: (creatinine greater than or equal to 1.2 mg/dL, age greater than or equal to 40, and AP greater than or equal to 3 x normal). However, this model should be confirmed by analysis of additional groups of patients treated with HIDAC.
The predictive value of ARv7 expression in localized prostate caner treated with abiraterone, degarelix, and bicalutamide.
Authors: Niall Corcoran, Christopher Hovens, Nicholas Howard, Patricia Bugeja, Michael Kerger, Justin Peters, David Clarke, Jeremy Grummet, Phillip Dundee, John Pedersen, Andrew Ryan, Anthony Costello, Paul Ruljancich, Phillip Parente
Journal: Journal of Clinical Oncology (2015)

71 Background: Androgen receptor splice variants (ARvs) are upregulated in response to castration, and can activate transcription in the absence of ligand. Recent evidence indicates that CTC ARv7 expression is an accurate predictor of absence of response to abiraterone and enzalutamide, providing strong clinical support for ARv7 upregulation as potential overarching mechanism of castration resistance. There is however limited data regarding the expression of ARv7 in clinically localized prostate cancer (CaP), and it is unknown if expression in the primary tumor is similarly predictive. We were therefore interested to determine the expression of ARv7 in high-risk disease, and correlate this with response to an abiraterone-containing castrating regimen. Methods: We performed an open label non-randomized Phase II neoadjuvant study of ‘supercastration’ in men with high-risk clinically localized CaP using an optimal 2-stage design (ACTRN12612000772842). Treatment consisted of degarelix 240/80mg q 1/12, abiraterone 1000mg OD, bicalutamide 50mg OD and prednisolone 5mg OD for 24 weeks. The primary endpoints were safety/tolerability and pT0 response rate. ARv7 expression was determined by immunohistochemistry and qRT-PCR in both pre- and post treatment tumor specimens, and correlated with pathological response. Fresh specimens from resistant tumors are currently being profiled by RNA-seq. Results: 17 patients were recruited to the study. The combination treatment was well tolerated, with hot flushes and fatigue being the most commonly reported side effects, and all patients completed six months of treatment. Six patients with asymptomatic elevation of liver transaminases required Abiraterone dose reductions, and there were no unexpected toxicities. 16 patients proceeded to prostatectomy, and a pT0 response observed in one patient, with minimal residual disease present in a further three patients. ARv7 expression was uniformly present in all pre-treatment specimens, and neither level nor localization of expression predicted tumor response. Conclusions: ARv7 expression in primary CaP does not predict response to abiraterone-based castration. Clinical trial information: ACTRN12612000772842.
Cisplatin-based chemotherapy for ovarian germ cell malignancies: the Australian experience.
Authors: E Segelov, J Campbell, M Ng, M Tattersall, R Rome, K Free, N Hacker, M L Friedlander
Journal: Journal of Clinical Oncology (1994)

This study was performed to evaluate the Australian experience with cisplatin-based treatment of ovarian germ cell tumors (OGCT) with respect to survival and toxicity of treatment.A retrospective review was undertaken based on a standardized questionnaire, which was sent to all major gynecologic oncology centers in Australia.Data on 58 patients were obtained. Overall survival at 5 years for all patients was 87%. There was one death from disease among 14 patients with dysgerminoma, and four deaths from disease among 44 patients with nondysgerminomas. Cisplatin-based chemotherapy was associated with a low incidence of serious complications, with only one treatment-related death (from bleomycin-induced respiratory failure).Our large series demonstrates that cisplatin-based chemotherapy is highly effective for patients with OGCT. Although direct comparisons cannot be made, the survival of our patients with advanced tumors was comparable to that seen in male germ cell tumors, rather than inferior as is commonly believed. Future studies should aim to refine treatment to minimize toxicity, while further increasing curability.
Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenström's macroglobulinemia.
Authors: M A Gertz, R A Kyle, P Noel
Journal: Journal of Clinical Oncology (1993)

PURPOSE To determine the natural history of amyloidosis associated with Waldenström's macroglobulinemia and immunoglobulin M (IgM) monoclonal gammopathy. PATIENTS AND METHODS From January 1968 to September 1990, 50 patients with a serum IgM monoclonal protein and biopsy-proven amyloidosis were evaluated at the Mayo Clinic. There were 32 men and 18 women (age range, 43 to 93 years). RESULTS Percentages of patients presenting with cardiac, renal, hepatic, and pulmonary amyloid were 44%, 32%, 14%, and 10%, respectively. Forty-two percent of the patients had an M protein value greater than 1.5 g/dL, and 12% had an M component greater than 3 g/dL. Subcutaneous fat, rectum, and bone marrow showed amyloid in 84%, 72%, and 50%, respectively, providing a simple technique for diagnosing amyloidosis. The bone marrow biopsy was consistent with Waldenström's macroglobulinemia in 10, a plasma-cell proliferative disorder in 10, and lymphoma or a lymphoproliferative disorder in 11; results were normal, nondiagnostic, or hypercellular in 17. Forty-three of 50 patients died. The median survival of the entire group was 24.6 months. Fifty-three percent of deaths were due to cardiac amyloid, 12% to respiratory failure, 7% to macroglobulinemia, 7% to liver failure, and 7% to kidney failure. CONCLUSION The presence of amyloid cardiomyopathy and an increased creatinine concentration at diagnosis had an adverse impact on survival. Of the 22 patients who presented with cardiomyopathy, the median survival was 11.1 months, with only two surviving longer than 5 years. The median survival of the 28 patients without cardiomyopathy at diagnosis was 27 months, with eight 5-year survivors (P = .013). All eight amyloid deposits studied stained for Ig light chain, indicating that this amyloidosis is of the primary (AL) type.
Intensive Multifactorial Intervention for Stable Coronary Artery Disease
Authors: David J. Maron, William E. Boden, Robert A. O'Rourke, Pamela M. Hartigan, Karen J. Calfas, G.B. John Mancini, John A. Spertus, Marcin Dada, William J. Kostuk, Merril Knudtson, Crystal L. Harris, Steven P. Sedlis, Robert G. Zoble, Lawrence M. Title, Gilbert Gosselin, Shah Nawaz, Gerald T. Gau, Alvin S. Blaustein, Eric R. Bates, Leslee J. Shaw, Daniel S. Berman, Bernard R. Chaitman, William S. Weintraub, Koon K. Teo
Journal: Journal of the American College of Cardiology (2010)
Autologous Mixed Lymphocyte Reaction in Patients with Hodgkin's Disease
Authors: Edgar G. Engleman, Claudia J. Benike, Richard T. Hoppe, Henry S. Kaplan, F. Ralph Berberich
Journal: Journal of Clinical Investigation (1980)

The proliferative response of T lymphocytes cultured with autologous non-T lymphocytes is known as the autologous mixed lymphocyte reaction (MLR). This reaction can be demonstrated reproducibly in healthy individuals and has been shown to generate specific cytotoxic T cells, as well as T cells that regulate antibody synthesis and cell-mediated immunity. In this study, we demonstrate that the autologous MLR is impaired or absent in most patients with Hodgkin's disease regardless of age, sex, pathologic stage, or histologic classification. In 64 patients, the mean autologous MLR was 3,084±1,878 cpm compared to 16,552±6,532 in 29 healthy donors. A defect in autologous MLR was observed in newly diagnosed patients before the initiation of therapy, but was also found in patients without evidence of recurrent disease up to 15 yr after treatment.
Mutism: review, differential diagnosis, and report of 22 cases [published erratum appears in Am J Psychiatry 1987 Apr;144(4):542]
Authors: L L Altshuler, J L Cummings, M J Mills
Journal: American Journal of Psychiatry (1986)

Mutism is a common manifestation of both psychiatric and neurologic illness. Psychiatric disturbances associated with mutism include schizophrenia, affective disorders, conversion reactions, dissociative states, and dementias. Neurologic disorders producing mutism involve the basal ganglia, frontal lobes, or limbic system structures. In psychiatric and neurologic conditions, mutism is often associated with other signs of catatonia. The authors review the literature on mutism, including psychiatric, neurologic, toxic-metabolic, and drug-induced causes. Methods to discriminate among the many causes of mutism in the clinical setting are discussed, and 22 new cases of mutism are reported to emphasize the wide differential diagnosis.
LTβR signalling preferentially accelerates oncogenic AKT-initiated liver tumours
Authors: Anthony J Scarzello, Qun Jiang, Timothy Back, Hien Dang, Deborah Hodge, Charlotte Hanson, Jeffrey Subleski, Jonathan M Weiss, Jimmy K Stauffer, Jitti Chaisaingmongkol, Siritida Rabibhadana, Mathuros Ruchirawat, John Ortaldo, Xin Wei Wang, Paula S Norris, Carl F Ware, Robert H Wiltrout
Journal: Gut (2015)

<h3>Objectives</h3> The relative contributions of inflammatory signalling and sequential oncogenic dysregulation driving liver cancer pathogenesis remain incompletely understood. Lymphotoxin-β receptor (LTβR) signalling is critically involved in hepatitis and liver tumorigenesis. Therefore, we explored the interdependence of inflammatory lymphotoxin signalling and specific oncogenic pathways in the progression of hepatic cancer. <h3>Design</h3> Pathologically distinct liver tumours were initiated by hydrodynamic transfection of oncogenic V-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT)/β-catenin or AKT/Notch expressing plasmids. To investigate the relationship of LTβR signalling and specific oncogenic pathways, LTβR antagonist (LTβR-Fc) or agonist (anti-LTβR) were administered post oncogene transfection. Initiated livers/tumours were investigated for changes in oncogene expression, tumour proliferation, progression, latency and pathology. Moreover, specific LTβR-mediated molecular events were investigated in human liver cancer cell lines and through transcriptional analyses of samples from patients with intrahepatic cholangiocarcinoma (ICC). <h3>Results</h3> AKT/β-catenin-transfected livers displayed increased expression of LTβ and LTβR, with antagonism of LTβR signalling reducing tumour progression and enhancing survival. Conversely, enforced LTβR-activation of AKT/β-catenin-initiated tumours induced robust increases in proliferation and progression of hepatic tumour phenotypes in an AKT-dependent manner. LTβR-activation also rapidly accelerated ICC progression initiated by AKT/Notch, but not Notch alone. Moreover, LTβR-accelerated development coincides with increases of Notch, Hes1, c-MYC, pAKT and β-catenin. We further demonstrate LTβR signalling in human liver cancer cell lines to be a regulator of Notch, pAKT<sub>ser473</sub> and β-catenin. Transcriptome analysis of samples from patients with ICC links increased LTβR network expression with poor patient survival, increased Notch1 expression and Notch and AKT/PI3K signalling. <h3>Conclusions</h3> Our findings link LTβR and oncogenic AKT signalling in the development of ICC.
The Challenges of Colorectal Cancer Survivorship
Authors: Crystal S. Denlinger, Andrea M. Barsevick
Journal: Journal of the National Comprehensive Cancer Network (2009)

With advances in treatment, colorectal cancer (CRC) is being transformed from a deadly disease into an illness that is increasingly curable. With this transformation has come increased interest in the unique problems, risks, needs, and concerns of survivors who have completed treatment and are cancer-free. Research has shown that physical and mental quality of life for CRC survivors was inferior compared with age-matched individuals without cancer. Although issues and symptoms were most prominent during the first 3 years, long-term effects of treatment can persist and include fatigue, sleep difficulty, fear of recurrence, anxiety, depression, negative body image, sensory neuropathy, gastrointestinal problems, urinary incontinence, and sexual dysfunction. The unique challenges and issues of CRC survivors can and should be addressed by health care providers and the research community to ensure effective interventions and models of care to manage these problems. This article discusses what is known about the long-term effects of CRC treatment on quality of life, the care of survivors, and existing models of survivorship care.
Monitoring of airway resistance (Raw) in exacerbation of asthma
Authors: Tajana Jalusic Gluncic, Latinka Basara Toromanovic
Journal: European Respiratory Journal (2013)

Background . While clinicians and researchers often use spirometry data in asthma exacerbation evaluation, it is our perception that plethysmography data is not given the right importance.   Aim.  The aim of this study was to show that in exacerbation of asthma besides decreasing of spirometric value (FVC, FEV1, FEF50, PEF) increasing of airway resistance (Raw) is also found.   Methods . The research included 35 patients with asthma, (age range 23-80) in exacerbation phase of disease. In all patients we measured spirometry and plethysmography, and also included proportioned therapy. After one month, spirometry and plethysmography tests were repeated. All patients reported about symptom reduction at the end of one month.   Results . After inclusion of therapy all spirometry values were significantly higher: FVC (p ) = -. 641. After implemented therapy 85,71 % of patients reported feeling better.   Conclusion.  With expected increase of spirometry values (objective parameters) and subjective enhance after implemented therapy, results show that in asthma there is a negative correlation between airway resistance (Raw) and level of obstruction. When obstruction is higher (FEV1 is lower), resistance is higher. Results also suggest that Raw is a variable value, and that adequate therapy affects its decrease.