tbuckley/cabot-search huggingface dataset:
Evaluation of the Safety and Benefit of Phase I Oncology Trials for Patients With Primary CNS Tumors
Authors: Mrinal M. Gounder, Lakshmi Nayak, Solmaz Sahebjam, Alona Muzikansky, Armando J. Sanchez, Serena Desideri, Xiaobu Ye, S. Percy Ivy, L. Burt Nabors, Michael Prados, Stuart Grossman, Lisa M. DeAngelis, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2015)

Purpose Patients with high-grade gliomas (HGG) are frequently excluded from first-in-human solid tumor trials because of perceived poor prognosis, excessive toxicities, concomitant drug interactions, and poor efficacy. We conducted an analysis of outcomes from select, single-agent phase I studies in patients with HGG. We compared outcomes to pooled analysis of published studies in solid tumors with various molecular and cytotoxic drugs evaluated as single agents or as combinations. Patient and Methods Individual records of patients with recurrent HGG enrolled onto Adult Brain Tumor Consortium trials of single-agent, cytotoxic or molecular agents from 2000 to 2008 were analyzed for baseline characteristics, toxicities, responses, and survival. Results Our analysis included 327 patients with advanced, refractory HGG who were enrolled onto eight trials involving targeted molecular (n = 5) and cytotoxic (n = 3) therapies. At enrollment, patients had a median Karnofsky performance score of 90 and median age of 52 years; 62% were men, 63% had glioblastoma, and the median number of prior systemic chemotherapies was one. Baseline laboratory values were in an acceptable range to meet eligibility criteria. Patients were on the study for a median of two cycles (range, &lt; one to 56 cycles), and 96% were evaluable for primary end points. During cycle 1, grade ≥ 3 nonhematologic and grade ≥ 4 hematologic toxicities were 5% (28 of 565 adverse events) and 0.9% (five of 565 adverse events), respectively, and 66% of these occurred at the highest dose level. There was one death attributed to drug. Overall response rate (complete and partial response) was 5.5%. Median progression-free and overall survival times were 1.8 and 6 months, respectively. Conclusion Patients with HGG who meet standard eligibility criteria may be good candidates for solid tumor phase I studies with single-agent molecular or cytotoxic drugs with favorable preclinical rationale and pharmacokinetic properties in this population.
GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence
Authors: Irmgard Tegeder, Michael Costigan, Robert S Griffin, Andrea Abele, Inna Belfer, Helmut Schmidt, Corina Ehnert, Jemiel Nejim, Claudiu Marian, Joachim Scholz, Tianxia Wu, Andrew Allchorne, Luda Diatchenko, Alexander M Binshtok, David Goldman, Jan Adolph, Swetha Sama, Steven J Atlas, William A Carlezon, Aram Parsegian, Jörn Lötsch, Roger B Fillingim, William Maixner, Gerd Geisslinger, Mitchell B Max, Clifford J Woolf
Journal: Nature Medicine (2006)
Perivascular Adipose Tissue Potentiates Contraction of Coronary Vascular Smooth Muscle
Authors: Meredith Kohr Owen, Frank A. Witzmann, Mikaela L. McKenney, Xianyin Lai, Zachary C. Berwick, Steven P. Moberly, Mouhamad Alloosh, Michael Sturek, Johnathan D. Tune
Journal: Circulation (2013)

This investigation examined the mechanisms by which coronary perivascular adipose tissue (PVAT)-derived factors influence vasomotor tone and the PVAT proteome in lean versus obese swine.Coronary arteries from Ossabaw swine were isolated for isometric tension studies. We found that coronary (P=0.03) and mesenteric (P=0.04) but not subcutaneous adipose tissue augmented coronary contractions to KCl (20 mmol/L). Inhibition of CaV1.2 channels with nifedipine (0.1 µmol/L) or diltiazem (10 µmol/L) abolished this effect. Coronary PVAT increased baseline tension and potentiated constriction of isolated arteries to prostaglandin F2α in proportion to the amount of PVAT present (0.1-1.0 g). These effects were elevated in tissues obtained from obese swine and were observed in intact and endothelium denuded arteries. Coronary PVAT also diminished H2O2-mediated vasodilation in lean and, to a lesser extent, in obese arteries. These effects were associated with alterations in the obese coronary PVAT proteome (detected 186 alterations) and elevated voltage-dependent increases in intracellular [Ca(2+)] in obese smooth muscle cells. Further studies revealed that the Rho-kinase inhibitor fasudil (1 µmol/L) significantly blunted artery contractions to KCl and PVAT in lean but not obese swine. Calpastatin (10 μmol/L) also augmented contractions to levels similar to that observed in the presence of PVAT.Vascular effects of PVAT vary according to anatomic location and are influenced by an obese phenotype. Augmented contractile effects of obese coronary PVAT are related to alterations in the PVAT proteome (eg, calpastatin), Rho-dependent signaling, and the functional contribution of K(+) and CaV1.2 channels to smooth muscle tone.
Podocyte Cell–Specific Expression of Doxycycline Inducible Cre Recombinase in Mice
Authors: Juuso Juhila, Ramon Roozendaal, Markus Lassila, Sjef J. Verbeek, Harry Holthofer
Journal: Journal of the American Society of Nephrology (2006)

Conventional silencing of many podocyte-specific genes in mice is associated with embryonic or perinatal lethality. Therefore, it would be of great importance to generate mouse models that allow the modification of genes that are expressed in podocytes at later stages of age. Herein is described a transgenic mouse with doxycycline-inducible podocyte-specific expression of Cre recombinase. For the generation of this binary system, a single transgenic construct that contained two separate genes was used: One encoding the optimized M2 version of the doxycycline-dependent transcription transactivator reverse tetracycline-controlled transcriptional activator (rtTA) under control of the human podocin (NPHS2) promoter and the other encoding the recombinase Cre under control of the rtTA/doxycycline-responsive minimal cytomegalovirus (CMV) Tet operator sequence 7 promotor. Microinjection of the JRC-CRE construct in fertilized oocytes from FVB/N mice resulted in 16 transgenic founders. Double-transgenic offspring from breeding of a selected founder with the Z/AP reporter mouse showed alkaline phosphatase staining only upon doxycycline administration and exclusively in podocytes. These data indicate that this new inducible Cre recombinase mouse line is an excellent tool in conditional, kidney glomerular podocyte-specific gene deletion in adult mice.
Thiazolidinedione Therapy Gets Complicated
Authors: Ann V. Schwartz, Deborah E. Sellmeyer
Journal: Diabetes Care (2007)

An escalating number of recent publications suggest that the thiazolidinedione (TZD) medications may have a negative effect on the skeleton. The manufacturers of the two currently available TZDs, rosiglitazone and pioglitazone, have both issued letters to health care providers, warning that these medications may cause an increased risk of fracture in women (1,2). TZDs improve insulin sensitivity and are widely prescribed for type 2 diabetes, but we are just beginning to understand their clinical effects on bone.

In December 2006, the ADOPT trial reported a higher risk of fractures in diabetic women randomized to rosiglitazone than in women randomized to metformin or glyburide (3). The ADOPT trial followed 4,360 (42% women) participants with a mean age of 57 years for a median of 4 years. The primary outcome was time to monotherapy failure as determined by fasting glucose. An imbalance in fracture rates was identified in a final review of adverse event reports. The proportion of women reporting a fracture was 9.3% for rosiglitazone, 5.1% for metformin, and 3.5% for glyburide, corresponding to an approximate relative risk (RR) of 2.18 (95% CI 1.52–3.13) for rosiglitazone versus the other treatments combined. Among male participants, 89 reported a fracture, distributed similarly across treatments (rosiglitazone 3.9%, metformin 3.4%, and glyburide 3.3%), corresponding to an approximate RR of 1.18 (0.77–1.80), for rosiglitazone versus the other treatments combined.

Pioglitazone, the other currently available TZD, may also have negative skeletal effects. In March 2007, Takeda (2) reported increased fracture risk in women, but not men, using pioglitazone, based on an analysis of their clinical trial database, including 24,000 person-years of follow-up. Among women, fracture incidence was 1.9 per 100 person-years for pioglitazone and 1.1 per 100 person-years for those using placebo or another active drug. The incidence for men was not reported but did …
Staging of Chronic Kidney Disease
Authors: Carolyn Bauer, Michal L. Melamed, Thomas H. Hostetter
Journal: Journal of the American Society of Nephrology (2008)

Awareness of chronic kidney disease (CKD) has increased in part because of the definitions and treatment guidelines set out by Kidney Disease Outcomes Quality Initiative (KDOQI); however, the staging system set forth by these guidelines has led to several problems and unforeseen consequences. Stages 1 and 2 CKD are difficult to determine using the standard Modification of Diet in Renal Disease (MDRD) estimation of GFR, and their clinical significance in the absence of other risk factors is unclear. Just because microalbuminuria in people without diabetes is a cardiovascular risk factor does not make it kidney disease. Most patients who receive a diagnosis of stage 3 CKD (GFR between 30 and 59 ml/min) are elderly people, and the vast majority of these patients will die before they reach ESRD. The staging system needs to be modified to reflect the severity and complications of CKD. It is suggested that stages 1 and 2 be eliminated and stages 3, 4, and 5, be simply termed moderate impairment, severe impairment, and kidney failure, respectively. In addition, age should be a modifying factor, especially in moderate kidney impairment. These changes would allow identification and treatment of clinically relevant disease and avoidance of what can seem exaggerated prevalence estimates.
Efficacy and Safety of Statin Therapy in Children With Familial Hypercholesterolemia
Authors: Saskia de Jongh, Leiv Ose, Tamás Szamosi, Claude Gagné, M. Lambert, Russell Scott, P. Perron, Dries Dobbelaere, M. Saborio, Mary B. Tuohy, Michael Stepanavage, Aditi Sapre, Barry Gumbiner, Michele Mercuri, A.S. Paul van Trotsenburg, Henk D. Bakker, John J.P. Kastelein
Journal: Circulation (2002)

A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate LDL cholesterol-lowering efficacy, overall safety, and tolerability and the influence on growth and pubertal development of simvastatin in a large cohort of boys and girls with heterozygous familial hypercholesterolemia (heFH).A total of 173 heFH children (98 boys and 75 girls) were included in this study. After a 4-week diet/placebo run-in period, children with heFH were randomized to either simvastatin or placebo in a ratio of 3:2. Simvastatin was started at 10 mg/d and titrated at 8-week intervals to 20 and then 40 mg/d. During a 24-week extension period, the patients continued to receive simvastatin (40 mg) or placebo according to their assignment. After 48 weeks of simvastatin therapy, there were significant reductions of LDL cholesterol (-41%), total cholesterol (-31%), apolipoprotein B (-34%), VLDL cholesterol (-21%), and triglyceride (-9%) levels. HDL cholesterol and apolipoprotein A-I levels were increased by 3.3% and 10.4%, respectively (not significant). No safety issues became evident. Except for small decreases in dehydroepiandrosterone sulfate compared with placebo, there were no significant changes from baseline in adrenal, gonadal, and pituitary hormones in either treatment group.Simvastatin significantly reduced LDL cholesterol, total cholesterol, triglyceride, VLDL cholesterol, and apolipoprotein B levels and was well tolerated in children with heFH. There was no evidence of any adverse effect of simvastatin on growth and pubertal development. Therefore, simvastatin at doses up to 40 mg is a well-tolerated and effective therapy for heFH children.
A self management plan in the treatment of adult asthma.
Authors: R Beasley, M Cushley, S T Holgate
Journal: Thorax (1989)

To determine whether routine assessment of peak expiratory flow (PEF) in association with a self management plan based on inhaled corticosteroid use is effective in the management of chronic asthma, 36 consecutive adult patients with asthma attending an outpatient chest clinic were admitted to an open prospective study. Patients were treated with inhaled salbutamol and beclomethasone dipropionate in an attempt to achieve normal lung function. Each patient had a "potential normal value," which was either the predicted normal or the maximum PEF value achieved by the patient, whichever was the higher. Patients measured PEF at home and if it fell by more than 30% from the potential normal value the dose of beclomethasone was doubled until PEF returned to the potential normal value, then continued at 20 mg/day for the same number of days. If PEF fell to below 150-200 l/min patients were asked to obtain emergency medical assistance. In the 30 patients who completed the trial the six months before and the six months after intervention with the self management plan were compared. There was a substantial improvement in both subjective and objective measurements of asthma severity, with a significant reduction in nights woken, days lost from work, and requirement for oral corticosteroids and a significant increase in baseline lung function. Routine measurement of PEF in association with a self management plan appears to be effective in reducing symptoms of asthma and improving lung function.
Identification of a Protein, G0S2, That Lacks Bcl-2 Homology Domains and Interacts with and Antagonizes Bcl-2
Authors: Christian Welch, Manas K. Santra, Wissal El-Assaad, Xiaochun Zhu, Wade E. Huber, Richard A. Keys, Jose G. Teodoro, Michael R. Green
Journal: Cancer Research (2009)

Abstract The Bcl-2 family of proteins consists of both antiapoptotic and proapoptotic factors, which share sequence homology within conserved regions known as Bcl-2 homology domains. Interactions between Bcl-2 family members, as well as with other proteins, regulate apoptosis through control of mitochondrial membrane permeability and release of cytochrome c. Here we identify a novel regulator of apoptosis that lacks Bcl-2 homology domains but acts by binding Bcl-2 and modulating its antiapoptotic activity. To identify regulators of apoptosis, we performed expression profiling in human primary fibroblasts treated with tumor necrosis factor-α (TNF-α), a potent inflammatory cytokine that can regulate apoptosis and functions, at least in part, by inducing expression of specific genes through NF-κB. We found that the gene undergoing maximal transcriptional induction following TNF-α treatment was G0-G1 switch gene 2 (G0S2), the activation of which also required NF-κB. We show that G0S2 encodes a mitochondrial protein that specifically interacts with Bcl-2 and promotes apoptosis by preventing the formation of protective Bcl-2/Bax heterodimers. We further show that ectopic expression of G0S2 induces apoptosis in diverse human cancer cell lines in which endogenous G0S2 is normally epigenetically silenced. Our results reveal a novel proapoptotic factor that is induced by TNF-α through NF-κB and that interacts with and antagonizes Bcl-2. [Cancer Res 2009;69(17):6782–9]
Cdk Inhibition in Human Cells Compromises Chk1 Function and Activates a DNA Damage Response
Authors: Shannon L. Maude, Greg H. Enders
Journal: Cancer Research (2005)

Cyclin-dependent kinases (Cdk) promote cell proliferation, are often deregulated in human cancers, and are targets of ongoing cancer chemotherapy trials. We show here that Cdk activity is also required in human cells to maintain function of the Chk1 pathway, a key component of the response to DNA damage or stalled replication. Chk1 expression was markedly reduced in primary fibroblasts and U2OS osteogenic sarcoma cells by treatment with small molecule Cdk inhibitors or induction of a dominant-negative mutant of Cdk2. The findings of decreased Chk1 activity and accumulation of Cdc25A, a protein targeted for degradation by Chk1, confirmed that Chk1 function was impaired. Furthermore, Cdk inhibition triggered a DNA damage response, characterized by the accumulation of activated forms of ATM and Chk2 as well as nuclear foci containing phosphorylated substrates of ATM/ATR, including histone H2AX (gammaH2AX). Time course experiments showed that the bulk of ATM activation followed Chk1 down-regulation. Chk1 RNA interference combined with partial inhibition of DNA replication was sufficient to evoke the DNA damage response. Conversely, ectopic expression of Chk1 blunted induction of gammaH2AX foci by Cdk inhibitors, indicating that Chk1 down-regulation was necessary to elicit the full phenotype. Finally, both Cdk and Chk1 inhibitors enhanced the cytotoxity of etoposide, a DNA-damaging agent. These results define a pathway through which Cdk inhibition can mediate DNA damage and potentially enhance the efficacy of extant cancer chemotherapies.
HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma
Authors: Bo Qiu, Daniel Ackerman, Danielle J. Sanchez, Bo Li, Joshua D. Ochocki, Alison Grazioli, Ekaterina Bobrovnikova-Marjon, J. Alan Diehl, Brian Keith, M. Celeste Simon
Journal: Cancer Discovery (2015)

Two hallmarks of clear-cell renal cell carcinoma (ccRCC) are constitutive hypoxia-inducible factor (HIF) signaling and abundant intracellular lipid droplets (LD). However, regulation of lipid storage and its role in ccRCC are incompletely understood. Transcriptional profiling of primary ccRCC samples revealed that expression of the LD coat protein gene PLIN2 was elevated in tumors and correlated with HIF2α, but not HIF1α, activation. HIF2α-dependent PLIN2 expression promoted lipid storage, proliferation, and viability in xenograft tumors. Mechanistically, lipid storage maintained integrity of the endoplasmic reticulum (ER), which is functionally and physically associated with LDs. Specifically, PLIN2-dependent lipid storage suppressed cytotoxic ER stress responses that otherwise result from elevated protein synthetic activity characteristic of ccRCC cells. Thus, in addition to promoting ccRCC proliferation and anabolic metabolism, HIF2α modulates lipid storage to sustain ER homeostasis, particularly under conditions of nutrient and oxygen limitation, thereby promoting tumor cell survival.We demonstrate that HIF2α promotes lipid storage, ER homeostasis, and cell viability in ccRCC via upregulation of the LD coat protein PLIN2, revealing a novel function for the well-documented "clear-cell" phenotype and identifying ER stress as a targetable vulnerability created by HIF2α/PLIN2 suppression in this common renal malignancy.
Evaluation of a portable respiratory recording device for detecting apnoeas and hypopnoeas in subjects from ageneral population
Authors: E. Ballester, M Solans, X Vila, L. Hernandez, LL. Quintó, I Bolivar, S Bardagi, J.M. Montserrat
Journal: European Respiratory Journal (2000)

This study was designed to validate a new home portable respiratory recording device (PRRD) to identify sleep apnoea and hypopnoea in a group of subjects (n=116), from a sample of the general population. Full night polysomnography (PSG) was used as the gold standard and simultaneously performed with PRRD. PRRD measurements included oronasal airflow (thermistry), chest wall impedance, oxygen saturation, snoring and body position. The sensors were unique for each recording system. Data obtained was blindly reviewed and analysed. A high level of agreement between both methods apnoea/hypopnoea index by PSG and the respiratory disturbance index (RDI) by PRRD was observed. Accuracy of the PRRD was evaluated in terms of sensitivity and specificity for different RDI-PRRD cut-off points with respect to AHI-PSG >10 and AHI-PSG >30. A logistic regression model was performed to estimate the chance per unit of RDI of apnoeas. A received operating characteristic (ROC) curve was drawn to obtain the sensitivity/specificity profile for each observed RDI value obtained. From the ROC curve the authors identified the better cut-off points, which represent a balanced sensitivity/specificity. Through a classification table defined by the cut-off point, the post-odds to exhibit the disease was calculated. For a full PSG cut-off point of 10 a PRRD of six showed a balanced sensitivity of 95% and a specificity of 92%. For a full PSG cut-off point of 30 a PRRD of 16 shows a balanced sensitivity/specificity (100% and 97%, respectively). Post odds of apnoea were calculated for each cut-off point. In conclusion, these data suggest that the portable respiratory recording device is an effective device to identify apnoeas and hypopnoeas in a general population and is therefore a suitable device to be used in epidemiological studies.
Management of end-stage sarcoidosis: pulmonary hypertension and lung transplantation
Authors: Oksana A. Shlobin, Steven D. Nathan
Journal: European Respiratory Journal (2012)

Sarcoidosis is not only a multisystem, but also a multinational disease that is prevalent throughout the world, including Europe, the USA and Japan. Lung involvement in sarcoidosis is seemingly invariable, with up to 95% of patients manifesting some form of pulmonary disease during the course of their lifetime. The natural history of sarcoidosis in the lung is quite variable and spans the spectrum from spontaneous resolution to advanced fibrocystic disease in ~5% of cases. Advanced sarcoidosis will be the subject of this review with a special focus on pulmonary hypertension and lung transplantation as a last-resort treatment option for some patients with end-stage disease.
Late prednisone withdrawal in cyclosporine-treated kidney transplant patients
Authors: A A Hollander, R J Hene, J Hermans, L A van Es, F J van der Woude
Journal: Journal of the American Society of Nephrology (1997)

Prednisone in combination with cyclosporine and/or azathioprine is commonly used after kidney transplantation to prevent graft rejection. Long-term use of prednisone can give rise to multiple side effects and morbidity. This randomized study was conducted to find out if prednisone could be withdrawn in recipients at least 1 yr after kidney transplantation. Eighty-four such recipients of a cadaveric kidney with stable renal function on cyclosporine and prednisone were randomized to continue prednisone (N = 42) or to withdraw prednisone in a 2-month period (N = 42). The main end point was the percentage of successful prednisone withdrawal. Both groups were compared for the incidence of infections and cardiovascular risk factors and for the incidence and cause of deterioration of renal function. All patients had a 14-month follow-up. In 67% (N = 28) of the patients, prednisone could be withdrawn successfully. Acute rejection was the main cause of withdrawal failure (N = 11, 26%). No grafts were lost due to rejection. In the prednisone withdrawal group, a tendency was noted for a lower incidence of infections (difference: 17%; 95% confidence interval [CI]: -4% to 37%). After withdrawal, less antihypertensive drugs were necessary to control hypertension (difference: 0.5 drugs/patient; 95% CI: -0.9 to -0.1) and 35% less patients (23 of 41 versus nine of 42) needed cholesterol-lowering drugs (95% CI: -54% to -15%). A reduction of the frequency of patients with Type II diabetes mellitus was found (difference 10%; 95% CI: -24% to 5%) with a decrease of glycosylated hemoglobin (difference: 0.4 mmol/L; 95% CI: 0.1 to 0.8). Disappearance of moonface was found in 25% of the patients. Elective withdrawal of prednisone > 1 yr after postmortal kidney transplantation can be accomplished safely provided that patients are controlled frequently. Beneficial effects were found regarding hypertension, hypercholesterolemia, hyperglycemia, and appearance.