tbuckley/cabot-search huggingface dataset:
Safety and early efficacy results from a phase I study of volociximab (V) in combination with carboplatin (C) and paclitaxel (P) in patients (pts) with advanced non small cell lung cancer (NSCLC)
Authors: B. Besse, S. Almokadem, D. Planchard, I. Chico, C. L. Tsao, F. Ringeisen, J. Soria, C. P. Belani
Journal: Journal of Clinical Oncology (2009)

e13513 Background: Volociximab is a chimeric monoclonal antibody that blocks fibronectin binding to α5β1 and induces apoptosis in proliferating endothelial cells. Its anti-angiogenic actions are independent of the VEGF pathway. This is the first clinical study of voloxicimab in patients with advanced NSCLC. Methods: This phase 1b multi-center open-label, dose-escalation study was designed to determine the maximum tolerated dose of V in combination with full doses of C (AUC=6mg/ml.min) P (200mg/m2) with cycles repeated every 3 wks for a maximum of 6 cycles followed by a maintenance treatment with V alone. Eligible pts had histologically confirmed untreated stage IIIb or IV NSCLC. In cohorts 1 and 2, pts received V at 10 mg/kg and 20mg/kg IV, respectively, on days 1 and 8, of the first 21 day cycle then every 21 days. In cohort 3, pts received V 30 mg/kg IV every 21 days from day 1. We present here the interim safety analysis and RECIST response data of the combination therapy. Results: A total of 22 patients (9, 6 and 7 in cohorts 1, 2 and 3 respectively) who received at least one dose of treatment constitute the safety population. Reported salient adverse events (any grade) were constipation (68%), asthenia (64%), nausea (59%), arthralgia (55%) and paresthesia (46%). Grade 3 bowel obstruction in one patient was considered a DLT in cohort 2. No DLT's were observed in cohort 3. Seven pts reported at least one serious adverse event (all Grade 3) including deep vein thrombosis (1), peripheral arterial occlusion (1), proteinuria (1), pneumonitis (1), small intestinal obstruction (1), pleural effusion (1), hypoxia (1), dehydration (1) and orthostatic hypotension (1). Partial response was seen in 6 pts and stable disease in 12 out of 18 pts who were evaluable for response by RECIST. Conclusions: The highest dose of V tested (30 mg/kg q3w) in combination with CP appears well tolerated and the regimen has promising clinical activity in advanced NSCLC. [Table: see text]
Gastric Cancer in Colombia. I. Cancer Risk and Suspect Environmental Agents2
Authors: Carlos Cuello, Pelayo Correa, William Haenszel, Guido Gordillo, Charles Brown, Michael Archer, Steven Tannenbaum
Journal: JNCI Journal of the National Cancer Institute (1976)

A case-control study of patients discharged from hospitals revealed fourfold differences in geographic variation in stomach cancer risk within the Department of Nariño (Colombia). Data from gastroscopic surveys of population groups, samples of water supplies, and urine and saliva in Nariño also indicated a generally positive correlation among the following parameters: 1) gastric cancer risk, 2) prevalence of chronic atrophic gastritis and intestinal metaplasia, 3) nitrate content of well waters, and 4) nitrate excretion by the population. Urinary excretion reflected the ingestion of nitrates, and this implied a higher average intake of nitrates in the populations at high risk for stomach cancer. The Nariño data could be construed as presumptive epidemiologic evidence for the role of nitrate availability in the etiology of stomach cancer.
FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy
Authors: Nadya Al-Yacoub, Ranad Shaheen, Salma Mahmoud Awad, Muhammad Kunhi, Nduna Dzimiri, Henry C. Nguyen, Yong Xiong, Jehad Al-Buraiki, Waleed Al-Habeeb, Fowzan S. Alkuraya, Coralie Poizat
Journal: Genome biology (2016)

Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes, mostly encoding sarcomeric proteins and proteins of the cytoskeleton, have been implicated in familial DCM to date. Yet, the majority of variants causing DCM remain to be identified. The goal of the study is to identify novel mutations causing familial dilated cardiomyopathy. We identify FBXO32 (ATROGIN 1), a member of the F-Box protein family, as a novel DCM-causing locus. The missense mutation affects a highly conserved amino acid and is predicted to severely impair binding to SCF proteins. This is validated by co-immunoprecipitation experiments from cells expressing the mutant protein and from human heart tissue from two of the affected patients. We also demonstrate that the hearts of the patients with the FBXO32 mutation show accumulation of selected proteins regulating autophagy. Our results indicate that abnormal SCF activity with subsequent impairment of the autophagic flux due to a novel FBXO32 mutation is implicated in the pathogenesis of DCM.
Therapeutic potential of antidepressants in malignant glioma: clinical experience with clomipramine
Authors: R. P. Beaney, R. W. Gullan, G. J. Pilkington
Journal: Journal of Clinical Oncology (2005)

1535 Background: Despite conventional therapeutic approaches available for the management of malignant glioma the outlook remains dismal. Current therapy consists of surgery and radiotherapy along with cytotoxic chemotherapy given concomittantly, sequentially or at time of relapse. This approach is rarely curative. Our laboratory-based research has shown that a number of heterocyclic drugs (including clomipramine, desmethyl clomipramine, doxepin and amitriptyline) and selective serotonin re-uptake inhibitors (including citalopram, fluoxetine and fluvoxamine maleate) elicit mitochondrially-mediated apoptosis in malignant glioma cells by targeting complex III of the respiratory chain and altering membrane potential which results in liberation of cytochrome C and activation of a caspase pathway to cell death. Methods: Over a 4.5 year period a series of 27 patients with malignant glioma were prescribed clomipramine as an adjuvant to their conventional treatment at an escalating dose from 25mg daily up to a maintenance dose of 150mg daily. Outcome in this small series, based on survival time and MRI imaging was recorded. The results were favourable when compared with the average survival times of historical controls. Results: 5 patients (19.2%) showed disease progression whilst on medication. 21 patients (80.8%) showed a good partial response (clinically and radiologically). Survival rates were calculated using the Kaplan-Meier method; the median survival being 27 months. Conclusions: These early results from a rather selected group of patients has led to a larger trial. The side-effect profile is good with only 5% of patients withdrawing due to gastro-intestinal or neurological side-effects. This well tolerated drug, designed to cross the blood-brain barrier is worthy of further study. No significant financial relationships to disclose.
An Atlas of Bacteriology, containing One Hundred and Eleven Original Photo-Micrographs with Explanatory Text.
Journal: JAMA (1899)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia
Authors: Borhane Guezguez, Mohammed Almakadi, Yannick D. Benoit, Zoya Shapovalova, Susann Rahmig, Aline Fiebig-Comyn, Fanny L. Casado, Borko Tanasijevic, Silvia Bresolin, Riccardo Masetti, Bradley W. Doble, Mickie Bhatia
Journal: Cancer Cell (2016)
Platelets and thromboxane receptors: pivotal players in arteriogenesis: Figure 1
Authors: Victor W.M. Van Hinsbergh, Dimitar Tasev
Journal: Cardiovascular Research (2015)

This editorial refers to ‘Thromboxane A2 induces blood flow recovery via platelet adhesion to ischaemic regions’ by H. Amano et al. , doi:10.1093/cvr/cvv139. 

The reconstitution of oxygen and nutrient supply in cases of disturbed blood flow caused by tissue damage or vascular occlusion is driven by sprouting angiogenesis, arteriogenesis as an adaptation of pre-collateral vessels into collateral conduit vessels, and vasculogenesis characterized by invasion of circulating monocytic and endothelial progenitor cells.1 To study these mechanisms, a mouse model is often used, in which ligation of the femoral artery causes interruption of blood flow in the hind leg and hypoxia in the distal tissue.2 To save the hind leg tissue, the body responds immediately by the stimulation of a collateral circulation that starts proximal to the ligation. In a healthy C57/BL6 mouse, the transformation of pre-existing narrow collaterals into arterial conduit vessels with a many-fold wider diameter restores the blood supply and tissue perfusion to the hind leg within 7–10 days. In the occluded hind leg model, arteriogenesis is usually accompanied by angiogenesis in the ischaemic muscle, which results in an increase in local microvascular density. This further facilitates blood distribution and oxygen diffusion to meet the increased oxygen demand of the injured tissue. 



Figure 1 
Involvement of platelets and TPs in arteriogenesis in mice.6,7 After femoral occlusion, altered shear forces and oxygen availability modulate endothelial functioning, after which platelets start adhering the endothelium of pre-existing collaterals and vessels that became ischaemic distal of the occlusion. These …
Synthetic DNA minor groove-binding drugs☆☆Editor's Note: Figures 1–99 appear throughout text. Structures 1–271 appear together at the end of this article, although Structures 25, 111–147, 162–181, 182–188, and 241–255 also appear within Tables 1–5.
Authors: B.S.Praveen Reddy, S.Murari Sondhi, J.William Lown
Journal: Pharmacology & Therapeutics (1999)
Neoadjuvant as Future for Drug Development in Breast Cancer—Response
Authors: Angela DeMichele, Douglas Yee, Melissa Paoloni, Don Berry, Laura J. Esserman
Journal: Clinical Cancer Research (2016)

We thank Buyse and colleagues ([1][1]) for their letter and agree with much of their perspective, most importantly the need to continue to test new regimens in the neoadjuvant setting to further elucidate the relationship between pathologic complete response (pCR) and event-free survival (EFS).
Abstract 17276: Implantable Cardioverter-Defibrillator Therapy in Women: Population-based Outomes
Authors: Simone Cowan, Maja Grubisic, Lillian Ding, Nathaniel Hawkins, Adam Raymakers, Paul Novak, Min Gao, Jamil Bashir
Journal: Circulation (2014)

Background: Due to the low enrolment of women in implantable cardioverter-defibrillator (ICD) trials, there is controversy whether the survival benefit of ICDs applies to both sexes. Population-based data examining sex differences in ICD outcomes may provide further clarification. Methods: Study data were derived from a provincial registry in British Columbia (BC), the Cardiac Services BC Registry, where all ICD recipients are recorded. Patients ≥18 years with a new ICD implant from Jan 2003 to Dec 2012 were included. Data were linked to BC Vital Statistics to determine all-cause mortality. Survival was assessed using Kaplan-Meier methods stratified by sex and compared using the log-rank test. The Cox proportional-hazards model was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) between sexes. The effect of demographics, comorbidities and medication use were explored and only factors with a p-value &lt; 0.15 were included in the final model. Statistical analyses were performed with SAS software, version 9.3 (Cary, NC). Results: There were 3905 new ICD implants; of these, 704 were women (18%). Women were younger and had a lower prevalence of comorbidities. Except for beta-blockers, women were less likely to be prescribed cardiac medications. The overall survival of women was greater than men; however, women had a higher re-operation rate for complications (Figure). After adjusting for age, diabetes, coronary artery disease, congestive cardiomyopathy, peripheral vascular disease, acquired heart surgery, and anti-arrhythmic drug use, the sex difference in mortality was attenuated, adjusted HR 0.91, (95% CI: 0.75,1.12). Conclusions: Women may derive the same survival benefit as men but have a higher re-operation rate for complications. Ongoing analyses will determine whether the impact of sex on mortality differs among patients receiving an ICD for primary versus secondary prevention.
Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia
Authors: Harald Zeisler, Elisa Llurba, Frederic Chantraine, Manu Vatish, Anne Cathrine Staff, Maria Sennström, Matts Olovsson, Shaun P. Brennecke, Holger Stepan, Deirdre Allegranza, Peter Dilba, Maria Schoedl, Martin Hund, Stefan Verlohren
Journal: New England Journal of Medicine (2016)

The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear.We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks.In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3).An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.).
Dasatinib Induced Thrombocytopenia Might Be Due To The Inhibition Of Proplatelet Formation Of Megakaryocytes Via The Pathways Including Rho/Rock and Rac
Authors: Kazunori Murai, Shugo Kowata, Yukiteru Fujishima, Yasuhiko Tsukushi, Takahiro Mine, Tatsuo Oyake, Shigeki Ito, Yoji Ishida
Journal: Blood (2013)
Abstract 13211: Loss of Mitochondrial Pyruvate Carrier 1 in Cardiomyocytes Leads to Compensated Cardiac Hypertrophy in Non-stressed Hearts
Authors: Yuan Zhang, Jared Rutter, E. Dale Abel
Journal: Circulation (2014)

Although normal adult hearts utilize fatty acid oxidation to generate the majority of ATP, glucose and lactate remain important fuel substrates, in response to hemodynamic stress such as pressure overload hypertrophy and in response to exercise training. Glucose and lactate are converted to pyruvate in the cytosol and then transported into mitochondria to be oxidized. Pyruvate enters mitochondria via a recently described transport complex - the mitochondrial pyruvate carrier that has two subunits, MPC1 and MPC2. The role of pyruvate uptake in regulating cardiac function and metabolism is incompletely understood. Thus, we generated cardiomyocyte-restricted MPC1 knockout mice (CMPC1-/-) to address this question. Loss of MPC1 resulted in degradation of MPC2 leading to functional inactivation of the MPC complex in CMPC1-/- mouse hearts. CMPC1-/- mice showed normal heart weight (HW), heart weight to body weight ratio (HW/BW) and heart weight to tibia length ratio (HW/TL) compared to their control littermates at the age of 4 weeks. Cardiac function examined by echocardiography also revealed that CMPC1-/- mice exhibited normal ventricular diastolic and systolic volumes, ejection fraction (EF) and cardiac mass compared to control mice. At the age of 8 weeks, both male and female CMPC1-/- mice exhibited compensated cardiac hypertrophy with preserved cardiac function as determined by echocardiography. Heart weights (HW) was increased by 1.41 fold (p<0.05) and HW normalized to tibia length, increased by 1.63 fold (p<0.01) in 8 week-old CMPC1-/- mice. Gene expression markers characteristic for pathological cardiac hypertrophy (NPPA, NPPB and Acta1) were also increased in 8 week-old CMPC1-/- hearts. Substrate metabolism measured in isolated working hearts, showed that glucose oxidation was significantly decreased by 58% (p=0.003) in CMPC1-/- mice relative to control mice. These data suggest that mitochondrial pyruvate uptake although dispensable for normal cardiac function in non-stressed hearts of young mice, reveals an important mechanism by which an imbalance between glycolysis and glucose oxidation may activate maladaptive hypertrophic signaling pathways in the myocardium.
Evidence for rCBV as an early response marker following bevacizumab treatment
Authors: Whitney B. Pope
Journal: Neuro-Oncology (2015)

I appreciate the thoughtful letter from Schmainda et al. regarding the utility of rCBV derived from MRI as a biomarker of response to bevacizumab therapy in patients with recurrent glioblastoma (GBM). The authors cite their recent work in which they found that tumoral rCBV changes were predictive of overall survival at 2 and 16 weeks, but not 8 weeks, after the start of bevacizumab therapy in patients with GBM.1 Certainly this issue is not settled science, and I hope that further studies will be performed by the authors or others to clarify the timing at which perfusion imaging adds value to standard MRI in the assessment of patients with brain tumors. In my editorial,2 I suggest that the use of rCBV as an early response marker for bevacizumab therapy is not well supported to date. On one hand, there are the data from the authors, based on a cohort of 13 patients (point of reference: n for the Kickingereder et al3 paper showing a relationship between pretreatment rCBV and outcomes was 71) suggesting a relationship between changes in rCBV and survival at 2 and 16 weeks. Interestingly, no relationship was found at 8 weeks, when the cohort size was 17 rather than 13. (In the interests of full disclosure, I was the associate editor who recommended that the authors′ paper be published.) On the other hand, because negative results are typically (and unfortunately) unreported, we do not know how many patients with perfusion data treated with bevacizumab were similarly analyzed over the last decade but whose data were never published because of the lack of association between rCBV changes and outcomes. Based on conversations with colleagues over the years, I would suggest this is not a few, so I think it is important to consider publication bias for positive results. This was part of the rationale for suggesting that Schmainda et al's1 recent study of 13 patients notwithstanding, the evidence in support of rCBV as an early response marker to bevacizumab therapy is not as robust today as would have been predicted 10 years ago.
Non-invasive testing of acquired long QT syndrome Evidence for multiple arrhythmogenic substrates
Authors: P Chevalier
Journal: Cardiovascular Research (2001)

Although well-defined clinically and electrocardiographically, Acquired Long QT Syndrome (LQTS) remains elusive from a pathophysiologic point of view. An increasingly accepted hypothesis is that it represents an attenuated form of Congenital Long QT Syndrome. To test this hypothesis further, we investigated patients with Acquired LQTS, using various investigations that are known to give information in patients with Congenital LQTS.All the investigations were performed in patients with a history of Acquired Long QT Syndrome, defined by marked transient QT lengthening (QT>600 ms) and/or torsades de pointes. Measurement of the QT interval dispersion, the interlead difference for the QT interval on a 12-lead ECG, was performed in 18 patients and compared with 18 controls, matched for age and sex. To assess sympathetic myocardial innervation, I-123 Meta-iodobenzylguanidine (I-123-MIBG) scintigraphy was performed in 12 patients, together with Thallium scintigraphy, to rule out abnormal myocardial perfusion. Time-frequency analysis of a high-resolution ECG using a wavelet technique, was made for nine patients and compared with 38 healthy controls. Finally, genetic studies were performed prospectively in 16 consecutive patients, to look for HERG, KCNE1, KCNE2 and KCNQ1 mutations. The functional profile of a mutated HERG protein was performed using the patch-clamp technique.Compared with the control group, a significant increase in QT dispersion was observed in the patients with a history of Acquired LQTS (55+/-15 vs. 33+/-9 ms, P<0.001). In another group of patients with Acquired LQTS, 123 I-MIBG tomoscintigraphy demonstrated a decrease in the sympathetic myocardial innervation. Time--frequency analysis using wavelet transform, demonstrated an abnormal frequency content within the QRS complexes, in the patients with Acquired LQTS, similar to that found in Congenital LQTS patients. Molecular screening in 16 consecutive patients, identified one patient with a missense mutation on HERG, one of the LQTS genes. Expression of the mutated HERG protein led to altered K(+) channel function.Our results suggest that Acquired and Congenital Long QT Syndromes have some common features. They allow the mechanism of the clinical heterogeneity, found in both syndromes, to be understood. Further multi-facet approaches are needed to decipher the complex interplay between the main determinants of these arrhythmogenic diseases.