tbuckley/cabot-search huggingface dataset:
Reply to M.L. Berger et al
Authors: Alberto Sobrero, Paolo Bruzzi
Journal: Journal of Clinical Oncology (2010)

Berger et al agree with us that “incrementalists” may not be clinically worthwhile, but they challenge as “imprudent” our suggestion that only paradigm-changing agents should be approved. And they conclude that “there is no reason to believe that any of the 350 drugs currently in development would meet these proposed hurdles for approval unless we aggressively pursue uniquely responding subsets.” Why “no reason to believe . . . ”? The median hazard ratio for progression-free survival in the 15 pivotal trials on nine biologicals tested against eight different solid tumors (Table 1 of our article) is 0.57, which means between 50% and 100% increment in median values. And if one excludes the criticized registration of erlotinib in pancreatic cancer, all the other hazard ratio values are below 0.68. This tells us that the “proposed hurdles” are within a plausible range and that the discovery of paradigm-changing drugs is a realistic goal. The point we are making in our article is that we need to be more courageous when designing the trials, shooting at higher deltas, and, yes, “aggressively pursue uniquely responding subsets.” Here are our short replies to the four points raised. Long-term or rare toxicities are not of fundamental concern in the advanced solid tumor setting. If it were so, why would independent data monitoring committees recommend trial discontinuation because of early evidence of strong efficacy? And why would regulatory authorities accept these preliminary data as the basis for early registration if the concern for rare toxicity was so prominent? We are still debating the accuracy of estrogen receptor status determination 40 years after the approval of tamoxifen. The accuracy of assays may become only a fine-tuning issue if major efficacy is proven. Our article does acknowledge that regulatory approval does not translate into reimbursement and access. But this means discharging onto society and national health systems the evaluation of what is clinically worthwhile. Halting the process at the beginning would promote international and regional uniformity, increasing the credibility of clinical research and restricting the migration of patients seeking what is incorrectly perceived as a miraculous drug. We agree that retrospective search of predictors may be helpful. Indeed, the so-called limbo level of approval was conceived by us for drugs not qualifying for direct approval as paradigm changing, but showing some degree of efficacy. The development of these drugs could be further pursued in subsequent studies, including (retrospective) studies/analyses in patients subgroups.
THE ANTIGENIC COMPLEX OF STREPTOCOCCUS HÆMOLYTICUS
Authors: Rebecca C. Lancefield
Journal: The Journal of Experimental Medicine (1928)

1. Hydrochloric acid extracts of Streptococcus haemolyticus contain type-specific, as well as non-type-specific, substances. The precipitates formed by these crude extracts with homologous antibacterial serum are flocculent, while those obtained with heterologous serum are usually disc-like. 2. The type-specific substance may be detected by the use of anti-bacterial sera absorbed with heterologous strains of hemolytic streptococci. Such absorbed sera are type-specific: they are precipitated only by extracts of strains of the homologous type. 3. Any heterologous strain of hemolytic streptococcus absorbs the antibodies for all other heterologous strains, but homologous strains absorb type-specific antibodies as well. Numerous repeated absorptions with heterologous hemolytic streptococci tend to lower the titer of the type-specific antibody. A possible explanation of this fact is suggested. 4. Three strains did not yield a type-specific substance; and it seems probable that they had lost this function because of long continued cultivation in artificial media. 5. Classification based on the precipitin test with absorbed serum agrees with that previously determined by agglutination and protection tests. The method is, therefore, applicable to the problem of classification of the hemolytic streptococci.
Diagnosis of Type 2 Diabetes at an Older Age
Authors: Hwee H. Tan, Ritchie R. McAlpine, Peter James, Philip Thompson, Marion E.T. McMurdo, Andrew D. Morris, Josie M.M. Evans
Journal: Diabetes Care (2004)

OBJECTIVE—To compare the mortality of people who were diagnosed with type 2 diabetes over 65 years of age with that of nondiabetic individuals. RESEARCH DESIGN AND METHODS—Using a population-based diabetes information system for an observational cohort study in Tayside, Scotland, people who were diagnosed with type 2 diabetes over the age of 65 years between 1993 and 2002 were identified. Nondiabetic comparators, matched for age and sex, were identified from the nondiabetic population. The two cohorts were followed up for mortality and cardiovascular mortality according to death certification records. RESULTS—There were 3,594 people with type 2 diabetes (48% male) and 7,188 matched comparators identified in the study. Over a mean follow-up period of 4.6 ± 2.9 years for 3,594 people with type 2 diabetes and 7,188 comparators, 909 (25.3%) patients in the diabetic cohort and 1,651 (23.0%) in the nondiabetic cohort died. The adjusted relative risk for mortality in the diabetic cohort compared with the nondiabetic cohort was 1.06 (95% CI 0.94–1.19) for men and 1.29 (1.15–1.45) for women. Cardiovascular deaths accounted for 49.4% of the deaths in people with and 45.2% in those without diabetes (adjusted relative risk 1.01 [0.93–1.10]). CONCLUSIONS—Men diagnosed with type 2 diabetes over the age of 65 years have no excess mortality compared with their nondiabetic counterparts, a finding that was not replicated for women.
Factors Determining Vulnerability to Ventricular Fibrillation Induced by 60-CPS Alternating Current
Authors: TSUNEAKI SUGIMOTO, STEPHEN F. SCHAAL, ANDREW G. WALLACE
Journal: Circulation Research (1967)

Very weak, 60-cps alternating current applied directly to the heart can cause ventricular fibrillation; greater current strength is required to induce ventricular fibrillation with a single shock delivered during the vulnerable period of the cardiac cycle. The present experiments were designed to examine the basis of this difference. The studies were performed in anesthetized open-chest dogs. The current strength required to induce ventricular fibrillation was 0.52± 0.16 ma with 60 cps for 5 sec, and 15.0±4.3 ma with a single square-wave pulse of 10 msec. However, when the duration of 60 cps was reduced to produced only 4, 3, 2, or1 ventricular response, the threshold for ventricular fibrillation after the last response was 0.4, 2, 18, or 24 ma respectively. After any given number of successive premature ventricular responses, the fibrillation threshold was comparable with either 60 cps or a single pulse. We concluded that, if an accelerating ventricular tachycardia that is produced by 60-cps stimulation is of sufficient duration (5 or 6 beats), the VF threshold is reduced progressively after each premature ventricular response, thus making it possible to include VF with very weak current.
Human Long Noncoding RNAs Are Substantially Less Folded than Messenger RNAs
Authors: Jian-Rong Yang, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2014)

Long noncoding RNAs (lncRNAs) do not code for proteins but function as RNAs. Because the functions of an RNA rely on either its sequence or secondary structure, lncRNAs should be folded at least as strongly as messenger RNAs (mRNAs), which serve as messengers for translation and are generally thought to lack secondary structure-dependent RNA-level functions. Contrary to this prediction, analysis of genome-wide experimental data of human RNA folding reveals that lncRNAs are substantially less folded than mRNAs even after the control of expression level and GC% (percentage of guanines and cytosines), although both lncRNAs and mRNAs are more strongly folded than expected by chance. In contrast to mRNAs, lncRNAs show neither the positive correlation between folding strength and expression level nor the negative correlation between folding strength and evolutionary rate. These and other results support that although RNA folding undoubtedly plays a role in RNA biology it is also important in translation and/or protein biology.
Clinical Outcomes of Medical Therapy and Timely Operation in Initially Diagnosed Type A Aortic Intramural Hematoma
Authors: Takeshi Kitai, Shuichiro Kaji, Atsushi Yamamuro, Tomoko Tani, Koichi Tamita, Makoto Kinoshita, Natsuhiko Ehara, Atsushi Kobori, Michihiro Nasu, Yukikatsu Okada, Yutaka Furukawa
Journal: Circulation (2009)

The management of aortic intramural hematoma (IMH) involving the ascending aorta (type A) has not been well-established. The purpose of this study was to clarify the long-term clinical outcomes of patients with type A IMH who were treated with medical therapy and timely operation.Clinical data including operative mortality, IMH-related events, and long-term survival were retrospectively reviewed in 66 patients with type A IMH, who were admitted to our institution from 1986 to 2006. Emergent surgical repair was performed in 16 (24%) patients because of severe complications, whereas 50 patients were treated with initial medical therapy. In medically treated patients, 15 (30%) patients who demonstrated progression to classic dissection or increase in hematoma size within 30 days underwent surgical repair except for 2 patients who refused surgery. The 30-day mortality rate was 6% with emergent surgery and 4% with supportive medial therapy. There were 7 late deaths and the actuarial survival rates of all patients were 96+/-3%, 94+/-3%, and 89+/-5% at 1, 5, and 10 years, respectively. In medically treated patients, maximum aortic diameter was the only predictor of early and late progression of ascending IMH (hazard ratio, 4.43; 95% CI, 2.04-9.64; P<0.001). Aortic diameter > or =50 mm predicted progression of ascending IMH with the positive and negative value of 83% and 84%, respectively.Combination of medical therapy and timely operation resulted in favorable long-term clinical outcomes in patients with type A IMH.
Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain
Authors: Andrew D Cook, Jarrad Pobjoy, Shannon Sarros, Stefan Steidl, Manuela Dürr, Derek C Lacey, John A Hamilton
Journal: Annals of the Rheumatic Diseases (2012)

Better therapies are needed for inflammatory pain. In arthritis the relationship between joint pain, inflammation and damage is unclear. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is important for the progression of a number of inflammatory/autoimmune conditions including arthritis; clinical trials targeting its action in rheumatoid arthritis are underway. However, its contribution to inflammatory and arthritic pain is unknown. The aims of this study were to determine whether GM-CSF controls inflammatory and/or arthritic pain.A model of inflammatory pain (complete Freund's adjuvant footpad), as well as two inflammatory arthritis models, were induced in GM-CSF(-/-) mice and development of pain (assessment of weight distribution) and arthritic disease (histology) was assessed. Pain was further assessed in a GM-CSF-driven arthritis (methylated bovine serum albumin/GM-CSF) model and the cyclooxygenase-dependence determined using indomethacin.GM-CSF was absolutely required for pain development in both the inflammatory pain and arthritis models, including for IL-1-dependent arthritic pain. Pain in a GM-CSF-driven arthritis model, but not the disease itself, was abolished by the cyclooxygenase inhibitor, indomethacin, indicating separate pathways downstream of GM-CSF for pain and arthritis control.GM-CSF is key to the development of inflammatory and arthritic pain, suggesting that pain alleviation could result from trials evaluating its role in inflammatory/autoimmune conditions.
FEV<sub>1</sub>decline in cystic fibrosis
Authors: Martin Miller
Journal: Thorax (2012)

I read the paper by Taylor-Robinson et al 1 with interest with regard to modelling the decline in forced expiratory volume in 1 second (FEV1) in patients with cystic fibrosis (CF). The authors have made the assumption that expressing spirometry results as a per cent of predicted (PP) is a valid way to …
Respiratory impedance in children with cystic fibrosis using forced oscillations in clinic
Authors: C. L. Gangell, F. Horak, H. J. Patterson, P. D. Sly, S. M. Stick, G. L. Hall
Journal: European Respiratory Journal (2007)

Measurement of lung function is an important component of clinical management in cystic fibrosis (CF), but has been difficult in young children. The present study aimed to characterise the utility of the forced oscillation technique for measurement of lung function in preschool-aged children with CF in a routine clinical setting. Lung function was assessed in 56 young children (aged 2–7 yrs) with CF. Respiratory system resistance ( R rs ) and reactance ( X rs ) at 6, 8 and 10 Hz were measured and expressed as Z-scores. Children were classified as asymptomatic or symptomatic based on an administered respiratory questionnaire and physical examination at the time of testing. Between-test repeatability was assessed in 25 children. Measurement of lung function using the forced oscillation technique was feasible in the CF clinic. The children with CF, as a group, had Z-scores for R rs at 6 Hz ( R rs,6 ) R rs,8 , R rs,10 , X rs at 6 Hz ( X rs,6 ) and X rs,8 that were significantly different from zero. Children with current symptoms showed significantly decreased X rs and increased R rs,6 compared with asymptomatic children. Measurement of lung function using the forced oscillation technique is feasible in young children with cystic fibrosis in a clinical setting. The technique has the potential to improve knowledge concerning early cystic fibrosis lung disease.
Clinical Trial Development as a Predictor of Accrual Performance—Response
Authors: Steven K. Cheng, David M. Dilts
Journal: Clinical Cancer Research (2011)

We thank Schoen for her comments and insights into accrual performance. The primary purpose of our research was to reveal the relationship between development time of National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP)-supported trials and a standard accrual milestone that was
BCL2 Suppresses PARP1 Function and Nonapoptotic Cell Death
Authors: Chaitali Dutta, Tovah Day, Nadja Kopp, Diederik van Bodegom, Matthew S. Davids, Jeremy Ryan, Liat Bird, Naveen Kommajosyula, Oliver Weigert, Akinori Yoda, Hua Fung, Jennifer R. Brown, Geoffrey I. Shapiro, Anthony Letai, David M. Weinstock
Journal: Cancer Research (2012)

Abstract BCL2 suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating outer mitochondrial membrane permeabilization. Many tumor types, including B-cell lymphomas and chronic lymphocytic leukemia, are dependent on BCL2 for survival but become resistant to apoptosis after treatment. Here, we identified a direct interaction between the antiapoptotic protein BCL2 and the enzyme PARP1, which suppresses PARP1 enzymatic activity and inhibits PARP1-dependent DNA repair in diffuse large B-cell lymphoma cells. The BH3 mimetic ABT-737 displaced PARP1 from BCL2 in a dose-dependent manner, reestablishing PARP1 activity and DNA repair and promoting nonapoptotic cell death. This form of cell death was unaffected by resistance to single-agent ABT-737 that results from upregulation of antiapoptotic BCL2 family members. On the basis of the ability of BCL2 to suppress PARP1 function, we hypothesized that ectopic BCL2 expression would kill PARP inhibitor–sensitive cells. Strikingly, BCL2 expression reduced the survival of PARP inhibitor–sensitive breast cancer and lung cancer cells by 90% to 100%, and these effects were reversed by ABT-737. Taken together, our findings show that a novel interaction between BCL2 and PARP1 blocks PARP1 enzymatic activity and suppresses PARP1-dependent repair. Targeted disruption of the BCL2–PARP1 interaction therefore may represent a potential therapeutic approach for BCL2-expressing tumors resistant to apoptosis. Cancer Res; 72(16); 4193–203. ©2012 AACR.
Isthmus Characteristics of Reentrant Ventricular Tachycardia After Myocardial Infarction
Authors: Christian de Chillou, Dominique Lacroix, Didier Klug, Isabelle Magnin-Poull, Christelle Marquié, Marc Messier, Marius Andronache, Claude Kouakam, Nicolas Sadoul, Jian Chen, Etienne Aliot, Salem Kacet
Journal: Circulation (2002)

Background — The reentrant mechanism of postinfarct ventricular tachycardia (VT) has been documented by surgical mapping analysis, but little is known about postinfarct VT circuits and the characteristics of their related protected isthmus with the use of 3D catheter mapping systems. Methods and Results — A 3D electroanatomic mapping was performed in 21 patients with well-tolerated, postinfarct, sustained VT. In total, 33 episodes of tachycardia (mean cycle length 432±74 ms) were induced and mapped. Complete maps demonstrated macroreentrant circuits with 1 loop (n=8) or 2 loops (n=25) rotating around a protected isthmus bounded by 2 approximately parallel conduction barriers that consisted of a line of double potentials, a scar area, or the mitral annulus. A total of 26 critical isthmi were identified for the 33 VTs mapped, with the same isthmus being shared by 2 to 4 different tachycardic morphologies in 5 patients. On average, isthmi were 31±7 mm long (ranging from 18 to 41 mm) and 16±8 mm wide (ranging from 6 to 36 mm) and harbored diastolic electrograms. The isthmus axis was oriented parallel to the mitral annulus plane in perimitral circuits and perpendicular to the mitral annulus plane in all other circuits. Linear radiofrequency ablation performed across the most accessible part of the isthmus prevented the recurrence of tachycardia in 19 patients (90%) with a follow-up at 16±8 months. Conclusions — Detailed 3D electroanatomic mapping is helpful in reconstructing postinfarct VT circuits and in defining the characteristics of their related protected isthmi. The wide range of isthmus width values supports the need of linear radiofrequency lesions to eliminate the reentrant substrate of postinfarct VTs.
Deficits in the Treatment of Alcoholism and Recommendations for Correction
Authors: WALTER E. BARTON
Journal: American Journal of Psychiatry (1968)

Existing treatment resources for the alcoholic patient are woefully inadequate, although there are a few outposts of good treatment. A round-the-clock resources are an exceptional and rare service. A description of some of the existing models of psychiatric services for alcoholism is given, and recommendations are formulated for improvement of psychiatric services for detoxification, evaluation and diagnosis, comprehensive treatment, and rehabilitation.
The clinical value of the quantitative detection of four cancer-testis antigen genes in multiple myeloma
Authors: Yao Zhang, Li Bao, Jin Lu, Kai-Yan Liu, Jin-Lan Li, Ya-Zhen Qin, Huan Chen, Ling-Di Li, Yuan Kong, Hong-Xia Shi, Yue-Yun Lai, Yan-Rong Liu, Bin Jiang, Shan-Shan Chen, Xiao-Jun Huang, Guo-Rui Ruan
Journal: Molecular Cancer (2014)

Cancer-testis (CT) antigen genes might promote the progression of multiple myeloma (MM). CT antigens may act as diagnostic and prognostic markers in MM, but their expression levels and clinical implications in this disease are not fully understood. This study measured the expression levels of four CT antigen genes in Chinese patients with MM and explored their clinical implications. Real-time quantitative polymerase chain reaction (qPCR) was used to quantify the expression of MAGE-C1/CT7, MAGE-A3, MAGE-C2/CT10 and SSX-2 mRNA in 256 bone marrow samples from 144 MM patients. In the newly diagnosed patients, the positive expression rates were 88.5% for MAGE-C1/CT7, 82.1% for MAGE-C2/CT10, 76.9% for MAGE-A3 and 25.6% for SSX-2. The expression levels and the number of co-expressed CT antigens correlated significantly with several clinical indicators, including the percentage of plasma cells infiltrating the bone marrow, abnormal chromosome karyotypes and the clinical course. MAGE-C1/CT7, MAGE-A3, MAGE-C2/CT10 and SSX-2 expression levels provide potentially effective clinical indicators for the auxiliary diagnosis and monitoring of treatment efficacy in MM.
Connexin 30 Deficiency Impairs Renal Tubular ATP Release and Pressure Natriuresis
Authors: Arnold Sipos, Sarah L. Vargas, Ildikó Toma, Fiona Hanner, Klaus Willecke, János Peti-Peterdi
Journal: Journal of the American Society of Nephrology (2009)

In the renal tubule, ATP is an important regulator of salt and water reabsorption, but the mechanism of ATP release is unknown. Several connexin (Cx) isoforms form mechanosensitive, ATP-permeable hemichannels. We localized Cx30 to the nonjunctional apical membrane of cells in the distal nephron and tested whether Cx30 participates in physiologically important release of ATP. We dissected, partially split open, and microperfused cortical collecting ducts from wild-type and Cx30-deficient mice <i>in vitro</i>. We used PC12 cells as ATP biosensors by loading them with Fluo-4/Fura Red to measure cytosolic calcium and positioning them in direct contact with the apical surface of either intercalated or principal cells. ATP biosensor responses, triggered by increased tubular flow or by bath hypotonicity, were approximately three-fold greater when positioned next to intercalated cells than next to principal cells. In addition, these responses did not occur in preparations from Cx30-deficient mice or with purinergic receptor blockade. After inducing step increases in mean arterial pressure by ligating the distal aorta followed by the mesenteric and celiac arteries, urine output increased 4.2-fold in wild-type mice compared with 2.6-fold in Cx30-deficient mice, and urinary Na<sup>+</sup> excretion increased 5.2-fold in wild-type mice compared with 2.8-fold in Cx30-deficient mice. Furthermore, Cx30-deficient mice developed endothelial sodium channel–dependent, salt-sensitive elevations in mean arterial pressure. Taken together, we suggest that mechanosensitive Cx30 hemichannels have an integral role in pressure natriuresis by releasing ATP into the tubular fluid, which inhibits salt and water reabsorption.