tbuckley/cabot-search huggingface dataset:
Epiphyseal Development in Fetal Malnutrition Syndrome
Authors: Kenneth E. Scott, Robert Usher
Journal: New England Journal of Medicine (1964)

FETAL malnutrition syndrome is a term used to describe the infant who is small for gestation and often wasted at birth. A wide variety of names have been used by others to describe this condition, including postmaturity, placental insufficiency, intrauterine growth retardation or simply the small term infant. External measurements of such newborn infants1 have shown them not long and scrawny, as usually described, but stunted in linear skeletal growth, indicating that fetal malnutrition affects growth of bone as well as soft tissue and suggesting that epiphyseal development might also be delayed.If epiphyseal development is delayed by malnutrition in . . .
Caloric Intake and Aging
Authors: Richard Weindruch, Rajindar S. Sohal
Journal: New England Journal of Medicine (1997)

In postindustrial societies, overeating, inactivity, and obesity have emerged as new challenges in public health.1,2 Considerable effort is now being devoted to determining the pathophysiologic consequences of overeating. Several lines of evidence suggest that caloric intake influences the rate of aging and the onset of associated diseases in animals and, possibly, humans.35 The observation that laboratory rats not only live longer but also have fewer age-associated diseases when their food intake is restricted dates back to the 1930s.37 Numerous subsequent studies have found that when the ad libitum food intake of mice and rats was reduced by . . .
Current Standard Technique for Modern Flexible Ureteroscopy: Tips and Tricks
Authors: Guido Giusti, Silvia Proietti, Luca Villa, Jonathan Cloutier, Marco Rosso, Giulio Maria Gadda, Steeve Doizi, Nazareno Suardi, Francesco Montorsi, Franco Gaboardi, Olivier Traxer
Journal: European Urology (2016)
Reduced PD-1/PD-L1 expression in KRAS-mutant versus wild-type microsatellite instable (MSI-H) colorectal cancer (CRC) and association of wnt pathway corepressor TLE-3.
Authors: Namrata Vijayvergia, Julie Innocent, Aarti Khushal Bhatia, Raji Shameem, Joanne Xiu, Zoran Gatalica, Sergei Grivennikov, Wafik S. El-Deiry
Journal: Journal of Clinical Oncology (2015)

3611 Background: MSI-H CRC comprises ~15% of CRC & has higher PD-1 & PD-L1 (P(+)) expression in CD4+ lymphocytes & tumor cells, respectively, compared to non-MSI-H CRC. Immune-checkpoint inhibitor therapy is being tested in clinical trials for MSI-H CRC (NCT02060188, NCT01876511). Human homologue of Groucho, Transducin-like-Enhancer of Split orthologue (TLE-3), inhibits Wnt signaling by competition with b-catenin for LEF/TCF binding. We investigated different biomarkers that may characterize P(+) MSI-H CRC. Methods: 55 MSI-H (including 13 Lynch Syndrome cases) CRCs were profiled at Caris Life Sciences (Phoenix, AZ). Immunohistochemistry (IHC) & mutation analysis was performed to compare P(+) & P(-) MSI-H CRC. PD-1 expression was measured on Tumor Infiltrating Lymphocytes (TIL) with the cutoff of 1+, 1% (1/HPF); PD-L1 expression was measured on tumor cells with the cutoff of 2+, 5%. IHC assays underwent a stringent validation process meeting CLIA/CAP criteria. Fisher's exact test was used to compare categorical variables. Results: Analysis of 55 MSI-H tumors revealed 39 (71%) were P(+) (39 PD-1(+); 1 also PD-L1(+)) & 16 (29%) were P(-). The P(+) group expressed TOPO-1/2 (43%/93%), EGF-R (88%), TS (90%), RRM1 (77%), PTEN (77%), c-MET (50%), and MGMT (53%) by IHC, and the expression was not significantly different compared to the P(-) group. TLE-3 protein expression, however, was 43% in P(+) and only 8% in P(-) MSI-H tumors (P = 0.04). Only 9 (27%) of P(+) tumors harbored a KRAS mutation, while 10 (62%) had KRAS mutation in P(-) tumors (P = 0.04). Conclusions: PD-1/PD-L1 protein expression is inversely associated with KRAS mutation status in MSI-H CRC. This is relevant to clinical trials testing immune checkpoint inhibitors in MSI-H CRC. The signaling between KRAS mutation & low or absent PD-1/PD-L1 should be further investigated. TLE-3 expression may dampen b-catenin signaling in P(+) tumors.
Gene signature of metformin actions on primary breast cancer within a window of opportunity randomized clinical trial.
Authors: S. M. Hadad, J. A. Dewar, E. Elseedawy, L. Jordan, C. Purdie, S. E. Bray, A. M. Thompson
Journal: Journal of Clinical Oncology (2010)

560 Background: Metformin has been linked to a reduced incidence of breast cancer and to increased pathological response when administered concurrently with neoadjuvant chemotherapy. The antineoplastic effect of metformin may be through direct activation of AMP-activated protein kinase (AMPK), since AMPK is dysfunctional in the majority of primary breast cancers, or via systemic effects. This open label, randomised clinical trial investigated the effects of metformin alone on gene expression in primary breast cancer. Methods: Nondiabetic women with histologically proven, operable, primary invasive breast cancer > 1 cm in size were offered the trial. The trial had 2 arms: trial A (8 patients), patients had tumor core biopsies (1) at presentation; (2) after a week of no treatment (internal control); and (3) after 2 weeks of metformin at the time of definitive surgery. In trial arm B (47 patients), patients had paired core biopsies and venous blood for insulin levels: before randomisation to either take metformin or not, and at the time of definitive breast surgery. RNA was extracted from paired pre/post metformin, formalin fixed cores and examined using a Breast Cancer Disease-Specific Array (ALMAC Diagnostics, Craigavon, UK). Analyses included differential gene selection using fold change and signature p-value filters. Results: Patients were age 38-82 (mean: 61) years, with grade II-III tumours, and 87% ER positive. Four genes were consistently downregulated by metformin on stringent testing in both trial arms A and B including PDE3B (student's t-test: p = 0.007 and 0.089), SSR3 (p = 0.009 and 0.007), TP53 (p = 0.062 and 0.012) and CCDC14 (0.091 and 0.003). No significant changes between the premetformin and postmetformin serum insulin levels were identified. Conclusions: Metformin directly affects primary breast cancer in vivo including downregulation of PDE3B, a critical regulator of cAMP which affects the activation/phosphorylation of AMPK, in the absence of significant effects on insulin. This study supports the use of metformin as an adjuvant treatment for breast cancer. No significant financial relationships to disclose.
The Biologic Activity of a Potent Analogue of Gonadotropin-Releasing Hormone in Normal and Hypogonadotropic Men
Authors: William F. Crowley, Inese Z. Beitins, Wylie Vale, Bernard Kliman, Jean Rivier, Catherine Rivier, Janet W. McArthur
Journal: New England Journal of Medicine (1980)

We studied the biologic activity of a long-acting analogue of luteinizing hormone-releasing hormone, D-Trp6-Pro9-NEt-LHRH (LHRHa), in five normal men and four hypogonadotropic men previously unresponsive to natural LHRH. All subjects responded to LHRAa, but there were quantitative and qualitative differences between the normal and hypogonadotropic men. Normal men showed a linear dose-response relation, endogenous gonadal steroid secretion, and an adult pattern of gonadotropin secretion characterized by a high ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH). Hypogonadotropic men had improving pituitary responses to each dose of LHRHa (priming response), no demonstrable gonadal steroid secretion, and a prepubertal pattern of gonadotropin release characterized by reversal of the normal ratio of LH to FSH. When compared with native LHRH, LHRHa had an augmented ability to discharge gonadotropins acutely and to sustain their release in normal and hypogonadotropic men.
Encore: A Randomized, Controlled, Open-Label Non-Inferiority Study Comparing Eliglustat To Imiglucerase In Gaucher Disease Type 1 Patients On Enzyme Replacement Therapy Who Have Reached Therapeutic Goals
Authors: Manisha Balwani, Timothy M. Cox, Guillermo Drelichman, Renata Cravo, Ana Maria Martins, Elena Lukina, Barry E. Rosenbloom, Leorah H. Ross, Jennifer Angell, Ana Cristina Puga
Journal: Blood (2013)
Extracellular cleaved HER2 (p95) confers partial resistance to trastuzumab but not HSP90 inhibitors in models of HER2 amplified breast cancer
Authors: S. Chandarlapaty, M. Scaltriti, J. Baselga, Q. Ye, D. Solit, L. Norton, N. Rosen
Journal: Journal of Clinical Oncology (2007)

10515 Background: Breast cancers containing an amplified copy of the HER2 receptor tyrosine kinase represent 20–30% of all cases and antibody directed therapy targeting the extracellular domain of HER2 with trastuzumab has proven broadly efficacious. However, resistance to trastuzumab is a common phenomenon. Recent work has identified a cleaved, 95kD version of HER2 that lacks the extracellular epitope in which the trastuzumab binding site is found. Presence of this so called “p95” has been correlated with a worse clinical prognosis. We hypothesized that p95 may enable tumor resistance to trastuzumab. Methods/Results: We established models of p95 expressing breast cancer by transfecting p95 into preexisting models of HER2 amplified breast cancer. We find that cells expressing p95 display increased resistance to the growth inhibitory effects of trastuzumab. The PI3K-AKT pathway that is downregulated by Trastuzumab is less affected in the p95 expressing cells. Furthermore, p95 demonstrates an association with HER3 that is unaffected by trastuzumab treatment. Next, we evaluated the efficacy of therapies targeted against the intracellular domain of HER2 such as the HSP90 inhibitor, 17-AAG. HER2 requires HSP90 for its conformational stability and inhibitors of HSP90 result in growth inhibition of HER2 + breast cancer. We find that p95 displays a similar requirement for HSP90 as inhibitors of HSP90 result in the degradation of p95. Moreover, cells overexpressing p95 are equally susceptible to the antitumor effects of HSP90 inhibitors as those without high levels of p95. Finally, we utilized an empirically derived, in vivo model of trastuzumab resistance that displays high level expression of p95. As with the transfected models, these tumors retain their sensitivity to HSP90 inhibitors as treatment of mice bearing tumors results in both degradation of HER2 and p95 as well as robust tumor growth inhibition. Conclusions: Given the presence of p95 in human breast tumor samples, the data suggest that p95 may play an important role in mediating clinical resistance to trastuzumab. They further suggest that such tumors may retain their sensitivity to targeted therapy against the intracellular portion of HER2 such as with lapatinib or 17-AAG. No significant financial relationships to disclose.
Role of VEGF and VEGFR2 single nucleotide polymorphisms (SNPs) in predicting treatment-induced hypertension (HTN) and clinical outcome (CO) in metastatic clear cell RCC (mccRCC) patients (pts) treated with sunitinib.
Authors: J. J. Kim, S. A. Vaziri, P. Elson, B. I. Rini, A. Patel, N. S. Basappa, M. Ganapathi, R. Ganapathi
Journal: Journal of Clinical Oncology (2010)

4629 Background: We previously reported that VEGF SNP-634 is associated with development of sunitinib-induced HTN in mccRCC pts (J Clin Oncol 27:15s, 2009). We have now expanded this analysis to include a panel of established SNPs within VEGF [-2578 C/A (rs 699947), -1154 G/A (rs 1570360), 936 C/T (rs 3025039)] and VEGFR2 [889 G/A (rs 2305948), 1416 A/T (rs 1870377)]. We tested the hypothesis that VEGF and VEGFR2 SNPs differ for association with HTN and CO [tumor shrinkage (TS), progression-free survival (PFS) and overall survival (OS)] in mccRCC pts receiving sunitinib. Methods: mccRCC pts receiving sunitinib (50mg 4/2) with germline DNA were retrospectively identified. Genomic DNA was isolated from peripheral blood lymphocytes and amplified using primers designed to flanking sequences for the respective SNPs. Genotypes were assigned following sequence analysis. Data was analyzed using the Wilcoxon rank sum and Cochran-Armitage trend tests, and proportional hazards models. Results: Sixty-four pts were identified of which 63 had SNP data. Pt characteristics included 78% male; median age 60 (range, 35-80); 67% ECOG performance status 0; 89% prior nephrectomy and 63% previously treated with cytokines (48%) and/or a tyrosine kinase inhibitor (TKI; 24%). Among candidate VEGF SNPs, 936 was associated with median TS (C/T – 48% and C/C – 24%, p=0.04) and -2578 was associated with prevalence of sunitinib-induced HTN (C/C – 100%, A/C – 89%, A/A – 69%, p=0.03). None of the VEGF SNPs were associated with PFS or OS. In contrast, VEGFR2 SNPs were not associated with HTN or TS. However, the most favorable combined VEGFR2 genotype [G/A (889) and A/A (1,416)] had significantly better OS (p=.03) than pts with less favorable combined genotypes. The impact of the combined genotype on OS remained significant after adjusting for Cleveland Clinic TKI risk group (p=.04). Conclusions: In mccRCC pts treated with sunitinib, VEGF SNPs (-2578 and -634) are associated with HTN, and 936 is associated with TS, while VEGFR2 SNPs (889 and 1,416) are correlated with OS. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer
Muramidase Studies in Philadelphia-Chromosome-Positive and Chromosome-Negative Chronic Granulocytic Leukemia
Authors: Pasquale E. Perillie, Stuart C. Finch
Journal: New England Journal of Medicine (1970)

Muramidasuria is most consistently demonstrated in acute monocytic leukemia. Detection of muramidasuria in some patients with chronic granulocytic leukemia led to a comparative study of 14 patients, demonstrating that the six patients with muramidasuria differed from the remaining eight patients in several ways. All were Philadelphia-chromosome negative. Serum muramidase levels were higher in the negative group, and the patients were older, with male-sex predominating, platelet counts were lower, and responsiveness to busulfan was poorer than in the positive group.
Death predicictive factor in terminal cancer patients
Authors: S. Koh, K. Lee, Y. Hong, J. Kang, I. Woo, M. Lee, S. Chang
Journal: Journal of Clinical Oncology (2006)

18627 Background: One of the most important role of a end-of-life care is to control physical symptoms of patients and help them to face comfortable end. In terminally ill cancer patients, accurate prediction of survival is necessary for clinical and ethical reasons, especially in helping to avoid harm, discomfort and inappropriate therapies and in planning specific care strategies. The aim of the study was to investigate prognostic factor of death for the patients with terminal cancer. Methods: We enrolled 121 patients with the terminal cancer of Kangnam St. Mary’s Hospital from September 2004 until their death. We observed symptoms shown in dying patients and assess 17 common symptoms shown in terminally ill cancer patients, performance status, pain and analgesic use. The common symptoms were measured in a score of 0-none, 1-mild, 2-moderate, 3-severe or 4-severe by objective criteria. Results: Mean period from enrollment to death was 34.7days. The most important prognostic factor is performance status (KPS), average KPS at enrollment is 52.2% and at last 48hours is 29.8%. Physical symptoms that have significant prognostic importance are weakness, anorexia, dry mouth, dysphagia, dyspnea. VAS and analgesic use dose not impact on the prognosis. But cognitive impairment and delirium are the reliable prognostic factor. Especially weakness, dry mouth, poor oral intake, drowsiness, edema, dyspnea, ascites, icterua gradually worsened with significance. Dying patients showed markedly decreased blood pressure, cyanosis, cold extremity, death rattle, abnormal respiration frequently at 48hours before death. Conclusions: Terminally ill cancer patients have various prognostic factor and the most important factor is performance status. The death predictive symptoms such as markedly decreased pressure, cyanosis, cold extremity, death rattle, abnormal respiration appeared at last 48hours. If we assess the symptoms more carefully, we can predict the more accurate prognosis. The communication about the prognostic information will influence the personal therapeutic decision and specific care planning. No significant financial relationships to disclose.
Ventriculostomy-Related Infections
Authors: R K Kanter, L B Weiner
Journal: New England Journal of Medicine (1984)

Abstract We conducted a prospective epidemiologic study of ventriculostomy-related infections (ventriculitis or meningitis) in 172 consecutive neurosurgical patients over a two-year period to determine the incidence, risk factors, and clinical characteristics of the infections. Ventriculitis or meningitis developed in 19 of 172 patients (11 per cent) undergoing a total of 213 ventriculostomies. When data from all these cases plus five cases of nonventriculostomy-related infection were combined, cerebrospinal-fluid pleocytosis was more significantly associated with the diagnosis of ventriculitis or meningitis (P<0.0001) than were fever and leukocytosis (P = 0.07). Risk factors for ventriculostomy-related infections included intracerebral hemorrhage with intraventricular hemorrhage (P = 0.027), neurosurgical operations (P = 0.016), intracranial pressure of 20 mm Hg or more (P = 0.019), ventricular catheterization for more than five days (P = 0.017), and irrigation of the system (P = 0.021). Previous ventric...
Abstract 4620: Somatic mutation profile of gastric cancer cases from the Hispanic population
Authors: Rodrigo Prieto-Sanchez, Ruta Madhusudan Sahasrabudhe, Paul Lott, Mabel Bohorquez, Jhon Jairo Suarez, Gilbert Mateus, Javier Torres, Magdalena Echeverry, Luis Carvajal-Carmona
Journal: Cancer Research (2015)

Abstract Gastric cancer contributes to a significant health care burden, being the third most common cause of cancer related deaths worldwide. In the US, gastric cancer incidence and mortality in the Hispanic population is more than double compared to Non-Hispanic whites (NHW). However, a majority of the large-scale gastric cancer genome characterization studies that have been carried so far have been largely limited to non-Hispanic (NH) populations, predominantly Non-Hispanic Whites (NHW). This “mono-ethnic” approach is likely to miss driver mutations that are unique or common in Hispanics but rare in NHWs and can lead to future genomic-driven cancer health disparities. Identification of driver mutations is important to understand the molecular basis of tumorigenesis and to develop better preventive and therapeutic strategies in minority groups like Hispanics. Therefore, the purpose of this study was to characterize gastric cancer somatic changes in the understudied Hispanic population. Somatic mutations were identified using whole exome sequencing (WES) of 36 tumor-normal pairs from Hispanic gastric cancer patients. Microsatellite stability tasting was also performed on all the samples and samples were divided into 27 microsatellite stable (MSS) and 9 microsatellite instable (MSI) cases. Interestingly, preliminary analysis of exome sequencing data delineates differences in mutational profile in our study population compared to publish studies in NH. For example, we found that the frequency of TP53, the most commonly mutated gastric cancer driver in NHs, had a significantly lower frequency in our Hispanic sample (33% in MSS tumors and 11% in MSI tumors compared to 50% in MSS and 35% in MSI tumors reported in TCGA dataset). Similar differences were also found in other frequently mutated gastric cancer genes, which suggest that the genetic pathways leading to gastric cancer in Hispanics are likely to be different to the ones involved in NHW tumors. In summary, our sequencing study of Hispanic gastric cancer cases have identified important differences with other populations, are likely to identify novel cancer drivers in this tumor type and would help bridge the gap in heath care disparities Citation Format: Rodrigo Prieto-Sanchez, Ruta Madhusudan Sahasrabudhe, Paul Lott, Mabel Bohorquez, Jhon Jairo Suarez, Gilbert Mateus, Javier Torres, Magdalena Echeverry, Luis Carvajal-Carmona. Somatic mutation profile of gastric cancer cases from the Hispanic population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4620. doi:10.1158/1538-7445.AM2015-4620
Effect of Marihuana and Placebo-Marihuana Smoking on Angina Pectoris
Authors: Wilbert S. Aronow, John Cassidy
Journal: New England Journal of Medicine (1974)

We evaluated the effect of smoking marihuana versus placebo marihuana on cardiovascular function and on exercise-induced angina in 10 patients with angina pectoris. With the subject resting smoking one marihuana cigarette increased the product of systolic blood pressure times heart rate and venous carboxyhemoglobin level and decreased the exercise time until angina 48 per cent. Smoking one placebo marihuana cigarette increased the venous carboxyhemoglobin level, did not affect the product of systolic blood pressure times heart rate of resting subjects, and decreased the exercise time until angina 8.6 per cent. Smoking marihuana significantly decreased the exercise time until angina more than smoking placebo marihuana (p<0.001). Smoking marihuana probably increases the myocardial oxygen demand and decreases myocardial oxygen delivery, causing patients with angina to experience agina after exercise sooner, and with less work, (N Engl J Med 291:65–67, 1974)
Myxoma of the Right Atrium Associated with Polycythemia
Authors: Julian P. Levinson, Owings W. Kincaid
Journal: New England Journal of Medicine (1961)

THE first intracardiac myxoma to be diagnosed during life was reported in 1952.1 Straus and Merliss2 mentioned 8 cases of atrial myxoma in 480,000 autopsies. Successful removal of intracardiac myxomas has been reported with increasing frequency since 1955.3 4 5 6 It appears that this has been made possible by greater suspicion of the diagnosis and by the use of angiocardiography5 , 6 to visualize the tumors. Regarding specifically myxoma of the right atrium there have been reports of 7 successful removals7 and also reports of some unsuccessful removals.7 , 8 Presented below is another case of successful extirpation of a myxoma from the right atrium. This . . .
Sjögren's Syndrome Associated with HLA-Dw3
Authors: Thomas M. Chused, Stuart S. Kassan, Gerhard Opelz, Haralampos M. Moutsopoulos, Paul I. Terasaki
Journal: New England Journal of Medicine (1977)

Sjögren's syndrome is associated with a serologically defined histocompatibility antigen of the HLA-B locus, HLA-B8. Another closely linked locus, HLA-D, determines lymphocyte-defined cell-surface antigens. In laboratory animals such antigens are closely linked to immune response genes. To determine whether Sjögren's syndrome is primarily associated with an HLA-D antigen or with HLA-B8, we typed 25 patients with the disorder for HLA-A and HLA-B antigens as well as HLA-Dw3, which is known to be in linkage disequilibrium with HLA-B8. We found the primary association of Sjögren's syndrome to be with HLA-Dw3, which we observed in 84 per cent of patients with Sjögren's syndrome in the absence of rheumatoid arthritis as compared to 24 per cent in controls (P<0.00001). The frequency of HLA-B8 and HLA-Dw3 in patients with both Sjögren's syndrome and rheumatoid arthritis did not differ from that in controls. Patients with Sjögren's syndrome alone and those with Sjögren's syndrome and rheumatoid arthritis comprise genetically distinct groups. (N Engl J Med 296:895–897, 1977)