tbuckley/cabot-search huggingface dataset:
Dose-dense neoadjuvant chemotherapy in breast cancer
Authors: R. Catane, B. Kaufman, L. Zach, I. Wolf, I. Gluck, T. Modiano, D. Barsuk, M. Shabtai, M. Papa, S. Paluch-Shimon
Journal: Journal of Clinical Oncology (2005)

807 Background: Neo-adjuvant chemotherapy has been proven to increase the rate of breast-conservation and represents the standard of care in patients with locally advanced breast cancer. Dose-dense chemotherapy has been shown to improve clinical outcomes in the adjuvant setting in node positive patients. We report here on the efficacy of dose-dense chemotherapy in the neo-adjuvant setting. Methods: We allocated 53 breast cancer patients to receive neo-adjuvant chemotherapy, because of locally advanced disease (T4 or N2+) or in the aim of maximizing breast conservation. All patients received doxorubicin (A) 60 mg/m2, cyclophosphamide (C) 600 mg/m2 and paclitaxel (T) 175 mg/m2, administered as concurrent AC x 4 every 2 weeks followed by T x 4 every 2 weeks. All patients received G-CSF, at an initial dose of 300 mcg, commencing on day 5 for 5 days. Nodal status was evaluated by physical examination, ultrasound, core-needle biopsy or sentinel biopsy prior to chemotherapy. Results: Median age of the patients was 45 (range 30–62), 77.5% were pre-menopausal and 8 of them presented with locally advanced disease while 45 had operable disease. The majority (90%) had hormone receptor (HR) positive tumors. Four patients discontinued the protocol because of toxicity. Response was evaluated in 49 patients (92%) who completed 8 courses of treatment and underwent surgery. Clinical complete response was observed in 10 (18%) and clinical partial response was observed in 34 (72%) of these patients. Overall, 39/49 patients (80%) underwent breast conserving surgery. Importantly, seven of the nine women who presented with locally advanced disease, underwent lumpectomy. Pathologic complete response was observed in the breast in 9 (18%), in the lymph nodes in 16 (33%) and in breast and lymph nodes in 6 (12%) of the 49 patients. Of the 53 patients, five had grade 3/4 hematological toxicity, two experienced Grade 3/4 nausea and only one had grade 4 vomiting. Conclusions: In this population of patients with mainly HR positive disease, dose-dense primary chemotherapy provided a feasible and safe short-duration treatment, yielded high clinical response rates and thus allowed conduction of breast conserving surgery in the vast majority of the patients. No significant financial relationships to disclose.
The COXIB Experience: A Look in the Rearview Mirror
Authors: Lawrence J. Marnett
Journal: The Annual Review of Pharmacology and Toxicology (2008)

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used prescription and nonprescription drugs in the world. The discovery of cyclooxygenase (COX) as the target of NSAIDs, the subsequent identification of two isoforms of COX (COX-1 and COX-2), and studies of their regulation and sites of expression led to the hypothesis that COX-2 is the molecular target for the anti-inflammatory and analgesic effects of NSAIDs. A corollary was that COX-2-selective inhibitors (COXIBs) would retain the desirable effects of NSAIDs without some of their liabilities (e.g., gastrointestinal toxicity, which was ascribed to COX-1 inhibition). The first marketed COXIBs exhibited reduced gastrointestinal side effects relative to traditional NSAIDs and were enormous commercial successes. However, clinical trials testing the hypothesis that COXIBs prevent recurrence of premalignant colon polyps uncovered adverse cardiovascular effects that are mechanism based. This review provides an overview of the discovery, development, and difficulties of the COXIBs, a perspective on what has been learned, and speculation on the way forward.
Constitutive Endocytosis of CD163 Mediates Hemoglobin-Heme Uptake and Determines the Noninflammatory and Protective Transcriptional Response of Macrophages to Hemoglobin
Authors: Christian A. Schaer, Gabriele Schoedon, Alexander Imhof, Michael O. Kurrer, Dominik J. Schaer
Journal: Circulation Research (2006)

Heme toxicity contributes to the pathogenesis of chronic inflammatory diseases, atherosclerosis, and hemolysis associated vasculopathy. Macrophage clearance of cell free hemoglobin (Hb) is thus an essential homeostatic function of these cells. We examined the transcriptional response of human PBMC derived macrophages to Hb by gene array analysis. The observed noninflammatory macrophage response was characterized by induction of an antioxidative and antiinflammatory gene expression pattern with most prominent induction of the inducible heme oxygenase (HO-1). The metabolically active Hb-CD163-HO-1 pathway resulted in synthesis of ferritin—1 of the antioxidative and antiinflammatory end products linked to heme breakdown by HO-1. This response was mediated by the Hb scavenger receptor CD163 and heme and was not related to Hb mediated depletion of reduced glutathione. In contrast to other cellular responses induced by CD163, there was no role of protein phosphorylation dependent CD163 signaling in the protective macrophage response to Hb. Instead, CD163 acted as an Hb transporter, which undergoes constitutive and ligand independent internalization and recycling between the cell surface and early endosomes. The expression of CD163 and HO-1 in macrophages of neovascularized atherosclerotic lesions suggests that the pathway described herein is active in vivo. Noninflammatory Hb clearance and intimately linked HO-1 expression may provide the long sought-after explanation for the antiinflammatory activity associated with CD163-positive macrophages.
Re: Ricardo L. Favaretto, Shahrokh F. Shariat, Daher C. Chade, et al. The Effect of Tumor Location on Prognosis in Patients Treated with Radical Nephroureterectomy at Memorial Sloan-Kettering Cancer Center. Eur Urol 2010;58:574–580
Authors: Shiu-Dong Chung, Shuo-Meng Wang, Shih-Chieh Chueh
Journal: European Urology (2010)
Prevalence of Metabolic Syndrome Among Hispanics/Latinos of Diverse Background: The Hispanic Community Health Study/Study of Latinos
Authors: Gerardo Heiss, Michelle L. Snyder, Yanping Teng, Neil Schneiderman, Maria M. Llabre, Catherine Cowie, Mercedes Carnethon, Robert Kaplan, Aida Giachello, Linda Gallo, Laura Loehr, Larissa Avilés-Santa
Journal: Diabetes Care (2014)

OBJECTIVE Approximately one-third of the adult U.S. population has the metabolic syndrome. Its prevalence is the highest among Hispanic adults, but variation by Hispanic/Latino background is unknown. Our objective was to quantify the prevalence of the metabolic syndrome among men and women 18–74 years of age of diverse Hispanic/Latino background. RESEARCH DESIGN AND METHODS Two-stage area probability sample of households in four U.S. locales, yielding 16,319 adults (52% women) who self-identified as Cuban, Dominican, Mexican, Puerto Rican, Central American, or South American. The metabolic syndrome was defined according to the American Heart Association/National Heart, Lung, and Blood Institute 2009 Joint Scientific Statement. The main outcome measures were age-standardized prevalence of the metabolic syndrome per the harmonized American Heart Association/National Heart, Lung, and Blood Institute definition and its component abnormalities. RESULTS The metabolic syndrome was present in 36% of women and 34% of men. Differences in the age-standardized prevalence were seen by age, sex, and Hispanic/Latino background. The prevalence of the metabolic syndrome among those 18–44, 45–64, and 65–74 years of age was 23%, 50%, and 62%, respectively, among women; and 25%, 43%, and 55%, respectively, among men. Among women, the metabolic syndrome prevalence ranged from 27% in South Americans to 41% in Puerto Ricans. Among men, prevalences ranged from 27% in South Americans to 35% in Cubans. In those with the metabolic syndrome, abdominal obesity was present in 96% of the women compared with 73% of the men; more men (73%) than women (62%) had hyperglycemia. CONCLUSIONS The burden of cardiometabolic abnormalities is high in Hispanic/Latinos but varies by age, sex, and Hispanic/Latino background. Hispanics/Latinos are thus at increased, but modifiable, predicted lifetime risk of diabetes and its cardiovascular sequelae.
Loss-of-Function Mutation in a Repressor Module of Human-Specifically Activated Enhancer HACNS1
Authors: K. Sumiyama, N. Saitou
Journal: Molecular Biology and Evolution (2011)

The cis-regulatory element contributed to gaining humanness is of great interest in human evolutionary studies. A human-accelerated region exceeding neutral evolutionary rates, termed HACNS1, was recently reported as a positively selected sequence acquiring novel TF-binding sites responsible for human-specific gain of limb enhancer function. However, another possibility is loss of function in repressor element in HACNS1. Signature of the human substitutions in the 81-bp region infers that a GC-biased gene conversion (BGC) might create these seemingly excessive substitutions. To evaluate the 81-bp function, we performed transgenic mouse assay of the HACNS1 construct lacking the 81-bp region. The deleted construct showed similar enhancer activity to the intact human HACNS1, suggesting that the function of the human 81-bp region is not an activating enhancer but rather a disrupted repressor. This result infers that loss of function in the HACNS1 81-bp region, possibly via a BGC, played an important role in human-specific evolution.
Long-term prognosis by lamivudine monotherapy for severe acute exacerbation in chronic hepatitis B infection: emergence of YMDD motif mutant and risk of breakthrough hepatitis – an open-cohort study
Authors: Norio Akuta, Akihito Tsubota, Fumitaka Suzuki, Yoshiyuki Suzuki, Tetsuya Hosaka, Takashi Someya, Masahiro Kobayashi, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada
Journal: Journal of Hepatology (2002)
Intraobserver and Interobserver Variations in Liver Biopsy Interpretation in Patients with Chronic Hepatitis C
Authors: P. Bedossa
Journal: Hepatology (1994)

Liver biopsy is used as the “gold standard” for the assessment of the stage and degree of activity in chronic hepatitis C and is of major importance in evaluating the effects of treatment. Because numerous therapeutic trials are undertaken with histological control, the reproducibility of liver biopsy interpretation appears essential. Therefore the aim of this study was to estimate intraobserver and interobserver variations in the assessment of features, classification, and numerical scoring of chronic viral hepatitis C among 10 pathologists specializing in liver diseases. These pathologists independently reviewed 30 liver biopsy specimens of viral hepatitis C and completed a histological form for each of the specimens. Five pairs of pathologists then were randomly designated. They independently reviewed the biopsy specimens and filled out a new coding form. The interobserver variation was calculated for each item among the 10 individuals and then among the five pairs with the intraclass correlation coefficient or ϰ statistics. Five features showed an almost perfect or a substantial degree of concordance among the 10 observers (i.e., cirrhosis, fibrosis, fibrosis grading of Knodell index, steatosis, portal lymphoid aggregates). The 17 other indicators showed a weaker concordance with, for instance, a moderate degree of concordance for piecemeal necrosis, disease activity, Knodell index, a fair degree of concordance for lobular necrosis, and only a slight degree of concordance for six items. Five items had a higher concordance when viewed by a pair of pathologists than when studied by only one pathologist (i.e., steatosis, periportal necrosis grading of Knodell index, lobular necrosis grading of Knodell index, centrilobular fibrosis, and ductular proliferation). Two showed a significant decrease, and the others were unchanged. This study reveals that certain features of major importance in assessing disease activity show significant observer variation. The acceptable degree of concordance of the Knodell index was related mainly to the substantial degree of concordance of the fibrosis score, whereas other numerical items displayed substantial observer variations. Simultaneous observation by two pathologists increased the reproducibility of numerical scoring and of certain viral hepatitis C lesions. A classification of chronic hepatitis C based on dissociated semiquantitative assessment of necroinflammatory lesions and fibrosis offered more reproducibility than the use of a global numerical index. (Hepatology 1994;20:15–20.)
Cardiovascular Risk Factors Associated With Insulin Resistance in Children Persist Into Late Adolescence
Authors: Peter D. Reaven, Tinna Traustadóttir, Jesse Brennan, Philip R. Nader
Journal: Diabetes Care (2005)

The current report is a follow-up evaluation of a cohort of Mexican-American and non-Hispanic white children 5.5 years after the previous study (1) to determine whether the increased features of insulin resistance observed in these Mexican Americans at age 11 years were still present at age 17 years. Furthermore, we determined which of these measures in childhood would best predict the risk for the insulin resistance syndrome (IRS) at age 17 years. As inflammation has recently been recognized as potentially playing important roles in the pathogenesis of insulin resistance, diabetes, and cardiovascular disease (2–4), measures of C-reactive protein (CRP) were also assessed in the follow-up study.

The study cohort was the San Diego Study of Children’s Activity and Nutrition, an ongoing observational study that began when the subjects were 4 years of age (with follow-up assessments at intervals of ∼5–7 years) and consisted of non-Hispanic white and Mexican-American children recruited through state-funded daycare programs. Detailed methods and health behavior results have been previously reported (1,5–11). The current study sample includes 83 adolescents: 29 non-Hispanic white (17 males and 12 females) and 54 Mexican-American (25 males and 29 females) subjects who had completed study visits at age 11 and again at age 17 years. Based on demographic and laboratory data, there was no evidence of a bias in the drop out of subjects between study visits. All blood samples were obtained in the fasting state.

### Anthropometric and blood pressure measures

Height, weight, waist circumference, …
Efficacy of Vemurafenib in a Trametinib-Resistant Stage IV Melanoma Patient—Letter
Authors: Mathias Bernhardt, Elias Orouji, Lionel Larribere, Christoffer Gebhardt, Jochen Utikal
Journal: Clinical Cancer Research (2014)

Targeted treatment of BRAF gene–mutated melanoma with BRAF and MEK inhibitors has prolonged progression-free and overall survival ([1, 2][1]). Several mechanisms of resistance to BRAF and MEK inhibition treatment have been described, most of which involve reactivation of downstream MAP–ERK
Familial renal glycosuria: a genetic reappraisal of hexose transport by kidney and intestine
Authors: Louis J. Elsas, Leon E. Rosenberg
Journal: Journal of Clinical Investigation (1969)

Renal glucose titration studies were carried out in 10 members of two pedigrees with familial renal glycosuria to test the accepted hypothesis of autosomal dominant inheritance and to investigate the genetic significance of "type A" and "type B" renal glycosuria. In one family, a brother and sister each had a moderately reduced threshold and tubular maximum for glucose (type A), but both of their parents reabsorbed glucose normally. In the second family, two brothers had severe type A renal glycosuria, their mother and one brother had a mild type A defect, and another brother demonstrated a reduced threshold, an exaggerated splay, and a normal tubular maximum, indicative of type B glycosuria.Hexose transport by intestinal mucosa was also investigated in controls and in the three brothers with the most severe renal glycosuria. D-glucose-(14)C and 3-O-methylglucose-(14)C were accumulated by jejunal mucosa from controls by processes which were saturable and concentrative. No differences in hexose transport were observed in the patients with renal glycosuria. We conclude that familial renal glycosuria can be inherited as an autosomal recessive trait; that mild and severe type A renal glycosuria and type B renal glycosuria can occur in the same pedigree; and that defective reabsorption of glucose by the kidney need not be accompanied by abnormalities in intestinal glucose transport. These findings indicate that glucose transport in the gut and kidney are not mediated by identical mechanisms, and that several different mutations are responsible for the phenotypic variability in familial renal glycosuria.
Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI
Authors: J-P Raynauld, J Martel-Pelletier, P Bias, S Laufer, B Haraoui, D Choquette, A D Beaulieu, F Abram, M Dorais, E Vignon, J-P Pelletier
Journal: Annals of the Rheumatic Diseases (2008)

In a multicentre study to explore the effects of licofelone as a disease-modifying osteoarthritis drug in comparison with naproxen in patients with knee osteoarthritis (OA), using MRI and x-ray examination.Patients with knee OA (n = 355) were randomised to receive either licofelone (200 mg twice a day) or naproxen (500 mg twice a day). MRI and x-ray examinations were performed at baseline, 6 months (MRI only), 12 and 24 months. MRI was used to assess quantitatively changes in cartilage volume, and x-ray examinations (Lyon-Schuss) to measure changes in the mean and minimum joint space width (JSW) in the medial compartment. Questionnaires probing symptoms were completed. Data were presented as intention to treat (ITT) and according to protocol (ATP).Cartilage volume loss in the global joint and medial and lateral compartments was significantly less in the licofelone than in the naproxen group for ITT at 12 and 24 months and for ATP at all times except in the medial compartment. Patients with medial meniscal extrusion had a greater loss of cartilage volume. In these patients, licofelone markedly reduced the cartilage loss for both ITT and ATP at 12 and 24 months. Although licofelone showed less reduction in the JSW than naproxen, this did not reach significance. All clinical variables were improved at 24 months (p<0.001) for both groups, with a good safety profile.Licofelone and naproxen were equally effective in reducing OA symptoms; however, licofelone significantly reduced cartilage volume loss over time, thus having a protective effect in patients with knee OA. This study proves the superiority of quantitative MRI over x-ray examinations in a multicentre clinical trial.
Healthy Lifestyle Through Young Adulthood and the Presence of Low Cardiovascular Disease Risk Profile in Middle Age
Authors: Kiang Liu, Martha L. Daviglus, Catherine M. Loria, Laura A. Colangelo, Bonnie Spring, Arlen C. Moller, Donald M. Lloyd-Jones
Journal: Circulation (2012)

Background— A low cardiovascular disease risk profile (untreated cholesterol &lt;200 mg/dL, untreated blood pressure &lt;120/&lt;80 mm Hg, never smoking, and no history of diabetes mellitus or myocardial infarction) in middle age is associated with markedly better health outcomes in older age, but few middle-aged adults have this low risk profile. We examined whether adopting a healthy lifestyle throughout young adulthood is associated with the presence of the low cardiovascular disease risk profile in middle age. Methods and Results— The Coronary Artery Risk Development in (Young) Adults (CARDIA) study sample consisted of 3154 black and white participants 18 to 30 years of age at year 0 (1985–1986) who attended the year 0, 7, and 20 examinations. Healthy lifestyle factors defined at years 0, 7, and 20 included average body mass index &lt;25 kg/m 2 , no or moderate alcohol intake, higher healthy diet score, higher physical activity score, and never smoking. Mean age (25 years) and percentage of women (56%) were comparable across groups defined by number of healthy lifestyle factors. The age-, sex-, and race-adjusted prevalences of low cardiovascular disease risk profile at year 20 were 3.0%, 14.6%, 29.5%, 39.2%, and 60.7% for people with 0 or 1, 2, 3, 4, and 5 healthy lifestyle factors, respectively ( P for trend &lt;0.0001). Similar graded relationships were observed for each sex-race group (all P for trend &lt;0.0001). Conclusions— Maintaining a healthy lifestyle throughout young adulthood is strongly associated with a low cardiovascular disease risk profile in middle age. Public health and individual efforts are needed to improve the adoption and maintenance of healthy lifestyles in young adults.
Gestational Diabetes Mellitus and the Offspring—Jack and Jill Are Different Still
Authors: Helen Murphy, Sarah Finer
Journal: Diabetes Care (2015)

Hyperglycemia is the most common metabolic disorder complicating pregnancies across the globe. With rising maternal age, obesity, physical inactivity (1), and increasingly stringent diagnostic criteria, about one in seven women now has a pregnancy complicated by hyperglycemia (2). The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) confirmed that treating women with gestational diabetes mellitus (GDM) reduces serious perinatal complications (infant death, shoulder dystocia, fracture and nerve palsy) (3). Likewise, a trial by Landon et al. (4) showed that treating women with hyperglycemia reduces maternal weight gain, gestational hypertension, preeclampsia, cesarean delivery, infant adiposity, and birth weight. Of note, the degree of glycemia in the Landon et al. trial was comparatively less than that in ACHOIS, as suggested by only 8% of women in the intervention arm requiring insulin therapy compared with 20% in ACHOIS. A secondary analysis in a subgroup of offspring in the original Landon et al. trial showed that male offspring had a lower birth weight percentile and fat mass and gained greater benefit from the maternal GDM intervention compared with female offspring (5). These landmark trials have changed the clinical practice of GDM, placing greater emphasis on glucose-lowering interventions to reduce obstetric and perinatal complications.

Emerging evidence suggests that the intrauterine and early postnatal environment can influence cardiovascular and metabolic health in later life. Maternal hyperglycemia in GDM is thought to confer a greater risk of diabetes and obesity in exposed offspring via fetal programming. Animal models suggest similar associations but are hampered by …