tbuckley/cabot-search huggingface dataset:
Loss of phylogenetic information in chorion gene families of Bombyx mori gene conversion.
Authors: J C Regier, B M Weigmann, R F Leclerc, T P Friedlander
Journal: Molecular Biology and Evolution (1994)

The silkmoth chorion has provided a stimulating model for the study of evolution and developmental regulation of gene families. Previous attempts at inferring relationships among chorion sequences have been based on pairwise comparisons of overall similarity, a potentially problematic approach. To remedy this, we identified the alignable regions of low sequence variability and then analyzed this restricted database by parsimony and neighbor-joining methods. At the deepest level, the chorion sequence tree is split into two branches, called "alpha" and "beta." Within each branch, early- and late-expressing genes each constitute monophyletic groups, while the situation with middle-expressing genes remains uncertain. The HcB gene family appears to be the most basal beta-branch group, but this conclusion is qualified because the effect of gene conversion on branching order is unknown. Previous studies by Eickbush and colleagues have strongly suggested that ErA, HcA, and HcB families undergo gene conversion within a gene family, whereas the ErB family does not. The occurrence of conversion correlates with a particular tree structure; namely, branch lengths are much greater at the base of the family than at higher internodes and terminal branches. These observations raise the possibility that chorion gene families are defined by gene conversion events (reticulate evolution) rather than by descent with modification (synapomorphy).
Nutritional Status over Time in Hemodialysis and Peritoneal Dialysis
Authors: KITTY J. JAGER, MARUSCHKA P. MERKUS, ROEL M. HUISMAN, ELISABETH W. BOESCHOTEN, FRIEDO W. DEKKER, JOHANNA C. KOREVAAR, JAN G. P. TIJSSEN, RAYMOND T. KREDIET
Journal: Journal of the American Society of Nephrology (2001)

Malnutrition is a risk factor for mortality in the dialysis population. So far, prospective studies comparing the time course of nutritional status in new hemodialysis (HD) and peritoneal dialysis (PD) patients have not been published. The aims of this study were to compare the time course of nutritional status in patients who were starting HD or PD and to identify the baseline determinants of that time course. In this prospective multicenter cohort study, data were collected from 3 (baseline) to 24 mo after the start of dialysis. Repeated measures ANOVA was used to establish the time course of nutritional status. Differences were adjusted for baseline characteristics. A total of 250 consecutive new patients were included: 132 started on HD, and 118 started on PD. A univariate analysis demonstrated a decrease in serum albumin (SA) in patients who started on HD and an increase in patients who started on PD. Body fat increased in PD; LBM did not change. The protein equivalent of nitrogen appearance normalized to ideal weight decreased in PD after 1 yr. In a multivariate analysis, SA at 2 yr was 2.0 g/L (95% confidence interval [CI], 0.3 to 3.8) higher in patients who started on PD compared with patients who started on HD. The increase in body fat was 3.2 kg (95% CI, 1.6 to 4.9) higher in women who started on PD than in others. Patients who had diabetes gained 2.3 kg (95% CI, 0.6 to 4.1) more fat than patients who did not have diabetes. Kt/V(urea) did not affect the time course of nutritional status, but a higher Kt(urea) was associated with a higher SA at 24 mo. Nutritional status at the start of dialysis, gender, and diabetic status might be considered in making the choice for dialysis modality. Furthermore, providing a higher Kt(urea) may improve protein metabolism.
DEC methods for appraising new drugs
Authors: B. Campbell, R. Peveler, K. Stein, C. Packer, D. Fidan, A. Stevens, N. Payne, R. Akehurst, R. Milne, J. Gabbay, A. Burls, N. Freemantle, J. Mason
Journal: BMJ (1999)

Editor—Freemantle and Mason are quite right to explore the difficult task that the National Institute for Clinical Excellence (NICE) will face in appraising new drugs.1 However, it is disappointing that there was so much in their article which misrepresented the work of our development and evaluation committee (DEC), and no recognition of the considerable activity of the committee relating to different interventions that are not new.

One of the main summary points stated that: “New drugs should be appraised in terms of physical outcomes that mean something to doctors and patients.” This principle is a major influence in all the deliberations of our development and evaluation committee. For example, in the recent appraisal of β interferons for multiple sclerosis, our discussions gave far more weight to possibly becoming wheelchair bound than to proxy measures such as changes on multiple resonance imaging. The debate also considered the impact of relapses on patients and their families, together with a whole range of issues relating to carers, health service delivery, and the complex matter of both documented and hidden costs. This breadth of discussion is exactly what Freemantle and Mason are proposing in their section on systematic profiles and is a routine part of appraisal by a development and evaluation committee. They also advocate “including the right people”—for example general practitioners “if a drug will mostly be prescribed in primary care.” Our committee includes two general practitioners and a lay member because we believe that their views are important across the whole range of interventions. The NICE appraisal committee is likely to do the same, including a broad range of interests.

With regard to getting all the information about new drugs, our development and evaluation committee aims to address focused questions about the application of new drugs within quite a short time frame, pointing out areas of uncertainty in the published literature, and giving an early “update category” when further information is likely to become available. It has been our experience that pharmaceutical companies have been rather slow to release information, which is often presented in a somewhat selective form, and which has not been subjected to peer review. For these reasons the committee is cautious about making decisions that may affect allocation of NHS resources on the basis of unpublished data.

Estimates of cost effectiveness are difficult, and “cost per QALY” ranges may be wide in an attempt to allow for all the possible variables and assumptions. However, with the explicit “cost per QALY” thresholds2 which our committee uses, a wide range does not influence our judgment unless it crosses one of the threshold values; in practice this seldom happens.

We hope that NICE will build on the experience of the development and evaluation committees in its appraisal work.
Prognostic significance of xCT gene single nucleotide polymorphisms (SNPs) in patients (pts) with advanced pancreatic cancer (PC) treated with gemcitabine (GEM) plus platinum analogues (PLAT).
Authors: T. J. Huang, D. Li, J. Weatherly, H. Tang, P. W. Gout, R. A. Wolff, J. L. Abbruzzese, M. M. Javle
Journal: Journal of Clinical Oncology (2010)

4065 Background: The plasma membrane xc- cystine/glutamate transporter mediates cellular uptake of cystine in exchange for intracellular glutamate and is highly expressed by PC cells. The xCT gene, encoding the cystine-specific xCT protein subunit of xc-, is important in regulating intracellular glutathione levels, critical for cancer cell protection against oxidative stress, tumor growth and resistance to chemotherapeutic agents including PLAT. Methods: We have investigated the relationship between xCT gene SNPs and overall survival (OS) of pts with PC treated with GEM ± PLAT. We examined 4 SNPs of the xCT gene in 269 advanced PC pts who received first line GEM with or without cisplatin or oxaliplatin. Genomic DNA was isolated from peripheral blood mononuclear cells. Genotyping was performed using Taqman real-time PCR assays. The association between SNPs and OS was analyzed by Kaplan-Meier plot, log-rank test and Cox proportional hazard regression models and corrected for previously identified prognostic factors, including CA 19-9, stage, and performance status. Results: A statistically significant correlation was noted between the 3’ untranslated region (UTR) xCT SNP rs7674870 and OS: Median survival time (MST) was 10.9 and 13.6 months, respectively, for the TT and TC/CC genotypes (p = 0.027). Stratified analysis showed the genotype effect was significant in pts receiving GEM+PLAT therapy (n = 145): MST was 10.5 vs. 14.1 months for the TT and TC/CC genotypes, respectively (p = 0.013). This effect remained statistically significant after adjusting for clinical factors (hazard ratio: 0.60, 95% CI, 0.40-0.89 and p = 0.011). The genotype effect was not significant in pts receiving GEM alone (n = 124): MST was 10.9 months for TT and 12.0 months for TC/CC genotypes (p = 0.47). None of the 3 synonymous SNPs examined were associated with outcome. Conclusions: The 3’ UTR xCT SNP rs7674870 may correlate with OS in PC pts receiving GEM+PLAT therapy. These data suggest that polymorphic variants of xCT may have predictive value, and that the xc- transporter may represent an important target for therapy in PC. No significant financial relationships to disclose.
Prospective surgico-pathologic registration study of colorectal cancer (Swiss Group for Clinical Cancer Research SAKK protocol 40/00): Current practices and short-term outcome.
Authors: C. A. Maurer, M. Mayer, M. Schilling, U. F. Metzger, U. T. Laffer, P. Buchmann, B. Lerf, P. Villiger, G. A. Melcher, K. Kessler
Journal: Journal of Clinical Oncology (2010)

e14053 Background: The short term aim of this study was to estimate the radicality of colorectal cancer resections and to assess the oncosurgical quality of the colorectal specimens. Methods: One German and 9 Swiss hospitals agreed to prospectively register all patients with primary colorectal cancer resected between September 2001 and June 2005. Out of 1,502 consecutive patients, informed consent was obtained from 1,010 patients for further analyses. The median number of included patients per center was 99 (13-219). Results: The median age at operation was 70.3 years, the mean ASA score was 2.2. Tumor disease: synchronous second primary 3.6%; emergency operation 6.4%; multivisceral resections 10%, 92.2% out of these as en-bloc resection; node positive patients 39.4%; UICC stage IV patients 17.7%. Radicality: local R2-resection 3.6%; median length of bowel specimen 26cm; median distances from tumor to nearest bowel resection margin 7 cm for colon cancer and 2.5 cm for rectal cancer; maximum length of mesocolon median 9 cm; median number of examined lymph nodes 16. Oncosurgical quality: no-touch technique 49.5%; tumor opened during dissection 4.6%; median blood loss 300 mL; death during hospital stay 2.6%; anastomotic leakage 4.5%; intraabdominal abscess 5%. Rectal cancer only (n = 412): local excision only 10.7%; mesorectal excision 95.2% of abdominal approaches; rectal stump washout 64.6%; stoma formation 79.8%; involvement of circumferential resection margin 8.9%. Calculating the medians of each center separately, the following variations of medians were found: length of bowel specimen 20–40 cm, maximum length of mesocolon 6.5–12cm, number of examined lymph nodes 9-24, blood loss 200–500 mL, percentage of abdominoperineal resection for rectal cancer 6%–30%. Conclusions: The presented results of colorectal cancer surgery are good to excellent with regard to radicality, oncosurgical quality and morbidity/mortality. Although all participating centers are at a high level of expertise in colorectal surgery and with special interest in surgical oncology, the results still show a potential for improvement in surgical technique in some. No significant financial relationships to disclose.
Should patients with malignant intracranial space occupying lesions (M-ICSOLs) be excluded from phase I trials? The Royal Marsden Hospital Drug Development Unit experience.
Authors: D. Papadatos-Pastos, M. Blanco-Codesido, C. P. Carden, R. S. Fehrmann, L. Trani, L. R. Molife, A. Brunetto, S. K. Sandhu, C. Massard, U. Banerji
Journal: Journal of Clinical Oncology (2010)

2516 Background: M-ICSOLs are often cited as an exclusion criteria in phase I trial protocols. This leads to patients with asymptomatic M-ICSOL being denied entry into phase I trials. We examined clinical outcomes of patients treated in such trials in our institution to determine if this exclusion criteria was justifiable. Methods: Data from consecutive patients who participated in 65 phase I trials from 1998 to 2009 were included in the analysis. For an initial analysis patients were divided into two groups: (A) those that had a known M-ICSOL prior to starting trial therapy and (B) those that did not. A further analysis was performed comparing patients with no known M-ICSOL at the start and at the end of the phase trial—group C—to those who subsequently developed a M-ICSOL—group D. The primary endpoint was time to progression (TTP) calculated for all groups; Kaplan-Meier analysis using a log rank test was used to determine the difference between groups. Results: Data from 885 patients, M:F (479:406), median age 58.6 years (range, 16-89) were studied. There was no significant difference in TTP between patients in group A (n=24) and group B (n=861): 8.0 weeks, (95% CI 7.57-8.43 weeks) versus 14.0 weeks, (95% CI 8.13-19.87 weeks), p = 0.071 respectively. There was no difference in TTP between groups C (n=804) and D (n= 57): 8.0 weeks, (95% CI 7.32-8.67 weeks) versus 8.0 weeks, (95% CI 6.43-9.57 weeks), p = 0.582 respectively. The median time to development of a M-ICSOL in patients in group D was 8 weeks. Conclusions: This analysis suggests that carefully selected patients with M-ICSOLs entered into phase I trials do not have a worse clinical outcome when compared to those who did not have a M-ICSOL at the start of therapy. In addition, patients who developed an M-ICOSL on trial did so after the conventional dose-limiting toxicity window. We recommend that, contrary to current trends, carefully selected patients with M-ICSOLs be included in phase I trials. No significant financial relationships to disclose.
Congenital Heart Disease.--II
Authors: P. Wood
Journal: BMJ (1950)

ACTION OF ANTIHISTAMINE COMPOUNDS BARrris 693 and other functions substances like anthisan, procaine, and quinidine are inhibiting the effect of the local hormones.SummaryMany substances used medicinally as local anaesthetics, as analgesics, and as spasmolytics have common properties, among which is included the ability to act like quinidine on the heart.Antihistamine compounds also belong to this large group of drugs.The side-effects they produce are therefore to be expected.They can also be used for other purposes-as local anaesthetics, as quinidine substitutes for fibrillation, as quinine substitutes for myotonia, for travel sickness, and to relieve pain.Similarly, local anaesthetics such as procaine, or analgesics such as pethidine, have an antihistamine action which is considerable.The basis of these common properties is that the substances which possess them depress the effects of acetylcholine, histamine, and adrenaline; these substances control activity locally in many tissues.
Circulating vascular endothelial growth factor (VEGF) as a biomarker for bevacizumab-based therapy in metastatic colorectal, non-small cell lung, and renal cell cancers: Analysis of phase III studies.
Authors: C. Bernaards, P. Hegde, D. Chen, E. Holmgren, M. Zheng, A. M. Jubb, H. Koeppen, S. J. Scherer, D. S. Chen
Journal: Journal of Clinical Oncology (2010)

10519 Background: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGF), has shown significant clinical benefit in a number of advanced or metastatic cancer settings. We assessed the value of circulating VEGF level as a prognostic biomarker for outcome and a predictive biomarker of benefit with bevacizumab-containing treatment across four randomized phase III studies in metastatic colorectal cancer, lung cancer, and renal cell cancer. We also evaluated the overall distribution of circulating VEGF levels across these different tumor types and its association with levels of tumor VEGF expression. Methods: Baseline plasma, collected from 1816 patients enrolled in bevacizumab studies in metastatic colorectal, lung, and renal cell cancers, was analyzed for VEGF using ELISA. Matched archival tumor samples from colorectal and renal cell cancer studies were analyzed for VEGF expression by in situ hybridization. Hazard ratios and 95% confidence intervals for study primary end points were estimated using Cox regression analysis. Results: Across all VEGF subgroups analyzed, the estimated hazard ratios for progression-free survival (PFS) were < 1 (range, 0.59–0.89) in favor of bevacizumab treatment. Higher circulating VEGF levels were associated with shortened PFS and overall survival regardless of bevacizumab treatment, but were not well associated with tumor expression of VEGF. The distributions of circulating VEGF levels were similar across the tumor types, supporting the indirect relationship between tumor VEGF levels and circulating VEGF levels. Conclusions: Measurement of baseline circulating VEGF levels may be useful as a prognostic biomarker, but not as a predictive biomarker for bevacizumab-based treatment benefit in metastatic colorectal, lung, and renal cell cancers. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Roche Roche
알코올성 간질환의 최신지견과 전망
Authors: 이헌주 ( Heon Ju Lee )
Journal: Clinical and Molecular Hepatology (2010)

Unlike many western countries, the most common clinically important chronic progressive liver disease in Korea has been hepatitis B virus (HBV) related ones. But after HBV vaccination and very effective antiviral therapy with nucleos (t)ide analogues over 30 and 10 years respectively have made relative increase of the incidence and the importance of alcohlic liver disease (ALD) nowadays. The pathogenesis of ALD is very complex and obscure depending on the individual variability and susceptibility to alcoholic liver injury with environmental factors. Even lots of high quality pathphysiological research and bulky papers with genetics and molecular biologic process on ALD, no concentrated clear theory is yet. But in Korea, reports on clinical study and not to mention about basic research on ALD are scanty. Most of the knowledge including epidemiology adopting in clinical fields are based on the foreigners and there is no standarized Korean guidelines for ALD. An exact evalauation of the clincal importance and the issue of ALD in Korean society is essential to control the devastating alcoholics effectively and economically. The update world and Korean literature on ALD was referred for the more understanding of ALD present in Korea including necessity of Korean guideline for the clinician and also for the establishment of study subjects in ALD study group in KASL.
Effect of zoledronic acid (Zol) compared with placebo on overall disease and bone lesion progression in patients (pts) with bone metastases from certain solid tumors: Stratification by baseline characteristics
Authors: K. Ucar, N. S. Tchekmedyian, N. Shrina, Y. Chen, T. Xie, Y. Hei
Journal: Journal of Clinical Oncology (2006)

18541 Background: Zol has been shown to significantly reduce the risk of skeletal complications compared with placebo in pts with bone metastases from a wide range of solid tumors including a delay of bone lesion progression in pts with renal cancer. To assess whether Zol may reduce the risk of overall disease or bone lesion progression in pts with solid tumors other than breast, non-small cell lung, and prostate cancers, we conducted a retrospective analysis of pts enrolled in a large, randomized, controlled trial. Methods: Pts treated with Zol or placebo were retrospectively stratified by baseline characteristics, including Brief Pain Inventory (BPI) composite pain score, time from initial cancer diagnosis to development of bone metastases, and duration of cancer. The relative risk (RR) of disease progression during 25 months on study was analyzed using the Cox proportional hazards model (stratified log rank). Results: Median baseline BPI pain score was 2.75, median time with cancer was 15 months, and median time to development of bone metastases was 8.5 months. In pts with a baseline BPI score ≥ 2.75 (n = 236), Zol treatment significantly reduced the RR of disease progression by 34% (hazard ratio [HR] = 0.657; P = .014) and the RR of bone lesion progression by 32% (HR = 0.680; P = .028) compared with placebo. Additionally, in pts with cancer duration &lt;15 months (n = 193), Zol treatment reduced the RR of disease progression by 45% (HR = 0.547; P = .002) and the RR of bone lesion progression by 40% (HR = 0.605; P = .016) compared with placebo. Similarly, among pts who developed bone metastases &lt; 8.5 months from initial diagnosis of cancer (n = 193), Zol treatment significantly reduced the RR of disease progression by 39% and the RR of bone lesion progression by 48% compared with placebo (HR = 0.611; P = .009 and HR = 0.519; P = .004, respectively). Conclusions: This exploratory analysis suggests that Zol has potential antitumor effects that may reduce the risk of overall disease and bone lesion progression in pts who have higher pain scores and shorter time to development of bone metastases. Prospective studies are needed to confirm this result. [Table: see text]
Delayed fertilization and Downs syndrome. (Letter)
Authors: Sampson Jl
Journal: JAMA (1977)

The writer refers to  previous article asking  question Can abnormal ovulation be an etiologic factor in Downs syndrome? The authors wondered whether a 21-day prematurely released ovum could be etiologically related to the defective child observed. In addition to  several unproved causes for nondisjunction noted by  respondent other phenomena are known to cause chromosomal abnormalities in animals.  Delayed fertilization could have occurred in  patient described.  If oocytes survive in  female tract over 48 hours after ovulation fertilization might still occur.  Fertilization at this time leads to both aneuploidy and polyploidy in amphibians mice rats rabbits guinea pigs and hamsters.  Several investigators have implicated delayed fertilization as  cause of aneuploidy in humans.  This might have happened in  patient in question assuming that animal data are analogous to humans.  Deleterious effects have not been ascribed to fertilization following prematurely released ova.