Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.

PURPOSE To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)-leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m(2)/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m(2), as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS Grade 3 to 4 toxicity from 5-FU-LV occurred in </= 5% of the patients (</= 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU-LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P <. 001). The median progression-free survival time was 6.1 months with 5-FU-LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU-LV (P =.048). Median survival times were 19.9 and 19.4 months, respectively. CONCLUSION By chronomodulating 5-FU-LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.
Engineering of a bispecific affibody molecule towards HER2 and HER3 by addition of an albumin‐binding domain allows for affinity purification and in vivo half‐life extension

Emerging strategies in cancer biotherapy include the generation and application of bispecific antibodies, targeting two tumor‐associated antigens for improved tumor selectivity and potency. Here, an alternative format for bispecific molecules was designed and investigated, in which two Affibody molecules were linked by an albumin‐binding domain (ABD). Affibody molecules are small (6 kDa) affinity proteins and this new format allows for engineering of molecules with similar function as full‐length bispecific antibodies, but in a dramatically smaller size (around eight‐fold smaller). The ABD was intended to function both as a tag for affinity purification as well as for in vivo half‐life extension in future preclinical and clinical investigations. Affinity‐purified bispecific Affibody molecules, targeting HER2 and HER3, showed simultaneous binding to the three target proteins (HER2, HER3, and albumin) when investigated in biosensor assays. Moreover, simultaneous interactions with the receptors and albumin were demonstrated using flow cytometry on cancer cells. The bispecific Affibody molecules were also able to block ligand‐induced phosphorylation of the HER receptors, indicating an anti‐proliferative effect. We believe that this compact and flexible format has great potential for developing new potent bispecific affinity proteins in the future, as it combines the benefits of a small size (e.g. improved tissue penetration and reduced cost of goods) with a long circulatory half‐life.
Modification of the Stat1 SH2 Domain Broadly Improves Interferon Efficacy in Proportion to p300/CREB-binding Protein Coactivator Recruitment*♦

A normal level of interferon (IFN) responsiveness via the Stat1 transcription factor is critical to the host, since decreased Stat1 signaling causes immune compromise and increased signaling is associated with inflammatory and neoplastic disease. Here we report how this balance may be influenced by novel alterations in the efficiency of Stat1 signaling. To enable disulfide-dependent and spontaneous formation of active Stat1 homodimer (as was done previously for Stat3), we engineered Stat1-CC with double-cysteine substitutions in the Src homology 2 (SH2)-homodimerization domain (at Ala-656 and Asn-658). In this case, however, mutant and wild-type Stat1 exhibited no difference inspontaneousdimerization. Moreover, Stat1-CC still required ligand-dependent Tyr-701 phosphorylation for function and exhibited hyperresponsiveness to IFN-β (that depends on Stat1/Stat2 heterodimerization) as well as IFN-γ (that depends on Stat1/Stat1 homodimerization). Hyperresponsivenss of Stat1-CC was accompanied by increased capacities for Tyr-701 phosphorylation and DNA binding, but these features were also found in a similarly substituted serine mutant (Stat1-SS) that showed no hyperresponsiveness to IFN-γ. This finding raised the possibility that SH2 domain mutations also influence downstream transcriptional efficiency. Indeed, each of these mutations also enhanced recruitment of the normally rate-limiting p300/CREB-binding Protein (CBP) coactivator to the transcriptional complex in proportion to the level of IFN-driven transactivation and gene expression. Additional modifications indicated that the mutant residues in the SH2 domain appeared to cooperate with Ser-727 in the C-terminal domain to regulate p300/CBP interaction with Stat1. The profile of IFN responsiveness translated into the same progressive increase in the level of viral clearance from Stat1- to Stat1-SS- to Stat1-CC-expressing cells. Thus, SH2 domain determinants may be modified to direct better Stat1 phosphorylation, DNA binding, and coactivator recruitment to fully improve IFN efficacy.
Association of serotonin transporter gene polymorphisms with obsessive-compulsive disorder (OCD) in a south Indian population

Background and Objectives: Serotonin transporter polymorphisms, 5-HTTVNTR and 5-HTTLPR, have been found to be associated with obsessive-compulsive disorder (OCD) and particularly with neurotic characteristics. In the present study we looked for an association between OCD and these polymorphisms in OCD patients and controls of south Indian origin. Methods: 5-HTTVNTR and 5-HTTLPR/rs25531 were genotyped in 93 OCD patients and 92 healthy controls. The allelic distribution and genotype frequency in cases and controls were compared using chi square test. In order to test for the effects of genotype on heterogeneity of the illness, linear regression analysis was undertaken for co-morbid depression status and YBOCS score (severity index). Results: There was no significant association with the 5-HTTVNTR or the 5-HTTLPR polymorphism. No significant association of OCD with the 5-HTTLPR genotype was found even on inclusion of the rs25531 locus, which is part of the transcription factor binding site as reported in earlier studies. However, severity of the illness showed a modest association with the dominant model. Interpretation & conclusions: Our data show that genetic variation in the SLC6A4 gene regulatory region may not have a significant effect on OCD in the present population. Further replication in a large and independent cohort with an equal number of female subjects would help to ascertain if the absence of association in this cohort is due to the nullifying effect of the larger proportion of male subjects in our sample population. The marginal effect of the 5-HTTLPR (A/G) genotype obtained on linear regression with disease severity is suggestive of a potential role for this locus in the disease process.
Stages in axon formation: observations of growth of Aplysia axons in culture using video-enhanced contrast-differential interference contrast microscopy

The regenerative growth in culture of the axons of two giant identified neurons from the central nervous system of Aplysia californica was observed using video-enhanced contrast-differential interference contrast microscopy. This technique allowed the visualization in living cells of the membranous organelles of the growth cone. Elongation of axonal branches always occurred through the same sequence of events: A flat organelle-free veil protruded from the front of the growth cone, gradually filled with vesicles that entered by fast axonal transport and Brownian motion from the main body of the growth cone, became more voluminous and engorged with organelles (vesicles, mitochondria, and one or two large, irregular, refractile bodies), and, finally, assumed the cylindrical shape of the axon branch with the organelles predominantly moving by bidirectional fast axonal transport. The veil is thus the nascent axon. Because veils appear to be initially free of membranous organelles, addition of membrane to the plasmalemma by exocytosis is likely to occur in the main body of the growth cone rather than at the leading edge. Veils almost always formed with filopodial borders, protruding between either fully extended or growing filopodia. Therefore, one function of the filopodia is to direct elongation by demarcating the pathway along which axolemma flows. Models of axon growth in which the body of the growth cone is pulled forward, or in which advance of the leading edge is achieved by filopodial shortening or contraction against an adhesion to the substrate, are inconsistent with our observations. We suggest that, during the elongation phase of growth, filopodia may act as structural supports.
Induction of CC chemokines in human peripheral blood mononuclear cells by staphylococcal exotoxins and its prevention by pentoxifylline

We investigated the inflammatory processes that might be associated with the arthrogenic activity of Staphylococcus aureus, the principal causative agent of bacterial arthritis. Human peripheral blood mononuclear cells (PBMC) were stimulated with the staphylococcal toxic shock syndrome toxin‐1 (TSST‐1) or enterotoxin B (SEB) and the production of chemokines was examined. Both TSST‐1 and SEB induced high levels (ng/mL) of MIP‐1α, MIP‐1β, and MCP‐1. The induction of these chemokines occurred mostly by direct stimulation of PBMC with staphylococcal exotoxins (SE), without requiring the intervention of IL‐1 and TNF‐α. The production of SE‐induced chemokines was blocked partially by anti‐DR and anti‐CD2 antibodies. Cell separation revealed monocytes as the cell source of these chemokines. However, addition of purified T cells amplified the levels of chemokine produced, suggesting that cognate interaction of SE bound on antigen‐presenting cells with T cells also contributes to chemokine production. The activation and recruitment of leukocytes by these chemokines may contribute to the pathophysiology of septic arthritis caused by staphylococci in humans through tissue injury and the recruitment of T lymphocytes, perhaps also initiating autoimmune responses. Pentoxifylline, an anti‐inflammatory agent, completely inhibited the production of these chemokines. J. Leukoc. Biol. 66: 158–164; 1999.
A new acupuncture method for management of irritable bowel syndrome: A randomized double blind clinical trial

Background: Irritable bowel syndrome (IBS) is gastrointestinal functional disorder which is multifactorial with unknown etiology. There are several modalities for treatment of it. Acupuncture is increasingly used in numerous diseases, also in gastrointestinal disorders like IBS. The purpose of the study was to assess the effects of catgut embedding acupuncture in improving of IBS. Materials and Methods: A randomized double blind sham control clinical trial was designed. A total of 60 IBS patients assigned to three separated groups. The first group received clofac as drug only group (DO). The second one received catgut embedding acupuncture in special point (AP) and the last group received sham acupuncture (SA). Symptoms, pain, depression and anxiety assessed before and after two weeks at the end of study. Results: There was statistically significant difference between AP and SA and DO in constipation and bloating. Differences that were statistically significant favored acupuncture on pain (F = 6.409, P = 0.003), and depression (F = 6.735, P = 0.002) as the other outcomes. The average (standard deviation (SD)) of weight loss was 2 kg (0.88) in acupuncture group. Conclusion: Our finding showed a significant positive associated between acupuncture and IBS. Catgut embedding acupuncture is a new method which can eliminated IBS symptoms and can use as alternative therapeutic method for improvement of IBS.
Oral health and treatment needs of institutionalized chronic psychiatric patients in Istanbul, Turkey.

OBJECTIVE To assess the oral health status and treatment needs in a group of hospitalized chronic psychiatric patients. METHOD The dental status was assessed using the DMFT index. Demographic and medical data were retrieved from the institutional clinical files. RESULTS 491 patients were examined in the study. 258 (52.5%) of the patients were males. The mean age was 52.3 +/- 12.3 years and the average length of hospitalization was 17.5 years. The majority of the patients (69%) were diagnosed with schizophrenia. The mean DMFT was 19.25 +/- 7.85. Missing teeth (81.4%) comprised the largest proportion of the DMFT while filled teeth (0.5%) the smallest. 18.1% of the DMFT consisted of decayed teeth. Stepwise logistic regression analysis showed that the DMFT significantly increased with age (p < 0.001) and was significantly higher in schizophrenia patients than those with mental retardation (p < 0.01). Males had significantly higher decayed teeth (p < 0.01) and fewer missing teeth (p < 0.01) than females. 58 dentate subjects (14.4%) were caries free. Two hundred and thirty five patients (58.5%) required restorative care, the mean number of treatments required per patient was 1.42 +/- 1.82. Eighty-nine subjects (18.1%) were found to be completely edentulous with only 17 wearing complete dentures. 70.6% of dentate patients needed tooth extraction for caries and 36.1% for periodontal disease. CONCLUSION The findings of this study demonstrate poor oral health status with extensive unmet dental and prosthetic needs. These underline the urgent need for specific preventive oral health programme to improve the dental care of these chronic psychiatric inpatients.
Spatial Decomposition of Climate Feedbacks in the Community Earth System Model

AbstractAn ensemble of simulations from different versions of the Community Atmosphere Model in the Community Earth System Model (CESM) is used to investigate the processes responsible for the intermodel spread in climate sensitivity. In the CESM simulations, the climate sensitivity spread is primarily explained by shortwave cloud feedbacks on the equatorward flank of the midlatitude storm tracks. Shortwave cloud feedbacks have been found to explain climate sensitivity spread in previous studies, but the location of feedback differences was in the subtropics rather than in the storm tracks as identified in CESM. The cloud-feedback relationships are slightly stronger in the winter hemisphere. The spread in climate sensitivity in this study is related both to the cloud-base state and to the cloud feedbacks. Simulated climate sensitivity is correlated with cloud-fraction changes on the equatorward side of the storm tracks, cloud condensate in the storm tracks, and cloud microphysical state on the poleward si.
E-privacy in 2nd generation E-commerce: privacy preferences versus actual behavior

As electronic commerce environments become more and more interactive, privacy is a matter of increasing concern. Many surveys have investigated households' privacy attitudes and concerns, revealing a general desire among Internet users to protect their privacy. To complement these questionnaire-based studies, we conducted an experiment in which we compared self-reported privacy preferences of 171 participants with their actual disclosing behavior during an online shopping episode. Our results suggest that current approaches to protect online users' privacy, such as EU data protection regulation or P3P, may face difficulties to do so effectively. This is due to their underlying assumption that people are not only privacy conscious, but will also act accordingly. In our study, most individuals stated that privacy was important to them, with concern centering on the disclosure of different aspects of personal information. However, regardless of their specific privacy concerns, most participants did not live up to their self-reported privacy preferences. As participants were drawn into the sales dialogue with an anthropomorphic 3-D shopping bot, they answered a majority of questions, even if these were highly personal. Moreover, different privacy statements had no effect on the amount of information disclosed; in fact, the mentioning of EU regulation seemed to cause a feeling of 'false security'. The results suggest that people appreciate highly communicative EC environments and forget privacy concerns once they are 'inside the Web'.
Identification of Predictors for Weight Reduction in Children and Adolescents with Overweight and Obesity (IDA-Insel Survey)

Introduction: Worldwide, overweight and obesity are known as posing serious health risks. Successful methods of prevention and therapy for overweight and obesity have remained elusive. It was the aim of the present trial to identify parameters and determinants to guarantee long-term weight reduction. Patients and methods: In total 143/159 children and adolescents (90%) with overweight and obesity completed the prospective, multicenter trial (age 13.9 ± 2.4 years, BMI 31.2 ± 5.4 kg/m2, BMI-SDS 2.51 ± 0.57). During a six-week rehabilitation patients participated in a structured treatment and teaching program (STTP). Following the inpatient treatment the children and adolescents were monitored over a period of 24 months (physical examination, measurements of BMI, BMI-SDS, body composition, carotid intima-media thickness, laboratory parameters, blood pressure, and standardized questionnaires to assess socio-demographic, socio-economic parameters, eating behavior, well-being, quality of life, intelligence, intrafamilial conflicts, self-efficacy, resilience, sense of coherence, stress-management, social support, and actual body shape). Results: 66% of the children and adolescents showed non-normal laboratory parameters as well as higher blood pressure and/or an increased carotid intima-media thickness. Mean thickness of carotid intima-media was 0.53 ± 0.09 mm (range, 0.40–0.80); 15% of the patients showed a normal range (<0.45 mm), 40% slightly elevated (0.45–0.50 mm) and 45% an elevated (>0.50 mm) thickness. After an inpatient treatment lasting 40.4 ± 4.1 (range, 28–49) days, children and adolescents reached a mean weight reduction of 5.52 ± 3.94 (0.4–13.3) kg (p < 0.01) accompanied by a reduction of body fat mass. Performing multivariate analyses, the most important psychological factors associated with long-term weight reduction were identified (R-square = 0.53): Well-being (β = −0.543), resilience (β = 0.434) and intrafamilial conflicts (β = 0.315). Conclusion: The different parameters (i.e., resilience, intrafamilial conflicts, structured daily schedule) have demonstrated their utility and strategies should be developed allowing an adaption of these into the STTPs and the integration of intervention into the therapeutic setting.
Is pharmacogenetic CYP 2 D 6 testing useful ?

Materials and method. We reviewed retrospectively all samples (n = 328) submitted to our laboratory with a request for CYP2D6 genotyping in the period 29 June 1998–28 December 2009 and classified them into three different indication groups on the basis of the information in the requisition. These samples and samples from a Control Group consisting of 100 healthy blood donors were scanned for the four most frequently occurring nonfunctional CYP2D6 alleles among Europeans and for duplications of the CYP2D6 gene associated with ultra-rapid drug metabolism.
Narratives of Response Error From Cognitive Interviews of Survey Questions About Normative Behavior

That rates of normative behaviors produced by sample surveys are higher than actual behavior warrants is well evidenced in the research literature. Less well understood is the source of this error. Twenty-five cognitive interviews were conducted to probe responses to a set of common, conventional survey questions about one such normative behavior: religious service attendance. Answers to the survey questions and cognitive probes are compared both quantitatively and qualitatively. Half of the respondents amended their answer during cognitive probing, all amendments indicating a lower rate of attendance than originally reported, yielding a statistically significant reduction in reported attendance. Narrative responses shed light onto the source of bias, as respondents pragmatically interpreted the survey question to allow themselves to include other types of religious behavior, to report on a more religious past, and discount current constraints on their religious behavior, in order to report aspirational or normative religious identities.
The p53 family member p73 modulates the proproliferative role of IGFBP3 in short children born small for gestational age

It is demonstrated that IGFBP3 is a direct p73 target gene and that mRNA expression levels of p73 and IGFBP3 are significantly lower in small for gestational age (SGA) children compared with controls; in particular, p73 mRNA expression is significantly lower in SGA children with respect to length, suggesting that p73 is a good biomarker of the clinical risk for SGA children to remain short into adulthood.
Beta-hemolytic streptococcal illness. Comparison of lincomycin, ampicillin, and potassium penicillin G in treatment.

THE INVESTIGATION reported in this communication is another in our series of clinical trials of various antibiotics in the treatment of β-hemolytic streptococcal disease in children. In this particular study we compared the effectiveness of lincomycin (Lincocin), ampicillin (Polycillin), and potassium penicillin G against these infections. Beta-hemolytic streptococci have been reported to be susceptible in vitro to both lincomycin 1-3 and ampicillin 4-7 in serum concentrations readily attained by oral administration. Lincomycin has also been shown to be effective clinically in children against infections caused by this organism. 8 The most recent report of its clinical effectiveness is that of Jackson et al. 9 However, other than the report of Scarzella 10 on the results of a few infections in children, there is no information on the clinical effectiveness of ampicillin against β-hemolytic streptococcal illness. Methods The method used was similar to our clinical trials with other antibiotics which we