Miracle-dz/UniFAR-FTUs huggingface dataset:
Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles.

Microarray technology, which allows one to quantitate the expression of thousands of genes simultaneously, has begun to have a major impact on many different areas of drug discovery and development. The question remains of whether microarray analysis and gene expression signature profiles can be applied to the field of toxicology. To date, there are very few published studies showing the use of microarrays in toxicology and important questions remain regarding the predictability and accuracy of applying gene expression profiles to toxicology. To begin to address these questions, we have treated rats with 15 different known hepatotoxins, including allyl alcohol, amiodarone, Aroclor 1254, arsenic, carbamazepine, carbon tetrachloride, diethylnitrosamine, dimethylformamide, diquat, etoposide, indomethacin, methapyrilene, methotrexate, monocrotaline, and 3-methylcholanthrene. These agents cause a variety of hepatocellular injuries including necrosis, DNA damage, cirrhosis, hypertrophy, and hepatic carcinoma. Gene expression analysis was done on RNA from the livers of treated rats and was compared against vehicle-treated controls. The gene expression results were clustered and compared to the histopathology findings and clinical chemistry values. Our results show strong correlation between the histopathology, clinical chemistry, and gene expression profiles induced by the agents. In addition, genes were identified whose regulation correlated strongly with effects on clinical chemistry parameters. Overall, the results suggest that microarray assays may prove to be a highly sensitive technique for safety screening of drug candidates and for the classification of environmental toxins.
Amplicon Sequencing and Improved Detection of Human Rhinovirus in Respiratory Samples

ABSTRACT Improved knowledge of the genotypic characteristics of human rhinovirus (HRV) is required, as are nucleic detection assays with the capacity to overcome both the similarities between members of the family Picornaviridae and the wide diversity of different HRV serotypes. The goal of the present study was to investigate the variability and the genotypic diversity of clinical strains circulating in the community. Since most reverse transcription (RT)-PCR assays available cannot differentiate HRV from other members of the family Picornaviridae, we also validated an assay specific for HRV detection. The 5′ noncoding regions of 87 different HRV serotypes and clinical isolates were sequenced. On the basis of sequence analysis and phylogenetic determination, we first confirmed that all clinical isolates were HRV. We then validated a real-time RT-PCR assay that was able not only to detect all HRV serotypes and all clinical isolates tested but also to accurately discriminate between rhinovirus and other viruses from the family Picornaviridae. This assay was negative with isolates of coxsackievirus (types A and B), echovirus, enterovirus, parechovirus, and poliovirus, as well as nonpicornaviruses. Among a series of bronchoalveolar lavage specimens, 4% (7 of 161) were positive by culture, whereas 13% (21 of 161) were positive by RT-PCR. In the present study we showed that to specifically identify HRV in clinical specimens, diagnostic assays need to overcome both the diversities and the similarities of picornaviruses. By sequencing the 5′ noncoding regions of rhinoviruses recovered from clinical specimens, we designed probes that could specifically detect rhinovirus.
Abrogation of De novo Lipogenesis by Stearoyl-CoA Desaturase 1 Inhibition Interferes with Oncogenic Signaling and Blocks Prostate Cancer Progression in Mice

Increased de novo fatty acid (FA) synthesis is one hallmark of tumor cells, including prostate cancer. We present here our most recent results showing that lipid composition in human prostate cancer is characterized by an increased ratio of monounsaturated FA to saturated FA, compared with normal prostate, and evidence the overexpression of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) in human prostate cancer. As a new therapeutic strategy, we show that pharmacologic inhibition of SCD1 activity impairs lipid synthesis and results in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells, abrogates the growth of prostate tumor xenografts in nude mice, and confers therapeutic benefit on animal survival. We show that these changes in lipid synthesis are translated into the inhibition of the AKT pathway and that the decrease in concentration of phosphatidylinositol-3,4,5-trisphosphate might at least partially mediate this effect. Inhibition of SCD1 also promotes the activation of AMP-activated kinase and glycogen synthase kinase 3α/β, the latter on being consistent with a decrease in β-catenin activity and mRNA levels of various β-catenin growth-promoting transcriptional targets. Furthermore, we show that SCD1 activity is required for cell transformation by Ras oncogene. Together, our data support for the first time the concept of targeting the lipogenic enzyme SCD1 as a new promising therapeutic approach to block oncogenesis and prostate cancer progression. Mol Cancer Ther; 9(6); 1740–54. ©2010 AACR.
Perforator-Based Forearm and Hand Adipofascial Flaps for the Coverage of Difficult Dorsal Hand Wounds

The author presents several case studies of alternative therapy for large and small dorsal hand and finger defects. These alternatives avoid the need for a lengthy free flap procedure, avoid the meticulous dissection required by the posterior interosseous flap, and avoid the loss of radial artery required by the reverse radial forearm flap. Distally based hand and forearm adipofascial flaps consist of the subcutaneous fat and fascia of the hand and/or forearm. They are easy to elevate, with operative times typically less than 2 hours, and can cover surfaces ranging from an individual finger to the entire dorsum of the hand. The blood supply is based on the rich profusion of perforators that exist in the hand and wrist. If desired, a skin paddle can be included with these flaps. These techniques are an important addition to the plastic and hand surgeon’s armamentarium.
A 0.6–6.2 GHz wideband LNA using resistive feedback and gate inductive peaking techniques for multiple standards application

This paper presents a 0.6-6.2 GHz wideband CMOS low noise amplifier (LNA) for multi-band application. The LNA design is based on a common source (CS) cascade amplifier with resistive feedback, gate inductive peaking, and source degeneration inductive topologies to realize the matching networks for broadband operation. The authors also derived the formula of the input and output impedances those help to select proper values of biasing and matching elements. The LNA achieves a peak gain S21 of 11.61 dB, a noise figure (NF) of 5.28 to 5.82 dB at frequency from 0.6 to 6.2 GHz, and an input third-intercept point (IIP3) of -2.55 dBm at 2.5 GHz under DC power of 8.45 mW from a 1.5 V supply voltage. The figure-of-merit (FOM) for wideband LNA is up to 0.51 at 2.5 GHz. The LNA is fabricated in tsmc™ 0.18-μm RF CMOS technology with a chip area of 0.8 mm2.
Towards Improved Myoelectric Prosthesis Control: High Density Surface EMG Recording After Targeted Muscle Reinnervation

The control of shoulder disarticulation prostheses remains a challenging problem. Recently, a novel method, using targeted muscle reinnervation to develop additional myoelectric control sites, has improved the control of myoelectric upper limb prosthesis in a patient with bilateral amputations at the shoulder disarticulation level. Encouraged by this achievement, we recorded high density surface electromyogram (EMG) signals from the patient's reinnervated muscles as he actuated a variety of different movements. We believe that the reinnervated muscle activation patterns revealed by the high density EMG recording have the potential to further improve the myoelectric prosthesis control. As the initial stage of the study, this paper presents the experiment of high density surface EMG recording, the preliminary EMG data analysis and the framework for future investigation with advanced feature extraction and pattern recognition techniques
Low-Forward-Voltage-Drop 4H-SiC BJTs Without Base Contact Implantation

Bipolar junction transistors (BJTs) of 4H-SiC, with a low collector-emitter forward voltage drop V<sub>CE</sub> have been fabricated without base contact implantation. A comparison of BJTs on the same wafer with and without base contact implantation shows less than 10% higher V<sub>CE</sub> for the BJTs without base contact implantation. Omitting the base contact implantation eliminates high concentrations of implantation-induced defects that act as recombination centers. This is advantageous because it allows a shorter distance W<sub>p+</sub> between the emitter edge and the base contact, without affecting the current gain when no base contact implantation is used. The BJTs without contact implantation show a constant current gain as W<sub>p+</sub> was reduced from 3 to 1 mum, whereas the gain decreased by 45% for the BJTs with base contact implantation for the same reduction of W<sub>p+</sub>. A key to the successful fabrication of low-forward-voltage-drop SiC BJTs without base contact implantation is the formation of low-resistivity Ni/Ti/Al ohmic contacts to the base. The contact resistivity on the base region (N<sub>A</sub> ap 4 times10<sup>17</sup> cm<sup>-3</sup>) was measured with linear transmission line method structures to rho<sub>C</sub> = 1.9 times 10<sup>-3</sup> Omegacm<sup>2</sup>, whereas the contact resistivity with the base contact implantation was rho<sub>C</sub> = 1.3 times 10<sup>-4</sup> Omegacm<sup>2</sup>, both after rapid thermal processing annealing at 800degC.
The U-shaped curve: various health measures and alcohol drinking patterns.

OBJECTIVE To determine whether the well-known U-shaped relationship between average alcohol intake and mortality also holds for other health measures and for aspects of drinking other than weekly average alcohol intake, such as frequency of heavy-drinking episodes. METHOD This study was carried out within the framework of a general population survey conducted in Eindhoven, The Netherlands (N = 18,973). Apart from mortality, the following health measures were considered: self-assessed health (based on perceived general health and the Nottingham Health Profile questionnaire), a list of chronic conditions and a list of health complaints. Respondents were categorized as abstainers, light (1-14 units/week), moderate (15-28 units/week) and excessive drinkers (> or =29 units/week). Information on the frequency with which heavy-drinking episodes occurred was also available. RESULTS Light or moderate drinkers had not only lower mortality but other health burdens were lower than for either abstainers or heavier drinkers. Frequent heavy-drinking episodes were observed to be directly related to increased mortality rates, although not significantly. A trend was observed for drinkers reporting seldom heavy-drinking episodes (once or twice in the previous 6 months) to report less health burdens and to have lower mortality rates than those reporting no heavy drinking episodes. CONCLUSIONS A U-shaped pattern was observed for mortality as well as for several other health measures. Frequent heavy-drinking episodes were related to an increased likelihood of mortality (not significant but suggesting a J-shaped pattern) and were not related to other health measures.
Changes in Diet During Adult Life and Risk of Colorectal Adenomas

Abstract: To evaluate the associations of changes in diet during adult life with adenoma risk, data from a case-control study of 146 colorectal adenomas and 226 controls were analyzed. Dietary habits during the year before sigmoidoscopy and when subjects were 30 yr old were collected using a food-frequency questionnaire. Change in frequency of consumption during adulthood was calculated by subtracting frequency of consumption of specific foods or food groups at age 30 yr from frequency of consumption during the previous year (recent consumption). Associations with changes in frequency of consumption were estimated by odds ratios (ORs) and 95% confidence intervals (CIs). There was no association for foods or food groups consumed at age 30 yr. For recent consumption, more frequent consumption of red meat, breakfast sausage, and pork chops/ham steaks and less frequent consumption of fish, chicken/turkey, and vegetables were related to a higher risk. Compared with individuals with the highest reduction in consumption since age 30 yr, risks were higher for those with smallest reduction in red meat intake (OR = 2.8; CI = 1.1-7.3), particularly for hamburgers/cheeseburgers (OR = 2.8; CI = 1.2-6.8) and pork chops/ham steaks (OR = 3.7; CI = 1.6-8.7). In contrast, individuals in the highest quartile of increased consumption of fish (OR = 0.6; CI = 0.3-1.1) and vegetables (OR = 0.5; CI = 0.3-1.1) had a lower risk compared with those with minimal increase in consumption. In conclusion, irrespective of frequency of consumption at age 30 yr, a greater reduction in consumption of red meat and a larger increase in consumption of vegetables since age 30 yr were associated with a decreased risk of colorectal adenomas later in life.
Human Immunodeficiency Virus (HIV)-Positive Sera Obtained Shortly after Seroconversion Neutralize Autologous HIV Type 1 Isolates on Primary Macrophages but Not on Lymphocytes

ABSTRACT The aim of this study was to analyze the role of humoral immunity in early human immunodeficiency virus (HIV) infection. As neutralizing activities in HIV-positive sera are rarely detectable earlier than 9 to 12 months after infection using primary lymphocytes as target cells in neutralization assays, humoral immunity is generally thought not to contribute significantly to early virus control in the patients. Besides lymphocytes, cells of the monocyte/macrophage lineage are known to be important target cells for HIV in vivo during the establishment of the infection. Therefore, we studied the neutralization of early primary HIV isolates by autologous serum samples using primary macrophages as target cells in the neutralization assays. We analyzed neutralizing activities against the autologous HIV-1 isolates in 10 patients' sera taken shortly after seroconversion, both on primary macrophages and, for comparison, on lymphocytes. Viruses were isolated and expanded in primary mixed cultures containing macrophages and lymphocytes in order to avoid selection for one particular cell type. All viruses replicated to different degrees in macrophages and lymphocytes; nine had a nonsyncytium-inducing phenotype, and one was syncytium inducing. The detection of neutralizing antibodies in acute primary HIV infection depended on the target cells used. Confirming previous studies, we did not find neutralizing activities on lymphocytes at this early time point. In contrast, neutralizing activities were detectable in the same sera if primary macrophages were used as target cells. Differences in neutralizing activities on macrophages and lymphocytes were not due to different virus variants being present in the different cell systems, as gp120 sequences derived from both cell types were homogeneous. Neutralization activities on macrophages did not correlate with the amount of β-chemokines in the sera. As affinity-purified immunoglobulin G preparations from an early patient serum also exhibited neutralization of the autologous virus isolate on primary macrophages, but not on lymphocytes, neutralization is very likely due to antibodies against viral epitopes necessary for infection of macrophages but not for infection of lymphocytes. Our data suggest that, along with cell-mediated immunity, humoral immunity may contribute to the reduction of primary viremia in the patient. This was further supported by a certain association between neutralizing antibody titers on macrophages and viral load in the patients.
100 Multivisceral Transplants at a Single Center

Objective:The objective of this study was to summarize the evolution of multivisceral transplantation over a decade of experience and evaluate its current status. Summary Background Data:Multivisceral transplantation can be valuable for the treatment of patients with massive abdominal catastrophes. Its major limitations have been technical and rejection of the intestinal graft. Methods:This study consisted of an outcome analysis of 98 consecutive patients who received multivisceral transplantation at our institution. This represents the largest single center experience to date. Results:The most common diseases in our population before transplant were intestinal gastroschisis and intestinal dysmotility syndromes in children, and mesenteric thrombosis and trauma in adults. Kaplan Meier estimated patient and graft survivals for all cases were 65% and 63% at 1 year, 49% and 47% at 3 years, and 49% and 47% at 5 years. Factors that adversely influenced patient survival included transplant before 1998 (P = 0.01), being hospitalized at the time of transplant (P = 0.05), and being a child who received Campath-1H induction (P = 0.03). Among 37 patients who had none of these 3 factors (15 adults and 22 children), estimated 1- and 3-year survivals were 89% and 71%, respectively. Patients transplanted since 2001 had significantly less moderate and severe rejections (31.6% vs 67.6%, P = 0.0005) with almost half of these patients never developing rejection. Conclusions:Multivisceral transplantation is now an effective treatment of patients with complex abdominal pathology. The incidences of serious acute rejection and patient survival have improved in the most recent experience. Our results show that the multivisceral graft seems to facilitate engraftment of transplanted organs and raises the possibility that there is a degree of immunologic protection afforded by this procedure.
Use of monoclonal antibodies to identify four neutralization immunogens on a common cold picornavirus, human rhinovirus 14

A collection of 35 mouse monoclonal antibodies, raised against human rhinovirus 14 (HRV-14), was used to isolate 62 neutralization-resistant mutants. When cross-tested against the antibodies in a neutralization assay, the mutants fell into four antigenic groups, here called neutralization immunogens: NIm-IA, -IB, -II, and -III. Sequencing the mutant RNA in segments corresponding to serotype-variable regions revealed that the amino acid substitutions segregated into clusters, which correlated exactly with the immunogenic groups (NIm-IA mutants at VP1 amino acid residue 91 or 95; NIm-II mutants at VP2 residue 158, 159, 161, or 162; NIm-III mutants at VP3 residue 72, 75, or 78; and NIm-IB mutants at two sites, either VP1 residue 83 or 85, or residue 138 or 139). Examination of the three-dimensional structure of the virus (M. G. Rossmann, E. Arnold, J. W. Erickson, E. A. Frankenberger, J. P. Griffith, H.-J. Hecht, J. E. Johnson, G. Kamer, M. Luo, A. G. Mosser, R. R. Rueckert, B. Sherry, and G. Vriend, Nature [London], 317:145-153, 1985) revealed that each of the substitution clusters formed a protrusion from the virus surface, and the side chains of the substituted amino acids pointed outward. Moreover, four of the amino acid substitutions, which initially appeared to be anomalous because they were encoded well outside the cluster groups, could be traced to surface positions immediately adjacent to the appropriate viral protrusions. We conclude that three of the four antigens, NIm-IB, -II, and -III, are discontinuous. Thus, the amino acid substitutions in all 62 mutants fell within the proposed immunogenic sites; there was no evidence for alteration of any antigenic site by a distal mutation.
Effect of Omalizumab as Add-On Therapy on Asthma-Related Quality of Life in Severe Allergic Asthma: A Brazilian Study (QUALITX)

Objective. To assess the impact of omalizumab as an add-on therapy to standard treatment with inhaled corticosteroids (ICS) and long-acting beta-2 agonists (LABA) on asthma-related quality of life (QoL) in patients with severe allergic asthma. Methods. This was a 20-week, randomized, open-label, study involving Brazilian patients (>12 years) with severe persistent allergic asthma inadequately controlled despite regular treatment with, at least, ICS (≥500 μg/day fluticasone or equivalent) + LABA. The primary objective was to assess the mean change from baseline in overall Asthma-related Quality of Life Questionnaire (AQLQ) score in omalizumab-treated patients compared with the control group. Secondary outcome measures included rescue medication use, incidence of asthma exacerbations, perception of treatment efficacy among patients, mean change from baseline in AQLQ score, and >1.5-point increase in overall AQLQ score. Results. In the omalizumab group, overall AQLQ score was 3.2 (0.9) (mean [SD]) at baseline and 4.4 (1.3) at week 20 versus 3.0 (1.0) at baseline and 3.0 (1.1) at week 20 in the control group. Mean change from baseline on overall AQLQ score at week 20 in the omalizumab group was 1.2 (0.2) versus 0 (0.1) in the control group, showing a significant increase in scores from baseline in the omalizumab group (p < .001). There was also a statistically significant difference (p < .001) in the number of patients who showed a >1.5-point increase from baseline in overall AQLQ score after 20 weeks, thus indicating a better QoL in the omalizumab group. There was no significant difference with respect to the use of rescue medication, incidence of asthma exacerbation, and adverse events between treatment groups. The global evaluation of treatment effectiveness was significantly better for omalizumab (p < .001). Conclusion. Omalizumab was well tolerated and significantly improved the overall AQLQ score. Hence, it is a potential add-on therapy for severe persistent allergic asthma not controlled by standard prescribed treatment in Brazilian patients.
Predictors of Adherence to an Integrated Multimodal Program for Fibromyalgia

Objective To describe treatment adherence to a multimodal integrated program for patients with fibromyalgia (FM), identify predictors of adherence to treatment recommendations, and examine the relationship between adherence and patient outcomes. Methods Sixty-three patients with FM were followed while participating in a 3-month outpatient program including physiotherapy, occupational therapy, nursing, and cognitive-behavior therapy. Patients completed a battery of psychosocial questionnaires pre- and post-treatment. At the end of each month of the treatment, patients completed 2 adherence questionnaires (for general and specific adherence) and 1 questionnaire about barriers to adherence to treatment. Generalized estimating equations extension of multivariable linear regression analyses for repeated measures examined predictors of general and specific adherence. Conventional linear regression analyses examined the relationships of general adherence with post-treatment FM disability and pain intensity. Results In general, adherence to treatment recommendations was good (mean general adherence score of 62 points, on a 0 to 100 scale), with no significant changes in mean level of general or specific adherence over the 3-month period. The main predictor for both general and specific adherence was barriers to adherence to treatment. Increased general adherence was significantly associated with lower pain at post-treatment. Conclusion The items described in the questionnaire for barriers to treatment are the main problem when it comes to adhering to a multimodal treatment program for FM. Healthcare professionals are advised to discuss these barriers directly with patients and assist in overcoming them.