Miracle-dz/UniFAR-FTUs huggingface dataset:
Preclinical and Clinical Evidence for the Collaborative Transport and Renal Secretion of an Oxazolidinone Antibiotic by Organic Anion Transporter 3 (OAT3/SLC22A8) and Multidrug and Toxin Extrusion Protein 1 (MATE1/SLC47A1)

N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (PNU-288034), an oxazolidinone antibiotic, was terminated in phase I clinical development because of insufficient exposure. Analysis of the drug pharmacokinetic and elimination profiles suggested that PNU-288034 undergoes extensive renal secretion in humans. The compound was well absorbed and exhibited approximately linear pharmacokinetics in the oral dose range of 100 to 1000 mg in human. PNU-288034 was metabolically stable in liver microsomes across species, and unchanged drug was cleared in the urine by an apparent active renal secretion process in rat and monkey (two to four times glomerular filtration rate) but not dog. In vitro studies conducted to characterize the transporters involved demonstrated PNU-288034 uptake by human organic anion transporter 3 (OAT3; Km = 44 ± 5 μM) and human multidrug and toxin extrusion protein 1 (hMATE1; Km = 340 ± 55 μM). The compound was also transported by multidrug resistance P-glycoprotein and breast cancer resistance protein. In contrast, human organic cation transporter 2, human OAT1, and hMATE2-K did not transport PNU-288034. Coadministration of PNU-288034 and the OAT3 inhibitor probenecid significantly increased PNU-288034 plasma area under the curve (170%) and reduced both plasma and renal clearance in monkey. Coadministration of PNU-288034 and cimetidine, a MATE1 inhibitor, also reduced plasma clearance in rat to a rate comparable with probenecid coadministration. Collectively, our results demonstrated a strong in vitro–in vivo correlation for active renal secretion coordinated through the vectorial transport process of OAT3 and MATE1, which ultimately resulted in limiting the systemic exposure of PNU-288034.
Group therapy for people with bulimia nervosa: systematic review and meta-analysis

Background Approximately 25% of people with bulimia nervosa (BN) who undertake therapy are treated in groups. National guidelines do not discriminate between group and individual therapy, yet each has potential advantages and disadvantages and it is unclear how their effects compare. We therefore evaluated how group therapy for BN compares with individual therapy, no treatment, or other therapies, in terms of remission from binges and binge frequency. Method We performed a systematic review and meta-analysis of randomized controlled trials of group therapies for BN, following standard guidelines. Results A total of 10 studies were included. Studies were generally small with unclear risk of bias. There was low-quality evidence of a clinically relevant advantage for group cognitive behavioural therapy (CBT) over no treatment at therapy end. Remission was more likely with group CBT versus no treatment [relative risk (RR) 0.77, 95% confidence interval (CI) 0.62–0.96]. Mean weekly binges were lower with group CBT versus no treatment (2.9 v. 6.9, standardized mean difference = −0.56, 95% CI −0.96 to −0.15). One study provided low-quality evidence that group CBT was inferior compared with individual CBT to a clinically relevant degree for remission at therapy end (RR 1.24, 95% CI 1.03–1.50); there was insufficient evidence regarding frequency of binges. Conclusions Conclusions could only be reached for CBT. Low-quality evidence suggests that group CBT is effective compared with no treatment, but there was insufficient or very limited evidence about how group and individual CBT compared. The risk of bias and imprecise estimates of effect invite further research to refine and increase confidence in these findings.
Predicting plant vulnerability to drought in biodiverse regions using functional traits

Significance Recent reports of widespread drought-induced plant die-back have enhanced the need to understand variation in plant hydraulic strategies and to determine which species are susceptible to drought-induced mortality. Finding meaningful ways to describe the many different types of responses plants might demonstrate in biodiverse regions can be extremely challenging. Here, we present the architecture in which functional traits can be incorporated into a known hydraulic framework to provide additional insight into the range of hydraulic strategies present in diverse communities. Merging stomatal regulation strategies that represent an index of water use behavior with xylem hydraulic strategies that represent water transport and vulnerability to water deficit behavior facilitates a more comprehensive framework to characterize plant response to drought. Attempts to understand mechanisms underlying plant mortality during drought have led to the emergence of a hydraulic framework describing distinct hydraulic strategies among coexisting species. This framework distinguishes species that rapidly decrease stomatal conductance (gs), thereby maintaining high water potential (Px; isohydric), from those species that maintain relatively high gs at low Px, thereby maintaining carbon assimilation, albeit at the cost of loss of hydraulic conductivity (anisohydric). This framework is yet to be tested in biodiverse communities, potentially due to a lack of standardized reference values upon which hydraulic strategies can be defined. We developed a system of quantifying hydraulic strategy using indices from vulnerability curves and stomatal dehydration response curves and tested it in a speciose community from South Africa’s Cape Floristic Region. Degree of stomatal regulation over cavitation was defined as the margin between Px at stomatal closure (Pg12) and Px at 50% loss of conductivity. To assess relationships between hydraulic strategy and mortality mechanisms, we developed proxies for carbon limitation and hydraulic failure using time since Pg12 and loss of conductivity at minimum seasonal Px, respectively. Our approach captured continuous variation along an isohydry/anisohydry axis and showed that this variation was linearly related to xylem safety margin. Degree of isohydry/anisohydry was associated with contrasting predictions for mortality during drought. Merging stomatal regulation strategies that represent an index of water use behavior with xylem vulnerability facilitates a more comprehensive framework with which to characterize plant response to drought, thus opening up an avenue for predicting the response of diverse communities to future droughts.
The effects of job rotation on the risk of reporting low back pain

Job rotation has been widely recommended as an administrative control to reduce the risk of developing work-related musculoskeletal disorders. However, evidence of its benefits are hard to find in the literature. The effect of job rotation on predictions for the risk of reporting low back pain was estimated using Low Back Pain Reporting (LBPR) and Time Weighted Average (TWA) approaches. Index scores calculated using the peak hand force, the peak L4/L5 shear force and the L4/L5 moment cumulated over the entire shift were used to estimate the effects of job rotation on the probability of reporting low back pain. Simulations of realistic rotations between two jobs showed that workers in low demand jobs who rotate into higher demand jobs experience a linear increase in reporting probability using the TWA approach. With the LBPR approach a step increase in reporting probability occurred because of the immediate exposure to the peak loading parameters associated with the more demanding job. With a 50-50 rotation the TWA and LBPR index scores increased by 39% and 57%, respectively. With the LBPR approach the redistribution of risk was not uniform with job rotation. The increase was greater for those who rotated into the demanding job compared to the reduction experienced by those who rotated out of the demanding job. The effects of job rotation are not easily estimated because of the complex effect that mixing jobs has on peak and cumulative tissue loading.
Phase II study of vinflunine in malignant pleural mesothelioma.

PURPOSE Malignant pleural mesothelioma (MPM) is a disease of increasing incidence for which treatment options are limited. This study reports the clinical efficacy data for vinflunine, a novel microtubule inhibitor, in MPM. PATIENTS AND METHODS Patients with a histologically confirmed diagnosis of MPM were eligible for enrollment onto this multicenter phase II trial if they had not received prior chemotherapy or radiotherapy and had measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Vinflunine 320 mg/m2 by 10-minute intravenous infusion was administered on day 1 of 21-day cycles. Modifications of dose and schedule were made according to National Cancer Institute Common Toxicity Criteria version 2.0. Efficacy was assessed by an external, independent radiologist. The one-sample multiple testing procedure of Fleming was applied at the predetermined recruitment stages of 20 and 40 assessable patients. RESULTS Sixty-seven patients were enrolled. Five patients were not assessable for tumor response. The response rate was 13.8% (95% CI, 6.5% to 24.7%). The median survival was 10.8 months (95% CI, 7.8 to 12.0 months). The most common adverse events were anemia, neutropenia, fatigue, constipation, and nausea. Of grade 3 and 4 toxicities, neutropenia and constipation were the most common (45% and 9% of patients, respectively). CONCLUSION Vinflunine can be delivered with high-dose intensity in patients with MPM. The response rate and median survival are encouraging for a single agent. These data suggest that vinflunine should be further evaluated in the management of MPM.
Highly soft viscoelastic robot skin with a contact object-location-sensing capability

This paper concerns the development of robot skin capable of accurately sensing the location of objects in area contact with the skin surface. There has been no report on tactile sensing which attained not only skin deformation detection but also contact object location sensing with high accuracy. In the category of optomechatronics technology, we apply optical fibers to transmit surface deformation information of soft skin for sensing the location of an object in contact with the soft skin accurately. In the paper, we illustrate the structure of the robot skin, and describe the principle of both detecting the position of the reflector chips and sensing the contact location of an object. The robot skin is characterized by the fact that the surface is low cost and easily replaceable, and the sensing performance is robust against any electromagnetic disturbance. We then show experimental results for verifying the principles using a wedge-shaped object. For evaluating the sensing accuracy, comparisons are made: 1) between the location of a real convex of the object and that of the corresponding estimated polygon and 2) for the position of two vertices of the object when independent fitting and Lagrangian fitting methods are applied.
Monomeric Kinesin Head Domains Hydrolyze Multiple ATP Molecules before Release from a Microtubule*

Transient kinetic analysis of microtubule-stimulated ATP hydrolysis by the monomeric kinesin motor domain DKH357 was performed to investigate the kinetic pattern of a monomer. Both ATP and ADP produced dissociation of the complex, microtubule (MT)·;E, of microtubules with DKH357 at a maximum rate of ∼45 s−1 as determined by decrease in turbidity. The maximum dissociation rate was independent of the KCl concentration between 25 and 200 mM. At subsaturating levels of nucleotide, ATP was more effective than ADP in dissociating DKH357 from MT·;E (1.6 and 0.4 μM−1 s−1 for ATP and ADP, respectively, at 50 mM KCl). Addition of ATP to MT·;E results in a burst of product formation with a maximum initial rate of ∼100 s−1 at saturating levels of ATP. This maximum hydrolysis rate of 100 s−1 is similar to the maximum steady state ATPase rate at saturating microtubules of ∼70 s−1, and thus hydrolysis is at least partially rate-limiting. When the MT lattice was highly occupied with bound DKH357, the amplitude of the burst was ∼2 per DKH357 active site (superstoichiometric). The rate constant for the burst transient was ∼45 s−1, which is the same as the rate for dissociation of DKH357 from the microtubule and this suggests that dissociation and termination of the burst phase are coupled. The size of the burst increased with decreasing initial occupancy of the MT lattice with bound DKH357 and approached the value of ∼4 ATP molecules predicted by previous steady state measurements (Jiang, W., Stock, M., Li, X., and Hackney, D. D., submitted for publication).
Assessing the asymmetry of free gait in healthy young subjects.

PURPOSE The purpose of this study was to derive reference values for a four-level scale intended to evaluate variation in free gait asymmetry measurements in healthy subjects. METHODS This evaluation is based on kinetic values for the left and right lower limbs during gait, registered with advanced measurement systems and assessed using the symmetry index (SI) developed by Robinson. RESULTS For the majority of parameters, the SI does not follow normal distribution. As such, quartile values were used to create intervals for a four-step scale of assessing symmetry of free gait in healthy subjects for each gait parameter of interest. The SI rating intervals were from 0% (very good symmetry) to 21.2% (very poor symmetry) for kinetic parameters. The poorest symmetry was observed for horizontal force F3. CONCLUSIONS The four-step scale of assessing symmetry in free gait in healthy subjects can be used in diagnosing gait disorders, devising surgical treatment strategies, and monitoring the rehabilitation process. Reference values for intervals of symmetry indicators in healthy subjects can be used as criteria for comparing individuals with/without disabilities.
Cross-Subtype Neutralizing Antibodies Induced in Baboons by a Subtype E gp120 Immunogen Based on an R5 Primary Human Immunodeficiency Virus Type 1 Envelope

ABSTRACT Global human immunodeficiency virus type 1 (HIV-1) diversity may require engineering vaccines to express antigens representing strains prevalent in the target population of vaccine testing. The majority (90%) of incident infections in Thailand are genetic subtype E, with a small percentage of subtype B infections in the intravenous drug user populations. We have evaluated and compared the binding and HIV-1 neutralizing properties of serum antibodies induced in baboons by CHO cell-expressed monomeric gp120 derived from a CCR5-using (R5) subtype E primary HIV-1CM235 or a CXCR4-using (X4) subtype B T-cell line-adapted (TCLA) HIV-1SF2 isolate. In contrast to the subtype-specific HIV-1 neutralizing antibodies induced with recombinant HIV-1SF2 gp120 (rgp120SF2), rgp120CM235 immunization induced antibodies capable of neutralizing both subtype E and subtype B TCLA HIV-1 isolates. However, neither immunogen induced antibodies capable of neutralizing primary HIV-1 isolates. Antibody induced by rgp120CM235 preferentially bound natively folded gp120 and retained strong cross-reactivity against multiple gp120 strains within subtype E as well as subtype B. In contrast, antibody responses to rgp120SF2 were directed predominantly to linear epitopes poorly exposed on native gp120 and had more limited cross-recognition of divergent gp120. Fine epitope mapping revealed differences in antibody specificities. While both rgp120CM235 and rgp120SF2 induced antibodies to regions within C1, V1/V2, V3, and C5, unique responses were induced by rgp120CM235 to multiple epitopes within C2 and by rgp120SF2 to multiple epitopes within C3, V4, and C4. These data demonstrate that strain and/or phenotypic differences of HIV-1 subunit gp120 immunogens can substantially alter antibody binding specificities and subsequent HIV-1 neutralizing capacity.
Evaluation of Long-term Survival After Hepatic Resection for Metastatic Colorectal Cancer: A Multifactorial Model of 929 Patients

Objective:To identify risk factors associated with cancer-specific survival and develop a predictive model for patients undergoing primary hepatic resection for metastatic colorectal cancer. Background:No published studies investigated collectively the inter-relation of factors related to patient cancer-specific survival after hepatectomy for metastatic colorectal cancer. Methods:Clinical, pathologic, and complete follow-up data were prospectively collected from 929 consecutive patients undergoing primary (n = 925) or repeat hepatic resection (n = 80) for colorectal liver metastases at a tertiary referral center from 1987 to 2005. Parametric survival analysis was used to identify predictors of cancer-specific survival and develop a predictive model. The model was validated using measures of discrimination and calibration. Results:Postoperative mortality and morbidity were 1.5% and 25.9%, respectively. 5-year and 10-year cancer-specific survival were 36% and 23%. On multivariate analysis, 7 risk factors were found to be independent predictors of poor survival: number of hepatic metastases >3, node positive primary, poorly differentiated primary, extrahepatic disease, tumor diameter ≥5 cm, carcinoembyonic antigen level >60 ng/mL, and positive resection margin. The first 6 of these criteria were used in a preoperative scoring system and the last 6 in the postoperative setting. Patients with the worst postoperative prognostic criteria had an expected median cancer-specific survival of 0.7 years and a 5-year cancer-specific survival of 2%. Conversely, patients with the best prognostic postoperative criteria had an expected median cancer-specific survival of 7.4 years and a 5-year cancer-specific survival of 64%. When tested both predictive models fitted the data well with no significant differences between observed and predicted outcomes (P > 0.05). Conclusion:Resection of liver metastases provides good long-term cancer-specific survival benefit, which can be quantified pre- or postoperatively using the criteria described. The “Basingstoke Predictive Index” may be used for risk-stratifying patients who may benefit from intensive surveillance and selection for adjuvant therapy and trials.
Immunotherapy for prostate cancer: False promises or true hope?

Prostate cancer is the most commonly diagnosed cancer, and the second leading cause of cancer‐related death for men in the United States. Despite the approval of several new agents for advanced disease, each of these has prolonged survival by only a few months. Consequently, new therapies are sorely needed. For other cancer types, immunotherapy has demonstrated dramatic and durable treatment responses, causing many to hope that immunotherapies might provide an ideal treatment approach for patients with advanced prostate cancer. However, apart from sipuleucel‐T, prostate cancer has been conspicuously absent from the list of malignancies for which immunotherapies have received recent approval from the US Food and Drug Administration. This has left some wondering whether immunotherapy will “work” for this disease. In this review, the authors describe current developments in immunotherapy, including approaches to engage tumor‐targeting T cells, disrupt immune regulation, and alter the immunosuppressive tumor microenvironment. The authors then describe the recent application of these approaches to the treatment of prostate cancer. Given the Food and Drug Administration approval of 1 agent, and the finding that several others are in advanced stages of clinical testing, the authors believe that immunotherapies offer real hope to improve patient outcomes for men with prostate cancer, especially as investigators begin to explore rational combinations of immunotherapies and combine these therapies with other conventional therapies. Cancer 2016;122:3598‐607. © 2016 American Cancer Society.
Biomechanical Responses of Thigh and Lower Leg During 10 Consecutive Soccer Instep Kicks

Amiri-Khorasani, M, Abu Osman, NA, and Yusof, A. Biomechanical responses of thigh and lower leg during 10 consecutive soccer instep kicks. J Strength Cond Res 25(4): 1177-1181, 2011-This study investigated the number of trials necessary to obtain optimal biomechanical responses in 10 consecutive soccer instep kicks. The kicking motions of dominant legs were captured from 5 experienced and skilled adult male soccer players (height: 184.60 ± 4.49 cm; mass: 80 ± 4.24 kg; and age: 25.60 ± 1.14 years) using a 3D infrared high-speed camera at 200 Hz. Some of the important kinematics and kinetics parameters are maximum thigh angular velocity, maximum lower leg angular velocity, maximum of thigh moment, maximum lower leg moment at forward and impact phases, and finally maximum ball velocity after impact selected to be analyzed. There was a significant decrease of ball velocity between the first and the fifth kick and the subsequent kicks. Similarly, the lower leg angular velocity showed a significant decrease after the fifth kick and thereafter. Compared with the first kick, the thigh angular velocity has been shown to decrease after the sixth kick and thereafter, and the thigh moment result of the sixth kick was significantly lower when compared with the first kick. Moreover, the lower leg moment result of the fourth kick was significantly lower in comparison with the first kick. In conclusion, it seems that 5 consecutive kicks are adequate to achieve high kinematics and kinetics responses and selecting more than 5 kicks does not result in any high biomechanical responses for analysis.
Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors.

The incidence of postengraftment invasive aspergillosis (IA) in hematopoietic stem cell transplant (HSCT) recipients increased during the 1990s. We determined risks for IA and outcomes among 1682 patients who received HSCTs between January 1993 and December 1998. Risk factors included host variables (age, underlying disease), transplant variables (stem cell source), and late complications (acute and chronic graft-versus-host disease [GVHD], receipt of corticosteroids, secondary neutropenia, cytomegalovirus [CMV] disease, and respiratory virus infection). We identified risk factors associated with IA early after transplantation (<or= 40 days) and after engraftment (41-180 days). Older patient age was associated with an increased risk during both periods. Chronic myelogenous leukemia (CML) in chronic phase was associated with low risk for early IA compared with other hematologic malignancies, aplastic anemia, and myelodysplastic syndrome. Multiple myeloma was associated with an increased risk for postengraftment IA. Use of human leukocyte antigen (HLA)-matched related (MR) peripheral blood stem cells conferred protection against early IA compared with use of MR bone marrow, but use of cord blood increased the risk of IA early after transplantation. Factors that increased risks for IA after engraftment included receipt of T cell-depleted or CD34-selected stem cell products, receipt of corticosteroids, neutropenia, lymphopenia, GVHD, CMV disease, and respiratory virus infections. Very late IA (> 6 months after transplantation) was associated with chronic GVHD and CMV disease. These results emphasize the postengraftment timing of IA; risk factor analyses verify previously recognized risk factors (GVHD, receipt of corticosteroids, and neutropenia) and uncover the roles of lymphopenia and viral infections in increasing the incidence of postengraftment IA in the 1990s.