Miracle-dz/UniFAR-FTUs huggingface dataset:
Permissiveness of Human Cancer Cells to Oncolytic Bovine Herpesvirus 1 Is Mediated in Part by KRAS Activity

ABSTRACT Oncolytic viruses (OVs) are attractive avenues of cancer therapy due to the absence of toxic side effects often seen with current treatment modalities. Bovine herpesvirus 1 (BHV-1) is a species-specific virus that does not induce cytotoxicity in normal primary human cells but can infect and kill various human immortalized and transformed cell lines. To gain a better understanding of the oncolytic breadth of BHV-1, the NCI panel of established human tumor cell lines was screened for sensitivity to the virus. Overall, 72% of the panel is permissive to BHV-1 infection, with corresponding decreases in cellular viability. This sensitivity is in comparison to a sensitivity of only 32% for a herpes simplex virus 1 (HSV-1)-based oncolytic vector. Strikingly, while 35% of the panel supports minimal or no BHV-1 replication, significant decreases in cellular viability still occur. These data suggest that BHV-1 is an OV with tropism for multiple tumor types and is able to induce cytotoxicity independent of significant virus replication. In contrast to other species-specific OVs, cellular sensitivity to BHV-1 does not correlate with type I interferon (IFN) signaling; however, mutations in KRAS were found to correlate with high levels of virus replication. The knockdown or overexpression of KRAS in human tumor cell lines yields modest changes in viral titers; however, overexpression of KRAS in normal primary cells elicits permissivity to BHV-1 infection. Together, these data suggest that BHV-1 is a broad-spectrum OV with a distinct mechanism of tumor targeting. IMPORTANCE Cancer remains a significant health issue, and novel treatments are required, particularly for tumors that are refractory to conventional therapies. Oncolytic viruses are a novel platform given their ability to specifically target tumor cells while leaving healthy cells intact. For this strategy to be successful, a fundamental understanding of virus-host interactions is required. We previously identified bovine herpesvirus 1 as a novel oncolytic virus with many unique and clinically relevant features. Here, we show that BHV-1 can target a wide range of human cancer types, most potently lung cancer. In addition, we show that enhanced KRAS activity, a hallmark of many cancers, is one of the factors that increases BHV-1 oncolytic capacity. These findings hold potential for future treatments, particularly in the context of lung cancer, where KRAS mutations are a negative predictor of treatment efficacy.
Radiofrequency ablation versus nephron-sparing surgery for small unilateral renal cell carcinoma: cost-effectiveness analysis.

PURPOSE To evaluate the relative cost-effectiveness of percutaneous radiofrequency (RF) ablation versus nephron-sparing surgery (NSS) in patients with small (<or=4-cm) renal cell carcinoma (RCC), given a commonly accepted level of societal willingness to pay. MATERIALS AND METHODS A decision-analytic Markov model was developed to estimate life expectancy and lifetime costs for 65-year-old patients with a small RCC treated with RF ablation or NSS. The model incorporated RCC presence, treatment effectiveness and costs, and short- and long-term outcomes. An incremental cost-effectiveness analysis was performed to identify treatment preference under an assumed $75,000 per quality-adjusted life-year (QALY) societal willingness-to-pay threshold level, within proposed ranges for guiding implementation of new health care interventions. The effect of changes in key parameters on strategy preference was addressed in sensitivity analysis. RESULTS By using base-case assumptions, NSS yielded a minimally greater average quality-adjusted life expectancy than did RF ablation (2.5 days) but was more expensive. NSS had an incremental cost-effectiveness ratio of $1,152,529 per QALY relative to RF ablation, greatly exceeding $75,000 per QALY. Therefore, RF ablation was considered preferred and remained so if the annual probability of post-RF ablation local recurrence was up to 48% higher relative to that post-NSS. NSS preference required an estimated NSS cost reduction of $7500 or RF ablation cost increase of $6229. Results were robust to changes in most model parameters, but treatment preference was dependent on the relative probabilities of local recurrence after RF ablation and NSS, the short-term costs of both, and quality of life after NSS. CONCLUSION RF ablation was preferred over NSS for small RCC treatment at a societal willingness-to-pay threshold level of $75,000 per QALY. This result was robust to changes in most model parameters, but somewhat dependent on the relative probabilities of post-RF ablation and post-NSS local recurrence, NSS and RF ablation short-term costs, and post-NSS quality of life, factors which merit further primary investigation.
In situ population structure and ex situ representation of the endangered Amur tiger

The Amur tiger (Panthera tigris altaica) is a critically endangered felid that suffered a severe demographic contraction in the 1940s. In this study, we sampled 95 individuals collected throughout their native range to investigate questions relative to population genetic structure and demographic history. Additionally, we sampled targeted individuals from the North American ex situ population to assess the genetic representation found in captivity. Population genetic and Bayesian structure analyses clearly identified two populations separated by a development corridor in Russia. Despite their well‐documented 20th century decline, we failed to find evidence of a recent population bottleneck, although genetic signatures of a historical contraction were detected. This disparity in signal may be due to several reasons, including historical paucity in population genetic variation associated with postglacial colonization and potential gene flow from a now extirpated Chinese population. Despite conflicting signatures of a bottleneck, our estimates of effective population size (Ne = 27–35) and Ne/N ratio (0.07–0.054) were substantially lower than the only other values reported for a wild tiger population. Lastly, the extent and distribution of genetic variation in captive and wild populations were similar, yet gene variants persisted ex situ that were lost in situ. Overall, our results indicate the need to secure ecological connectivity between the two Russian populations to minimize loss of genetic diversity and overall susceptibility to stochastic events, and support a previous study suggesting that the captive population may be a reservoir of gene variants lost in situ.
Exon 5 Polymorphisms in the O6-Alkylguanine DNA Alkyltransferase Gene and Lung Cancer Risk in Non–Smokers Exposed to Second-Hand Smoke

Purpose: The objective of the study was to examine the association of three exon 5 variants in the O6-alkylguanine DNA alkyltransferase (AGT) gene involved in the repair of the mutagenic DNA lesion O6-alkylguanine formed by nitrosamines, with lung cancer risk in never-smokers. Experimental Design: Exon 5 of the AGT gene was sequenced in genomic DNA from 136 cases and 133 hospital- or population-based controls for whom questionnaire information on second-hand smoke and diet was available to determine the frequencies of the Gly160Arg, Ile143Val, and Lys178Arg variant alleles. Results: No codon 160Arg variant alleles were found in the study population. The codon 143Val and 178Arg variant alleles, present at allele frequencies of 0.07, showed 100% linkage. The odds ratio (OR) of lung cancer for these variant carriers was 2.05 [95% confidence interval (CI) 1.03–4.07]. The risk varied between the different lung cancer pathologies with an increased risk for adenocarcinoma (OR 2.67, 95% CI 1.21–5.87) or small cell carcinoma (OR 4.83, 95% CI 0.91–25.7) but not for squamous cell carcinoma (OR 1.07, 95% CI 0.27–4.18). Compared with individuals carrying the mutant alleles unexposed to second-hand smoke, the OR for exposed variant carriers was 1.95 (95% CI 0.53–1.15); a similar interaction, although not significative, was observed for low consumption of cruciferous vegetables and for green vegetables and tomatoes. Conclusions: These results point toward a role of AGT polymorphisms in lung cancer susceptibility among never-smokers, in particular among subjects exposed to environmental carcinogens.
Expression of Perineuronal Nets, Parvalbumin and Protein Tyrosine Phosphatase σ in the Rat Visual Cortex During Development and After BFD

Abstract Purpose of the Study: Protein tyrosine phosphatase σ (PTPσ) acts as a neuronal receptor for chondroitin sulfate proteoglycans (CSPGs). CSPGs have inhibitory effects on experience-dependent plasticity and usually form lattice-like cell coatings that surround the parvalbumin (PV) interneurons in the visual cortex (VC). We investigated developmental changes and the effect of binocular form deprivation (BFD) on PTPσ, perineuronal nets (PNNs) and their tempo-spatial relationships with PV neurons in the VC. Materials and Methods: Double-immunostaining was used to observe the coexpression pattern of PNNs staining by biotinylated wisteria floribunda lectin (WFA) with PV neurons. The expression of PTPσ in the VC of Long Evans rats was detected by real-time quantitative PCR, immunohistochemistry and western blots. The changes in the number of PV/WFA/PTPσ labeled cells in layer IV of the VC and its proportion of PV neurons were examined during development and after BFD. Results: The expression of PV neurons wrapped by PNNs was increased, particularly in the first half of the critical period, and the ratio for PV neurons reached the highest level (over 75%) at adulthood, indicating that PNNs may play an important role in the maturation of PV neurons during the critical period. BFD decreased the density of PNNs and the percentage of PV neurons with PNNs. This result suggests that the number of PNNs surrounding PV neurons may be experience-dependent. Meanwhile, the CSPG receptor PTPσ was maintained at its lowest level during the critical period and could be modulated by BFD after the critical period. The percentage of PV/WFA/PTPσ-positive cells in PV population increased during development and reached its highest ratio at adulthood, which could also be reversed by BFD. Conclusions: The changes in the coexpression of PNNs, PV and PTPσ provide valuable insights into the connection between CSPGs and PV neurons.
Transmission electron microscopy analysis for the process of crystallization of Cu 2 ZnSnS 4 ?> film from sputtered Zn/CuSn precursor

The mechanism of crystallization of Cu 2 ZnSnS 4 ? > (CZTS) made by the sulfurization of a sputtered Zn/CuSn stack was studied by transmission electron microscopy. At 250 ° C ? > , the Zn buried at the bottom of the metallic stack was found to be driven to the upper layer by alloying with Cu and reacting with S to form ZnS. At 500 ° C ? > , CZTS was found to be formed and elemental Sn was observed in the vicinity of the back contact region, while large quantities of Cu 2 S ? > and ZnS were segregated at the film surface. At 575 ° C ? > , Cu 2 SnS 3 ? > was found, while all the elemental Sn had vanished. Upon extending the duration of the annealing to 10 min, at 575 ° C ? > , all the secondary phases except ZnS were consumed and the CZTS formation was completed, while around 200 nm of MoS 2 ? > was formed between the CZTS layer and Mo back contact. The finished solar cell exhibits an efficiency of 2.66%, an open-circuit voltage of 666.9 mV and a short-circuit current density of 9.14 mA cm − 2 ? > . The solar cell performance is possibly limited by the thick MoS 2 ? > layer and the large density of voids in the back contact region due to the Sn loss at high sulfurization temperatures.
Mania and Stroke: A Systematic Review

Background: Mania is a rare consequence of stroke and according to the sparse published information it is difficult to describe its demographic, clinical and prognostic characteristics. Methods: We performed a systematic review of all cases of mania and stroke to describe those characteristics. Studies were identified from comprehensive searches of electronic databases, reference lists of the studies collected and handbooks. Two authors independently assessed abstracts, and collected and extracted data. Results: From 265 abstracts, 139 were potentially relevant. For the first analysis, which tries to answer the clinical question of the relationship between mania and stroke, 49 studies met the inclusion criteria and described 74 cases. For the second analysis, we looked for an explicit temporal and causal relationship between manic symptoms and stroke, and selected 32 studies describing 49 cases. In both analyses, the typical patient was male, without a personal or family history of psychiatric disorder, with at least one vascular risk factor, but without subcortical atrophy and had suffered a right cerebral infarct. The majority of patients (92%) presented elevated mood as the first symptom. The other frequent symptoms were an increased rate or amount of speech (71%), insomnia (69%) and agitation (63%). Conclusions: Post-stroke mania should be considered in any manic patient who presents concomitant neurological focal deficits and is older than expected for the onset of primary mania. The results of a systematic study of mania in acute stroke with subsequent follow-up and data from diffusion MR or perfusion CT in a multicenter study with a central database would be relevant.
Crash course in EPaCCS (Electronic Palliative Care Coordination Systems): 8 years of successes and failures in patient data sharing to learn from

Background Electronic Palliative Care Coordination Systems (EPaCCS) are England's pre-eminent initiative in enabling advance care planning and improved communication and coordination at the end of life. EPaCCS have been under development for 8 years after being proposed, as Locality Registers, in the 2008 End of Life Care Strategy for England. EPaCCS are electronic registers or tools and processes for sharing data which aim to enable access to information about dying patients. Striking outcomes have been reported around EPaCCS, such as 77.8% of ‘Coordinate My Care’ patients dying in their preferred place. EPaCCS have, however, been extremely challenging to develop and implement, with many projects remaining continuously ‘under development’ or folding. They also continue to be suboptimally integrated with other data sharing initiatives. Rigorous research is non-existent. Discussion points We discuss the current EPaCCS landscape and way forward. We summarise key facts concerning the availability, uptake, outcomes and costs of EPaCCS. We outline 5 key challenges (scope of projects, unrealistic expectations set by existing guidance, the discrepancy between IT realities in healthcare and our broader lives, information governance and ‘death register’ associations) and 6 key drivers (robust concept, striking outcomes, national support and strong clinical leadership, clinician commitment, education and funding). Conclusions The priorities for advancing EPaCCS we propose include linking to other work streams and reframing the concept, potentially making it less ‘end of life’, overview of current EPaCCS and lessons learnt, continuing work on information standards, rethinking of national funding and new levels of individual and community involvement.
Gender dimorphic formation of Mallory‐Denk bodies and the role of xenobiotic metabolism and oxidative stress

Mallory‐Denk bodies (MDBs) are hepatocyte cytoplasmic inclusions associated with alcoholic steatohepatitis. Understanding the significance of MDBs and devising ways of manipulating their formation has clinical relevance to protein aggregation diseases beyond liver. Current appreciation of MDBs comes from established models whereby feeding mice the porphyrinogenic compound 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) induces inclusions resembling human MDBs. Given the significant gender differences in predisposition to liver injury, we hypothesized that gender is an important factor in MDB formation. Male DDC‐fed mice formed significantly more MDBs, which correlated with hepatocyte apoptosis, fat globules and lipid peroxidation. Female mice had significantly less MDBs and oxidative stress, but elevated ductular reaction and protoporphyrin‐IX accumulation. There were significant gender differences in the expression and activity of cytochrome‐P450 (CYP) enzymes before and after DDC treatment, resulting in differences in formation of a CYP3A‐derived DDC metabolite, which may contribute to oxidative stress. The data provide a mechanistic explanation for the gender dimorphic formation of MDBs and aid in understanding how inter‐individual differences in microsomal metabolism may alter susceptibility to diseases underlying protein aggregation. Support: DK52951 and UL1RR024986.
Accounting for Interim Safety Monitoring of an Adverse Event Upon Termination of a Clinical Trial

Upon termination of a clinical trial that uses interim evaluations to determine whether the trial can be stopped, a proper statistical analysis must account for the interim evaluations. For example, in a group-sequential design where the efficacy of a treatment regimen is evaluated at interim stages, and the opportunity to stop the trial based on positive efficacy findings exists, the terminal p-value, point estimate, and confidence limits of the outcome of interest must be adjusted to eliminate bias. While it is standard practice to adjust terminal statistical analyses due to opportunities to stop for “positive” findings, adjusting due to opportunities to stop for “negative” findings is also important. Stopping rules for negative findings are particularly useful when monitoring a specific rare serious adverse event in trials designed to show safety with respect to the event. In these settings, establishing conservative stopping rules are appropriate, and therefore accounting for the interim monitoring can have a substantial effect on the final results. Here I present a method to account for interim safety monitoring and illustrate its usefulness. The method is demonstrated to have advantages over methodology that does not account for interim monitoring.
Serum Albumin, Body Weight and Inflammatory Parameters in Chronic Hemodialysis Patients: A Three-Year Longitudinal Study

Backgrounds and Aims: The present study aimed at making prospective longitudinal measurements of nutritional and inflammatory parameters to determine whether nutritional and inflammatory status decline or increase over time in a cohort of prevalent hemodialysis patients, and to evaluate which factors influence eventual changes. Patients: 64 hemodialysis patients were followed at 0, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, and 36 months. At each follow-up visit, dry body weight, serum albumin, serum total cholesterol, total white blood cells, total lymphocyte count, serum glucose, C-reactive protein, ferritin, fibrinogen, hemoglobin, and weekly erythropoietin dose were assessed. Main Outcome Measures: Changes in nutritional and inflammatory parameters over time. Results: 43 patients completed the study at 36 months. Mean serum albumin levels (g/dl) improved significantly between baseline (3.76 ± 0.24) and 36 months (3.93 ± 0.27) (F = 4.005; p = 0.0009). Dialytic age was significantly associated with changes of serum albumin (F = 2.797; p = 0.028). The mean dry weight slightly remained stable over time (F = 1.473; p = 1.0) as well as the level of total cholesterol (p = 0.77) and lymphocyte count (F = 1.539; p = 0.186). Over time, the levels of C-reactive protein tended to decrease, although the differences were not statistically significant (F = 1.332; p = 0.19). Over time, the serum level of fibrinogen (F = 0.422; p = 0.17) and ferritin (F = 0.314; p = 0.52) remained stable. The number of white blood cells significantly decreased over time (F = 4.691; p = 0.0079) and dialytic age (F = 3.214; p = 0.015) was the variable significantly associated with such decline. The hemoglobin levels (F = 1.423; p = 0.14) and the weekly erythropoietin dose did not change significantly during the study (F = 1.019; p = 0.61), nor did the serum glucose levels (F = 1.231; p = 0.10). Conclusion: These results support the hypothesis that end-stage renal disease and HD are not necessarily associated with deterioration of the nutritional status over time.
Platelet Rich Plasma Injection Compared To Corticosteroid Injection in the Treatment of Chronic Plantar Fasciitis

To Compare The Efficacy Of Patients Treated With Platelet Rich Plasma Vs Corticosteroid Injection In Chronic Plantar Fasciitis. This is a prospective cohort study and a total of 110 patients were studied. They were divided into group-A(PRP injection) and group-B(Corticosteroid injection). All patients were diagnosed as plantar fasciitis by clinical and radiological evaluation. Group-A(60 patients) were given PRP injection and Group-B(50 patients) were given Corticosteroid injection. 6 cases lost in follow up were excluded from the study. Patients were assessed functionally using VAS and FAOS scores and radiologically by Ultrasound of the foot and X-ray lateral view of the foot. The PRP and Corticosteroid injection groups at the initial visit had VAS of 6.85 and 6.95 respectively which was reduced to 1.80 and 2.82 at the end of 6 months. The PRP and Corticosteroid injection groups at the initial visit had FAOS of 32.8 and 34.1 respectively which increased to 86.93 and 81.18 at the end of 6 months. On sonographic evaluation the plantar fascia thickness in PRP and Corticosteroid group are at the same baseline prior to injection. After injection the PRP group had significant reduction(36.45%) in the thickness of plantar fascia as compared to Corticosteroid group(28.33%). Chronic heel pain is a difficult condition to treat and takes a long time to resolve. Our study has shown that local Corticosteroid injection is effective for immediate pain relief which may last upto 3months. We have established the efficacy of our method of extracting PRP from peripheral blood by low spin technique. Our study has shown that PRP injection is effective long term treatment for chronic heel pain with no side effects. Further study needs to be done to see the effects of combined Corticosteroid and PRP injection for chronic heel pain.
Acute physiological response to aerobic short-interval training in trained runners.

PURPOSE To analyze the acute physiological response to aerobic short-interval training (AESIT) at various high-intensity running speeds. A minor anaerobic glycolytic energy supply was aimed to mimic the characteristics of slow continuous runs. METHODS Eight trained male runners (maximal oxygen uptake [VO(2max)] 55.5 ± 3.3 mL · kg(-1) · min(-1)) performed an incremental treadmill exercise test (increments: 0.75 km · h(-1)· min(-1)). Two lactate turn points (LTP1, LTP2) were determined. Subsequently, 3 randomly assigned AESIT sessions with high-intensity running-speed intervals were performed at speeds close to the speed (v) at VO(2max) (vVO(2max)) to create mean intensities of 50%, 55%, and 60% of vLTP1. AESIT sessions lasted 30 min and consisted of 10-s work phases, alternated by 20-s passive recovery phases. RESULTS To produce mean velocities of 50%, 55%, and 60% of vLTP1, running speeds were calculated as 18.6 ± 0.7 km/h (93.4% vVO(2max)), 20.2 ± 0.6 km/h (101.9% vVO(2max)), and 22.3 ± 0.7 km/h (111.0% vVO(2max)), which gave a mean blood lactate concentration (La) of 1.09 ± 0.31 mmol/L, 1.57 ± 0.52 mmol/L, and 2.09 ± 0.99 mmol/L, respectively. La at 50% of vLTP1 was not significantly different from La at vLTP1 (P = .8894). Mean VO(2) was found at 54.0%, 58.5%, and 64.0% of VO(2max), while at the end of the sessions VO(2) rose to 71.1%, 80.4%, and 85.6% of VO(2max), respectively. CONCLUSION The results showed that AESIT with 10-s work phases alternating with 20 s of passive rest and a running speed close to vVO(2max) gave a systemic aerobic metabolic profile similar to slow continuous runs.