Miracle-dz/UniFAR-FTUs huggingface dataset:
Small molecule c-Met kinase inhibitors: a review of recent patents

Importance of the field: c-Met kinase is the receptor for hepatocyte growth factor. Primarily expressed on epithelial and mesenchymal cells its normal function is associated with wound healing, liver regeneration and embryo development. However, dysregulation of c-Met through overexpression, gene amplification, mutation or a ligand-dependent autocrine/paracrine loop is associated with tumorigenesis. c-Met dysregulation in human cancer patients is typically associated with a poor prognosis, aggressive disease, increased metastasis and shortened patient survival. Targeting the hepatocyte growth factor/c-Met signalling pathway as a means of cancer therapy has, therefore, become increasingly popular with a number of different therapeutic approaches undergoing clinical trials. Areas covered by this review: This review covers the patent applications for small molecule c-Met kinase inhibitors since 2007, attempts to place them in context from a structural point of view and examines their potential applications in cancer therapy. What the reader will gain: Readers will gain an overview of the structural types of c-Met inhibitors, the major players in the field and an insight into what is progressing into the clinic. Take home message: This area is developing rapidly and the results of the various ongoing clinical trials will generate an increased understanding of the potential benefits and pitfalls of c-Met inhibitors as therapeutic agents.
Impact of Wind Forecast Error Statistics Upon Unit Commitment

Driven by a trend towards renewable forms of generation, in particular wind, the nature of power system operation is changing. Systems with high wind penetrations should be capable of managing the uncertainty contained within the wind power forecasts. Stochastic unit commitment with rolling planning and input scenarios, based on wind forecasts, is one way of achieving this. Here, a scenario tree tool is developed which allows forecast error statistics to be altered and facilitates the study of how these statistics impact on unit commitment and system operation. It is shown that the largest individual impact on system operation is from the inclusion of variance and that variance, kurtosis, and skewness together produced the error information with the lowest system cost. Similar impacts for inaccurate error statistics are observed but generalization of these results will need more studies on a range of test systems.
Outperforming Benchmarks with Their Derivatives: Theory and Empirical Evidence

Recent literature has demonstrated the existence of an unbounded risk premium if one combines the most important models for pricing and hedging derivatives with coherent risk measures. There may exist combinations of derivatives (good deals) whose pair (return risk) converges to the pair (+∞, −∞). This paper goes beyond existence properties and looks for optimal explicit constructions and empirical tests. It will be shown that the optimal good deal above may be a simple portfolio of options. This theoretical finding will enable us to implement empirical experiments involving three international stock index futures (Standard & Poor's 500, Eurostoxx 50 and DAX 30) and three commodity futures (gold, Brent and the Dow Jones-UBS Commodity Index). According to the empirical results, the good deal always outperforms the underlying index/commodity. The good deal is built in full compliance with the standard derivative pricing theory. Properties of classical pricing models totally inspire the good deal construction. This is a very interesting difference in our paper with respect to previous literature attempting to outperform a benchmark.
Engraftment of human kidney tissue in rat radiation chimera: I. A new model of human kidney allograft rejection.

BACKGROUND We have recently shown that lethally irradiated normal strains of mice and rats, reconstituted with bone marrow from severe combined immune deficiency (SCID) mice, can be engrafted with human peripheral blood mononuclear cells (PBMC). METHODS The feasibility of transplanting human renal tissue under the kidney capsule of the SCID/Lewis and SCID/nude radiation chimera and the effects of intraperitoneal infusion of allogeneic human PBMC on the human renal implants were investigated by histology, electron microscopy, immunohistochemistry, and fluorescence-activated cell sorter analysis. RESULTS Sequential evaluation of the human renal implants from 10 days to 2 months after transplantation showed that human parenchymal elements survive in the implants up to 2 months after transplantation. The overall architecture of the transplanted kidney tissue and the normal structure of individual cells in the glomeruli and tubuli were preserved. Infusion of allogeneic human PBMC after kidney implantation resulted in patchy cellular infiltrates, composed mainly of activated human T cells, and led to prompt rejection of the human renal tissue, whereas no signs of inflammation were observed in human renal implants of chimeric rats that did not receive human PBMC. Treatment with OKT3 antibody, anti-human CD25 antibody, or CTLA4Ig fusion protein in vivo ameliorated the rejection process. CONCLUSIONS Human adult kidney fragments transplanted into SCID-like rats transiently retain competent parenchymal structures. When these grafts are combined with allogeneic human PBMC, acute cellular rejection develops. We suggest that this chimeric model might be useful for the investigation of the effects of experimental manipulation on the kinetics of the inflammatory response during human renal allograft rejection.
Bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a fixed-combination syrup versus an oral reference product

Objectives The primary objective of this study was to compare the bioavailability of paracetamol, phenylephrine hydrochoride and guaifenesin in a new oral syrup with an established oral reference product. The secondary objective was to compare the safety of the new syrup and the reference product. Methods This was a single-centre, open-label, randomized, reference-replicated, crossover study. Healthy adult volunteers received one dose of syrup and two separate doses of a reference oral liquid formulation in a randomized sequence over three study periods, with a washout interval of ≥7 days between study periods. Blood samples were taken regularly postdose and analysed for paracetamol, phenylephrine hydrochoride and guaifenesin concentrations; adverse events were recorded. Results This study enrolled 45 subjects. For paracetamol and guaifenesin, the syrup and reference product were considered to be bioequivalent. Bioequivalence was not shown for phenylephrine hydrochoride. All adverse events were mild or moderate, most of which were considered formulation related. Conclusions The syrup did not reach bioequivalence with the reference product, as bioequivalence could not be shown for phenylephrine hydrochoride. This may be due to differences in the excipients between the two products. Both the syrup and the reference product had a good safety profile and were well tolerated.
Hematopoietic Stem Cell Transplantation: A Bioethical Lens

Hematopoietic stem cell transplantation (HSCT) is one of a range of therapeutic options available to patients suffering from various diseases. HSCT procedure involves important ethical and legal aspects that can occur at every phase of the procedure: the clinical choice of whether to perform the procedure, pretransplantation preparation regimens, donor selection, stem cell harvest procedure, transplantation phase, and short-term and long-term follow-up care. In this discussion paper, we outline the ethical issue-facing physicians involved in HSCT. Currently, HSCT is a widely accepted treatment for many life-threatening diseases. It thus represents a real therapeutic hope for many patients. It does, however, carry a burden of possible morbidity and mortality. Consequently, there are substantial information and communication issues involved in the consent process for HSCT. In the final decision, the judgements of different parties, such as patients, family members, and healthcare professionals, intersect and overlap and this is particularly true when the patient is a minor. Finally, HSCT is a very expensive procedure. The social and economic concerns of HSCT are discussed within the actual contextual framework of the dramatic increase in healthcare costs and inequalities in healthcare in relation to socioeconomic status, educational status, and ethnicity.
Fetal Growth, Preterm Birth, Neonatal Stress and Risk for CNS Tumors in Children: A Nordic Population- and Register-Based Case-Control Study

Background: The peak incidence of central nervous system (CNS) tumors in childhood indicates that intrauterine or neonatal characteristics are potential risk factors or symptoms of early onset of disease. Methods: We conducted a registry-based case-control study nested in the childhood populations of Denmark, Finland, Sweden, and Norway on the association between indicators of fetal growth and neonatal stress and childhood CNS tumor risk diagnosed during the period 1985-2006. Each of the 3,443 cases was matched individually on date of birth, sex, and country to five controls sampled randomly from population registries. Information on birth characteristics was obtained from national birth registries. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) by conditional logistic regression analyses. Results: We observed a U-shaped relation between risk for CNS tumors and birthweight, at >4.5 kg (OR, 1.27; 95% CI, 1.03-1.55) and <2.0 kg (OR, 1.50; 95% CI, 1.13-1.99), the latter being attenuated after adjustment for gestational age. Moreover, small-for-gestational age (OR, 1.28; 95% CI, 0.98-1.66) and large-for-gestational age (OR, 1.26; 95% CI, 1.02-1.55) were both associated with CNS tumors. The OR for preterm births was increased per 1-week decrease in gestational age (OR, 1.58; 95% CI, 1.04-2.44). Increased ORs were also observed for head circumference >38 cm (1.80; 95% CI, 1.18-2.74), 5-minute Apgar score <7 (1.44; 95% CI, 0.98-2.12), and breech presentation (1.33; 95% CI, 1.04-1.69). The observed associations varied little by histologic subgroup. Conclusions: This study supports intrauterine or neonatal onset of childhood CNS tumors. The findings provide insight into the natural history of childhood CNS tumors indicating an early onset or, alternatively, potentially harmful exposures in the neonatal period that might be preventable. Cancer Epidemiol Biomarkers Prev; 19(4); 1042–52. ©2010 AACR.
Outcome of hepatectomy in hepatocellular carcinoma patients aged 80 years and older.

BACKGROUND/AIMS The aim of this retrospective study was to determine the effect of age on the outcome of hepatic resection in octogenarian patients with hepatocellular carcinoma (HCC). METHODOLOGY Data of 408 consecutive primary HCC patients who underwent curative hepatectomy were studied. The surgical results of the younger group (<80 years of age) and the elderly group (≥80 years of age) were compared. RESULTS Preoperative parameters, such as comorbid conditions and liver function tests, of the younger group (n=385) were comparable with those of the elderly group (n=23). Surgical data and the prevalence of postoperative complications did not differ significantly between the two groups. The long-term prognosis of the elderly group patients was almost identical to that of the younger group patients. Overall 3-year survival rates for the elderly group and the younger group were 95.7% vs. 84.8%, respectively (p=0.56). Disease-free three-year survival rates for the elderly group and the younger group were 47.2% vs. 47.7%, respectively (p=0.65). CONCLUSIONS Hepatectomy is a viable treatment alternative with satisfactory surgical outcome for HCC even in patients aged 80 years or older.
PATTERN OF ASSAULT-RELATED MAXILLOFACIAL INJURIES TREATED AT THE GENERAL HOSPITAL, LAGOS, NIGERIA.

BACKGROUND The human face often constitutes the first point of contact in various human interactions and it is frequently the preferred target for blows in assault cases. AIM To analyze the pattern of assault-related maxillofacial injuries treated at the General Hospital, Lagos over a period of one year. METHODOLOGY This is one year prospective study of assault-related maxillofacial injuries treated at the Department of Oral-Maxillofacial Surgery, Dental Centre, General Hospital, Lagos, Nigeria. A face-to-face interviewer-administered structured proforma was used to obtain information from study subjects. RESULTS Thirty-three patients with maxillofacial injuries met the inclusion criteria for this study. Their age ranged between 16 and 48 years with a mean age of 28.2 ± 7.4 years. There were 25(75.8%) males and 8(24.2%) females with a male/female ratio of 3:1. Majority of the patients, 24(72.7%) did not have any skilled employment while the remaining 9(27.3%) were road transport workers, specifically commercial bus drivers and motorcycle riders. The most frequently seen soft tissue injury was contusion which accounted for 17(51.5%) cases while 13 (39%) of the patients sustained mandibular fracture which was the most common hard tissue injury. CONCLUSION Assault-related maxillofacial injuries are most common amongst young adult males who are not skillfully employed; this can be attributed to the increased disposition to violence in males in our environment.
Laser photostimulation accelerates wound healing in diabetic rats

In this study, we examined the hypothesis that laser photostimulation can facilitate healing of impaired wounds in experimental diabetes using a rat model. Diabetes was induced in male rats by streptozotocin injection and two 6 mm diameter circular wounds were created on either side of the spine. The left wound of each animal was treated with a 632.8nm He:Ne laser at a dose of 1.0J/cm2 for five days a week until the wounds closed (three weeks). Measurements of the biomechanical properties of the laser‐treated wounds indicated there was a marginal increase in maximum load (16%), stress (16%), strain (27%), energy absorption (47%) and toughness (84%) compared to control wounds of diabetic rats. Biochemical assays revealed that the amount of total collagen was significantly increased in laser treated wounds (274 ± 8.7 μg) over the control wounds (230 ± 8.4 μg). Sequential extractions of collagen from healing wounds showed that laser treated wounds had significantly greater concentrations of neutral salt soluble (15%) and insoluble collagen (16%) than control wounds, suggesting accelerated collagen production in laser treated wounds. There was an appreciable decrease in pepsin soluble collagen (19%) in laser treated wounds over control wounds, indicating higher resistance to proteolytic digestion. In conclusion, the biomechanical and biochemical results collectively suggest that laser photostimulation promotes the tissue repair process by accelerating collagen production and promoting overall connective tissue stability in healing wounds of diabetic rats.
Stroke in estrogen receptor-alpha-deficient mice.

BACKGROUND AND PURPOSE Recent evidence suggests that endogenous estrogens or hormone replacement therapy can ameliorate brain damage from experimental stroke. Protective mechanisms involve enhanced cerebral vasodilation during ischemic stress as well as direct preservation of neuronal viability. We hypothesized that if the intracellular estrogen receptor subtype-alpha (ERalpha) is important to estrogen's signaling in the ischemic brain, then ERalpha-deficient (knockout) (ERalphaKO) female mice would sustain exaggerated cerebral infarction damage after middle cerebral artery occlusion. METHODS The histopathology of cresyl violet-stained tissues was evaluated after reversible middle cerebral artery occlusion (2 hours, followed by 22 hours of reperfusion) in ERalphaKO transgenic and wild-type (WT) mice (C57BL/6J background strain). End-ischemic cerebral blood flow mapping was obtained from additional female murine cohorts by using [(14)C]iodoantipyrine autoradiography. RESULTS Total hemispheric tissue damage was not altered by ERalpha deficiency in female mice: 51.9+/-10.6 mm(3) in ERalphaKO versus 60.5+/-5.0 mm(3) in WT. Striatal infarction was equivalent, 12.2+/-1.7 mm(3) in ERalphaKO and 13.4+/-1.0 mm(3) in WT mice, but cortical infarction was paradoxically smaller relative to that of the WT (20.7+/-4.5 mm(3) in ERalphaKO versus 30.6+/-4.1 mm(3) in WT). Intraocclusion blood flow to the parietal cortex was higher in ERalphaKO than in WT mice, likely accounting for the reduced infarction in this anatomic area. There were no differences in stroke outcomes by region or genotype in male animals. CONCLUSIONS Loss of ERalpha does not enhance tissue damage in the female animal, suggesting that estrogen inhibits brain injury by mechanisms that do not depend on activation of this receptor subtype.
Awake tracheal intubation using Pentax airway scope in 30 patients: A Case series

Background and Aims: Pentax airway scope (AWS) has been successfully used for managing difficult intubations. In this case series, we aimed to evaluate the success rate and time taken to complete intubation, when AWS was used for awake tracheal intubation. Methods: We prospectively evaluated the use of AWS for awake tracheal intubation in 30 patients. Indication for awake intubation, intubation time, total time to complete tracheal intubation, laryngoscopic view (Cormack and Lehane grade), total dose of local anaesthetic used, anaesthetists rating and patient′s tolerance of the procedure were recorded. Results: The procedure was successful in 25 out of the 30 patients (83%). The mean (standard deviation) intubation time and total time to complete the tracheal intubation was 5.4 (2.4) and 13.9 (3.7) min, respectively in successful cases. The laryngeal view was grade 1 in 24 and grade 2 in one of 25 successful intubations. In three out of the five patients where the AWS failed, awake tracheal intubation was successfully completed with the assistance of flexible fibre optic scope (FOS). Conclusion: Awake tracheal intubation using AWS was successful in 83% of patients. Success rate can be further improved using a combination of AWS and FOS. Anaesthesiologists who do not routinely use FOS may find AWS easier to use for awake tracheal intubation using an oral route.
Mechanisms of pHi regulation studied in individual neurons cultured from mouse cerebral cortex

Maintenance and regulation of intracellular pH (pHi) was studied in single cultured mouse neocortical neurons using the fluorescent probe 2′,7′‐bis‐(2‐carboxyethyl)‐5,6‐carboxyfluorescein (BCECF). Reversal of the Na+ gradient by reduction of the extracellular Na+ concentration ([Na+]o) resulted in rapid intracellular acidification, inhibited by 5′‐(N‐ethyl‐N‐isopropyl)amiloride (EIPA), an inhibitor of Na+/H+ exchange. In the presence of EIPA and/or 4′,4′‐diisothiocyano‐stilbene‐2′,2′‐sulfonic acid (DIDS), an inhibitor of Na+‐coupled anion exchangers and Na+‐HCO3− cotransport, a slow decline of pHi was seen. Following intracellular acidification imposed by an NH4Cl prepulse, pHi recovered at a rapid rate, which was reduced by reduction of [Na+]o and was virtually abolished by EIPA and DIDS in combination. Creating an outward Cl− gradient by removal of extracellular Cl− significantly increased the rate of pHi recovery. In HCO3−‐free media, the pHi recovery rate was reduced in control cells and was abolished at zero [Na+]o and by EIPA. After intracellular alkalinization imposed by an acetate prepulse, pHi recovery was unaffected by DIDS but was significantly reduced in the absence of extracellular Cl−, as well as in the presence of Zn2+, which is a blocker of proton channels. Together, this points toward a combined role of DIDS‐insensitive Cl−/HCO3− and passive H+ influx in the recovery of pHi after alkalinization. J. Neurosci. Res. 51:431–441, 1998. © 1998 Wiley‐Liss, Inc.
Point-of-care Capillary Blood Lactate Measurements in Human Immunodeficiency Virus–uninfected Children With In Utero Exposure to Human Immunodeficiency Virus and Antiretroviral Medications

Objectives: To estimate the prevalence of elevated point-of-care (POC) capillary blood lactate concentrations in human immunodeficiency virus (HIV)-exposed, uninfected children (HEU) and to determine if POC lactate varies with in utero antiretroviral (ARV) exposure. Methods: The Surveillance Monitoring for Antiretroviral Therapy Toxicities protocol of the Pediatric HIV/AIDS Cohort Study enrolled 1934 children between 2007 and 2009, 0 to 12 years of age, born to HIV-infected mothers. POC lactate was measured annually on capillary blood using the Lactate Pro device. Associations of POC lactate with in utero ARV exposure and other characteristics were evaluated using logistic regression models, adjusting for maternal characteristics and other confounders. Results: Of 1641 children with POC measurements (median age, 3.0 years), 3.4% had POC lactate >3 mmol/L. Median POC lactate level decreased with age (1.9 mmol/L, 1.7 mmol/L, and 1.6 mmol/L for children 0–<6 months [99% ⩽6 weeks of life], 6–<24 months, and ≥24 months of age, respectively; P < 0.001). Prevalence of elevated POC lactate did not differ by in utero ARV exposure drug class, but was significantly higher in children exposed in utero to emtricitabine or efavirenz, cocaine or opiates, and those of white race. Conclusions: POC lactate testing is a useful rapid laboratory screening assay for HEU children with ARV exposure. ARV use during pregnancy has resulted in a dramatic decrease in mother-to-child transmission of HIV, and the risk of elevated lactate in HEU children is low. However, as new ARVs and more complex regimens are used during pregnancy by HIV-infected women, continued monitoring for infant toxicities is essential.
Mental time travel and default-mode network functional connectivity in the developing brain

A core brain network is engaged in remembering the past and envisioning the future. This network overlaps with the so-called default-mode network, the activity of which increases when demands for focused attention are low. Because of their shared brain substrates, an intriguing hypothesis is that default-mode activity, measured at rest, is related to performance in separate attention-focused recall and imagination tasks. However, we do not know how functional connectivity of the default-mode network is related to individual differences in reconstruction of the past and imagination of the future. Here, we show that functional connectivity of the default-mode network in children and adolescents is related to the quality of past remembering and marginally to future imagination. These results corroborate previous findings of a common neuronal substrate for memory and imagination and provide evidence suggesting that mental time travel is modulated by the task-independent functional architecture of the default-mode network in the developing brain. A further analysis showed that local cortical arealization also contributed to explain recall of the past and imagination of the future, underscoring the benefits of studying both functional and structural properties to understand the brain basis for complex human cognition.