Unlocking Clinical Insights: Lymphocyte-Specific Protein Tyrosine Kinase Candidates as Promising Therapeutic Targets for Pancreatic Cancer Risk Stratification.

Background: Uncover the pivotal link between lymphocyte-specific protein tyrosine kinase (Lck)-related genes and clinical risk stratification in pancreatic cancer. Methods: This study identifies shared genes between differentially expressed genes (DEGs) and Lck-related genes in pancreatic cancer using a methodological framework rooted in The Cancer Genome Atlas database. Feature gene selection is accomplished and a signature model is constructed. Statistical significant clinical endpoints such as overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) were defined. Results: After performing random survival forest, Lasso regression, and multivariate Cox regression model, 7 trait genes out of 272 Lck-associated DEGs are selected to create a signature model that is independent of other clinical factors and can predict OS and DSS. It appears that high-risk patients have activated the TP53 signaling pathway and the cell cycle signaling pathway. LAMA3 turned out to be the hub gene of the signature with high expression in pancreatic cancer. Patients with increased expression of LAMA3 had a short OS, DSS, and PFI in comparison. The candidate competing endogenous RNA network of LAMA3 turned out to be OPI5-AS1/hsa-miR-186-5p/LAMA3 axis. Conclusions: A characteristic signature of seven Lck-related genes, especially LAMA3, has been shown to be a key factor in clinical risk stratification for pancreatic cancer.

A multicentre, phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B-cell lymphoma.

This international, multicentre phase II study was conducted to assess ofatumumab, a human anti-CD20 monoclonal antibody, in patients with relapsed/progressive diffuse large B-cell lymphoma (DLBCL) who were ineligible for autologous stem cell transplantation (TI) or who had relapse/progression after transplantation (PT). Eighty-one patients received ofatumumab 300 mg intravenously (IV) on Day 1, followed by seven weekly IV infusions of 1000 mg. Patients in the TI and PT groups had received a median of 3 (range, 1-7) and 5 (range, 2-7) prior therapies, respectively. One-third of patients did not respond to the last prior therapy, and 53% had failed two or more rituximab-containing therapies. Overall response rate was 13% for the TI group (seven partial responses) and 8% for the PT group (two complete responses). Median progression-free survival was 2·6 months, and median duration of response was 9·5 months. The most common Grade 3-4 adverse events were neutropenia (11%), leucopenia (6%), lymphopenia (6%) and thrombocytopenia (6%). Sixteen deaths have been reported, with disease progression as the most common cause of death. In conclusion, ofatumumab monotherapy was well tolerated and provided clinical benefit to some DLBCL patients in this study.

Nationwide Screening for Bee Viruses and Parasites in Belgian Honey Bees.

The health of honey bees is threatened by multiple factors, including viruses and parasites. We screened 557 honey bee (Apis mellifera) colonies from 155 beekeepers distributed all over Belgium to determine the prevalence of seven widespread viruses and two parasites (Varroa sp. and Nosema sp.). Deformed wing virus B (DWV-B), black queen cell virus (BQCV), and sacbrood virus (SBV) were highly prevalent and detected by real-time RT-PCR in more than 95% of the colonies. Acute bee paralysis virus (ABPV), chronic bee paralysis virus (CBPV) and deformed wing virus A (DWV-A) were prevalent to a lower extent (between 18 and 29%). Most viruses were only present at low or moderate viral loads. Nevertheless, about 50% of the colonies harbored at least one virus at high viral load (>107 genome copies/bee). Varroa mites and Nosema sp. were found in 81.5% and 59.7% of the honey bee colonies, respectively, and all Nosema were identified as Nosema ceranae by real time PCR. Interestingly, we found a significant correlation between the number of Varroa mites and DWV-B viral load. To determine the combined effect of these and other factors on honey bee health in Belgium, a follow up of colonies over multiple years is necessary.

Changes in ventilation-perfusion during and after an COPD exacerbation: an assessment using fluid dynamic modeling.

Introduction: Severe exacerbations associated with chronic obstructive pulmonary disease (COPD) that require hospitalization significantly contribute to morbidity and mortality. Definitions for exacerbations are very broad, and it is unclear whether there is one predominant underlying mechanism that leads to them. Functional respiratory imaging (FRI) with modeling provides detailed information about airway resistance, hyperinflation, and ventilation-perfusion (V/Q) mismatch during and following an acute exacerbation. Materials and methods: Forty-two patients with COPD participating in a multicenter study were assessed by FRI, pulmonary function tests, and self-reported outcome measures during an acute exacerbation and following resolution. Arterial blood gasses and lung function parameters were measured. Results: A significant correlation was found between alveolar-arterial gradient and image-based V/Q (iV/Q), suggesting that iV/Q represents V/Q mismatch during an exacerbation (p<0.05). Conclusion: Recovery of an exacerbation is due to decreased (mainly distal) airway resistance (p<0.05). Improvement in patient-reported outcomes were also associated with decreased distal airway resistance (p<0.05), but not with forced expiratory volume. FRI is, therefore, a sensitive tool to describe changes in airway caliber, ventilation, and perfusion during and after exacerbation. On the basis of the fact that FRI increased distal airway resistance seems to be the main cause of an exacerbation, therapy should mainly focus on decreasing it during and after the acute event.

A novel factor XI gene mutation associated with mild factor XI deficiency in a symptomatic patient.

Congenital factor XI deficiency is a rare condition, in which plasma factor XI levels correlate poorly with the severity of haemorrhage. The condition is typically characterized by post-traumatic bleeding. The factor XI gene is located on chromosome 4 and contains 15 exons. More than 80 mutations have so far been described. We describe a novel mutation in the factor XI gene associated with mild factor XI deficiency. The patient, who is of Irish descent, has a history of post-traumatic bleeding and was found to have a borderline factor XI deficiency. DNA sequence analysis of the factor XI gene revealed a novel T to A mutation at nucleotide 168 resulting in the substitution of the cysteine residue at codon 38 with a stop codon (Cys38STOP). The mutation predicts the premature termination of translation of factor XI mRNA resulting in a truncated, and probably unstable, factor XI protein. The presence of the mutation is consistent with the patient's borderline factor XI deficiency.

Is screening for factor V Leiden and prothrombin G20210A mutations in renal transplantation worthwhile? Results of a large single-center U.K. study.

This single center study is the largest series of renal transplant recipients and donors screened for the commonest prothrombotic genotypes. A total of 562 transplant recipients and 457 kidney donors were genotyped for the factor V Leiden and prothrombin G20210A mutations. The prevalence of heterozygous factor V Leiden was 3.4% and 2.6% and prothrombin G20210A was 2.0% and 1.1% in recipients and donors, respectively, similar frequencies to that of the general U.K. population. The 30-day and 1-year graft survival rates in recipients with thrombophilic mutations were 93% and 93%, compared with 88% and 82% in patients without these mutations (log-rank P=0.34). Thrombophilia in recipients (odds ratio 0.55; confidence interval 0.06-2.29; P=0.56) or in donors (odds ratio 1.53; confidence interval 0.27-5.74; P=0.46) did not correlate with graft loss at 30 days after transplantation. In contrast to recent reports, this study did not demonstrate an association between thrombophilia and renal allograft loss, and routine screening is not recommended.

The effects of cyclosporin on the collagenolytic activity of gingival fibroblasts.

BACKGROUND: The immunosuppressive agent cyclosporin is associated with a number of major side-effects including the development of gingival overgrowth. Although the pathogenesis of cyclosporin-induced gingival overgrowth remains unclear, it has been suggested that the finely regulated balance between extracellular matrix synthesis and degradation may be disturbed, resulting in an accumulation of excess connective tissue components within the gingival tissue. The aim of this study was to investigate the effect of cyclosporin on matrix metalloproteinases (MMP)-1 and tissue inhibitors of MMP (TIMP)-1 expression at the mRNA, protein, and enzyme activity levels. METHODS: Gingival fibroblasts were grown to confluence and then cultured in serum-free medium supplemented with cyclosporin over the concentration range of 0 to 2000 ng/ml. MMP-1 and TIMP-1 mRNA levels in cultures were determined by reverse transcription polymerase chain reaction (RT-PCR), protein levels in whole conditioned medium were assessed by enzyme-linked immunosorbent assay (ELISA), and collagenolytic activity determined using a 3H-acetylated type I collagen degradation assay. Tissue mRNA levels in normal and overgrown gingiva were also determined by RT-PCR. RESULTS: Results indicated that cyclosporin inhibited MMP-1 expression at both the mRNA and protein level in a dose- and time-dependent fashion. The effects on TIMP-1 expression were less clear, cyclosporin inhibiting mRNA expression, but having no effect on TIMP-1 protein levels at any concentration studied. Addition of the drug resulted in reduced levels of collagenolytic activity in the culture medium. MMP-1 mRNA expression was significantly reduced in overgrown compared to normal tissue. CONCLUSIONS: These results add support to the hypothesis that the accumulation of collagen seen in gingival overgrowth can be explained by a cyclosporin-induced inhibition of collagenolytic activity within the gingival tissues.

Professional motivation and career plan differences between African-American and Caucasian dental students: implications for improving workforce diversity.

Vast disparities in oral health status coupled with projected decreases in African Americans enrolling in and graduating from dental school have heightened concern about the underrepresentation of African Americans in the dental profession. The purpose of this study was to explore differences between African-American and white American students regarding demographics, professional motivations, and career plans. African-American (n = 104) and white American (n = 226) dental students completed a biographical data survey instrument, which included information about family background and professional motivations and plans, and rated descriptions of three practice arrangements. African-American students were more motivated to become a dentist to serve the public, plan to specialize, work in an urban area, and work part-time. White American students were more motivated to become a dentist based on factors related to family commitments. Race was a significant predictor for student ratings for both solo and employee practice. Study results have implications for health professions educators, administrators, and policy makers in their efforts to improve the recruitment and retention of African-American students, shape dental curricula to meet diverse student needs, and implement loan forgiveness programs to enhance minority student recruitment.

Surgeon and haematologist: a review of comprehensive care for patients with inherited bleeding disorders in Northern Ireland.

BACKGROUND: Management of patients with inherited bleeding disorders has improved since the introduction of Comprehensive Care Centres (CCC) in the United Kingdom (UK). In the event such patients need surgery, the aim of the multidisciplinary team is to facilitate outcomes as good as what would be expected in a non-bleeding disorder patient. A review of such comprehensive care was carried out in patients with inherited bleeding disorders when they needed surgery at Northern Ireland CCC. Aims of the study were to evaluate surgical morbidity and mortality in these patients. METHODS: All patients with inherited bleeding disorders who underwent non-orthopaedic surgery between 2008 and 2012 were identified from the CCC records within the Belfast Health and Social Care Trust (BHSCT) in Northern Ireland (NI) and their case records reviewed. RESULTS: 28 patients received elective and emergency surgery during this period. There was minimum morbidity and no mortality in this cohort. CONCLUSIONS: Surgery in patients with inherited bleeding disorders has become safe with the advent of multidisciplinary CCCs. Close communication between surgeon and haematologist is key in the successful management of these complex patients.

The pathogenesis of venous thromboembolism in cancer: emerging links with tumour biology.

Venous thromboembolism (VTE) is a frequent complication in individuals with cancer and is considered to be a cause of substantial mortality. Epidemiological studies identify malignancy as an independent VTE risk factor and show that cancer patients are at increased risk of both initial and recurrent VTE events. The risk due to cancer is compounded by the effects of chemotherapy and other treatments. The pathogenesis of cancer-associated VTE is complex involving multiple interactions between tumours and various components of haemostasis. The development of a systemic hypercoagulable state is considered a key pathogenetic feature and is attributed to tumour expression of tissue factor and other procoagulants, activation of vascular cells by tumour-derived cytokines and adhesive interactions between tumour cells and host cells. An increasing body of evidence indicates that the activation of haemostasis in malignant disease contributes to tumour growth and progression by stimulation of intracellular signalling pathways. The interaction of tissue factor, thrombin and other coagulation factors with protease activated receptor (PAR) proteins expressed by tumour cells and host vascular cells leads to the induction of genes related to the processes of angiogenesis, cell survival and cell adhesion and migration.

The dynamics of conformational isomerization in flexible biomolecules. I. Hole-filling spectroscopy of N-acetyl tryptophan methyl amide and N-acetyl tryptophan amide.

The conformational isomerization dynamics of N-acetyl tryptophan methyl amide (NATMA) and N-acetyl tryptophan amide (NATA) have been studied using the methods of IR-UV hole-filling spectroscopy (HFS) and IR-induced population transfer spectroscopy (IR-PTS), which were developed for this purpose. Single conformations of these molecules were selectively excited in well-defined NH stretch fundamentals. This excess energy was used to drive conformational isomerization. By carrying out the infrared excitation early in a supersonic expansion, the excited molecules were recooled into their zero-point levels, partially refilling the hole created in the ground state population of one of the conformers, and creating gains in population in other conformers. These changes in population were detected using laser-induced fluorescence downstream in the expansion. In HFS, the IR wavelength is fixed and the UV laser tuned in order to determine where the population went following selective infrared excitation. In IR-PTS, the UV is fixed to monitor the population of a given conformation, and the IR is tuned to record the IR-induced changes in the population of the monitored conformer. Besides demonstrating the capability of the experiment to change the downstream conformational population distribution, the IR-PTS scans were used to extract two quantitative results: (i) The fractional populations of the conformers in the absence of the infrared, and (ii) the isomerization quantum yields for each of the six unique amide NH stretch fundamentals (three conformers each with two amide groups). The method for obtaining quantum yields is described in detail. In both NATMA and NATA, the quantum yields show modest conformational specificity, but only a hint of vibrational mode specificity. The prospects for the hole-filling technique for providing insight into energy flow in large molecules are discussed, leaving a more detailed theoretical modeling to the adjoining paper [Evans et al. J. Chem. Phys. 120, 148 (2004)].

Combined experimental/theoretical investigation of the He+ICl interactions. I. Rovibronic spectrum of He...ICl complexes in the ICl B-X, 3-0 region.

Transitions of two different stereoisomers of the He...ICl(X,v" = 0) weakly bound complex, one with a T-shaped orientation and another that is most likely linear, have been observed in laser-induced fluorescence experiments performed in the ICl B-X region. Here we present experimental and theoretical results aimed at confirming the previous assignments and at gaining additional insights into the He+ICl interactions. High resolution action spectra were recorded in the same region to identify those features that could be attributed to transitions of the He...I35Cl(X,v" = 0) isomers and not to higher-order complexes, Hen...I35Cl, where n > or = 2, or I37Cl containing species. Calculations of the rovibronic spectra of the He...I35Cl complexes in the ICl B-X, 2-0 and 3-0 regions were performed using an ab initio potential energy surface for the He+ICl(X,v" = 0) ground state and two different pairwise additive potentials for the He+ICl(B,v' = 2,3) excited states. The rotation-vibration energies and wave functions for the He cdots, three dots, centered I35Cl complexes were obtained for all bound states with total angular momentum J < 10 using both of these potentials. Electronic spectra were generated using these results, assuming that the transition moment lies along the ICl bond and is not perturbed by the presence of the helium atom. The calculations qualitatively reproduce the He cdots, three dots, centered I35Cl action spectrum and strongly support the previous assignments. The calculations also indicate that some of the spectral congestion observed near the linear band may be attributed to transitions of the linear isomer to multiple intermolecular levels in the excited state. Coriolis coupling strongly mixes He cdots, three dots, centered ICl(B,v') states with rotational excitation, making simulations and assignments of the linear band observed in the experimental spectrum difficult.