A prospective study of smoking and risk of prostate cancer

We evaluated the hypothesis that smoking increases the incidence of and mortality from prostate cancer. High-quality smoking information was collected in 1971–1975 in a nationwide cohort of 135,006 male construction workers in Sweden. We achieved virtually complete follow-up through record linkages and ascertained as of December 1991 2,368 incident cases of prostate cancer and 709 deaths due to this disease. Rate ratios (RR) of prostate cancer incidence and mortality, with 95% confidence intervals (CI), were estimated in Poisson-based age-adjusted models, with amount and duration of smoking as independent variables. We found no convincing association between current smoking status, number of cigarettes smoked or years since onset and risk of prostatic cancer. The age-adjusted incidence RR among previous smokers was 1.09 and among current smokers 1.11 compared with non-smokers. Weak and inconsistent trends were seen with increasing number of cigarettes smoked per day and increasing duration among current smokers. Smokers of 15 or more cigarettes daily for at least 30 years experienced an incidence RR of 1.30. Mortality in ex-smokers was similar to that in never-smokers; it was, however, slightly increased among current smokers without any trend with amount smoked or duration. The weak and inconsistent associations between smoking and prostate cancer could easily have arisen due to bias or confounding. We therefore conclude that smoking is most likely not causally linked to the occurrence of prostate cancer. © 1996 Wiley-Liss, Inc.     

Challenges and satisfaction in Cardiothoracic Surgery Residency Programmes: insights from a Europe-wide survey

Open in a separate window OBJECTIVESThe increasing complexity of surgical patients and working time constraints represent challenges for training. In this study, the European Association for Cardio-Thoracic Surgery Residents’ Committee aimed to evaluate satisfaction with current training programmes across Europe. METHODSWe conducted an online survey between October 2018 and April 2019, completed by a total of 219 participants from 24 countries.RESULTSThe average respondent was in the fourth or fifth year of training, mostly on a cardiac surgery pathway. Most trainees follow a 5–6-year programme, with a compulsory final certification exam, but no regular skills evaluation. Only a minority are expected to take the examination by the European Board of Cardiothoracic Surgery. Participants work on average 61.0 ± 13.1 h per week, including 27.1 ± 20.2 on-call. In total, only 19.7% confirmed the implementation of the European Working Time Directive, with 42.0% being unaware that European regulations existed. Having designated time for research was reported by 13.0%, despite 47.0% having a postgraduate degree. On average, respondents rated their satisfaction 7.9 out of 10, although 56.2% of participants were not satisfied with their training opportunities. We found an association between trainee satisfaction and regular skills evaluation, first operator experience and protected research time.CONCLUSIONSOn average, residents are satisfied with their training, despite significant disparities in the quality and structure of cardiothoracic surgery training across Europe. Areas for potential improvement include increasing structured feedback, research time integration and better working hours compliance. The development of European guidelines on training standards may support this.     

Basal cell carcinoma—Primary closure of moderate defect of mid forehead

This is a case presentation of successful defect repair after radical surgical excision of a moderately large basal cell carcinoma by a simple procedure taking advantage of a patient's individual face features.     

Novel engineered TRAIL-based chimeric protein strongly inhibits tumor growth and bypasses TRAIL resistance

Targeting of the TRAIL-DR4/5 pathway was proposed as a promising approach for specific induction of apoptosis in cancer cells. Clinical trials, however, showed inadequate efficiency of TRAIL as a monotherapy. It is a widely held view that the application of multifunctional molecules or combination therapy may lead to substantial improvement. Here, we demonstrate the effectiveness and safety of a novel chimeric protein, AD-O51.4, which is a TRAIL equipped with positively charged VEGFA-derived effector peptides. The study was performed in multiple cancer cell line- and patient-derived xenografts. A pharmacokinetic profile was established in monkeys. AD-O51.4 strongly inhibits tumor growth, even leading to complete long-term tumor remission. Neither mice nor monkeys treated with AD-O51.4 demonstrate symptoms of drug toxicity. AD-O51.4 exhibits a satisfactory half-life in plasma and accumulates preferentially in tumors. The cellular mechanism of AD-O51.4 activity involves both cytotoxic effects in tumor cells and antiangiogenic effects on the endothelium. The presence of DRs in cancer cells is crucial for AD-O51.4-driven apoptosis execution. The TRAIL component of the fusion molecule serves as an apoptosis inducer and a cellular anchor for the effector peptides in TRAIL-sensitive and TRAIL-resistant cancer cells, respectively. The FADD-dependent pathway, however, seems to be not indispensable in death signal transduction; thus, AD-O51.4 is capable of bypassing the refractoriness of TRAIL. AD-O51.4-driven cell death, which exceeds TRAIL activity, is achieved due to the N-terminally fused polypeptide, containing VEGFA-derived effector peptides. The high anticancer efficiency of AD-O51.4 combined with its safety has led to the entry of AD-O51.4 into toxicological studies.     

NiO–Ba0.95Ca0.05Ce0.9Y0.1O3−δ as a Modified Anode Material Fabricated by the Tape Casting Method

The development of new chemically resistant anodes for protonic ceramic fuel cells (PCFCs) is urgently required to avoid the costly deep hydrogen purification method. Ba_0.95Ca_0.05Ce_0.9Y_0.1O_3−δ (5CBCY), which is more chemically resistant than BaCaCe_0.9Y_0.1O_3−δ, was here tested as a component of a composite NiO–5CBCY anode material. A preparation slurry comprising 5CBCY_, NiO, graphite, and an organic medium was tape cast, sintered and subjected to thermal treatment in 10 vol.% H₂ in Ar at 700 °C. Differential thermal analysis, thermogravimetry, quadrupole mass spectrometry, X-ray diffraction analysis, scanning electron microscopy, the AC four-probe method and electrochemical impedance spectroscopy were used for the investigation. The electrical conductivity of the Ni–5CBCY in H₂–Ar at 700 °C was 1.1 S/cm. In the same gas atmosphere but with an additional 5 vol.% CO₂, it was slightly lower, at 0.8 S/cm. The Ni–5CBCY cermet exhibited repeatable electrical conductivity values during Ni-to-NiO oxidation cycles and NiO-to-Ni reduction in the 5CBCY matrix, making it sufficient for preliminary testing in PCFCs.     

Eosinophilic gastroenteritis and graft‐versus‐host disease induced by transmission of Norovirus with fecal microbiota transplant

Fecal microbiota transplantation (FMT) was performed to decolonize gastrointestinal tract from antibiotic‐resistant bacteria before allogeneic hematopoietic cells transplantation (alloHCT). AlloHCT was complicated by norovirus gastroenteritis, acute graft‐versus‐host disease, and eosinophilic pancolitis. Norovirus was identified in samples from FMT material. Symptoms resolved after steroids course and second norovirus‐free FMT from another donor.     

Cytotoxic Potential of Denture Adhesives on Human Fibroblasts—In Vitro Study

(1) In recent years, there has been a significant increase in the availability of denture adhesives for stabilizing removable dentures. The aim of the present study was to assess the cytotoxicity of three denture adhesives on human fibroblasts. (2) Methods: Three denture adhesives were analyzed. Fibroblast cultures were established for the study and control groups in order to assess the incidence of necrosis and to evaluate the microscopic intracellular alterations induced. Following incubation with (study groups) or without adhesives (control group), trypan blue dye exclusion assay was used to determine the number of viable and/or dead cells. Microscopic specimens were stained with haematoxylin and eosin, scanned, digitally processed and then analyzed by a histopathologist. (3) Results: All three denture adhesives analyzed demonstrated various toxic effects in vitro on human fibroblast: quantitative evaluation—45.87–61.13% reduction of cell viability (p = 0.0001) and slight to moderate cytotoxicity in qualitative evaluation. (4) Conclusions: Denture adhesive creams demonstrated a toxic effect on human fibroblasts in vitro in quantitative and qualitative evaluation. In vivo observations are needed to find out if denture adhesives present a cytotoxic effect in patients.     

Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery

The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH₂ but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast, there was near-complete abrogation of the cAMP response to an allosteric agonist, compound 2, but preservation of ERK phosphorylation. Collectively, this indicates that GLP-1R dimerization is important for control of signal bias. Furthermore, we reveal that two small molecule ligands are unaltered in their ability to allosterically modulate signaling from peptide ligands, demonstrating that these modulators act in cis within a single receptor protomer, and this has important implications for small molecule drug design.     

Immunosenescence increases the rate of acceptance of kidney allotransplants in elderly recipients through exhaustion of CD4 T-cells

Compromised immunity is the hallmark of ageing. Paradoxically, it may be “an ally” in facilitating acceptance of allogeneic grafts in the elderly. In this retrospective study we looked for biomarkers of immunosenescence that distinguish elderly recipients less prone to reject kidney allografts.Recruited kidney recipients aged ≥60 or <60 were designated ‘elderly’ and ‘young’, respectively. Both age-groups were divided according to the history of acute rejection. The phenotype, length of telomeres, expression of FoxP3 and proliferative responses were assessed in CD4⁺ and CD8⁺ T-cell subsets. In addition, IL6, IL10 and TGFβ were measured on the level of mRNA and serum protein.Acute-rejection-free history in elderly transplant recipients was associated with short telomeres, a decreased proportion of CD28⁺ T-cells associated with CMV-seropositivity and low proliferation of CD4⁺ T-cells. In contrast, elderly recipients who experienced acute rejection kept preserved telomere length, had a higher number of functional CD4⁺CD28⁺ cells and exhibited vigorous proliferation in vitro. These differences were not found in the young group.The major conclusion of this study is that the impaired condition of CD4⁺ T-cells, so-called immunosenescence, renders transplant recipients less responsive to an allogeneic kidney graft, an effect that was limited to transplant recipients of >60 years of age.