Effects of a phorbol ester and diacyglycerols on secretion of mucin and arginine esterase by rat submandibular gland cells

The effects of a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) and a diacylglyceride, 1-oleoyl-2-acetyl-glycerol (OAG) on the secretion of two major exocrine products by dispersed rat submandibular cells were investigated. TPA stimulated the release of acinar cell mucin and ductal cell protease (arginine esterase) in a dose- and time-dependent manner. Mucin secretion was also provoked by OAG, which, however, had no effect on arginine esterase release. The unsaturated diacylglycerol, 1,2-diolein, elicited a greater mucosecretory response than did OAG at the same concentration, while the saturated 1,2-distearin produced a smaller response.Mucin and enzyme secretion caused by TPA or OAG in the rat submandibular model was not inhibited by either of two putative antagonists, the antipsychotic drug, fluphenazine, and the antibiotic, polymyxin B.The involvement of extracellular Ca²⁺ in TPA-induced secretion was examined by comparing responses of cells maintained in normal or Ca²⁺-free medium, or in medium containing the ionophore A23187. Although extracellular Ca²⁺ was not an absolute requirement for a secretory response, the results indicate a synergistic relationship between TPA and Ca²⁺ in stimulating the release of both mucin and arginine esterase.These results suggest a role for the Ca²⁺-, phospholipid-dependent enzyme, protein kinase C in the secretory mechanism of mucous and serous cells in the submandibular gland. This is consistent with the proposal that receptor-mediated hydrolysis of membrane phosphoinositides is an initial event in stimulus-response coupling in exocrine cells.     

An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome

The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype. We describe two siblings from a non-consanguineous couple who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia. Whole-exome sequencing in the two patients identified the novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1. Sanger sequencing confirmed the mutation in the siblings and revealed it in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47. Identification of a novel AP4B1 alteration in two patients with clinical manifestations highly similar to other individuals with mutations affecting one of the four AP-4 subunits further supports the observation that loss of AP-4 assembly or functionality underlies the common clinical features in these patients and underscores the existence of the clinically recognizable AP-4 deficiency syndrome.     

Type I interferons have opposing effects during the emergence and recovery phases of colitis

The contribution of the innate immune system to inflammatory bowel disease (IBD) is under intensive investigation. Research in animal models has demonstrated that type I interferons (IFN‐Is) protect from IBD. In contrast, studies of patients with IBD have produced conflicting results concerning the therapeutic potential of IFN‐Is. Here, we present data suggesting that IFN‐Is play dual roles as regulators of intestinal inflammation in dextran sodium sulfate (DSS)‐treated C57BL/6 mice. Though IFN‐Is reduced acute intestinal damage and the abundance of colitis‐associated intestinal bacteria caused by treatment with a high dose of DSS, they also inhibited the resolution of inflammation after DSS treatment. IFN‐Is played an anti‐inflammatory role by suppressing the release of IL‐1β from the colon MHC class II⁺ cells. Consistently, IL‐1 receptor blockade reduced the severity of inflammation in IFN‐I receptor‐deficient mice and myeloid cell‐restricted ablation of the IFN‐I receptor was detrimental. The proinflammatory role of IFN‐Is during recovery from DSS treatment was caused by IFN‐I‐dependent cell apoptosis as well as an increase in chemokine production and infiltrating inflammatory monocytes and neutrophils. Thus, IFN‐Is play opposing roles in specific phases of intestinal injury and inflammation, which may be important for guiding treatment strategies in patients.     

Induced arginine transport via cationic amino acid transporter‐1 is necessary for human T‐cell proliferation

Availability of the semiessential amino acid arginine is fundamental for the efficient function of human T lymphocytes. Tumor‐associated arginine deprivation, mainly induced by myeloid‐derived suppressor cells, is a central mechanism of tumor immune escape from T‐cell‐mediated antitumor immune responses. We thus assumed that transmembranous transport of arginine must be crucial for T‐cell function and studied which transporters are responsible for arginine influx into primary human T lymphocytes. Here, we show that activation via CD3 and CD28 induces arginine transport into primary human T cells. Both naïve and memory CD4⁺ T cells as well as CD8⁺ T cells specifically upregulated the human cationic amino acid transporter‐1 (hCAT‐1), with an enhanced and persistent expression under arginine starvation. When hCAT‐1 induction was suppressed via siRNA transfection, arginine uptake, and cellular proliferation were impaired. In summary, our results demonstrate that hCAT‐1 is a key component of efficient T‐cell activation and a novel potential target structure to modulate adaptive immune responses in tumor immunity or inflammation.     

Guidelines for genomic array analysis in acquired haematological neoplastic disorders

Genetic profiling is important for disease evaluation and prediction of prognosis or responsiveness to therapy in neoplasia. Microarray technologies, including array comparative genomic hybridization and single‐nucleotide polymorphism‐detecting arrays, have in recent years been introduced into the diagnostic setting for specific types of haematological malignancies and solid tumours. It can be used as a complementary test or depending on the neoplasia investigated, also as a standalone test. However, comprehensive and readable presentation of frequently identified complex genomic profiles remains challenging. To assist diagnostic laboratories, standardization and minimum criteria for clinical interpretation and reporting of acquired genomic abnormalities detected through arrays in neoplastic disorders are presented. © 2016 Wiley Periodicals, Inc.     

Sleep Questionnaire Versus Sleep Diary: Which Measure Is Better?

One questionnaire about a typical week's sleep is more convenient than asking individuals to complete daily sleep diaries. Yet, most clinical evaluations and much sleep and insomnia research rely upon self monitoring via daily sleep diaries. These are often problematic to administer and can be reactive. Therefore, we investigated comparability of two measurement modalities (self monitoring and questionnaire) in a sample of 156 community dwelling older adults, both good and poor sleepers. Results indicate significant and high correlations between corresponding scores on a retrospective sleep questionnaire and on 7 days of self monitoring on a daily sleep diary, thereby suggesting that the two measurement modalities are tapping the same domains. There were, however, significant differences between means on several variables, but there was no systematic pattern to the differences. These findings illustrate the need to tailor measurement modality—retrospective or ongoing—to the setting and the purpose of the evaluation.     

Breast cancer and hormonal therapy

Valid evidence from randomized-controlled trials indicates that breast cancer risk is increased with combined estrogen/progestogen use and that such treatment implies a risk greater than that of estrogen alone. Overall, risk estimates from observational studies are somewhat higher than in randomized-controlled trials but remain modest as compared with other risk factors even after long-term treatment. For combined estrogen/progestogen therapy, risk increases gradually to reach statistical significance after 4 to 5 years. Apart from its many beneficial health effects, the safety data for use of estrogen alone are quite reassuring. The only justifications for progestogen addition are for bleeding control and endometrial protection. At present, there are several new therapeutic compounds and concepts in development, which hold promise to provide both endometrial protection and breast safety.     

Chromosome banding analysis and genomic microarrays are both useful but not equivalent methods for genomic complexity risk stratification in chronic lymphocytic leukemia patients

Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK) (46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity (0-2, 3-4 and ≥5 abnormalities) was also analyzed. No significant differences in the percentage of patients in each group were detected, but only a moderate agreement was observed between methods when focusing on individual cases (κ=0.507; P<0.001). Discordant classification was obtained in 100 patients (29.4%), including 3% classified in opposite risk groups. Most discrepancies were technique-dependent and no greater correlation in the number of abnormalities was achieved when different filtering strategies were applied for GM. Nonetheless, both methods showed a similar concordance index for prediction of time to first treatment (TTFT) (CBA: 0.67 vs. GM: 0.65) and overall survival (CBA: 0.55 vs. GM: 0.57). High complexity maintained its significance in the multivariate analysis for TTFT including TP53 and IGHV status when defined by CBA (hazard ratio [HR] 3.23; P<0.001) and GM (HR 2.74; P<0.001). Our findings suggest that both methods are useful but not equivalent for risk stratification of CLL patients. Validation studies are needed to establish the prognostic value of genome complexity based on GM data in future prospective studies.     

Face Mask Wastes as Cementitious Materials: A Possible Solution to a Big Concern

After more than two years wearing surgical masks due to the COVID-19 pandemic, used masks have become a significant risk for ecosystems, as they are producing wastes in huge amounts. They are a potential source of disturbance by themselves and as microplastic contamination in the water system. As 5500 tons of face masks are estimated to be used each year, there is an urgent need to manage them according to the circular economy principles and avoid their inadequate disposal. In this paper, surgical wear masks (WM), without any further pretreatment, have been introduced as addition to mortars up to 5% in the weight of cement. Mechanical and microstructural characterization have been carried out. The results indicate that adding MW to the cement supposes a decrease in the properties of the material, concerning both strength and durability behavior. However, even adding a 5% of WM in weight of cement, the aspect of the mortars is quite good, the flexural strength is not significantly affected, and the strength and durability parameters are maintained at levels that—even lower than the reference—are quite reasonable for use. Provided that the worldwide production of cement is around 4.1 Bt/year, the introduction of a 5% of WM in less than 1% of the cement produced, would make it possible to get rid of the mask waste being produced.