Heterogeneity in regional changes in body composition induced by androgen deprivation therapy in prostate cancer patients: potential impact on bone health-the BLADE study.

BACKGROUND: It is not clear whether changes in body composition induced by androgen deprivation therapy (ADT) in prostate cancer (PC) patients are uniform or vary in the different body districts and whether regional lean body mass (LBM) and fat body mass (FBM) could have an impact on bone health. OBJECTIVE: To prospectively evaluate the regional changes in LBM and FBM in PC patients submitted to degarelix; to explore the relationship of regional body composition and bone mineral density (BMD) and bone turnover markers. DESIGN, SETTING, AND PARTICIPANTS: 29 consecutive non metastatic PC patients enrolled from 2017 to 2019. FBM, LBM and bone mineral density (BMD) evaluated by dual-energy x-ray absorptiometry (DXA) at baseline and after 12-month of ADT. Alkaline phosphate (ALP) and C-terminal telopeptide of type I collagen (CTX) assessed at baseline, 6 and 12 months. INTERVENTION: All patients underwent degarelix administration. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: T-test or sign test and Pearson or Spearman test for continuous variables were used when indicated. RESULTS AND LIMITATIONS: Median percent increase in FBM ranged from + 14.5% in trunk to + 25.4% in the left leg after degarelix. LBM changes varied from + 2% in the trunk to - 4.9% in the right arm. LBM in both arms and legs and their variations after degarelix directly correlated with ALP and inversely correlated with CTX. Lean mass of limbs, trunk and legs significantly correlated with BMD of the hip, lean mass of the trunk significantly correlated with spine BMD. These are post-hoc analysis of a prospective study and this is the main limitation. CONCLUSIONS: an heterogeneous change in body composition among body district is observed after ADT and bone turnover is influenced by lean mass and its variation. A supervised physical activity is crucial to maintain general physical performance and preserving bone health.

Semen impairment and occurrence of SARS-CoV-2 virus in semen after recovery from COVID-19.

STUDY QUESTION: How is the semen quality of sexually active men following recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection? SUMMARY ANSWER: Twenty-five percent of the men with recent SARS-Cov-2 infections and proven healing were oligo-crypto-azoospermic, despite the absence of virus RNA in semen. WHAT IS KNOWN ALREADY: The presence of SARS-CoV-2 in human semen and its role in virus contagion and semen quality after recovery from coronavirus disease 2019 (COVID-19) is still unclear. So far, studies evaluating semen quality and the occurrence of SARS-CoV-2 in semen of infected or proven recovered men are scarce and included a limited number of participants. STUDY DESIGN, SIZE, DURATION: A prospective cross-sectional study on 43 sexually active men who were known to have recovered from SARS-CoV2 was performed. Four biological fluid samples, namely saliva, pre-ejaculation urine, semen, and post-ejaculation urine, were tested for the SARS-CoV-2 genome. Female partners were retested if any specimen was found to be SARS-CoV-2 positive. Routine semen analysis and quantification of semen leukocytes and interleukin-8 (IL-8) levels were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Questionnaires including International Index of Erectile Function and Male Sexual Health Questionnaire Short Form were administered to all subjects. The occurrence of virus RNA was evaluated in all the biological fluids collected by RT-PCR. Semen parameters were evaluated according to the World Health Organization manual edition V. Semen IL-8 levels were evaluated by a two-step ELISA method. MAIN RESULTS AND THE ROLE OF CHANCE: After recovery from COVID-19, 25% of the men studied were oligo-crypto-azoospermic. Of the 11 men with semen impairment, 8 were azoospermic and 3 were oligospermic. A total of 33 patients (76.7%) showed pathological levels of IL-8 in semen. Oligo-crypto-azoospermia was significantly related to COVID-19 severity (P < 0.001). Three patients (7%) tested positive for at least one sample (one saliva; one pre-ejaculation urine; one semen and one post-ejaculation urine), so the next day new nasopharyngeal swabs were collected. The results from these three patients and their partners were all negative for SARS-CoV-2. LIMITATIONS, REASONS FOR CAUTION: Although crypto-azoospermia was found in a high percentage of men who had recovered from COVID-19, clearly exceeding the percentage found in the general population, the previous semen quality of these men was unknown nor is it known whether a recovery of testicular function was occurring. The low number of enrolled patients may limit the statistical power of study. WIDER IMPLICATIONS OF THE FINDINGS: SARS-CoV-2 can be detected in saliva, urine, and semen in a small percentage of men who recovered from COVID-19. One-quarter of men who recovered from COVID-19 demonstrated oligo-crypto-azoospermia indicating that an assessment of semen quality should be recommended for men of reproductive age who are affected by COVID-19. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Search for Lepton Number and Flavor Violation in K

Searches for the lepton number violating K^{+}→π^{-}µ^{+}e^{+} decay and the lepton flavor violating K^{+}→π^{+}µ^{-}e^{+} and π^{0}→µ^{-}e^{+} decays are reported using data collected by the NA62 experiment at CERN in 2017-2018. No evidence for these decays is found and upper limits of the branching ratios are obtained at 90% confidence level: B(K^{+}→π^{-}µ^{+}e^{+})<4.2×10^{-11}, B(K^{+}→π^{+}µ^{-}e^{+})<6.6×10^{-11} and B(π^{0}→µ^{-}e^{+})<3.2×10^{-10}. These results improve by 1 order of magnitude over previous results for these decay modes.

Genotoxicity Evaluation of the Soybean Isoflavone Genistein in Human Papillary Thyroid Cancer Cells. Study of Its Potential Use in Thyroid Cancer Therapy.

Genistein is one of the several known isoflavonic phytoestrogens found in a number of plants, with soybeans and soy products being the primary food source. The aim of the study is to evaluate if genistein is able to exert antineoplastic action in primary human papillary thyroid cancer (PTC) cells. Thyroid tissues were treated with genistein (1-10-50-100 µM). Cell viability, proliferation, DNA primary damage and chromosomal damage were evaluated. An antiproliferative effect was induced by the highest doses of genistein, and such an effect was synergistically enhanced by the cotreatment with the antineoplastic drug sorafenib. Comet assay did not show any genotoxic effect in terms of primary DNA damage at all the times (4 and 24 h) and tested doses. A reduction of hydrogen peroxide-induced DNA primary damage in primary thyrocytes from PTC cells pretreated with genistein was observed. Data suggest that genistein exerts antineoplastic action, does not induce genotoxic effects while reduces oxidative-induced DNA damage in primary thyrocytes from PTC cells, supporting its possible use in therapeutic intervention.

Both 3,5-diiodo-L-thyronine (T2) and T3 modulate glucose-induced insulin secretion.

3,5-diiodo-L-thyronine (T2), a naturally existing iodothyronine, has biological effects on humans, but no information is available on its action on pancreatic b-cells. We evaluated its effect vs triiodothyronine (T3), on glucose-induced insulin secretion in INS-1e cells, a rat insulinoma line, and on human islets. INS-1e were incubated in the presence/absence of T2 or T3 (0.1 nmol/L-10 µmol/L), and glucose (3.3, 7.5, 11.0, and 20 mmol/L). Insulin release and content (at 11.0 and 20 mmol/L glucose) were significantly (p less than 0.01) stimulated by 1-100 nmol/L T2 and 0.1 nmol/L-1.0 µmol/L T3, and inhibited with higher concentrations of both (1–10 µmol/L T2 and 10 µmol/L T3). Human islets were incubated with 3.3 mmol/L glucose in presence/absence of T3 or T2 (0.1 nmol/L, 0.1 µmol/L, and 1 µmol/L). T2 (0.1 nmol/L-0.1 µmol/L) significantly (p less than0.01) stimulated insulin secretion, while higher concentrations (1 µmol/L) inhibited it. A modest increase in insulin secretion was evidenced with 1 µmol/L T3. In conclusion, T2 and T3 have a direct regulatory role in insulin secretion, depending on their concentrations and the glucose level itself. At concentrations near the physiological range, T2 enhances glucose-induced insulin secretion in both rat b-cells and human islets.

Estimating carrier relaxation times in the Ba8Ga16Ge30 clathrate in the extrinsic regime.

We used a semi-empirical method to extract carrier relaxation times at different temperatures (τ(T)) in thermoelectric materials from a combination of experimental results and first-principles calculations. The methodology is based on the Boltzmann transport equation formalism within the relaxation time approximation. It can be applied to single crystals and polycrystalline materials. We applied the method to investigate the electronic transport properties of the clathrate compound Ba8Ga16Ge30 type-I. The calculations indicate that the carrier relaxation process in single crystals is dominated by electron-phonon scattering (τ ∝ T-3/2), while in polycrystalline materials scattering at grain boundaries dominates (τ ∼ cte). The Seebeck coefficient, electrical conductivity, and electron heat conduction are in consistent agreement with experiment. Furthermore, the Slack relation for lattice heat conductivity was successfully applied to the material. The calculated figure of merit is in good agreement with experimental results.

MRI and US in the evaluation of fetal anomalies: The need to work together.

PURPOSE: Real-time virtual sonography (RVS) is a new technique that synchronizes real-time ultrasonography (US) and multiplanar reconstructed magnetic resonance imaging (MRI). The purpose of this study was to evaluate the feasibility and ability of RVS to assess the main pathologies in fetuses with suspected US anomalies. METHOD AND MATERIALS: Real-time virtual sonography (Hitachi, HI VISION Ascendus) was offered to 30 patients who had undergone fetal MRI. The acquired MRI image dataset was loaded into the fusion system and displayed together with the real-time US image. The ability of RVS to assess the main anatomical sites and fetal anomalies was evaluated. RESULTS: Real-time virtual sonography was technically possible in all cases. From a total of 30 patients, RVS helped the diagnosis in 10 cases. In 15 cases of encephalic pathology, fusion imaging improved the accuracy of the diagnosis; in the other 5 cases, MRI was superior to US even when using the RVS. CONCLUSION: This is a study on the feasibility and practical use of RVS. Thanks to information from both US and MRI, RVS allowed better identification of the fetal pathologies and improved the performance of the ultrasound examination. In our experience, it was really helpful in pathologies that would benefit from US follow-up.

Population-based analysis of hospitalizations in a West-European region revealed major changes in hospital utilization for patients with systemic lupus erythematosus over the period 2001-2012.

OBJECTIVE: The objective of this paper is to evaluate hospital admissions in systemic lupus erythematosus (SLE) patients through a retrospective population-based study analyzing hospitalization data during 2001-2012 in Sardinia, an Italian region with universal health system coverage. METHODS: Data on the hospital discharge records with the ICD-9-CM code for SLE (710.0) were obtained from the Department of Health and Hygiene and analyzed, mostly focusing on primary and non-primary diagnosis and Diagnosis-Related Group (DRG) code. In order to establish the significance of the annual trend for number and type of primary and non-primary discharge diagnosis, the two-tailed Cochran-Armitage test for trend was applied. In order to estimate SLE prevalence, data from administrative database and medical records were assembled. RESULTS: This study included 6222 hospitalizations in 1675 patients (87% women). Hospitalizations with SLE as primary diagnosis were 3782 (58.0%) and significantly decreased during the study period. The annual number of renal, hematologic and neuropsychiatric disorders as non-primary diagnosis associated with SLE remained constant; however, their percentage increased (p < 0.0001) because of a declining number of admissions for SLE without associated diagnosis and without complications. Hospitalizations with SLE as non-primary diagnosis showed a significant upward trend in number and percentage of cerebrovascular accident (p = 0.0004), acute coronary syndrome (p = 0.0004) and chronic renal failure (p = 0.0003) as underlying primary diagnosis, while complications of pregnancy, labor and childbirth (p = 0.3375), malignancies (p = 0.6608) and adverse drug reactions (p = 0.2456) did not show statistically significant changes. Infections showed an increasing trend between 2001 and 2012 but did not reach statistical significance (p = 0.0304). After correction for hospitalization (93.8%) and survival (91.1%) rates calculated over the study period, the 2012 SLE prevalence in Sardinia was estimated to be 99.3 per 100,000 inhabitants. CONCLUSIONS: While overall hospitalizations for SLE patients declined, those for cerebrovascular accident, acute coronary syndrome and chronic renal failure as underlying primary diagnosis increased during the study period.

Selective inhibitors of aurora kinases inhibit proliferation, reduce cell viability and impair cell cycle progression in papillary thyroid carcinoma cells.

The three members of the Aurora kinase family, Aurora-A, -B and -C, regulate several aspects of the mitotic process, and their aberrant expression and/or function causes mitotic abnormalities leading either to cell death or aneuploidy. They are found overexpressed in several human malignancies, including the papillary thyroid carcinoma (PTC). In the present study, we sought to establish whether Aurora kinase inhibition could be of any therapeutic value in the treatment of aggressive forms of PTC, enduring to radioactive iodide (RAI) ablation. To this end, the effects of selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) were analyzed on 3 human PTC cell lines expressing either wild-type (K1 and TPC1) or mutant p53 (BCPAP). The two inhibitors were capable of reducing cell proliferation in a time- and dose-dependent manner, with IC50 comprised between 65.4 and 114.9 nM for MLN8237, and between 26.6 and 484.6 nM for AZD1152. Immunofluorescence experiments confirmed that AZD1152 inhibited Aurora-B phosphorylation of histone H3 on Ser10, however, it did not affect Aurora-A autophosphorylation. MLN8237 inhibited Aurora-A autophosphorylation as expected, but at concentrations required to achieve the maximum antiproliferative effects it also abolished H3 (Ser10) phosphorylation. Time-lapse videomicroscopy evidenced that both inhibitors prevented the completion of cytokinesis, and cytofluorimetric analysis showed accumulation of cells in G2/M phase and/or polyploidy. Apoptosis was induced in all the cells by both inhibitors independently from the p53 status. In conclusion, in the present preclinical study MLN8237 and AZD1152 have emerged as promising drug candidates for RAI-insensitive PTC.

Polyamorphism in tetrahedral substances: Similarities between silicon and ice.

Tetrahedral substances, such as silicon, water, germanium, and silica, share various unusual phase behaviors. Among them, the so-called polyamorphism, i.e., the existence of more than one amorphous form, has been intensively investigated in the last three decades. In this work, we study the metastable relations between amorphous states of silicon in a wide range of pressures, using Monte Carlo simulations. Our results indicate that the two amorphous forms of silicon at high pressures, the high density amorphous (HDA) and the very high density amorphous (VHDA), can be decompressed from high pressure (∼20 GPa) down to the tensile regime, where both convert into the same low density amorphous. Such behavior is also observed in ice. While at high pressure (∼20 GPa), HDA is less stable than VHDA, at the pressure of 10 GPa both forms exhibit similar stability. On the other hand, at much lower pressure (∼5 GPa), HDA and VHDA are no longer the most stable forms, and, upon isobaric annealing, an even less dense form of amorphous silicon emerges, the expanded high density amorphous, again in close similarity to what occurs in ice.

IP-10 in autoimmune thyroiditis.

The interferon-γ-inducible protein 10 (IP-10) was initially identified as a chemokine that is induced by interferon (IFN)-γ. IP-10 exerts its function through binding to chemokine (C-X-C motif) receptor 3 (CXCR3). IP-10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, Graves' disease and ophthalmopathy), or systemic (such as systemic lupus erythematosus, mixed cryoglobulinemia, Sjogren syndrome, or systemic sclerosis). The secretion of IP-10 by (CD)4+, CD8+, and natural killer is dependent on IFN-γ. Under the influence of IFN-γ, IP-10 is secreted by thyrocytes. Determination of high level of IP-10 in peripheral fluids is therefore a marker of a T helper 1 orientated immune response. High levels of circulating IP-10, have been shown in patients with autoimmune thyroiditis (AT). Among patients with AT, IP-10 levels were significantly higher in those with a hypoechoic ultrasonographic pattern, which is a sign of a more severe lympho-monocytic infiltration, and in those with hypothyroidism. For these reasons, it has been postulated that IP-10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism. Further studies are needed to investigate whether IP-10 is a novel therapeutic target in AT.

Open partial horizontal laryngectomies: a proposal for classification by the working committee on nomenclature of the European Laryngological Society.

We present herein the proposal of the European Laryngological Society working committee on nomenclature for a systematic classification of open partial horizontal laryngectomies (OPHL). This is based on the cranio-caudal extent of laryngeal structures resected, instead of a number of different and heterogeneous variables present in existing nomenclatures, usually referring to eponyms, types of pexy, or inferior limit of resection. According to the proposed classification system, we have defined three types of OPHLs: Type I (formerly defined horizontal supraglottic laryngectomy), Type II (previously called supracricoid laryngectomy), and Type III (also named supratracheal laryngectomy). Use of suffixes "a" and "b" in Type II and III OPHLs reflects sparing or not of the suprahyoid epiglottis. Various extensions to one arytenoid, base of tongue, piriform sinus, and crico-arytenoid unit are indicated by abbreviations (ARY, BOT, PIR, and CAU, respectively). Our proposal is not intended to give a comprehensive algorithm of application of different OPHLs to specific clinical situations, but to serve as the basis for obtaining a common language among the head and neck surgical community. We therefore intend to present this classification system as a simple and intuitive teaching instrument, and a tool to be able to compare surgical series with each other and with non-surgical data.

Effects of saline nebulization on SARS-CoV-2 RNA spreading and exhaled bio-aerosol particles in COVID-19 patients.

BACKGROUND: Nebulized therapy is the mainstay for treating obstructive airway diseases, but there is heightened concern about the potential risk for SARS-CoV-2 transmission during nebulization in COVID-19 patients. AIM: To investigate the effects of 0.9% saline nebulization on SARS-CoV-2 RNA spreading in 11 COVID-19 patients (five females, mean age 62.45 ± 9.31 years); also to ascertain whether saline nebulization changed the number of exhaled bio-aerosol particles in six out of the 11 patients. METHODS: Air samples were collected using suction pumps equipped with 0.45 µm PTFE filters and positioned around the patient's bed. Exhaled particles were quantified by using an optical particle counter. FINDINGS: At baseline (i.e. before nebulization) SARS-CoV-2 was detected more frequently in the pumps close to the patient than in those far away. After saline nebulization, the detection of SARS-CoV-2 in the pumps close to the patient was comparable to that observed at baseline. In the pumps far from the patient, saline nebulization slightly, but not significantly, increased SARS-CoV-2 RNA detection compared to baseline. Overall, no significant changes in the SARS-CoV-2 RNA detection were observed after saline nebulization. At baseline, exhaled particle emission varied among patients, with two of them showing higher emission of particles than the remaining patients. Saline nebulization induced a marked decrease in exhaled particles in the two patients who displayed high emission at baseline, whereas no changes were observed in the remaining patients. Saline nebulization did not significantly change SARS-CoV-2 RNA spreading. CONCLUSION: Saline nebulization does not significantly increase SARS-CoV-2 spreading.

The global distribution of plants used by humans.

Plants sustain human life. Understanding geographic patterns of the diversity of species used by people is thus essential for the sustainable management of plant resources. Here, we investigate the global distribution of 35,687 utilized plant species spanning 10 use categories (e.g., food, medicine, material). Our findings indicate general concordance between utilized and total plant diversity, supporting the potential for simultaneously conserving species diversity and its contributions to people. Although Indigenous lands across Mesoamerica, the Horn of Africa, and Southern Asia harbor a disproportionate diversity of utilized plants, the incidence of protected areas is negatively correlated with utilized species richness. Finding mechanisms to preserve areas containing concentrations of utilized plants and traditional knowledge must become a priority for the implementation of the Kunming-Montreal Global Biodiversity Framework.

Peroxisome proliferator-activated receptor γ agonists reduce cell proliferation and viability and increase apoptosis in systemic sclerosis fibroblasts.

BACKGROUND: No study has evaluated the effect of the peroxisome proliferator-activated receptor γ (PPARγ) agonists on cell viability, proliferation and apoptosis in cultured systemic sclerosis (SSc) fibroblasts. OBJECTIVES: The effects of two pure PPARγ agonists (rosiglitazone and pioglitazone) in cultured SSc fibroblasts were evaluated and compared with effects in normal fibroblasts. METHODS: The study included evaluation of cell viability and proliferation (based on the cleavage of tetrazolium salts and measurement of absorbance of the cell proliferation reagent WST-1), and determination of cell apoptosis (by means of the Hoechst dye uptake). RESULTS: Rosiglitazone or pioglitazone (20µmolL(-1) ) significantly reduced cell proliferation (cell count of 75% and 83% compared with baseline, respectively, after 2h) and cell viability (absorbance reductions of 25% and 22% compared with baseline, respectively, after 2 h), and increased apoptosis (apoptotic cell percentages 9·9% and 8·6%, respectively, after 48h of incubation) in SSc fibroblasts, whereas they did not present a significant influence on control fibroblasts. CONCLUSIONS: The effects of rosiglitazone or pioglitazone shown on SSc fibroblasts raise the hypothesis of a therapeutic role for PPARγ agonists in patients affected by SSc.

High circulating chemokines (C-X-C motif) ligand 9, and (C-X-C motif) ligand 11, in hepatitis C-associated cryoglobulinemia.

(C-X-C motif) ligand 9 and (C-X-C motif) ligand 11 (CXCL9 and CXCL11), are potent chemoattractants for activated T cells, and play an important role in T helper 1 (Th)1 cell recruitment in chronic hepatitis C. No study has evaluated CXCL9, together with CXCL11, circulating levels in patients with mixed cryoglobulinemia and hepatitis C (MC+HCV-p). The aim of the present study therefore was to measure serum CXCL9, and CXCL11 levels, in MC+HCV-p, and to relate the findings to the clinical phenotype. Serum CXCL9 and CXCL11 were measured in 71 MC+HCV-p and in matched controls. MC+HCV-p showed significantly higher mean CXCL9 and CXCL11 levels than controls (P less than 0.001, for both), in particular, in 32 patients with active vasculitis (P less than 0.001). By defining high CXCL9 or CXCL11 level as a value of at least 2 SD above the mean value of the control group ( greater than 100 pg/mL): 89 percent MC+HCV-p and 5 percent controls had high CXCL9 (P less than 0.0001, chi-square); 90 percent MC+HCV-p and 6 percent controls had high CXCL11 (P less than 0.0001, chi-square). In a multiple linear regression model of CXCL9 vs age, ALT, CXCL11, only CXCL11 was significantly (r = 0.452, P less than 0.0001) and independently related to CXCL9. Our study demonstrates in MC+HCV-p vs controls: (i) high serum CXCL9, and CXCL11, significantly associated with the presence of active vasculitis; (ii) a strong relationship between circulating CXCL9 and CXCL11. Future studies on a larger cohort of patients are needed to evaluate the relevance of serum CXCL9 and CXCL11 determination as clinico-prognostic marker of MC+HCV.

The dual Aurora kinase inhibitor ZM447439 prevents anaplastic thyroid cancer cell growth and tumorigenicity.

The anaplastic thyroid cancer (ATC) is among the most aggressive human tumors which fail to respond to all the currently available therapeutic approaches. As a consequence most patients die within a few months from diagnosis. In the present preclinical study, the effects of the ZM447439, a functional inhibitor of Aurora kinases, on the growth and tumorigenicity of a panel of ATC derived cell lines (CAL-62, 8305C, 8505C and BHT-101) were evaluated. The treatment of the different ATC cells with ZM447439 inhibited proliferation in a time- and dose-dependent manner, with IC50 comprised between 0.5 mM and 5 mM. Moreover, the drug remarkably impaired the formation of colonies in soft agar of all the cell lines. Consistently with Aurora inhibition, immunofluorescence and immunoblotting experiments demonstrated that Aurora auto-phosphorylation following drug treatment was completely abrogated, and treated cells were characterized by the presence of multiple spindles with short microtubules. In the same experiments we observed the loss of histone H3 phosphorylation on Ser10, specifically due to Aurora-B, after ZM447439 treatment. Time-lapse videomicroscopy and flow cytometric analysis demonstrated that in presence of ZM447439 the cells were able to enter mitosis but not to complete it, becoming polyploid. Almost all the ATC cell lines studied showed increased apoptosis after only 48 h of treatment. In conclusion, our data demonstrate that ZM447439 is effective in reducing cell growth and tumorigenicity of different ATC derived cell lines, and further investigations are needed to exploit its potential therapeutic value for ATC treatment.