Diffusive Release of Photosensitizing Agents (PS) from Novel PVA-Borate Semi-Solid Drug Carriers Through In Vitro Oral Streptococcus mutans Biofilm

Background: Streptococcus mutans, one of the agent of human dental caries, is particularly effective at forming biofilms on the hard tissues of the human oral cavity; the purpose of this study was to investigate and quantify the diffusional release of photosentising agents (PS): methylene blue (MB), toludine blue (TB), rose bengal (RB) and methyl orange (MO) from Polyvinyl alcohol (PVA)-borate semi-solid gels in the presence of in vitro oral Streptococcus mutans biofilm. Methods: S. mutans biofilm growths were ascertained to ensure proper dental plaque formation and were characterized using confocal microscopy. Release profiles for MB, TB, RB and MO-loaded PVA-borate semi-solids in the absence of biofilms were directly compared to their counterparts in the presence of S. mutans biofilms. In addition, their diffusion coefficients and resistances were determined. Results: The confocal imaging results showed that biofilms grown over a 5-day period had a generally uninterrupted film of colonies occupying the entire surface area of growth surface of a nylon mesh support with approximately 60 µm biofilm size. The overall diffusion resistance of all PVA-borate semi-solids in the presence of S. mutans biofilms was about 1.2 times lower than the diffusion resistance for PVAborate semi-solids in the absence of biofilms. The diffusion resistances for all studied PS, indicate that electrostatic forces and molecular size play an important part in controlled and sustained drug release from PVA-borate semi-solids. Conclusions: PVA-borate semi-solids as novel PSs carriers might offer an innovative delivery system in the treatment against Streptococcus mutans

Dietary Changes During COVID-19 Lockdown in Adults With Type 1 Diabetes on a Hybrid Artificial Pancreas

In this retrospective analysis, we examine the impact of the lockdown of the coronavirus pandemic (COVID-19) on eating habits in individuals with type 1 diabetes (T1D) on a hybrid artificial pancreas (HAP). Dietary composition before and during lockdown was assessed by 7-day food records of 12 participants with T1D on HAP (three men and nine women, ages 38 ± 13 years, HbA1c 6.8 ± 0.3%, M ± SD). Continuous glucose monitoring (CGM) metrics and lifestyle changes (online questionnaire) were also assessed. Compared to prelockdown, reported body weight tended to increase during lockdown with no changes in total energy intake. Participants significantly decreased animal protein intake (−2.1 ± 3.7% of total energy intake, p = 0.048), but tended to increase carbohydrate intake (+17 ± 28 g/day, p = 0.052). These changes were induced by modifications of eating habits at breakfast and lunch during weekdays. Patients consumed more cereals (+21 ± 33 g/day, p = 0.038), whole grain (+22 ± 32 g/day, p = 0.044), and sweets (+13 ± 17 g/day, p = 0.021), and less animal protein sources (−42 ± 67 g/day, p = 0.054). Participants showed a more regular meal timing and decreased physical activity. Blood glucose control remained optimal (time-in-range 76 ± 8 vs. 75 ± 7% before lockdown), and daily total insulin infusion increased (42 ± 10 vs. 39 ± 12 I.U., p = 0.045). During the lockdown, patients with T1D on HAP modified dietary habits by decreasing animal protein and increasing carbohydrate intake. This increase, mainly concerning whole grain and low-glycemic-index products, did not influence blood glucose control

The evolving therapeutic landscape of trastuzumab-drug conjugates: Future perspectives beyond HER2-positive breast cancer

A novel class of drugs, antibody-drug conjugates (ADCs), are now rapidly emerging as highly effective treatments for solid tumours. ADCs conjugate conventional chemotherapeutics with highly selective targeted monoclonal antibodies. Anti-HER2 therapies selectively target cancer cells expressing human epidermal growth factor receptor 2 (HER2), among them trastuzumab has been the first HER2-targeting monoclonal antibody to achieve successful results that made it the backbone of anti-HER2 therapies. Trastuzumab drug conjugates (T-DCs), use trastuzumab as a selective antibody to lead cytotoxic drugs inside cancer cells. Trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-Dxd) are the two approved T-DCs. T-Dxd along with other five T-DCs represents “second generation ADCs” that has been firstly tested in HER2 positive breast cancer (BC) and then in HER2-low BC and other cancers showing promising results thanks to extraordinary and innovative pharmacokinetic and pharmacodynamic characteristics. The evidence generated so far are establishing them as a completely new class of agents effective in solid cancer treatments but also warrants physicians against unconventional toxicity profiles. The role of T-DCs in HER2-positive BC has been largely reviewed, while in this review, we provided for the first time in literature an overview of trastuzumab drug conjugates (T-DCs) approved and/or in clinical development with a specific focus on their efficacy and safety profile in HER2-low BC and other solid tumours different from BC. We started by analysing T-DCs biological characteristics that underly the differences in T-DCs pharmacodynamics and safety profile, then presented the main evidence on the activity and efficacy of these emerging T-DCs in HER2-low BC and other HER2 overexpressing and/or mutated solid tumours and lastly, we provided an overview of the complex and still evolving scenario in which these compounds should be allocated. A specific focus on possible combination strategies with other drugs such as immunotherapy, chemotherapy and target therapy, to increase T-DCs activity and eventually overcome future upcoming resistance mechanisms, are here also critically reviewed

Mometasone Furoate in Non-Allergic Rhinitis: A Real-Life Italian Study

Background: In order to evaluate the efficacy of intranasal mometasone furoate in patients with non-allergic rhinitis (NAR), a real-life, observational, prospective study is performed. Methods: Thirty-one patients (age 18-64 years) receive intranasal (mometasone furoate, 200 mu g b.i.d. for 15 consecutive days per month for 6 consecutive months), plus isotonic nasal saline. The cytologic pattern of local inflammation, nasal airflow, through peak nasal inspiratory flow (PNIF), quality of life (QoL), through the rhinitis quality of life questionnaire (RQLQ), the sinonasal outcome test (SNOT-22), the short-form 36-item health survey (SF-36v2), and the combined symptom medication score (CSMS), and, finally, olfactory function, through Sniffin' sticks-16 identification test (SSIT-16), are evaluated at baseline and after treatment. Results: NARNE is the most frequent cytological pattern (48% of the total sample). The therapeutic response shows improvement in olfactory function and QoL. Conclusions: The results of this study confirm that intranasal mometasone furoate is an effective treatment for patients with NAR

Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting CSCs compartment via YAP inhibition

Background: Despite the introduction of several novel therapeutic approaches that improved survival, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease. Herein we report the synergistic antitumor interaction between two well-known drugs used for years in clinical practice, the antiepileptic agent with histone deacetylase inhibitory activity valproic acid and the cholesterol lowering agent simvastatin, in mCRPC models. Methods: Synergistic anti-tumor effect was assessed on PC3, 22Rv1, DU145, DU145R80, LNCaP prostate cancer cell lines and EPN normal prostate epithelial cells, by calculating combination index (CI), caspase 3/7 activation and colony formation assays as well as on tumor spheroids and microtissues scored with luminescence 3D-cell viability assay. Cancer stem cells (CSC) compartment was studied evaluating specific markers by RT-PCR, western blotting and flow cytometry as well as by limiting dilution assay. Cholesterol content was evaluated by 1H-NMR. Overexpression of wild-type YAP and constitutively active YAP5SA were obtained by lipofectamine-based transfection and evaluated by immunofluorescence, western blotting and RT-PCR. 22Rv1 R_39 docetaxel resistant cells were selected by stepwise exposure to increasing drug concentrations. In vivo experiments were performed on xenograft models of DU145R80, 22Rv1 parental and docetaxel resistant cells, in athymic mice. Results: We demonstrated the capacity of the combined approach to target CSC compartment by a novel molecular mechanism based on the inhibition of YAP oncogene via concurrent modulation of mevalonate pathway and AMPK. Because both CSCs and YAP activation have been associated with chemo-resistance, we tested if the combined approach can potentiate docetaxel, a standard of care in mCRCP treatment. Indeed, we demonstrated, both in vitro and in vivo models, the ability of valproic acid/simvastatin combination to sensitize mCRPC cells to docetaxel and to revert docetaxel-resistance, by mevalonate pathway/YAP axis modulation. Conclusion: Overall, mCRPC progression and therapeutic resistance driven by CSCs via YAP, can be tackled by the combined repurposing of two generic and safe drugs, an approach that warrants further clinical development in this disease

The Impact of Lockdown on Couples' Sex Lives

Background: the aim of this study was to perform an Italian telematics survey analysis on the changes in couples' sex lives during the coronavirus disease 2019 (COVID-19) lockdown. Methods: a multicenter cross sectional study was conducted on people sexually active and in stable relationships for at least 6 months. To evaluate male and female sexual dysfunctions, we used the international index of erectile function (IIEF-15) and the female sexual function index (FSFI), respectively; marital quality and stability were evaluated by the marital adjustment test (items 10-15); to evaluate the severity of anxiety symptoms, we used the Hamilton Anxiety Rating Scale. The effects of the quarantine on couples' relationships was assessed with questions created in-house. Results: we included 2149 participants. The sex lives improved for 49% of participants, particularly those in cohabitation; for 29% it deteriorated, while for 22% of participants it did not change. Women who responded that their sex lives deteriorated had no sexual dysfunction, but they had anxiety, tension, fear, and insomnia. Contrarily, men who reported deteriorating sex lives had erectile dysfunctions and orgasmic disorders. In both genders, being unemployed or smart working, or having sons were risk factors for worsening the couples' sex lives. Conclusion: this study should encourage evaluation of the long-term effects of COVID-19 on the sex lives of couples

‘Sometimes there’s racism towards the French here’: xenophobic microaggressions in pre-2016 London as articulations of symbolic violence

This article discusses xenophobic microaggressions (Pierce, 1970) experienced by members of the French community in London prior to the EU-Membership Referendum in 2016. Acting at the interface of agency and passivity, implicitness and complicity, they go unseen in the social space despite their omnipresence. Through a close reading of empirical data collected as part of an ethnographic study, the article posits that these microaggressions are articulations of historically embedded anti-French ‘symbolic violence’ (Bourdieu and Wacquant, 1992; Bourdieu, 1993). The three main areas addressed are humour, intersectionality and the reproductive nature of the phenomenon (Bourdieu and Passeron, 1970; Bourdieu, 1972)

Biosurfactants produced by Bacillus subtilis A1 and Pseudomonas stutzeri NA3 reduce longevity and fecundity of Anopheles stephensi and show high toxicity against young instars

Anopheles stephensi acts as vector of Plasmodium parasites, which are responsible for malaria in tropical and subtropical areas worldwide. Currently, malaria management is a big challenge due to the presence of insecticide-resistant strains as well as to the development of Plasmodium species highly resistant to major antimalarial drugs. Therefore, the present study focused on biosurfactant produced by two bacteria Bacillus subtilis A1 and Pseudomonas stutzeri NA3, evaluating them for insecticidal applications against malaria mosquitoes. The produced biosurfactants were characterized using FT-IR spectroscopy and gas chromatography-mass spectrometry (GC-MS), which confirmed that biosurfactants had a lipopeptidic nature. Both biosurfactants were tested against larvae and pupae of A. stephensi. LC50 values were 3.58 (larva I), 4.92 (II), 5.73 (III), 7.10 (IV), and 7.99 (pupae) and 2.61 (I), 3.68 (II), 4.48 (III), 5.55 (IV), and 6.99 (pupa) for biosurfactants produced by B. subtilis A1 and P. stutzeri NA3, respectively. Treatments with bacterial surfactants led to various physiological changes including longer pupal duration, shorter adult oviposition period, and reduced longevity and fecundity. To the best of our knowledge, there are really limited reports on the mosquitocidal and physiological effects due to biosurfactant produced by bacterial strains. Overall, the toxic activity of these biosurfactant on all young instars of A. stephensi, as well as their major impact on adult longevity and fecundity, allows their further consideration for the development of insecticides in the fight against malaria mosquitoes

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types