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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has heavily impacted Italy. The government's restriction measures have attenuated the burden on hospitals. The association of high viral replication with disease severity suggests the potential for lower viral load in milder clinical presentations.

The reverse-transcription-polymerase-chain-reaction (RT-PCR) profile of 944 consecutive, non-replicate, positive retropharyngeal swabs was collected from 3 March to 8 June 2020 to investigate the temporal profile of SARS-CoV-2 viral load in the region of Capitanata, Apulia. Cycle threshold (Ct) values of 3 targets (N [nucleocapsid protein], E [envelope protein] and RdRP [RNA-dependent RNA-polymerase]) were analysed.

The median Ct values of the 3 targets increased considerably over the study period, showing a progressive and constant weekly change. The negative detection rate of E and RdRP increased over time. These data suggest that SARS-CoV-2 viral load progressively decreased along the outbreak course. During the first epidemic peak (March and April) the viral load among patients >80-years was significantly higher than for younger subjects. However, in May this age-dependent difference disappeared, underlying viral load reduction in the elderly.

An attenuation of viral transmission or pathogenicity during the epidemic course is suggested, likely due to restriction measures, although viral factors might also be considered.
An attenuation of viral transmission or pathogenicity during the epidemic course is suggested, likely due to restriction measures, although viral factors might also be considered.All vertebrates have baroreflexes that provide fast regulation of arterial blood pressure (PA) to maintain adequate tissue perfusion and avoid vascular lesions from excessive pressures. The baroreflex is a negative feedback loop, where altered PA results in reciprocal changes in heart rate (fH) and systemic vascular conductance to restore pressure. In terrestrial environments, gravity usually leads to blood pooling in the lower body reducing venous return, cardiac filling, cardiac output and PA. Conversely, in aquatic environments, the hydrostatic pressure of surrounding water mitigates blood pooling and prevents vascular distensions. In this context, we aimed to test the hypothesis that vertebrate species that were exposed to gravity-induced hemodynamic disturbances throughout their evolutionary histories have a more effective barostatic reflex than those that were not. We examined the cardiac baroreflex of fish that perform (Clarias gariepinus and Hoplerythrinus unitaeniatus) and do not perform (Hoplias malabaricus and Oreochromis niloticus) voluntary terrestrial sojourns, using pharmacological manipulations of PA to characterize reflex changes in fH using a four-variable sigmoidal logistic function (i.e. the "Oxford technique"). Our results revealed that amphibious fish exhibit higher baroreflex gain and responsiveness to hypotension than strictly aquatic fish, suggesting that terrestriality and the gravitational circulatory stresses constitute a relevant driving force for the evolution of a more effective baroreflex in vertebrates. We also demonstrate that strictly aquatic teleosts have considerable baroreflex gain, supporting the view that the baroreflex is an ancient cardiovascular trait that appeared before vertebrates colonized the gravity-dominated realm of land.Cardiovascular disease is the leading cause of death and disability worldwide. Effective delivery of cell-selective therapies that target atherosclerotic plaques and neointimal growth while sparing the endothelium remains the Achilles heel of percutaneous interventions. The current study utilizes synthetic microRNA switch therapy that self-assembles to form a compacted, nuclease-resistant nanoparticle less then 200 nM in size when mixed with cationic amphipathic cell-penetrating peptide (p5RHH). These nanoparticles possess intrinsic endosomolytic activity that requires endosomal acidification. When administered in a femoral artery wire injury mouse model in vivo, the mRNA-p5RHH nanoparticles deliver their payload specifically to the regions of endothelial denudation and not to the lungs, liver, kidney, or spleen. Moreover, repeated administration of nanoparticles containing a microRNA switch, consisting of synthetically modified mRNA encoding for the cyclin-dependent kinase inhibitor p27Kip1 that contains one complementary target sequence of the endothelial cell-specific miR-126 at its 5' UTR, drastically reduced neointima formation after wire injury and allowed for vessel reendothelialization. This cell-selective nanotherapy is a valuable tool that has the potential to advance the fight against neointimal hyperplasia and atherosclerosis.Lymphatic metastasis constitutes a leading cause of recurrence and mortality in bladder cancer. Accumulating evidence indicates that lymphangiogenesis is indispensable to trigger lymphatic metastasis. However, the specific mechanism is poorly understood. In the present study, we revealed a pathway involved in lymphatic metastasis of bladder cancer, in which a circular RNA (circRNA) facilitated lymphangiogenesis in a vascular endothelial growth factor C (VEGF-C)-independent manner. Novel circRNA circEHBP1 was markedly upregulated in bladder cancer and correlated positively with lymphatic metastasis and poor prognosis of patients with bladder cancer. circEHBP1 upregulated transforming growth factor beta receptor 1 (TGFBR1) expression through physically binding to miR-130a-3p and antagonizing the suppression effect of miR-130a-3p on the 3' UTR region of TGFBR1. Subsequently, circEHBP1-mediated TGFβR1 overexpression activated the TGF-β/SMAD3 signaling pathway, thereby promoting the secretion of VEGF-D and driving lymphangiogenesis and lymphatic metastasis in bladder cancer. Importantly, administration of VEGF-D neutralizing antibodies remarkably blocked circEHBP1-induced lymphangiogenesis and lymphatic metastasis in vivo. Our findings highlighted that the circEHBP1/miR-130a-3p/TGFβR1/VEGF-D axis contributes to lymphangiogenesis and lymphatic metastasis of bladder cancer independent of VEGF-C, which might lead to the development of circEHBP1 as a potential biomarker and promising therapeutic target for lymphatic metastasis in bladder cancer.Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR target genes. In this study, we designed an ATF6f/XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has a stronger effect in reducing the abnormal aggregation of mutant huntingtin and α-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson's disease and Huntington's disease. These results support the concept in which directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.Dynamic regulation has been widely applied to optimize metabolic flux distribution. However, compared with prokaryotes, quorum sensing-mediated pathway control is still very limited in Saccharomyces cerevisiae. In this study, we designed quorum sensing-regulated protein degradation circuits for dynamic metabolic pathway control in S. cerevisiae. The synthetic quorum sensing circuits were developed by integration of a plant hormone cytokinin system with the endogenous yeast Ypd1-Skn7 signal transduction pathway and the positive feedback circuits were optimized by promoter engineering. We then constructed an auxin-inducible protein degradation system and used quorum sensing circuits to regulate auxin synthesis to achieve dynamic control of protein degradation. As a demonstration, the circuits were applied to control Erg9 degradation to produce α-farnesene and the titer of α-farnesene increased by 80%. The population-regulated protein degradation system developed here extends dynamic regulation to the protein level in S. cerevisiae and is a promising approach for metabolic pathway control.
To conduct a systematic review and meta-analysis of the role of SBRTdrug combination in patients affected by mRCC and associated oncologic outcomes and toxicity profiles.

We performed a critical review of the Pubmed, Medline, and Embase databases from January 1, 2000 through April 30, 2020 according to the Preferred Reporting Items and Meta-Analyses statement. To assess the overall quality of the literature reviewed, we used a modified Delphi tool.

A total of 6 studies were included, corresponding to a cohort of 216 patients. Tyrosine Kinases Inhibitors were the most widely used drugs in combination with SBRT, being administered in 93% patients. No study reported an increase of radiation-induced toxicity.

SBRT resulted to be safe, without increase in terms of drugs-related adverse events in this setting. Moreover, this approach showed promising clinical outcomes in terms of LC and OS.
SBRT resulted to be safe, without increase in terms of drugs-related adverse events in this setting. Moreover, this approach showed promising clinical outcomes in terms of LC and OS.
Advanced upper tract urothelial carcinoma (UTUC) has different molecular and genetic features from the commonest carcinoma of the bladder, suggesting a possible different sensitivity to immune-checkpoint inhibitors (ICI).

A systematic review and meta-analysis of all relevant clinical studies including advanced UTUC patients treated with ICI was conducted according to PRISMA guidelines.

Six prospective trials for a total 2537 patients, including 396 (15.6 %) with advanced UTUC, were eligible for the analysis. UNC6852 ic50 In UTUC patients, the pooled ORR was 21.2 % (95 % CI, 12.5 %-33.7 %); the risk of death was reduced by 24 % over the standard platinum-based chemotherapy, but this was not statistically significant (hazard ratio = 0.76; 95 % confidence interval, 0.41-1.40; p = 0.37, χ2 = 3.28, p = 0.07; I2 = 70 %).

The current evidence does not support a statistically significant effect from ICI over the standard treatment for advanced UTUC patients. Properly performed pre-planned subgroup analyses from randomized clinical trials are eagerly awaited.
The current evidence does not support a statistically significant effect from ICI over the standard treatment for advanced UTUC patients. Properly performed pre-planned subgroup analyses from randomized clinical trials are eagerly awaited.
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