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Patients with SM are at increased risk of hypersensitivity reactions. Although hymenoptera venoms are the predominant triggers, cases of CMIHR have also been reported and prophylactic premedication is often performed. However, data from larger series are limited and differences between indolent and advanced systemic mastocytosis have not yet been investigated.

To determine the incidence and severity of CMIHR in all subtypes of SM.

We analyzed 162 adult patients with SM (ISM, n=65; advSM, n=97). Firstly, the cumulative incidence of CMIHR was retrospectively assessed in the patient's history. Secondly, at our institution, patients underwent 332 CM-enhanced imagings including 80 CT scans with iodine-based contrast agent and 252 MRI with gadoliniumbased contrast agent and tolerance was assessed.

Previous CMIHRs to CT (vomiting, n=1, erythema, n=1, cardiovascular shock, n=1) and MRI (dyspnea, n=1, cardiovascular shock, n=1) had been reported by 4/162 (2.5%) patients (ISM, n=3; advSM, n=1). In contrast, during or after 332 CM-enhanced CT/MRI examinations at our institution, no CMIHRs were reported. Premedication was solely given to 3 patients prior to CT scans, including one with previous CMIHR, who tolerated the imaging well.

We conclude that i) there is a significant discrepancy between perception and prevalence of hypersensitivity reactions to CM in SM, ii) reactions are scarce in ISM and even rarer in advSM, iii) in SM patients without previous history of CM hypersensitivity, prophylactic premedication prior to CM enhanced-CT/MRI is dispensable.
We conclude that i) there is a significant discrepancy between perception and prevalence of hypersensitivity reactions to CM in SM, ii) reactions are scarce in ISM and even rarer in advSM, iii) in SM patients without previous history of CM hypersensitivity, prophylactic premedication prior to CM enhanced-CT/MRI is dispensable.Strategies for cancer treatment have traditionally focused on suppressing cancer cell behavior, but many recent studies have demonstrated that regulating the tumor microenvironment (TME) can also inhibit disease progression. Macrophages are major TME components, and the direction of phenotype polarization is known to regulate tumor behavior, with M2-like polarization promoting progression. It is also known that reactive oxygen species (ROS) in macrophages drive M2 polarization, and M2 polarization promote lung cancer progression. Lung cancer patients with lower expression of the antioxidant enzyme peroxiredoxin 5 (Prx5) demonstrate poorer survival. This study revealed that Prx5 deficiency in macrophages induced M2 macrophage polarization by lung cancer. We report that injection of lung cancer cells produced larger tumors in Prx5-deficit mice than wild-type mice independent of cancer cell Prx5 expression. Through co-culture with lung cancer cell lines, Prx5-deficient macrophages exhibited M2 polarization, and reduced expression levels of the M1-associated inflammatory factors iNOS, TNFα, and Il-1β. Moreover, these Prx5-deficient macrophages promoted the proliferation and migration of co-cultured lung cancer cells. Conversely, suppression of ROS generation by N-acetyl cysteine (NAC) inhibited the M2-like polarization of Prx5-deficient macrophages, increased expression levels of inflammatory factors, inhibited the proliferation and migration of co-cultured lung cancer cells, and suppressed tumor growth in mice. These findings suggest that blocking the M2 polarization of macrophages may promote lung cancer regression.Toll like receptor 5 (TLR5) plays a crucial role in the innate immune response by recognizing bacterial flagellin proteins. In the present study, the genomic and 5'-flanking sequences of LcTLR5M (membrane) and LcTLR5S (soluble) were cloned from the large yellow croaker, Larimichthys crocea. Then, their promoter activities were determined in human embryonic kidney (HEK293T) cells. LcTLR5M contained 4 exons and 3 introns, and LcTLR5S contained 2 exons and 1 intron. Bioinformatic prediction of transcription factor binding sites (TFBSs) indicated that the promoter structures were different between LcTLR5M and LcTLR5S. Hydroxydaunorubicin HCl A dual luciferase assay showed that the deletion mutant -471 to +189 of LcTLR5M promoter possessed the greatest activity with 36 times activity of the control (P less then 0.05). For LcTLR5S, two deletion mutants, -1687 to +106 and - 720 to +106, showed high promoter activity. Furthermore, site-directed mutation demonstrated that a -392 to -391 AT/GG substitution in Oct-1 binding site, and a -104 to -103 GG/TT and a -98 to -97 CC/AA substitution in the NF-κB binding site of TLR5S caused a significant decline of luciferase activity (P less then 0.05). Moreover, the co-transfection of an NF-κB/p65 over-expression plasmid with wild type TLR5S (-720 to +106) resulted in an extremely significant increase of promoter activity by more than 9 times compared with the NF-kB mutant (P less then 0.01). Our findings suggest that the genomic organization and promoter structure may differ between LcTLR5M and LcTLR5S. Oct1 and NF-κB binding sites might be cis-regulatory elements in the LcTLR5S promoter. NF-κB/p65 plays an important role in LcTLR5S promoter activation through binding with the NF-κB binding site.
ATM, the protein defective in the human genetic disorder, ataxia telangiectasia (A-T) plays a central role in the response to DNA double strand breaks (DSBs) and in protecting the cell against oxidative stress. We recently showed that A-T cells are hypersensitive to metabolic stress which can be accounted for by a failure to exhibit efficient endoplasmic reticulum (ER)-mitochondrial signalling and Ca2
transfer in response to nutrient deprivation resulting in mitochondrial dysfunction. The objective of the current study is to use an anaplerotic approach using the fatty acid, heptanoate (C7), a metabolic product of the triglyceride, triheptanoin to correct the defect in ER-mitochondrial signalling and enhance cell survival of A-T cells in response to metabolic stress.

We treated control cells and A-T cells with the anaplerotic agent, heptanoate to determine their sensitivity to metabolic stress induced by inhibition of glycolysis with 2 deoxyglucose (2DG) using live-cell imaging to monitor cell survival f-deficient cells was accompanied by more reliance on aerobic glycolysis as shown by increased lactate dehydrogenase A (LDHA), accumulation of lactate and reduced levels of both acetyl CoA and ATP which are all restored by heptanoate.

These data together show that heptanoate corrects metabolic stress in A-T cells by restoring ER-mitochondria signalling and mitochondrial function and suggest that the parent compound, triheptanoin, has great potential as a novel therapeutic agent for patients with A-T.
These data together show that heptanoate corrects metabolic stress in A-T cells by restoring ER-mitochondria signalling and mitochondrial function and suggest that the parent compound, triheptanoin, has great potential as a novel therapeutic agent for patients with A-T.A high-quality dataset of 3289 complete SARS-CoV-2 genomes collected in Europe and European Economic Area (EAA) in the early phase of the first wave of the pandemic was analyzed. Among all single nucleotide mutations, 41 had a frequency ≥ 1%, and the phylogenetic analysis showed at least 6 clusters with a specific mutational profile. These clusters were differentially distributed in the EU/EEA, showing a statistically significant association with the geographic origin. The analysis highlighted that the mutations C14408T and C14805T played an important role in clusters selection and further virus spread. Moreover, the molecular analysis suggests that the SARS-CoV-2 strain responsible for the first Italian confirmed COVID-19 case was already circulating outside the country.Microbial production of natural compounds has attracted extensive attention due to their high value in pharmaceutical, cosmetic, and food industries. Constructing efficient microbial cell factories for biosynthesis of natural products requires the fine-tuning of gene expressions to minimize the accumulation of toxic metabolites, reduce the competition between cell growth and product generation, as well as achieve the balance of redox or co-factors. In this review, we focus on recent advances in fine-tuning gene expression at the DNA, RNA, and protein levels to improve the microbial biosynthesis of natural products. Commonly used regulatory toolsets in each level are discussed, and perspectives for future direction in this area are provided.Innovative technologies have been designed to improve efficacy and safety of chemical UV filters. Encapsulation can enhance efficacy and reduce transdermal permeation and systemic exposure. The aims of this work were (i) to determine the cutaneous biodistribution of avobenzone (AVO), oxybenzone (OXY), and octyl methoxycinnamate (OMC) incorporated in mesoporous silica SBA-15 and (ii) to perform preclinical (in vitro) and (iii) clinical safety studies to demonstrate their innocuity and to evaluate sun protection factor (SPF) in humans. Skin penetration studies showed that deposition of OXY and AVO in porcine and human skin after application of stick formulation with incorporated filters (stick incorporated filters) was significantly lower than from a marketed (non-encapsulated) stick. Cutaneous deposition and transdermal permeation of OXY in and across human skin were 3.8-and 13.4- fold lower, respectively, after application of stick entrapped filters. Biodistribution results showed that encapsulation in SBA-15 decreased AVO and OXY penetration reaching porcine and human dermis. Greater deposition (and permeation) of OXY in porcine skin than in human skin, pointed to the role of follicular transport. Stick incorporated filters had good biocompatibility in vivo and safety profiles, even under sun-exposed conditions. Entrapment of UV filters improved the SPF by 26% and produced the same SPF profile as a marketed stick. Overall, the results showed that SBA-15 enabled safety and efficacy of UV filters to be increased.The effect of sex hormones on global-local tasks has rarely been studied, offering, when done, conflicting results possibly modulated by the congruency between hierarchical stimuli, and by the attentional demands. Here, we examined the global advantage (GA) effect in men (with high testosterone levels), women in the mid-luteal phase (with high levels of estradiol and progesterone), in the ovulatory phase (with high estradiol but low progesterone levels); and in the early follicular phase and with hormonal contraceptive (HC) use (with low sex hormone levels). The level of processing (global-local), the congruency (congruent vs. incongruent), and attentional demands (divided vs. selective) were manipulated. The divided-incongruent condition was sensible to estradiol and progesterone levels and, in this condition, mid-luteal women performed more locally while men performed more globally. The selective-incongruent condition was sensible to the testosterone level and, in this condition, men were faster. The HC group showed a congruency effect in the GA reaction times (RTs) during both, divided and selective conditions. Finally, the GA RTs of the ovulatory group differed from the early follicular and mid-luteal groups only in the congruent-selective condition, but the performance was not related with sex hormone levels. This result is interpreted in relation with the brain effects of estradiol in the absence but not in the presence of progesterone. Thus, sex, menstrual cycle, HC, task difficulty and sex hormones seem to modulate performance in the global-local task. These factors represent an important source of variability in studies focused on the processing of hierarchical stimuli and allow apparently inconsistent data to be explained.
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