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Exosomes derived from solid tumour cells are involved in immune suppression, angiogenesis and metastasis; however, the role of leukaemia-derived exosomes has less been investigated. Hence, changes in immune response-related genes and human T cells apoptosis co-incubated with exosomes isolated from patients' pre-B cell acute lymphoblastic leukaemia were evaluated in this in vitro study. Vein blood sample was obtained from each newly diagnosed acute lymphoblastic leukaemia (ALL) patient prior any therapy. ALL serum exosomes were isolated by ultrafiltration and characterized using Western blotting and transmission electron microscopy. Exosomes were then co-incubated with T lymphocytes and the gene expressions, as well as functions of human T cells were quantified by qRT-PCR. Apoptosis and caspase-3 and caspase-9 protein expression were also evaluated by flowcytometry and Western blotting analysis, respectively. Exosomes isolated from ALL patients affected T lymphocytes and elevated the apoptosis. Moreover, these exosomes altered the T cells profile into regulatory type by increasing the expression of FOXP3 and Tregs-related cytokines, including TGF-B and IL-10. The expression level of Th17-related transcription factors (RoR gamma t) and interleukins (IL-17 and IL-23) decreased after this treatment. According to our findings, exosomes derived from ALL patients' sera carry immunosuppressive molecules, indicating the possible effect of exosomes as liquid biomarkers for cancer staging. The authors would acknowledge the stem cell research center at Tabriz University of Medical Sciences (TUOMS), Tabriz, Iran, for their great help. This work was financially supported by Tabriz University of Medical Sciences [63611 as grant number].

Concerning the impact of neurogenic lower urinary tract dysfunction (NLUTD) on quality of life, besides the lack of standard psychometrically-analyzed Persian tools, the present study investigated the validity and reliability of the Persian version of the neurogenic bladder symptom score (NBSS) questionnaire.A total of 279 multiple sclerosis (MS) or stroke/cerebrovascular accident (CVA) patients over 18 years of age with NLUTD referred to the neurology clinics entered the study in 2021-2022. After translation, back-translation, and developing a Persian version, its validity and reliability were determined. The content validity index (CVI) and content validity ratio (CVR) were calculated quantitatively. To determine the internal consistency and scale reliability, a test-retest was used.The Cronbach's α coefficient was 0.83 and the intraclass correlation coefficient (95% confidence interval) was 0.85 (0.82, 0.88). Cronbach's α in all domains (incontinence, storage and voiding, and consequence) was greater than 0.70. The criterion validity also showed a positive correlation of NBSS with the International Consultation on Incontinence Questionnaire-overactive bladder (p lt; 0.001 and r = 0.55). The face validity was acceptable according to the opinion of 10 participants. To determine the CVI and the CVR, 10 experts' panels reviewed all items related to the questionnaire in terms of necessity, clarity, transparency, and relevancy. Based on the expert panel all NBSS criteria got a high score, and all criteria were essential to assess NLUTD (CVI: 0.78-1).Regarding validity and reliability, the Persian version NBSS questionnaire can properly evaluate NLUTD in MS or stroke/CVA patients.

This meta-analysis was conducted to determine the relationship between neutrophil to lymphocyte ratio (NLR) and febrile seizure (FS). Our study was registered with the PROSPERO (ID: CRD42021259944). Web of Science, Embase, PubMed, Scopus, and ProQuest Central were searched, and finally, 17 studies were included. Standardized mean difference (SMD) was reported with a 95% confidence interval (CI) for the NLR levels. Compared with the febrile control group, the FS patients’ NLR levels were significantly higher ( SMD = 0.49 ; 95 % CI = 0.26 to 0.72, P < 0.001 ). Furthermore, we conducted a comparison of NLR levels between febrile controls against simple and complex FS cases separately and found that NLR levels of children with either simple or complex FS were higher compared with those of febrile controls ( SMD = 0.42 , 95 % CI = 0.14 to 0.69, P = 0.003 and SMD = 0.90 , 95 % CI = 0.71 to 1.09, P < 0.001 , respectively). Also, in comparison with the NLR levels of the simple FS group, the complex FS patients’ NLR levels were significantly higher ( SMD = 0.59 , 95 % CI = 0.34 to 0.85, P < 0.001 ). Our study indicated that NLR could be recommended as an inexpensive diagnostic biomarker for FS. In addition, it can be useful when distinguishing between simple FS and complex FS.

Animal environments for the growth of stem cells cause the transmission of some diseases and immune problems for the recipient. Accordingly, replacing these environments with healthy environments, at least with human resources, is essential. One of the media that can be used as an alternative to animal serums is Wharton acellular jelly (AWJ). Therefore, in this study, we intend to replace FBS with Wharton jelly and investigate its effect on the expression of megakaryocyte-related genes and markers in stem cells.In this study, cord blood-derived CD34 positive HSCs were cultured and expanded in the presence of cytokines including SCF, TPO, and FLT3-L. Then, the culture of expanded CD34 positive HSCs was performed in two groups: 1) IMDM culture medium containing 10% FBS and 100 ng / ml thrombopoietin cytokine 2) IMDM culture medium containing 10% AWJ, 100 ng / ml thrombopoietin cytokine. Finally, CD41 expressing cells were analyzed with the flow cytometry method. The genes related to megakaryocyte lineage including FLI1 and GATA2 were also evaluated using the RT-PCR technique. Results: The expression of CD41, a specific marker of megakaryocyte lineage in culture medium containing Wharton acellular jelly was increased compared to the FBS group. Additionally, the expression of GATA2 and FLI1 genes was significantly increased related to the control group.This study provided evidence of differentiation of CD34 positive hematopoietic stem cells from umbilical cord blood to megakaryocytes in a culture medium containing AWJ.br /.

The aim of the current review was to explore the association between various dietary antioxidants and the risk of developing Parkinson's disease (PD). PubMed, Scopus, Web of Science, and Google Scholar were searched up to March 2021. Prospective, observational cohort studies, nested case-control, and case-control designs that investigated the association between antioxidants and PD risk were included. A random-effects model was used to pool the RRs. The certainty of the evidence was rated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluations) scoring system. In addition, a dose-response relation was examined between antioxidant intake and PD risk. Six prospective cohort studies and 2 nested case-control (total n = 448,737 with 4654 cases), as well as 6 case-control (1948 controls, 1273 cases) studies were eligible. The pooled RR was significantly lower for the highest compared with the lowest intake categories of vitamin E (n = 7; 0.84; 95% CI: 0.71, 0.99) and anthocyanins (n = 2; 0.76; 95% CI: 0.61, 0.96) in cohort studies. Conversely, a significantly higher risk of PD was observed for higher lutein intake (n = 3; 1.86; 95% CI: 1.20, 2.88) among case-control studies. Dose-response meta-analyses indicated a significant association between a 50-mg/d increase in vitamin C (n = 6; RR: 0.94; 95% CI: 0.88, 0.99), a 5-mg/d increment in vitamin E (n = 7; RR: 0.84; 95% CI: 0.70, 0.99), a 2-mg/d increment in β-carotene (n = 6; RR: 0.94, 95% CI: 0.89, 0.99), and a 1-mg/d increment in zinc (n = 1; OR: 0.65; 95% CI: 0.49, 0.86) and a reduced risk of PD. Overall, higher intake of antioxidant-rich foods may be associated with a lower risk of PD. Future well-designed prospective studies are needed to validate the present findings. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (https://www.crd.york.ac.uk/PROSPERO, CRD42021242511).

The emergence and global spread of multidrug-resistant Helicobacter pylori (MDR H. pylori) is a major health problem in children, which can increase the risk of serious complications such as gastric cancer. The aim of this study was to determine the prevalence of primary MDR H. pylori in children via a comprehensive systematic literature review and meta-analysis.All potential studies were collected from international databases like: ISI Web of Science, Embase, PubMed, Google Scholar, and Scopus from 2011-July 24, 2022. Ultimately, primary MDR H. pylori in children was measured as an event rate with corresponding 95% confidence intervals.A total of 19 studies met the inclusion criteria. The overall prevalence of primary MDR H. pylori in children was measured at 6.0% (95% CI: 3.1-11.6); There was a significant difference in primary MDR H. pylori resistance rates between Asian populations and Western countries.The global spread of MDR H. pylori strains could significantly limit the options of anti-H. pylori treatment regimens. The frequency of primary MDR H. pylori infection differs between various geographical regions. Thus, drug susceptibility testing and the eradication of H. pylori infection can effectively reduce and control the spread of H. pylori antibiotic resistance throughout the world.

The outbreak of the COVID-19 virus dramatically changed daily life and created many obstacles for adolescents to engage in physical activity (PA). This study tracked rates of self-reported PA and examined its impact on adjustment among adolescents during the first 14 months of the pandemic. Canadian adolescents (N = 1068, 14–18 y, meanage = 16.95 y) reported on their frequency of PA, context of activity, and adjustment across 4 time points (April 2020 to June 2021). In line with our hypothesis, higher average levels of vigorous PA across the pandemic predicted less anxiety and depression and higher self-esteem at our study’s end. Vigorous PA also buffered the relationships COVID-19 stress had with anxiety and self-esteem. The results further support recommendations for PA throughout the pandemic and while dealing with lockdown situations.

Despite the beneficial effects of sperm cryopreservation, increased reactive oxygen species (ROS) production during this process can affect spermatozoon structure and function. Moreover, ROS production is associated with elevated DNA damage and alterations in DNA methylation. There is little information about the effects of cryopreservation on epigenetic modulation in sperm and the health of children born with frozen spermatozoa. Considering the potential consequences of cryopreservation in ART-conceived children, it is necessary to assure that cryopreservation does not modify sperm DNA methylation status. This review summarizes reports on epigenetic modifications of spermatozoa during cryopreservation and the probable effects of this process on offspring health. Contradictory results have reported the influence of sperm cryopreservation on DNA methylation in imprinted genes. Multiclinical studies with larger sample sizes under the same conditions of cryopreservation and DNA methylation analysis are needed to make any definitive conclusion about the effect of the cryopreservation process on sperm DNA methylation.

Background: Inversion of chromosome 9 (inv[9]) is known as one of the most common structural balanced chromosomal variations. Chromosome 9 is highly susceptible to structural rearrangements, specifically to pericentric inversions. Various investigators have posited that inv(9) with different breakpoints could be the cause of several abnormal conditions in individuals, whereas others have considered it a benign variant. To our knowledge, a consensus regarding the effects of this inversion has yet to emerge. Objective: This study aims to discuss the pathogenic/benign effects of inv(9) in all possible clinical conditions detected in the occurrence of this abnormality. Methods: Studies on inv(9) were collected via PubMed, MalaCards, Google Scholar, and NORD, along with the search terms of inv(9), pericentric inv(9), and chromosome 9 variants. Additionally, the incidence of inv(9) and the karyotype and clinical findings of individuals reported with this variant were investigated. Results: The collection of the studies reviewed shows that inv(9) is associated with various conditions such as congenital anomalies, growth retardation, infertility, recurrent pregnancy loss, and cancer. The clinical features associated with this variant in humans vary between growth stages. Further, there have been no shared clinical findings in a specific period. Conclusions: Although there is no conclusive evidence for the pathogenicity of this rearrangement, prenatal genetic counseling on inv(9) and further clinical and molecular studies would be helpful in chromosome 9-related problems.

Background One of the key limitations of targeted cancer therapies is the rapid onset of therapy resistance. Taking BRAF-mutant melanoma as paradigm, we previously identified the lipogenic regulator SREBP-1 as a central mediator of resistance to MAPK-targeted therapy. Reasoning that lipogenesis-mediated alterations in membrane lipid poly-unsaturation lie at the basis of therapy resistance, we targeted fatty acid synthase (FASN) as key player in this pathway to evoke an exquisite vulnerability to clinical inducers of reactive oxygen species (ROS), thereby rationalizing a novel clinically actionable combination therapy to overcome therapy resistance. Methods Using gene expression analysis and mass spectrometry-based lipidomics of BRAF-mutant melanoma cell lines, melanoma PDX and clinical data sets, we explored the association of FASN expression with membrane lipid poly-unsaturation and therapy-resistance. Next, we treated therapy-resistant models with a preclinical FASN inhibitor TVB-3664 and a panel of ROS inducers and performed ROS analysis, lipid peroxidation tests and real-time cell proliferation assays. Finally, we explored the combination of MAPK inhibitors, TVB-3664 and arsenic trioxide (ATO, as a clinically used ROS-inducer) in Mel006 BRAF mutant PDX as a gold model of therapy resistance and assessed the effect on tumor growth, survival and systemic toxicity. Results We found that FASN expression is consistently increased upon the onset of therapy resistance in clinical melanoma samples, in cell lines and in Mel006 PDX and is associated with decreased lipid poly-unsaturation. Forcing lipid poly-unsaturation in therapy-resistant models by combining MAPK inhibition with FASN inhibition attenuated cell proliferation and rendered cells exquisitely sensitive to a host of ROS inducers. In particular, the triple combination of MAPK inhibition, FASN inhibition, and the clinical ROS-inducing compound ATO dramatically increased survival of Mel006 PDX models from 15 to 72% with no associated signs of toxicity. Conclusions We conclude that under MAPK inhibition the direct pharmacological inhibition of FASN evokes an exquisite vulnerability to inducers of ROS by increasing membrane lipid poly-unsaturation. The exploitation of this vulnerability by combining MAPK and/or FASN inhibitors with inducers of ROS greatly delays the onset of therapy resistance and increases survival. Our work identifies a clinically actionable combinatorial treatment for therapy-resistant cancer.

This study aimed to evaluate serum 25-hydroxyvitmain D and zinc levels in coronavirus disease 2019 (COVID-19) patients in comparison to healthy subjects.This was a single-center case-control study performed from March 20, 2020, to January 20, 2021, in Tehran, Iran. All patients diagnosed with COVID-19 based on a positive nasopharyngeal swab polymerase chain reaction (PCR) test were included in the case group. Controls were selected from patients referred for routine checkups who had a negative COVID-19 PCR test. Age, sex, marital and educational status, comorbidities, and serum 25-hydroxyvitmain D and zinc levels of patients were recorded.Ninety patients in the case group and 95 subjects in the control group who were sex and age-matched were studied. 25-hydroxyvitmain D levels higher than 20 ng/ml were observed in 58 (64%) cases and 72 (76%) controls (P = 0.09). The median 25-hydroxyvitmain D level in the case group was significantly lower than controls (26 (interquartile range [IQR] = 24) ng/ml vs. 38 (IQR = 22) ng/ml, respectively, P 0.01). The median zinc level in the case group was 56 (IQR = 23) mcg/dL, while it was 110 (IQR = 27) mcg/dL among the controls (P 0.01). There was no significant difference in the level of 25-hydroxyvitmain D and zinc between cases with and without comorbidities (P 0.05). Susceptibility to SARS-CoV-2 infection could be predicted by serum 25-hydroxyvitmain D levels below 25.2 ng/ml (81% sensitivity; 48% specificity) or zinc levels below 86.3 mcg/dL (93% sensitivity; 92% specificity).Low serum zinc and 25-hydroxyvitmain D levels appear to be risk factors for COVID-19 affliction; thus, the treatment of individuals with such deficiencies is recommended.

This study aims to evaluate the expression of genes associated with the fertilisation potential and embryo development, sperm DNA fragmentation (SDF), and acrosome reaction in male partners of infertile couples with different sperm parameters compared to fertile men. First, male partners of infertile couples with abnormal (N = 25) and normal sperm parameters (N = 25), and fertile men (N = 10) were included in experimental groups I, II, and controls respectively. The mRNA levels of the Annexin A2 (ANXA2), Sperm protein 17 (SP17), Plasma serine protease inhibitor (SERPINA5), and Peroxiredoxin-2 (PRDX2) genes and SDF were evaluated. To evaluate the maturity of the sperm and oxidative stress, the acrosome reaction, the lipid peroxidation, and total antioxidant were measured. As result, SP17 showed a significantly lower expression in both experimental groups. SERPINA5 was significantly down-regulated in experimental group I that was aligned with the low rate of acrosome reaction. Significant overexpression of PRDX2 was found between experimental group II and controls. Significant higher rates of SDF were seen in both experimental groups compared to the controls. Finally, our data suggest that differentially gene expression of SP17 is a potential diagnostic biomarker in infertile men either with normal or abnormal sperm parameters. SDF is one of the causes of male infertility, independent of the sperm parameters.

Neurodegenerative diseases are incongruous, commonly age-related disorders characterized by progressive neuronal loss, comprising the most prevalent being Alzheimer's disease, Parkinson's disease, and Huntington's disease. Perilous health states are anticipated following the neurodegeneration. Their etiology remains largely ambiguous, while various mechanisms are ascribed to their pathogenesis. A recommended conception is regarding the role of p53, as a transcription factor regulating numerous cellular pathways comprising apoptosis. Neuronal fates are a feasible occurrence that contributes to all neurodegenerative diseases. In this work, we review the research investigated the potential role of p53 in the pathogenesis of these diseases. We put special emphasis on intricate We not only describe aberrant changes in p53 level/activity observed in CNS regions affected by particular diseases but, most importantly, put special attention to the complicated reciprocal tuning connections prevailing between p53 and molecules considered in pathological hallmarks of these disorders. Natural and synthetic medications regulating p53 expression are regarded as well.

Drug resistance and relapse are common challenges in acute myeloid leukemia (AML), particularly in an aggressive subset bearing internal tandem duplications (ITDs) of the FLT3 receptor (FLT3-ITD+). The tyrosine kinase inhibitor gilteritinib is approved for the treatment of relapse/refractory AML with FLT3 mutations, yet resistance to gilteritinib remains a clinical concern, and the underlying mechanisms remain incompletely understood. Using transcriptomic analyses and functional validation studies, we identified the calcium-binding proteins S100A8 and S100A9 (S100A8/A9) as contributors to gilteritinib resistance in FLT3-ITD+ AML. Exposure of FLT3-ITD+ AML cells to gilteritinib increased S100A8/A9 expression in vivo and in vitro and decreased free calcium levels, and genetic manipulation of S100A9 was associated with altered sensitivity to gilteritinib. Using a transcription factor screen, we identified the transcriptional corepressor BCL6, as a regulator of S100A9 expression and found that gilteritinib decreased BCL6 binding to the S100A9 promoter, thereby increasing S100A9 expression. Furthermore, pharmacological inhibition of BCL6 accelerated the growth rate of gilteritinib-resistant FLT3-ITD+ AML cells, suggesting that S100A9 is a functional target of BCL6. These findings shed light on mechanisms of resistance to gilteritinib through regulation of a target that can be therapeutically exploited to enhance the antileukemic effects of gilteritinib.

We aimed to explore the relationship between intakes of food-derived antioxidants (zinc, vitamin E, β-carotene, and selenium) and semen parameters in an infertile male population. This is a cross-sectional study among infertile men (> 18 years) referred to Isfahan Fertility and Infertility Center in Iran from March 2019 to October 2019. The main outcome measures were semen volume, sperm count, concentration, total motility, and morphology. Micronutrients considered in this analysis were zinc, selenium, β-carotene, and vitamin E. A total of 350 infertile men with a mean (SE) age of 34.77 (0.42) were included in this study. Selenium intake tended to be positively associated with higher semen volume (β = 0.79; 95% CI: - 0.01, 1.59) and sperm total motility after adjustment for main confounders (β = 2.64; 95% CI: - 3.61, 8.89). Intake of β-carotene was only associated with higher sperm total motility (β = 5.46; 95% CI: - 0.84, 11.77). No significant association was detected between intakes of zinc and vitamin E and semen parameters.In a population of infertile adult men, selenium intake was associated with higher sperm total motility and semen volume, and in the case of β-carotene, better sperm total motility. Further, prospective studies are warranted.

Phytosterols (PSs), classified into plant sterols and stanols, are bioactive compounds found in foods of plant origin. PSs have been proposed to exert a wide number of pharmacological properties, including the potential to reduce total and low-density lipoprotein (LDL) cholesterol levels and thereby decreasing the risk of cardiovascular diseases. Other health-promoting effects of PSs include anti-obesity, anti-diabetic, anti-microbial, anti-inflammatory, and immunomodulatory effects. Also, anticancer effects have been strongly suggested, as phytosterol-rich diets may reduce the risk of cancer by 20%. The aim of this review is to provide a general overview of the available evidence regarding the beneficial physiological and pharmacological activities of PSs, with special emphasis on their therapeutic potential for human health and safety. Also, we will explore the factors that influence the physiologic response to PSs.

Adjuvant-aided combination chemotherapy is one of the most effective ways of cancer treatment by overcoming the multidrug resistance (MDR) and reducing the side-effects of anticancer drugs. In this study, Conferone (Conf) was used as an adjuvant in combination with Doxorubicin (Dox) for inducing apoptosis to MDA-MB-231 cells. Herein, the novel biodegradable amphiphilic β-cyclodextrin grafted poly maleate-co-PLGA was synthesized by thiol-ene addition and ring-opening process. Micelles obtained from the novel copolymer showed exceptional properties such as small size of around 34.5 nm, CMC of 0.1 μg/mL, and cell internalization of around 100% at 30 min. These novel engineered micelles were used for combination delivery of doxorubicin-conferone with high encapsulation efficiency of near 100% for both drugs. Our results show that combination delivery of Dox and Conf to MDA-MB-231 cells had synergistic effects (CI IC50 = 0.259 μg/mL). RT-PCR and western-blot tests show that Dox-Conf loaded βCD-g-PMA-co-PLGA micelle induced apoptosis via intrinsic pathway. Therefore, the unique design of multi-functional pH-sensitive micelles open a new perspective for the development of nanomedicine for combination chemo-adjuvant therapy against malignant cancer.

Inflammatory bowel disease is a chronic inflammatory disease of the gastrointestinal tract. The gut microbiota is an important factor in the pathogenesis of inflammatory bowel disease (IBD). Due to a link between the gut microbiota and IBD, studying microbiota changes using an accurate, sensitive and rapid method for detection of the disease seems necessary. This study aimed to compare the composition of gut microbiota in three groups of people, including IBD patients, cured Inflammatory bowel disease (CIBD), and healthy groups.For this study, 45 stool samples (15 from each group) were collected. Using real-time PCR, the abundance of 11 bacterial 16S rRNA gene sequences was examined.In the IBD group, the number of three bacterial phyla, including Firmicutes, Actinobacteria, and Bacteroidetes, decreased (p0.01, p0.01, and p0.001, respectively), while the population of γ-Proteobacteria increased significantly (p0.0001). In the CIBD group, the number of Actinobacteria enhanced (p0.01), but that of Bacteroidetes and Firmicutes decreased (p0.01, and p0.05, respectively).Findings of this study indicate that decrease in Firmicutes and increase in γ-Proteobacteria could be used as an indicator of IBD instead of employing invasive and costly detection methods such as colonoscopy and other tests.

Conventional sperm processing uses centrifugation has a negative effect on sperm parameters and DNA integrity. We designed and fabricated a novel microfluid device based on chemotaxis and thermotaxis, and compared it with the swim-up method. Twenty normal samples with high DNA fragmentation were included. Each sample was divided into four groups: Group 1, control, Group 2: sperm selection by thermotaxis, Group 3: sperm selection by chemotaxis, and Group 4: sperm selection with thermotaxis and chemotaxis. We used cumulus cells in a microfluid device to create chemotaxis, and, two warm stages to form a temperature gradient for thermotaxis. The spermatozoa were assessed based on the concentration, motility, and fine morphology using Motile Sperm Organelle Morphology Examination, mitochondrial membrane potential (MMP), acrosome reaction (AR), and sperm DNA fragmentation. Concentration (22.40 ± 5.39 vs. 66.50 ± 19.21; p 0.001) and DNA fragmentation (12.30 ± 3.96% vs. 17.95 ± 2.89%; p 0.001) after selection in the chemotaxis and thermotaxis microfluid device were significantly lower than control group. The progressive motility (93.75 ± 4.39% vs. 75.55 ± 5.86%, p 0.001), normal morphology (15.45 ± 2.50% vs. 10.35 ± 3.36, p 0.001), MMP (97.65 ± 1.81% vs. 94 ± 3.89%, p = 0.02), and AR status (79.20 ± 5.28% vs. 31.20 ± 5.24%, p 0.001) in the chemotaxis and thermotaxis microfluid device were significantly increased compared to control group. According to these findings, spermatozoa that have penetrated the cumulus oophorus have better morphology and motility, as well as acrosome reactivity and DNA integrity.

Chronic myeloid leukemia (CML) is a model of leukemogenesis in which the exact molecular mechanisms underlying blast crisis still remained unexplored. The current study identified multiple common and rare important findings in myeloid blast crisis CML (MBC-CML) using integrated genomic sequencing, covering all classes of genes implicated in the leukemogenesis model. Integrated genomic sequencing via Whole Exome Sequencing (WES), Chromosome-seq and RNA-sequencing were conducted on the peripheral blood samples of three CML patients in the myeloid blast crisis. An in-house filtering pipeline was applied to assess important variants in cancer-related genes. Standard variant interpretation guidelines were used for the interpretation of potentially important findings (PIFs) and potentially actionable findings (PAFs). Single nucleotide variation (SNV) and small InDel analysis by WES detected sixteen PIFs affecting all five known classes of leukemogenic genes in myeloid malignancies including signaling pathway components (ABL1, PIK3CB, PTPN11), transcription factors (GATA2, PHF6, IKZF1, WT1), epigenetic regulators (ASXL1), tumor suppressor and DNA repair genes (BRCA2, ATM, CHEK2) and components of spliceosome (PRPF8). These variants affect genes involved in leukemia stem cell proliferation, self-renewal, and differentiation. Both patients No.1 and No.2 had actionable known missense variants on ABL1 (p.Y272H, p.F359V) and frameshift variants on ASXL1 (p.A627Gfs*8, p.G646Wfs*12). The GATA2-L359S in patient No.1, PTPN11-G503V and IKZF1-R208Q variants in the patient No.3 were also PAFs. RNA-sequencing was used to confirm all of the identified variants. In the patient No. 3, chromosome sequencing revealed multiple pathogenic deletions in the short and long arms of chromosome 7, affecting at least three critical leukemogenic genes (IKZF1, EZH2, and CUX1). The large deletion discovered on the short arm of chromosome 17 in patient No. 2 resulted in the deletion of TP53 gene as well. Integrated genomic sequencing combined with RNA-sequencing can successfully discover and confirm a wide range of variants, from SNVs to CNVs. This strategy may be an effective method for identifying actionable findings and understanding the pathophysiological mechanisms underlying MBC-CML, as well as providing further insights into the genetic basis of MBC-CML and its management in the future.

Biodiversity refers to genetic diversity and complex sets of communities and ecosystems. Environmental degradation can jeopardize biodiversity and decrease ecosystem service quality. Biodiversity is not an endless and free commodity, and the costs of its destruction must be taken into account. Thus, estimating the monetary value of a region's biodiversity can help stakeholders understand its economic, social, and cultural status, and ultimately, by increasing public awareness, community demands for protection and investment are properly shaped. This study aims to estimate the monetary value of biodiversity in the Central Alborz Protected Area in Iran. This area is part of the Alborz Mountain range and the wildlife and plant species of this region have a unique biodiversity. For this purpose, the willingness to pay was estimated. In designing the Choice Experiment, five attributes including "wildlife species status," "plant species status," "natural landscape," "research facilities," and "tourism facilities" have been considered. The results showed that maintaining and improving the status of animal species and tourism conditions among respondents has a higher priority than the other three attributes. The annual value of marginal willingness to pay was 13020 Tomans per person and the conservation value of biodiversity is estimated at 23 billion Tomans. Also, the results of the simple Logit model showed that the average per capita willingness to pay the respondents to protect the region is 16,369 Tomans and the value of biodiversity protection is about 28.6 billion Tomans.

Objective As part of the bioinformatics studies, we utilized National Cancer Institute (NCI)'s Breast Cancer Risk Assessment Tool to estimate the five-year period and lifetime risk of breast cancer development among Iraqi risky women. Methods Totally, 110 risky women aged 21-67 (mean=36±7.4) years were interviewed by a series of questions regarding the risk of breast cancer development. Moreover, 100 cases with mutation in the BRCA1 or BRCA2 genes were included. Results Our results demonstrated that the patient's estimated risk of breast cancer development during the next five years and lifetime (until the age 90 years) included 0.96% (p=0.211) and 9.97% (p=0.002), respectively being relatively low. Accordingly, the lifetime risk for the breast cancer development was significantly higher (10.38%) than that of 5-year. However, the age of patients was not significantly associated to the breast cancer development as there was no significant difference among various age groups. Conclusion It was concluded that long-term or lifetime period plays as a significant risk factor for developing breast cancer among female patients who had had a screening episode in Iraq.

Purpose The aim of the study was to evaluate the additional effect of vestibular rehabilitation therapy (VRT) compared with the modified Epley procedure alone on residual dizziness after a successful modified Epley procedure in patients with posterior canal benign paroxysmal positional vertigo (BPPV). Method In this cross-sectional analytical comparative study, 47 patients (35 women and 12 men) aged 18–80 years with posterior canal BPPV were randomly assigned to one of two following groups: the control group, who received the modified Epley procedure only, and the VRT group, who received the modified Epley procedure plus vestibular rehabilitation for 4 weeks. Outcome measures, including the Dizziness Handicap Inventory (DHI), the Vertigo Symptom Scale–Long Version (VSS-L), and the Vertigo Symptom Scale–Short Form (VSS-SF), were conducted on the same session before initial therapy (T1), at 48 hr later (T2), and at 4 weeks later (T3). Presence or absence of residual dizziness was evaluated at T2. Results Residual dizziness was found in 20 (42.6%) patients after a successful modified Epley procedure. There was no statistically significant difference between the mean DHI, VSS-L, and VSS-SF scores at T1, T2, and T3 in patients who manifested with residual dizziness and those without residual dizziness in both groups. The average DHI, VSS-L, and VSS-SF score reduced during the time in both groups. These results were demonstrated that the VRT group and the control group have similar reductions in symptoms after treatment with the VRT plus modified Epley procedure and the modified Epley procedure only, respectively. Conclusions Residual dizziness is a common condition after a successful modified Epley procedure for BPPV. The VRT plus modified Epley procedure is as effective as modified Epley procedure alone in the management of residual dizziness. Further studies with supervised and customized VRT and longer follow-up periods are needed. Supplemental Material https://doi.org/10.23641/asha.14825508

The leakage of toluene from damaged tanks can threaten both workers and the environment; ergo, the effects and consequences of toluene leaks can be modeled and quantified to aid in emergency planning and response management. This study modeled the effects and consequences on various scenarios of toluene release via the ALOHA and PHAST programs: evaporation puddle formation, dispersion of toxic and flammable vapor clouds, the distribution of lethal concentrations, and the probability of death from a toluene leak from a height of 6 m of the tank wall. The outputs of the two modeling programs were analyzed and compared. The results showed that the maximum threat zone distances associated with high hazards of toxicity, flammability, and thermal radiation of toluene were respectively 736, 132, and 52 m in ALOHA and 1626, no result, and 239 m for PHAST from the accident point in the downwind. The highest probability of death was 92%, which occurred at a distance of 1 m in the cold seasons. The output values for the PHAST program were higher than those for ALOHA. The results also showed that the survival zone in which the probability of death was low could be determined from a distance of 51 m onwards. Although the assessment of the results indicated no matching between the results obtained by ALOHA and PHAST, the program outputs could still help decision-makers in emergency response planning and the allocation of medical and support services during emergencies.

Delay in help-seeking for sexual health issues may lead to relationship discord and impact the quality of life. The study aimed to explore the factors related to HSBs (help seeking behaviors) for sexual health issues and to determine the role of negative attitudes relating to sexual concerns in the HSBs of Iranian women. This cross-sectional study was performed in 2020. Participants were 390 randomly selected women from Rasht, Iran. The data were collected using a demographic and a sexual history checklist, the Female Sexual Function Index-6-item (FSFI-6), the Attitudes-related Sexual Concern Scale (ASCS), and a help-seeking behavior questionnaire. Formal help-seeking in women with sexual concern was 16.2% and 48.6% engaged informal HSB. Informal HSB was associated with younger age (OR = 0.93; CI = 0.89-0.97), having a university degree (OR = 3.42; CI = 1.89-6.18), sexual abuse in adulthood (OR = 2.59; CI = 1.07-6.26) and lower negative attitudes-related sexual concerns (OR = 0.53; CI = 0.32-0.87). Formal HSB was related to having a university degree (OR = 3.03; CI = 1.32-6.98) and history of a chronic disease (OR = 3.43; CI = 1.68-6.98). Negative attitudes relating to sexual concerns greatly impact informal HSBs of women, so it should be considered in their health care programming.

Medication reconciliation based on complete medication histories has been introduced to minimize medication errors and its associated healthcare costs in the transitions of care. In this study, to evaluate the routine process of medication reconciliation in an academic medical center, medication history taken at the time of admission by physicians and the first order prescribed in the hospital was compared to a comprehensive reconciliation form filled by a pharmacist using direct interview of the patients and caregivers, patient's insurance records and medication packages they brought from home. Two hundred and fifty-seven patients admitted in the internal wards of an academic medical center between June and September 2019 were investigated. In 6% of the patients, drug history was not included in the medical history form. Other patients were using 8.59 drugs in average, with a mean of 3.55 medication discrepancies in the history-taking process. Most commonly occurring errors were drug omissions (2.23 per patient on average) and incorrect frequency (0.96 per patient on average). There was a mean of 0.7 potentially harmful discrepancies for each patient. The mean number of drug discrepancies in new prescriptions from the hospital was 1.25, and almost half of patients had a potentially harmful discrepancies reordered in the hospital. There was no statistically meaningful relationship between patients' gender, physicians' gender, or the time of history taking and the total number of medication errors. History of ischemic heart disease was significantly associated with higher number of medication errors (p = 0.05). The results suggest that the medication reconciliation process in this academic center is inefficient. Using a systematic approach in medication reconciliation and gathering the best possible medication history, with a pharmacist who has better understanding of drugs' potential interactions and harmful errors can improve this process and prevent such errors in the future.

Background This study aimed to evaluate the effect of Neuromuscular Electrical Stimulation (NMES) on serum glucose level in children and adolescents with type-1 diabetes. Methods This before-after, single-group, clinical trial was conducted on 29 patients with type-1 diabetes mellitus with the age range of 7–18 years. The patients underwent NMES in two 20-minute phases on the quadriceps and hamstrings muscles, three sessions per week for a period of 8 weeks. Fasting Blood Sugar (FBS), measured in two ways, by glucometer and laboratory testing, was considered as the primary outcome and the glycated hemoglobin (HbA1c) and the total daily dose (TDD) of insulin were measured as the secondary outcomes. The laboratory FBS and HbA1c were measured 1 day before the intervention (as a baseline value) and then 2 and 6 weeks after the last session of intervention. FBS by glucometer and total daily dose of insulin were recorded daily from 2 weeks before the intervention to the last day of the intervention and consequently, the weekly average of these variables was calculated and used for statistical analysis. Results The serum level of FBS (measured by glucometer) and the total daily dose of insulin reduced significantly 2 weeks after beginning of intervention. The laboratory serum level of FBS decreased significantly in the second week after the end of intervention compared to the baseline values. Although the HbA1c level decreased at follow-up period (2 and 6 weeks after the intervention), it was not significant. Conclusion It seems that 8 weeks of NMES has beneficial effects on the reduction of FBS and TDD of insulin therefore, it could be suggested as the contributory treatment in management of children and adolescents with type-1 diabetes. Trial registration The study was registered at https://fa.irct.ir/user/trial/51739/view (IRCT20100523003998N1) in date of 25/10/2020.

Significance. Primates from the Americas and Madagascar are predominantly arboreal but occasionally descend to the ground. This increased ground use was associated with multiple ecological drivers, including increased temperature and a decrease in canopy cover, as well as species-specific traits, including a dietary shift away from fruits and larger group size. As anthropogenic impacts to habitats and climate worsen, our results suggest that diurnal species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use., Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use.

Background Tumor-specific neoantigens are ideal targets for cancer immunotherapy. As research findings have proved, neoantigen-specific T cell activity is immunotherapy’s most important determinant. Main text There is sufficient evidence showing the role of neoantigens in clinically successful immunotherapy, providing a justification for targeting. Because of the significance of the pre-existing anti-tumor immune response for the immune checkpoint inhibitor, it is believed that personalized neoantigen-based therapy may be an imperative approach for cancer therapy. Thus, intensive attention is given to strategies targeting neoantigens for the significant impact with other immunotherapies, such as the immune checkpoint inhibitor. Today, several algorithms are designed and optimized based on Next-Generation Sequencing and public databases, including dbPepNeo, TANTIGEN 2.0, Cancer Antigenic Peptide Database, NEPdb, and CEDAR databases for predicting neoantigens in silico that stimulates the development of T cell therapies, cancer vaccine, and other ongoing immunotherapy approaches. Conclusions In this review, we deliberated the current developments in understanding and recognition of the immunogenicity of newly found gastrointestinal neoantigens as well as their functions in immunotherapies and cancer detection. We also described how neoantigens are being developed and how they might be used in the treatment of GI malignancies.

Sheep is a major contributor to global food production among livestock and one of the great sources of red meat for human consumption. Several QTL and numerous genes with major and minor effects have been identified in association with the muscle characteristics in sheep breeds worldwide. Understanding the genetic background of growth and carcass-related traits in sheep is a major factor in increasing muscle growth, muscle hypertrophy and, eventually, meat production. This review concisely shows how major signaling pathways control skeletal muscle growth. Herein we aimed to discuss and summarize different research findings on genomic regions related to carcass traits and meat production in sheep. Several causative mutations with major effects on different muscle-related traits have been reported in various sheep breeds. A general overview of the studies on main candidate genes showed that some alleles have major phenotypic effects in different breeds with commercial and farm level usability. However, numerous genes with minor effects were also reported regarding the polygenic nature of muscle-related traits. The knowledge of the candidate genes involved in growth traits and their effects provides valuable information for breeding and selection of muscularity traits.

Pharmacogenetic testing in patients with cancer requiring cytotoxic chemotherapy offers the potential to predict, prevent, and mitigate chemotherapy-related toxicities. While multiple drug-gene pairs have been identified and studied, few drug-gene pairs are currently used routinely in the clinical status. Here we review what is known, theorized, and unknown regarding the use of pharmacogenetic testing in cancer.

Targeted therapies have significantly altered the landscape of available cancer therapies across all diagnoses and patient populations, and supportive care therapies have steadily improved throughout the years to make therapy more tolerable for patients. Even so, these therapies have varied efficacy and toxicity among patients with cancer, and pharmacogenomics presents an opportunity to identify which patients are most at risk of toxicities and most likely to benefit from them. While the field of pharmacogenomics in targeted cancer therapy is still growing, we review current knowledge, hypotheses, and clinical practices in this chapter, along with a brief review of pharmacogenomics in supportive therapies in cancer treatment.

In order to investigate the effect of diazinon and chlorpyrifos on agricultural workers exposed to pesticides, urinary metabolites 2-Isopropyl-6-methyl-4-pyrimidinol (IMPy) and 3,5,6-Trichloro-2-pyridinol (TPCy) in farm workers, sprayer operators, and non-exposed people as a control group were measured. The modified QuEChERS method was applied to extract samples and was measured using a gas chromatograph/nitrogen-phosphorus detector. The obtained results showed that the median concentrations of TCPy were 36.92-547.7 and 7.7-49.58 ng/mL for sprayer operators and farm workers, respectively. Moreover, the median concentrations of IMPy were 81.66-593.1 ng/mL for sprayer operators and 40.6-66.1 ng/mL for farm workers. The control group had no measurable metabolites. The IMPy level of 60% of sprayer operators was significantly higher (

Cancer is a general term for more than 100 unique malignancies in different organs of the body. Each cancer type and subtype has its own unique genetic, epigenetic, and cellular factors accountable for malignant progression and metastasis. Small non-coding RNAs called miRNAs target mRNAs and play a vital part in the pathogenesis of human diseases, specifically cancer. Recent investigations provided knowledge of the deregulation of miR-211 in various cancer types and disclosed that miR-211 has an oncogenic or tumor-suppressive impact on tumourigenesis and cancer development. Moreover, recent discoveries which clarify the essential functions of miR-211 might provide proof for its prognosis, diagnostic and therapeutic impact on cancer. Thereby, this review will discuss recent findings regarding miR-211 expression level, target genes, and mechanisms in different cancers. In addition, the most recent results that propose miR-211 usefulness as a noninvasive biomarker and therapeutic factor for the diagnosis and treatment of cancer will be explained.

Aims Patients with heart failure with reduced ejection fraction (HFrEF) are at significant risk of stroke. Anticoagulation reduces this risk in patients with and without atrial fibrillation (AF), but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy. Methods and results In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level), was validated. Of the 20 159 patients included, 12 751 patients did not have AF at baseline. Among patients without AF, 346 (2.7%) experienced a stroke over a median follow up of 2.0 years (rate 11.7 per 1000 patient-years). The risk for stroke increased with increasing risk score: fourth quintile hazard ratio (HR) 2.35 [95% confidence interval (CI) 1.60–3.45]; fifth quintile HR 3.73 (95% CI 2.58–5.38), with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years). Model discrimination was good with a C-index of 0.84 (0.75–0.91). Conclusion It is possible to identify a subset of HFrEF patients without AF with a stroke-risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively.

Implant design and biomaterial composition are contributing factors in stress distribution throughout the implant body and the surrounding bone. The aim of this study was to evaluate the pattern of stress distribution using four different implant systems based on finite element analysis. This study was conducted using a cone beam computed tomography scan and four implant systems (ITI, SPI, 3i, and IDCAM); mandibular and implant models were constructed by a computer-aided design software (CATIA). Stress distribution under axial, mesio-distal, and combination static loading was assessed using finite element analysis in ABAQUS. The maximum von Mises stress value in dental implants was recorded for IDCAMs and IDCAMm implants considering all types of loading directions; however, these implant models showed the least stress distribution in the surrounding bone. The maximum stress occurred using combination followed by axial and mesio-distal loading. The stress distribution was concentrated, in all designs, at the level of the most coronal portion of the cortical bone. Within the limitations of the present study, it could be assumed that implant design may affect the distribution of stress in the implant body, and it could be used as a strategy to reduce stress concentration in the surrounding bone.

Members of the solute carrier family of organic anion transporting polypeptides are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. In particular, the polymorphic transporters OATP1B1 and OATP1B3 are highly expressed in the liver and have been identified as critical regulators of hepatic elimination. As these transporters are also expressed in cancer cells, the function alteration of these proteins have important consequences for an individual's susceptibility to certain drug-induced side effects, drug-drug interactions, and treatment efficacy.In this mini-review, we provide an update of this rapidly emerging field, with specific emphasis on the direct contribution of genetic variants in OATP1B1 and OATP1B3 to the transport of anticancer drugs, the role of these carriers in regulation of their disposition and toxicity profiles, and recent advances in attempts to integrate information on transport function in patients to derive individualized treatment strategies.Based on currently available data, it appears imperative that different aspects of disease, physiology, and drugs of relevance should be evaluated along with an individual's genetic signature, and that tools such as biomarker levels can be implemented to achieve the most reliable prediction of clinically relevant pharmacodynamic endpoints.

Background Childhood obesity is one of the most important health problems in the present century. It is imperative to plan preventive programs through risk factor identification. The present study was conducted to examine the association between the dietary acid load (DAL) and anthropometric indices in a sample of Iranian children and adolescents. Methods In the current survey, students aged 11–18 years were recruited. To assess usual dietary intake, a validated self-administered 168-item food frequency questionnaire was used. Potential renal acid load (PRAL) and net endogenous acid production (NEAP) was used to estimate DAL. The association between DAL and anthropometric indices was evaluated using logistic regression and reported as an odds ratio (OR) with a 95% confidence interval (CI). Results In total, 456 students (267 girls), with a mean age of 14.44 years participated in the current study. After controlling for potential confounders, the PRAL was positively associated with the risk of obesity (OR = 4.56, 95% CI: 2.26, 9.17), abdominal obesity (OR = 12.64, 95% CI: 3.05, 52.27), and adiposity based on the percent of body fat (PBF) (OR = 3.58, 95% CI: 1.83, 6.99). The NEAP was also significantly associated with the risk of obesity (OR = 5.17, 95% CI: 2.56, 10.43), abdominal obesity (OR = 15.08, 95% CI: 3.35, 67.81), and adiposity based on PBF (OR = 4.53, 95% CI: 2.30, 8.92). Conclusion Our findings suggest that higher adherence to the acidogenic diet, expressed as DAL, was associated with a higher risk of general and central obesity among children and adolescents.

Sperm processing for assisted reproductive technologies (ART) aims to separate immotile and debris from the motile spermatozoa in the semen. The purpose of this study was to assess the effect of free centrifuge sorting (FCS) approach based on a combination of rheotaxis and swim-up on sperm biological characteristics and ICSI clinical outcomes. Each semen sample was splitted into two equal parts for 67 ICSI cycles with donation oocytes. Parts were processed with the Direct Swim Up (DSU) (control) and with the FCS method (experimental). Sperm quality was assessed in terms of motility, fine morphology, mitochondrial membrane potential, lipid peroxidation and sperm DNA fragmentation. Also Following ICSI, the clinical outcomes were compared between the groups. Sperm progressive motility (93.5 ± 4.1% vs. 78.6 ± 8.2%; p 0.001), the fraction of Class I (good) morphology (30.2 ± 9.4% vs. 23.7 ± 8.5%; p 0.0001) and the rate of mitochondrial membrane potential (77.4 ± 7.2% vs. 66.9 ± 5.7%; p 0.0001) were significantly higher in the FCS compared to DSU groups. The level of lipid peroxidation (0.5 ± 0.05% vs. 0.6 ± 0.06%; p 0.0001) and concentration of DNA fragmentation (DF) (7.4 ± 1.6% vs. 15.4 ± 2.6%; p 0.0001) were lower in sperm from the FCS group compared to DSU group. There were higher rates of high-quality embryo formation (p 0.001), implantation and clinical pregnancy rates (p = 0.03) in the FCS group compared to the control group. The processing of seminal samples using FCS collected spermatozoa with better biological quality and resulted in higher reproductive outcomes in ICSI cycles.

The prevalence of long-term symptoms of coronavirus disease 2019 (COVID-19) in nonhospitalized pediatric populations in the United States is not well described. The objective of this analysis was to examine the presence of persistent COVID symptoms in children by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody status.Data were collected between October 2020 and May 2022 from the Texas Coronavirus Antibody REsponse Survey, a statewide prospective population-based survey among 5-90 years old. Serostatus was assessed by the Roche Elecsys Anti-SARS-CoV-2 Immunoassay for detection of antibodies to the SARS-CoV-2 nucleocapsid protein. Self-reported antigen/polymerase chain reaction COVID-19 test results and persistent COVID symptom status/type/duration were collected simultaneously. Risk ratios for persistent COVID symptoms were calculated versus adults and by age group, antibody status, symptom presence/severity, variant, body mass index and vaccine status.A total of 82 (4.5% of the total sample [n = 1813], 8.0% pre-Delta, 3.4% Delta and beyond) participants reported persistent COVID symptoms (n = 27 [1.5%] 4-12 weeks, n = 58 [3.3%]12 weeks). Compared with adults, all pediatric age groups had a lower risk for persistent COVID symptoms regardless of length of symptoms reported. Additional increased risk for persistent COVID symptoms12 weeks included severe symptoms with initial infection, not being vaccinated and having unhealthy weight (body mass index ≥85th percentile for age and sex).These findings highlight the existence of nonhospitalized youth who may also experience persistent COVID symptoms. Children and adolescents are less likely to experience persistent COVID symptoms than adults and more likely to be symptomatic, experience severe symptoms and have unhealthy weight compared with children/adolescents without persistent COVID symptoms.

Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12-15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, leaving patients with limited options. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer is not known. Here, we show that a subgroup of resistant tumors decreases phosphoglycerate dehydrogenase (PHGDH) expression at relapse after platinum-based chemotherapy. Mechanistically, we observe that this phenomenon is accompanied by a specific oxidized nicotinamide adenine dinucleotide (NAD+) regenerating phenotype, which helps tumor cells in sustaining Poly (ADP-ribose) polymerase (PARP) activity under platinum treatment. Our findings reveal metabolic vulnerabilities with clinical implications for a subset of platinum resistant ovarian cancers. ispartof: NATURE COMMUNICATIONS vol:13 issue:1 ispartof: location:England status: published

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window.

Millions have died due to the COVID-19 pandemic. The irrepressible propensity of the pandemic, which was highlighted by the outbreak of the Delta variant, should not be underestimated. The Omicron SARS-CoV-2 variant is thought to have originated from Africa. Sequences of the omicron variant show that it carries the highest number of point mutations detected in a betacoronavirus. High hospitalization numbers due to the Omicron variant has retriggered precautionary restrictions and border closures even in countries which have attained herd immunity by mass vaccinations. Surveillance systems for accurate screening of the Omicron variant are needed to guide implementation of hygiene principles and restrictions. Development of vaccines against the variants is important as the pandemic evolves. Whether Omicron is the last variant depends on the success of the local and global public-health strategies against SARS-CoV-2.

Thymoquinone is a monoterpenoid compound, which is derived from volatile and fixed oil of Nigella sativa (Ranunculaceae). This phytochemical compound has several biological effects, including antioxidant, antibacterial, antineoplastic, nephroprotective, hepatoprotective, gastroprotective, neuroprotective, anti-nociceptive, and anti-inflammatory activities. Thymoquinone shows pharmacological activities, including anti-hepatocellular carcinoma, nephroprotection, neuroprotection, retina protection, gastroprotection, cardioprotection, anti-allergy, reproductive system protection, bladder protection, and respiratory protection. It was found that these beneficial effects are mostly related to modulation of the Nrf2 signaling pathway by blockage of Keap1, stimulating the expression of the Nrf2 gene, and inducing the nuclear translocation of Nrf2. In the present review, the therapeutic effects of thymoquinone are overviewed through the Nrf2 signaling pathway.

Regarding the epidemiological studies, neurological dysfunctions caused by cerebral ischemia or neurodegenerative diseases (NDDs) have been considered a pointed matter. Mount-up shreds of evidence support that both autophagy and reactive oxygen species (ROS) are involved in the commencement and progression of neurological diseases. Remarkably, oxidative stress prompted by an increase of ROS threatens cerebral integrity and improves the severity of other pathogenic agents such as mitochondrial damage in neuronal disturbances. Autophagy is anticipated as a cellular defending mode to combat cytotoxic substances and damage. The recent document proposes that the interrelation of autophagy and ROS creates a crucial function in controlling neuronal homeostasis. This review aims to overview the cross-talk among autophagy and oxidative stress and its molecular mechanisms in various neurological diseases to prepare new perceptions into a new treatment for neurological disorders. Furthermore, natural/synthetic agents entailed in modulation/regulation of this ambitious cross-talk are described.