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Objective Tyrosine kinase inhibitors (TKIs) are considered standard first-line treatment in patients with chronic myeloid leukemia. Because ABL kinase domain mutations are the most common causes of treatment resistance, their prevalence and assessment during treatment may predict subsequent response to therapy. Methods The molecular response in Bcr-Abl1IS was tested via quantitative real-time polymerase chain reaction. We used the direct sequencing technique to discover the mutations in the ABL kinase domain. The IRIS trial established a standard baseline for measurement – (100% BCR-ABL1 on the ‘international scale’) and a major molecular response (good response to therapy) was defined as a 3-log reduction in the amount of BCR-ABL1 – 0.1% BCR-ABL1 on the international scale. Results We observed 11 different mutations in 13 patients, including E255K, which had the highest mutation rate. A lack of hematologic response was found in 22 patients, who showed a significantly higher incidence of mutations. Conclusion Detection of kinase domain mutations is a reliable method for choosing the best treatment strategy based on patients’ conditions, avoiding ineffective treatments, and running high-cost protocols in patients with acquired resistance to TKIs.

Infantile hypotonia, with psychomotor retardation and characteristic facies 1 (IHPRF1), is a rare disorder characterized by global developmental delay and dysmorphic features. This syndrome is caused by genetic anomalies within the NALCN gene. The current report examines a 9-year-old female IHPRF1 patient. Our objective was to contribute to the delineation of the underlying factors influencing this rare condition. Whole exome sequencing (WES) was utilized to identify the disease-causing mutation in the affected individual. Subsequently, Sanger sequencing was performed for the patient, her parents, and two close relatives in order to confirm the detected mutation. Moreover, detailed clinical examinations including EEG, echocardiography, and biochemical/physical tests were carried out to elucidate the effects of the mutation. WES identified a homozygous nonsense mutation in the NALCN gene (c.2563C>T p.R855X). This mutation was confirmed by Sanger sequencing in the patient and her family members and segregated with the autosomal recessive inheritance pattern of IHPRF1. Moreover, genotype-phenotype correlation analysis confirmed the disease-causing nature of this mutation. The current report provides the first detailed description of a patient with this homozygous nonsense mutation (c.2563C>T p.R855X) and expands the clinical spectrum of IHPRF1 disease. Possible influences of sex and other factors on this disease are discussed and a review of the literature is also provided.

The major current focus on treating rheumatoid arthritis is to put an end to long-term treatments and instead, specifically block widespread immunosuppression by developing antigen-specific tolerance, while also permitting an intact immune response toward other antigens to occur. There have been promising preclinical findings regarding adoptive Treg cells immunotherapy with a critically responsible function in the prevention of autoimmunity, tissue repair and regeneration, which make them an attractive candidate to develop effective therapeutic approaches to achieve this interesting concept in many human immune-mediated diseases, such as rheumatoid arthritis. Ex vivo or invivo manipulation protocols are not only utilized to correct Treg cells defect, but also to benefit from their specific immunosuppressive properties by identifying specific antigens that are expressed in the inflamedjoint. The methods able to address these deficiencies can be considered as a target for immunity interventions to restore appropriate immune function.

Infantile hypotonia, with psychomotor retardation and characteristic facies 1 (IHPRF1), is a rare disorder characterized by global developmental delay and dysmorphic features. This syndrome is caused by genetic anomalies within the NALCN gene. The current report examines a 9-year-old female IHPRF1 patient. Our objective was to contribute to the delineation of the underlying factors influencing this rare condition. Whole exome sequencing (WES) was utilized to identify the disease-causing mutation in the affected individual. Subsequently, Sanger sequencing was performed for the patient, her parents, and two close relatives in order to confirm the detected mutation. Moreover, detailed clinical examinations including EEG, echocardiography, and biochemical/physical tests were carried out to elucidate the effects of the mutation. WES identified a homozygous nonsense mutation in the NALCN gene (c.2563C>T p.R855X). This mutation was confirmed by Sanger sequencing in the patient and her family members and segregated with the autosomal recessive inheritance pattern of IHPRF1. Moreover, genotype-phenotype correlation analysis confirmed the disease-causing nature of this mutation. The current report provides the first detailed description of a patient with this homozygous nonsense mutation (c.2563C>T p.R855X) and expands the clinical spectrum of IHPRF1 disease. Possible influences of sex and other factors on this disease are discussed and a review of the literature is also provided.

Hematopoietic stem cells (HSCs) are quiescent cells with self-renewal capacity and potential multilineage development. Various molecular regulatory mechanisms such as epigenetic modifications and transcription factor (TF) networks play crucial roles in establishing a balance between self-renewal and differentiation of HSCs. Histone/DNA methylations are important epigenetic modifications involved in transcriptional regulation of specific lineage HSCs via controlling chromatin structure and accessibility of DNA. Also, TFs contribute to either facilitation or inhibition of gene expression through binding to enhancer or promoter regions of DNA. As a result, epigenetic factors and TFs regulate the activation or repression of HSCs genes, playing a central role in normal hematopoiesis. Given the importance of histone/DNA methylation and TFs in gene expression regulation, their aberrations, including changes in HSCs-related methylation of histone/DNA and TFs (e.g., CCAAT-enhancer-binding protein α, phosphatase and tensin homolog deleted on the chromosome 10, Runt-related transcription factor 1, signal transducers and activators of transcription, and RAS family proteins) could disrupt HSCs fate. Herewith, we summarize how dysregulations in the expression of genes related to self-renewal, proliferation, and differentiation of HSCs caused by changes in epigenetic modifications and transcriptional networks lead to clonal expansion and leukemic transformation.

Background: There was an increase in number of patients presented with early-stage cervical cancer (CC). Tumors with favorable pathological features might be candidates for less radical surgery.Methods: We retrospectively reviewed 700 patients with histologically confirmed CC between January 2011 and March 2020. Chi-square, Fisher's exact tests and multivariate logistic regression analysis were used to assess relations between parametrial involvement (PI) and clinic-pathological variables.Results: Total number of 132 patients with stage IA to IIA were eligible to participate. Squamous cell carcinoma was reported in 100 (75.8%) patients, adenocarcinoma and other tumor pathologies were found in 24(18.2%) and 8(6.1%), respectively. Considering the FIGO stage, 11 (8.4%) patients had IA, 111 (83%%) IB and 10 (7.6%) IIA. Nine patients (6.8%) had PI on permanent pathologic report. Univariate analysis demonstrated that following variables were statistically different between patients with and without PI: age ≥ 50, tumor size ≥ 3cm, lower segment involvement, poorly differentiated pathology, deep stromal invasion, pelvic lymph node, lympho-vascular involvement and positive surgical margin (all p values < 0.05). Among these variables only tumor size ≥ 3 cm (OR: 2.1, 95% CI: 1.11-4.16, p value: 0.02), deep stromal invasion (OR: 2.2, 95% CI: 1.9-7.43, p value: 0.02) and positive surgical margin (OR: 5.1, 95% CI: 3.97-11.15, p value: 0.008) were independent risk factor of PI in multivariate analysis.Conclusions: Early stage CC can be surgically approached in a more conservative manner if patients have tumor size < 3 cm and do not have deep stromal invasion in conization.

The recently developed pathogenic virus, SARS-CoV-2, was found in the Hubei Province, China. Giving rise to a broad spectrum of symptoms, SARS-CoV-2 rapidly spread across the globe, causing multi-systemic and dangerous complications, with death in extreme cases. Thereby, the number of research cases increases every day on preventing infection and treating its resulting damage. Accumulating evidence suggests noncoding RNAs (ncRNAs) are necessary for modifying virus infection and antiviral immune reaction, along with biological processes regulating SARS-CoV-2 and subsequent disease states. Therefore, understanding these mechanisms might provide a further understanding of the pathogenesis and feasible therapy alternatives against SARS-CoV2. Consequently, the molecular biology of SARS-CoV-2, ncRNA's role in its infection, and various RNA therapy tactics against the virus have been presented in this review section.

Diffusion tensor imaging (DTI) is now having a strong momentum in research to evaluate the neural fibers of the CNS. This technique can study white matter (WM) microstructure in neurodegenerative disorders, including Parkinson's disease (PD). Previous neuroimaging studies have suggested cerebellar involvement in the pathogenesis of PD, and these cerebellum alterations can correlate with PD symptoms and stages. Using the PRISMA 2020 framework, PubMed and EMBASE were searched to retrieve relevant articles. Our search revealed 472 articles. After screening titles and abstracts, and full-text review, and implementing the inclusion criteria, 68 papers were selected for synthesis. Reviewing the selected studies revealed that the patterns of reduction in cerebellum WM integrity, assessed by fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity measures can differ symptoms and stages of PD. Cerebellar diffusion tensor imaging (DTI) changes in PD patients with "postural instability and gait difficulty" are significantly different from "tremor dominant" PD patients. Freezing of the gate is strongly related to cerebellar involvement depicted by DTI. The "reduced cognition," "visual disturbances," "sleep disorders," "depression," and "olfactory dysfunction" are not related to cerebellum microstructural changes on DTI, while "impulsive-compulsive behavior" can be linked to cerebellar WM alteration. Finally, higher PD stages and longer disease duration are associated with cerebellum white matter alteration depicted by DTI. Depiction of cerebellar white matter involvement in PD is feasible by DTI. There is an association with disease duration and severity and several clinical presentations with DTI findings. This clinical-imaging association may eventually improve disease management.

The aim of this open study was to delineate domains of benefit and effect size measures to design an appropriately powered randomized control trial to assess the efficacy of Brain Balance

Ethnopharmacological studies for drug discovery from natural compounds play an important role for developing current therapeutical platforms. Plants are a group of natural sources which have been served as the basis in the treatment of many diseases for centuries. In this regard, Ceratonia siliqua (carob) is one of the herbal medicine which is traditionally used for male infertility treatments. But so far the main mechanisms for effects of carob are unknown. Here, we intend to investigate the ability of carob extract to induce spermatogenesis in an azoospermia mouse model and determine the mechanisms that underlie its function.This is a pre-clinical animal model study to evaluate the effect of carob extract in spermatogenesis recovery.We established an infertile mouse model with the intent to examine the ability of carob extract as a potential herbal medicine for restoration of male fertility. Sperm parameters, as well as gene expression dynamics and levels of spermatogenesis hormones, were evaluated 35 days after carob administration.Significant enhanced sperm parameters (P 0.05) showed that the carob extract could induce spermatogenesis in the infertile mouse model. Our data suggested an anti-apototic and inducer role in the expressions of cell cycle regulating genes. Carob extract improved the spermatogenesis niche by considerable affecting Sertoli and Leydig cells (P 0.05). The carob-treated mice were fertile and contributed to healthy offspring that matured. Our data confirmed that this extract triggered the hormonal system, the spermatogenesis-related gene expression network, and signaling pathways to induce and promote sperm production with notable level (P 0.05). We found that the aqueous extract consisted of a polar and mainly well water-soluble substance. Carob extract might upregulate spermatogenesis hormones via its amino acid components, which were detected in the extract by liquid chromatography-mass spectrometry (LC-MS).Our results strongly suggest that carob extract might be a promising future treatment option for male infertility. This finding could pave the way for clinical trials in infertile men. This is the first study that has provided reliable, strong pre-clinical evidence for carob extract as an effective candidate for fertility recovery in cancer-related azoospermia.

MicroRNAs (miRNAs), small non-coding RNAs approximately 20-25 nt in length, play important roles via directly binding to the corresponding 3' UTR of target mRNAs. Recent research has shown that miRNAs cover a wide range of diseases, including several types of cancer. It is interesting to note that miR-206 operates as a tumor suppressor and is downregulated in abundant cancer types, such as breast cancer, lung cancer, colorectal cancer, and so forth. Interestingly, a growing number of studies have also reported that miR-206 could function as an oncogene and promote tumor cell proliferation. Thereby, miR-206 may act as either oncogenes or tumor suppressors under certain conditions. In addition, it was widely acknowledged that restoring tumor-suppressor miR-206 has emerged as an unconventional cancer therapy strategy. Therefore, miR-206 might be a newfangled procedure for achieving a more significant treatment outcome for cancer patients. This review summarizes the role of miR-206 in several cancer types and the contributions made between miR-206 and the diagnosis, treatment, and drug resistance of solid tumors.

The article's abstract is not available.

Histone-to-protamine transition is an essential step in the generation of fully functional spermatozoa in various mammalian species. In human and mouse, one of the two protamine-encoding genes produces a precursor pre-protamine 2 (pre-PRM2) protein, which is then processed and assembled. Here, we design an original approach based on the generation of pre-PRM2-specific antibodies to visualize the unprocessed pre-PRM2 by microscopy, flow cytometry and immunoblotting. Using mouse models with characterized failures in histone-to-protamine replacement, we show that pre-PRM2 retention is tightly linked to impaired nucleosome disassembly. Additionally, in elongating/condensing spermatids, we observe that pre-PRM2 and transition protein are co-expressed spatiotemporally, and their physical interaction suggests that these proteins act simultaneously rather than successively during histone replacement. By using our anti-human pre-PRM2 antibody, we also measured pre-PRM2 retention rates in the spermatozoa from 49 men of a series of infertile couples undergoing ICSI, which shed new light on the debated relation between pre-PRM2 retention and sperm parameters. Finally, by monitoring 2-pronuclei embryo formation following ICSI, we evaluated the fertilization ability of the sperm in these 49 patients. Our results suggest that the extent of pre-PRM2 retention in sperm, rather than pre-PRM2 accumulation per se, is associated with fertilization failure. Hence, anti-pre-PRM2 antibodies are valuable tools that could be used in routine monitoring of sperm parameters in fertility clinics, as well as in experimental research programmes to better understand the obscure process of histone-to-protamine transition.

Reduced venous return is an important trigger of vasovagal syncope (VVS). Elastic compression stockings (ECS) can modify venous return and be of therapeutic interest; however, evidence for ECS efficacy in VVS is scarce. This randomized controlled trial was designed to address the issue.COMFORTS-II is a multicenter, triple-blind, parallel design, randomized controlled trial aimed to assess the efficacy of ECS in preventing VVS recurrences. Using central online randomization, 268 participants will be allocated to 2 arms (1:1 ratio), wearing intervention ECS (25-30 mm Hg pressure) or sham ECS (≤10 mm Hg pressure). All participants will receive standard VVS treatment in the form of education, and lifestyle modification recommendations (drinking 2-3 l/d of fluids and consuming 10 g/d-roughly half a tablespoon-of table salt). Adherence to ECS treatment will be evaluated through diary sheets, and compared between study arms. Follow-up continues for 1 year, and is conducted via a 24/7 phone line available to patients and trimonthly visits. The co-primary outcomes are proportion of participants with any syncopal recurrence and time to first syncopal episode. Secondary outcomes include frequency of VVS spells, time intervals between recurrences, and incidence of any patient-reported adverse effects.To the best of our knowledge, COMFORTS-II is the first clinical trial to assess ECS efficacy among patients with VVS, addressing an important gap in evidence for VVS treatments.

Background: Inflammation and its master regulator, Nuclear Factor-kB (NF-kB), have been implicated in the development of endometriosis. Inhibition of NF-kB pathway using small molecules ameliorated disease progression and reduced the lesion size; nevertheless, the underlying mechanism is not fully understood. Therefore, this study, is an attempt to assess whether inhibiting NF-kB signaling by aloe-emodin (AE) or aspirin (Asp), as anti-inflammatory compounds, can suppresses the invasive activity of human endometrial stromal cells at stage IV endometriosis. Methods: The eutopic and healthy endometrial biopsies from a total of 8 infertile women with confirmed endometriosis and 8 women without endometriosis were digested and the single cells were cultured. Gene and protein markers of proliferation, migration, adhesion, and invasion of eutopic endometrial stromal cells (EuESCs) with and without treatment with AE or Asp, as well as control endometrial stromal cells (CESCs) was analyzed using q-PCR and immunofluorescence staining, respectively. Comparison between groups was performed using one-way ANOVA and the Bonferroni post hoc and p≤0.5 was considered statistically significant. Results: There was an association between NF-kB overexpression and higher proliferation/adhesion capacity in EuESCs. EuESCs (at stage IV endometriosis) displayed no invasive and migratory behaviors. Pre-treatment of EuESCs with AE or Asp significantly attenuated NF-kB expression and reduced proliferative, adhesive, invasive, and migratory activity of endometrial cells (p≤0.5). Conclusion: Eutopic endometrial stromal cells seem to have a semi-invasive activity which is largely suppressed by AE or Asp. It can be suggested that both Asp and AE (as potent NF-kB inhibitors) can be used as a supplement in conventional endometriosis treatments.

Background: Herbal and natural medicines play significant roles in treatment of diseases and development of novel drugs. Salsola vermiculata is an annual plant which is broadly distributed in southwest of Asia, and is used for treatment of stomach disorders. Results: This present study aimed at identifying and comparing the metabolic profiles of different parts of Salsola vermiculata and to evaluate the inhibitory potential of their extracts and fractions towards acetylcholinesterase and α-glucosidase. LC-ESI-MS, GC, and GC-MS analytical methods were employed for metabolite profiling of the extracts, and their fractions. The α-glucosidase and acetylcholinesterase inhibitory activities of the samples were determined by microplate colorimetric methods. Based on results, 44 metabolites were identified in different parts of S. vermiculata. In roots, vanillic acid, rutin, salsoline, salsoline A, palmitic acid, oleic acid, linoleic acid, cumin aldehyde, and carvone; in seeds, vanillic acid, salsoline A, palmitic acid, oleic acid, linoleic acid, carvone, and β-caryophyllene; in leaves, gallic acid, vanillic acid, caffeic acid, rosmaric acid, rutin, quercetin, limonene, and carvone, and in flowers, gallic acid, vanillic acid, cinnamic acid, rosmaric acid, rutin, kaempferol, limonene, linalool, and carvone were recorded as the main components. According to the inhibitory activities results, the ethyl acetate fractions of leaves and the aqueous-acid fraction of roots displayed highest inhibitory activity towards acetylcholinesterase (IC50: 17.24 µg/mL), and α-glucosidase (IC50: 62.37 µg/mL), respectively. Conclusion: Finally, the leaves and roots of S. vermiculata are rich of phenolic and alkaloids compounds and the findings of this study depict them as a promising acetylcholinesterase and α-glucosidase inhibitors, and therefore, can be utilized for the development of new drugs.

Background There is a little evidence about the infectiousness of recovered COVID-19 patients. Considering that the circumstance of the isolation of the COVID-19 patients after-discharge is not always optimal, it is not very unlikely that viral transmission still occurs after hospital discharge. This study aims to investigate the incidence of symptomatic COVID-19 in close contacts of recovered patients after discharge from hospital. Methods Four hundred fifty discharged COVID-19 patients discharged from the largest public treatment center in Tehran, capital city of Iran, were followed up. Demographic and clinical data of participants were collected from medical records. Follow-up data were acquired via telephone call interviews with patients or their main caregivers at home. Results The study’s response rate was 93.77% (422 participated in the study). 60.90% patients were male and 39.10% were female (sex ratio = 1.55 male). The most prevalent comorbidities in these patients were hypertension (29.68%) and diabetes (24.80%). The mean of home isolation after discharge was 25.85. Forty-one (9.71%) patients had at least one new case in their close contacts, up to 3 weeks after they were discharged. There was a significant association between having at least a comorbidity with the odds of getting infected in close contacts [OR (CI) 2.22 (1.05–4.68)]. Density of inhabitant per room in a house’ and the quality of isolation had significant associations with observing new cases in the patients’ close contacts [high to moderate; OR (CI) 2.44 (1.06–5.61], [bad to good; OR (CI) 2.31 (1.17–4.59)], respectively. Conclusion After hospital discharge, COVID-19 transmission can still occur, when a large number of people lives together in a single house. Another explanation can be that the less precaution measures are taken by recovered patients’ cohabitants. Such conditions are also likely to happen when the recovered patient has other chronic diseases and requires additional care.

Infertility is a complex multifactorial problem that affects about 7% of men and 15% of couples worldwide. Many molecular mechanisms involved in male infertility. Destructive effects of infertility on the next generations are not well understood. Approximately 60-75% of male infertility cases have idiopathic causes, and there is a need for additional investigations other than routine examinations. Molecular factors that surround DNA, which are mitotically stable and independently regulate genome activity of DNA sequences, are known as epigenetics. The known epigenetic mechanisms are DNA methylation, histone modifications and non-coding RNAs. Prevalence of metabolic diseases has been increased dramatically because of changes in lifestyle and the current levels of inactivity. Metabolic disorders, suchbr /as obesity and diabetes, are prevalent reasons for male infertility; despite the association between metabolic diseases and male infertility, few studies have been conducted on the effects of epigenetic alterations associated with these diseases and sperm abnormalities. Diabetes can affect the reproductive system and testicular function at multiple levels;br /however, there are very few molecular and epigenetic studies related to sperm from males with diabetes. On the other hand, obesity has similar conditions, while male obesity is linked to notable alterations in the sperm molecular architecture affecting both function and embryo quality. Therefore, in this review article, we presented new and developed technologies to study different patterns of epigenetic changes, and explained the exact mechanisms of epigenetic changes linked to metabolic diseases and their relationship with male infertility.

Study question Does inhibiting nuclear factor-kB (NF-kB) signaling by aloe-emodin (AE) or aspirin (Asp), as anti-inflammatory compounds, suppress the invasive activity of stage IV human endometriotic stromal cells? Summary answer Eutopic endometriotic stromal cells (EuESCs) seem to have a semi-invasive activity which is largely suppressed by AE or Asp. What is known already Inflammation and its master regulator, NF-kB, have been implicated in the development of endometriosis. Inhibition of NF-kB pathway using small molecules ameliorated disease progression and reduced the lesion size; nevertheless, underlying mechanism is not fully understood. Study design, size, duration In this cross-sectional study, a total of 8 infertile patients with proven endometriosis and 8 women without endometriosis (Control group) undergoing infertility treatment cycles, were enrolled between October 2018 and December 2019. The invasiveness of collected endometriotic stromal cells before and after treatment with AE or Asp, was analyzed and compared with the control group. Participants/materials, setting, methods The eutopic endometriotic and healthy endometrial biopsies were digested and the single cells were cultured. Gene and protein expression of proliferation, adhesion, and invasion markers of eutopic endometriotic stromal cells (EuESCs) with and without treatment with AE or Asp, as well as control endometrial stromal cells (CESCs) were analyzed using q-PCR and immunofluorescence staining, respectively. Cell migration capacity was assessed by wound closure assay. Main results and the role of chance We observed an association between NF-kB overexpression and higher proliferation/adhesion capacity in EuESCs. TNF-α, as a known NF-kB inducer, further potentiated this association. EuESCs at stage IV, displayed silent invasive and migratory behaviors. Pretreatment of EuESCs with AE or Asp significantly attenuated NF-kB expression and reduced proliferative, adhesive, invasive and migratory activity. Limitations, reasons for caution Due to some adverse effects observed following treatment with AE or Asp on the normal activity of EuESCs, more investigations on possible toxicity of the treatment, must be considered. Wider implications of the findings: We suggest that both Asp and AE (as potent NF-kB inhibitors) may be useful as a supplement to conventional endometriosis treatments. Trial registration number Not applicable