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The prognosis of patients diagnosed with relapsed or refractory (R/R) T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) has consistently been unsatisfactory, with limited treatment options. As reports, the CAG regimen can serve as a salvage treatment for R/R T-ALL/LBL, but there remains a subset of patients who do not benefit from it. Recent studies have indicated that daratumumab (Dara) and venetoclax (Ven) may offer promising therapeutic benefits for T-ALL/LBL. In light of these findings, we conducted a safety and efficacy evaluation of the enhanced treatment regimen, combining Dara and Ven with aclarubicin, cytarabine, granulocyte colony-stimulating factor, and etoposide (CAGE), in patients suffering from R/R T-ALL/LBL. The participants in this phase I trial were patients with R/R T-ALL/LBL who fail to standard treatment regimens. During each 28-day cycle, the patients were treated by Dara, Ven, cytarabine, aclarubicin, granulocyte colony-stimulating factor, etoposide. The primary endpoint of this study was the rate of remission. This report presents the prospective outcomes of 21 patients who received the salvage therapy of Dara and Ven combined with the CAGE regimen (Dara + Ven + CAGE). The objective remission rate (ORR) was determined to be 57.1%, while the complete remission (CR) rate was 47.6%. Notably, patients with the early T-cell precursor (ETP) subtype exhibited a significantly higher remission rate in the bone marrow compared to non-ETP patients (100% vs. 44.4%, p = 0.044). The Dara + Ven + CAGE regimen demonstrated a favorable remission rate in patients with R/R T-ALL/LBL. Moreover, the treatment was well-tolerated. [ABSTRACT FROM AUTHOR]

Psoriasis is characterized by inflammation and hyperproliferation of epidermal keratinocytes. Cycloastragenol (CAG) is an active molecule of Astragalus membranaceus that potentially plays a repressive role in psoriasis. Activated cell autophagy is an effective pathway for alleviating psoriasis progression. Thus, we investigated the role of CAG in the proliferation and autophagy of interleukin (IL)-22-stimulated keratinocytes. A psoriasis model was established by stimulating HaCaT cells with IL-22. Gene or protein expression levels were measured by qRT-PCR or western blot. Autophagy flux was observed with mRFP-GFP-LC3 adenovirus transfection assay under confocal microscopy. Stanniocalcin-1 (STC1) secretion levels were determined using ELISA kits. The apoptosis rate was assessed using flow cytometry. Interactions between miR-145 and STC1 or STC1 and Notch1 were validated by luciferase reporter gene assays, RIP, and Co-IP assays. CAG repressed cell proliferation and promoted apoptosis and autophagy in IL-22-stimulated HaCaT cells. Additionally, CAG promoted autophagy by enhancing miR-145. STC1 silencing ameliorated autophagy repression in IL-22-treated HaCaT cells. Moreover, miR-145 negatively regulated STC1, and STC1 was found to activate Notch1. Lastly, STC1 overexpression reversed CAG-promoted autophagy. CAG alleviated keratinocyte hyperproliferation through autophagy enhancement via regulating the miR-145/STC1/Notch1 axis in psoriasis. [ABSTRACT FROM AUTHOR]

BackgroundAchieving the 95–95–95 targets require an efficient and innovative person-centered approach, specifically community-based differentiated service delivery (DSD), to improve access to human immunodeficiency virus (HIV) services and reduce burdens on the health system. Therefore, this study aimed to assess the uptake of community-based DSD models and associated factors among people living with HIV (PLHIV).MethodsA multicenter cross-sectional study was conducted among PLHIV in public health facilities in South Ethiopia. Data were collected and entered into EpiData version 3.1 before being exported to Stata version 14 for further analysis. In the bivariable logistic regression analysis, variables with a p-value of ≤0.25 were included in the multivariable logistic regression analysis. A p-value of

Genetic mutations in the androgen receptor (AR) gene have been identified as the cause of androgen insensitivity syndrome. These mutations are linked to inconsistent development of the Wolffian duct and may result in conditions such as micropenis, hypospadias, and cryptorchidism. The androgen receptor has two polymorphic sites located in exon 1, which consists of varying amounts of CAG and GGN repeats. These repetitions lead to the formation of polyglutamine and polyglycine stretches of varied lengths. Increased CAG repeats lead to a decrease in androgen receptor transcriptional activity, but the impact of GGN triplets is less well understood. This research examined the CAG and GGN repeat lengths in males who had a past medical record of cryptorchidism. Prospective and retrospective observational studies from PubMed, Science Direct, and Embase were systematically searched up to 15th November 2020. Primary outcomes were analyzed using a fixed or random effect model regarding its heterogeneity and continued with multilevel modeling of each polymorphism and ethnicity. CAG and GGN repeat polymorphism was found to be significantly different compared to control in contributing to cryptorchidism (CAG: 0.55 [CI 95%=0.19-0.91]; p-value=0.003 and GGN 0.90 [CI95%=0.65-1.15]; p value

It is essential that communities at risk from TB are involved in TB research. Community advisory groups (CAGs) are one mechanism for involving communities in research and creating platforms for discussions between researchers and community members. We organised a CAG meeting with community members and people with lived experience in Ho Chi Minh City, Vietnam, to explore the community’s knowledge about TB and their perspectives on different diagnostic tests in Vietnam, a low-middle-income country with a high TB burden. Researchers shared basic information and addressed questions about TB. CAG members commented on preference of TB screening tests, and suggested that chest X-rays and blood tests were more acceptable than sputum tests because of the difficulty in sputum expectoration. In addition, clinical studies that required fewer visits to the hospitals would be preferred, even if this meant a greater reliance on blood sampling.

To examine the risk factors associated with coronary heart disease (CHD) in young males and assess the distinctive features of coronary angiography (CAG). The clinical data of 266 young men who underwent CAG were collected and categorized into CHD group and control group based on the results of CAG. Binary logistic regression was used to analyze the risk factors for CHD in young men. Additionally, we selected 112 middle-aged and elderly men with CHD to form the middle-aged and elderly case group. We then compared the CAG characteristics and short-term prognosis with those of the CHD group. The CAG examination revealed a CHD detection rate of 42.11% (112/266) in young men, with 154 patients (57.89%) exhibiting no significant stenosis. Notably, the CHD group had higher rates of family history, hypertension and an elevated triglyceride glucose product (TyG) index (p < 0.05), along with a shorter duration of sleep compared to the control group (p < 0.05). Binary logistic regression analysis confirmed family history of CHD, hypertension, TyG index ≥8.83, and insufficient sleep duration as risk factors for CHD in young men. Additionally, the CHD group had a higher proportion of single-vessel coronary artery disease compared to the middle-aged and elderly case group (p < 0.05). Conversely, the middle-aged and elderly case group had a higher proportion of multi-vessel coronary artery disease, left circumflex artery involvement, and right coronary artery involvement (p < 0.05). The CHD group exhibited a lower overall incidence of major adverse cardiovascular events compared to the middle-aged and elderly case group (p < 0.05). The incidence of CHD in young men is closely associated with a family history of CHD and hypertension. High TyG index and insufficient sleep duration may also increase the risk of CHD.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a highly aggressive subtype of T-ALL. No standard chemotherapy regimen exists for patients with recurrent/refractory (R/R) ETP-ALL; in these patients, the primary goal of salvage therapy is to achieve remission as a foundation for consolidation and intensification treatments. This study reports cases of two patients with R/R ETP-ALL who underwent salvage therapy of venetoclax combined with the CAG regimen and achieved complete remission in the bone marrow. Flow cytometry results were negative for minimal residual disease. Both patients were bridged to allogeneic hematopoietic stem cell transplantation (HSCT) and in complete remission over a 3-year follow-up period. These cases show that the use of venetoclax combined with the CAG regimen may offer patients with R/R ETP-ALL an opportunity for allogeneic HSCT.

Design: The androgen receptor (AR) mediates peripheral effects of testosterone. Previous data suggests an association between the number of CAG repeats in exon‐1 of the AR gene and AR transcriptional activity. The aim of this analysis was to determine the association between the number of AR CAG repeats and all‐cause mortality in men and the influence of testosterone level on the association. Patients and Measurements: Follow‐up data to 27 January 2018 were available for men aged 40–79 years recruited across six countries of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios (HR)/95% confidence intervals (CI). Results: One thousand nine hundred and seventy‐seven men were followed up. Mean baseline age was 60 ± 11.1 years. Mean duration of follow‐up was 12.2 years. At follow up 25.1% of men had died. CAG repeat length ranged from 6 to 39, with the highest proportion of CAG repeat number at 21 repeats (16.4%). In a multivariable model, compared to men with 22–23 AR CAG repeats: for men with <22 and >23 AR CAG HR, 95% CI for mortality were, <22 CAG repeats 1.17 (0.93–1.49) and >23 CAG repeats 1.14 (0.88–1.47). In a post‐hoc analysis, the association was significant for men in the lowest tertile of baseline testosterone (<14.2 nmol/L) with >23 CAG repeats: in the adjusted model for <22 and >23 CAG repeats, respectively, 1.49 (0.97–2.27) and 1.68 (1.06–2.67) versus 22–23 repeats. Conclusions: Our European‐wide cohort data overall found no association of androgen receptor CAG repeat number and mortality in men. However, post hoc analysis suggested that an association might be present in men with lower baseline testosterone concentrations, which merits further investigation. [ABSTRACT FROM AUTHOR]

Background and objectives: Huntington's disease (HD) is characterized by motor, cognitive and psychiatric manifestations and caused by an expansion of CAG repeats over 35 triplets on the huntingtin (HTT) gene. However, expansions in the range 27–35 repeats (intermediate allele) can be associated with pathological phenotypes. The onset of HD is conventionally defined by the onset of motor symptoms, but psychiatric disturbances can precede the motor phase by up to twenty years. The aims of the present study are to identify HD patients in the pre-motor phase of the disease among patients diagnosed with bipolar disorders and evaluate any differences between bipolar patients carrying the normal HTT allele and patients with the expanded HTT gene. Methods: We assessed the HTT genotype in an Italian cohort of 69 patients who were affected by either type 1 or type 2 bipolar disorder. Results: No patient was found to be a carrier of the pathological HTT allele, but 10% of bipolar subjects carried an intermediate allele. Carriers of the intermediate allele were older at the onset of psychiatric symptoms than non-carriers. Conclusion: The pathological HTT gene was not associated with bipolar disorder, while we found a higher frequency of the intermediate allele among the bipolar population with respect to healthy controls. The identification of this subset of bipolar subjects has implications for the clinical management of patients and their family members and promotes further investigation into possible pathological mechanisms common to both HD and bipolar disorder. [ABSTRACT FROM AUTHOR]

Background: STEMI is a significant cause of morbidity and mortality in patients with CAD. All STEMI patients should undergo risk stratification at the earliest as these patients are at highest risk for developing complications. TIMI risk score is used to predict both early and one year mortality. MHR has emerged a prognostic marker and has been related to cardiovascular outcomes in various CVDs. Methods: 103 acute STEMI cases admitted to KIMS Hospital, Hubballi meeting the inclusion criteria were considered in 2year time period. Of these, 75 patients with a diagnosis of STEMI who underwent PCI with significant CAG findings were selected as the STEMI group and the remaining 28 patients, who had normal coronary arteries, were selected as the control group. The STEMI patients were then divided into two subgroups based on TIMI scores. Results: Among 103 study participants ,75.73 % were males and 24.27 % were females Mean age of STEMI group is 60.8 years.DM was found in 26.21 % and HTN was found in 45.63 % of participants. Mean HDL of the STEMI group is 41.6 mg/dl. Mean monocyte count of the STEMI group is 0.9 ×10³/μL. Mean MHR of STEMI group is 3 and mean TIMI score of STEMI group is 3.3. MHR is significantly higher in STEMI group. Conclusion: In this study it has been observed that MHR is associated with TIMI score in patients with STEMI. MHR can be used as a novel prognostic marker for risk stratification and may be as an predictor of future cardiovascular events in STEMI patients. [ABSTRACT FROM AUTHOR]

Abstract Background Genes, principal units of genetic information, vary in complexity and evolutionary history. Less-complex genes (e.g., long non-coding RNA (lncRNA) expressing genes) readily emerge de novo from non-genic sequences and have high evolutionary turnover. Genesis of a gene may be facilitated by adoption of functional genic sequences from retrotransposon insertions. However, protein-coding sequences in extant genomes rarely lack any connection to an ancestral protein-coding sequence. Results We describe remarkable evolution of the murine gene D6Ertd527e and its orthologs in the rodent Muroidea superfamily. The D6Ertd527e emerged in a common ancestor of mice and hamsters most likely as a lncRNA-expressing gene. A major contributing factor was a long terminal repeat (LTR) retrotransposon insertion carrying an oocyte-specific promoter and a 5′ terminal exon of the gene. The gene survived as an oocyte-specific lncRNA in several extant rodents while in some others the gene or its expression were lost. In the ancestral lineage of Mus musculus, the gene acquired protein-coding capacity where the bulk of the coding sequence formed through CAG (AGC) trinucleotide repeat expansion and duplications. These events generated a cytoplasmic serine-rich maternal protein. Knock-out of D6Ertd527e in mice has a small but detectable effect on fertility and the maternal transcriptome. Conclusions While this evolving gene is not showing a clear function in laboratory mice, its documented evolutionary history in Muroidea during the last ~ 40 million years provides a textbook example of how a several common mutation events can support de novo gene formation, evolution of protein-coding capacity, as well as gene’s demise.

Introduction The androgen receptor (AR) mediates peripheral effects of testosterone. Evidence suggests that the number of CAG repeats in exon-1 of the AR gene negatively correlates with AR transcriptional activity. The aim of this analysis was to determine the association between CAG repeat number and mortality in men. Methods Men aged 40–79 years were recruited from primary care for participation in the UK arm of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios(HR)/95% confidence intervals (CI). Results 312 men were followed up. The mean baseline age was 59.5 years. At follow up, 85/312(27%) men had died. CAG repeat length ranged from 14 to 39, with the highest proportion of CAG repeat number at 21 repeats(16.4%). In a multivariable model, using men with CAG repeat numbers of 22-23 as the reference, men with a lower number of CAG repeats(23) (1.37 (0.65, 2.91)). Conclusion Our data suggest that CAG repeat number may partially influence the risk of mortality in men. Further larger studies are required to quantify the effect.

Accumulating evidence indicates that the increased burden of senescent cells (SCs) in aged organisms plays an important role in many age-associated diseases. The pharmacological elimination of SCs with "senolytics" has been emerging as a new therapy for age-related diseases and extending the healthy lifespan. In the present study, we identified that cycloastragenol (CAG), a secondary metabolite isolated from Astragalus membrananceus, delays age-related symptoms in mice through its senolytic activity against SCs. By screening a series of compounds, we found that CAG selectively kills SCs by inducing SCs apoptosis and that this process is associated with the inhibition of Bcl-2 antiapoptotic family proteins and the PI3K/AKT/mTOR pathway. In addition, CAG treatment also suppressed the development of the senescence-associated secretory phenotype (SASP) in SCs, thereby inhibiting cell migration mediated by the SASP. Furthermore, the administration of CAG for 2 weeks to mice with irradiation-induced aging alleviated the burden of SCs and improved the animals' age-related physical dysfunction. Overall, our studies demonstrate that CAG is a novel senolytic agent with in vivo activity that has the potential to be used in the treatment of age-related diseases. [ABSTRACT FROM AUTHOR]

Objective: RADPAD is a lead-free sterile drape that reduces scattered radiation during fluoroscopic procedures. We aimed to study the effect of using RADPAD on primary operator (PO) and secondary operator (SO) during coronary angiography (CAG) as well as percutaneous coronary intervention (PCI). Methods: 137 patients undergoing elective CAG and PCIwere randomized in a 1:1 pattern with or without the RADPAD. The ratio of PO received dose in mrem to total Air Kerma (AK) in mGy, Dose Area Product (DAP) in mGycm2 and Cine Adjusted Screening Time (CAST) in minute, at the end of the procedure with or without RADPAD were measured and designated as dose relative to AK, DAP and CAST. The exposure ratios were compared for both cohorts. Results: There was no significant difference in CAST, DAP and AK between the two patient cohorts. PO radiation dose relative to CAST was 0.15 ± 0.18 mrem/min for RADPAD cohort and 0.43 ± 0.31 mrem/min for No RADPAD cohort (p

Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease caused by CAG expansion in mutant ATXN3 gene. The resulting PolyQ tract in mutant ataxin-3 protein is toxic to neurons and currently no effective treatment exists. Function of both normal and mutant ataxin-3 is pleiotropic by their interactions and the influence on protein level. Our new preclinical Ki150 model with over 150 CAG/Q in ataxin-3 has robust aggregates indicating the presence of a process that enhances the interaction between proteins. Interactions in large complexes may resemble the real-life inclusion interactions and was never examined before for mutant and normal ataxin-3 and in homozygous mouse model with long polyQ tract. We fractionated ataxin-3-positive large complexes and independently we pulled-down ataxin-3 from brain lysates, and both were followed by proteomics. Among others, mutant ataxin-3 abnormally interacted with subunits of large complexes such as Cct5 and 6, Tcp1, and Camk2a and Camk2b. Surprisingly, the complexes exhibit circular molecular structure which may be linked to the process of aggregates formation where annular aggregates are intermediate stage to fibrils which may indicate novel ataxin-3 mode of interactions. The protein complexes were involved in transport of mitochondria in axons which was confirmed by altered motility of mitochondria along SCA3 Ki150 neurites.

Background: Genes, principal units of genetic information, vary in complexity and evolutionary history. Less-complex genes (e.g., long non-coding RNA (lncRNA) expressing genes) readily emerge de novo from non-genic sequences and have high evolutionary turnover. Genesis of a gene may be facilitated by adoption of functional genic sequences from retrotransposon insertions. However, protein-coding sequences in extant genomes rarely lack any connection to an ancestral protein-coding sequence. Results: We describe remarkable evolution of the murine gene D6Ertd527e and its orthologs in the rodent Muroidea superfamily. The D6Ertd527e emerged in a common ancestor of mice and hamsters most likely as a lncRNA-expressing gene. A major contributing factor was a long terminal repeat (LTR) retrotransposon insertion carrying an oocyte-specific promoter and a 5′ terminal exon of the gene. The gene survived as an oocyte-specific lncRNA in several extant rodents while in some others the gene or its expression were lost. In the ancestral lineage of Mus musculus, the gene acquired protein-coding capacity where the bulk of the coding sequence formed through CAG (AGC) trinucleotide repeat expansion and duplications. These events generated a cytoplasmic serine-rich maternal protein. Knock-out of D6Ertd527e in mice has a small but detectable effect on fertility and the maternal transcriptome. Conclusions: While this evolving gene is not showing a clear function in laboratory mice, its documented evolutionary history in Muroidea during the last ~ 40 million years provides a textbook example of how a several common mutation events can support de novo gene formation, evolution of protein-coding capacity, as well as gene's demise. [ABSTRACT FROM AUTHOR]

The post-budget placement in June in Bangladesh brings with itself an inundation of various scrutiny and assessment of the most crucial public policy document of the year. However, both ex-ante and ex-post oversight is an area where there has been a gaping hole for years. With analysis drawn from interviewing 52 stakeholders and review of relevant literature, the paper stocktakes the role of Bangladesh Parliament in the nation's budgetary process. The paper elaborates the theoretical basis for selecting global indexes used to evaluate the parliament's capacity of budget oversight. In fine, Jatiya Sangsad is a 'budget-approving' parliament dictated by the executive. [ABSTRACT FROM AUTHOR]

Currently, X-ray diffraction analysis (XRD) with high spatial and time resolution (TR-XRD) is based on the known theory of X-ray scattering, where the main parameter of USP—its duration—is not taken into account. In the present work, it is shown that, for scattering of attosecond USPs on DNA and RNA trinucleotides, the pulse length is the most important scattering parameter. The diffraction pattern changes considerably in comparison with the previously known scattering theory. The obtained results are extremely important in TR-XRD when using attosecond pulses to study trinucleotides of DNA and RNA, because with the previously known scattering theory, which does not take into account the duration of USP, one cannot correctly interpret, and therefore "decode", DNA and RNA structures. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) mediates peripheral effects of testosterone. Evidence suggests that the number of CAG repeats in exon-1 of the AR gene negatively correlates with AR transcriptional activity. The aim of this analysis was to determine the association between CAG repeat number and mortality in men. Men aged 40–79 years were recruited from primary care for participation in the UK arm of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios(HR)/95% confidence intervals (CI). 312 men were followed up. The mean baseline age was 59.5 years. At follow up, 85/312(27%) men had died. CAG repeat length ranged from 14 to 39, with the highest proportion of CAG repeat number at 21 repeats(16.4%). In a multivariable model, using men with CAG repeat numbers of 22-23 as the reference, men with a lower number of CAG repeats(<22) showed a trend for a higher mortality in the follow-up period (HR 1.46 (0.75, 2.81)) as did men with higher number of repeats (>23) (1.37 (0.65, 2.91)). Our data suggest that CAG repeat number may partially influence the risk of mortality in men. Further larger studies are required to quantify the effect. [ABSTRACT FROM AUTHOR]

目的：探讨含去甲基化药物（hypomethylating agent, HMA）方案治疗中高危骨髓增生异常综合征/骨髓增殖性肿瘤 （myelodysplastic/myeloproliferative neoplasms, MDS/MPN）患者的临床疗效及安全性。方法：对2012年11月—2022年1月在南 京医科大学第一附属医院血液科接受含HMA方案治疗的29例中高危MDS/MPN患者进行回顾性分析, 按治疗方案分为单用 HMA组和地西他滨（decitabine, DAC）联合小剂量化疗（D-CAG）组, 比较两组患者的临床缓解率、中位总生存期（overall survival, OS） 及无白血病生存期（leukemia-free survival, LFS）。结果：29例MDS/MPN患者中男22例, 女7例, 中位年龄66岁。单用HMA组 16例, D-CAG组13例, 两组患者临床特征差异无统计学意义（P > 0.05）。两组患者临床有效率差异无统计学意义（P > 0.05）。 生存分析结果显示D-CAG组患者中位OS较单用HMA组明显延长（26.3个月vs. 13.5个月, P=0.009 5）, 且与单用HMA组患者 相比, D-CAG组患者有较长的中位LFS（24.2个月vs. 8.7个月, P=0.045 5）。单因素分析发现初诊时血红蛋白（≥70 g/L vs. <70 g/L） 和治疗方案是OS的影响因素；多因素分析结果表明仅有治疗方案是影响患者OS的独立预后因素。两组患者主要不良反应为 3~4级骨髓抑制、肺部感染、发热（未查明感染灶）。与单用HMA方案相比, D-CAG组更容易发生3~4级骨髓抑制, 但并未增加 患者感染的风险。结论：D-CAG方案应用于MDS/MPN患者安全有效, 并可能带来生存获益, 这将为临床治疗提供参考。 [ABSTRACT FROM AUTHOR]

Xiaoyu Liu,1 Hua Shi,2 Jing Shen,1 Yang Li,1 Wei Yan,1 Ying Sun,1 Aijun Liao,1 Yehui Tan,3 Wei Yang,1,&ast; Huihan Wang1,&ast; 1Haematology Department of Shengjing Hospital, China Medical University, Shenyang, Liaoning, 110004, People’s Republic of China; 2Haematology Department of Sun Yat-sen Memorial Hospital, Sun Yat-sen University Shen Shan Central Hospital, Guangzhou, People’s Republic of China; 3Haematology Department of The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Yang; Huihan WangHaematology Department of Shengjing Hospital, China Medical University, Shenyang, Liaoning, 110004, People’s Republic of ChinaTel +86-18940251012; +86-18940256966Email yangw@sj-hospital.org; wanghh@sj-hospital.orgAbstract: Acute myeloid leukemia (AML) is a disease affecting older adults, although optimal strategies for treating such patients remain unclear. This prospective phase II, open-label, multicenter study was designed to assess the efficacy and safety of two hematologic growth factors, recombinant human thrombopoietin (rhTPO) and granulocyte colony-stimulating factor (G-CSF), in combination with decitabine, cytarabine, and aclarubicin (D-CTAG regimen) to treat older adults with newly diagnosed AML (Identifier: NCT04168138). The above agents were administered as follows: decitabine (15 mg/m2 daily, days 1– 5); low-dose cytarabine (10 mg/m2 q12 h, days 3– 9); rhTPO (15,000 U daily, days 2, 4, 6, 8, 10– 24 or until > 50× 109/L platelets); aclarubicin (14 mg/m2 daily, days 3– 6); and G-CSF (300 μg daily, days 2– 9). We concurrently monitored historic controls treated with decitabine followed by cytarabine, aclarubicin, and G-CSF (D-CAG) only. After the first D-CTAG cycle, the overall response rate (ORR) was 84.2% (16/19), including 13 (73.7%) complete remissions (CRs) and three (15.8%) partial remissions. This CR rate surpassed that of the D-CAG treatment (p < 0.05). Median overall survival (OS) time in the D-CTAG group was 20.2 months (range, 4– 31 months), compared with 14 months in the D-CAG group, and 1-year OS was 78%. The proportion of those experiencing grade III–IV thrombocytopenia was significantly lower for D-CTAG (57.9%) than for D-CAG (88.4%; p < 0.05). Ultimately, the curative effect of adding rhTPO was not inferior to that of D-CAG, and D-CTAG proved safer for elderly patients, especially in terms of hematologic toxicity. A prospective phase III randomized study is warranted to confirm these observations.Keywords: rhTPO, elderly, acute myeloid leukemia, CAG, decitabine

Pathogenic DNA secondary structures have been identified as a common and causative factor for expansion in trinucleotide, hexanucleotide, and other simple sequence repeats. These expansions underlie about fifty neurological and neuromuscular disorders known as “anticipation diseases”. Cell toxicity and death have been linked to the pathogenic conformations and functional changes of the RNA transcripts, of DNA itself and, when trinucleotides are present in exons, of the translated proteins. We review some of our results for the conformations and dynamics of pathogenic structures for both RNA and DNA, which include mismatched homoduplexes formed by trinucleotide repeats CAG and GAC; CCG and CGG; CTG(CUG) and GTC(GUC); the dynamics of DNA CAG hairpins; mismatched homoduplexes formed by hexanucleotide repeats (GGGGCC) and (GGCCCC); and G-quadruplexes formed by (GGGGCC) and (GGGCCT). We also discuss the dynamics of strand slippage in DNA hairpins formed by CAG repeats as observed with single-molecule Fluorescence Resonance Energy Transfer. This review focuses on the rich behavior exhibited by the mismatches associated with these simple sequence repeat noncanonical structures.

Expansions of RNA AUUCU, CCUG, CAG, and CUG repeats cause spinocerebellar ataxia type 10, myotonic dystrophy type 2, Huntington’s disease, and myotonic dystrophy type 1, respectively. By performing extensive molecular dynamic simulations, we investigated the bending propensities and conformational landscapes adopted by 3×3, 2×2, and 1×1 internal loops observed in RNA AUUCU, CCUG, CAG, and CUG repeat expansions using model systems having biologically relevant repeat sizes. We show that the conformational variability experienced by these loops is more complex than previous reports where a variety of unconventional hydrogen bonds are formed. At the global scale, strong bending propensity was observed in r(AUUCU)10, r(CCUG)15, r(CAG)20, and r(CUG)20, and, to a lesser extent, in r(AUUCU)4, r(CCUG)10, r(CAG)10, and r(CUG)10. Furthermore, RNA CAG repeats exhibit a tendency toward bent states with more than 50% of observed conformations having bending angles greater than 50°, while RNA CUG repeats display relatively linear-like conformations with extremely bent conformations accounting for less than 25% of the observed structures. Conformations experienced by RNA AUUCU repeats are a combination of strongly bent and kinked structures. The bent states in RNA CCUG repeats mostly fall into the moderately bent category with a marginal ensemble experiencing extreme bending. The general pattern observed in all the bent structures indicates the collapse of the major groove width as the mechanical trigger for bending, which is caused by alteration of base pair step parameters at multiple locations along the RNA due to local distortions at the loop sites. Overextension is also observed in all the RNA repeats that is attributed to widening of the major groove width as well as undertwisting phenomenon. This information and the rich structural repository could be applied for structure based small molecule design targeting disease-causing RNAs. The bending propensities of these constructs, at the global level, could also have implications on how expanded RNA repeats interact with proteins.

Tarihsel serüven boyunca teknolojide pek çok önemli gelişmeler yaşanmıştır. İnsan hayatını doğrudan etkileyen bu gelişmeler, toplumların değişmesine ve dönüşmesine yol açmıştır. Kişilerin hayatına sirayet eden bu dönüşüm dinleri ve dinlerin sunuluş biçimlerini de büyük oranda etkilemiştir. İnternetle birlikte dinlerin yayılma ve anlaşılma biçimleri, geleneksel dini araştırmaların farklı bir sentezine dönüşmüştür. İnternet dinin/maneviyatın bireysel, özel ve otonom pratiklerinin yayılmasında önemli bir rol oynamıştır. Bu yüzden internetin ve dijitalliğin din üzerine derin etkileri olmuştur.

Background: Achieving the 95-95-95 targets require an efficient and innovative person-centered approach, specifically community-based differentiated service delivery (DSD), to improve access to human immunodeficiency virus (HIV) services and reduce burdens on the health system. Therefore, this study aimed to assess the uptake of community-based DSD models and associated factors among people living with HIV (PLHIV)., Methods: A multicenter cross-sectional study was conducted among PLHIV in public health facilities in South Ethiopia. Data were collected and entered into EpiData version 3.1 before being exported to Stata version 14 for further analysis. In the bivariable logistic regression analysis, variables with a p -value of ≤0.25 were included in the multivariable logistic regression analysis. A p -value of <0.05 was used to identify statistically significant factors., Results: Among 381 stable PLHIV, 55.91% were women. The median age (interquartile range) was 40 years (27-53). The uptake of community-based DSD models was 19.16%. Residence and disclosure were the two independent factors significantly associated with the uptake of community-based DSD models., Conclusion: One out of five stable PLHIV on antiretroviral therapy uptake the community-based DSD models. Improvement in uptake is needed in Ethiopia's resource-limited healthcare system to better achieve the 95-95-95 targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Merid, Toma, Anbesie and Guyo.)

Abstract Background The focus of the community anti-retroviral therapy Group model is on drug refill, adherence and support groups. However, laboratory services are completely neglected in this model, and stable patient still have to go to the clinic for blood draws after drugs refills from the community. Due to the introduction of new ART drugs, the guidelines now recommend the use of viral loads to guide decision in switching all patients from NNRTI to dolutegravir based first line ART regimens. But the national viral load testing coverage stands at 37% and and falls short of meeting the global UNAIDS and phlebotomy delivery system is congested. The purpose of this study was to identify the perceptions in decentralizing phlebotomy services into the community anti-retroviral therapy Group model. Method A qualitative case study design was used. Data were collected through ten Focused group discussions among community anti-retroviral therapy Group members, community and health care workers at anti-retroviral therapy clinics and in-depth interviews with five key informants. Data were managed with the help of Nvivo version 10 and analyzed using thematic method. Results Positive perceptions were identified as those which contributed to decongesting phlebotomy rooms, reduced missing phlebotomy appointments, work Load, and lost results. Improved quality of phlebotomy service delivery and testing coverage, innovative access to laboratory services and encouraged patient’s accountability. The negative perceptions were compromised sample integrity, inability to perform prevention control and patients less contact with clinicians. Conclusion The study has demonstrated that decentralizing phlebotomy services within the CAG model has greater potential to improve the quality of services delivery for patients. In addition, it has perceived threats on the quality of specimen collected, patient’s safety, and health care.

The vast majority of therapeutic recombinant proteins are produced in mammalian cell lines. However, proteins generated in nonhuman cell lines, such as Chinese hamster ovary (CHO) cells, are decorated with human‐like glycan structures that differ from those of human cells, and these may induce immunogenic responses in human cells. Human embryonic kidney cells (HEK293F) are also extensively used as hosts for the expression of recombinant therapeutic proteins, but their utility is limited by the low expression of transgenes in these cells. Here, we investigated recombinant protein expression from eight frequently used promoters in transfected HEK293F cells. The expression levels and stability of the transgenes were evaluated by flow cytometry and qRT‐PCR. The most efficient expression (in terms of both mRNA and protein yields) was achieved using a cytomegalovirus (CMV) major immediate‐early enhancer combined with the chicken beta‐actin promoter (CAG) promoter, as compared to all other tested promoters under both transient and stable transfection conditions. In addition, application of mild hypothermia (i.e., 33 °C) after transfection improved the positive effect of the CMV enhancer fused to the chicken beta‐actin promoter (CAG promoter) on enhanced green fluorescent protein (eGFP) expression. Although the temperature sensitivity of the CMV promoter is greater than that of CAG promoter, recombinant protein levels were still highest when expression was driven by the CAG promoter. When eGFP was replaced with hepatitis B surface antigen, the CAG promoter still showed the highest transgene expression. In conclusion, our data show that the CAG promoter is a strong promoter for recombinant protein expression in HEK293F cells. [ABSTRACT FROM AUTHOR]

Purpose: The present study aimed to investigate the efficacy and severity of adverse effects of HCAG and CAG re-induction chemotherapy in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia (AML) following induction failure. Methods: A total of 94 AML patients were enrolled in the study, of whom 46 were treated with HCAG chemotherapy, while 48 were treated with CAG chemotherapy. Result: The complete remission (CR) was 39.6% in the patients with HCAG, while the CR was 33.3% in the CAG group. The overall remission (ORR) was 63.0% and 43.5% in patients of the HCAG and CAG groups, respectively (P = 0.038). The median survival time of progression free survival (PFS) was 8.0 (95% CI 3.843–10.157) months in the HCAG group and 7.0 (95% CI 2.682–13.318) months in the CAG group (P = 0.032). A total of 31 patients in the HCAG group suffered from grade 4 hematological toxicity, whereas 29 patients were treated with CAG (P = 0.622). A total of 27 (58.7%) cases indicated apparent pulmonary infection in the HCAG group, while 25 (52.1%) were noted with this complication in the CAG group (P = 0.519). Oral cavity toxicity was evident for 13 (28.3%) and 11 (23.0%) cases in the HCAG and CAG groups, respectively (P = 0.216). Conclusion: The HCAG regimen was more effective than the CAG regimen in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia although the HCAG regimen exhibited similar toxicity with that of the CAG group. [ABSTRACT FROM AUTHOR]

Type IV secretion systems are protein secretion machineries that are frequently used by pathogenic bacteria to inject their virulence factors into target cells of their respective hosts. In the case of the human gastric pathogen Helicobacter pylori, the cytotoxin-associated gene (Cag) type IV secretion system is considered a major cause for severe disease, such as gastric cancer, and thus constitutes an attractive target for specific treatment options against H. pylori infections. Here, we have used a Cag type IV secretion reporter assay for screening a repurposing compound library for inhibitors targeting this system. We found that the antitumor agent cisplatin, a platinum coordination complex that kills target cells by formation of DNA crosslinks, is a potent inhibitor of the Cag type IV secretion system. Strikingly, we found that this inhibitory activity of cisplatin depends on a ligand exchange reaction which incorporates a solvent molecule (dimethylsulfoxide) into the complex, a modification which is known to be deleterious for DNA crosslinking, and for its anticancer activity. We extended our analysis to several analogous platinum complexes containing N-heterocyclic carbene, as well as DMSO or other ligands, and found varying inhibitory activities toward the Cag system which were not congruent with their DNA-binding properties, suggesting that protein interactions may cause the inhibitory effect. Inhibition experiments under varying conditions revealed effects on adherence and bacterial viability as well, and showed that the type IV secretion-inhibitory capacity of platinum complexes can be inactivated by sulfur-containing reagents and in complex bacterial growth media. Taken together, our results demonstrate DNA binding-independent inhibitory effects of cisplatin and other platinum complexes against different H. pylori processes including type IV secretion.

The pathogenic bacterium Helicobacter pylori is genetically highly diverse and a major risk factor for the development of peptic ulcer disease and gastric adenocarcinoma in humans. During evolution, H. pylori has acquired multiple type IV secretion systems (T4SSs), and then adapted for various purposes. These T4SSs represent remarkable molecular transporter machines, often associated with an extracellular pilus structure present in many bacteria, which are commonly composed of multiple structural proteins spanning the inner and outer membranes. By definition, these T4SSs exhibit central functions mediated through the contact-dependent conjugative transfer of mobile DNA elements, the contact-independent release and uptake of DNA into and from the extracellular environment as well as the secretion of effector proteins in mammalian host target cells. In recent years, numerous features on the molecular functionality of these T4SSs were disclosed. H. pylori encodes up to four T4SSs on its chromosome, namely the Cag T4SS present in the cag pathogenicity island (cagPAI), the ComB system, as well as the Tfs3 and Tfs4 T4SSs, some of which exhibit unique T4SS functions. The Cag T4SS facilitates the delivery of the CagA effector protein and pro-inflammatory signal transduction through translocated ADP-heptose and chromosomal DNA, while various structural pilus proteins can target host cell receptors such as integrins or TLR5. The ComB apparatus mediates the import of free DNA from the extracellular milieu, whereas Tfs3 may accomplish the secretion or translocation of effector protein CtkA. Both Tfs3 and Tfs4 are furthermore presumed to act as conjugative DNA transfer machineries due to the presence of tyrosine recombinases with cognate recognition sequences, conjugational relaxases, and potential origins of transfer (oriT) found within the tfs3 and tfs4 genome islands. In addition, some extrachromosomal plasmids, transposons and phages have been discovered in multiple H. pylori isolates. The genetic exchange mediated by DNA mobilization events of chromosomal genes and plasmids combined with recombination events could account for much of the genetic diversity found in H. pylori. In this review, we highlight our current knowledge on the four T4SSs and the involved mechanisms with consequences for H. pylori adaptation to the hostile environment in the human stomach.

Type IV secretion systems are protein secretion machineries that are frequently used by pathogenic bacteria to inject their virulence factors into target cells of their respective hosts. In the case of the human gastric pathogen Helicobacter pylori , the cytotoxin-associated gene (Cag) type IV secretion system is considered a major cause for severe disease, such as gastric cancer, and thus constitutes an attractive target for specific treatment options against H. pylori infections. Here, we have used a Cag type IV secretion reporter assay for screening a repurposing compound library for inhibitors targeting this system. We found that the antitumor agent cisplatin, a platinum coordination complex that kills target cells by formation of DNA crosslinks, is a potent inhibitor of the Cag type IV secretion system. Strikingly, we found that this inhibitory activity of cisplatin depends on a ligand exchange reaction which incorporates a solvent molecule (dimethylsulfoxide) into the complex, a modification which is known to be deleterious for DNA crosslinking, and for its anticancer activity. We extended our analysis to several analogous platinum complexes containing N-heterocyclic carbene, as well as DMSO or other ligands, and found varying inhibitory activities toward the Cag system which were not congruent with their DNA-binding properties, suggesting that protein interactions may cause the inhibitory effect. Inhibition experiments under varying conditions revealed effects on adherence and bacterial viability as well, and showed that the type IV secretion-inhibitory capacity of platinum complexes can be inactivated by sulfur-containing reagents and in complex bacterial growth media. Taken together, our results demonstrate DNA binding-independent inhibitory effects of cisplatin and other platinum complexes against different H. pylori processes including type IV secretion. [ABSTRACT FROM AUTHOR]

The pathogenic bacterium Helicobacter pylori is genetically highly diverse and a major risk factor for the development of peptic ulcer disease and gastric adenocarcinoma in humans. During evolution, H. pylori has acquired multiple type IV secretion systems (T4SSs), and then adapted for various purposes. These T4SSs represent remarkable molecular transporter machines, often associated with an extracellular pilus structure present in many bacteria, which are commonly composed of multiple structural proteins spanning the inner and outer membranes. By definition, these T4SSs exhibit central functions mediated through the contact-dependent conjugative transfer of mobile DNA elements, the contact-independent release and uptake of DNA into and from the extracellular environment as well as the secretion of effector proteins in mammalian host target cells. In recent years, numerous features on the molecular functionality of these T4SSs were disclosed. H. pylori encodes up to four T4SSs on its chromosome, namely the Cag T4SS present in the cag pathogenicity island (cag PAI), the ComB system, as well as the Tfs3 and Tfs4 T4SSs, some of which exhibit unique T4SS functions. The Cag T4SS facilitates the delivery of the CagA effector protein and pro-inflammatory signal transduction through translocated ADP-heptose and chromosomal DNA, while various structural pilus proteins can target host cell receptors such as integrins or TLR5. The ComB apparatus mediates the import of free DNA from the extracellular milieu, whereas Tfs3 may accomplish the secretion or translocation of effector protein CtkA. Both Tfs3 and Tfs4 are furthermore presumed to act as conjugative DNA transfer machineries due to the presence of tyrosine recombinases with cognate recognition sequences, conjugational relaxases, and potential origins of transfer (oriT) found within the tfs3 and tfs4 genome islands. In addition, some extrachromosomal plasmids, transposons and phages have been discovered in multiple H. pylori isolates. The genetic exchange mediated by DNA mobilization events of chromosomal genes and plasmids combined with recombination events could account for much of the genetic diversity found in H. pylori. In this review, we highlight our current knowledge on the four T4SSs and the involved mechanisms with consequences for H. pylori adaptation to the hostile environment in the human stomach. [ABSTRACT FROM AUTHOR]

Objective: To analyze the effect of decitabine combined with conventional chemotherapy on myelodysplastic syndrome (MDS) and its influencing factors. Methods: Eighty patients with MDS who were admitted to our hospital were selected by this study between February 2017 and February 2018. The selected patients were divided into a traditional group (CAG/DA scheme) and the combined group (DAC combined with CAG/DA scheme) according to the random number table method, 40 each. The clinical treatment effects of the two groups were compared, and the influencing factors of the effect were analyzed. Results: After four courses of treatment, the difference in the total effective rate between the two groups were statistically significant (P<0.05); the difference in the incidence of adverse reactions and in the overall survival (OS) rate between the two groups were not statistically significant (P>0.05). However, the progression free survival (PFS) rate of the combined group was significantly higher compared with the traditional group (P<0.05); the Hb level, WHO stage and and karyotype of the patients before treatment had significant influence on the treatment effect (P<0.05). Conclusion: DAC in combination with conventional chemotherapy has good effect in the treatment of MDS, and it will not increase adverse reactions. In addition to treatment scheme, the influencing factors of the effect of treatment for MDS also include Hb, WHO stage and karyotype. [ABSTRACT FROM AUTHOR]

It is essential that communities at risk from TB are involved in TB research. Community advisory groups (CAGs) are one mechanism for involving communities in research and creating platforms for discussions between researchers and community members. We organised a CAG meeting with community members and people with lived experience in Ho Chi Minh City, Vietnam, to explore the community's knowledge about TB and their perspectives on different diagnostic tests in Vietnam, a low-middle-income country with a high TB burden. Researchers shared basic information and addressed questions about TB. CAG members commented on preference of TB screening tests, and suggested that chest X-rays and blood tests were more acceptable than sputum tests because of the difficulty in sputum expectoration. In addition, clinical studies that required fewer visits to the hospitals would be preferred, even if this meant a greater reliance on blood sampling., Competing Interests: Conflicts of interest: none declared., (© 2024 The Authors.)

Spinocerebellar ataxia type 3 (SCA3/MJD) is a polyQ neurodegenerative disease where the presymptomatic phase of pathogenesis is unknown. Therefore, we investigated the molecular network of transcriptomic and proteomic triggers in young presymptomatic SCA3/MJD brain from Ki91 knock-in mouse. We found that transcriptional dysregulations resulting from mutant ataxin-3 are not occurring in young Ki91 mice, while old Ki91 mice and also postmitotic patient SCA3 neurons demonstrate the late transcriptomic changes. Unlike the lack of early mRNA changes, we have identified numerous early changes of total proteins and phosphoproteins in 2-month-old Ki91 mouse cortex and cerebellum. We discovered the network of processes in presymptomatic SCA3 with three main groups of disturbed processes comprising altered proteins: (I) modulation of protein levels and DNA damage (Pabpc1, Ddb1, Nedd8), (II) formation of neuronal cellular structures (Tubb3, Nefh, p-Tau), and (III) neuronal function affected by processes following perturbed cytoskeletal formation (Mt-Co3, Stx1b, p-Syn1). Phosphoproteins downregulate in the young Ki91 mouse brain and their phosphosites are associated with kinases that interact with ATXN3 such as casein kinase, Camk2, and kinases controlled by another Atxn3 interactor p21 such as Gsk3, Pka, and Cdk kinases. We conclude that the onset of SCA3 pathology occurs without altered transcript level and is characterized by changed levels of proteins responsible for termination of translation, DNA damage, spliceosome, and protein phosphorylation. This disturbs global cellular processes such as cytoskeleton and transport of vesicles and mitochondria along axons causing energy deficit and neurodegeneration also manifesting in an altered level of transcripts at later ages. [ABSTRACT FROM AUTHOR]

High expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor has been found in myelomonocytic or monocytic subtypes (M4/M5) of acute myeloid leukemia. Herein, we aimed to improve the effect of CAG [Ara-C, ACR, and G-CSF (granulocyte colony-stimulating factor)] regimen for acute monocytic leukemia by replacing G-CSF with GM-CSF. Results showed that the percentage of cells in S phase was higher with GM-CSF than with G-CSF treatment at 20 ng/mL (P < 0.05). When THP-1 and SHI-1 cells were primed with 20 ng/mL G-CSF or GM-CSF followed by Ara-C and ACR, cell proliferation rate in the CAGM (Ara-C, ACR, and GM-CSF) regimen was lower than in the CAG regimen (P < 0.05). Furthermore, CAGM regimen induced more obvious cell apoptosis than CAG regimen probably by reducing Bcl-2/Bax ratio (P < 0.05). Similar results were seen in primary cells from M5 patients. Collectively, our study suggests that priming with GM-CSF may be more effective than G-CSF in CAG regimen in acute monocytic leukemia. [ABSTRACT FROM AUTHOR]

To describe the phenotype of individuals with intermediate allele (IA) CAG repeat length in the huntingtin (HTT) gene evaluated at the Parkinson's Disease Center and Movement Disorders Clinic (PDCMDC) at Baylor College of Medicine (BCM). Huntington disease (HD) is caused by a mutation in the HTT gene of 36 or more CAG trinucleotide repeats. Since our original case report of pathologically proven HD with 29 CAG repeats, a growing body of evidence has accumulated supporting the observation that individuals with IA (27 to 35 CAG repeats) may exhibit clinical, imaging, and pathologic manifestations of HD. About 6% of the general population has CAG repeats in the IA range in at least one allele of the HTT gene. The presence of IA is a challenge for genetic counseling. Medical records of patients with IAs seen at the PDCMDC at BCM from January 2008 to the present were reviewed to assess age at symptom onset, dominant clinical features and presence of psychiatric and cognitive symptoms. Four men and five women were found to have IAs (range: 27–35) in the course of their evaluation at the PDCMDC. The age at onset of clinically evident symptoms ranged from 27 to 78 years. Six individuals had chorea, three had gait disturbance, two had stereotypies, and one patient had multiple motor tics. All nine had psychiatric symptoms, with depression being the most common. Our series of 9 individuals with IA in the HTT gene exhibit a variety of motor and non-motor features that overlap with the HD phenotype. These individuals and their offspring should be considered at risk for development of progressive HD. • Huntington disease (HD) is caused by a mutation resulting in 36 or more CAG repeats • Intermediate length repeats (IA) are defined as 27–35 CAG repeats in the HTT gene • About 6% of the general population has CAG repeats in the IA range • Individuals with IA may exhibit clinical and pathological manifestations of HD [ABSTRACT FROM AUTHOR]

Background: Transcatheter aortic valve replacement (TAVR) is a well-established treatment option for severe aortic stenosis (AS). AS and coronary artery disease frequently coincide, and therefore some patients may require coronary angiography (CAG) and/or intervention (PCI) post-TAVR. Due to valve stent design, most self-expanding prostheses always cover the coronary ostium, and therefore may hinder future access. The objective of this research was to evaluate the incidence, safety and feasibility of CAG/PCI in patients with prior self-expanding TAVR valves.Methods: Among 2170 patients (age 82 ± 6 years, 43% male) who underwent TAVR with Corevalve or Evolut prostheses, as part of the Italian CoreValve ClinicalService® framework (data from 13 Italian centers), the occurrence of CAG/PCI following TAVR and periprocedural characteristics were examined.Results: During median follow-up of 379 days, 41 patients (1.9%) required CAG and/or PCI (total 46; 16 CAG, 14 PCI, 16 both PCI/CAG). 56.5% of the procedures were performed under emergency/urgency settings. Left system coronary angiography was successfully performed in most cases (28/32, 87.5%), while right coronary angiography was successful only in 50.0% (16/32). PCI procedures (20 for left system, 3 for right system, 4 for graft) were successfully performed in 93.3% (28/30) of the procedures. No CAG/PCI procedure-related complications including prosthesis dislodgment or coronary ostium dissection occurred.Conclusions: CAG and PCI procedures following CoreValve TAVR is safe and mostly feasible, although the success rate of selective right coronary angiography was relatively low when compared to the left system. Further investigations are required to explore this issue. [ABSTRACT FROM AUTHOR]

Introduction: Acne vulgaris (AV) is a multifactorial, inflammatory disease of the pilosebaceous unit. Hormones play a major role in the pathogenesis of acne. In cases of hyperandrogenism; hirsutism, acne, seborrhoea and alopecia appear in women. However, severe acne can also be seen without evidence of hyperandrogenism. In this case, hypersensitivity of the androgen receptor gene (ARG) encoded in the X chromosome, which is the only receptor for androgens, can be considered. ARG contains a polymorphic CAG triple loop encoding the polyglutamine pathway at the 5'end of exon 1. Aim: To investigate CAG repeat polymorphism in the ARG in nodulocystic acne patients in Turkish population. Material and methods: This prospective clinical study was conducted between 2016 and 2017 in accordance with the tenets of the Declaration of Helsinki. DNA isolation from blood was performed using the RTA® Genomic DNA Isolation Kit. The fragment lengths obtained from the device to determine CAG repeat numbers were analysed based on -288 bp length 22 CAG repeat content. Results: A total of 199 subjects; 100 patients (51 males, 49 females) and 99 controls (49 males, 50 females) were included in the study. The mean allele length in the patient group was 19.34; and 19.7 in the control group. There was a statistically significant difference between female patients and the control group, when the patients and control groups were compared by gender (p = 0.0059). Conclusions: The CAG trinucleotide repeat count in the ARG may be associated with acne, without hirsutism findings. [ABSTRACT FROM AUTHOR]

Objectives: This study was conducted to determine the correlation among prolactin gene (PRG), growth differentiation factor 9 (GDF-9), and calpastatin (CAG) genes polymorphism with growth traits in Awassi lambs. Materials and Methods: Records of 779 Awassi lambs from 264 dams and 15 sires were used. The sex, type of birth (single versus twins), weight at birth, average daily gain (ADG), and the adjusted weight at 60 days of age were determined for each animal. Blood samples were collected from all lambs to determine PRG, GDF-9, and CAG polymorphism using polymerase chain reaction-Restriction fragment length polymorphism. Results: Three PRG genotypes (AA, AB, and BB) were determined with a frequency of 0.88, 0.05, and 0.07, respectively. The frequency of each allele was 0.84 and 0.16 for A and B alleles, respectively. For GDF-9, there were only two genotypes detected (AB and BB) with a frequency of 0.96 and 0.04, respectively. The frequency of each allele was 0.92 and 0.08 for A and B alleles, respectively. For CAG, two genotypes were also detected (AB and BB) with a frequency of 0.92 and 0.08, respectively. The frequency of each allele was 0.96 and 0.04 for A and B alleles, respectively. A significant (p = 0.04) effect of PRG genotype on birth weight was detected but this effect was not significant on ADG and weight at weaning. There were no associations between any of the pre-weaning growth traits and GDF-9 and CAG variants. Conclusion: The results of this study show that PRG could be used to select dams with a high frequency of dystocia to reduce birth weight of newborn lambs and therefore conserve the dam's reproductive functions and improve lamb survivability. [ABSTRACT FROM AUTHOR]

There is a known negative association between cytosine–adenine–guanine (CAG) repeat length and the age of motor onset (AMO) in adult-onset Huntington’s Disease (AOHD). This relationship is less clear in patients with juvenile-onset Huntington’s disease (JOHD), however, given the rarity of this patient population. The aim of this study was to investigate this relationship amongst a relatively large group of patients with JOHD using data from the Kids-JOHD study. Additionally, we analyzed data from the Enroll-HD platform and the Predict-HD study to compare the relationship between CAG repeat length and AMO amongst patients with AOHD to that amongst patients with JOHD using linear regression models. In line with previous reports, the variance in AMO that was predicted by CAG repeat length was 59% (p < 0.0001) in the Predict-HD study and 57% from the Enroll-HD platform (p < 0.0001). However, CAG repeat length predicted 84% of the variance in AMO amongst participants from the Kids-JOHD study (p < 0.0001). These results indicate that there may be a stronger relationship between CAG repeat length and AMO in patients with JOHD as compared to patients with AOHD. These results provide additional information that may help to model disease progression of JOHD, which is beneficial for the planning and implementation of future clinical trials.

The recently published high-resolution R388 T4SS structure provides exciting new details about the complete complex of T4SS, including the components making up the stalk and arches, numerous symmetry mismatches between regions of the complex, and an intriguing interpretation of the closed stalk and radial symmetry of the inner membrane complex, which is related to pilus biogenesis assembly. However, there are a few unidentified densities in the electron microscopy map and portions of the identified component sequences for which the structure is not yet known. It is also unclear how well this minimized DNA-transporting T4SS predicts the structure of other T4SSs, such as expanded systems and those that transport proteins rather than DNA. In this review, we evaluate what can be inferred from the recent high-resolution structure of the R388 T4SS with respect to the Cag and Dot/Icm systems. These systems were selected because, given what is currently known about these systems, we expect them to present most structural differences compared to the R388 T4SS structure. Furthermore, we discuss bacterial physiology and diversity, the T4SS structures and their variations between different bacterial species. These insights may prove beneficial for researchers who elucidate the structure and functions of T4SS in different bacterial species.