Nuclear architecture and the structural basis of mitotic memory.

The nucleus is a complex organelle that hosts the genome and is essential for vital processes like DNA replication, DNA repair, transcription, and splicing. The genome is non-randomly organized in the three-dimensional space of the nucleus. This functional sub-compartmentalization was thought to be organized on the framework of nuclear matrix (NuMat), a non-chromatin scaffold that functions as a substratum for various molecular processes of the nucleus. More recently, nuclear bodies or membrane-less subcompartments of the nucleus are thought to arise due to phase separation of chromatin, RNA, and proteins. The nuclear architecture is an amalgamation of the relative organization of chromatin, epigenetic landscape, the nuclear bodies, and the nucleoskeleton in the three-dimensional space of the nucleus. During mitosis, the nucleus undergoes drastic changes in morphology to the degree that it ceases to exist as such; various nuclear components, including the envelope that defines the nucleus, disintegrate, and the chromatin acquires mitosis-specific epigenetic marks and condenses to form chromosome. Upon mitotic exit, chromosomes are decondensed, re-establish hierarchical genome organization, and regain epigenetic and transcriptional status similar to that of the mother cell. How this mitotic memory is inherited during cell division remains a puzzle. NuMat components that are a part of the mitotic chromosome in the form of mitotic chromosome scaffold (MiCS) could potentially be the seeds that guide the relative re-establishment of the epigenome, chromosome territories, and the nuclear bodies. Here, we synthesize the advances towards understanding cellular memory of nuclear architecture across mitosis and propose a hypothesis that a subset of NuMat proteome essential for nucleation of various nuclear bodies are retained in MiCS to serve as seeds of mitotic memory, thus ensuring the daughter cells re-establish the complex status of nuclear architecture similar to that of the mother cells, thereby maintaining the pre-mitotic transcriptional status.

Qualitative Findings From a Survey on Patient Experiences and Satisfaction with Lung Cancer Screening.

BACKGROUND: To reveal successes and potential limitations of the lung cancer screening program, we conducted a survey that included both quantitative and open-ended questions to measure patient experiences and satisfaction with screening. METHODS: We report on the five open-ended items related to barriers to returning for screening, experience with other cancer prevention screenings, positive and negative experiences, and suggestions for improving future appointments. The open-ended responses were analyzed using constant comparison method and inductive content analysis. RESULTS: Respondents (182 patients, 86% response rate for open-ended questions) provided generally positive comments about their lung cancer screening experience. Negative comments were related to desire for more information about results, long wait times for results, and billing issues. Suggestions for improvements included: scheduling on-line appointments and text or email reminders, lower costs, and responding to uncertainty about eligibility criteria. CONCLUSION: Findings provide insights about patient experiences and satisfaction with lung cancer screening which is important given low uptake. Ongoing patient-centered feedback may improve the lung cancer screening experience and increase follow-up screening rates.

Isolation, characterization, development and evaluation of phytoconstituent based formulation for diabetic neuropathy.

Background: Morus alba Linn, referred to as white mulberry, is a potential traditional medicine for diabetes and neuroprotection. Aim: Isolation, characterization, development and evaluation of phytoconstituent based formulation for diabetic neuropathy. Material and methods: The stem Bark of M. alba was peeled and subjected to extraction. A phytoconstituent was then isolated by column chromatography and characterized using Mass spectroscopy, FTIR, and NMR. The isolated phytoconstituent was used to formulate a nanoemulsion. Nanoemulsion was also characterized for viscosity, surface tension, refractive index, pH, and particle size. Selected nanoemulsion formulations were then tested for acute oral toxicity and diabetic neuropathy, including behavioral, hematological, histopathological, and biomarker examinations. Results: The spectral analysis affirmed that the isolated compound was found to be chrysin. A nanoemulsion formulation was made using the chrysin and was characterized and found to be stable during the stability testing and fulfilled all other testing parameters. Then acute oral toxicity study of the formulations was found to be safe. Formulations were found to possess significant results against diabetic neuropathy in rats. Biomarkers were analyzed for their mechanistic involvement in reducing neuropathy in rats, and it was found that the oxidative pathway was considerably restored, suggesting that chrysin causes these effects via this pathway. Conclusions: Results suggests that isolated phytoconstituent (chrysin) from the bark of Morus alba derived nanoemulsion has protective and beneficial effects by diminishing the oxidative damage against alloxan-induced diabetic neuropathy in rats.

Gastroprotective evaluation of Medicago sativa L. (Fabaceae) on diabetic rats.

Traditional uses for the plant Medicago sativa (M. sativa) (Alfalfa) (Family: Fabaceae) include liver protection, antioxidant activity, and the treatment of bleeding and digestive issues. This study aims to assess the effect of ethanol extract of M. sativa (EEMS) on experimental-induced ulcers in diabetic rats. By pylorus ligation and ethanol administration, gastric ulcers were induced in diabetic rats. Five groups each consisting of six rats in each model were used. All other groups except Group I were made diabetic by giving rats alloxan (140 mg/kg i.p.). Vehicles were given to Group I (normal control) and Group II (diabetes control) rats. Group III (positive control) received ranitidine 50 mg/kg, and Group IV and V received EEMS at doses of 100 and 400 mg/kg, respectively. In the pylorus ligation and ethanol-induced stomach ulcer model of rats, the findings demonstrated that EEMS (100 mg/kg) showed a decreased ulcer index of 2.01 ± 0.41 and was found statistically significant against the diabetes control group (p < 0.001) as well as, an ulcer index of 0.68 ± 0.22 by EEMS (400 mg/kg) with a significant reduction in the ulcer index (p < 0.001). EEMS (100 and 400 mg/kg) reduce free acidity by 13.16 ± 0.65 mEq/L and 9.83 ± 0.30 mEq/L, respectively. EEMS also showed a protective impact on the liver and kidneys of diabetic rats. Antihyperglycemic action was also discovered in diabetic animals. The findings of the current investigation demonstrated that ethanolic extract of M. sativa possesses anti-ulcer activity in diabetic rats. Ethanolic extract of M. sativa may be a treatment option for stomach ulcers that also have diabetes.

Structural and developmental dynamics of Matrix associated regions in Drosophila melanogaster genome.

BACKGROUND: Eukaryotic genome is compartmentalized into structural and functional domains. One of the concepts of higher order organization of chromatin posits that the DNA is organized in constrained loops that behave as independent functional domains. Nuclear Matrix (NuMat), a ribo-proteinaceous nucleoskeleton, provides the structural basis for this organization. DNA sequences located at base of the loops are known as the Matrix Attachment Regions (MARs). NuMat relates to multiple nuclear processes and is partly cell type specific in composition. It is a biochemically defined structure and several protocols have been used to isolate the NuMat where some of the steps have been critically evaluated. These sequences play an important role in genomic organization it is imperative to know their dynamics during development and differentiation. RESULTS: Here we look into the dynamics of MARs when the preparation process is varied and during embryonic development of D. melanogaster. A subset of MARs termed as "Core-MARs" present abundantly in pericentromeric heterochromatin, are constant unalterable anchor points as they associate with NuMat through embryonic development and are independent of the isolation procedure. Euchromatic MARs are dynamic and reflect the transcriptomic profile of the cell. New MARs are generated by nuclear stabilization, and during development, mostly at paused RNA polymerase II promoters. Paused Pol II MARs depend on RNA transcripts for NuMat association. CONCLUSIONS: Our data reveals the role of MARs in functionally dynamic nucleus and contributes to the current understanding of nuclear architecture in genomic context.

Prolonged effects of DPP-4 inhibitors on steato-hepatitic changes in Sprague-Dawley rats fed a high-cholesterol diet.

OBJECTIVE: Sitagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors/gliptins are antidiabetic drugs known to improve lipid profile, and confer anti-inflammatory and anti-fibrotic effects, which are independent of their hypoglycemic effects. However, in our previous short-term (35 days) studies, we showed that sitagliptin accentuates the hepato-inflammatory effects of high dietary cholesterol (Cho) in male Sprague-Dawley rats. Since most type 2 diabetics also present with lipid abnormalities and use DPP-4 inhibitors for glucose management, the present study was conducted to assess the impact of sitagliptin during long-term (98 days) feeding of a high Cho diet. An additional component of the present investigation was the inclusion of other gliptins to determine if hepatic steatosis, necro-inflammation, and fibrosis were specific to sitagliptin or are class effects. METHODS: Adult male Sprague-Dawley rats were fed control or high Cho (2.0%) diets, and gavaged daily (from day 30 through 98) with vehicle or DPP-4 inhibitors (sitagliptin or alogliptin or saxagliptin). On day 99 after a 4 h fast, rats were euthanized. Blood and liver samples were collected to measure lipids and cytokines, and for histopathological evaluation, determination of hepatic lesions (steatosis, necrosis, inflammation, and fibrosis) using specific staining and immunohistochemical methods. RESULTS: Compared to controls, the high Cho diet produced a robust increase in NASH like phenotype that included increased expression of hepatic (Tnfa, Il1b, and Mcp1) and circulatory (TNFα and IL-1ß) markers of inflammation, steatosis, necrosis, fibrosis, and mononuclear cell infiltration. These mononuclear cells were identified as macrophages and T cells, and their recruitment in the liver was facilitated by marked increases in endothelium-expressed cell adhesion molecules. Importantly, treatment with DPP-4 inhibitors (3 tested) neither alleviated the pathologic responses induced by high Cho diet nor improved lipid profile. CONCLUSIONS: The potential lipid lowering effects of DPP-4 inhibitors were diminished by high Cho (a significant risk factor for inducing liver damage). The robust inflammatory responses induced by high Cho feeding in long-term experiment were not exacerbated by DPP-4 inhibitors and a consistent hepatic inflammatory environment persisted, implying a prospective physiological adaptation.

Should we abandon annual physical examination? - A meta-analysis of annual physical examination and all-cause mortality in adults based on observational studies.

Several meta-analyses based on randomized clinical trials data have failed to find an association between the annual physical examination (APE) and reduced mortality; however, no comparable meta-analysis based on observational data exists. We conducted a meta-analysis of observational studies comparing APE versus non-APE in adults for all-cause mortality. English-language searches of four databases (PubMed, CINAHL, EMBASE, and Google Scholar) between the years 2000 to 2019 yielded seven observational studies that investigated APE versus non-APE in healthy adults in relation to all-cause mortality. Random effects models were used to calculate pooled hazard ratios and 95% confidence intervals (CI), and to incorporate variation between studies. During follow-up periods that ranged from two to 25 years, there were 35,055 deaths among 633,957 participants. APE was significantly associated with a 45% lower hazard of all-cause mortality, with pooled hazard ratio of 0.55 (95% CI 0.48 to 0.64, P < 0.01) for all participants. This meta-analysis of seven observational studies in the past 20 years provides evidence of an association between APE and a lower hazard of all-cause mortality, a finding that contrasts with findings based on meta-analyses of randomized clinical trials data. Nonetheless, at present the evidence available about the effectiveness or ineffectiveness of APE on all-cause mortality still needs further study.

Measurement of Pharmacist-Physician Collaborative Care on Therapeutic Inertia in Patients With Type 2 Diabetes.

BACKGROUND: Team-based care practice models have been shown to improve diabetes-related therapeutic inertia, yet the method and type of antidiabetic treatment intensification (TI) leading to improvements in glycemic control are not well understood. OBJECTIVE: To evaluate time to TI in a pharmacist-physician practice model (PPM) as compared with usual medical care (UMC), explore the method and type of antidiabetic TI, and evaluate achievement of hemoglobin A1C (A1C) goal among each cohort. METHODS: This was a retrospective cohort study conducted between January 1, 2017, and December 31, 2018. Median time to TI was calculated and compared between patients in the PPM and UMC groups using the log rank test. Descriptive statistics were used to evaluate the method and type of TI and A1C goal achievement. RESULTS: A total of 56 patients were included. The median (interquartile range) time to antidiabetic TI among the PPM cohort was 37.5 days (8, 216.5), as compared with 142 days (16, 465) in the UMC cohort (P = 0.19). At 1 year post-index date, 25% of patients in the PPM cohort reached their A1C goal compared with 18.8% of patients in the UMC cohort. This effect was maintained in the subgroup (n = 49) of patients receiving TI (23.1% vs 17.8%). CONCLUSION AND RELEVANCE: A shorter time to TI and improvement in A1C goal achievement was observed with pharmacist-physician care compared with UMC. These findings suggest that pharmacist-physician care may be one of several interventions necessary to overcome therapeutic inertia in diabetes care.

Prevalence of and Characteristics Associated With Overbasalization Among Patients With Type 2 Diabetes Using Basal Insulin: A Cross-Sectional Study.

This article describes a cross-sectional analysis of 655 patients to determine the prevalence of and patient-specific characteristics associated with overbasalization in patients with type 2 diabetes. Overbasalization was defined as uncontrolled A1C (>8%) plus a basal insulin dose >0.5 units/kg/day. The period prevalence of overbasalization was found to be 38.1, 42.7, and 42% for those with an A1C >8, ≥9, and ≥10%, respectively. Those with an A1C ≥9% had the greatest likelihood of experiencing overbasalization. These results suggest that overbasalization may play a role in patients not achieving optimal glycemic control in type 2 diabetes.

Comparison of Nuclear Matrix and Mitotic Chromosome Scaffold Proteins in Drosophila S2 Cells-Transmission of Hallmarks of Nuclear Organization Through Mitosis.

Chromatin condenses several folds to form mitotic chromosomes during cell division and decondenses post-mitotically to reoccupy their nuclear territory and regain their specific transcriptional profile in a precisely lineage specific manner. This necessitates that the features of nuclear architecture and DNA topology persist through mitosis. We compared the proteome of nuclease and high salt resistant fraction of interphase nucleus known as nuclear matrix (NuMat) and an equivalent biochemical fraction in the mitotic chromosome known as mitotic chromosome scaffold (MiCS). Our study elucidates that as much as 67% of the NuMat proteins are retained in the MiCS indicating that the features of nuclear architecture in interphase nucleus are retained on the mitotic chromosomes. Proteins of the NuMat/MiCS have large dynamic range of MS signal and were detected in sub-femtomolar amounts. Chromatin/RNA binding proteins with hydrolase and helicase activity are highly enriched in NuMat as well as MiCS. Although several transcription factors involved in functioning of interphase nucleus are present exclusively in NuMat, protein components responsible for assembly of membrane-less nuclear bodies are uniquely retained in MiCS. Our study clearly indicates that the features of nuclear architecture, in the structural context of NuMat, are retained in MiCS and possibly play an important role in maintenance of cell lineage specific transcriptional status during cell division and thereby, serve as components of cellular memory.

Sperm methylome alterations following yoga-based lifestyle intervention in patients of primary male infertility: A pilot study.

A majority of the cases of primary male infertility are idiopathic with the underlying molecular mechanisms contributing to the pathophysiology as yet unknown. Effects of the environment can alter the sperm epigenome thereby impacting male reproductive health. Epigenetic mechanisms are crucial to understanding health and disease, and methylome alterations are now known to have far-reaching clinical implications. Here, we report the results from our pilot study, a first of its kind analysis of the effect of the traditional practice of yoga on human sperm quality. We find marked improvement in sperm characteristics in patients of idiopathic male infertility following a supervised 21-day yoga regimen. Furthermore, next-generation sequencing-based methylome analysis reveals alterations in the sperm epigenome of these patients. We find that the practice of yoga is associated with DNA methylation changes at nearly 400 genes, 147 of which were hypermethylated while 229 were hypomethylated. These included promoters of several genes linked to maintenance of fertility and genomic integrity. This novel piece of work draws a direct link between positive lifestyle practices and male reproductive health.

The incretin enhancer, sitagliptin, exacerbates expression of hepatic inflammatory markers in rats fed a high-cholesterol diet.

OBJECTIVE: Hypercholesterolemia is associated with the development of a pro-inflammatory state and is a documented risk factor for progression to insulin resistance, nonalcoholic fatty liver and cardiovascular diseases. Sitagliptin is an incretin enhancer that improves glucose tolerance by inhibiting dipeptidyl peptidase-4, but it also has reported anti-inflammatory effects. The current study was thus undertaken to examine the interactions of dietary Cholesterol (Cho) and sitagliptin on markers of inflammation. METHODS: Male Sprague-Dawley rats were provided diets high in Cho and gavaged with vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day) from day 10 through day 35. Molecular methods were used to analyze the lipid profile and inflammatory markers in liver and serum samples. H&E-stained liver sections were used for histopathological evaluation. Hepatic influx of mononuclear cells and necrosis were assessed by immunohistochemistry. RESULTS: Sitagliptin reduced triglyceride and Cho levels in serum of rats on the control diet but these effects were abrogated in rats on the high-Cho diet. Sitagliptin produced a significant increase in the expression of hepatic inflammatory markers (Tnfa, Il1b, and Mcp1) and a corresponding increase in serum TNFα and IL-1ß in rats on the high-Cho diet, but it had no effect on rats on the control diet. Additionally, sitagliptin had no effect on liver morphology in rats on the control diet, but it produced hepatic histopathological changes indicative of necrosis and mononuclear cell infiltration in rats on the high-Cho diet. These mononuclear cells were identified as macrophages and T cells. CONCLUSION: When provided in the context of a high-Cho diet, these findings reveal previously unrecognized hepato-inflammatory effects of sitagliptin that are accompanied by evidence of hepatic necrosis and mononuclear cell infiltration.

Reducing Dendrimer Generation and PEG Chain Length Increases Drug Release and Promotes Anticancer Activity of PEGylated Polylysine Dendrimers Conjugated with Doxorubicin via a Cathepsin-Cleavable Peptide Linker.

PEGylation typically improves the systemic exposure and tumor biodistribution of polymeric drug delivery systems, but may also restrict enzyme access to peptide-based drug linkers. The impact of dendrimer generation (G4 vs G5) and PEG length (570 vs 1100 Da) on the pharmacokinetics, tumor biodistribution, drug release kinetics, and anticancer activity of a series of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-B cleavable valine-citrulline linker was therefore investigated in rodents. Although the smallest G4 PEG570 dendrimer showed the most efficient cathepsin-mediated doxorubicin release, systemic exposure and tumor uptake were limited. The largest G5 PEG1100 dendrimer showed good tumor uptake and retention but restricted drug liberation and therefore limited anticancer activity. Superior anticancer activity was achieved using an intermediate sized dendrimer that showed better drug release kinetics, systemic exposure, tumor uptake, and retention. The data suggest that balancing PEG molecular weight and dendrimer size is critical when designing chemotherapeutic dendrimers.

Long Noncoding RNAs in Mammalian Development and Diseases.

Following analysis of sequenced genomes and transcriptome of many eukaryotes, it is evident that virtually all protein-coding genes have already been discovered. These advances have highlighted an intriguing paradox whereby the relative amount of protein-coding sequences remain constant but nonprotein-coding sequences increase consistently in parallel to increasing evolutionary complexity. It is established that differences between species map to nonprotein-coding regions of the genome that surprisingly is transcribed extensively. These transcripts regulate epigenetic processes and constitute an important layer of regulatory information essential for organismal development and play a causative role in diseases. The noncoding RNA-directed regulatory circuit controls complex characteristics. Sequence variations in noncoding RNAs influence evolution, quantitative traits, and disease susceptibility. This chapter presents an account on a class of such noncoding transcripts that are longer than 200 nucleotides (long noncoding RNA-lncRNA) in mammalian development and diseases.

Genome-wide mapping of matrix attachment regions in Drosophila melanogaster.

BACKGROUND: Eukaryotic genome acquires functionality upon proper packaging within the nucleus. This process is facilitated by the structural framework of Nuclear Matrix, a nucleo-proteinaceous meshwork. Matrix Attachment Regions (MARs) in the genome serve as anchoring sites to this framework. RESULTS: Here we report direct sequencing of the MAR preparation from Drosophila melanogaster embryos and identify >7350 MARs. This amounts to ~2.5% of the fly genome and often coincide with AT rich non-coding regions. We find significant association of MARs with the origins of replication, transcription start sites, paused RNA Polymerase II sites and exons, but not introns, of highly expressed genes. We also identified sequence motifs and repeats that constitute MARs. CONCLUSION: Our data reveal the contact points of genome to the nuclear architecture and provide a link between nuclear functions and genomic packaging.

Adverse Cardiac Events of Hypercholesterolemia Are Enhanced by Sitagliptin Administration in Sprague Dawley Rats.

Background: Cardiovascular disease (CVD) affects millions worldwide and is the leading cause of death among non-communicable diseases. Western diets typically comprise of meat and dairy products, both of which are rich in cholesterol (Cho) and methionine (Met), two well-known compounds with atherogenic capabilities. Despite their individual effects, literature on a dietary combination of the two in the context of CVD are limited. An additional interest was to investigate the cardioprotective potential of sitagliptin, an anti-type 2 diabetic drug. Thus, we hypothesized that atherogenic feeding would result in adverse cardiac effects and would attenuate upon sitagliptin administration. Methods: Six-week-old adult male Sprague-Dawley rats were fed either a control (Con), high Met (1.5%), high Cho (2.0%), or high Met (1.5%) + high Cho (2.0%) diet for 35 days. They were orally gavaged with vehicle (water) or sitagliptin (100 mg/kg/d) from day 10 through 35. On day 36, rats were euthanized, and tissues were collected for analysis. Results: Histopathological evaluation revealed a reduction in myocardial striations and increased collagen deposition in hypercholesterolemia (HChol), responses that became exacerbated upon sitagliptin administration. Cardiac pro-inflammatory and pro-fibrotic responses were adversely impacted in similar fashion. The addition of Met to Cho (MC) attenuated all adverse structural and biochemical responses, with or without sitagliptin. Conclusion: Adverse cardiac outcomes in HChol were enhanced with sitagliptin administration and such effects were alleviated by Met. Our findings could be significant for understanding the risk-benefit of sitagliptin in type 2 diabetics who are known to consume atherogenic diets.

Phytochemicals, Herbal Extracts, and Dietary Supplements for Metabolic Disease Management.

Comprehensive and effective care techniques have become essential due to the global epidemic dimensions of metabolic disorders, including diabetes, obesity, and cardiovascular ailments. Recent research highlights the potential of dietary supplements, herbal extracts, and phytochemicals in treating metabolic diseases. This abstract conveys the current state of the science in this field by highlighting these findings' underlying mechanisms and potential therapeutic applications. Plant-based diets contain naturally occurring bioactive molecules termed phytochemicals, which have shown promise in treating various metabolic illnesses. Examples include curcumin, flavonoids, and polyphenols' insulin-sensitizing, antioxidant, and antiinflammatory properties. Herbal extracts, derived from ancient medicinal herbs, have been used by people for years to treat a wide range of ailments. Recent studies have shown the efficacy of these strategies in improving lipid profiles, glucose metabolism, and overall cardiovascular health. Omega-3 fatty acids, vitamins, and minerals are just a few of the numerous nutritional supplements that are critical to metabolic health. These vitamins improve insulin sensitivity, regulate blood sugar, and decrease inflammation. Probiotics and prebiotics also affect the gut flora, which significantly affects metabolic function. These natural medicines' ability to treat metabolic diseases either by themselves or in combination with conventional medical interventions. However, when using it therapeutically, one must consider the differences in doses, individual responses, and bioavailability. The article concludes that phytochemicals, plant extracts, and food supplements offer a promising avenue for the management of metabolic illnesses. Comprehensive research, including clinical studies, is needed to ascertain their safety and efficacy characteristics. When added to treatment strategies, these natural therapies could be helpful supplements that improve overall health and the quality of life among individuals with metabolic diseases. Naringenin, a citrus flavonoid, can potentially prevent kidney injury in hyperuricemia by reducing uric acid, inflammation, apoptosis, DNA damage, and activating antioxidants. Further research and professional consultation are essential. Factors contributing to metabolic diseases, current approaches to management nutritional approaches for managing obesityassociated metabolic impairments in the liver and small intestine, and nutritional approaches for managing obesity-associated metabolic dysregulation are also explained briefly.

Surgical Delay-Associated Mortality Risk Varies by Subtype in Loco-Regional Breast Cancer Patients in SEER-Medicare.

Substantial evidence supports that delay of surgery after breast cancer diagnosis is associated with increased mortality risk, leading to the introduction of a new Commission on Cancer quality measure for receipt of surgery within 60 days of diagnosis for non-neoadjuvant patients. Breast cancer subtype is a critical prognostic factor and determines treatment options; however, it remains unknown whether surgical delay-associated breast cancer-specific mortality (BCSM) risk differs by subtype. This retrospective cohort study aimed to assess whether the impact of delayed surgery on survival varies by subtype (hormone [HR]+/HER2-, HR-/HER2-, and HER2+) in patients with loco-regional breast cancer who received surgery as their first treatment between 2010-2017 using the SEER-Medicare. Continuous time to surgery from diagnostic biopsy (TTS; days) in reference to TTS = 30 days. BCSM were evaluated as flexibly dependent on continuous time (days) to surgery from diagnosis (TTS) using Cox proportional hazards and Fine and Gray competing-risk regression models, respectively, by HR status. Inverse propensity score-weighting was used to adjust for demographic, clinical, and treatment variables impacting TTS. Adjusted BCSM risk grew with increasing TTS across all subtypes, however, the pattern and extent of the association varied. HR+/HER2- patients exhibited the most pronounced increase in BCSM risk associated with TTS, with approximately exponential growth after 42 days, with adjusted subdistribution hazard ratios (sHR) of 1.21 (95% CI: 1.06-1.37) at TTS = 60 days, 1.79 (95% CI: 1.40-2.29) at TTS = 90 days, and 2.83 (95% CI: 1.76-4.55) at TTS = 120 days. In contrast, both HER2 + and HR-/HER2- patients showed slower, approximately linear growth in sHR, although non-significant in HR-HER2-.

Association of Age and Sex at Onset With Glenohumeral Osteoarthritis: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of the present systematic review is to synthesize existing evidence (qualitative and quantitative) regarding age- and sex-specific differences with glenohumeral osteoarthritis. DESIGN: The electronic databases PubMed, MEDLINE, and Web of Science were searched up to March 15, 2023. Articles reporting on the association of risk factors (age and sex) with glenohumeral osteoarthritis were considered. We used Newcastle-Ottawa Scale to assess study quality. Meta-analysis was conducted to quantitatively summarize the association of age and sex with glenohumeral osteoarthritis. RESULTS: A total of 24 articles were retrieved for full-text review. Of 24 articles, 8 reporting age-specific and 5 articles reporting sex-specific associations with glenohumeral osteoarthritis were included. The odds ratio for the age (odds ratio = 3.18; 95% confidence interval = 1.10-15.92) and female sex (odds ratio = 1.78; 95% confidence interval = 0.95-3.42) were increased and observed statistically significant. CONCLUSIONS: The present systematic review and meta-analysis suggests the role of increasing age as one of the significant contributors to glenohumeral osteoarthritis. However, association of female sex with glenohumeral osteoarthritis is least convincing. Future studies are required to understand the molecular mechanisms behind the contributory role of increasing age and female sex in the establishment of glenohumeral osteoarthritis.

AAGAG repeat RNA is an essential component of nuclear matrix in Drosophila.

Eukaryotic nucleus is functionally as well as spatially compartmentalized and maintains dynamic organization of sub-nuclear bodies. This organization is supported by a non-chromatin nuclear structure called the nuclear matrix. Although the precise molecular composition and ultra-structure of the nuclear matrix is not known, proteins and RNA molecules are its major components and several nuclear matrix proteins have been identified. However, the nature of its RNA component is unknown. Here we show that in Drosophila melanogaster, transcripts from AAGAG repeats of several hundred nucleotide in length are critical constituents of the nuclear matrix. While both the strands of this repeat are transcribed and are nuclear matrix associated, the polypurine strand is predominantly detected in situ. We also show that AAGAG RNA is essential for viability. Our results reveal the molecular identity of a critical RNA component of the nuclear architecture and point to one of the utilities of the repetitive part of the genome that has accumulated in higher eukaryotes.