Origins and diversity of pan-isotype human bone marrow plasma cells.

Bone marrow plasma cells (BMPCs) produce durable, protective IgM, IgG, and IgA antibodies, and in some cases, pro-allergic IgE antibodies, but their properties and sources are unclear. We charted single BMPC transcriptional and clonal heterogeneity in food-allergic and non-allergic individuals across CD19 protein expression given its inverse correlation to BMPC longevity. Transcriptional and clonal diversity revealed distinct functional profiles. Additionally, distribution of somatic hypermutation and intraclonal antibody sequence variance suggest that CD19low and CD19high BMPCs arise from recalled memory and germinal center B cells, respectively. Most IgE BMPCs were from peanut-allergic individuals; two out of 32 from independent donors bound peanut antigens in vitro and in vivo. These findings shed light on BMPC origins and highlight the bone marrow as a source of pathogenic IgE in peanut allergy.

Combination MEG3 lncRNA and Ciprofloxacin dramatically decreases cell migration and viability as well as induces apoptosis in GC cells in vitro.

Gastric cancer (GC) is a prominent cause of cancer-related mortality worldwide. Long noncoding RNA (lncRNA) maternal expression gene3 (MEG3) participates in numerous signaling pathways by targeting the miRNA-mRNA axis. Studies on human tumors have demonstrated that the antibiotic Ciprofloxacin induces cell cycle changes, programmed cell death, and growth suppression. In this study, we transfected MEG3 lncRNA and Ciprofloxacin into the MKN-45 GC cell line. qRT-PCR was employed to evaluate the effects on the specific microRNA and mRNA. The wound healing test, MTT assay, and flow cytometry were used to assess the impact of their administration on cell migration, viability, and apoptosis, respectively. Research showed that miR-147 expression fell even more after MEG3 lncRNA transfection, leading to an increase in B-cell lymphoma 2 (BCL-2) levels. Ciprofloxacin transfection did not significantly affect the axis, except for MEG3, which led to its slight upregulation. MEG3 lncRNA inhibited the migration of MKN-45 cells compared to the control group. When MEG3 lncRNA was coupled with Ciprofloxacin, there was a significant reduction in cell migration compared to untreated groups and controls. MTT assay and flow cytometry demonstrated that MEG3 lncRNA decreased cell viability and triggered apoptosis. Simultaneous administration of MEG3 lncRNA and Ciprofloxacin revealed a significant reduction in cell viability caused by increased apoptosis obtained from MTT or flow cytometry assays. Modulating the miR-147-BCL-2 axis decreases cell migration and survival while promoting cell death. In conclusion, combining MEG3 lncRNA with Ciprofloxacin may be an effective therapeutic approach for GC treatment by influencing the miR-14-BCl-2 axis, resulting in reduced cell viability, migration, and increased apoptosis.

miR-142-3p/5p role in cancer: From epigenetic regulation to immunomodulation.

MicroRNAs (miRNAs) play critical roles in cancer pathobiology, acting as regulators of gene expression and pivotal drivers of tumorigenesis. It is believed that miRNAs act through canonical mechanisms, involving the binding of mature miRNAs to target messenger RNAs (mRNAs) and subsequent repression of protein translation or degradation of target mRNAs. miR-142-3p/5p has been extensively studied and established as a key regulator in various malignancies. Recent discoveries have revealed miR-142-3p/5p serve as either oncogene or tumor suppressor in cancer. By targeting epigenetic factor and cancer-related signaling pathway, miR-142-3p/5p can regulate wide range of downstream genes. The immune modulatory role of miR-142-3p/5p has been shown in various cancers, which provides significant insight into immunosuppression and tumor escape from the immune response. Exosomes with miR-142-3p/5p facilitate cell communication and can affect cancer cell behavior, offering potential therapeutic, and diagnosis applications in cancer therapy. In this review, for the first time, we comprehensively summarize the current knowledge regarding mentioned functions of miR-142-3p/5p in cancer pathobiology.

EZH2-interacting lncRNAs contribute to gastric tumorigenesis; a review on the mechanisms of action.

Gastric cancer (GC) remains one of the deadliest malignancies worldwide, demanding new targets to improve its diagnosis and treatment. Long non-coding RNAs (lncRNAs) are dysregulated through gastric tumorigenesis and play a significant role in GC progression and development. Recent studies have revealed that lncRNAs can interact with histone-modifying polycomb protein, enhance Zeste Homolog 2 (EZH2), and mediate its site-specific functioning. EZH2, which functions as an oncogene in GC, is the catalytic subunit of the PRC2 complex that induces H3K27 trimethylation and epigenetically represses gene expression. EZH2-interacting lncRNAs can recruit EZH2 to the promoter regions of various tumor suppressor genes and cause their transcriptional deactivation via histone methylation. The interactions between EZH2 and this lncRNA modulate different processes, such as cell cycle, cell proliferation and growth, migration, invasion, metastasis, and drug resistance, in vitro and in vivo GC models. Therefore, EZH2-interacting lncRNAs are exciting targets for developing novel targeted therapies for GC. Subsequently, this review aims to focus on the roles of these interactions in GC progression to understand the therapeutic value of EZH2-interacting lncRNAs further.

Atorvastatin Effect on COVID-19 Outcomes: A Propensity Score Matched Study on Hospitalized Patients.

BACKGROUND: This study investigated the association of atorvastatin use on survival, need for intensive care unit (ICU) admission, and length of hospital stay (LOS) among COVID-19 inpatients. MATERIALS AND METHODS: A retrospective study was conducted between March 20th, 2020, and March 18th, 2021, on patients with confirmed COVID-19 admitted to three hospitals in Tehran, Iran. The unadjusted and adjusted effects of atorvastatin on COVID-19 prognosis were investigated. Propensity score matching (PSM) was used to achieve a 1:1 balanced dataset with a caliper distance less than 0.1 and the nearest neighbor method without replacement. RESULTS: Of 4322 COVID-19 patients, 2136 (49.42%) were treated with atorvastatin. After PSM, 1245 atorvastatin inpatients and 1245 controls were included with a median age of 62.0 (interquartile range [IQR]: 51.0, 76.0) and 63.0 (IQR: 51.0, 75.0) years, respectively. The standardized mean differences were less than 0.1 for all confounders, suggesting a good covariate balance. The use of atorvastatin was associated with decreased COVID-19 mortality (HR: 0.80; 95% CI: 0.68-0.95), whereas no relationship was found between atorvastatin and the need for ICU admission (HR: 1.21; 95% CI: 0.99-1.47). LOS was significantly higher in the atorvastatin cohort than controls (Atorvastatin vs. others: 7 [5, 11] vs. 6 [4, 10] days; p = 0.003). The survival rate was higher in combination therapy of atorvastatin plus enoxaparin than in those who received atorvastatin alone (p-value=0.001). CONCLUSION: Atorvastatin may reduce the risk of COVID-19 in-hospital mortality and could be a beneficial option for an add-on therapy. Randomized trials are warranted to confirm the results of the current observational studies.

The role and function of autophagy through signaling and pathogenetic pathways and lncRNAs in ovarian cancer.

Lysosomal-driven autophagy is a tightly controlled cellular catabolic process that breaks down and recycles broken or superfluous cell parts. It is involved in several illnesses, including cancer, and is essential in preserving cellular homeostasis. Autophagy prevents DNA mutation and cancer development by actively eliminating pro-oxidative mitochondria and protein aggregates from healthy cells. Oncosuppressor and oncogene gene mutations cause dysregulation of autophagy. Increased autophagy may offer cancer cells a pro-survival advantage when oxygen and nutrients are scarce and resistance to chemotherapy and radiation. This finding justifies the use of autophagy inhibitors in addition to anti-neoplastic treatments. Excessive autophagy levels can potentially kill cells. The diagnosis and treatment of ovarian cancer present many difficulties due to its complexity and heterogeneity. Understanding the role of autophagy, a cellular process involved in the breakdown and recycling of cellular components, in ovarian cancer has garnered increasing attention in recent years. Of particular note is the increasing amount of data indicating a close relationship between autophagy and ovarian cancer. Autophagy either promotes or restricts tumor growth in ovarian cancer. Dysregulation of autophagy signaling pathways in ovarian cancers can affect the development, metastasis, and response to tumor treatment. The precise mechanism underlying autophagy concerning ovarian cancer remains unclear, as does the role autophagy plays in ovarian carcinoma. In this review, we tried to encapsulate and evaluate current findings in investigating autophagy in ovarian cancer.

Diverse activity of miR-150 in Tumor development: shedding light on the potential mechanisms.

There is a growing interest to understand the role and mechanism of action of microRNAs (miRNAs) in cancer. The miRNAs are defined as short non-coding RNAs (18-22nt) that regulate fundamental cellular processes through mRNA targeting in multicellular organisms. The miR-150 is one of the miRNAs that have a crucial role during tumor cell progression and metastasis. Based on accumulated evidence, miR-150 acts as a double-edged sword in malignant cells, leading to either tumor-suppressive or oncogenic function. An overview of miR-150 function and interactions with regulatory and signaling pathways helps to elucidate these inconsistent effects in metastatic cells. Aberrant levels of miR-150 are detectable in metastatic cells that are closely related to cancer cell migration, invasion, and angiogenesis. The ability of miR-150 in regulating of epithelial-mesenchymal transition (EMT) process, a critical stage in tumor cell migration and metastasis, has been highlighted. Depending on the cancer cells type and gene expression profile, levels of miR-150 and potential target genes in the fundamental cellular process can be different. Interaction between miR-150 and other non-coding RNAs, such as long non-coding RNAs and circular RNAs, can have a profound effect on the behavior of metastatic cells. MiR-150 plays a significant role in cancer metastasis and may be a potential therapeutic target for preventing or treating metastatic cancer.

Cytokine sustained delivery for cancer therapy; special focus on stem cell- and biomaterial- based delivery methods.

As immune regulators, cytokines serve critical role as signaling molecules in response to danger, tissue damage, or injury. Importantly, due to their vital role in immunological surveillance, cytokine therapy has become a promising therapeutics for cancer therapy. Cytokines have, however, been used only in certain clinical settings. Two key characteristics of cytokines contribute to this clinical translational challenge: first, they are highly pleiotropic, and second, in healthy physiology, they are typically secreted and act very locally in tissues. Systemic administration of the cytokines can consequently result in serious side effects. Thus, scientists have sought various strategies to circumvent theses hurdles. Recent in vivo reports signify that cytokine delivery platforms can increase their safety and therapeutic efficacy in tumor xenografts. Meanwhile, cytokine delivery using multipotent stem cells, in particular mesenchymal stem/stromal cells (MSCs), and also a diversity of particles and biomaterials has demonstrated greater capability in this regards. Herein, we take a glimpse into the recent advances in cytokine sustained delivery using stem cells and also biomaterials to ease safe and effective treatments of a myriad of human tumors.

A comprehensive survey into the role of exosomes in pancreatic cancer; from the origin of cancer to the progress and possibility of diagnosis and treatment.

Pancreatic cancer is the fourth most common malignant tumor in the world, which has a high mortality rate due to high invasiveness, early metastases, lack of specific symptoms, and high invasiveness. Recent studies have shown that exosomes can be essential sources of biomarkers in pancreatic cancer. Over the past ten years, exosomes have been implicated in multiple trials to prevent the growth and metastasis of many cancers, including pancreatic cancer. Exosomes also play essential roles in immune evasion, invasion, metastasis, proliferation, apoptosis, drug resistance, and cancer stemness. Exosomes help cells communicate by carrying proteins and genetic material, such as non-coding RNAs, including mRNAs and microRNAs. This review examines the biological significance of exosomes in pancreatic cancer and their functions in tumor invasion, metastasis, treatment resistance, proliferation, stemness, and immune evasion. We also emphasize recent advances in our understanding of the main functions of exosomes in diagnosing and treating pancreatic cancer.

A comprehensive review of the role of lncRNAs in gastric cancer (GC) pathogenesis, immune regulation, and their clinical applications.

Gastric cancer (GC) is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide. Although numerous studies have been conducted on advanced GC, the molecular mechanisms behind it remain obscure. Long non-coding RNAs (lncRNAs) are a family of RNA transcripts capable of regulating target genes at transcriptional, post-transcriptional, and translational stages. They do this by modifying mRNAs, miRNAs, and proteins. These RNAs are critical regulators of many biological processes, including gene epigenetics, transcription, and post-transcriptional levels. This article highlights recent results on lncRNAs involved in drug resistance, proliferation, migration, angiogenesis, apoptosis, autophagy, and immune response in GC. The potential clinical implications of lncRNAs as biomarkers and therapeutic targets in GC are also discussed.

Clinical potential of PD-1/PD-L1 blockade therapy for renal cell carcinoma (RCC): a rapidly evolving strategy.

Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy has become a game-changing therapeutic approach revolutionizing the treatment setting of human malignancies, such as renal cell carcinoma (RCC). Despite the remarkable clinical activity of anti-PD-1 or anti-PD-L1 monoclonal antibodies, only a small portion of patients exhibit a positive response to PD-1/PD-L1 blockade therapy, and the primary or acquired resistance might ultimately favor cancer development in patients with clinical responses. In light of this, recent reports have signified that the addition of other therapeutic modalities to PD-1/PD-L1 blockade therapy might improve clinical responses in advanced RCC patients. Until, combination therapy with PD-1/PD-L1 blockade therapy plus cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor (ipilimumab) or various vascular endothelial growth factor receptors (VEGFRs) inhibitors axitinib, such as axitinib and cabozantinib, has been approved by the United States Food and Drug Administration (FDA) as first-line treatment for metastatic RCC. In the present review, we have focused on the therapeutic benefits of the PD-1/PD-L1 blockade therapy as a single agent or in combination with other conventional or innovative targeted therapies in RCC patients. We also offer a glimpse into the well-determined prognostic factor associated with the clinical response of RCC patients to PD-1/PD-L1 blockade therapy.

Epidemiology of COVID-19 in Tehran, Iran: A Cohort Study of Clinical Profile, Risk Factors, and Outcomes.

Background: The outbreak of coronavirus disease 2019 (COVID-19) dates back to December 2019 in China. Iran has been among the most prone countries to the virus. The aim of this study was to report demographics, clinical data, and their association with death and CFR. Methods: This observational cohort study was performed from 20th March 2020 to 18th March 2021 in three tertiary educational hospitals in Tehran, Iran. All patients were admitted based on the WHO, CDC, and Iran's National Guidelines. Their information was recorded in their medical files. Multivariable analysis was performed to assess demographics, clinical profile, outcomes of disease, and finding the predictors of death due to COVID-19. Results: Of all 5318 participants, the median age was 60.0 years, and 57.2% of patients were male. The most significant comorbidities were hypertension and diabetes mellitus. Cough, dyspnea, and fever were the most dominant symptoms. Results showed that ICU admission, elderly age, decreased consciousness, low BMI, HTN, IHD, CVA, dialysis, intubation, Alzheimer disease, blood injection, injection of platelets or FFP, and high number of comorbidities were associated with a higher risk of death related to COVID-19. The trend of CFR was increasing (WPC: 1.86) during weeks 25 to 51. Conclusions: Accurate detection of predictors of poor outcomes helps healthcare providers in stratifying patients, based on their risk factors and healthcare requirements to improve their survival chance.

Risk of hypertension in school-aged children with different parental risk: a longitudinal study from childhood to young adulthood.

BACKGROUND: Although previous studies have shown the relationship between different parental factors and children's blood pressure status, there is limited data on the cumulative effect of these factors. Considering parental socio-demographic, behavioral and cardio-metabolic characteristics, the current study aimed to distinguish parental risk clusters and their impact on the incidence of hypertension in school-age children over 13 years. METHODS: Parental characteristics of 1669 children, including age, education, employment, smoking, physical activity, metabolic syndrome (MetS), hypertension (HTN), weight status, and diabetes were considered to categorize parents into low and high-risk clusters. Crude incidence rates (per 10,000 person-years) of HTN in children were assessed in each maternal and paternal cluster. Using Cox proportional hazard model, results on the association between parental risk clusters and HTN incidence in children were reported in five different models. RESULTS: Mean age of children was 13.96 ± 2.89 years, and 51.2% (n = 854) were girls. MetS, HTN, and weight status were the most important factors distinguishing low and high-risk parental clusters, respectively. Crude incidence rates (per 10,000 person-years) of HTN were 86 (95% CI: 71-106) and 38 (95% CI, 29-52) in boys and girls, respectively. Moreover, incidence rates (per 10,000 person-years) of HTN were 50 (95% CI, 40-63) and 80 (95% CI, 64-102) in maternal low and high-risk clusters, respectively. The incidence rates (per 10,000 person-years) of HTN in paternal low and high-risk clusters were 53 (95% CI, 41-70) and 68 (95% CI, 56-84), respectively. CONCLUSION: Our findings underscore the prognostic value of maternal characteristics in predicting the incidence of HTN in their offspring. The current results could be valuable in planning related programs to prevent hypertension in similar communities.