Spatio-temporal modeling of human leptospirosis prevalence using the maximum entropy model.

BACKGROUND: Leptospirosis, a zoonotic disease, stands as one of the prevailing health issues in some tropical areas of Iran. Over a decade, its incidence rate has been estimated at approximately 2.33 cases per 10,000 individuals. Our research focused on analyzing the spatiotemporal clustering of Leptospirosis and developing a disease prevalence model as an essential focal point for public health policymakers, urging targeted interventions and strategies. METHODS: The SaTScan and Maximum Entropy (MaxEnt) modeling methods were used to find the spatiotemporal clusters of the Leptospirosis and model the disease prevalence in Iran. We incorporated nine environmental covariates by employing a spatial resolution of 1 km x 1 km, the finest resolution ever implemented for modeling Human Leptospirosis in Iran. These covariates encompassed the Digital Elevation Model (DEM), slope, displacement areas, water bodies, and land cover, monthly recorded Normalized Difference Vegetation Index (NDVI), monthly recorded precipitation, monthly recorded mean and maximum temperature, contributing significantly to our disease modeling approach. The analysis using MaxEnt yielded the Area Under the Receiver Operating Characteristic Curve (AUC) metrics for the training and test data, to evaluate the accuracy of the implemented model. RESULTS: The findings reveal a highly significant primary cluster (p-value < 0.05) located in the western regions of the Gilan province, spanning from July 2013 to July 2015 (p-value < 0.05). Moreover, there were four more clusters (p-value < 0.05) identified near Someh Sara, Neka, Gorgan and Rudbar. Furthermore, the risk mapping effectively illustrates the potential expansion of the disease into the western and northwestern regions. The AUC metrics of 0.956 and 0.952 for the training and test data, respectively, underscoring the robust accuracy of the implemented model. Interestingly, among the variables considered, the influence of slope and distance from water bodies appears to be minimal. However, altitude and precipitation stand out as the primary determinants that significantly contribute to the prevalence of the disease. CONCLUSIONS: The risk map generated through this study carries significant potential to enhance public awareness and inform the formulation of impactful policies to combat Leptospirosis. These maps also play a crucial role in tracking disease incidents and strategically directing interventions toward the regions most susceptible.

Autophagy and unfolded protein response induction: a crosstalk between street rabies virus and the host.

The endoplasmic reticulum (ER) response mechanism to cellular stress is mediated by the unfolded protein response/ER-associated degradation (UPR/ERAD) pathway. A viral infection can trigger ER stress and engage some transcription factors, depending on the host cell and virus type, activating or inhibiting autophagy. The relationship between ER response and autophagy in rabies has not been investigated yet. In the present study, the mouse brain was infected with street rabies virus (SRABV). Total RNA was extracted from the brains of animals, and cDNA was synthesized. Next, real-time PCR assay was performed using specific primers. The expression of hypoxanthine-guanine phosphoribosyltransferase (Hprt), CCAAT/enhancer binding protein homologous protein (CHOP), apoptosis signal-regulating kinase 1 (ASK1), activating transcription factor 6 (ATF6), and caspase 3 (CASP3) genes was also investigated. Based on the results, SRABV caused significant changes in the mRNA expression of ATF6, CHOP, and ASK1 genes in the brains of infected mice in the control group (group V). Treatment of infected cells with the pIRES-EGFP-Beclin-1 vector and rapamycin caused changes in nearly most of the parameters. However, alterations in CASP3 gene expression were only observed when the vector and the virus were simultaneously injected into the cells. Overall, protection and autophagy against cell death induced by SRABV infection can be achieved by activating the ER stress pathway, followed by a marked increase in the expression of ATF6, CHOP, ASK1, and CASP3 genes.

Prognostic Significance of CHEK2 Mutation in Progression of Breast Cancer.

Breast cancer (BC) is one of the most common cancers among women; genetic mutations reflect the development of this disease. Mutations in cell signaling factors can be the main cause of BC development. In this study, we focused on mutations in checkpoint kinase 2 (CHEK2) and their impact as a prognostic factor in the pathogenesis of BC. CHEK2 is controlled in cell signaling pathways through the influence of upstream genes. Also, several downstream genes are regulated by CHEK2. In addition, mutations in CHEK2 lead to resistance of BC cells to chemotherapy and metastasis of cancer cells to other parts of the body. Finally, detection of mutations in CHEK2 can be used as a prognostic factor for patient response to treatment and for targeting downstream molecules of CHEK2 that are involved in the proliferation of breast tumor cells. Mutations such as c.1100delC and I157T can distinguish which patients are susceptible to metastasis.

Protective role of heat shock transcription factor 1 in heart failure: A diagnostic approach.

OBJECTIVE: Nonexpression or expression inhibition of protective factors has been determined in the occurrence of heart failure (HF). Heat shock transcription factor 1 (HSF1) is among such factors, which reduces the incidence of HF by controlling cardiac hypertrophy and fibrosis. In this study, molecular mechanisms for nonexpression of HSF1 in HF patients have been investigated. MATERIALS AND METHODS: This review paper is based on the material obtained via PubMed search of 1996-2018. The key search terms were "heart failure," "heat shock transcription factor 1," "hypertrophy", "fibrosis," and "apoptosis." RESULTS: Although factors such as janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and heat shock proteins (HSPs) may respectively increase and decrease susceptibility to HF, in some circumstances, these factors may unexpectedly prevent HF progression. CONCLUSION: Finally, identification of molecular pathways expressed by various factors could be used to design appropriate treatments or to employ strategies inducing the expression of HSF1 to prevent HF.

T-bet transcription factor in cardiovascular disease: Attenuation or inflammation factor?

T-bet is a major transcription factor increasing inflammatory responses in the immune system. Recently, it has been shown that this factor leads to inflammation in cardiovascular disease (CVD). In this study, we examine the dual role of T-bet in inducing and suppressing inflammatory reactions as well as angiogenesis induction due to inflammatory cytokines in CVD. Relevant literature was identified by a Pubmed search (1992-2018) of English-language papers using the terms "T-bet," "Cardiovascular disease," "Immune response," and "Angiogenesis." Although T-bet causes differentiation of Th1 cells and activation of immune cells such as NK and DC, it suppresses inflammatory responses and replaces damaged vessels with new ones by activating regulatory T-cells and stimulating angiogenesis. It can be stated that T-bet acts as double-edged sword. Therefore, the identification of pathways that can increase the function of T-bet in activating Tregs and inducing angiogenesis might be used as a new therapeutic option in future investigations.

Endothelial Cells: From Dysfunction Mechanism to Pharmacological Effect in Cardiovascular Disease.

Endothelial cells (ECs) are the innermost layer of blood vessels that play important roles in homeostasis and vascular function. However, recent evidence suggests that the onset of inflammation and the production of reactive oxygen species impair the function of ECs and are a main factor in the development of cardiovascular disease (CVD). In this study, we investigated the effects of inflammatory markers, oxidative stress, and treatment on ECs in CVD patients. This review article is based on the material obtained from PubMed up to 2018. The key search terms used were "Cardiovascular Disease," "Endothelial Cell Dysfunction," "Inflammation," "Treatment," and "Oxidative Stress." The generation of reactive oxygen species (ROS) as well as reduced nitric oxide (NO) production by ECs impairs the function of blood vessels. Therefore, treatment of CVD patients leads to the expression of transcription factors activating anti-oxidant mechanisms and NO production. In contrast, NO production by inflammatory agents can cause ECs repair due to differentiation of endothelial progenitor cells (EPCs). Therefore, identifying the molecular pathways leading to the differentiation of EPCs through mediation of factors induced by inflammatory factors can be effective in regenerative medicine for ECs repair.

The impact of Mir-9 regulation in normal and malignant hematopoiesis.

MicroRNA-9 (MiR-9) dysregulation has been observed in various cancers. Recently, MiR-9 is considered to have a part in hematopoiesis and hematologic malignancies. However, its importance in blood neoplasms is not yet well defined. Thus, this study was conducted in order to assess the significance of MiR-9 role in the development of hematologic neoplasia, prognosis, and treatment approaches. We have shown that a large number of MiR-9 targets (such as FOXOs, SIRT1, CCND1, ID2, CCNG1, Ets, and NFkB) play essential roles in leukemogenesis and that it is overexpressed in different leukemias. Our findings indicated MiR-9 downregulation in a majority of leukemias. However, its overexpression was reported in patients with dysregulated MiR-9 controlling factors (such as MLLr). Additionally, prognostic value of MiR-9 has been reported in some types of leukemia. This study generally emphasizes on the critical role of MiR-9 in hematologic malignancies as a prognostic factor and a therapeutic target.

Role of chemokines in metastatic niche: new insights along with a diagnostic and prognostic approach.

Chemokines are cytokines that are involved in the movement of leukocytes and the occurrence of immune responses. It has recently been noted that these cytokines play a role in the movement of cancer cells to different parts of the body and create a suitable environment [i.e. (pre) metastatic niche] for their growth and proliferation. We studied the role of chemokines in the metastasis of cancer cells, as well as their involvement in the proliferation and growth of these cells. Relevant literature was identified by a PubMed search (2005-2017) of English language papers using the terms 'chemokine,' 'metastasis niche,' and 'organotropism.' Based on the nature of cancer cells, the expression of chemokine receptors on these cells leads to metastasis to various organs, which ultimately causes changes in different signaling pathways. Finally, the targeting of chemokines on cancer cells could prevent the metastasis of cancer cells toward different organs.

Oxidative stress in normal hematopoietic stem cells and leukemia.

Leukemia is developed following the abnormal proliferation of immature hematopoietic cells in the blood when hematopoietic stem cells lose the ability to turn into mature cells at different stages of maturation and differentiation. Leukemia initiating cells are specifically dependent upon the suppression of oxidative stress in the hypoglycemic bone marrow (BM) environment to be able to start their activities. Relevant literature was identified by a PubMed search (2000-2017) of English-language literature using the terms 'oxidative stress,' 'reactive oxygen species,' 'hematopoietic stem cell,' and 'leukemia.' The generation and degradation of free radicals is a main component of the metabolism in aerobic organisms. A certain level of ROS is required for proper cellular function, but values outside this range will result in oxidative stress (OS). Long-term overactivity of reactive oxygen species (ROS) has harmful effects on the function of cells and their vital macromolecules, including the transformation of proteins into autoantigens and increased degradation of protein/DNA, which eventually leads to the change in pathways involved in the development of cancer and several other disorders. According to the metabolic disorders of cancer, the relationship between OS changes, the viability of cancer cells, and their response to chemotherapeutic agents affecting this pathway are undeniable. Recently, studies have been conducted to determine the effect of herbal agents and cancer chemotherapy drugs on oxidative stress pathways. By emphasizing the role of oxidative stress on stem cells in the incidence of leukemia, this paper attempts to state and summarize this subject.

Acute myeloid leukemia in the vascular niche.

The greatest challenge in treating acute myeloid leukemia (AML) is refractory disease. With approximately 60-80% of AML patients dying of relapsed disease, there is an urgent need to define and target mechanisms of drug resistance. Unfortunately, targeting cell-intrinsic resistance has failed to improve clinical outcomes in AML. Emerging data show that cell-extrinsic factors in the bone marrow microenvironment protect and support AML cells. The vascular niche, in particular, regulates AML cell survival and cell cycling by both paracrine secretion and adhesive contact with endothelial cells. Moreover, AML cells can functionally integrate within vascular endothelia, undergo quiescence, and resist cytotoxic chemotherapy. Together, these findings support the notion of blood vessels as sanctuary sites for AML. Therefore, vascular targeting agents may serve to remit AML. Several early phase clinical trials have tested anti-angiogenic agents, leukemia mobilizing agents, and vascular disrupting agents in AML patients. In general, these agents can be safely administered to AML patients and cardiovascular side effects were reported. Response rates to vascular targeting agents in AML have been modest; however, a majority of vascular targeting trials in AML are monotherapy in design and indiscriminate in patient recruitment. When considering the chemosensitizing effects of targeting the microenvironment, there is a strong rationale to build upon these early phase clinical trials and initiate phase IB/II trials of combination therapy where vascular targeting agents are positioned as priming agents for cytotoxic chemotherapy.