Resistance to Dopamine Agonists in Pituitary Tumors: Molecular Mechanisms

Pituitary neuroendocrine tumors (PitNET) are commonly benign tumors accounting for 10-25% of intracranial tumors. Prolactin-secreting adenomas represent the most predominant type of all PitNET and for this subtype of tumors, the medical therapy relies on the use of dopamine agonists (DAs). DAs yield an excellent therapeutic response in reducing tumor size and hormonal secretion targeting the dopamine receptor type 2 (D2DR) whose higher expression in prolactin-secreting adenomas compared to other PitNET is now well established. Moreover, although DAs therapy does not represent the first-line therapy for other PitNET, off-label use of DAs is considered in PitNET expressing D2DR. Nevertheless, DAs primary or secondary resistance, occurring in a subset of patients, may involve several molecular mechanisms, presently not fully elucidated. Dopamine receptors (DRs) expression is a prerequisite for a proper DA function in PitNET and several molecular events may negatively modify DR membrane expression, through the DRs down-regulation and intracellular trafficking, and DR signal transduction pathway. The current mini-review will summarise the presently known molecular events that underpin the unsuccessful therapy with DAs.

THC and CBD Fingerprinting of an Elite Cannabis Collection from Iran: Quantifying Diversity to Underpin Future Cannabis Breeding

Cannabis (Cannabis sativa L.) has a rich history of human use, and the therapeutic importance of compounds produced by this species is recognized by the medical community. The active constituents of cannabis, collectively called cannabinoids, encompass hundreds of distinct molecules, the most well-characterized of which are tetrahydrocannabinol (THC) and cannabidiol (CBD), which have been used for centuries as recreational drugs and medicinal agents. As a first step to establish a cannabis breeding program, we initiated this study to describe the HPLC-measured quantity of THC and CBD biochemistry profiles of 161 feral pistillate cannabis plants from 20 geographical regions of Iran. Our data showed that Iran can be considered a new region of high potential for distribution of cannabis landraces with diverse THC and CBD content, predominantly falling into three groups, as Type I = THC-predominant, Type II = approximately equal proportions of THC and CBD (both CBD and THC in a ratio close to the unity), and Type III = CBD-predominant. Correlation analysis among two target cannabinoids and environmental and geographical variables indicated that both THC and CBD contents were strongly influenced by several environmental–geographical factors, such that THC and CBD contents were positively correlated with mean, min and max annual temperature and negatively correlated with latitude, elevation, and humidity. Additionally, a negative correlation was observed between THC and CBD concentrations, suggesting that further studies to unravel these genotype × environment interactions (G × E interactions) are warranted. The results of this study provide important pre-breeding information on a collection of cannabis that will underpin future breeding programs.

Correlation Between β2-Microglobulin, Grobulin Levels & The Number of Plasmatic Cells in Patients with Multiple Myeloma

Introduction: Multiple myeloma is multifocal neoplasia of plasmatic cells that affects the bone marrow. It is associated with the production of a urinary or serum protein. It represents approximately 1 percent of cancer cases worldwide and between 10 to 15 percent of all cases of hematological malignancy. Furthermore, it has been proposed that the β2-microglobulin levels are correlated with other factors that can predict multiple myelomas such as the number of plasmatic cells and the creatine levels. Goals: To determine the correlation between β2-microglobulin, globulin levels, and the number of plasmatic cells in patients with multiple myeloma. Methods and techniques: We conducted an observational, retrospective, transversal, and analytical study in the Hospital of the Mexican Institute of Social Security at the Veracruz port. Our population analyzed comprehended 45 patients between the ages 30 and 80 with a confirmed diagnosis of multiple myeloma. We measured the β2-microglobulin levels and globulin levels, and the number of plasmatic cells during the diagnosis of patients. Furthermore, we conducted a statistical analysis using a Pearson correlation. Results: The average age was 61 years with a margin of error of 11.48 years. The myeloma of IgG type was the one of major prevalence and represent 82.2 percent. It was followed by the IgA type and the IgM type, which represented 15.5 and 2.2 percent respectively. The Pearson correlation coefficient (Pearson's r) between the β2-microglobulin levels and globulin levels was 0.92. The Pearson's r between the number of plasmatic cells and β2-microglobulin, excluding patients with high serum creatine levels (i.e. larger than 1.2 mg/dl), was 0.371. Conclusions: The predominant type of myeloma in the analyzed population was the IgG type. Furthermore, this myeloma affected mainly men in our study. The average age was 61 years with a margin of error of 11.48 years when compared to other populations in our study.

Data Homogeneity Effect in Deep Learning-Based Prediction of Type 1 Diabetic Retinopathy

This study is aimed at evaluating a deep transfer learning-based model for identifying diabetic retinopathy (DR) that was trained using a dataset with high variability and predominant type 2 diabetes (T2D) and comparing model performance with that in patients with type 1 diabetes (T1D). The Kaggle dataset, which is a publicly available dataset, was divided into training and testing Kaggle datasets. In the comparison dataset, we collected retinal fundus images of T1D patients at Chang Gung Memorial Hospital in Taiwan from 2013 to 2020, and the images were divided into training and testing T1D datasets. The model was developed using 4 different convolutional neural networks (Inception-V3, DenseNet-121, VGG1, and Xception). The model performance in predicting DR was evaluated using testing images from each dataset, and area under the curve (AUC), sensitivity, and specificity were calculated. The model trained using the Kaggle dataset had an average (range) AUC of 0.74 (0.03) and 0.87 (0.01) in the testing Kaggle and T1D datasets, respectively. The model trained using the T1D dataset had an AUC of 0.88 (0.03), which decreased to 0.57 (0.02) in the testing Kaggle dataset. Heatmaps showed that the model focused on retinal hemorrhage, vessels, and exudation to predict DR. In wrong prediction images, artifacts and low-image quality affected model performance. The model developed with the high variability and T2D predominant dataset could be applied to T1D patients. Dataset homogeneity could affect the performance, trainability, and generalization of the model.

A method for analyzing generalized characteristics of the South Asia Low structure taking into account a thermal regime of underlying surface

The South Asia Low is considered, that is a seasonal center of atmospheric action, a predominant type of circulation in the lower troposphere during the warm season over the Near and Middle East. The generalized factorial model of the low for the levels of 1000, 925, and 850 hPa is presented. The dependence of generalized characteristics of the low structure on surface air temperature in the summer months is estimated for different types of the low. The results of the present study extend information about the seasonal center of atmospheric action: they allow obtaining typical fields of the low taking into account the features of internal structure; revealing peculiarities of meteorological conditions for different types of the low (in different parts of the analyzed macroregion). The identified generalized characteristics of the low structure can be used for constructing forecast models. Keywords: South Asia Low, geopotential height, reanalysis, isobaric level, factor, cluster, correlation coefficient

Molecular Characterization of Rifampicin-Resistant Staphylococcus aureus Isolates from Retail Foods in China

This study investigated the molecular characteristics of rifampin-resistant (RIF-R) Staphylococcus aureus isolates recovered from 4300 retail food samples covering most provincial capitals in China, from 2011 to 2016. Of the 1463 S. aureus enrolled, 149 isolates (142 MSSA and 7 MRSA) were identified as rifampicin-resistant, including 20 high-level (MICs ≥ 8 μg/mL) and 129 low-level (MICs between 2 and 4 μg/mL) rifampicin-resistant strains. Most of the RIF-R S. aureus isolates were resistant to more than three antibiotics. The mutations in the rifampicin resistance-determining region of the rpoB gene were studied in all RIF-R strains. All of the strains presented the mutational change 481 His/Asn and five isolates presented an additional mutation, including 477 Asp/Tyr, 527 Ile/Met, and 466 Leu/Ser, respectively. Thirteen STs and twenty-one spa types were represented, in which five MRSA showed non-type SCCmec and the remaining MRSA belonged to SCCmec type IV—where, ST1-t127 was the predominant type from all of the isolates, while ST398-t034 was the predominant type for the MRSA isolates. In this study, we found that the food-related RIF-R S. aureus may have a unique genetic background selection. However, the scenario regarding the presence of RIF-R S. aureus, especially MRSA, in retail food in China is not favorable and warrants public attention.

Analysis of the daily consumption of potable water in the urban area of the Ambato city in the Province of Tungurahua-Ecuador

The consumption of drinking water has increased over the years worldwide, therefore, the analysis of daily consumption in a certain sector is important, to know the existing demand of the population of the sector under analysis. The study of water consumption not only allows the knowledge of the amount of water consumed in a population, it also enables future projects for the design and redesign of potable water distribution networks. The main methodology for this analysis was the daily record for a period of 60 days, in each of the sectors corresponding to the urban area of Ambato city; this methodology allowed the analysis of the typical week of the sector and therefore the amount of water consumed per day in the urban sector,it was concluded that the San Francisco parish presents the highest demand for water consumption per capita with a requirement of 256.48 L/inhab/day, the predominant type of residence in the urban area of the city of Ambato is type B, which is characterized by having a typical structural system in which reinforced concrete predominates.

Circulating dengue virus serotypes and vertical transmission in Aedes larvae during outbreak and inter-outbreak seasons in a high dengue risk area of Sri Lanka

Background Spatial and temporal changes in the dengue incidence are associated with multiple factors, such as climate, immunity among a population against dengue viruses (DENV), circulating DENV serotypes and vertical transmission (VT) of DENV in an area at a given time. The level of VT in a specific location has epidemiological implications in terms of viral maintenance in vectors. Identification of the circulating DENV serotypes in both patients and Aedes mosquito larvae in an area may be useful for the early detection of outbreaks. We report here the results of a prospective descriptive study that was conducted to detect the levels of VT in Aedes mosquito larvae and circulating DENV serotypes in patients and Aedes mosquito larvae from December 2015 to March 2017 in an area of Sri Lanka at high risk for dengue. Methods A total of 200 patients with clinically suspected dengue who had been admitted to a tertiary care hospital during a dengue outbreak (3 study periods: December 2015–January 2016, June–August 2016, December 2016–January 2017) and in the inter-outbreak periods (February–May 2016 and September–November 2016) were investigated. Blood samples were drawn from the study participants to test for DENV. The houses of the study participants were visited within 7 days of admission to the hospital, and Aedes larvae were also collected within a radius of 400 m from the houses. The larvae were separately identified to species and then pooled according to each patient’s identification number. Patients’ sera and the Aedes larvae were tested to identify the infecting DENV serotypes using a reverse transcription PCR (RT-PCR) method. Levels of VT in Aedes mosquito larvae were also identified. Results All four DENV serotypes (DENV-1 to -4) were identified in the study area. In the early part of the study (December 2015–February 2016), DENV-3 was predominant and from April 2016 to March 2017, DENV-2 became the most predominant type. Four cases of DENV co-infections were noted during the study period in patients. Interestingly, all four DENV serotypes were detected in Aedes albopictus larvae, which was the prominent immature vectorial form identified throughout the study period in the area, showing 9.8% VT of DENV. With the exception of DENV-4, the other three DENV serotypes were identified in Aedes aegypti larvae with a VT of 8.1%. Conclusion Comparatively high rates of VT of DENV was detected in Ae. albopictus and Ae. aegypti larvae. A shift in the predominant DENV serotype with simultaneous circulation of all four DENV serotypes was identified in the study area from December 2015 to March 2017. Graphical Abstract

Whole-Genome Epidemiology and Characterization of Methicillin-Susceptible Staphylococcus aureus ST398 From Retail Pork and Bulk Tank Milk in Shandong, China

Staphylococcus aureus (S. aureus) is now regarded as a zoonotic agent. Methicillin-susceptible S. aureus (MSSA) ST398 is a livestock-associated bacterium that is most prevalent in China, but there are currently no data available for Shandong. Therefore, the aim of this study was to investigate the epidemiology and characterization of MSSA ST398 from retail pork and bulk tank milk (BTM) in Shandong. A total of 67 S. aureus isolates were collected from retail pork between November 2017 and June 2018. Among the isolates, high antimicrobial resistance rates were observed for penicillin (97.0%), and 92.5% of the isolates were multi-drug resistant (MDR). Eight sequence types (STs) were identified in the retail pork isolates, and the predominant type was ST15 (n=26), which was followed by ST398 (n=14). Staphylococcal protein A gene (spa) typing identified spa types t034 and t1255 in MSSA ST398 from retail pork. Using whole-genome sequencing analysis, we described the phylogeny of 29 MSSA ST398 isolates that were obtained from retail pork (n=14) and BTM (n=15). The phylogenetic tree showed that the MSSA ST398 isolates from different sources had the same lineage. Among the 29 MSSA ST398 isolates, five resistance genes were detected, and all isolates carried DHA-1. Fifteen toxin genes were detected, and all isolates carried eta, hla, and hlb. In conclusion, this study found that a high risk for MSSA ST398 was present in retail pork and BTM. These findings have major implications for how investigations of MSSA ST398 outbreaks should be conducted in the One-Health context.

RNA Binding Protein-Mediated Immunosuppressive Tumor Microenvironment Contributes to Poor Prognosis in High-Grade Gliomas

The abnormal expression of RNA binding proteins (RBPs) in tumors can regulate the functions of immune genes and affect immune microenvironment. The characterization of immune infiltration and its regulatory mechanism from the perspective of RBPs and RBP-regulated immune genes in high-grade gliomas were comprehensively studied by bioinformatics. Prognosis-related RBPs and associated immune genes were obtained from the cancer genome atlas database (TCGA). By clustering RBPs, the potential relationship between the different clusters of RBPs expression and immune infiltration was explored. Immune-related RBP constructs immunosuppressive microenvironment in glioma by regulating immune genes and immune-related genes. Immunosuppression was the predominant type of phenotype with poor prognosis, while immunoinflammation was the predominant type of immunoinflammatory phenotype with good prognosis. RBP can construct immunosuppressive microenvironment by regulating immunosuppressive cells and stromal activation-related factors through directly and indirectly ways. Stromal activation plays a bridging role in tumor immunosuppressive regulation. The immunophenotyp depends on different enrichment states of immune-related RBP, which can change dynamically with the change of tumor pathological grade and affect the prognosis of patients.Our study suggests glioma related RBPs can potentially establish an immunosuppressive microenvironment by regulating immune genes and immune-related genes, which can be directly affected by RBPs clusters with distinct prognosis.