Antimicrobial resistance (AMR) is a significant and growing public health threat. Sequencing of bacterial isolates is becoming more common, and therefore automatic identification of resistant bacterial strains is of pivotal importance for efficient, wide-spread AMR detection. To support this approach, several AMR databases and gene identification algorithms have been recently developed. A key problem in AMR detection, however, is the need for computational approaches detecting potential novel AMR genes or variants, which are not included in the reference databases. Toward this direction, here we study the relation between AMR and relative solvent accessibility (RSA) of protein variants from an in silico perspective. We show how known AMR protein variants tend to correspond to exposed residues, while on the contrary their susceptible counterparts tend to be buried. Based on these findings, we develop RSA-AMR, a novel relative solvent accessibility-based AMR scoring system. This scoring system can be applied to any protein variant to estimate its propensity of altering the relative solvent accessibility, and potentially conferring (or hindering) AMR. We show how RSA-AMR score can be integrated with existing AMR detection algorithms to expand their range of applicability into detecting potential novel AMR variants, and provide a ten-fold increase in Specificity. The two main limitations of RSA-AMR score is that it is designed on single point changes, and a limited number of variants was available for model learning.

Hypoxia is a universal feature in the tumor microenvironment (TME). Nonetheless, the heterogeneous hypoxia patterns of TME have still not been elucidated in hepatocellular carcinoma (HCC). Using consensus clustering algorithm and public datasets, we identified heterogeneous hypoxia subtypes. We also revealed the specific biological and clinical characteristics via bioinformatic methods. The principal component analysis algorithm was employed to develop a hypoxia-associated risk score (HARS). We identified the two hypoxia subtypes: low hypoxia pattern (C1) and high hypoxia pattern (C2). C1 was less sensitive to immunotherapy compared to C2, consistent with the lack of immune cells and immune checkpoints (ICPs) in C1, whereas C2 was the opposite. C2 displayed worse prognosis and higher sensitivity to obatoclax relative to C1, while C1 was more sensitive to sorafenib. The two subtypes also demonstrated subtype-specific genomic variations including mutation, copy number alteration, and methylation. Moreover, we developed and validated a risk signature: HARS, which had excellent performance for predicting prognosis and immunotherapy. We revealed two hypoxia subtypes with distinct biological and clinical characteristics in HCC, which enhanced the understanding of hypoxia pattern. The risk signature was a promising biomarker for predicting prognosis and immunotherapy.

Senescence is activated in response to gemcitabine to prevent the propagation of cancer cells. However, there is little evidence on whether senescence is involved in gemcitabine resistance in pancreatic cancer. Increasing evidence has demonstrated that microRNAs (miRs) are potential regulators of cellular senescence. The present study aimed to investigate whether aberrant miR-7 expression modulated senescence to influence pancreatic cancer resistance to chemotherapy. In the present study, cell senescence assay, ALDEFLUOR™ assay, luciferase reporter assay, flow cytometry, quantitative PCR, immunohistochemistry and western blot analysis were performed to explore the association between senescence and gemcitabine therapy response, and to clarify the underlying mechanisms. The present study revealed that gemcitabine-induced chronically existing senescent pancreatic cells possessed stemness markers. Therapy-induced senescence led to gemcitabine resistance. Additionally, it was found that miR-7 expression was decreased in gemcitabine-resistant pancreatic cancer cells, and that miR-7 acted as an important regulator of cellular senescence by targeting poly (ADP-ribose) polymerase 1 (PARP1)/NF-κB signaling. When miR-7 expression was restored, it was able to sensitize pancreatic cancer cells to gemcitabine. In conclusion, the present study demonstrated that miR-7 regulated cellular senescence and relieved gemcitabine resistance by targeting the PARP1/NF-κB axis in pancreatic cancer cells.

Small cell lung cancer (SCLC) is a subtype of lung cancer with a poor prognosis, with bone metastasis being one of the main causes of treatment failure. Therefore, investigating new biomarkers associated with bone metastasis may result in positive treatment outcomes. The present study detected the expression levels of annexin A1 (ANXA1) in the serum of 82 patients with SCLC using ELISA. ANXA1 expression in patients with SCLC with bone metastasis was significantly higher compared with that in patients without bone metastasis. Receiver operating characteristic analysis revealed that ANXA1 expression was significant in the diagnosis of bone metastasis in SCLC. ANXA1 was inhibited in SBC-5 cells and overexpressed in SBC-3 cells. Results revealed that ANXA1 was able to enhance SCLC cell proliferation, invasion, migration and bone adhesion in vitro. In vivo xenograft bone metastasis assays indicated that ANXA1 had the potential to promote the bone-metastasis ability of SCLC cells in NOD/SCID mice. Furthermore, ANXA1 increased parathyroid hormone-related protein secretion and enhanced Smad2 phosphorylation following TGF-β treatment in SCLC cells. Overall, ANXA1 may be involved in the pathogenesis of bone metastasis in SCLC and may be a potential biomarker for the diagnosis of SCLC.

Substantial evidence suggests that cancer stem cells (CSCs) are the main cause of the initiation, progression and recurrence of tumors. Benzidine has been identified as a risk factor for bladder cancer. The aim of the present study was to investigate the effects of benzidine on bladder CSCs (BCSCs) and the possible mechanism underlying its action. The bladder cancer cell lines UM-UC-3 and EJ were maintained in serum-free medium and cells forming three-dimensional spheres were characterized as BCSCs. The sphere-forming cells were exposed to different concentrations of benzidine and vismodegib, and western blotting was performed to evaluate the expression of markers associated with CSCs and the Sonic hedgehog (SHH) signaling pathway. Flow cytometry was used to detect the distribution of cells in different phases of the cell cycle, and immunofluorescence staining was used to detect the protein expression of CD44. The results revealed that the levels of BCSC markers, namely CD133, CD44, aldehyde dehydrogenase 1-A1, Nanog and octamer-binding transcription factor-4, in the cell spheres were markedly elevated compared with those in cells cultured in serum-supplemented medium. Furthermore, benzidine increased the expression of BCSC markers and promoted the sphere-forming ability of the cells. In addition, it was observed that benzidine activated the SHH pathway, while inhibition of the Shh pathway using vismodegib diminished the promoting effects of benzidine on BCSCs. The findings of the present study indicate that benzidine promoted the stemness of BCSCs via activation of the SHH pathway, which may support further exploration of the molecular basis of the association between benzidine exposure and bladder oncogenesis.

The aim of the present study was to investigate the molecular characteristics of hereditary multiple osteochondromas (HMO) in a subset of Jordanian patients with a focus on the genetic variants of exostosin (EXT1)/(EXT2) and their protein expression. Patients with HMO and their family members were included. Recorded clinical characteristics included age, sex, tumors number and location, joint deformities and associated functional limitations. Mutational analysis of EXT1 and EXT2 exonic regions was performed. Immunohistochemical staining for EXT1 and EXT2 was performed manually using two different commercially available rabbit anti-human EXT1 and EXT2 antibodies. A total of 16 patients with HMO from nine unrelated families were included, with a mean age of 13.9 years. A total of 75% (12/16) of the patients were male and (69%) (11/16) had a mild disease (class I). EXT mutation analysis revealed only EXT1 gene mutations in 13 patients. Seven variants were detected, among which three were novel: c.1019G>A, p. (Arg340His), c.962+1G>A and c.1469del, p. (Leu490Argfs*9). Of the 16 patients, 3 did not harbor any mutations for either EXT1 or EXT2. Immunohistochemical examination revealed decreased expression of EXT1 protein in all patients with EXT1 mutation. Surprisingly, EXT2 protein was not detected in these patients, although none had EXT2 mutations. The majority of Jordanian patients with HMO, who may represent an ethnic group that is infrequently investigated, were males and had a mild clinical disease course; whereas most patients with EXT1 gene mutations were not necessarily associated with a severe clinical disease course. The role of EXT2 gene remains a subject of debate, since patients with EXT1 mutations alone did not express the non-mutated EXT2 gene.

Pancreatic cancer, one of the most malignant gastrointestinal tumors, is prone to liver metastasis. However, due to the lack of appropriate and comprehensive diagnostic methods, it is difficult to accurately predict the survival outcomes. Therefore, there is a need to identify effective biomarkers, such as UDP-GlcNAc: βGal β-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3), that predict the survival outcome of patients with pancreatic cancer. In the present study, based on data from 171 cases of pancreatic cancer obtained from The Cancer Genome Atlas portal, the differential expression of mRNAs was screened by comparing cancerous tissues with adjacent tissues. Univariate Cox regression analysis demonstrated that B3GNT3 had prognostic capability and could be an independent prognostic factor for pancreatic adenocarcinoma (PAAD). Using the Tumor Immune Estimation Resource tool and Tumor-Immune System Interaction Database, a potential relationship between B3GNT3 expression and immune cell infiltration was identified in pancreatic carcinoma. Furthermore, 177 samples of pancreatic carcinoma were collected and the association of CD68 expression with B3GNT3 was assessed by immunohistochemical staining. B3GNT3 expression was associated with clinical outcomes in pancreatic carcinoma and related to infiltrating levels of immune cells, which indicated that B3GNT3 could be used as an immunotherapy target for PAAD.

Helicobacter pylori (H. pylori) is a main risk factor for gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is involved in the development and progression of H. pylori-associated GC. However, the exact molecular mechanism of this process remains unclear. The AKT/GSK3β signaling pathway has been demonstrated to promote EMT in several types of cancer. The present study investigated whether H. pylori infection induced EMT, and promoted the development and metastasis of cancer in the normal gastric mucosa, and whether this process was dependent on AKT activation. The expression levels of the EMT-associated proteins, including E-cadherin and N-cadherin, were determined in 165 gastric mucosal samples of different disease stages by immunohistochemical analysis. The expression levels of E-cadherin, N-cadherin, AKT, phosphorylated (p-)AKT (Ser473), GSK3β and p-GSK3β (Ser9) were further determined in H. pylori-infected Mongolian gerbil gastric tissues and cells co-cultured with H. pylori by immunohistochemical analysis and western blotting. The results indicated that the expression levels of the epithelial marker E-cadherin were decreased, whereas the expression levels of the mesenchymal marker N-cadherin were increased during gastric carcinogenesis. Their expression levels were associated with H. pylori infection. Furthermore, H. pylori infection resulted in downregulation of E-cadherin expression and upregulation of N-cadherin expression in Mongolian gerbils and GES-1 cells. In addition, an investigation of the associated mechanism of action revealed that p-AKT (Ser473) and p-GSK3β (Ser9) were activated in GES-1 cells following co-culture with H. pylori. Furthermore, following pretreatment of the cells with the AKT inhibitor VIII, the expression levels of E-cadherin, N-cadherin, p-AKT and p-GSK3β did not show significant differences between GES-1 cells that were co-cultured with or without H. pylori. The levels of p-AKT and p-GSK3β were increased in H. pylori-infected Mongolian gerbils. In conclusion, the present study demonstrated that H. pylori infection activated AKT and resulted in the phosphorylation and inactivation of GSK3β, which in turn promoted early stage EMT. These effects were AKT-dependent. This mechanism may serve as a prerequisite for GC development.

Human giant larvae-1 (Hugl-1) is a human homologue of Drosophila tumor suppressor lethal (2)-giant larvae and has been reported to be involved in the development of human malignancies. Previous studies performed by our group demonstrated that Hugl-1 inhibits glioma cell proliferation in an intracranial model of nude mice. However, the exact molecular mechanisms underlying the participation of Hugl-1 in glioma invasion and migration, and in the depolarizing process remain largely unknown. Utilizing the U251-MG cells with stable expression of Hugl-1, the present study used wound healing, Transwell invasion and western blot assays to explore the role and specific mechanism of Hugl-1 in glioma invasion and migration. The results of the present study demonstrated that overexpression of Hugl-1 decreased cell-cell adhesion and increased cell-cell extracellular matrix adhesion. In addition, overexpression of Hugl-1 promoted pseudopodia formation, glioma cell migration and invasion. The molecular mechanism of action involved the negative regulation of N-cadherin protein levels by Hugl-1. Overexpression or knockdown of N-cadherin partially suppressed or enhanced the effects of Hugl-1 on glioma cell migration and invasion, respectively. Furthermore, Hugl-1 inhibited cell proliferation, while promoting cell migration, which suggests that it may serve a two-sided biological role in cellular processes. Taken together, these results suggest that Hugl-1 promotes the migration and invasion of malignant glioma cells by decreasing N-cadherin expression. Thus, Hugl-1 may be applied in the development of targeted and personalized treatment.

Xanthogranulomatous inflammation is characterized histologically by a collection of lipid-laden macrophages admixed with lymphocytes, plasma cells, neutrophils, and often multinucleated giant cells with or without cholesterol clefts.

Congestive heart failure (CHF) exacerbations are a frequent cause of hospitalization. Thyroid hormones impact myocardial function; elevated levels of thyroxine, as seen in hyperthyroidism (HT), can worsen CHF symptoms. We retrospectively evaluated the Hospital Corporation of America (HCA) Enterprise Data Warehouse and examined mortality and length of stay (LOS) in patients hospitalized with CHF with and without a diagnosis of HT. 55,031 patients with CHF were identified. The presence of HT was not significantly associated with mortality (p = 0.24) nor LOS (p = 0.32). A significant difference in the distribution of sex (p = 0.001) and age (p = 0.002) was noted, with a higher percentage of females and a lower median age in patients with HT. There was a significant difference in LOS (p = 0.04) for patients with a cardiovascular comorbidity, who had a mean LOS of 6.33 days versus 5.31 days for patient without HT.

With a rapidly growing list of candidate immune-based cancer therapeutics, there is a critical need to generate highly reliable animal models to preclinically evaluate the efficacy of emerging immune-based therapies, facilitating successful clinical translation. Our aim was to design and validate a novel in vivo model (called Xenomimetic or 'X' mouse) that allows monitoring of the ability of human tumor-specific T cells to suppress tumor growth following their entry into the tumor.

Intimate partner violence during pregnancy is a strong predictor of maternal postpartum depression. In Ethiopia, evidence on the association of intimate partner violence during pregnancy with postpartum depression is very limited. To design appropriate intervention, it is thus important to understand how postpartum depression varies as a function of the type and severity of intimate partner violence victimization during pregnancy. The aim of this study is to explore the association of different types of intimate partner violence during pregnancy and its severity with postpartum depression in Eastern Ethiopia.

The Score for Trauma Triage in the Geriatric and Middle-Aged (STTGMA) is a validated mortality risk score that evaluates 4 major physiologic criteria: age, comorbidities, vital signs, and anatomic injuries. The aim of this study was to investigate whether the addition of ASA physical status classification system to the STTGMA tool would improve risk stratification of a middle-aged and elderly trauma population.

Multiple Myeloma (MM) is a malignant disorder of plasma cells which, despite significant advances in treatment, remains incurable. Daratumumab, the first CD38 directed monoclonal antibody, has shown promising activity alone and in combination with other agents for MM treatment. Daratumumab is thought to have pleiotropic mechanisms of activity including natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). With the knowledge that CD38-expressing NK cells are depleted by daratumumab, we sought to investigate a potential mechanism of enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) by combining daratumumab with cyclophosphamide (CTX). Cyclophosphamide's immunomodulatory function was investigated by conditioning macrophages with tumor cell secretome collected from cyclophosphamide treated MM cell lines (CTX-TCS). Flow cytometry analysis revealed that CTX-TCS conditioning augmented the migratory capacity of macrophages and increased CD32 and CD64 Fcγ receptor expression on their cell surface. Daratumumab-specific tumor clearance was increased by conditioning macrophages with CTX-TCS in a dose-dependent manner. This effect was impeded by pre-incubating macrophages with Cytochalasin D (CytoD), an inhibitor of actin polymerization, indicating macrophage-mediated ADCP as the mechanism of clearance. CD64 expression on macrophages directly correlated with MM cell clearance and was essential to the observed synergy between cyclophosphamide and daratumumab, as tumor clearance was attenuated in the presence of a FcγRI/CD64 blocking agent. Cyclophosphamide independently enhances daratumumab-mediated killing of MM cells by altering the tumor microenvironment to promote macrophage recruitment, polarization to a pro-inflammatory phenotype, and directing ADCP. These findings support the addition of cyclophosphamide to existing or novel monoclonal antibody-containing MM regimens.

The Growth-Regulating Factor (GRF) family encodes a type of plant-specific transcription factor (TF). GRF members play vital roles in plant development and stress response. Although GRF family genes have been investigated in a variety of plants, they remain largely unstudied in bread wheat (Triticum aestivum L.). The present study was conducted to comprehensively identify and characterize the T. aestivum GRF (TaGRF) gene family members. We identified 30 TaGRF genes, which were divided into four groups based on phylogenetic relationship. TaGRF members within the same subgroup shared similar motif composition and gene structure. Synteny analysis suggested that duplication was the dominant reason for family member expansion. Expression pattern profiling showed that most TaGRF genes were highly expressed in growing tissues, including shoot tip meristems, stigmas and ovaries, suggesting their key roles in wheat growth and development. Further qRT-PCR analysis revealed that all 14 tested TaGRFs were significantly differentially expressed in responding to drought or salt stresses, implying their additional involvement in stress tolerance of wheat. Our research lays a foundation for functional determination of TaGRFs, and will help to promote further scrutiny of their regulatory network in wheat development and stress response.

The daily average natural rainfall amounts in the five regions of Thailand can be estimated using the confidence intervals for the common mean of several delta-lognormal distributions based on the fiducial generalized confidence interval (FGCI), large sample (LS), method of variance estimates recovery (MOVER), parametric bootstrap (PB), and highest posterior density intervals based on Jeffreys' rule (HPD-JR) and normal-gamma-beta (HPD-NGB) priors. Monte Carlo simulation was conducted to assess the performance in terms of the coverage probability and average length of the proposed methods. The numerical results indicate that MOVER and PB provided better performances than the other methods in a variety of situations, even when the sample case was large. The efficacies of the proposed methods were illustrated by applying them to real rainfall datasets from the five regions of Thailand.

New sequencing technologies facilitate the generation of large-scale molecular data sets for constructing the plant tree of life. We describe a new probe set for target enrichment sequencing to generate nuclear sequence data to build phylogenetic trees with any flagellate land plants, including hornworts, liverworts, mosses, lycophytes, ferns, and all gymnosperms.

Introduction Many approaches to performing total hip arthroplasty (THA) exist, primarily due to an insufficient amount of research that would favor one approach over the other. This study aimed to compare the risk of nerve injury, dislocation, Trendelenburg gait, and stem malposition between the direct lateral and posterior approaches to THA. Methods The study was a retrospective cohort study, and it was conducted in King Abdulaziz Medical City. It was directed toward adult patients who underwent THA from November 1, 2003, to November 1, 2018. All figures were obtained through the BESTCare system (ezCareTech, Saudi Arabia). Categorical variables were presented as frequencies and proportions. Quantitative variables were measured as mean and standard deviation. Fisher's exact test was used to compare the risk of complications between the two approaches. Results The posterior approach displayed a greater risk of stem malposition (p< 0.001) when compared with the direct lateral approach. However, neither approach showed a higher risk of dislocation, nerve injury, or Trendelenburg gait. Conclusions A higher risk of stem malposition was observed in the posterior approach, and there were no remarkable variances between the two approaches in the risk of dislocation, nerve injury, and Trendelenburg gait. Until more meticulous nationwide studies are available to provide evidence that would favor an approach over the other, the choice of surgical approach for THA remains to depend on the patient's characteristics and the surgeon's prior experience. Regardless of the approach, preoperative, intraoperative, and postoperative factors that increase the risk of complications should also be identified and addressed adequately.

In order to solve the problems of receptor promiscuity and poor blood-brain barrier (BBB) penetration in the treatment of glioblastomas (GBM), a novel dual-functional nanocomplex drug delivery system is developed based on the strategy of peptide-drug conjugates. In this study, SynB3-PVGLIG-PTX is designed and screened out by matrix metalloproteinase-2 (MMP-2), to which it exhibits the best affinity. The MMP-2-sensitive peptide (PVGLIG) and a cell-penetration peptide (SynB3) are combined to form a dual-functional peptide. Moreover, as a drug-peptide nanocomplex, SynB3-PVGLIG-PTX exhibited a high potential to form an aggregation with good solubility that can release paclitaxel (PTX) through the cleavage of MMP-2. From a functional perspective, it is found that SynB3-PVGLIG-PTX can specifically inhibit the proliferation, migration, and invasion of GBM cells in vitro in the presence of MMP-2, in contrast to that observed in MMP-2 siRNA transfected cells. Further investigation in vivo shows that SynB3-PVGLIG-PTX easily enters the brain of U87MG xenograft nude mice and can generate a better suppressive effect on GBM through a controlled release of PTX from SynB3-PVGLIG-PTX compared with PTX and temozolomide. Thus, it is proposed that SynB3-PVGLIG-PTX can be used as a novel drug-loading delivery system to treat GBM due to its specificity and BBB permeability.