BACKGROUND: There are varying reports of immunohistochemically detected prostatic marker protein distribution in glands associated with the female urethra that may be related to tissue integrity at the time of fixation.
OBJECTIVE: In this study we used tissue derived from rapid autopsies of female patients to determine the distribution of glandular structures expressing prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) along the female urethra and in surrounding tissues, including the anterior vaginal wall (AVW).
METHODS: Tissue blocks from 7 donors that contained the entire urethra and adjacent AVW were analyzed. These tissue samples were fixed within 4-12 hours of death and divided into 5-mm transverse slices that were paraffin embedded. Sections cut from each slice were immunolabeled for PSA or PSAP and a neighboring section was stained with hematoxylin and eosin. The sections were reviewed by light microscopy and analyzed using QuPath software.
METHODS: In tissue from all donors, glandular structures expressing PSA and/or PSAP were located within the wall of the urethra and were present along its whole length.
RESULTS: In the proximal half of the urethra from all donors, small glands expressing PSAP, but not PSA, were observed adjacent to the and emptying into the lumen. In the distal half of the urethra from 5 of the 7 donors, tubuloacinar structures lined by a glandular epithelium expressed both PSA and PSAP. In addition, columnar cells at the surface of structures with a multilayered transitional epithelium in the distal half of the urethra from all donors expressed PSAP. No glands expressing PSA or PSAP were found in tissues surrounding the urethra, including the AVW.
CONCLUSIONS: Greater understanding of the distribution of urethral glands expressing prostatic proteins in female patients is important because these glands are reported to contribute to the female sexual response and to urethral pathology, including urethral cysts, diverticula, and adenocarcinoma.
UNASSIGNED: Strengths of the present study include the use of rapid autopsy to minimize protein degradation and autolysis, and the preparation of large tissue sections to demonstrate precise anatomical relations within all the tissues surrounding the urethral lumen. Limitations include the sample size and that all donors had advanced malignancy and had undergone previous therapy which may have had unknown tissue effects.
CONCLUSIONS: Proximal and distal glands expressing prostate-specific proteins were observed in tissue from all donors, and these glands were located only within the wall of the urethra.

There is evidence from multiple studies that dysregulation of the Eyes Absent (EYA) protein plays multiple roles in many cancers. Despite this, little is known about the prognostic significance of the EYAs family in clear cell renal cell carcinoma (ccRCC). We systematically analyzed the value of EYAs in Clear Cell Renal Cell Carcinoma. Our analysis included examining transcriptional levels, mutations, methylated modifications, co-expression, protein-protein interactions (PPIs), immune infiltration, single-cell sequencing, drug sensitivity, and prognostic values. We based our analysis on data from several databases, including the Cancer Genome Atlas database (TCGA), the Gene Expression Omnibus database (GEO), UALCAN, TIMER, Gene Expression Profiling Interactive Analysis (GEPIA), STRING, cBioPortal and GSCALite. In patients with ccRCC, the EYA1 gene was significantly highly expressed, while the expression of EYA2/3/4 genes showed the opposite trend. The level of expression of the EYA1/3/4 gene was significantly correlated with the prognosis and clinicopathological parameters of ccRCC patients. Univariate and multifactorial Cox regression analyses revealed EYA1/3 as an independent prognostic factor for ccRCC, establishing nomogram line plots with good predictive power. Meanwhile, the number of mutations in EYAs was also significantly correlated with poor overall survival (OS) and progression-free survival (PFS) of patients with ccRCC. Mechanistically, EYAs genes play an essential role in a wide range of biological processes such as DNA metabolism and double-strand break repair in ccRCC. The majority of EYAs members were related to the infiltration of immune cells, drug sensitivity, and methylation levels. Furthermore, our experiment confirmed that EYA1 gene expression was upregulated, and EYA2/3/4 showed low expression in ccRCC. The increased expression of EYA1 might play an important role in ccRCC oncogenesis, and the decreased expression of EYA3/4 could function as a tumor suppressor, suggesting EYA1/3/4 might serve as valuable prognostic markers and potential new therapeutic targets for ccRCC.

Hearing loss (HL) is a heterogeneous condition that causes partial or complete hearing impairment. Hundreds of variants in >60 genes have been reported to be associated with Hereditary HL (HHL), variants of the GJB2 gene are the most common cause of congenital SNHL, with >100 variants reported. The HHL prevalence is thought to be high in the Arab population; however, the genetic epidemiology of HHL among Emirati populations is understudied.
To shed light on the mutational spectrum of NSHL in Emirati patients seen in the genetic clinic over 10 years and to capture founder mutation(s) if any were identified.
Retrospective chart review of all Emirati patients assessed by clinical geneticists due to NSHL during the period between January 2010 to December 2020. Genetic tests were done based on clinical phenotypes of the patient and family history including targeted mutation testing, next-generation sequencing, or whole-exome sequencing (solo or trio). The authors did literature reviews using PubMed for all previously reported articles related to NSHL genes from UAE.
A total of 162 patients with HL, were evaluated during the period between January 2010 to December 2020. There were 82 patients with NSHL, and only 72 patients who completed the genetic evaluations were included in this retrospective study. Among the studied group, 42 (51.2%) were males and 40 (48.78%) were females. The youngest patient was 2 years old and the oldest patient was 50 years old. Consanguinity was documented in 76 patients (92.68%). A total of 14 mutations reported here are novel (23/72 i.e., 31.9%). Twelve missense mutations, 6 nonsense mutations, 6 frameshift mutations, 2 in-frame deletion mutations, and 1 splice site mutation was found. Variants in the GJB2 gene are the most commonly identified cause of NSHL, with c.35delG being the most followed by c.506G > A. The second commonly found variant is c.934C > G (p.Arg312Gly) in the CDC14A gene, found in 9 patients. This was followed by variants in OTOF and SLC26A4 genes, found in 8 patients, respectively. Chromosomal microdeletions encompassing genes causing NSHL were found in 3 patients. No mitochondrial mutations were found in this study group. A total of 11 previous reports about Emirati patients with NSHL were reviewed, with a total of 35 patients.
Emirati patients with NSHL have several mutations, most notably missense mutations. Novel mutations are worth further testing and represent the area for future researches.

UNASSIGNED: The aim of this study was to investigate the expression of phosphatase of regenerating live-3 (PRL-3) in human stage III colorectal cancer (CRC) and to evaluate its correlation with metachronous liver metastasis (MLM) and prognosis.The retrospective cohort study included 116 stage III CRC primary tumors and 60 normal colorectal tissues. PRL-3 expression was measured by immunohistochemistry. We investigated the correlation of PRL-3 with clinicopathologic features by the chi-square test. The association of PRL-3 expression with MLM was assessed by binary logistic regression. Overall survival (OS) and disease-free survival (DFS) between patients with positive PRL-3 expression and those with negative PRL-3 expression were compared by the Kaplan-Meier method and Cox proportional hazards regression model.We found that 32.8% of stage III CRC primary tumors were PRL-3 positive, and 15.0% of normal colorectal epithelia showed high PRL-3 expression (P = .012). Seventeen tumors (47.2%) among 36 cases that developed MLM were PRL-3 positive, and only 21 tumors (26.3%) in the 80 cases that did not develop MLM had positive PRL-3 expression (P = .026). PRL-3 expression was associated with MLM (P = .028). Patients with positive expression of PRL-3 showed a significantly shorter OS (40.32 ± 3.97 vs 53.96 ± 2.77 months, P = .009) and DFS (34.97 ± 4.30 vs 44.48 ± 2.89 months, P = .036). A multivariate analysis indicated that PRL-3 expression was an independent unfavorable prognostic factor for OS (P = .007).Our study suggested that high PRL-3 expression is an independent risk factor for MLM and poor prognosis. PRL-3 is expected to be a promising biomarker for predicting the incidence of MLM and prognosis in patients with stage III CRC.

A series of novel triaryl-based sulfamic acid analogs was designed, synthesized and evaluated as inhibitors of human protein tyrosine phosphatase beta (HPTPβ). A novel, easy and efficient synthetic method was developed for target compounds, and the activity determination results showed that most of compounds were good HPTPβ inhibitors. Interestingly, the compounds G4 and G25 with simple structure not only showed potent inhibitory activity on HPTPβ but also had good inhibitory selectivity over other PTPs (PTP1B, SHP2, LAR and TC-PTP). The molecular docking simulation of compounds with the protein HPTPβ helped us understand the structure-activity relationship and clarify some confusing assay results. This research provides references for further drug design of HPTPβ and other PTPs inhibitors.

BACKGROUND: PTP4A3 is a subclass of a protein tyrosine phosphatase super family and is expressed in a range of epithelial neoplasms. We evaluated PTP4A3 expression and its association with clinicopathological parameters in different types of functioning pituitary adenomas.
METHODS: A total of 34 functioning pituitary adenomas samples were evaluated in this observational study. PTP4A3 expression was examined by immunohistochemical staining, and, possible correlations between PTP4A3 and some clinicopathological variables were investigated.
RESULTS: PTP4A3 was expressed in 19 out of 34 tumours (55%), at the cytoplasmic level of tumorous cells. Moreover, there was significant association (p=0.042) between PTP4A3 expression and tumorous size.
CONCLUSIONS: PTP4A3 was expressed in more than half of the tumours analysed, with there being a significant association with the tumorous size of functioning adenomas. This allows to speculate that PTP4A3 may regulate tumour growth, although further investigations are necessary to determine if this phosphatase can serve as a biomarker or used as a therapeutic target in pituitary macroadenomas.

The low molecular weight protein tyrosine phosphatase (LMW-PTP) could regulate many signaling pathways, and it had drawn attention as a potential target for cancer. As previous report has indicated that the aplidin could inhibit the LMW-PTP, and thus, the relevant cancer caused by the abnormal regulation of the LMW-PTP could be remission. However, the molecular mechanism of inhibition of the LMW-PTP by the aplidin had not been fully understood. In this study, various computational approaches, namely molecular docking, MDs and post-dynamic analyses were utilized to explore the effect of the aplidin on the LMW-PTP. The results suggested that the intramolecular interactions of the residues in the two sides of the active site (Ser43-Ala55 and Pro121-Asn134) and the P-loop region (Leu13-Ser19) in the LMW-PTP was disturbed owing to the aplidin, meanwhile, the π-π interaction between Tyr131 and Tyr132 might be broken. The Asn15 might be the key residue to break the residues interactions. In a word, this study may provide more information for understanding the effect of inhibition of the aplidin on the LMW-PTP.

Some heterocycles, namely 2-amino-4H-pyran-3-carbonitriles, were synthesized in a three-component reaction from substituted benzaldehydes, malononitrile, and ethyl acetoacetate. These heterocycles have been converted subsequently into 4H-pyrano[2,3-d]pyrimidine ring by ring-closing reaction with acetic anhydride in the presence of the concentrated sulfuric acid as catalyst. The successive alkylation reaction of lactam NH bond on pyrimidine-4-one ring was carried out using propargylic bromide in dry acetone in the presence of anhydrous potassium carbonate. The click chemistry of 3-propargyl-4H-pyrano[2,3-d]pyrimidine compounds has been accomplished by reaction with tetra-O-acetyl-α-d-glucopyranosyl azide using the metal-organic framework Cu@MOF-5 as a catalyst in absolute ethanol. All the synthesized 1H-1,2,3-triazoles 8a-y were screened for their in vitro Mycobacterium tuberculosis protein tyrosine phosphatase B (MtbPtpB) inhibition. Kinetic studies of the most active compounds 8v, 8x, and 8y showed their competitive inhibition toward the MtbPtpB enzyme. The detailed structure-activity relationship (SAR) in vitro and in silico studies suggested that the interaction of Arg63 amino acids with anion type of para-hydroxyl group via a salt bridge of iminium cation was essential for strong inhibitory activity against MtbPtpB.

Protein tyrosine phosphatases (PTPs) originating from eukaryotes or bacteria have been under intensive structural and biochemical investigation, whereas archaeal PTP proteins have not been investigated extensively; therefore, they are poorly understood. Here, we present the crystal structures of Tk-PTP derived from the hyperthermophilic archaeon Thermococcus kodakaraensis KOD1, in both the active and inactive forms. Tk-PTP adopts a common dual-specificity phosphatase (DUSP) fold, but it undergoes an atypical temperature-dependent conformational change in its P-loop and α4-α5 loop regions, switching between the inactive and active forms. Through comprehensive analyses of Tk-PTP, including additional structural determination of the G95A mutant form, enzymatic activity assays, and structural comparison with the other archaeal PTP, it was revealed that the presence of the GG motif in the P-loop is necessary but not sufficient for the structural flexibility of Tk-PTP. It was also proven that Tk-PTP contains dual general acid/base residues unlike most of the other DUSP proteins, and that both the residues are critical in its phosphatase activity. This work provides the basis for expanding our understanding of the previously uncharacterized PTP proteins from archaea, the third domain of living organisms.

Male breast cancer (MBC) is rare and little is known about its biological behavior. In this study we described clinical characteristics and prognosis of MBC and evaluated roles of different factors between MBC and female breast cancer (FBC).
We retrospectively reviewed 42 MBC patients matched with 84 consecutive FBC patients with similar year, age, tumor, node, metastases (TNM) stage, and estrogen receptor (ER) expression from 2003 to 2016. Their clinical characteristics, treatments, and prognosis were analyzed, and immunohistochemistry for androgen receptor (AR), dachshund 1 (DACH1), sine oculis 1 (SIX1), eyes absent 1, B-cell lymphoma-2, and p53 were performed on paraffin sections.
MBC constituted 0.56% (42 of 7561) of consecutive breast cancer and had a median age of 55 years. The 14 paraffin samples from men and 28 from women expressed all the assessed proteins, and DACH1 was significantly higher in women (P = .043). Body mass index (P = .023) and DACH1 (P = .034) were correlated with MBC prognosis, whereas the expression of AR (P = .049), SIX1 (P = .048), surgery (P < .001), and chemotherapy (P = .001) were important for FBC in addition to already known factors: tumor size and location, TNM stage (lymph nodes and organ metastasis), radiotherapy, and ER and human epidermalgrowth factor receptor-2 (HER2) expression. No distinct difference in recurrence was observed between MBC and FBC (P = .667).
In this study we found that DACH1 was expressed less in MBC and HER2 was expressed more in FBC. They were respectively correlated with MBC and FBC prognosis. Although no significant differences were observed between MBC and FBC prognosis, DACH1, SIX1, and AR expression requires greater attention to develop treatment strategies for MBC and FBC.