Placental insufficiency is a common cause of intrauterine growth restriction (IUGR). It affects ~10% of pregnancies and increases fetal and neonatal morbidity and mortality. Although Wnt and Hh pathways are crucial for embryonic development and placentation, their role in the pathology of IUGR is still not sufficiently explored. The present study analyzed the expression of positive regulators of the Wnt pathway, WNT5A and β-catenin, and the expression of the Hh pathway negative regulator suppressor of fused (SUFU). Immunohistochemical and reverse transcription-quantitative PCR (RT-qPCR) assays were performed on 34 IUGR and 18 placental tissue samples from physiologic singleton-term pregnancies. Epigenetic mechanisms of SUFU gene regulation were also investigated by methylation-specific PCR analysis of its promoter and RT-qPCR analysis of miR-214-3p and miR-378a-5p expression. WNT5A protein expression was higher in endothelial cells of placental villi from IUGR compared with control tissues. That was also the case for β-catenin protein expression in trophoblasts and endothelial cells and SUFU protein expression in trophoblasts from IUGR placentas. The SUFU gene promoter remained unmethylated in all tissue samples, while miR-214-3p and miR-378a-5p were downregulated in IUGR. The present results suggested altered Wnt and Hh signaling in IUGR. DNA methylation did not appear to be a mechanism of SUFU regulation in the pathogenesis of IUGR, but its expression could be regulated by miRNA targeting.

Introduction Immune checkpoint blockade (ICB)-based therapy is revolutionizing cancer treatment by fostering successful immune surveillance and effector cell responses against various types of cancers. However, patients with HER2+ cancers are yet to benefit from this therapeutic strategy. Precisely, several questions regarding the right combination of drugs, drug modality, and effective dose recommendations pertaining to the use of ICB-based therapy for HER2+ patients remain unanswered. Methods In this study, we use a mathematical modeling-based approach to quantify the growth inhibition of HER2+ breast cancer (BC) cell colonies (ZR75) when treated with anti-HER2; trastuzumab (TZ) and anti-PD-1/PD-L1 (BMS-202) agents. Results and discussion Our data show that a combination therapy of TZ and BMS-202 can significantly reduce the viability of ZR75 cells and trigger several morphological changes. The combination decreased the cell’s invasiveness along with altering several key pathways, such as Akt/mTor and ErbB2 compared to monotherapy. In addition, BMS-202 causes dose-dependent growth inhibition of HER2+ BC cell colonies alone, while this effect is significantly improved when used in combination with TZ. Based on the in-vitro monoculture experiments conducted, we argue that BMS-202 can cause tumor growth suppression not only by mediating immune response but also by interfering with the growth signaling pathways of HER2+BC. Nevertheless, further studies are imperative to substantiate this argument and to uncover the potential crosstalk between PD-1/PD-L1 inhibitors and HER2 growth signaling pathways in breast cancer.

Congenital anomalies (CA) are any abnormality present at birth, either structural or functional, that may potentially affect an infant’s health, development, and/or survival. There is a paucity of studies on clinical characteristics and outcomes of CA in Bosnia and Herzegovina, mainly due to the lack of a nationwide congenital malformations monitoring system. A 5-year hospital-based study was conducted to determine the prevalence at birth and clinical characteristics of selected major CA in Sarajevo Canton, Bosnia and Herzegovina. Ninety-one CA were observed from 2012 to 2016 (the overall prevalence was 39.6 cases/10,000 live births). The mean age of neonates at diagnosis was 3 days. The gastrointestinal tract was the most commonly affected system (76.9%), with esophageal atresia (EA) being the most frequent (17.6% of all CA). Major CA were more prevalent among preterm infants than term infants (P = .001), particularly in males (61.5% vs. 38.5%; P = .028; M:F ratio was 1.59). Multiple CA were seen in 37.4% of neonates. The overall mortality rate of neonates was 11%, and the median length of hospital stay was 19.8 days. Our study revealed the distribution and clinical patterns of common major CA in the largest tertiary care facility in Bosnia and Herzegovina. It also confirmed a relatively high mortality rate, which requires further efforts to improve the quality of neonatal care in the country.

The human papillomavirus (HPV) is a non-enveloped double-stranded DNA virus capable of infecting skin and mucosa epithelial cells. Commonly, HPV infection is associated with sexually transmitted diseases and is considered the leading cause of cervical cancer and other carcinomas of the anogenital tract. However, several studies reported their involvement in cancers of non-sexual regions, including colorectal, head and neck, and breast cancers. There are several studies from the Middle East and North Africa (MENA) regions on the potential association between high-risk HPVs and cancer; nevertheless, there are limited studies that address the significance of HPV vaccination as a potential guard against these cancers. In the current review, we present a comprehensive description of the current HPV-associated cancers prevalence rates in the MENA region, demonstrating their steady increase with time, especially in African regions. Moreover, we discuss the potential impact of vaccination against HPV infections and its outcome on human health in this region.

In the present review, we briefly discuss the breakthrough advances in precision medicine using a tumor-agnostic approach and focus on BRAF treatment modalities, the mechanisms of resistance and the diagnostic approach in cancers with BRAF mutations. Tumor-type agnostic drug therapies work across cancer types and present a significant novel shift in precision cancer medicine. They are the consequence of carefully designed clinical trials that showed the value of tumor biomarkers, not just in diagnosis but in therapy guidance. Six tumor-agnostic drugs (with seven indications) have been approved through October 2022 by FDA. The first tumor-agnostic treatment modality was pembrolizumab for MSI-H/dMMR solid tumors, approved in 2017. This was followed by approvals of larotrectinib and entrectinib for cancers with NTRK fusions without a known acquired resistance mutation. In 2020, pembrolizumab was approved for all TMB-high solid cancers, while a PD-L1 inhibitor dostarlimab-gxly was approved for dMMR solid cancers in 2021. A combination of BRAF/MEK inhibitors (dabrafenib/trametinib) was approved as a tumor-agnostic therapy in June 2022 for all histologic types of solid metastatic cancers harboring BRAFV600E mutations. In September 2022, RET inhibitor selpercatinib was approved for solid cancers with RET gene fusions. Conclusion. Precision cancer medicine has substantially improved cancer diagnostics and treatment. Tissue type-agnostic drug therapies present a novel shift in precision cancer medicine. This approach rapidly expands to provide treatments for patients with different cancers harboring the same molecular alteration.

Immunotherapy, based on immune checkpoint inhibitors (ICIs) targeting the programmed cell death ligand 1 (PD-L1) and/or programmed death receptor 1 (PD-1), has substantially improved the outcomes of patients with various cancers. However, only ~30% of patients benefit from ICIs. Tumor PD-L1 expression, assessed by immunohistochemistry (IHC), is the most widely validated and used predictive biomarker to guide the selection of patients for ICIs. PD-L1 assessment may be challenging due to the necessity of different companion diagnostic assays for required specific ICIs and a relatively high level of inter-assay variability in terms of performance and cutoff levels. In this review, we discuss the role of PD-L1 IHC as a predictive test in immunotherapy (immuno-oncology), highlight the complexity of the PD-L1 testing landscape, discuss various preanalytical, analytical, and clinical issues that are associated with PD-L1 assays, and provide some insights into optimization of PD-L1 as a predictive biomarker in immuno-oncology.

Alpha-methylacyl-CoA racemase (AMACR/P504S) is a mitochondrial and peroxisomal enzyme involved in the branched-chain fatty acid and bile acid metabolism. AMACR is a useful diagnostic biomarker for prostate carcinomas and several other malignancies. Its expression in apocrine breast lesions had been previously reported, but its role in breast cancer progression has not been fully investigated. One hundred fifty breast samples (80 with invasive carcinomas) were studied. The expression of AMACR protein was analyzed using the immunohistochemical method (IHC). Lesions were considered positive if AMACR was detected in ≥10% of the cells at any intensity comprising a histologically defined normal epithelial structure or a pathologic lesion. In addition, AMACR mRNA relative expression was calculated from the whole-transcript RNA-Seq performed on >20,000 diverse tumor samples using a 20,000+ hybrid-capture NGS assay with the transcript capture panel based on the Agilent SureSelect Human All ExonV7. Expression of AMACR protein was restricted to epithelia. It was uncommon in the normal breast (7/81 samples, 9%). Increasing AMACR expression was observed with proliferative epithelial lesions (18% of usual ductal hyperplasias/adenosis, 70% of atypical lesions and 72% of DCIS/LCIS). Invasive ductal carcinomas NST and invasive lobular carcinomas expressed AMACR in 64% and 46%, respectively. The highest AMACR expression was observed in luminal B and HER2-positive breast carcinomas (86-100%). Triple-negative breast carcinomas exhibited AMACR in 50% of the cases. Apocrine lesions showed strong, nearly uniform overexpression of AMACR (100% of metaplasias, hyperplasias and in situ carcinomas and 88% of invasive apocrine carcinomas were positive). RNA-Seq analysis also confirmed AMACR expression in breast carcinomas, although its median value was substantially lower with a lower standard deviation than in prostate carcinomas. Over-expression of AMACR characterizes various proliferative, preinvasive and invasive breast lesions and is not specific to the apocrine morphology. It points to altered lipid metabolism (branched fatty acids) as one of the general characteristics of breast carcinogenesis, like several other malignancies. Its early detection may represent a potential target for cancer progression intervention.

No abstract available.

Aim A standardized assessment for the optimal repair of hypospadias remains elusive. The aim of this study was to assess a postoperative cosmetic outcome of hypospadias repair using a validated questionnaire, Hypospadias Objective Scoring Evaluation (HOSE). Methods During the period between January 2016 and May 2019, 40 patients who underwent hypospadias repair were identified and they agreed to a follow-up using the HOSE. Distal hypospadias repairs underwent a cross-sectional assessment of the cosmetic outcome. Cosmetic assessment was performed by an independent physician using the HOSE scoring system. Results The native meatus was coronal in 10 (25%), subcoronal in eight (20%), and distal penile in 22 (55%) patients. Mean followup was 35.90 months (SD ±29.58) postoperatively (range 12-162 months). Complications occurred in one (2.5%) patient. Out of 40 uncomplicated repairs, 39 (97.5%) were satisfactory. A vertical slit-like meatus located at the distal glans was created in 33 (82.5%) boys, and at the proximal glans in seven (17.5%). The urinary stream was single and straight in 39 and spray in one patient. A straight erection was observed in 39 (97.5%) boys. The median HOSE score was 16 (range 12-16). One patient had a small, single coronal fistula. The technique used included tubularised incised plate urethroplasty. Conclusion The HOSE score is simple, easy, non-invasive and non-expensive tool for objective assessment of long-term outcomes of hypospadias repair.