Breast cancer is one of the most prevalent diseases among women worldwide and is highly associated with cancer-related mortality. Of the four major molecular subtypes, HER2-positive and triple-negative breast cancer (TNBC) comprise more than 30% of all breast cancers. While the HER2-positive subtype lacks estrogen and progesterone receptors and overexpresses HER2, the TNBC subtype lacks estrogen, progesterone and HER2 receptors. Although advances in molecular biology and genetics have substantially ameliorated breast cancer disease management, targeted therapies for the treatment of estrogen-receptor negative breast cancer patients are still restricted, particularly for TNBC. On the other hand, it has been demonstrated that microRNAs, miRNAs or small non-coding RNAs that regulate gene expression are involved in diverse biological processes, including carcinogenesis. Moreover, circulating miRNAs in serum/plasma are among the most promising diagnostic/therapeutic tools as they are stable and relatively easy to quantify. Various circulating miRNAs have been identified in several human cancers including specific breast cancer subtypes. This review aims to discuss the role of circulating miRNAs as potential diagnostic and prognostic biomarkers as well as therapeutic targets for estrogen-receptor negative breast cancers, HER2+ and triple negative.

Water-pipe smoking (WPS) is becoming the most popular form of tobacco use among the youth, especially in the Middle East, replacing cigarettes rapidly and becoming a major risk of tobacco addiction worldwide. Smoke from WPS contains similar toxins as those present in cigarette smoke and is linked directly with different types of cancers including lung and head and neck (HN) carcinomas. However, the underlying molecular pathways and/or target genes responsible for the carcinogenic process are still unknown. In this study, human normal oral epithelial (HNOE) cells, NanoString PanCancer Pathways panel of 770 gene transcripts and quantitative real-time polymerase chain reaction (qRT-PCR) analysis were applied to discover differentially expressed genes (DEG) modulated by WPS. In silico analysis was performed to analyze the impact of these genes in HN cancer patient’s biology and outcome. We found that WPS can induce the epithelial–mesenchymal transition (EMT: hallmark of cancer progression) of HNOE cells. More significantly, our analysis of NanoString revealed 23 genes deregulated under the effect of WPS, responsible for the modulation of cell cycle, proliferation, migration/invasion, apoptosis, signal transduction, and inflammatory response. Further analysis was performed using qRT-PCR of HNOE WPS-exposed and unexposed cells supported the reliability of our NanoString data. Moreover, we demonstrate those DEG to be upregulated in cancer compared with normal tissue. Using the Kaplan–Meier analysis, we observed a significant association between WPS-deregulated genes and relapse-free survival/overall survival in HN cancer patients. Our findings imply that WPS can modulate EMT as well as a set of genes that are directly involved in human HN carcinogenesis, thereby affecting HN cancer patients’ survival.

BACKGROUND Cryptorchidism is the most common male urogenital tract disorder identified at birth. Treatment delays of cryptorchidism may be associated with significant complications such as subfertility and testicular cancer. The currently recommended age for performing orchidopexy is between 6 and 12 months of age and no later than 18 months. The aim of this study was to investigate the trends in the pattern of referral and age of boys at the time of operative treatment of congenital cryptorchidism at the largest tertiary care center in Bosnia and Herzegovina. METHODS The study included all boys who underwent orchidopexy for congenital cryptorchidism during two equivalents periods: 2008-2010 and 2015-2017. We assessed the referral age of patients, the age of patients at the time of orchidopexy, laterality of cryptorchidism, position of cryptorchidic testes palpated before surgery, the intraoperative position of cryptorchidic testis, a clinical position of the testis at follow up, and risk factors for late orchidopexy. RESULTS In total, 324 patients with 386 testes underwent orchidopexy for congenital cryptorchidism during the study periods. Of these patients, 62 received a bilateral orchidopexy (19.1%). Total referral age of patients with congenital cryptorchidism was 23 months (range, 4-74.5 months). Total median age at surgery was 24 months (range, 6-74 months). One hundred and eleven patients (28.8%) underwent surgery at less than the age of 12 months, 136 (35.2%) at less than the age of 18 months, and 250 (64.8%) patients underwent surgery after the age of 18 months. The analysis of the observed two periods (2008-2010 and 2015-2017) showed a statistically significant decrease in the mean referral age and the mean age at surgery over the last 5 years (2015-2017) (p = 0.007 and p = 0.003, respectively). CONCLUSIONS Current guidelines for timely operative treatment for congenital cryptorchidism have not been fully implemented in Bosnia and Herzegovina but a gradual improvement is evident. The main factor contributing to delays in orchidopexy was delayed or neglected referral by referring physicians. Optimizing the time of orchidopexy will require an improved coordination at all levels of pediatric health care to diminish the long-term consequences of cryptorchidism. TYPE OF STUDY Retrospective. LEVEL OF EVIDENCE III.

High-risk human papillomaviruses (high-risk HPVs) have been recently reported to be co-present with Epstein–Barr virus (EBV) in different types of human cancers including head and neck (HN), where they can cooperate in the initiation and/or progression of this cancer. Accordingly, we herein explored the prevalence of high-risk HPVs and EBV in 80 HN cancer tissues from the Syrian population using polymerase chain reaction, immunohistochemistry, and tissue microarray methodologies. We report that high-risk HPVs and EBV are present in 35/80 (43.7%) and 41/80 (51.2%) of our samples, respectively, and the most frequent HPV types are 33, 16, 18, 45, 52, 58, 35, 51, and 31, in this order. More significantly, our data reveal that 25/80 (31.2%) of cancer cases are positive for high-risk HPVs as well as EBV, and their co-presence is associated with high/intermediate-grade squamous cell carcinomas. These data confirm the co-presence of high-risk HPVs and EBV in HN cancers in the Syrian population of the Middle East and demonstrate that their co-incidence is linked to a more aggressive cancer phenotype. Thus, future studies are required to confirm these data and elucidate the exact role of high-risk and EBV cooperation in human HN carcinogenesis.

Objectives To evaluate the clinical outcome and complications in the pediatric population who had splenectomy at our institution, emphasizing the incidence of postplenectomy reactive thrombocytosis (RT) and its clinical significance in children without underlying hematological malignancies. Materials and methods The medical records of pediatric patients undergoing splenectomy were retrospectively reviewed for the period 1999–2018. The following variables were analyzed: Demographic parameters (age, sex), indications for surgery, operative procedures, preoperative and postoperative platelet count (postplenectomy RT), the use of anticoagulant therapy, and postoperative complications. The patients were divided into two groups according to indications for splenectomy: The non-neoplastic hematology group and the non-hematology group (splenectomy for trauma or other spleen non-hematological pathology). Results Fifty-two pediatric (37 male and 15 female) patients who underwent splenectomy at our institution were reviewed. Thirty-four patients (65%) were in the non-hematological group (splenic rupture, cysts, and abscess) and 18 patients (35%) in the non-neoplastic hematological group (hereditary spherocytosis and immune thrombocytopenia). The two groups did not differ significantly in regards to the patients’ age, sex, and preoperative platelet count (P>0.05 for all variables). Forty-nine patients (94.2%) developed postplenectomy RT. The percentages of mild, moderate and extreme thrombocytosis were 48.9%, 30.7%, and 20.4%, respectively. The comparisons of RT patients between the non-neoplastic hematology and the non-hematology group revealed no significant differences in regards to the patients’ age, sex, preoperative and postoperative platelet counts, preoperative and postoperative leukocyte counts, and the average length of hospital stay (P>0.05 for all variables). None of the patients from the cohort was affected by any thrombotic or hemorrhagic complications. Conclusions We confirm that RT is a very common event following splenectomy, but in this study it was not associated with clinically evident thrombotic or hemorrhagic complications in children undergoing splenectomy for trauma, structural lesions or non-neoplastic hematological disorders.

Glycogen synthase kinase 3 (GSK3) is a monomeric serine-threonine kinase discovered in 1980 in a rat skeletal muscle. It has been involved in various cellular processes including embryogenesis, immune response, inflammation, apoptosis, autophagy, wound healing, neurodegeneration, and carcinogenesis. GSK3 exists in two different isoforms, GSK3α and GSK3β, both containing seven antiparallel beta-plates, a short linking part and an alpha helix, but coded by different genes and variously expressed in human tissues. In the current review, we comprehensively appraise the current literature on the role of GSK3 in various cancers with emphasis on ovarian carcinoma. Our findings indicate that the role of GSK3 in ovarian cancer development cannot be decisively determined as the currently available data support both prooncogenic and tumor-suppressive effects. Likewise, the clinical impact of GSK3 expression on ovarian cancer patients and its potential therapeutic implications are also limited. Further studies are needed to fully elucidate the pathophysiological and clinical implications of GSK3 activity in ovarian cancer.

Background Human papillomaviruses (HPVs) and Epstein–Barr virus (EBV), known oncoviruses, can be co-present and cooperate in the initiation and/or progression of human carcinomas, including head and neck. Based on this fact, we recently reported the prevalence of both HPVs and EBV in cervical and breast cancers. Methods We herein explore for the first time the co-prevalence of high-risk HPVs and EBV in 98 head and neck (HN) squamous cell carcinoma (SCC) tissues from Bosnian patients using polymerase chain reaction (PCR) and immunohistochemistry (IHC) analysis, as well as tissue microarray methodology. Results The majority of these cancer tissue cases were from the oral cavity (68%). We found that high-risk HPVs and EBV are co-present in 34.7% of the SCC samples; with a significant correlation between the various HPV types and EBV co-incidence (p = 0.03). Our data showed that 30.8% of oral SCCs are positive for E6 oncoprotein of high-risk HPVs and 44.6% are positive for LMP1 of EBV. The most commonly expressed HPVs in our HNSCC samples include HPV types 16, 18, 45 and 58. Additionally, 37.5% of oral SCCs are positive for both HPVs and EBV, with statistically significant association between high-risk HPV types and EBV (p < 0.05). More importantly, our data revealed that the co-presence of HPV and EBV is strongly correlated with advanced tumor stage (p = 0.035). Conclusion In this study we show that HPV and EBV oncoviruses are co-present in HNSCC, particularly in oral cancer, where they can cooperate in the initiation and/or progression of this cancer. Thus, further studies are necessary to elucidate the mechanism of this cooperation.

Human papillomaviruses (HPVs) and Epstein–Barr virus (EBV), known oncoviruses, can be co-present and cooperate in the initiation and/or progression of human carcinomas, including head and neck. Based on this fact, we recently reported the prevalence of both HPVs and EBV in cervical and breast cancers. We herein explore for the first time the co-prevalence of high-risk HPVs and EBV in 98 head and neck (HN) squamous cell carcinoma (SCC) tissues from Bosnian patients using polymerase chain reaction (PCR) and immunohistochemistry (IHC) analysis, as well as tissue microarray methodology. The majority of these cancer tissue cases were from the oral cavity (68%). We found that high-risk HPVs and EBV are co-present in 34.7% of the SCC samples; with a significant correlation between the various HPV types and EBV co-incidence (p = 0.03). Our data showed that 30.8% of oral SCCs are positive for E6 oncoprotein of high-risk HPVs and 44.6% are positive for LMP1 of EBV. The most commonly expressed HPVs in our HNSCC samples include HPV types 16, 18, 45 and 58. Additionally, 37.5% of oral SCCs are positive for both HPVs and EBV, with statistically significant association between high-risk HPV types and EBV (p < 0.05). More importantly, our data revealed that the co-presence of HPV and EBV is strongly correlated with advanced tumor stage (p = 0.035). In this study we show that HPV and EBV oncoviruses are co-present in HNSCC, particularly in oral cancer, where they can cooperate in the initiation and/or progression of this cancer. Thus, further studies are necessary to elucidate the mechanism of this cooperation.

Human coronaviruses, especially SARS-CoV-2, are emerging pandemic infectious diseases with high morbidity and mortality in certain group of patients. In general, SARS-CoV-2 causes symptoms ranging from the common cold to severe conditions accompanied by lung injury, acute respiratory distress syndrome in addition to other organs’ destruction. The main impact upon SARS-CoV-2 infection is damage to alveolar and acute respiratory failure. Thus, lung cancer patients are identified as a particularly high-risk group for SARS-CoV-2 infection and its complications. On the other hand, it has been reported that SARS-CoV-2 spike (S) protein binds to angiotensin-converting enzyme 2 (ACE-2), that promotes cellular entry of this virus in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2). Today, there are no vaccines and/or effective drugs against the SARS-CoV-2 coronavirus. Thus, manipulation of key entry genes of this virus especially in lung cancer patients could be one of the best approaches to manage SARS-CoV-2 infection in this group of patients. We herein provide a comprehensive and up-to-date overview of the role of ACE-2 and TMPRSS2 genes, as key entry elements as well as therapeutic targets for SARS-CoV-2 infection, which can help to better understand the applications and capacities of various remedial approaches for infected individuals, especially those with lung cancer.

Abstract Rationale: Circumcision like any other surgical procedure is not devoid of complications. Serious complications are rare and include iatrogenic hypospadias, glans ischemia/necrosis, and glans amputation, all of which require an emergent treatment. Patient concerns: We report here a case of 6 months-old-boy with a superficial glans ischemia following circumcision. Diagnosis: Physical examination revealed a severely cyanotic glans with the moderate edema of the dorsal penile skin. Plasma levels of D-dimer were 8.57 mg/L. Urine passage was unremarkable while color Doppler ultrasonography revealed a normal blood flow. Interventions: The patient was successfully treated with subcutaneous injection of enoxaparin (low-molecular-weight heparin) and topical 2.5% dihydrotestosterone. Outcomes: The appearance of the glans penis on the 5th day was close to normal while the control levels of D-dimer dropped to the reference range. The patient was discharged from the hospital on the 6th day. At 6-month follow-up, the appearance of the glans penis was normal. Lessons: Acute glans penis ischemia following circumcision is a rare complication. Its successful treatment with enoxaparin and topical dihydrotestosterone has not been previously reported in the literature.

Cervical cancer is the fourth most common malignancy in women worldwide and a leading cause of cancer-related mortality in developing countries. Important etiological factors in this cancer are high-risk human papillomaviruses (HPV), as roughly 96% of cervical cancer cases are positive for these oncoviruses. On the other hand, it has been recently pointed out that E6/E7 oncoproteins of high-risk HPV can upregulate the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) axis. Likewise, several recent reports showed that checkpoint blockades targeting PD-1/PD-L1 pathways have achieved efficient clinical responses via suppressing cancer progression and improving survival in several types of human cancers including metastatic cervical cancer. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway and its interaction with high-risk HPV and their oncoproteins, which could have an important impact on the management of HPV-associated cancers including cervical.

Functional activation of human epidermal growth factor receptor 2 (HER2) has been shown to strongly promote carcinogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 genomic alterations. This has been best documented in the context of HER2 gene amplification in breast and gastric/gastroesophageal junction carcinomas for which several HER2-directed agents are available and have become a part of standard treatment regimens. Somatic HER2 gene mutations have been recently described at low frequency in a variety of human cancers and have emerged as a novel predictive biomarker for HER2-directed therapies. Preclinical data also indicate that activating HER2 mutations are potent oncogenic drivers in a manner that is analogous to HER2 amplification. HER2 mutations may clinically confer sensitivity to HER2-directed agents as recently shown in a phase II clinical trial with antibody-drug conjugate against HER2 trastuzumab deruxtecan in patients with non-squamous non-small cell lung carcinoma.

Colorectal cancer (CRC) is a common malignancy with a high mortality rate worldwide. It is a complex, multifactorial disease that is strongly impacted by both hereditary and environmental factors. The role of microbes (e.g., viruses) in the pathogenesis of CRC is poorly understood. In the current study, we explored the status of high-risk human papillomaviruses (HPV) and Epstein–Barr virus (EBV) in a well-defined CRC cohort using immunohistochemistry and polymerase chain reaction assays. Our data showed that high-risk HPVs were common (~80%) and EBV had a low presence (14–25%) in the CRC samples. The most common high-risk HPVs are HPV16, 31, 18, 51, 52 and 45 genotypes. The co-presence of high-risk HPV and EBV was observed in ~16% of the sample population without any significant association with the clinicopathological variables. We conclude that high-risk HPVs are very prevalent in CRC samples while EBV positivity is relatively low. The co-expression of the two viruses was observed in a minority of cases and without any correlation with the studied parameters. Further studies are necessary to confirm the clinical relevance and potential therapeutic (preventive) effects of the observations reported herein.

E-cigarette smoking (ECS) is a new method of tobacco smoking that is gaining popularity as it is thought to be a “healthy method” of tobacco consumption. The adverse outcomes of ECS on the respiratory and cardiovascular systems in humans have been recently demonstrated. Nevertheless, the effect of e-cigarette liquid (ECL) on the early stage of embryogenesis and angiogenesis has not been explored yet. Chicken embryo at 3 days of incubation and its chorioallantoic membrane (CAM) of 5 days were used to explore the outcome of ECL on the embryo. Real-time PCR was also employed to study the regulation of a set of key controller genes of embryogenesis as well as angiogenesis. Our study revealed that ECL exposure is associated with a high rate of mortality in embryos as around 70% of treated embryos, at 3 days of incubation, die after 5 days of exposure. Additionally, ECL inhibits angiogenesis of the CAM of 5 days of incubation by more than 30%. These effects could be explained by the upregulation of ATF-3, FOXA2, INHBA, MAPRE-2, and RIPK-1, as well as the downregulation of SERPINA-4 and VEGF-C genes, which are important key controller genes of embryogenesis as well as angiogenesis. Our data suggest clearly that ECS can have dramatic toxic outcomes on the early stage of embryogenesis as well as angiogenesis. Accordingly, we believe that further studies to assess the effects of ECS on human health are essential.