Mechanisms of SARS-CoV-2 Placental Transmission.

The widespread occurrence of SARS-CoV-2 infections and the diverse range of symptoms have placed significant strain on healthcare systems worldwide. Pregnancy has also been affected by COVID-19, with an increased risk of complications and unfavorable outcomes for expectant mothers. Multiple studies indicate that SARS-CoV-2 can infiltrate the placenta, breach its protective barrier, and infect the fetus. Although the precise mechanisms of intrauterine transmission remain unclear, factors such as perinatal infection, macrophages, sexual intercourse, and the virus' interaction with host angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP-1) proteins appear to play a role in this process. The integrity of the placental barrier fluctuates throughout pregnancy and appears to influence the likelihood of fetal transmission. The expression of placental cell receptors, like ACE2, changes during pregnancy and in response to placental damage. However, due to the consistent presence of others, such as NRP-1, SARS-CoV-2 may potentially enter the fetus at different stages of pregnancy. NRP-1 is also found in macrophages, implicating maternal macrophages and Hofbauer cells as potential routes for viral transmission. Our current understanding of SARS-CoV-2's vertical transmission pathways remains limited. Some researchers question the ACE2-associated transmission model due to the relatively low expression of ACE2 in the placenta. Existing studies investigating perinatal transmission and the impact of sexual intercourse have either involved small sample sizes or lacked statistical significance. This review aims to explore the current state of knowledge regarding the potential mechanisms of COVID-19 vertical transmission, identifying areas where further research is needed to fill the gaps in our understanding.

Refining PD-1/PD-L1 assessment for biomarker-guided immunotherapy: A review.

Anti-programmed cell death ligand 1 (anti-PD-L1)  immunotherapy is an increasingly crucial in cancer treatment. To date, the Federal Drug Administration (FDA) has approved four PD-L1 immunohistochemistry (IHC) staining protocols, commercially available in the form of "kits", facilitating testing for PD-L1 expression. These kits comprise four PD-L1 antibodies on two separate IHC platforms, each utilizing distinct, non-interchangeable scoring systems. Several factors, including tumor heterogeneity and the size of the tissue specimens assessed, can lead to PD-L1 status misclassification, potentially hindering the initiation of therapy. Therefore, the development of more accurate predictive biomarkers to distinguish between responders and non-responders prior to anti-PD-1/PD-L1 therapy warrants further research. Achieving this goal necessitates refining sampling criteria, enhancing current methods of PD-L1 detection, and deepening our understanding of the impact of additional biomarkers. In this article, we review potential solutions to improve the predictive accuracy of PD-L1 assessment in order to more precisely anticipate patients' responses to anti-PD-1/PD-L1 therapy, monitor disease progression and predict clinical outcomes.

Targeting circulating tumor cells to prevent metastases.

Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor, enter the bloodstream or body fluids, and spread to other body parts, leading to metastasis. Their presence and characteristics have been linked to cancer progression and poor prognosis in different types of cancer. Analyzing CTCs can offer valuable information about tumors' genetic and molecular diversity, which is crucial for personalized therapy. Epithelial-mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), play a significant role in generating and disseminating CTCs. Certain proteins, such as EpCAM, vimentin, CD44, and TGM2, are vital in regulating EMT and MET and could be potential targets for therapies to prevent metastasis and serve as detection markers. Several devices, methods, and protocols have been developed for detecting CTCs with various applications. CTCs interact with different components of the tumor microenvironment. The interactions between CTCs and tumor-associated macrophages promote local inflammation and allow the cancer cells to evade the immune system, facilitating their attachment and invasion of distant metastatic sites. Consequently, targeting and eliminating CTCs hold promise in preventing metastasis and improving patient outcomes. Various approaches are being explored to reduce the volume of CTCs. By investigating and discussing targeted therapies, new insights can be gained into their potential effectiveness in inhibiting the spread of CTCs and thereby reducing metastasis. The development of such treatments offers great potential for enhancing patient outcomes and halting disease progression.

The prognostic role of p53 and its correlation with CDK9 in urothelial carcinoma.

PURPOSE: The mutation of p53 is considered a pivotal step in bladder cancer pathogenesis. Recently, distinct interactions between p53 and CDK9, a transcription regulator, have been described. In this work, we explored the prognostic role of p53 expression and evaluated its associations with CDK9 in urothelial carcinoma. MATERIALS AND METHODS: The research group consisted of 67 bladder cancer samples and 32 normal urothelial mucosa samples. All specimens were analyzed using ImageJ and the IHC profiler plugin. To validate the results, 406 cases from The Cancer Genome Atlas database were analyzed. RESULTS: P53 and CDK9 are overexpressed in urothelial cancer tissues when compared to normal urothelial tissues (p < 0.05). High p53 expression was observed in metastatic tumors and tumors with high CDK9 expression (p < 0,05). High p53 expression was predictive for shorter survival in patients with non-muscle-invasive bladder cancer (HR = 0.107 [0.012-0.96]; p = 0.046) but did not correlate with prognosis in the muscle-invasive group. In high CDK9 cancers, high p53 expression correlated with the occurrence of high-grade and muscle-invasive tumors (p < 0.05). CONCLUSION: High expression of p53 correlates with unfavorable clinical features of bladder cancer. CDK9 is associated with the expression of p53, possibly through interactions with p53 inhibitors. Since the blockade of CDK9 in other malignancies reactivates wild-p53 activity, confirming the crosstalk between p53 and CDK9 in bladder cancer may be another step to explain the mechanism of tumor progression in its early stages.

TOLLIP Protein Expression Predicts Unfavorable Outcome in Renal Cell Carcinoma.

Resistance to systemic therapy is one of the hallmarks of renal cell carcinoma (RCC). Recently, TOLLIP has emerged as a possible driver of autophagy and chemoresistance. We explored the relationship between primary and metastatic RCC tumor characteristics, patient survival, and TOLLIP expression. The tissue microarrays cohort contained 95 cores of the primary tumor, matched metastases, and matched adjacent tissues derived from 32 RCC patients. TOLLIP expression in tumor samples was evaluated using the H-score. All examined samples showed cytoplasmic TOLLIP expression, with a median value of 100 in primary tumors, 107.5 in metastases, and 220 in the control group. The expression was significantly higher in the normal adjacent tissues compared to primary or metastatic RCC (p < 0.05). We found a positive correlation between expressions of TOLLIP in the primary tumor and its metastases (p < 0.05; k = 0.48). TOLLIP expression significantly correlates with a lower overall survival rate (p = 0.047). TOLLIP functions as a ubiquitin-LC3 adaptor in the intracellular pathway associated with autophagy. Relative TOLLIP overexpression may augment autophagy-related signaling, limiting susceptibility to therapy. The blockade of TOLLIP physiological function seems to be a promising approach to overcoming resistance to systemic therapy.

The Role of Inflammatory Cytokines in the Pathogenesis of Colorectal Carcinoma-Recent Findings and Review.

The inflammatory process plays a significant role in the development of colon cancer (CRC). Intestinal cytokine networks are critical mediators of tissue homeostasis and inflammation but also impact carcinogenesis at all stages of the disease. Recent studies suggest that inflammation is of greater importance in the serrated pathway than in the adenoma-carcinoma pathway. Interleukins have gained the most attention due to their potential role in CRC pathogenesis and promising results of clinical trials. Malignant transformation is associated with the pro-tumorigenic and anti-tumorigenic cytokines. The harmony between proinflammatory and anti-inflammatory factors is crucial to maintaining homeostasis. Immune cells in the tumor microenvironment modulate immune sensitivity and facilitate cancer escape from immune surveillance. Therefore, clarifying the role of underlying cytokine pathways and the effects of their modulation may be an important step to improve the effectiveness of cancer immunotherapy.

The Prognostic Role of CDK9 in Bladder Cancer.

Introduction: Most patients with urothelial carcinoma are diagnosed with non-invasive tumors, but the prognosis worsens with the progression of the disease. Overexpression of cyclin-dependent kinase 9 has been recently linked to increased cancer proliferation, faster progression, and worse prognosis. However, some cancers seem to contradict this rule. In this work, we explored the prognostic role of CDK9 expression in urothelial carcinoma. Materials and Methods: We performed immunohistochemical analysis on 72 bladder cancer samples. To assess a larger group of patients, the Cancer Genome Atlas (TCGA) database containing 406 cases and transcriptomics information through the Human Pathology Atlas were analyzed. Results: CDK9 is overexpressed in urothelial cancer tissues when compared to normal urothelial tissues (p < 0.05). High CDK9 expression was observed in low-stage, low-grade, and non-muscle-invasive tumors (p < 0.05). The patients with high CDK9 expression had a significantly higher 5-year overall survival rate than those with low CDK9 expression (77.54% vs. 53.6% in the TMA group and 57.75% vs. 35.44% in the TCGA group, respectively) (p < 0.05). The results were consistent in both cohorts. Multivariate Cox regression analysis indicated that low CDK9 status was an independent predictor for poor prognosis in the TCGA cohort (HR 1.60, CL95% 1.1−2.33, p = 0.014). Conclusions: High CDK9 expression predicts a favorable prognosis in urothelial carcinoma and is associated with clinicopathological features characteristic for early-stage disease. The decrease in CDK9 expression can be associated with the build-up of genetic instability and may indicate a key role for CDK9 in the early stages of urothelial carcinoma.