Impact of Human Umbilical Cord Blood Mononuclear Cells on Gentamicin-Induced Renal Injury and Genotoxicity in Rats.

Background: Acute kidney injury (AKI), also known as acute renal failure (ARF), has received considerable critical attention in recent years. Gentamicin (GM) is an antibiotic whose prolonged use results in AKI with a high mortality rate. Methods: Fifty adult female albino rats weighing 150-200 g were used. The animals were divided into five groups: the first group was the normal healthy control one, the second group received only 1 × 106 HUCB mononuclear cells (MNCs)/rat by intravenous (iv) injection, the third diseased group was given GM 100 mg/kg for 10 consecutive days by intraperitoneal injections, the fourth preventive group received 1 × 106 HUCB MNCs/rat by iv injection 24 h before gentamicin treatment, and the fifth treated group received 1 × 106 HUCB MNCs/rat by iv injection 24 h after gentamicin treatment. After 1 week of treatment, blood samples were collected, and kidneys were removed for histopathological examination. Results: Rats treated with HUCB MNCs in the treated group had a significant decrease in renal damage, low levels of biomarkers for nephrotoxicities such as serum creatinine and blood urea nitrogen, and low chromosomal aberrations compared to the diseased third group. The gene expression of KIM-1 and NGAL was decreased in response to HUCB treatment. Conclusions: HUCB MNCs have a curative effect against AKI and gentamicin-induced genotoxicity owing to their regenerative property.

Programmed death ligand-1 and CD8 tumor-infiltrating lymphocytes (TILs) as prognostic predictors in ovarian high-grade serous carcinoma (HGSC).

BACKGROUND: P D-L1 is expressed in tumor cells and plays a crucial role in tumor immune escape. Tumor-infiltrating lymphocytes (TILs) as CD8 T cells contribute to reduced tumor growth. Few studies investigated the prognostic effect of PD-L1 and CD8 TILs in ovarian high-grade serous carcinoma (HGSC). In the present study, we analyzed the expression of PD-L1 and CD8 TILs in HGSC by immunohistochemistry, and results were correlated to prognosis. It was carried on 54 cases of ovarian HGSC who attended the Oncology Centre, Mansoura University, Egypt, from 2012 till 2019. RESULTS: Nearly 60% of cases showed positive PD-L1 expression in tumor cells. Regarding the clinicopathological characteristics, higher PD-L1 expression was found among patients with residual tumor (82.4%) compared to patients with no residual tumor (54.5%), with marginal statistical significance (p 0.07). PD-L1 was significantly associated with CD8 TILs expression. Higher PD-L1 expression was found among tumors with low expression of CD8 TILs with statistically significant difference (p≤0.001). Disease-free survival (DFS) was significantly lower among the group with positive expression of PD-L1 compared to the group with negative expression of PD-L1 (p 0.01), while overall survival (OS) was not associated with PD-L1 expression. On the other hand, the overall survival (OS) in patients with high CD8 expression was significantly higher than patients with low CD8 expression (p 0.043), while DFS was not significantly different among both CD8 TILS groups. CONCLUSIONS: PD-L1 and CD8 TILs may become a promising therapeutic target for patients with ovarian HGSC. More studies are needed to further validate their prognostic effect. Precise identification of patients who will benefit from PD-L1 checkpoint blockade and TILs adaptive immunotherapy is mandatory.

Human Endogenous Retrovirus-H Long Terminal Repeat- Associating Protein 2 (HHLA2) is a Novel Immune Checkpoint Protein in Lung Cancer which Predicts Survival.

ackground: Lung cancer is one of the most frequently diagnosed malignancies. Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a recently discovered ligand of the B7 family. Blocking this immune checkpoint has become an important treatment option for lung cancer. METHODS: The study includes 62 biopsy specimens either bronchoscopic or CT-guided biopsies diagnosed as lung cancer in Hospitals of Faculty of Medicine, Mansoura University, Egypt during the period from 2016 to 2020. Immunohistochemical Staining for HHLA2 and EGFR was performed. HHLA2 expression was assessed in different pathological types of lung Cancer, and it was correlated with other clinicopathologic parameters and patient prognosis. RESULTS: We found a significant association between HHLA2 expression and metastasis. About 83% of patients presented with metastasis showed positive expression of HHLA2 compared to 44.4% in patients with no metastasis (p=0.02). Also, results show significant mild positive correlation between expression of HHLA2 and EGFR markers (p=0.045). The mean OS time in cases with positive HHLA2 expression was nearly half that of patients with negative expression of the markers. However, this difference was not statistically significant. But, PFS of patients was significantly lower among the group with positive expression of HHLA2 compared to the group with negative expression of HHLA2 (p= 0.01). CONCLUSIONS: This study reports that recently discovered, HHLA2 is over expressed in lung cancer associating with higher stage. It is also correlated with EGFR overexpression. HHLA2 could serve as a predictor of progression and distant metastasis. Also, it has potential to be effective immune target in lung cancer immunotherapy such as checkpoint blockade and antibody-drug conjugate treatment.
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PDL-1 expression in lung carcinoma and its correlation with clinicopathological and prognostic characteristics.

Lung cancers have high incidence and high mortality rates. The immune checkpoints as programmed death ligand 1 (PDL-1) can suppress the tumor immune reaction. So, their blocking seems to be a way to treat tumors. This study assesses PDL-1 immunohistochemical expression in lung cancer, and its correlation with prognosis. It included 62 specimens of lung cancer in Hospitals of Mansoura Faculty of Medicine, Egypt. Seventy-one percent of cases showed positive PDL-1 and about 59.1% of them showed high expression. PDL-1 expression in NSCLC was significantly higher than in SCLC (P = 0.019). There were no significant associations between PDL-1 expression and other clinicopathological parameters. A significant mild positive correlation between PDL-1 and EGFR marker was found (P = 0.006). The mean overall survival in cases with positive PDL-1 was lower than negative cases (P = 0.37). Also, progression-free survival was lower among PDL-1 positive cases compared to negative cases (P = 0.5). This study reports that immune checkpoint, PDL-1 is overexpressed in lung cancer especially NSCLC. It is correlated with EGFR overexpression. PDL-1 could have potential to be an effective immune target for lung cancer immunotherapy. But the presence of PD-L1-negative tumors highlights the importance of searching for alternative or combination treatment strategies.Abbreviations: AC: Adenocarcinoma; COPD: Chronic Obstructive Pulmonary Diseases; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; EGFR: Epidermal Growth Factor Receptor; IHC: Immunohistochemical; NSCLC: Non-Small Cell Lung Cancer; OS: Overall Survival; PD1: Programmed Death 1; PDL-1: Programmed Death ligand 1; PFS: Progression Free Survival; SCC: Squamous cell carcinoma; SCLC: Small Cell Lung Cancer; SD: Standard Deviation; TCR: T-cell receptor; TPS: Tumor Proportion Score.

"Switch of E-Cadherin to N-Cadherin expression in different molecular subtypes of breast invasive duct carcinomas and its correlation with clinicopathological features".

BACKGROUND: In breast cancer, metastasis and recurrence is the main culprit in treatment failure. This study aimed to explore the role of E-cadherin/N-cadherin Switch in progression, spread and metastasis in breast invasive duct carcinoma. MATERIALS AND METHODS: A cross-sectional study on 118 formalinfixed paraffinembedded mastectomy specimens of invasive breast duct carcinoma. Primary antibodies for E-cadherin (monoclonal, clone HECD-1; Zymed Laboratories; dilution 1:600) and N-cadherin (monoclonal, clone 3B9; Zymed Laboratories, Inc., Montrouge, France; dilution 1:200) were applied for all cases. The study revealed that E-cadherin high expression was significantly associated with advanced TNM clinical stage (P = 0.021), and nodal metastasis (P < 0.001). High expression of N-cadherin was significantly positively correlated with tumor sizes (P < 0.00), advanced clinical stage (P < 0.00), and nodal metastasis (P < 0.008). Mean OS was 39.99 months in cases with negative expression versus 41.8 months in cases with positive expression. Mean DFS in cases with positive E. cadh expression was 41.89 months was higher than mean DFS in cases with negative E. cadh expression which was 40.52 months, but it showed no statistical significance (P = 0.57). CONCLUSIONS/SIGNIFICANCE: This study demonstrated that loss of E-cadherin and gain of N-cadherin promotes invasion, migration, and metastasis in invasive ductal carcinoma cells. Importantly, these findings may exploit new cancer therapies using N-cadherin antagonists.

Calretinin expression as a reliable prognostic marker in different molecular subtypes of breast carcinoma.

BACKGROUND: Calretinin (CR), a known mesothelial marker, is expressed in both epithelial and mesenchymal malignancies including breast cancer. AIMS: We aimed to measure the frequency of CR expression in correlation with other clinicopathological parameters of different molecular subtypes of invasive breast carcinoma and to study its prognostic implications in this common cancer. STUDY DESIGN: Tissue microarrays were constructed from 225 tissue samples of breast carcinoma cases. SUBJECTS AND METHODS: Immunostaining for CR in addition to estrogen receptors, progesterone receptors, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor, CK5/6, and Ki-67 for molecular subtyping. STATISTICAL ANALYSIS USED: Chi-square and Fisher's exact tests were done using SPSS 18.0 software (IBM Inc.). Survival data were analyzed using Kaplan-Meier test, Log-rank test, and Cox proportional hazard models. RESULTS: Cases of invasive breast carcinomas with different grades were classified into 84 luminal A, 45 luminal B, 27 HER2 positive, 40 basal-like, and 29 unclassified. High CR expression was associated with tumors of high grade (P < 0.0001), high locoregional recurrence (P = 0.005), hormonal receptors negative, and high Ki-67 indices. They frequently display a basal-like phenotype (70%, P < 0.0001), HER2 (59.3%), and luminal B (33.3%) tumors compared to luminal A (9.5%) and unclassified subtypes (17.2%). Moreover, it is associated with poor overall patient survival (P = 0.034), but it does not affect disease-free survival. CONCLUSIONS: Calretinin could be a reliable predictor marker of adverse prognosis in breast cancer.