Osseous Metastases in Thyroid Cancer: Unveiling Risk Factors, Disease Outcomes, and Treatment Impact.

Bone is the second most common site of metastasis in patients with thyroid cancer (TC) and dramatically impacts overall survival and quality of life with no definitive cure, yet there is no extensive study of the demographic and clinical risk factors in the recent literature. Data regarding 120,754 TC patients with bone metastasis were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses were used to identify the risk factors of bone metastasis occurring in various histologies of TC. Cox regression was performed to analyze the influence of bone metastasis on overall survival. Hazard ratios were computed to analyze the association between bone metastasis and the primary outcomes. Of the 120,754 records collected from the SEER database from 2000 to 2019, 976 (0.8%) presented with bone metastasis, with occurrence being the greatest in patients of age ≥ 55 years (OR = 5.63, 95%CI = 4.72-6.71), males (OR = 2.60, 95%CI = 2.27-2.97), Blacks (OR = 2.38, 95%CI = 1.95-2.9) and Asian or Pacific Islanders (OR = 1.90, 95%CI = 1.58-2.27), and single marital status. TC patients presenting with bone metastasis (HR = 2.78, 95%CI = 2.34-3.3) or concurrent bone and brain metastases (HR = 1.62, 95%CI = 1.03-2.55) had a higher mortality risk. Older age, gender, race, and single marital status were associated with bone metastasis and poorer prognosis in TC patients at initial diagnosis. Understanding such risk factors can potentially assist clinicians in making early diagnoses and personalized treatment plans, as well as researchers in developing more therapeutic protocols.

Prognostic Value of BRAF, Programmed Cell Death 1 (PD1), and PD Ligand 1 (PDL1) Protein Expression in Colon Adenocarcinoma.

Patients with colorectal cancer in different stages show variable outcomes/therapeutic responses due to their distinct tumoral biomarkers and biological features. In this sense, this study aimed to explore the prognostic utility of BRAF, programmed death-1 (PD1), and its ligand (PDL1) protein signatures in colon adenocarcinoma. The selected protein markers were explored in 64 archived primary colon adenocarcinomas in relation to clinicopathological features. BRAF overexpression was found in 39% of the cases and was significantly associated with grade 3, N1, advanced Dukes stage, presence of relapse, and shorter overall survival (OS). PD1 expression in the infiltrating immune cells (IICs) exhibited significant association with T2/T3, N0/M0, early Dukes stage, and absence of relapse. PDL1 expression in IICs is significantly associated with advanced nodal stage/distant metastasis, advanced Dukes stage, and shorter OS. Meanwhile, PDL1 expression in neoplastic cells (NC) was associated with the advanced lymph node/Dukes stage. A positive combined expression pattern of PDL1 in NC/IICs was associated with poor prognostic indices. Tumor PDL1 expression can be an independent predictor of OS and DFS. The multivariate analyses revealed that short OS was independently associated with the RT side location of the tumor, PD1 expression in stromal IICs, and PDL1 expression in NC. In conclusion, overexpression of BRAF in colon adenocarcinoma is considered a poor prognostic pathological marker. In addition, PDL1 expression in NC is considered an independent prognostic factor for DFS/OS. Combined immunohistochemical assessment for BRAF and PD1/PDL1 protein expressions in colon adenocarcinoma might be beneficial for selecting patients for future targeted therapy.

Genetic Variation in DEAD-Box Helicase 20 as a Putative Marker of Recurrence in Propensity-Matched Colon Cancer Patients.

Variants of the DEAD-Box Helicase 20 (DDX20), one of the microRNAs (miRNAs) machinery genes, can modulate miRNA/target gene expressions and, hence, influence cancer susceptibility and prognosis. Here, we aimed to unravel the association of DDX20 rs197412 T/C variant with colon cancer risk and/or prognosis in paired samples of 122 colon cancer and non-cancer tissue specimens by TaqMan allelic discrimination analysis. Structural/functional bioinformatic analyses were carried out, followed by a meta-analysis. We found that the T allele was more frequent in cancer tissues compared to control tissues (60.2% vs. 35.7%, p < 0.001). Furthermore, the T variant was highly frequent in primary tumors with evidence of recurrence (73% vs. 47.5%, p < 0.001). Genetic association models, adjusted by age and sex, revealed that the T allele was associated with a higher risk of developing colon cancer under heterozygote (T/C vs. C/C: OR = 2.35, 95%CI = 1.25−4.44, p < 0.001), homozygote (T/T vs. C/C: OR = 7.6, 95%CI = 3.5−16.8, p < 0.001), dominant (T/C-T/T vs. C/C: OR = 3.4, 95%CI = 1.87−8.5, p < 0.001), and recessive (T/T vs. C/C-T/C: OR = 4.42, 95%CI = 2.29−8.54, p = 0.001) models. Kaplan−Meier survival curves showed the shift in the C > T allele to be associated with poor disease-free survival. After adjusting covariates using a multivariate cox regression model, patients harboring C > T somatic mutation were 3.5 times more likely to develop a recurrence (p < 0.001). A meta-analysis of nine studies (including ours) showed a higher risk of CRC (81%) in subjects harboring the T/T genotype than in T/C + C/C genotypes, supporting the potential clinical utility of the specified study variant as a biomarker for risk stratification in CRC cases. However, results were not significant in non-colorectal cancers. In conclusion, the DDX20 rs197412 variant is associated with increased colon cancer risk and a higher likelihood of recurrence in the study population.

Prognostic Value of LINC-ROR (rs1942347) Variant in Patients with Colon Cancer Harboring BRAF Mutation: A Propensity Score-Matched Analysis.

Emerging studies show that long intergenic non-protein coding RNA, regulator of reprogramming (LINC-ROR) is aberrantly expressed in several types of cancer, including colon cancer (CC). LINC-ROR intronic variant rs1942347 may impact gene regulation and disease phenotype. We aimed to explore the potential association of LINC-ROR (rs1942347) with the clinicopathological features and outcome of CC cases. Archived FFPE (n = 180) CC samples were enrolled. Taq-Man allelic discrimination PCR was used for genotyping in propensity-matched cohorts with/without positive staining for mutant BRAF protein after eliminating confounders bias. The rs1942347*A allele variant was associated with high pathological grade, larger tumor size, distant metastasis, and mortality. Multiple logistic regression analysis adjusted by sex and BRAF mutation showed A/A genotype carriers to have 3 times more risk of early onset of cancer (OR = 3.13, 95%CI = 1.28-7.69, p = 0.034) than T/T genotype carriers. Overall analysis showed that rs1942347*A allele carriers had higher risk of mortality under heterozygote (OR = 2.13, 95%CI = 1.08-4.35, p = 0.003), homozygote (OR = 5.0, 95%CI = 1.69-14.29, p = 0.003), dominant (OR = 3.33, 95%CI = 1.20-9.09, p = 0.003), and recessive (OR = 2.63, 95%CI = 1.37-5.0, p = 0.011) models compared to T/T allele carriers. Stratified analysis by BRAF status revealed that the ancestor T/T allele conferred protection in BRAF mutant CC patients and was associated with a 73-93% reduced risk of mortality under heterozygote/homozygote comparison models. Using Kaplan-Meier curves, carriers of the A/A genotype had shorter survival times than T/T cohorts. The univariate Cox regression model revealed that the A/A genotype was associated with a 3.5 times greater mortality risk than the T/T genotype. However, after adjustment by multiple Cox regression analysis, the risk was insignificant. In conclusion, this is the first study identifying the potential association of the LINC-ROR (rs1942347) variant with CC prognosis.

Supplement With Calcium or Alendronate Suppresses Osteopenia Due to Long Term Rabeprazole Treatment in Female Mice: Influence on Bone TRAP and Osteopontin Levels.

BACKGROUND AND PURPOSE: Rabeprazole, a proton pump inhibitor (PPIs) is much endorsed to patients with increased gastric acidity. PPIs were accused to have osteoporotic effects on patients who chronically use them. The point of the current investigation was to decide the impact of rabeprazole on osteoporosis and to explore the modulatory effects of dietary calcium or alendronate on this side effect. METHODS: 80 female mice were alienated into four groups maintained for 18 weeks: [1] Vehicle group: given distilled water in 12 ml/kg, P.O. [2] Rabeprazole control group: given rabeprazole in a dose equals 10 mg/kg every 48 h, P.O. [3] Rabeprazole + calcium: given rabeprazole (10 mg/kg every 48 h) along with calcium supplement. [4] Rabeprazole + alendronate: given rabeprazole (10 mg/kg every 48 h) and alendronate (1 mg/kg per week, i.p.). Serum calcium, phosphorus and parathyroid hormone were measured. Both femurs were kept in paraformaldehyde, and then the right one was used for X-ray examination with analysis by Digora software and the left one for histopathological examination (H&E) and immunohistochemical stains for osteopontin and tartrate resistant acid phosphatase (TRAP). RESULTS: Calcium supplementation or administration of alendronate along with rabeprazole significantly restored the mean bone density as shown by X-ray analysis. Femurs from mice received rabeprazole showed widely separated, thin-walled bone trabeculae and increased number of osteoclasts. Calcium or alendronate with rabeprazole showed thick bone trabeculae without full recovery from rabeprazole induced damage. Adding calcium supplementation to rabeprazole did not affect the histological abnormalities related to osteoclasts meanwhile alendronate produced inactivation of osteoclasts. Both calcium and alendronate decreased the rabeprazole-induced increment in the femur osteopontin level. CONCLUSION: Calcium or alendronate can be recommended for female patients on PPI therapy who are at risk of osteopenia.

MicroRNA-34a: A Key Regulator in the Hallmarks of Renal Cell Carcinoma.

Renal cell carcinoma (RCC) incidence has increased over the past two decades. Recent studies reported microRNAs as promising biomarkers for early cancer detection, accurate prognosis, and molecular targets for future treatment. This study aimed to evaluate the expression levels of miR-34a and 11 of its bioinformatically selected target genes and proteins to test their potential dysregulation in RCC. Quantitative real-time PCR for miR-34a and its targets; MET oncogene; gene-regulating apoptosis (TP53INP2 and DFFA); cell proliferation (E2F3); and cell differentiation (SOX2 and TGFB3) as well as immunohistochemical assay for VEGFA, TP53, Bcl2, TGFB1, and Ki67 protein expression have been performed in 85 FFPE RCC tumor specimens. Clinicopathological parameter correlation and in silico network analysis have also implicated. We found RCC tissues displayed significantly higher miR-34a expression level than their corresponding noncancerous tissues, particularly in chromophobic subtype. MET and E2F3 were significantly upregulated, while TP53INP2 and SOX2 were downregulated. ROC analysis showed high diagnostic performance of miR-34a (AUC = 0.854), MET (AUC = 0.765), and E2F3 (AUC = 0.761). The advanced pathological grade was associated with strong TGFB1, VEGFA, and Ki67 protein expression and absent Tp53 staining. These findings indicate miR-34a along with its putative target genes could play a role in RCC tumorigenesis and progression.

Gestational protein restriction: study of the probable effects on cardiac muscle structure and function in adult rats.

Intrauterine growth restriction (IUGR) has been linked to heart disease in adulthood. This study aimed to examine the effect of gestational protein restriction during fetal and early postnatal life on the cardiac muscle structure and function in adult offspring. Pregnant female rats were randomly divided into two dietary groups: normal-protein diet (NP) and low-protein diet (LP). Fifteen male offspring from each group were included in the study. Offspring body weights were recorded at birth and monthly from weaning until 24 weeks of age while systolic blood pressure was measured weekly. At the end of the experiment, hearts were weighed and processed for light and electron microscopy and immunohistochemical study. Immunohistochemical staining for localization of inducible nitric oxide synthase (iNOS) and connexin 43 proteins was performed. The gestational protein restriction induced deleterious effects on adult offspring including decreased birth weight, heart weight, and heart rate, and increased systolic blood pressure. Histologically, the number of cardiomyocytes decreased and cardiac fibrosis increased. Signs of degeneration at both structural and ultra-structural levels of cardiomyocytes were also seen. The iNOS was up regulated in LP offspring which was a promoter for apoptosis, while connexin 43 was down regulated which would affect heart conductivity and contractility. Our results demonstrate that adult offspring body weight and cardiac muscle structure and function can be programmed by maternal gestational nutrition. These adverse outcomes suggest the criticality of dietary behavior during pregnancy on long-term offspring cardiac health.