Protective Effect of Vitamin D against Hepatic Molecular Apoptosis Caused by a High-Fat Diet in Rats.

The protective effects of vitamin D (VitD) in different diseases were studied. The liver is of great interest, especially with the presence of VitD receptors. A high-fat diet (HFD) is associated with many diseases, including liver injury. Consumption of saturated fatty acids triggers hepatic apoptosis and is associated with increased inflammation. We aimed in this study to investigate the protective effects of VitD on hepatic molecular apoptotic changes in response to an HFD in rats. Forty male Wistar albino rats were used and divided into four groups: control, HFD, control + VitD, and VitD-supplemented HFD (HFD + VitD) groups. After six months, the rats were sacrificed, and the livers were removed. RNA was extracted from liver tissues and used for the quantitative real-time RT-PCR of different genes: B-cell lymphoma/leukemia-2 (BCL2), BCL-2-associated X protein (Bax), Fas cell surface death receptor (FAS), FAS ligand (FASL), and tumor necrosis factor α (TNF-α). The results showed that an HFD increased the expression of the pro-apoptotic genes Bax, FAS, and FASL, and reduced the expression of the anti-apoptotic gene BCL2. Interestingly, a VitD-supplemented HFD significantly increased the BCL2 expression and decreased the expression of all pro-apoptotic genes and TNFα. In conclusion, VitD has a protective role against hepatic molecular apoptotic changes in response to an HFD.

Prevalence and Association of Transfusion Transmitted Infections with ABO and Rh Blood Groups among Blood Donors in the Western Region of Saudi Arabia: A 7-Year Retrospective Analysis.

This study was aimed at determining the prevalence estimate and association of transfusion-transmitted infections (TTIs) with ABO and Rh blood groups among blood donors at the King Faisal Specialist Hospital and Research Center (KFSH & RC) in the western region of Saudi Arabia. A retrospective study was conducted at the blood bank center of KFSH and RC from 1 January 2013 to 31 December 2019. Data on ABO and Rh blood group testing, serological testing, molecular investigations, serological assays, nucleic acid testing (NATs), and socio-demographic information were gathered. During the study period, there were 959,431 blood donors at the KFSH and RC. The overall 7-year cumulative prevalence estimate of blood transfusion-transmitted infections among blood donors was low at 7.93%, with an average prevalence estimate of 0.66%. Donors with the O blood group, the O RhD +ve blood group, in particular, were more at risk of developing TTIs, whereas donors with the AB blood group, the AB RhD -ve blood group, in particular, were at the lowest risk of developing TTIs. In total, 96.9% of the blood donors were males (n = 916,567). Almost half of the blood donors belong to the O blood group (49.4%). A total of 861,279 (91.0%) donors were found to be RhD positive. The percentages of TTIs were found to be higher in RhD +ve donors compared with RhD -ve donors. The prevalence estimate of the hemoglobin C (HbC) infection was the most common TTI among the blood donors being 3.97%, followed by malaria being 2.21%. The least prevalence estimate of TTI in the present study was for NAT HIV being 0.02%. Significant associations were observed between RhD +ve and RhD -ve among the malaria-infected donors (A: χ2 = 26.618, p = 0.001; AB: χ2 = 23.540, p = 0.001; B: χ2 = 5.419, p = 0.020; O: χ2 = 68.701, p = 0.001). The current 7-year retrospective study showed a low level of TTIs among blood donors. However, we urge that more research encompassing the entire country be conducted in order to obtain more representative results in terms of the prevalence estimate and association of transfusion-transmitted infections with ABO and Rh blood groups in communities.

Evaluation of the Idylla KRAS and NRAS mutation test in colorectal cancer tissue.

INTRODUCTION: The currently approved techniques for RAS mutations testing in colorectal cancer (CRC) tissue are labor-intensive and time consuming. The Idylla technology (IT) is a rapid and fully automated diagnostics system. The primary aim of this study is to compare the Idylla performance against that of conventional techniques (CT). METHODOLOGY: Archival CRC tumor samples from 2 hospitals were tested for KRAS and NRAS mutations using the IT. Results were compared to those obtained earlier by CT performed in accredited laboratories. Unexplained discordant results were verified locally by next generation sequencing (NGS) to ascertain the accuracy of IT. RESULTS: Forty five samples were processed. All samples underwent dual testing (CT & IT) for KRAS mutations. IT identified mutations in 2 samples that were not detected by CT. Primary concordance rate for KRAS was 93.3% and the accuracy rate improved to 100% after verification and explanation of discordant results. Only 18 samples underwent dual testing for NRAS. Primary concordance and accuracy rates for NRAS were 94.4%. The mean time from dispatching the specimen for RAS testing by CT until receipt of results was 12 (7-28) days compared to few hours when IT was used. CONCLUSION: IT provides a quick and reliable mean for RAS testing. In addition, it identifies mutations that are not detected by CT and thus may provide better guidance to treatment choices.

Anticancer Profiling for Coumarins and Related O-Naphthoquinones from Mansonia gagei against Solid Tumor Cells In Vitro.

Napthoquinones and coumarins are naturally occurring compounds with potential anticancer activity. In the current study, two O-naphthoquinons (mansonone-G and mansonone-N) and six coumarins (mansorin-A, mansorin-B, mansorin-C, mansorins-I, mansorin-II, and mansorin-III) were isolated from the heartwood of Mansonia gagei family Sterculariaceae. Isolated compounds were examined for their potential anticancer activity against breast (MCF-7), cervix (HeLa), colorectal (HCT-116) and liver (HepG2) cancer cells using Sulfarhodamine-B (SRB) assay. Mansorin-II and mansorin-III showed relatively promising cytotoxic profile in all cell lines under investigation with inhibitory concentrations (IC50s) in the range of 0.74 µM to 36 µM and 3.95 µM to 35.3 µM, respectively. In addition, mansorin-B, mansorin-C, mansorin-II and mansorin-III significantly increased cellular entrapment of the P-glycoprotein (P-gp) substrate, doxorubicin, in colorectal cancer cells expressing the P-gp pump. The inhibitory effect of the isolated compounds on P-gp pump was examined using human recombinant P-gp molecules attached to ATPase subunit. Mansorin-B and mansonone-G were found to inhibit the P-gp attached ATPase subunit. On the other hand, mansorin-C, mansorin-III and mansorin-II inhibited P-gp pump via dual action (P-gp related ATPase subunit inhibition and P-gp substrate binding site occupation). However, mansorin II was examined for its potential chemomodulatory effect to paclitaxel (PTX) against colorectal cancer cells (HCT-116 and CaCo-2). Mansorin-II significantly reduced the IC50 of PTX in HCT-116 cells from 27.9 ± 10.2 nM to 5.1 ± 1.9 nM (synergism with combination index of 0.44). Additionally, Mansorin-II significantly reduced the IC50 of PTX in CaCo-2 cells from 2.1 ± 0.8 µM to 0.13 ± 0.03 µM (synergism with combination index of 0.18). Furthermore, cell cycle analysis was studied after combination of mansorin-II with paclitaxel using DNA flow cytometry analysis. Synergism of mansorin-II and PTX was reflected in increasing apoptotic cell population in both HCT-116 and CaCo-2 cells compared to PTX treatment alone. Combination of mansorin-II with PTX in CaCo-2 cells significantly increased the cell population in G2/M phase (from 2.9 ± 0.3% to 7.7 ± 0.8%) with reciprocal decrease in G0/G1 cell fraction from 52.1 ± 1.1% to 45.5 ± 1.0%. Similarly in HCT-116 cells, mansorin-II with PTX significantly increased the cell population in G2/M phase (from 33.4 ± 2.8% to 37.6 ± 1.3%) with reciprocal decrease in the S-phase cell population from 22.8 ± 1.7% to 20.2 ± 0.8%. In conclusion, mansorin-II synergizes the anticancer effect of paclitaxel in colorectal cancer cells, which might be partially attributed to enhancing its cellular entrapment via inhibiting P-gp efflux pump.

Biochemical recurrence after radical prostatectomy: what does it mean?

BACKGROUND: Radical prostatectomy (RP) has been used as the main primary treatment for prostate cancer (PCa) for many years with excellent oncologic results. However, approximately 20-40% of those patients has failed to RP and presented biochemical recurrence (BCR). Prostatic specific antigen (PSA) has been the pivotal tool for recurrence diagnosis, but there is no consensus about the best PSA threshold to define BCR until this moment. The natural history of BCR after surgical procedure is highly variable, but it is important to distinguish biochemical and clinical recurrence and to find the correct timing to start multimodal treatment strategy. Also, it is important to understand the role of each clinical and pathological feature of prostate cancer in BCR, progression to metastatic disease and cancer specific mortality (CSM). Review design: A simple review was made in Medline for articles written in English language about biochemical recurrence after radical prostatectomy. OBJECTIVE: To provide an updated assessment of BCR definition, its meaning, PCa natural history after BCR and the weight of each clinical/pathological feature and risk group classifications in BCR, metastatic disease and CSM.

Optimal Settings for the Noncontact Holmium:YAG Stone Fragmentation Popcorn Technique.

PURPOSE: The purpose of this study was to evaluate the popcorn technique using a wide range of holmium laser settings and fiber sizes in a systematic in vitro assessment. MATERIALS AND METHODS: Evaluations were done with 4 artificial stones in a collection tube. A fixed ureteroscope was inserted through a ureteral access sheath to provide constant irrigation flow and the laser was placed 1 mm from the bottom. Combinations of 0.5 to 1.5 J, 10 to 20 and 40 Hz, and long and short pulses were tested for 2 and 4 minutes. We used 273 and 365 µm laser fibers. All tests were repeated 3 times. The stones were weighed before and after the experiments to evaluate the setting efficiency. Significant predictors of a highly efficient technique were assessed. RESULTS: A total of 144 tests were performed. Mean starting weight of the stones was 0.23 gm, which was consistent among the groups. After the experiment the median weight difference was 0.07 gm (range 0.01 to 0.24). When designating a 50% reduction in stone volume as the threshold indicating high efficiency, the significant predictors of an efficient popcorn technique were a long pulse (OR 2.7, 95% CI 1.05-7.15), a longer duration (OR 11.4, 95% CI 3.88-33.29), a small (273 µm) laser fiber (OR 0.23, 95% CI 0.08-0.70) and higher power (W) (OR 1.14, 95% CI 1.09-1.20). CONCLUSIONS: Higher energy, a longer pulse, frequencies higher than 10 Hz, a longer duration and a smaller laser fiber predict a popcorn technique that is more efficient at reducing stone volume.

Effect of Prior Focal Therapy on Perioperative, Oncologic and Functional Outcomes of Salvage Robotic Assisted Radical Prostatectomy.

PURPOSE: We assessed the impact of focal therapy on perioperative, oncologic and functional outcomes in men who underwent salvage robotic assisted radical prostatectomy compared to primary robotic assisted radical prostatectomy. MATERIALS AND METHODS: Focal therapy was performed in patients presenting with Gleason score 3 + 3 or 3 + 4, clinical stage cT2a or less, serum prostate specific antigen 15 ng/ml or less, unilateral positive biopsy, maximum length of any positive core less than 10 mm and life expectancy greater than 10 years. Focal therapy was defined as target ablation of the index lesion plus a 1 cm safety margin in the normal ipsilateral prostatic parenchyma. The salvage group included 22 men who underwent salvage prostatectomy after focal therapy failure. The primary group was defined using matched pair 1:2 selection of 44 of 2,750 patients treated with primary prostatectomy. The primary and secondary end points were the between group differences in functional and oncologic outcomes, respectively. RESULTS: Complication rates were comparable (p >0.05). Pad-free probability was comparable between the groups at 1 and 2 years (p = 0.8). Recovery of erectile function was significantly lower after salvage robotic assisted radical prostatectomy (p = 0.008), which also showed a significantly lower probability of cumulative biochemical recurrence-free survival compared to primary robotic assisted radical prostatectomy (56.3% vs 92.4% at 2 years, p = 0.001). Salvage prostatectomy demonstrated a significantly increased risk of biochemical recurrence (HR 4.8, 95% CI 1.67-13.76, p = 0.004). Study limitations included the retrospective nature, the lack of randomization and the short followup. CONCLUSIONS: Salvage robotic assisted radical prostatectomy after focal therapy failure is feasible with acceptable complication rates. However, patients assigned to primary focal therapy should be advised about a poorer prognosis in terms of oncologic control and lower erectile recovery rates in case of a future salvage surgery.

Comparison of laser fiber passage in ureteroscopic maximum deflection and their influence on deflection and irrigation: Do we really need the ball tip concept?

PURPOSE: To examine laser fiber passage capabilities through flexible ureterorenoscopes (fURSs) and to measure deflections and flow characteristics. METHODS: For this in vitro study, eight fURSs were examined (Olympus® URF-P6, URF-P6, URF-V, URF-V2; Storz® Xc and Flex-X2; Richard Wolf® Cobra Vision; and Lithovue). Four laser fibers standard 200- and 273-µm (uncleaved and cleaved), sheath-coated and ball-tip fibers were attempted to pass through each fURS while deflected at 120°, 180°, maximum deflection, and maximum deflection with reduced 9-mm radius. Measurements included maximal (up/down) deflections and irrigation flow rates achieved with each fiber. RESULTS: Wolf Cobra Vision demonstrated minimal loss of deflections with mean differences of -2°/0° (p > 0.05) when loaded with the 200-µm fiber. The 273-µm fiber provoked utmost deflections that decline when loaded in Olympus URF-P5: mean differences of -52°/-35° (p < 0.001 for upward deflection). Of overall deflections, sheath-coated fiber induced least insult (p > 0.05), while standard 273-µm fiber incited maximum degradation (p < 0.00001). With few exceptions, sheath-coated and ball-tip fibers passed through all maximally deflected scopes. Uncleaved 200- and 273-µm fibers failed to pass through most maximally deflected fURS. However, cleaving their ends allowed 200- and 273-µm fiber to pass through all angles of deflections expect in the Olympus URF-P5 and Olympus URF-P5 and URF-V, respectively. The irrigation through all fURSs was significantly impaired (p < 0.00001). CONCLUSIONS: fURS deflection was least affected by sheath-coated fibers and most affected by the 273-µm fiber. Uncleaved 200- and 273-µm fibers showed least passage capabilities; while removing the ends, the fibers greatly facilitated their passage capabilities as much as the other fibers tested.

Surgical method influences specimen margins and biochemical recurrence during radical prostatectomy for high-risk prostate cancer: a systematic review and meta-analysis.

PURPOSE: To perform a meta-analysis comparing the rates of positive surgical margins (PSM) and biochemical recurrence (BCR) between open radical prostatectomy (ORP) and robot-assisted radical prostatectomy (RARP) in patients with high-risk prostate cancer. METHODS: A systematic review was performed on Pubmed, Embase and Scopus databases in August 2016, according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. References retrieved were evaluated using the Newcastle-Ottawa scale and the Black and Down's tool for quality assessment. RESULTS: Nine retrospective cohorts comparing ORP and RARP were selected and included in the meta-analysis. All studies reported the PSMs. Patients treated with RARP presented less risk of PSMs (risk difference -0.04, p 0.02) than those treated with ORP. Five articles reported hazard ratios for BCR-free survival. Patients treated with RARP had less risk of BCR (HR 0.72, 95% CI 0.58-0.89) than those treated with ORP. Reports for PSM assessment were considered of adequate quality, while the studies retrieved for BCR assessment were considered limited because of the heterogeneity of their results. CONCLUSION: Patients with high-risk prostate cancer treated with RARP have less risk of having PSM and BCR when compared to those treated with ORP. A strong conclusion is precluded due to the observational nature of the studies retrieved for our analysis.

Evaluation of the Spies TM modalities image quality.

INTRODUCTION: The Spies™ system (Karl-Storz®) was introduced into digital ureteroscopy to improve endoscopic vision. To date, there is no data to either indicate which of the Spies modalities is better for improving diagnosis and treatment procedures, nor to compare the modalities in terms of image quality. The aim of this study was to evaluate and compare the image quality of five Spies™ modalities (SM) to the standard white light in an in-vitro model. MATERIALS AND METHODS: Two standardized grids and 3 stones of different composition were recorded in white light and the 5SM (Clara, Chroma, Clara+Chroma), Spectra A and B) using 4 standardized aqueous scenarios. Twelve templates were done in order to simultaneously compare the same objective in the different modalities. Six urologists, five medical students, five urology residents, and five persons not involved with urology evaluated each video on a scale of 1 (very bad) to 5 (very good). RESULTS: Comparing white light to SM, subjects scored better the quality of Clara and Clara+Chroma than white light (p=0.0139 and p<0.05) and scored worse Spectra A and B (p=0.0005 and p=0.0023). When comparing Clara to the other SM, it was ranked equivalent to Clara+Chroma (p=0.67) and obtained a higher rank than Chroma, Spectra A and B (p<0.05, p=0.0001 and p=0.0001). In the multivariate analysis mean scores were higher among urologists. CONCLUSION: In all analyzed scenarios, the subjects ranked Clara and Clara+Chroma as the modalities with better image quality compared to white light.

Gingerol Synergizes the Cytotoxic Effects of Doxorubicin against Liver Cancer Cells and Protects from Its Vascular Toxicity.

Hydroxyphenylalkanes and diarylheptanoids possess potential therapeutic value in different pathophysiological conditions, such as malignancy. In the current study, naturally isolated hydroxyphenylalkane and diarylheptanoid compounds were investigated for potential chemo-modulatory effects in addition to potential vascular protective roles with doxorubicin. Diarylheptanoids showed stronger antioxidant effects, in comparison to hydroxyphenylalkanes, as demonstrated by DPPH assay and amelioration of CCl4-induced disturbed intracellular GSH/GSSG balance. Shogaol and 4'-methoxygingerol showed considerable cytotoxic effects against HCT116, HeLa, HepG2 and MCF7 cells, with IC50 values ranging from 3.1 to 19.4 µM. Gingerol significantly enhanced the cytotoxic profile of doxorubicin against HepG2 and Huh7, cells decreasing its IC50s by 10- and 4-fold, respectively. Cell cycle distribution was studied using DNA cytometry. Doxorubicin alone induced cell accumulation at S-phase and G2/M-phase, while in combination with gingerol it significantly induced cell cycle arrest at the G2/M-phase. Additionally, the vascular protective effect of gingerol against doxorubicin (10 µM) was examined on isolated aortic rings. Co-incubation with 6-gingerol (30 µM) completely blocked the exaggerated vasoconstriction and impaired vascular relaxation induced by doxorubicin. In conclusion, despite its relatively weak antioxidant properties, gingerol protected from DOX-induced vascular damage, apparently not through a ROS scavenging mechanism. Besides, gingerol synergized the cytotoxic effects of DOX against liver cancer cells without influencing the cellular pharmacokinetics.

Variants of Human Mucin Genes in Clear Cell Renal Cell Carcinoma and their Potential Prognostic and Predictive Values.

BACKGROUND: There is no reliable prognostic and predictive biomarkers for clear cell renal cell carcinoma (cc-RCC). METHODS: DNA from 47 cc-RCC tissue samples were sequenced using next generation sequencing and a customized gene panel testing for tumor-driver genes including 19 Mucin genes. RESULTS: Distinctive variants in 12 Mucin genes were present in all samples. These genes are: MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC12, MUC16, MUC17, MUC19, and MUC22. The numbers of distinctive and non-distinctive variants were counted for each sample. The median number of variants was 455. High variant number (HVN) (>455) was associated with shorter overall survival compared to low variant number (≤455) [Median 50 months vs. not reached; P=0.041]. In the 11 patients who received anti-angiogenic tyrosine kinase inhibitors (TKIs), HVN was associated with a trend of shorter progression free survival. CONCLUSION: Alterations in Mucin family genes are common in ccRCC. HVN is associated with worse prognosis and may predict decreased benefit from anti-angiogenic TKIs. KEY WORDS: Mucin; Variants; Renal cell carcinoma; Biomarker; Tyrosine kinase inhibitors.

Snacking behavior is associated with snack quality, overall diet quality, and body weight among US college students.

Snacking behavior may affect snack quality, overall diet quality, and body weight; however, the associations between these variables have not been studied among college students. The objective of this study was to associate snacking behaviors with snack quality, diet quality, and weight status among college students with overweight and obesity. We hypothesized that a higher snacking frequency, accessibility and availability of unhealthy snacks, and lack of knowledge would be associated with lower snack and diet quality, and higher weight. Participants (n = 140) completed a snack behavior questionnaire, three 24-hour dietary recalls to assess diet quality using Healthy Eating Index 2015 (HEI-2015), and snack score using an algorithm based on the US DA Smart Snack guidelines and reported weight and height to calculate body mass index (BMI). Analysis of variance and Pearson correlation was used in the analyses. After adjusting for confounders, snack frequency was not associated with snack score, HEI-2015 score, or BMI, but evening snacks had a significantly lower snack score compared with late afternoon snacks (P = .017). Also, those with more accessibility and availability of unhealthy snacks had a lower snack score (P = .001), lower HEI-2015 score (P = .006), and higher BMI (P = .019). Snacking for pleasure was significantly associated with a lower snack score (P = .037). Snack score was positively correlated with HEI-2015 score but not with BMI. In conclusion, late snacking, unhealthy snack environment, and snacking for pleasure were associated with lower snack and diet quality. These findings could be used in future intervention strategies to improve snacking behaviors and the food environment.

Susceptibility of Diabetic Patients to COVID-19 Infections: Clinico-Hematological and Complications Analysis.

BACKGROUND: Coronavirus disease 2019 has become a global health threat resulting in a catastrophic spread and more than 3.8 million deaths worldwide. It has been suggested that there is a negative influence of diabetes mellites (DM), which is a complex chronic disease, on COVID-19 severe outcomes. Other factors in diabetic patients may also contribute to COVID-19 disease outcomes, such as older age, obesity, hyperglycaemia, hypertension, and other chronic conditions. METHODS: A cohort study was conducted on the demographics, clinical information, and laboratory findings of the hospitalised COVID-19 with DM and non-DM patients were obtained from the medical records in King Faisal Specialist Hospital and Research Centre, Saudi Arabia. RESULTS: Among the study population, 108 patients had DM, and 433 were non-DM patients. Patients with DM were more likely to present symptoms such as fever (50.48%), anorexia (19.51%), dry cough (47.96%), shortness of breath (35.29%), chest pain (16.49%), and other symptoms. There was a significant decrease in the mean of haematological and biochemical parameters, such as haemoglobin, calcium, and alkaline phosphate in people with diabetes compared to non-diabetics and a considerable increase in other parameters, such as glucose, potassium, and cardiac troponin. CONCLUSIONS: According to the findings of this study, patients who have diabetes have a greater risk of developing more severe symptoms associated with COVID-19 disease. This could result in more patients being admitted to the intensive care unit as well as higher mortality rates.

Regulation of Protein-Induced Apoptosis and Autophagy in Human Hepatocytes Treated with Metformin and Paclitaxel In Silico and In Vitro.

Metformin and paclitaxel therapy offer promising outcomes in the treatment of liver cancer. Combining paclitaxel with metformin enhances treatment effectiveness and mitigates the adverse effects associated with paclitaxel alone. This study explored the anticancer properties of metformin and paclitaxel in HepG2 liver cancer cells, MCF-7 breast cancer cells, and HCT116 colon cancer cells. The results demonstrated that the combination of these agents exhibited a lower IC50 in the tested cell lines compared to paclitaxel monotherapy. Notably, treating the HepG2 cell line with this combination led to a reduction in the G0/G1 phase and an increase in the S and G2/M phases, ultimately triggering early apoptosis. To further investigate the interaction between the cellular proteins with paclitaxel and metformin, an in silico study was conducted using proteins chosen from a protein data bank (PDB). Among the proteins studied, AMPK-α, EGFRK, and FKBP12-mTOR exhibited the highest binding free energy, with values of -11.01, -10.59, and -15.63 kcal/mol, respectively, indicating strong inhibitory or enhancing effects on these proteins. When HepG2 cells were exposed to both paclitaxel and metformin, there was an upregulation in the gene expression of AMPK-α, a key regulator of the energy balance in cancer growth, as well as apoptotic markers such as p53 and caspase-3, along with autophagic markers including beclin1 and ATG4A. This combination therapy of metformin and paclitaxel exhibited significant potential as a treatment option for HepG2 liver cancer. In summary, the combination of metformin and paclitaxel not only enhances treatment efficacy but also reduces side effects. It induces cell cycle alterations and apoptosis and modulates key cellular proteins involved in cancer growth, making it a promising therapy for HepG2 liver cancer.

Biweekly cetuximab in combination with capecitabine and oxaliplatin (XELOX) or irinotecan (XELIRI) in the first-line and second-line treatment of patients with RAS wild-type metastatic colorectal cancer.

Background: Oral capecitabine in combination with intravenous oxaliplatin (XELOX) or irinotecan (XELIRI) are acceptable substitutions to fully intravenous regimens. Biweekly (as opposed to weekly) cetuximab is more convenient when combined with biweekly chemotherapy. Here, we report the tolerability and efficacy of biweekly cetuximab in combination with biweekly XELOX or XELIRI in patients with RAS wild-type metastatic colorectal cancer (RAS-WT mCRC). Methods: Clinical data of consecutive patients with mCRC who received biweekly cetuximab (500 mg/m2) in combination with XELOX or XELIRI between January 2009 and May 2019 in the first- or second-line settings was extracted. Dosage of XEL (Capecitabine/XELODA) was 1,000 mg/m2 twice daily for 9 days, plus on day 1 oxaliplatin 85 mg/m2 or irinotecan 180 mg/m2. Treatment dose reduction and delay for ≥7 days was analysed as surrogates for toxicity. Extended RAS testing was performed in the context of this study for patients who received treatment based on limited KRAS-WT genotype. Results: Sixty one patients with RAS-WT mCRC fulfilled the eligibility criteria. XELOX was administered to 26 (42.6%) and XELIRI to 35 (57.4%) of patients. For all patients in the first-line setting, the objective response rate (ORR), median progression free survival (PFS) and median overall survival (OS) were 54%, 8 months and 25 months, respectively. The corresponding outcomes for the subgroup of patients who received first-line XELOX were 68%, 10 months and not reached, respectively. For all patients in the second-line setting, the ORR, PFS and OS were 50%, 7 months and 20 months, respectively. Chemotherapy components dose reduction and delays were observed in 18 (29.5%) and 25 (41%) patients, respectively. The corresponding frequencies for cetuximab were 3 (5%) and 31 (50.8%). Conclusion: Biweekly cetuximab in combination with XELOX or XELIRI is tolerable and effective. The addition of cetuximab to capecitabine and oxaliplatin is associated with favourable outcome.

Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males.

Although ovarian sex steroids could have protective roles against colorectal cancer (CRC) in women, little is currently known about their potential anti-tumorigenic effects in men. Hence, this study measured the therapeutic effects of 17ß-oestradiol (E2) and/or progesterone (P4) against azoxymethane-induced CRC in male mice that were divided into (n = 10 mice/group): negative (NC) and positive (PC) controls, E2 (580 µg/Kg/day; five times/week) and P4 (2.9 mg/Kg/day; five times/week) monotherapies, and concurrent (EP) and sequential (E/P) co-therapy groups. Both hormones were injected intraperitoneally to the designated groups for four consecutive weeks. Similar treatment protocols with E2 (10 nM) and/or P4 (20 nM) were also used in the SW480 and SW620 human male CRC cell lines. The PC group showed abundant colonic tumours alongside increased colonic tissue testosterone levels and androgen (AR) and oestrogen (ERα) receptors, whereas E2 and P4 levels with ERß and progesterone receptor (PGR) decreased significantly compared with the NC group. E2 and P4 monotherapies equally increased ERß/PGR with p21/Cytochrome-C/Caspase-3, reduced testosterone levels, inhibited ERα/AR and CCND1/survivin and promoted apoptosis relative to the PC group. Both co-therapy protocols also revealed better anti-cancer effects with enhanced modulation of colonic sex steroid hormones and their receptors, with E/P the most prominent protocol. In vitro, E/P regimen showed the highest increases in the numbers of SW480 (2.1-fold) and SW620 (3.5-fold) cells in Sub-G1 phase of cell cycle. The E/P co-therapy also disclosed the lowest percentages of viable SW480 cells (2.8-fold), whilst both co-therapy protocols equally showed the greatest SW620 apoptotic cell numbers (5.2-fold) relative to untreated cells. Moreover, both co-therapy regimens revealed maximal inhibitions of cell cycle inducers, cell survival markers, and AR/ERα alongside the highest expression of cell cycle suppressors, pro-apoptotic molecules, and ERß/PGR in both cell lines. In conclusion, CRC was associated with abnormal levels of colonic sex steroid hormones alongside aberrant protein expression of their receptors. While the anti-cancer effects of E2 and P4 monotherapies were equal, their combination protocols showed boosted tumoricidal actions against CRC in males, possibly by promoting ERß and PGR-mediated androgen deprivation together with inhibition of ERα-regulated oncogenic pathways.

Saudi Urological Association consensus guidelines on the use of robotic surgery in urology.

Over the past three decades, minimally invasive robotic technology has evolved substantially in urological practice, replacing many open procedures and becoming part of routine clinical practice. The Health Sector Transformation Program for the Kingdom's Vision 2030 aims to restructure the health sector and optimize its status and prospects as an effective and integrated ecosystem centered on the patient's health. Therefore, this consensus seeks to endorse the clinical practice guidelines for robotic surgery (RS) in the KSA, highlighting its effectiveness, safety, and favorable outcomes compared to open and laparoscopic surgeries in certain procedures when used by trained surgeons in well-structured RS programs.

Chemopreventive effects of vitamin D3 and its analogue, paricalcitol, in combination with 5-fluorouracil against colorectal cancer: The role of calcium signalling molecules.

BACKGROUND: Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium (Ca2+)-mediated anti-tumorigenic actions. Therefore, this study compared between VD and its non-calcaemic analogue, Paricalcitol (Pcal), ± 5-FU in relation to chemoprevention and Ca2+-mediated apoptosis in vivo and in vitro. METHODS: Seventy male mice were distributed to: negative controls, positive controls (PC), VD, Pcal, 5-FU, VD + 5-FU and Pcal+5-FU groups. All groups, except negative, received two consecutive azoxymethane (AOM)-injections (10 mg/Kg/week) for CRC induction. VD3 (1000 IU/kg; three times/week) and Pcal (1.25 µg/kg; three times/week) injections started week-16 post-AOM and for 10 weeks. Three successive 5-FU cycles began at week-21 (50 mg/Kg/week). Similar protocols with VD3, Pcal and/or 5-FU were applied in the HT29 colon cancer cells. RESULTS: The PC group had abundant malignant tumours, markedly elevated proliferation markers (survivin/CCND1) and declines in cyclin-dependent kinase-inhibitor-1A, pro-apoptotic molecules (p53/BAX/cytochrome_C/caspase-3), tissue Ca2+ concentrations and Ca2+-dependent proteins (CaSR/CAM/CAMKIIA). All monotherapies equally reduced tumour numbers and proliferation markers whilst promoting the anti-tumorigenic molecules. VD and/or 5-FU, but not Pcal monotherapy, enhanced Ca2+ levels and Ca2+-related molecules (CaSR/CAM/CAMKIIA/BAX/cytochrome_C) in vivo and in vitro. However, VD + 5-FU co-therapy showed the lowest tumour numbers, the highest cell numbers in sub-G1 phase of cell cycle, alongside the most effective modulations of oncogenes, tumour suppressors and Ca2+-related molecules at the gene and protein levels in vivo and in vitro. CONCLUSIONS: VD3 was superior than Paricalcitol in potentiating 5-FU cytotoxicity, possibly by upregulating several Ca2+-related molecules involved in tumour suppression.

Profiling Activins and Follistatin in Colorectal Cancer According to Clinical Stage, Tumour Sidedness and Smad4 Status.

This study explored the roles of activins and follistatin in colorectal cancers. Paired malignant and normal colonic tissues were collected from archived paraffin-embedded (n = 90 patients) alongside fresh (n = 40 patients) specimen cohorts. Activin ß-subunits, follistatin and Smad4 mRNAs and proteins were measured by real-time PCR and immunohistochemistry (IHC). Mature activin-A, -B, -AB and follistatin proteins were measured by ELISA. Cancer tissues having ≤ the 20th percentile of the Smad4 IHC score were considered as low (L-S4) group. The Smad4-intact SW480 and Smad4-null HT29 colon cancer cell lines were treated with activins and follistatin, and cell cycle was analysed by flow cytometry. The cell cycle inducing (CCND1/CCND3) and inhibitory (p21/p27) proteins alongside the survival (survivin/BCL2) and pro-apoptosis (Casp-8/Casp-3) markers were measured by immunofluorescence. Thirty-nine patients had right-sided cancers (30%) and showed higher rates of L-S4 tumours (n = 17; 13.1%) alongside worse clinicopathological characteristics relative to left-sided cancers. The ßA-subunit and activin-A increased, whilst ßB-subunit and activin-AB decreased, in malignant sites and the late-stage cancers revealed the greatest abnormalities. Interestingly, follistatin declined markedly in early-stage malignant tissues, whilst increased significantly in the advanced stages. All activin molecules were comparable between the early stage right- and left-sided tumours, whereas the late-stage right-sided cancers and L-S4 tumours showed more profound deregulations. In vitro, activin-A increased the numbers of the SW480 cells in sub-G1 and G0/G1-phases, whereas reduced the HT29 cell numbers in the sub-G1 phase with simultaneous increases in the G0/G1 and S phases. The p21/p27/Casp-8/Casp-3 proteins escalated, whilst CCND1/CCND3/BCL2/survivin declined in the SW480 cells following activin-A, whereas activin-A only promoted p21 and p27 alongside reduced CCND3 in the HT29 cells. By contrast, activin-AB increased the numbers of SW480 and HT29 cells in Sub-G1 and G0/G1-phases and promoted the anti-cancer and reduced the oncogenic proteins in both cell lines. In conclusion, activins and follistatin displayed stage-dependent dysregulations and were markedly altered during the advanced stages of right-sided and L-S4 cancers. Moreover, the activin-A actions in CRC could be Smad4-dependent, whereas activin-AB may act as a Smad4-independent tumour suppressor protein.