The platinum coordination complex inhibits cell invasion-migration and epithelial-to-mesenchymal transition by altering the TGF-ß-SMAD pathway in colorectal cancer.

Introduction: There is a steady increase in colorectal cancer (CRC) incidences worldwide; at diagnosis, about 20 percent of cases show metastases. The transforming growth factor-beta (TGF-ß) signaling pathway is one of the critical pathways that influence the expression of cadherins allowing the epithelial-to-mesenchymal transition (EMT), which is involved in the progression of the normal colorectal epithelium to adenoma and metastatic carcinoma. The current study aimed to investigate the impact of a novel coordination complex of platinum (salicylaldiminato) PT(II) complex with dimethyl propylene linkage (PT-complex) on TGF-ß and EMT markers involved in the invasion and migration of the human HT-29 and SW620 CRC cell lines. Methods: Functional study and wound healing assay showed PT-complex significantly reduced cell motility and the migration and invasion of CRC cell lines compared to the untreated control. Western blot performed in the presence and absence of TGF-ß demonstrated that PT-complex significantly regulated the TGF-ß-mediated altered expressions of EMT markers. Results and Discussion: PT-complex attenuated the migration and invasion by upregulating the protein expression of EMT-suppressing factor E-cadherin and suppressing EMT-inducing factors such as N-Cadherin and Vimentin. Moreover, PT-complex significantly suppressed the activation of SMAD3 in both CRC cell lines. Further, the microarray data analysis revealed differential expression of genes related to invasion and migration. In conclusion, besides displaying antiproliferative activity, the PT complex can decrease the metastasis of CRC cell lines by modulating TGF-ß-regulated EMT markers. These findings provide new insight into TGF-ß/SMAD signaling as the molecular mechanism involved in the antitumoral properties of novel PT-complex.

Targeting MUCL1 protein inhibits cell proliferation and EMT by deregulating ß­catenin and increases irinotecan sensitivity in colorectal cancer.

With >1.85 million cases and 850,000 deaths annually, colorectal cancer (CRC) is the third most common cancer detected globally. CRC is an aggressive malignancy with metastasis and, in spite of advances in improved treatment regimen, distant disease failure rates remain disappointingly high. Mucin­like 1 (MUCL1) is a small glycoprotein highly expressed mainly in breast cancer. The involvement of the MUCL1 protein in CRC progression and the underlying mechanism have been largely unknown. The aim of the present study was to investigate the MUCL1 expression profile and its functional significance in CRC. The Cancer Genome Atlas dataset revealed that MUCL1 expression was higher in colorectal tumor compared with normal tissues. MUCL1 was also revealed to be expressed in human CRC cell lines. The results demonstrated that MUCL1 promoted cell proliferation and colony formation, confirming its oncogenic potential. Silencing MUCL1 with short interfering RNA inhibited the protein expression of Bcl2 family proteins, such as Bcl2 and BclxL. Targeting MUCL1 resulted in significant inhibition in cell invasive and migratory behavior of HT­29 and SW620 cells. In addition, the expression of E­cadherin increased whereas the expression of vimentin decreased in MUCL1­silenced cells, confirming inhibition of epithelial­mesenchymal transition (EMT) process. Thus, it was revealed that MUCL1 plays a notable role in cell invasion and migration by inhibiting EMT in CRC. Mechanistically, MUCL1 drives ß­catenin activation by Ser­552 phosphorylation, nuclear accumulation and transcriptional activation. Targeting MUCL1 increases the drug sensitivity of CRC cells towards irinotecan. These findings thus demonstrated that MUCL1 acts as a modifier of other pathways that play an important role in CRC progression and MUCL1 was identified as a potential target for CRC therapeutics.

Expression of VEGF, EGF and HGF in early- and late-stage colorectal cancer.

The heterogenous nature of colorectal cancer (CRC) highlights the need for a better understanding of the growth factors that affect tumour growth and cancer progression. The aim of the present study was to evaluate the role of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in the early (I and II) and late (III and IV) stages of CRC. The serum levels and mRNA expression (n=30) of the aforementioned growth factors were measured and immunohistochemistry (n=20) was performed in patients with CRC. Histological examination revealed comparable distribution of early-stage [I: 8 (26.7%) and II: 7 (23.3%)] and late-stage [III: 8 (26.7%) and IV: 7 (23.3%)] CRC. The mean serum concentrations of VEGF during the early (152.9±14.5 vs. 88.39±3.99 pg/ml; P=0.001) and late (182.7±25.8 vs. 88.39±3.99 pg/ml; P=0.002) stages were significantly higher compared with those in controls. Similarly, the mean serum concentrations of EGF in the early (409.4±7.96 vs. 153.7±13.8 pg/ml; P=0.05) and HGF in the late (90.4±17.4 vs. 56.9±4.97 pg/ml; P=0.05) stages were significantly higher compared with those in controls. The serum concentrations of VEGF, EGF and HGF were comparable between the early and late stages of CRC. Compared to normal tissues, the mRNA expression of both VEGF (P<0.001) and HGF (P<0.01) was upregulated in early-stage and downregulated in late-stage CRC. The expression of EGF remained significantly elevated during both the early and late stages of CRC (P<0.01). Histopathological analyses confirmed increased expression of VEGF in cancerous tissues compared with that in normal tissues. The present study emphasized the need for monitoring the serum levels and tissue expression of growth factors to fully elucidate their role in patients with CRC.

Prevalence of vasovagal syncope following bariatric surgery.

BACKGROUND: Obesity is a major global public health problem. Observational studies have shown an increasing incidence of syncope and pre-syncope following bariatric surgery in obese patients. However, there is paucity of the true incidence of syncope following bariatrics sugary in the literature. METHODS: We have randomly surveyed 200 patients who underwent bariatric surgery between 2016-2018 using Calgary Syncope Score (CSS). RESULTS: Of the 200 patients enrolled, 107 (53.5%) were female with 167 patients (83.5%) between 18 and 50 years of age. The most-reported comorbidities were diabetes mellitus 26 (13%) hypertension 25 (12.5%) and pulmonary disease 18 (9%). The majority 98 (49%) of the patients had pre-operative body mass index (BMI) of 40-50 kg/m 2, and most of them had laparoscopic sleeve gastrectomy (LSG). Sixty-two (31%) patients had vasovagal syncope (VVS), 52 (26%) patients had non-VVS and 86 (43%) had no syncope. CONCLUSION: Vasovagal syncope in patients following bariatric sugary is quite common and affects 15% of bariatric patients in our series in the first year postoperatively. Further randomized controlled trials are required to prove our results.

Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer.

In the current work, a new set of carbohydrazide linked benzofuran-isatin conjugates (5a-e and 7a-i) was designed and synthesised. The anticancer activity for compounds (5b-d, 7a, 7b, 7d and 7g) was measured against NCI-55 human cancer cell lines. Compound 5d was the most efficient, and thus subjected to the five-dose screen where it showed excellent broad activity against almost all tested cancer subpanels. Furthermore, all conjugates (5a-e and 7a-i) showed a good anti-proliferative activity towards colorectal cancer SW-620 and HT-29 cell lines, with an excellent inhibitory effect for compounds 5a and 5d (IC50 = 8.7 and 9.4 µM (5a), and 6.5 and 9.8 µM for (5d), respectively). Both compounds displayed selective cytotoxicity with good safety profile. In addition, both compounds provoked apoptosis in a dose dependent manner in SW-620 cells. Also, they significantly inhibited the anti-apoptotic Bcl2 protein expression and increased the cleaved PARP level that resulted in SW-620 cells apoptosis.

Association of the microbiome with colorectal cancer development (Review).

Colorectal cancer (CRC) is the second most common malignancy causing cancer­related mortality globally. It is the third most common type of cancer detected worldwide. The recent concept of the human body supporting a diverse community of microbes has revealed the important role these microbes play synergistically in maintaining normal homeostasis. The balance between the microbiomes and epithelial cells of the human body is essential for normal physiology. Evidence from meta­genome analysis indicates that an imbalance in the microbiome is prominent in the guts of patients with CRC. Several studies have suggested that the gut microbiota can secrete metabolites [short­chain fatty acids (SCFAs), vitamins, polyphenols and polyamines] that modulate the susceptibility of the colon and rectum by altering inflammation and DNA damage. The state of microbiome imbalance (dysbiosis) has been reported in patients with CRC, with an increasing population of 'bad' microbes and a decrease in 'good' microbes. The 'good' microbes, also known as commensal microbes, produce butyrate; however, 'bad' microbes cause a pro­inflammatory state. The complex association between pathological microbial communities leading to cancer progression is not yet fully understood. An altered microbial metabolite profile plays a direct role in CRC metabolism. Furthermore, diet plays an essential role in the risk of gastrointestinal cancer development. High­fiber diets regulate the gut microbiome and reduce the risk of CRC development, and may be fruitful in the better management of therapeutics. In the present review, the current status of the microbiome in CRC development is discussed.12.

Urolithin A induces cell cycle arrest and apoptosis by inhibiting Bcl-2, increasing p53-p21 proteins and reactive oxygen species production in colorectal cancer cells.

Colorectal cancer (CRC) is the second most common gastrointestinal cancer globally. Prevention of tumor cell proliferation and metastasis is vital for prolonging patient survival. Polyphenols provide a wide range of health benefits and prevention from cancer. In the gut, urolithins are the major metabolites of polyphenols. The objective of our study was to elucidate the molecular mechanism of the anticancer effect of urolithin A (UA) on colorectal cancer cells. UA was found to inhibit the cell proliferation of CRC cell lines in a dose-dependent and time-dependent manner in HT29, SW480, and SW620 cells. Exposure to UA resulted in cell cycle arrest in a dose-dependent manner along with alteration in the expression of cell cycle-related protein. Treatment of CRC cell lines with UA resulted in the induction of apoptosis. Treatment of HT29, SW480, and SW620 with UA resulted in increased expression of the pro-apoptotic proteins, p53 and p21. Similarly, UA treatment inhibited the anti-apoptotic protein expression of Bcl-2. Moreover, exposure of UA induced cytochrome c release and caspase activation. Furthermore, UA was found to generate reactive oxygen species (ROS) production in CRC cells. These findings indicate that UA possesses anticancer potential and may be used therapeutically for the treatment of CRC.

Correction to: A novel coordination complex of platinum (PT) induces cell death in colorectal cancer by altering redox balance and modulating MAPK pathway.

An amendment to this paper has been published and can be accessed via the original article.

Survival and outcomes after laparoscopic versus open curative resection for colon cancer.

BACKGROUND: Many studies have shown that open and laparoscopicsurgery for resection of colonic cancers produce similar short- and long-term results, but no data have been reported from Saudi Arabia. OBJECTIVE: Compare 3-year disease-free and overall survival after laparoscopic versus open curative resection for potentially curable colon cancer. DESIGN: Multicenter retrospective cohort study. SETTING: Tertiary academic hospital. PATIENTS AND METHODS: We analyzed data of patients who underwent curative resection for potentially curable colon cancer using the laparoscopic or open approach at three tertiary care centers during the period 2000-2015. MAIN OUTCOME MEASURES: Overall and disease-free 3-year survival were the primary endpoints. Secondary endpoints included conversion rate, duration of surgery, length of hospital stay, rate of wound infection, resumption of bowel function, number of lymph nodes retrieved, adequacy of resection and rate of recurrence. Risk factors for recurrence, including complete mesocolic excision, were assessed. SAMPLE SIZE: 721. RESULTS: Patient and tumor characteristics were similar in the two groups except for ASA class ( P<.01), weight ( P<.05) and tumor stage ( P<.05). Over a median follow-up of 46 months, the 3-year overall survival was 76.7% for open resection and 90.3% for laparoscopic colon resection ( P<.05). The 3-year disease-free survival was 55.3% for open colon resection and 64.9% for laparoscopic colon resection ( P=.0714). CONCLUSION: Overall and disease-free survival after the laparoscopic approach for curative resection of colon cancer is comparable to the open approach. LIMITATIONS: Retrospective design and the possibility of selection bias. CONFLICT OF INTEREST: None.

The Current Status of Peritoneal Surface Oncology in Saudi Arabia.

Peritoneal carcinomatosis (PC) is a common evolution of abdominal cancers. It may arise from the peritoneum itself (primary) or originate from another type of cancer especially those of gastrointestinal or gynecological origin (secondary). Without aggressive multimodal therapeutic approaches, PC is associated with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been used to treat PC since 1990. In Saudi Arabia, the first CRS and HIPEC were done in 2008. In 2018, Saudi Arabia population is 32 millions of people and the demand for such procedures has grown up. This article gives outlines of the current status of peritoneal surface oncology in Saudi Arabia and the future perspective.

Enterocutaneous fistula in patients with peritoneal malignancy following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Incidence, management and outcomes.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an effective treatment for peritoneal carcinomatosis (PC) from multiple origins, however is associated with increased complications compared to conventional gastrointestinal surgery. The aetiology of enterocutaneous fistulas (ECF) in most cases is a result of various contributing factors and therefore remains a major clinical problem, occurring in 4-34% of patients post-CRS. The aim of this study was to analyze the incidence and outcome of ECF following CRS/HIPEC. METHOD: From April 1999 to September 2015, 53 patients of 918 CRS/HIPEC procedures developed an ECF. Patient, operative and postoperative data were retrospectively analyzed to determine aetiology, classification outcome and possible contributing factors were reviewed on univariate and multivariate analysis. RESULTS: We report a 5.8% ECF rate, diagnosed at a median of 13 days. The mortality rate was 5.7% and other morbidity was significantly increased (p = 0.0001). Twenty-five (47.2%), 8 (15.1%) and 20 patients (37.7%) had low, moderate and high output ECF respectively. Patients that had a CC2 cytoreduction, abdominal VAC or smoked had a higher risk of fistula (p = 0.004, p < 0.0001, p = 0.008). Spontaneous closure was achieved in 49.2% with conservative treatment (median 29 days) and 33.9% underwent surgical intervention. Preoperative serum albumin <35 g/L (p = 0.04), PCI>17 (p = 0.025) and operation >8.6 h s (p = 0.001) were independent risk factors on multivariate analysis. Overall and 5-year survival was significantly reduced (p < 0.0001,p = 0.016). CONCLUSION: CRS/HIPEC remains an effective treatment modality for PC in selected patients with a comparable ECF incidence to reported elective gastrointestinal surgery rates. This study identifies multiple risk factors that should be considered in patients undergoing CRS/HIPEC.

Fatal air embolism during sigmoidoscopy performed under spinal anesthesia.

Air embolism is an uncommon but potentially catastrophic event that occurs when air enters the vasculature. Because of a scared and friable colorectal mucosa, patients with anastomotic stricture are at an increased risk of complications associated with sigmoidoscopy such as bowel perforation and bleeding. This is a report of fatal air embolism confirmed on an immediate postmortem chest radiograph in a patient with a high colorectal anastomotic stricture undergoing sigmoidoscopy under spinal anesthesia is reported. The literature on air embolism in patients undergoing sigmoidoscopy/colonoscopy is reviewed.