Human papillomavirus prevalence and dynamics: Insights from a 5-year population-based study in Jeddah, Kingdom of Saudi Arabia.

OBJECTIVES: To estimate the prevalence and dynamics of human papillomavirus (HPV) infection, over a 5-year period, among Saudi women. METHODS: A 2-phase, population-based study combining cross-sectional and cohort designs was carried out with 5360 ever-married women aged 30-65 from Jeddah, Saudi Arabia, between 2013 and 2018. Participants were enrolled in a designated screening program and screened using the hybrid capture 2 HPV test. Women testing positive for HPV were followed up after one year to estimate the HPV clearance rate, while those testing negative had a follow-up after 5 years to assess new HPV infections. Factors associated with HPV positivity and clearance, including sociodemographic and clinical aspects, were analyzed. RESULTS: Participant's mean age was 44.3 and the average marriage duration was 22.6 years. The initial HPV prevalence was 4.7%. After one year, the HPV clearance rate among initially positive women was 84.3%. The rate of new HPV infections among initially negative women after 5 years was 0.2%, resulting in a cumulative HPV prevalence of 5% over the study period. The incidence rate was estimated at 47 per 100,000 person-years. Parity was the only independent factor inversely associated with HPV positivity, with an odds ratio of 0.93 (95% confidence interval: 0.8 - 0.99). CONCLUSION: The prevalence of HPV in Saudi women was relatively low, suggesting a low transmission rate of HPV. This finding indicates the need for continuous monitoring and tailored prevention strategies.

Overall and progression-free survival in endometrial carcinoma: A single-center retrospective study of patients treated between 2000-2018.

BACKGROUND: Investigating survival in endometrial cancer (EC) is crucial to determine the effectiveness of overall management as it will reflect on the level of care provided among this population. OBJECTIVE: The study was conducted to analyze the overall survival (OS) and progression-free survival (PFS) in treated endometrial carcinoma and to determine the associated predictors. DESIGN: Retrospective SETTING: Department of obstetrics and gynecology in university tertiary hospital PATIENTS AND METHODS: Baseline demographic and clinical data, tumor characteristics and perioperative and outcome data were collected from consecutive patients treated for EC between 2000 and 2018. Kaplan-Meier method and multivariate Cox regression were used to analyze factors and predictors of OS and PFS. MAIN OUTCOME MEASURES: OS, PFS and prognostic factors SAMPLE SIZE: 200 RESULT: Endometrioid type was the most common type accounting for 78.5% of the cases, followed by papillary serous carcinoma (18.5%). At diagnosis, 21.5% were stage III, and 12.0% were stage IV. Invasiveness features showed involvement of the myometrium (96.5%), lymph vessels (36.5%), cervix stroma (18.5%), lower segment (22.0%), and parametrium (7.0%). The majority of patients had open surgery (80.0%), while 11.5% and 7.0% had laparoscopy and robotic surgery, respectively. Staging and debulking were performed in 89.0% of patients, and 12.5% of patients had residual disease of more than 2 cm. The mean OS and PFS were 104.4 (95% CI=91.8-117.0) months and 96.8 (95% CI=83.9-109.7) months, respectively. The 5-year OS and PFS were 62.5% and 46.9%, respectively. The majority of the factors we assessed were significantly associated with OS or PFS. However, reduced OS was independently associated age ≥60 years (hazard ratio [HR]=1.99, P=.010), papillary serous carcinoma (HR=2.35, P=.021), and residual disease (HR=3.84, P=.007); whereas PFS was predicted by age ≥60 years (HR=1.87, P=.014) and residual disease (HR=3.22, P=.040). CONCLUSION: There is a need for a national strategy to tackle the growing burden of EC, by identifying the locally-specific incidence, delayed diagnosis and survival outcome. LIMITATIONS: This was a single-center study conducted at a tertiary center, which may question the generalizability of the findings, as the sample may be biased by overrepresentation with patients who were diagnosed at an advanced stage.

Corrigendum: Human Wharton's Jelly stem cell (hWJSC) extracts inhibit ovarian cancer cell lines OVCAR3 and SKOV3 in vitro by inducing cell cycle arrest and apoptosis.

[This corrects the article DOI: 10.3389/fonc.2018.00592.].

Clinical and pathological patterns of non-epithelial malignant ovarian tumours in Western Saudi Arabia.

Objective: To report a single-center experience in non-epithelial malignant ovarian tumours (NEMOT), by presenting different clinical and pathological characteristics, management and outcomes. Methods: We retrospectively reviewed electronic files of all female patients who underwent surgery for NEMOT at the Gynecology Department of King Abdulaziz University Hospital, Jeddah, Saudi Arabia, from July 2003 to July 2019. We collected baseline demographic, anthropomorphic and clinical data; pathological characteristics; management and follow-up data; and outcomes including residual disease, recurrence and last follow-up status (deceased or alive). Results: Thirty-three women were included; mean (standard deviation) age = 33.24 (17.72) years, range = 4, 86 years. Granulosa cell tumor was the most frequent subtype diagnosed in 17 (51.5%) patients, followed by germ cell tumours 13 (39.4%). The majority of patients were diagnosed at FIGO Stage I (22, 66.7%) and with tumor Grade 1 (23, 69.7%), while 8 (24.2%) were diagnosed with Grade 3 tumors. Granulosa cell and Sertoli-Leydig cell tumours were diagnosed at an older age (mean age = 39.30 vs. 23.92 years) compared to germ cell tumours, respectively (P = 0.012). Two-third of the patients benefited from conservative surgery including oophorectomy + staging, and 16 (48.5%) benefited from chemotherapy with bleomycin, etoposide and platinum being the most common protocol (13, 39.4%) for germ cell tumours. Postoperatively, only 2 (6.1%) patients had residual disease. Recurrence and mortality were reported in one and four patients, respectively, resulting in recurrence rate = 3.0% (95% confidence interval [CI] = 0.01%, 15.8%) and mortality rate = 12.1% (95% CI = 3.4%, 28.2%). Conclusions: The present series of NEMOT was predominated by sex cord-stromal cell tumors, which were diagnosed in patients with older age, while germ cell tumours were underrepresented. Although survival rates were comparable to those reported internationally, more consideration should be given to following up patients regarding fertility outcomes to provide a more comprehensive evaluation of treatment success and quality of care.

The Diagnosis of Cervical Dysplasia in a University Hospital Using Pap Smear and Colposcopy in the Western Region of Saudi Arabia: A Correlational Study.

Objectives To assess the diagnostic performance of Pap smear screening with or without human papillomavirus (HPV) testing and colposcopy in detecting preinvasive lesions of the cervix among women with reference to histopathological findings. Materials and methods We performed a retrospective study in a tertiary care center of the clinical and pathological records of women with evocative symptomatology. The diagnostic performance of Pap smear screening and colposcopy was analyzed. The sensitivity and specificity of Pap smear screening and colposcopy in detecting preinvasive lesions of the cervix were calculated in 388 patients. Results The mean age was 45.12 years, and the most frequent gynecological symptoms included abnormal bleeding (17.2%) and postcoital bleeding (10.9%). Histopathology showed abnormal results in 26.5% of the 388 patients, including cervical intraepithelial neoplasia 1 (CIN 1; 20.4%), CIN 2 (2.8%), CIN 3 (1.3%), and SCC (1.3%). Both Pap smear screening and colposcopy were highly sensitive in detecting CIN 1+ (94.2%vs.93.2%, respectively) and CIN 2+ (100.0% vs.95.8%, respectively) intraepithelial lesions; however, Pap smears had very low specificity in detecting both CIN 1+ (8.1% vs.73.7%, respectively) and CIN 2+ (8.0% vs. 59.3%, respectively) compared with colposcopy. When combined with HPV status, the specificity of Pap smear increased considerably. Conclusion It has become a high priority to improve the efficiency of cervical cancer (CC) screening programs by optimizing the practice of Pap smear screening, increasing the test specificity, and implementing systematic cytology-HPV co-testing.

Survival and prognostic factors in women treated for epithelial ovarian cancer in western region of Saudi Arabia.

OBJECTIVES: To assess survival and prognostic factors among women with epithelial ovarian cancer in Western Saudi Arabia. METHODS: A retrospective cohort study was carried out between October 2000 and May 2018, reviewing clinical and pathology data of all women who underwent staging or debulking surgery for epithelial ovarian cancer. Analysis of disease-free survival (DFS), overall survivals (OS) and the associated factors used Kaplan-Meier method in addition to cox multivariate regression. RESULTS: A total of 144 patients were included (median age=49.5 years), with a median follow-up time was 3.4 years. Majority (59.7%) of the patients were diagnosed at an advanced stage (III or IV). The mean (95% CI) DFS was 82.3 (67.8-96.8) months, OS was 96.2 (81.3-111.2) months, and the 5-year survival rate was estimated as 38.9%. Univariate analysis showed that older age, clear cell or papillary carcinoma subtypes, serous type, advanced International Federation of Gynecology and Obstetrics (FIGO) stage and the presence of residual disease were associated with poorer DFS and OS (log rank <0.05). Cox regression showed FIGO stage and residual disease >1cm as the strongest prognostic factors independently associated with DFS and OS. CONCLUSION: Improving early diagnosis and achieving optimal cytoreduction are the most critical challenges to achieve significant positive impact on survival of women with epithelial ovarian cancer.

Prognostic value of E-Cadherin and its tumor suppressor role in Saudi women with advanced epithelial ovarian cancer.

The extracellular matrix (ECM) disruption and cytoskeleton reorganization are crucial events in tumor proliferation and invasion. E-Cadherin (E-CAD) is a member of cell adhesion molecules involved in cell-cell junctions and ECM stability. The loss of E-CAD expression is associated with cancer progression and metastasis. This retrospective study aimed to assess E-CAD protein expression in ovarian cancer (OC) tissues and to evaluate its prognostic value. PATIENTS AND METHODS: 143 formalin-fixed and paraffin-embedded (FFPE) blocks of primary advanced stages OC were retrieved and used to construct Tissue microarrays. Automated immunohistochemistry technique was performed to evaluate E-CAD protein expression patterns in OC. RESULTS: E-CAD protein expression was significantly correlated with OC histological subtype (p < 0.0001), while borderline significant correlations were observed with both tumor grade (p = 0.06) and stage (p = 0.07). Interestingly, Kaplan-Meier survival analysis showed that OC patients with membranous E-CAD expression survived longer than those with no E-CAD expression mainly those at advanced stages (p < 0.009). Further in silico analysis confirms the key roles of E-CAD in OC molecular functions. CONCLUSION: we reported a prognosis value of membranous E-CAD in advanced stage OC patients. Further validation using larger cohorts is recommended to extract clinically relevant outcomes towards better OC management and individualized oncology.

Assessment of clinical variables as predictive markers in the development and progression of colorectal cancer.

Colorectal cancer (CRC) is graded as one of the most common cancer. It accounts for the second leading cause of cancer deaths worldwide. The present study intends to investigate the role and importance of different biochemical variables in the development of colorectal cancer.In this cross-sectional study we recruited ninety-one patients diagnosed with colorectal cancer and fifty-three age-sex matched controls from June 2017 to June 2018. Different variables i.e. SOD, GSH, CAT, MDA, TGF, VEGF, TNF, ILs, MMPs, etc., were estimated with the help of their respective methods. Our findings suggest a significant increase in the levels of different inflammatory and stress-related markers. The NFκB, TGF-ß, VEGFß, 8OHdG, IsoP-2α were significantly found to be increased in patients with colon cancer (0.945 ± 0.067 µg/ml, 18.59 ± 1.53 pg/ml, 99.35 ± 4.29 pg/ml, 21.26 ± 1.29 pg/ml, 102.25 ± 4.25 pg/ml) as compared to controls (0.124 ± 0.024 µg/ml, 8.26 ± 0.88 pg/ml, 49.58 ± 2.62 pg/ml, 0.93 ± 0.29 pg/ml, 19.65 ± 3.19 pg/ml). Notably, the levels of different antioxidants were shown to be significantly lower in patients of colon cancer. The present study concluded that excessive oxidative stress and lipid peroxidation result in a decrease in the antioxidative capacity of cells which may influence diverse signaling cascades including NF-KB, which results in DNA modification and gene transcription that ultimately involved in the progression of colon cancer.

MDR1 Gene Polymorphisms and Its Association With Expression as a Clinical Relevance in Terms of Response to Chemotherapy and Prognosis in Ovarian Cancer.

In spite of the significant advancements in the treatment modalities, 30% of advanced stage ovarian cancer (OC) patients do not respond to the standard chemotherapeutic regimen and most of the responders finally relapse over time due to the escalation of multidrug resistance (MDR) Phenomenon. Our present study evaluated chemotherapeutic sensitivity response among 47 ovarian tumor patients of which we found 37 (78.8%) sensitive and remaining 10 (21.2%) resistant. Among the resistant, seven tumor samples were found to be platinum resistant or refractory to platinum (CB/TX), one to carboplatin, and two to 5FU. Notably, all these resistant cases were observed in the disease recurrence group of patients identified at stage III or IV. The stage III resistant cases revealed heterozygous mutation (C/T) in exon 12 (C1236T) and 26 (C3435T) and increased level of mRNA, whereas homozygous mutation (T/T) was found at stage IV tumor patients. The genotypic difference was found to be significant (p = 0.03) for exon 12, and p = 0.003 for exon 26 mutant genotypes. No significant association between genotypes of different exons with tumor stages and tumor grade was observed (p > 0.05). However, a significant association was observed between the genotype of exon-12 and histopathology of tumor tissue (p = 0.028). Statistically, the chemotherapy response was found to be significantly associated with the tumor stage (p = 0.019). We also observed a significant difference in PFS (P = 0.019) and OS (P = 0.047) between tumor grades 1 and 3. Notably, the highest mRNA expression was observed in resistant tumor sample T-32, where interestingly we found homozygosity TT in all of the exons 12, 21, and 26. Thus, we suggest that exons 12 (C1236T) and exon 26 (C3435T) polymorphism may play a role in inducing drug resistance by altering the expression level of the MDR1 gene. To summarize, we suggest that the expression of MDR1 in OC is influenced by tumor stage and genotype variants as well as by chemotherapeutic drugs. Thus our findings suggest that inter individual variability in platinum based therapy may be anticipated by MDR1 genotypes. Further studies on a large number of samples shall eventually lead to provide beneficial information for the individualized chemotherapy.

Indicators of survival and prognostic factors in women treated for cervical cancer at a tertiary care center in Saudi Arabia.

BACKGROUND: Investigating survival in cervical cancer at the local level is crucial to determine the effectiveness of overall management, as it reflects the level of care provided and awareness among the population about screening and early diagnosis. OBJECTIVES: Analyze overall survival (OS) and disease-free survival (DFS) among patients treated for cervical cancer and to investigate clinical, management- and outcome-related independent factors associated with survival. DESIGN: A retrospective medical record review. SETTING: Gynecology oncology unit in a tertiary care center. PATIENTS AND METHODS: All women with cervical cancer who were treated and followed up between January 1999 and December 2017. Baseline demographic and clinical data, tumor characteristics, treatment options and outcomes including recurrence were collected and analyzed as factors and predictors of survival. MAIN OUTCOME MEASURES: OS and DFS among patients treated for cervical cancer. SAMPLE SIZE: 190 patients. RESULTS: The 190 patients had a mean (SD) age of 54.2 (13.1) years (median 52.0, interquartile range, 46-62), and median (IQR) follow-up time was 37.0 (12.0-69.0) months. Tumor characteristics showed FIGO stage (I [19.0%], II [48.9%], III [18.4%], IV [13.6%]), grade (I [15.8%], II [46.8%], III [35.8%]) and the most frequent histological type was squamous cell carcinoma (77.4%). Patients received initial radiotherapy with concurrent chemotherapy (53.2%), initial radical hysterectomy (24.7%), systemic chemotherapy (6.3%) and palliative care (4.7%). Mean OS and DFS were 97.1 (82.2, 111.9) and 85.2 (70.4, 100.0) months, respectively. Recurrence and mortality rates were 25.8% and 46.8%, occurring after a median (IQR) time=13.0 (6.0-28.0) and 20.0 (9.0-45.0) months, respectively. Survival was independently associated with grade II (hazard ratio [HR]=3.6, 95%CI: 1.3-9.7, P=.012), grade III (HR=4.5, 95%CI:1.6-12.6, P=.004), number of regional organs involved (1-3 organs: HR=7.8, 95%CI: 1.2, 49.1, P=.030), and recurrence (HR=2.23, P=.001). CONCLUSION: Survival was about 8 years in our institution, which is predicted by the tumor grade, regional organs involved and recurrence. Remarkably, this study found a high percentage of patients diagnosed at an advanced stage, which probably impacts survival and stresses the need for improving early detection. LIMITATIONS: Retrospective design, resulting in recall bias and missing data. CONFLICT OF INTEREST: None.

Appropriate Management of Subcutaneous Tissue of Midline Abdominal Incisions.

Objectives To identify the optimal method for subcutaneous tissue management following midline abdominal incisions among patients with high thickness of subcutaneous fat (TSF). Methods A single-center prospective controlled trial among women undergoing elective gynecologic surgery by midline incision with TSF ≥ 3 cm. Incision was managed by suture approximation of Camper's fascia (group 1), closed suction drainage (group 2), or no intervention (control). Groups were compared for the incidence of four-week postop wound complications including surgical site infection (SSI), superficial wound dehiscence (SWD), and seroma; and baseline and perioperative factors were analyzed using multivariate regression. Results Among 145 patients included (43.4% suture, 29.7% drain, 26.9% control), the overall incidence of wound complications was 15.2% (SSI 8.3%, SWD 0.7%, seroma 6.2%). The incidence of SSI was higher with suture (14.3%) versus drain (4.7%) and control (2.6%), while seroma was more frequent in drain (11.6%) versus suture (3.2%) and control (5.1%); however, both results were not statistically significant. Wound complication was independently associated with hemoglobin level (OR = 0.58, p = 0.019) and the occurrence of intraoperative complications (OR = 8.67, p = 0.048). Conclusion There is no statistical evidence about the optimal method of wound closure in the study population. Specific risk profiles can be constructed with an emphasis on preoperative anemia and intraoperative complications.

Molecular docking analysis of HER-2 inhibitor from the ZINC database as anticancer agents.

The human epidermal growth factor (HER2) is a transmembrane receptor that is highly expressed in breast cancer and in different other cancers. Therefore, it is of interest to identify the new HER2 inhibitors from a selected 300 compounds in the ZINC database. The top two hit compounds (ZINC000014780728 (-11.0 kcal/mol) and ZINC000014762512 (-10.8 kcal/mol)) showed a high affinity with HER2 relative to the reference compound (lapatinib (-10.2 kcal/mol)) for further consideration.

Physician's knowledge and opinions on human papillomavirus vaccination: a cross-sectional study, Saudi Arabia.

BACKGROUND: In a transition period of prevention strategy against HPV infection and cervical cancer in Saudi Arabia, it becomes necessary to appraise physicians' preparedness to undertake the inherent actions and responsibilities, by evaluating their knowledge and opinions regarding HPV infection and vaccine. METHODS: A cross-sectional study carried out between Jan 2017 and Nov 2018, included 2000 physicians working in 21 public centers from the five regions of Saudi Arabia. A self-administered questionnaire was used to assess physicians' perception about HPV infection prevalence (1 item), knowledge about HPV infection and vaccine (9 items), and opinions and attitudes toward vaccine (4 items). A knowledge score (range 0-9) was calculated and adequate knowledge was assumed for a score ≥ median. Factors associated with opinions and attitudes were explored and multivariate regression was used to analyze independent factors of inadequate knowledge (score < median). RESULTS: Majority of the participants replied correctly to all knowledge questions, and 63.0% perceived HPV infection as a frequently encountered infection. Median knowledge score was 8 and 62.0% had adequate knowledge (score ≥ 8). Inadequate knowledge was independently associated with Saudi nationality (OR = 1.51, p = 0.003), practice level (resident: OR = 3.53, p < 0.001; junior OR = 1.67, p = 0.002), and non Ob-Gyne specialty (OR = 5.40, p < 0.001); in addition to disparities across region and age. Among the participants, 7.6% were immunized and 41.2% accepted to receive the vaccine, while majority were favorable to have their children vaccinated (77.6%) and to include HPV vaccine in the local immunization program (69.6%). Self-perceived underexposure to HPV infection (58.5%), lack of knowledge about the vaccine (21.1%) and being sexually inactive (14.7%) were the most frequently reported reasons for refusing the vaccine. Overall negative attitude regarding vaccine was typically associated with male, older, Saudi, senior consultant in other than Ob/Gyn specialty. Inadequate knowledge level as well as lowly perceived prevalence of HPV infection were associated with less favorable attitude to vaccination. CONCLUSIONS: More specific educational interventions are warranted to trigger physicians' active engagement in the fight against HPV infection and cervical cancer. Such interventions should demystify the HPV vaccine by exposing its efficacy, availability and safety, along with providing practical information about the vaccination procedure and goals to achieve successful prevention strategy.

Cervical Cancer Staging in Saudi Arabia Clinicoradiological Correlation.

OBJECTIVE: The aim of this study was to compare the finding of pelvic MRI with clinical staging using cystoscopy and sigmoidoscopy for cervical cancer patients. METHOD: We reviewed all patients with cervical cancer between January 2001 and December 2015. We correlate the clinical examination, cystoscopy, and sigmoidoscopy with MRI findings. RESULT: A total of 152 patients were enrolled. 114 (74.9%) were with locally advanced cervix cancer. The true positives for MRI in the detection of parametrium were in 94 patients, with sensitivity, specificity, positive, PPV, and NPV of 72%, 82%, 96%, and 33%, respectively. The false negative of the MRI to detect the bladder invasion was 2. Nineteen patients reported having bladder invasion on MRI not confirmed by cystoscopy. None of the patients who had a negative rectal invasion by MRI were found to have rectal involvement by sigmoidoscopy with a specificity of 91%. CONCLUSION: The combined MRI and clinical staging for parametrial evaluation should still be carried out for the staging of cervical cancer. However, in the absence of the bladder and the rectal invasion in the MRI, it will be safe to avoid the need for a cystoscopy and/or sigmoidoscopy for complete staging in the majority of patients with cervical cancer.

Growing teratoma syndrome with porta hepatis involvement - a case report.

Growing teratoma syndrome is a rare entity of tumors, it arises seldomly from ovarian and testicular carcinoma. It presents with disseminating masses of mature teratoma during or following chemotherapy of malignant germ cell tumors. We are reporting a 19-year old presented with recurrent left ovarian mass and supra renal large mass close to the porta hepatis was seen on magnetic resonance imaging. This patient was treated 3 years ago for stage I immature teratoma with left ovarian cystectomy and chemotherapy. Surgical excision of the left ovary and the abdominal mass required meticulous dissection, and the mass was shaved off the porta hepatis with no intraoperative or postoperative complications. Pathology showed mature teratoma. She has no recurrent 5 years after treatment. To the best of our knowledge, this is the first case report describing close relation of growing teratoma syndrome to the porta hepatis, no such case report like this has been reported in our region.

Cytokines secreted by human Wharton's jelly stem cells inhibit the proliferation of ovarian cancer (OVCAR3) cells in vitro.

Cytokines enhance tumour cell recognition via cytotoxic effector cells and are therefore effectively used in cancer immunotherapy. Mesenchymal stem cells have efficient homing potential and have been used to target and inhibit various types of cancer mediated by the release of soluble/bioactive factors. Initial evaluation of the human Wharton's jelly stem cell conditioned medium (hWJSC-CM) and cell lysate (hWJSC-CL) against an ovarian cancer cell line (OVCAR3) demonstrated their inhibitory effect in vitro. The secreted cytokine profile was then studied to understand whether the OVCAR3 inhibitory effect was mediated by the cytokines. Expression of cytokines in OVCAR3 following 48 h treatment with hWJSC extracts, namely the hWJSC-CM (50%) and hWJSC-CL (10 µg/ml), was evaluated using multiplex cytokine assay. Paclitaxel (5 nM) was used as a positive control. Cytokines tumour necrosis factor α, interleukin (IL)-4, IL-6, IL-8, IL-10, IL-13, IL-17, IL-1ß and granulocyte colony-stimulating factor, reported to be involved in tumour growth, invasion and migration, were significantly decreased. Cytokines with antitumour effects, namely IL-1 receptor antagonist (IL-1RA), IL-2, IL-2 receptor, IL-5, IL-7, IL-12, IL-15, interferon (IFN)-α and IFN-γ, were mildly increased or decreased. Only the increases in IL-1RA (with paclitaxel, hWJSC-CM and hWJSC-CL) and granulocyte-macrophage colony-stimulating factor (with hWJSC-CL) were statistically significant. The chemokines monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP)-1α, MIP-1ß and Regulated Upon Activation, Normally T-Expressed, and Secreted were significantly decreased while monokine induced by IFN-γ, IFN-γ induced protein 10 and Eotaxin demonstrated mild decreases. The growth factors basic fibroblast growth factor, vascular endothelial growth factor and hepatocyte growth factor were significantly decreased. Heatmaps demonstrated differential fold changes in cytokines and hierarchical cluster analysis revealed 3 major and 7 minor sub-clusters of associated cytokines, chemokines and growth factors. In conclusion, the hWJSC extracts decreased the expression of oncogenic cytokines, chemokines and growth factors, which mediated the inhibition of OVCAR3 cells in vitro.

Human Wharton's Jelly Stem Cell (hWJSC) Extracts Inhibit Ovarian Cancer Cell Lines OVCAR3 and SKOV3 in vitro by Inducing Cell Cycle Arrest and Apoptosis.

Ovarian cancer is a highly lethal and the second highest in mortality among gynecological cancers. Stem cells either naïve or engineered are reported to inhibit various human cancers in both in-vitro and in-vivo. Herein we report the cancer inhibitory properties of human Wharton's jelly stem cell (hWJSC) extracts, namely its conditioned medium (hWJSC-CM) and cell lysate (hWJSC-CL) against two ovarian cancer cell lines (OVCAR3 and SKOV3) in-vitro. Cell metabolic activity assay of OVCAR3 and SKOV3 cells treated with hWJSC-CM (12.5, 25, 50, 75, 100%) and hWJSC-CL (5, 10, 15, 30, and 50 µg/ml) demonstrated concentration dependent inhibition at 24-72 h. Morphological analysis of OVCAR3 and SKOV3 cells treated with hWJSC-CM (50, 75, 100%) and hWJSC-CL (15, 30, and 50 µg/ml) for 24-72 h showed cell shrinkage, membrane damage/blebbings and cell death. Cell cycle assay demonstrated an increase in the sub-G1 and G2M phases of cell cycle following treatment with hWJSC-CM (50, 75, 100%) and hWJSC-CL (10, 15, and 30 µg/ml) at 48 h. Both OVCAR3 and SKOV3 cells demonstrated mild positive expression of activated caspase 3 following treatment with hWJSC-CM (50%) and hWJSC-CL (15 µg/ml) for 24 h. Cell migration of OVCAR3 and SKOV3 cells were inhibited following treatment with hWJSC-CM (50%) and hWJSC-CL (15 µg/ml) for 48 h. Tumor spheres (TS) of OVCAR3 and SKOV3 treated with hWJSC-CM (50, 75, 100%) and hWJSC-CL (10, 15, 30 µg/ml) for 48 h showed altered surface changes including vacuolations and reduction in size of TS. TS of OVCAR3 and SKOV3 also showed the presence of few ovarian cancer stem cells (CSCs) in minimal numbers following treatment with hWJSC-CM (50%) or hWJSC-CL (15 µg/ml) for 48 h. Real-time gene expression analysis of OVCAR3 and SKOV3 treated with hWJSC-CM (50%) or hWJSC-CL (15 µg/ml) for 48 h demonstrated decreased expression of cell cycle regulatory genes (cyclin A2, Cyclin E1), prostaglandin receptor signaling genes (EP2, EP4) and the pro-inflmmatory genes (IL-6, TNF-α) compared to untreated controls. The results indicate that hWJSC-CM and hWJSC-CL inhibit ovarian cancer cells at mild to moderate levels by inducing cellular changes, cell cycle arrest, apoptosis, decreasing the expression of CSC markers and related genes regulation. Therefore, the stem cell factors in hWJSCs extracts can be useful in cancer management.

Evaluation of in vitro chondrocytic differentiation: A stem cell research initiative at the King Abdulaziz University, Kingdom of Saudi Arabia.

Mesenchymal stem cells (MSCs) from various sources have been used in cartilage differentiation with variable success. Therefore, it is of interest to evaluate the in vitro differentiation potential of the hWJSCs derived from the human umbilical cords into chondrocytes at the stem cell research facility at the King Abdulaziz University. hWJSCs are an attractive choice for tissue engineering and regenerative medical applications including cartilage regeneration. We evaluated the hWJSCs using classical histological and cartilage related gene expression studies. Some of the known parameters were re-examined for consistency at the current laboratory conditions. Early passages (P1-P4) showed short fibroblastic morphology and high expression of MSC related surface markers namely CD29 (99.9%), CD44 (97.8%), CD73 (99.6%), CD90 (95.1%) and CD105 (98.9%). MTT assay showed time dependent increase in hWJSCs proliferation by 61.06% and 206.31% at 48h and 72h respectively. Toluidine blue histology showed that hWJSCs were successfully differentiated into chondrocytes in chondrocytic differentiation medium for 21 days. Differentiated hWJSCs also showed significantly increased expression of collagen type II, aggrecan and SOX9 compared to the undifferentiated control. It should be noted that the determination of the average cell yield, the population doubling time and histological staining wtih alcian blue and/or safronin O is required in future studies for improved evaluation of differentiation. Painless derivation, abundance of stem cells that are hypo-immunogenic and safety issues makes this method advantages to MSCs derived from other sources.

Translational Shift of HSP90 as a Novel Therapeutic Target from Cancer to Neurodegenerative Disorders: An Emerging Trend in the Cure of Alzheimer's and Parkinson's Diseases.

BACKGROUND: Despite having extensive research, the apparent pathogenic mechanism of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDs) have not yet fully understood. The Heat Shock Protein 90 (HSP90), a ubiquitous molecular chaperone, found to have an important role in averting protein misfolding and aggregation through inhibition of apoptotic activity in neuro-inflammatory diseases. Various researchers have confirmed its role in maintaining aberrant neuronal protein's functional stability to a great capacity. It is also involved in regulating the activity of the heat shock factor-1 (HSF-1), a vital regulator of the heat shock response mechanism that cells employ to protect themselves against stress conditions. This quality makes the HSP90 an ideal candidate for novel inhibitory target for therapeutic modality in NDs. METHODS: An extensive literature search was conducted for relevant studies on PubMed, ScienceDirect, Springer- Link etc. The articles were carefully read in their entirety to determine whether they contained information on the topic of interest. Additionally, the reference sections of these articles were searched manually to get more relevant and eligible studies. RESULTS: We have taken an attempt to reveal how HSP90 play important roles with key neuronal proteins involved in supporting the AD and PD pathology. We have further on structure-function relationship of HSP90 to understand its efficacy as a new target in AD and PD by utilizing new generation of HSP90 inhibitors such as geldanamycin and its derivatives, 17-AAG, 17-DMAG, IPI-504, radicicol and its derivatives. HSP90 inhibition leads to suppress atypical neuronal activity by assisting in improving protein aggregation and its related toxicity. Further, the formation of neuronal aggregates is also influenced by HSP90 inhibitors and provides protection from toxicity of protein through HSF-1 activation and HSP70 induction in AD. CONCLUSION: HSP90 inhibition has emerged as a potential target in treating diverse array of diseases especially NDs. In spite of a large amount of research in this direction, the clear cut molecular mechanisms of HSPs associated with neuroprotection are still poorly elucidated and hence more focus is needed toward HSPs and its inhibitory mechanism. The development of HSP90 inhibitors that induce heat-shock response without cytotoxicity for treatment of NDs are still in its early stage. A panel of novel designed research and clinical trial studies are greatly needed to establish the therapeutic reliability and efficacy of HSPs in order to provide best cure for NDs.

Primary ovarian cancer cell inhibition by human Wharton's Jelly stem cells (hWJSCs): Mapping probable mechanisms and targets using systems oncology.

Ovarian cancer is one of the most lethal gynaecological cancers. Its subtle onset and absence of symptoms in early stages are associated with poor prognosis and high mortality. Identification of early biomarkers would aid in ovarian cancer control. Mesenchmal stem cells (MSCs) and/or their secretory products are identified to have cancer inhibitory properties. Therefore, it is of interest to study the anticancer properties of human Wharton's jelly stem cells conditioned medium (hWJSCs-CM) on primary ovarian carcinoma cells in vitro. Primary cultures of epithelial ovarian carcinoma cells (EOCs) and hWJSCs were used in this study. EOCs were exposed to hWJSC-CM (100%) for 24h-72h and changes in mophology and cell proliferation were monitored. Treatment with hWJSC-CM showed altered morphological changes that resulted in death of EOCs. Colorimetric assay [MTT, (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide)] showed mean decreases in EOC proliferation by 16.21%, 23.89% and 40.08% at 24h, 48h and 72h respectively compared to control. Ingenuity Pathway Analysis (IPA, Igenuity Systems, USA) deduced important molecular pathways and signaling networks associated with cancer cell death and these correlated with significant expression of tumour suppresors and apoptotic genes in hWJSCs. Secretory products of hWJSC-CM induced cell death of EOCs via apoptosis. IPA identification of canonical genes/pathways involved in EOCs that overlap with hWJSCs tumour suppressors and apoptosis genes further support this hypotheis. Additional in vitro and in vivo studies are necessary to validate EOCs inhibition with hWJSC-extracts towards their mechanism of action.