Organoids Increase the Predictive Value of in vitro Cancer Chemoprevention Studies for in vivo Outcome

Epidemiological and preclinical data suggest that antioxidants are protective against prostate cancer whose pathogenesis has been linked to oxidative stress. However, the selenium and vitamin E Cancer Prevention Trial (SELECT), found no efficacy for selenium in reducing prostate cancer incidence while vitamin E was associated with an increased risk of the disease. These results have called in to question the models used in preclinical chemoprevention efficacy studies and their ability to predict in vivo outcomes. Chemoprevention agents have traditionally been tested on two dimensional monolayer cultures of cell lines derived from advanced prostate cancers. But as SELECT demonstrates, results from advanced disease models were not predictive of the outcome of a primary chemoprevention trial. Additionally, lack of cell-matrix interactions in two dimensional cultures results in loss of biochemical and mechanical cues relevant for native tissue architecture. We use recent findings in three dimensional organoid cultures that recapitulated the SELECT trial results to argue that the organoid model could increase the predictive value of in vitro studies for in vivo outcomes

The prevalence of ectopic pregnancy in Jos, North Central Nigeria: a reproductive health challenge

Background: Ectopic pregnancy is a life threatening gynecological emergency with a rising incidence of maternal morbidity especially in resource poor settings. Most cases present in the emergency unit when ruptured.Objective: The objective of this study was to determine the prevalence, identifiable risk factors, clinical presentation and management outcome of ectopic pregnancy.Method: This was a retrospective review of cases of ectopic pregnancies seen and managed in the gynecological unit of Plateau State Specialist Hospital (PSSH) Jos from 1st September 2012 to 31st August, 2017. The medical records of the patients managed for ectopic pregnancy as well as the delivery register from the labor room, theater register and gynecological admissions during the study period were retrieved. The data were collected with the aid of data entry form designed for this purpose. The relevant data collected were analyzed using epi info 16 version and presented in tables.Results: During the period, a total number of 13,596 deliveries were recorded while there were 2067 gynecological admissions. One hundred and seventy two (172) patients had ectopic pregnancies accounting for 1.27% of all deliveries and 8.3% of gynecological admissions. The mean age of the patients was 29±5years. The peak age group was 20-25 years (32.0%); 92(53.5%) had secondary school as their highest level of education; 135(78.5%) were married and 49(28.4%) were multigravida. All the patients; 172(100%) presented with a history of abdominal pain while 8(4.7%) presented in shock. A total of 161(93.6%) were diagnosed based on history and clinical examination findings; 152(88.4%) had trans-abdominal scan and 12(7.0%) had abdominal paracentesis (though frowned at in modern day practice). The commonest identifiable risk factors for ectopic pregnancies were pelvic inflammatory disease(PID) in 111(64.5%) of patients followed by previous history of abortions in 17(9.9%) of patients. A total number of 169(98.3%) of the patients had total salpingectomy for ruptured ectopic pregnancies via open abdominal surgeries with 87(50.6%) done on the right fallopian tubes. Three (1.7%) of the patients had oophorectomy. Eighty one(47.1%) of the patients had blood transfusion with no case fatality.Conclusion: Ectopic pregnancy still remains a major health challenge among women of reproductive age group in Nigeria. Efforts should therefore be directed at prompt and timely management to reduce maternal morbidity and mortality in developing countries, availability and accessibility of contraceptive methods, accessibility to healthcare centers and affordable healthcare, proper treatment of PID, use of better technologies in management of cases and human capacity development.Keywords: Prevalence, reproductive age group, ectopic pregnancy, resource poor settings, life threatening, emergenc

The Conundrum of Low COVID-19 Mortality Burden in sub-Saharan Africa: Myth or Reality?

The burden of coronavirus disease (COVID-19) in sub-Saharan Africa (SSA) has been substantially lower compared to other regions of the world. Extensive morbidity and mortality were not observed among countries in SSA during the first wave of the COVID-19 pandemic. To explain this phenomenon, several hypotheses have been formulated, including the low median age of the population in most SSA countries, lack of long-term care facilities, cross-protection from other local coronaviruses, insufficient testing and reporting resulting in an undercounting of COVID-related deaths, genetic risk factors, or the benefit of early lockdowns that were extensive in many SSA countries. Early lockdowns in SSA have been some of the strictest and resulted in devastating economic and social consequences and increased mortality from other health-related problems including maternal deaths. We review the literature and rationale supporting the various hypotheses that have been put forward to account for relatively low hospitalization and death rates for COVID-19 in SSA. We conclude that the strongest evidence would support the demographic age structure with a very low median age as the primary factor in leading to the low mortality seen in the first wave of the pandemic. The impact of new variants of concern in SSA raises the risk of more severe waves. Nevertheless, furthering the understanding of the underlying explanations for the low morbidity and mortality seen across SSA countries may allow the adoption of unique strategies for limiting the spread of COVID-19 without the need for stringent lockdowns

Investigation of livestock for presence of Trypanosoma brucei gambiense in Tafa Local Government Area of Niger State, Nigeria

The study investigated the presence of Trypanosoma brucei gambiense in livestock to ascertain their reservoir role and also screened for other pathogenic trypanosomes of animals in Tafa Local Government Area of Niger state, Nigeria. A total of 460 livestock comprising (cattle, sheep, goats, and dogs) selected at random were bled, examined using the buffy coat and Giemsa stained thin film and packed cell volume estimated. Questionnaire was filled for each animal on demography, awareness and management practices. An overall prevalence of 2.17% with Trypanosoma brucei, T. congolense, T. vivax and a mixed infection of T. brucei and T. congolense observed microscopically awaiting characterization. Interviews revealed high awareness (82.8%) of tsetse and trypanosomiasis described as bush disease and abortion in four cows. The PCV values were within the normal range, however, a significant decrease (P<0.05) was observed in sheep aged 7months to 4years in two communities. Therefore, the study indicated the presence of T. brucei and other trypanosomes suggesting that animal trypanosomiasis is still a problem to animal health and wellbeing in the study area. The study recommends effective integrated chemotherapy and vector control including livestock rearing under intensive management system to boost livestock production and productivity

Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity

<p>Abstract</p> <p>Background</p> <p>The serine/threonine kinase PIM1 has been implicated as an oncogene in various human cancers including lymphomas, gastric, colorectal and prostate carcinomas. In mouse models, Pim1 is known to cooperate with c-Myc to promote tumorigenicity. However, there has been limited analysis of the tumorigenic potential of Pim1 overexpression in benign and malignant human prostate cancer cells <it>in vivo</it>.</p> <p>Methods</p> <p>We overexpressed Pim1 in three human prostate cell lines representing different disease stages including benign (RWPE1), androgen-dependent cancer (LNCaP) and androgen-independent cancer (DU145). We then analyzed <it>in vitro </it>and <it>in vivo </it>tumorigenicity as well as the effect of Pim1 overexpression on c-MYC transcriptional activity by reporter assays and gene expression profiling using an inducible MYC-ER system. To validate that Pim1 induces tumorigenicity and target gene expression by modulating c-MYC transcriptional activity, we inhibited c-MYC using a small molecule inhibitor (10058-F4) or RNA interference.</p> <p>Results</p> <p>Overexpression of Pim1 alone was not sufficient to convert the benign RWPE1 cell to malignancy although it enhanced their proliferation rates when grown as xenografts <it>in vivo</it>. However, Pim1 expression enhanced the <it>in vitro </it>and <it>in vivo </it>tumorigenic potentials of the human prostate cancer cell lines LNCaP and DU145. Reporter assays revealed increased c-MYC transcriptional activity in Pim1-expressing cells and mRNA expression profiling demonstrated that a large fraction of c-MYC target genes were also regulated by Pim1 expression. The c-MYC inhibitor 10058-F4 suppressed the tumorigenicity of Pim1-expressing prostate cancer cells. Interestingly, 10058-F4 treatment also led to a reduction of Pim1 protein but not mRNA. Knocking-down c-MYC using short hairpin RNA reversed the effects of Pim1 on Pim1/MYC target genes.</p> <p>Conclusion</p> <p>Our results suggest an <it>in vivo </it>role of Pim1 in promoting prostate tumorigenesis although it displayed distinct oncogenic activities depending on the disease stage of the cell line. Pim1 promotes tumorigenicity at least in part by enhancing c-MYC transcriptional activity. We also made the novel discovery that treatment of cells with the c-MYC inhibitor 10058-F4 leads to a reduction in Pim1 protein levels.</p

A Role for Polyploidy in the Tumorigenicity of Pim-1-Expressing Human Prostate and Mammary Epithelial Cells

Polyploidy is a prominent feature of many human cancers, and it has long been hypothesized that polyploidy may contribute to tumorigenesis by promoting genomic instability. In this study, we investigated whether polyploidy per se induced by a relevant oncogene can promote genomic instability and tumorigenicity in human epithelial cells.When the oncogenic serine-threonine kinase Pim-1 is overexpressed in immortalized, non-tumorigenic human prostate and mammary epithelial cells, these cells gradually converted to polyploidy and became tumorigenic. To assess the contribution of polyploidy to tumorigenicity, we obtained sorted, matched populations of diploid and polyploid cells expressing equivalent levels of the Pim-1 protein. Spectral karyotyping revealed evidence of emerging numerical and structural chromosomal abnormalities in polyploid cells, supporting the proposition that polyploidy promotes chromosomal instability. Polyploid cells displayed an intact p53/p21 pathway, indicating that the viability of polyploid cells in this system is not dependent on the inactivation of the p53 signaling pathway. Remarkably, only the sorted polyploid cells were tumorigenic in vitro and in vivo.Our results support the notion that polyploidy can promote chromosomal instability and the initiation of tumorigenesis in human epithelial cells

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700