Novel Hybrid Analogs of Estrone Origin Exhibits Cytotoxic Effects against EGFR-dependent Cancers

Cancer is second only to cardiovascular illnesses as the deadliest human disease globally. Currently, non-small cell lung cancer (NSCLC) and triple negative breast carcinoma (TNBC) are the most frequent types of cancer and have the highest mortalities. Epidermal growth factor receptor (EGFR), a central regulator of tumor progression, is frequently overexpressed in both cancers and is a key clinical target for therapeutic intervention. Natural products and their synthetic analogs have been utilized as EGFR tyrosine kinase inhibitors (TKIs) with potent antitumor effects. However, acquired resistance limits the long-term efficacy of these drugs. Estrone has been used as a scaffold in some studies where pharmacophores with antitumor properties were introduced to generate lead candidates with improved efficacy and safety. In our research group, estrone is employed as a starting material to synthesize novel hybrid analogs. Many of our estrone analogs, especially those bearing cucurbitacin pharmacophores have been documented to exhibit potent cytotoxic effects against distinct cancers. However, these hybrid analogs have never been explored as potential agents targeting EGFR-dependent cancers. Here, we describe the cytotoxic effects of novel estrone analogs: a hybrid of estrone base-scaffold and modified cucurbitacin (MMA series) or triazole (Fz series) pharmacophores as potent agents against EGFR-dependent cancers, viz. NSCLC (NCIH226) and TNBC (MDA-MB- 231, MDA-MB-468) tumor models. Molecular docking studies were carried out with OpenEye software. The MTT cell viability and trypan blue stain assays were used to perform cytotoxicity studies. Morphological changes and cell cycle arrest were carried out by microscopy and flow cytometric techniques, respectively. Annexin V assay was utilized to evaluate initial apoptosis induction in all cells and In-cell western assay was used to detect protein expression levels associated with mitochondrial apoptosis, cell cycle, EGFR and its downstream AKT and ERK1/2 pathways. Molecular docking studies revealed that most estrone analogs exhibited improved potency and binding compared to the positive controls, erlotinib and sorafenib when docked against the EGFR kinase-domain (pdb codes: 2ITW, 1M17). Subsequently, several estrone analogs exhibited significant cytotoxic effects against the different cancer cell lines in vitro. Notably, MMA307 and MM320 recorded lower IC50 molarities of 2.88 ± 0.21 and 9.68 ± 0.24 μM compared to the positive control, sorafenib, IC50 value of 20.62 ± 1.32 μM in NCIH226 cells. Similarly, administration of MMA307 and MMA321 to MDA-MB-468 cells yielded potent IC50 concentrations of 0.85 ± 0.00 and 0.56 μM ± 0.01 μM, respectively, when compared to sorafenib, IC50 value of 10.09 ± 0.68 μM. Furthermore, Fz25 recorded IC50 dose of 8.13 ± 0.15 μM in MDA-MB-231 cell lines when compared to sorafenib, 12.21 ± 0.96 μM. Treatment with the MMA307 and MMA320 resulted in downregulation of Dyrk1B (dual-specificity tyrosine phosphorylation-regulated kinase B), cyclin D1 and concomitant upregulation of phospho-cyclin D1 and p21waf1/cip1 contributing to cell cycle arrest in the G1 phase. Also, downregulation of EGFR and phospho-EGFR levels as well as suppression of activated MAP kinase signaling proteins-phospho-B-Raf, phospho-MEK1/2 and phospho-ERK1/2 were observed after NCIH226 cells were exposed to estrone analogs. Similarly, MMA307 and MMA321 downregulated cyclin D1 expression levels resulting in G1 phase cell cycle arrest in MDA-MB-468 cells. Also, these compounds halted the MAPK and AKT signaling pathways due to their ability to downregulate EGFR and activated EGFR expressions. Moreover, mitochondrial apoptosis was induced in the TNBC model, MDA-MB-468, upon MMA307 and MMA321 exposures. In a different study, treatment of MDA-MB-231 cells with Fz25 induced mitochondrial apoptosis and contributed to the G1 phase of cell cycle arrest due to decreased expressions of cyclin D1 and Dyrk1B. Interestingly, this compound impacted the MAPK and AKT signaling pathways due to its ability to decrease EGFR and activated EGFR expressions. To conclude, the present study is the first to report on the cytotoxic potential of novel estrone analogs and provide evidence that MMA307, MMA320, MMA321 and Fz25 are promising novel lead compounds. Further investigations are needed to develop these potent compounds as the next generation anti-EGFR therapies for treating serious EGFR dependent lung and breast cancers

Quantifying the spatio-temporal patterns of settlement growth in a metropolitan region of Ghana

This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10708-016-9719-xRetrospective understanding of the magnitude and pace of urban expansion is necessary for effective growth management in metropolitan regions. The objective of this paper is to quantify the spatial– temporal patterns of urban expansion in the Greater Kumasi Sub-Region (GKSR)—a functional region comprising eight administrative districts in Ghana, West Africa. The analysis is based on Landsat remote sensing images from 1986, 2001 and 2014 which were classified using supervised maximum likelihood algorithm in ERDAS IMAGINE. We computed three complementary growth indexes namely; Average Annual Urban Expansion Rate, Urban Expansion Intensity Index (UEII) and Urban Expansion Differentiation Index to estimate the amount and intensity of expansion over the 28-year period. Overall, urban expansion in the GKSR has been occurring at an average annual rate of 5.6 %. Consequently, the sub-region’s built-up land increased by 313 km^2 from 88 km^2 in 1986 to 400 km^2 in 2014. The analysis further show that about 72 % of the total built-up land increase occurred in the last 13 years alone, with UEII value of 0.605 indicating a moderate intensity of urban expansion. Moreover, the metropolitan-core of the sub-region, being the focal point of urban development and the historical origins of expansion, accounted for more than half of the total built-up land increase over the 28-year period. Over the last decade and half however, urban expansion has spilled into the neighbouring peripheral districts, with the highest intensity and fastest rate of expansion occurring in districts located north and north east of the sub-regional core. We recommend a comprehensive regional growth management strategy grounded in effective strategic partnerships among the respective administrative districts to curb unsustainable urban expansion

Anti-proliferative effect of Ficus pumila Linn. on human leukemic cell lines

Background: Cancer is one of the many diseases of global concern due to its high mortality rate with drug resistance becoming a major challenge to chemotherapy and this have propelled many cancer patients to seek alternative and complementary methods of treatment. The objective for this study was, therefore, to determine the antiproliferative activity as well as phytochemical, total phenolic content (TPC), and antioxidant activity of the stem and leaf extracts (FPS and FPL) of Ficus pumila (L.) using standard methods.Methods: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to evaluate anti-proliferative effect and spectrophotometric-based assays for antioxidant and TPC. Phytochemical constituents were accessed by standard methods.Results: The hydroethanolic extracts of the leaves and stems were rich in tannins, general glycosides, saponins, terpenoids, alkaloids, flavonoids (leaves only), and sterols (stem only). Strong total antioxidant activities were observed with FPL and FPS with EC50 values of 0.07 mg/ml and 0.089 mg/ml, respectively. All the crude extracts showed anti-proliferative effect towards the three human leukemic cell lines used (Jurkat, CEM, and HL-60). However, FPL gave the strongest inhibition concentration at 50% values of 130.97 µg/ml (Jurkat) and 56.31 µg/ml (HL-60).Conclusion: These findings suggest that crude extracts of FPS and FPL have anti-proliferative effect on the leukemia cells. The antioxidant properties of the plant including phenolics may be partly responsible for the anti-proliferative activity. Further studies are required to isolate chemical components of the plant and establish their anti-proliferative activities and mechanism of action

Prevalence, knowledge, and lifestyle-associated risk factors of dyslipidemia among Ghanaian type-2 diabetes mellitus patients in rural and urban areas: A multicenter cross-sectional study

Background and Aims: Dyslipidemia in diabetes mellitus has been linked to unhealthy lifestyle and bad eating habits. However, this association has not been well studied among rural and urban Ghanaian populations. In this study, we determined the prevalence, knowledge, and lifestyle-associated risk factors of dyslipidemia among Ghanaian type-2 diabetes mellitus (T2DM) patients in rural and urban areas. Methods: This comparative multicentre-cross-sectional study recruited 228 T2DM outpatients attending the St. Michael Hospital, Pramso (rural) and Kumasi South Regional Hospital (urban), Ghana for routine check-ups. Self-structured questionnaire was used to collect sociodemographic, knowledge, and lifestyle characteristics. Fasting blood samples were taken to measure lipid profiles. Dyslipidemia was defined per the American Diabetes Association criteria. All p \u3c 0.05 were considered statistically significant. Results: The overall prevalence of dyslipidemia was 79/228 (34.7%). Dyslipidemia was more prevalent among urban participants 43 (18.9%) than rural participants 36 (15.8%). Twenty-seven (11.7%) had adequate knowledge about the risk factors, complications, and management of diabetes. Eating supper after 7 p.m. [adjusted odds ratio = 3.77, 95% confidence interval (1.70–8.37), p = 0.001] significantly increased one\u27s risk of having dyslipidemia by 3.8-fold compared to eating supper earlier (before 5 p.m.). Conclusion: Dyslipidemia is increasing among T2DM patients in both urban and rural areas and it\u27s independently influenced by eating supper after 7 p.m. Most participants were ignorant of the risk factors, complications, and management of diabetes. Adjusting eating habits and increasing diabetes awareness programs to sensitize the general public can mitigate the increasing prevalence of dyslipidemia in both urban and rural areas

Towards sustainable urban development: the social acceptability of high-rise buildings in a Ghanaian city

Over the years, many city managers, policy makers and academics alike have turned to high-rise buildings as pathway to sustainable urban development. However, the sustainability of such types of development in various geographical contexts, especially in sub-Saharan Africa, is a subject less explored. Amidst the promotion of high-rise development in a rapidly urbanizing metropolis in Ghana, Kumasi, the research empirically examined the social acceptability of high-rise residential facilities and the institutional capacity for their effective management. By conducting face-to-face interviews with sampled households, and critical public service providers in the metropolis, the study uncovered that, contrary to the evidence from many Asian cities, there is generally low social acceptability of high-rise developments, and a weak institutional capacity for effective service delivery. The research concludes that, whilst it is tempting to embrace high-rise buildings as sustainable development pathway, it is crucial they are pursued with much circumspection. In addition to their design being tailored to the local needs of the people for whom they are built, the promotion of high-rise development should recognize the importance of effective service delivery, and general social acceptability

Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans.

BACKGROUND: The COVID-19 pandemic has disrupted routine hospital services globally. This study estimated the total number of adult elective operations that would be cancelled worldwide during the 12 weeks of peak disruption due to COVID-19. METHODS: A global expert response study was conducted to elicit projections for the proportion of elective surgery that would be cancelled or postponed during the 12 weeks of peak disruption. A Bayesian β-regression model was used to estimate 12-week cancellation rates for 190 countries. Elective surgical case-mix data, stratified by specialty and indication (surgery for cancer versus benign disease), were determined. This case mix was applied to country-level surgical volumes. The 12-week cancellation rates were then applied to these figures to calculate the total number of cancelled operations. RESULTS: The best estimate was that 28 404 603 operations would be cancelled or postponed during the peak 12 weeks of disruption due to COVID-19 (2 367 050 operations per week). Most would be operations for benign disease (90·2 per cent, 25 638 922 of 28 404 603). The overall 12-week cancellation rate would be 72·3 per cent. Globally, 81·7 per cent of operations for benign conditions (25 638 922 of 31 378 062), 37·7 per cent of cancer operations (2 324 070 of 6 162 311) and 25·4 per cent of elective caesarean sections (441 611 of 1 735 483) would be cancelled or postponed. If countries increased their normal surgical volume by 20 per cent after the pandemic, it would take a median of 45 weeks to clear the backlog of operations resulting from COVID-19 disruption. CONCLUSION: A very large number of operations will be cancelled or postponed owing to disruption caused by COVID-19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.  We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent.  We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines.  Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website