Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition.

Excessive genomic instability coupled with abnormalities in DNA repair pathways induces high levels of 'replication stress' when cancer cells propagate. Rather than hampering cancer cell proliferation, novel treatment strategies are turning their attention towards targeting cell cycle checkpoint kinases (such as ATR, CHK1, WEE1, and others) along the DNA damage response and replicative stress response pathways, thereby allowing unrepaired DNA damage to be carried forward towards mitotic catastrophe and apoptosis. The selective ATR kinase inhibitor elimusertib (BAY 1895344) has demonstrated preclinical and clinical monotherapy activity; however, reliable predictive biomarkers of treatment benefit are still lacking. In this study, using gene expression profiling of 24 cell lines from different cancer types and in a panel of ovarian cancer cell lines, we found that nuclear-specific enrichment of checkpoint kinase 1 (CHK1) correlated with increased sensitivity to elimusertib. Using an advanced multispectral imaging system in subsequent cell line-derived xenograft specimens, we showed a trend between nuclear phosphorylated CHK1 (pCHK1) staining and increased sensitivity to the ATR inhibitor elimusertib, indicating the potential value of pCHK1 expression as a predictive biomarker of ATR inhibitor sensitivity. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma.

Large numbers of neutrophils infiltrate tumors and comprise a notable component of the inflammatory tumor microenvironment. While it is established that tumor cells exhibit the Warburg effect for energy production, the contribution of the neutrophil metabolic state to tumorigenesis is unknown. Here, we investigated whether neutrophil infiltration and metabolic status promotes tumor progression in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC). We observed a large increase in the proportion of neutrophils in the blood and tumor upon orthotopic transplantation. Intriguingly, these tumor-infiltrating neutrophils up-regulated glycolytic factors and hypoxia-inducible factor 1-alpha (HIF-1α) expression compared to neutrophils from the bone marrow and blood of the same mouse. This enhanced glycolytic signature was also observed in human PDAC tissue samples. Strikingly, neutrophil-specific deletion of HIF-1α (HIF-1αΔNφ) significantly reduced tumor burden and improved overall survival in orthotopic transplanted mice, by converting the pro-tumorigenic neutrophil phenotype to an anti-tumorigenic phenotype. This outcome was associated with elevated reactive oxygen species production and activated natural killer cells and CD8+ cytotoxic T cells compared to littermate control mice. These data suggest a role for HIF-1α in neutrophil metabolism, which could be exploited as a target for metabolic modulation in cancer.

Data Set for the Reporting of Ovarian, Fallopian Tube and Primary Peritoneal Carcinoma: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

The move toward consistent and comprehensive surgical pathology reports for cancer resection specimens has been a key development in supporting evidence-based patient management and consistent cancer staging. The International Collaboration on Cancer Reporting (ICCR) previously developed a data set for reporting of the ovarian, fallopian tube and primary peritoneal carcinomas which was published in 2015. In this paper, we provide an update on this data set, as a second edition, that reflects changes in the 2020 World Health Organization (WHO) Classification of Female Genital Tumours as well as some other minor modifications. The data set has been developed by a panel of internationally recognized expert pathologists and a clinician and consists of "core" and "noncore" elements to be included in surgical pathology reports, with detailed commentary to guide users, including references. This data set replaces the widely used first edition, and will facilitate consistent and accurate case reporting, data collection for quality assurance and research, and allow for comparison of epidemiological and pathologic parameters between different populations.

A multi-ethnic analysis of immune-related gene expression signatures in patients with ovarian clear cell carcinoma.

Little is known about the immune environment of ovarian clear cell carcinoma (OCCC) and its impact on various ethnic backgrounds. The aim of this OCCC immune-related gene expression signatures (irGES) study was to address the interaction between tumour and immune environment of ethnically-diverse Asian and Caucasian populations and to identify relevant molecular subsets of biological and clinical importance. Our study included 264 women from three different countries (Singapore, Japan, and the UK) and identified four novel immune subtypes (PD1-high, CTLA4-high, antigen-presentation, and pro-angiogenic subtype) with differentially expressed pathways, and gene ontologies using the NanoString nCounter PanCancer Immune Profiling Panel. The PD1-high and CTLA4-high subtypes demonstrated significantly higher PD1, PDL1, and CTLA4 expression, and were associated with poorer clinical outcomes. Mismatch repair (MMR) protein expression, assessed by immunohistochemistry, revealed that about 5% of OCCCs had deficient MMR expression. The prevalence was similar across the three countries and appeared to cluster in the CTLA4-high subtype. Our results suggest that OCCC from women of Asian and Caucasian descent shares significant clinical and molecular similarities. To our knowledge, our study is the first study to include both Asian and Caucasian women with OCCC and helps to shine light on the impact of ethnic differences on the immune microenvironment of OCCC. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma.

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1ß inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.

Decoding transcriptomic intra-tumour heterogeneity to guide personalised medicine in ovarian cancer.

The evaluation of intra-tumour heterogeneity (ITH) from a transcriptomic point of view is limited. Single-cell cancer studies reveal significant genomic and transcriptomic ITH within a tumour and it is no longer adequate to employ single-subtype assignment as this does not acknowledge the ITH that exists. Molecular assessment of subtype heterogeneity (MASH) was developed to comprehensively report on the composition of all transcriptomic subtypes within a tumour lesion. Using MASH on 3431 ovarian cancer samples, correlation and association analyses with survival, metastasis and clinical outcomes were performed to assess the impact of subtype composition as a surrogate for ITH. The association was validated on two independent cohorts. We identified that 30% of ovarian tumours consist of two or more subtypes. When biological features of the subtype constituents were examined, we identified significant impact on clinical outcomes with the presence of poor prognostic subtypes (Mes or Stem-A). Poorer outcomes correlated with having higher degrees of poor prognostic subtype populations within the tumour. Subtype prediction in several independent datasets reflected a similar prognostic trend. In addition, paired analysis of primary and recurrent/metastatic tumours demonstrated Mes and/or Stem-A subtypes predominated in recurrent and metastatic tumours regardless of the original primary subtype. Given the biological and prognostic value in delineating individual subtypes within a tumour, a clinically applicable MASH assay using NanoString® technology was developed as a classification tool to comprehensively describe constituents of molecular subtypes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A multicenter phase II randomized trial of durvalumab (MEDI-4736) versus physician's choice chemotherapy in recurrent ovarian clear cell adenocarcinoma (MOCCA).

BACKGROUND: The optimal treatment of recurrent ovarian clear cell carcinoma remains unknown. There is increasing rationale to support the role of immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in ovarian clear cell carcinoma. PRIMARY OBJECTIVE: To evaluate the efficacy of durvalumab (MEDI-4736) compared with standard chemotherapy in patients with recurrent ovarian clear cell carcinoma. STUDY HYPOTHESIS: Patients with recurrent ovarian clear cell carcinoma treated with durvalumab will have improved progression-free survival compared with those treated with chemotherapy of physician's choice. TRIAL DESIGN: The MOCCA study is a multicenter, open-label, randomized phase II trial in patients with recurrent ovarian clear cell carcinoma, which recruited from eight sites across Gynecologic Cancer Group Singapore (GCGS), Korean Gynecologic-Oncology Group (KGOG), and Australia New Zealand Gynecological Oncology Group (ANZGOG). Enrolled patients were randomized in a 2:1 ratio to receive durvalumab or physician's choice of chemotherapy until disease progression, intolerable toxicity, or withdrawal of patient consent. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients required histologically documented diagnosis of recurrent ovarian clear cell carcinoma, as evidenced by WT1 negativity. All patients must have been of Eastern Cooperative Oncology Group (ECOG) performance status 2 or better, and have had previous treatment with, and progressed or recurred after prior platinum-based chemotherapy. No more than four prior lines of treatment were allowed and prior immune checkpoint inhibitor treatment was not permitted. PRIMARY ENDPOINTS: The primary endpoint was the median progression-free survival following treatment with durvalumab, compared with physician's choice of chemotherapy. Progression-free survival was defined as the time from the first day of treatment to the first observation of disease progression, or death due to any cause, or last follow-up. SAMPLE SIZE: The target sample size was 46 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual has been completed and results are expected to be presented by mid-2021. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03405454.

Multicentre collaborative cohort study of the use of Kirschner wires for the management of supracondylar fractures in children.

PURPOSE: Supracondylar fractures of the humerus cause significant morbidity in children. Nerve damage and loss of fracture reduction are common recognised complications in patients with this injury. Uncertainty surrounds the optimal Kirschner wire configuration and diameter for closed reduction and pinning of these fractures. This study describes current practice and examined the association between wire configuration or diameter and outcomes (clinical and radiological) in the operative management of paediatric supracondylar fractures. METHODS: Children presenting with Gartland II or III supracondylar fractures at five hospitals in south-west England were eligible for inclusion. Collaborators scrutinised paper and electronic case notes. Outcome measures were maintenance of reduction and iatrogenic nerve injury. RESULTS: Altogether 209 patients were eligible for inclusion: 15.7% had a documented neurological deficit at presentation; 3.9% who were neurologically intact at presentation sustained a new deficit caused by treatment and 13.4% experienced a clinically significant loss of reduction following fixation. Maintenance of reduction was significantly better in patients treated specifically with crossed ×3 Kirschner wire configuration compared to all other configurations. The incidence of iatrogenic nerve injury was not significantly different between groups treated with different wire configurations. CONCLUSION: We present a large multicentre cohort study showing that crossed ×3 Kirschner wires are associated with better maintenance of reduction than crossed ×2 or lateral entry wires. Greater numbers would be required to properly investigate nerve injury relating to operative management of supracondylar fractures. We found significant variations in practice and compliance with the British Orthopaedic Association Standard for Trauma (BOAST) 11 guidelines.

Value of a molecular screening program to support clinical trial enrollment in Asian cancer patients: The Integrated Molecular Analysis of Cancer (IMAC) Study.

The value of precision oncology initiatives in Asian contexts remains unresolved. Here, we review the institutional implementation of prospective molecular screening to facilitate accrual of patients into biomarker-driven clinical trials, and to explore the mutational landscape of advanced tumors occurring in a prospective cohort of Asian patients (n = 396) with diverse cancer types. Next-generation sequencing (NGS) and routine clinicopathological assays, such as immunohistochemistry, copy number analysis and in situ hybridization tests, were performed on tumor samples. Actionable biomarker results were used to identify eligibility for early-phase, biomarker-driven clinical trials. Overall, NGS was successful in 365 of 396 patients (92%), achieving a mean depth of 1,943× and coverage uniformity of 96%. The median turnaround time from sample receipt to return of genomic results was 26.0 days (IQR, 19.0-39.0 days). Reportable mutations were found in 300 of 365 patients (82%). Ninety-one percent of patients at study enrollment indicated consent to receive incidental findings and willingness to undergo genetic counseling if required. The most commonly mutated oncogenes included KRAS (19%), PIK3CA (16%), EGFR (5%), BRAF (3%) and KIT (3%); while the most frequently mutated tumor suppressor genes included TP53 (40%), SMARCB1 (12%), APC (8%), PTEN (6%) and SMAD4 (5%). Among 23 patients enrolled in genotype-matched trials, median progression-free survival was 2.9 months (IQR, 1.5-4.0 months). Nine of 20 evaluable patients (45%; 95% CI, 23.1-68.5%) derived clinical benefit, including 3 partial responses and 6 with stable disease lasting ≥ 8 weeks.

Immunoexpression of p16 in uterine leiomyomas with infarct-type necrosis: an analysis of 35 cases.

AIMS: Uterine leiomyosarcomas frequently show p16 immunoexpression. However, p16 may also be expressed in some benign leiomyoma variants such as leiomyomas with bizarre nuclei and cellular leiomyomas, limiting its utility as a biomarker to distinguish between benign and malignant neoplasms. We investigated p16 expression in leiomyomas with infarct-type necrosis, tumours which may sometimes be misinterpreted as smooth muscle tumours of uncertain malignant potential or even leiomyosarcoma on conventional light microscopy. METHODS AND RESULTS: p16 immunostaining was performed on 35 leiomyomas with infarct-type necrosis and the staining pattern was analysed. Staining was classified as absent, scattered/isolated, <33-, 33-66- or >66%-positive cells, and was assessed in the areas immediately surrounding and distant from the infarct. The median age of patients was 44 years. Seventeen had hormonal/non-hormonal drugs and three were pregnant. The median tumour size was 7.25 cm. The mean mitotic count was 0.9/10 high-power fields. Only one tumour had multifocal mild nuclear atypia. Positive p16 was noted in 34 of 35 (97.2%) tumours. It was typically patchy, and was concentrated in areas immediately surrounding the necrosis. Distant from the necrosis, p16 positivity was seen predominantly in scattered/isolated cells. One tumour without any worrisome microscopic features showed diffuse p16 positivity throughout. Median follow-up was 55 months, and none of the patients experienced any recurrence. CONCLUSION: p16 expression in benign uterine smooth muscle tumours with infarct-type necrosis is common. The staining is particularly concentrated adjacent to areas of necrosis. It is important to be aware of this potential pitfall when interpreting p16 expression.

Optogenetic mapping after stroke reveals network-wide scaling of functional connections and heterogeneous recovery of the peri-infarct.

We used arbitrary point channelrhodopsin-2 (ChR2) stimulation and wide-scale voltage sensitive dye (VSD) imaging in mice to map altered cortical connectivity at 1 and 8 weeks after a targeted cortical stroke. Network analysis based on optogenetic stimulation revealed a symmetrical sham network with distinct sensorimotor and association groupings. This symmetry was disrupted after stroke: at 1 week after stroke, we observed a widespread depression of optogenetically evoked activity that extended to the non-injured hemisphere; by 8 weeks, significant recovery was observed. When we considered the network as a whole, scaling the ChR2-evoked VSD responses from the stroke groups to match the sham group mean resulted in a relative distribution of responses that was indistinguishable from the sham group, suggesting network-wide down-scaling and connectional diaschisis after stroke. Closer inspection revealed that connections that had little connectivity with the peri-infarct, such as contralateral visual areas, tended to escape damage, whereas some connections near the peri-infarct were more severely affected. When connections within the peri-infarct were isolated, we did not observe equal down-scaling of responses after stroke. Peri-infarct sites that had weak connection strength in the sham condition tended to have the greatest relative post-stroke recovery. Our findings suggest that, during recovery, most cortical areas undergo homeostatic upscaling, resulting in a relative distribution of responses that is similar to the pre-stroke (sham) network, albeit still depressed. However, recovery within the peri-infarct zone is heterogeneous and these cortical points do not follow the recovery scaling factor expected for the entire network.

Histological features associated with occult lymph node metastasis in FIGO clinical stage I, grade I endometrioid carcinoma.

AIMS: Lymph node involvement affects prognosis/treatment in endometrial carcinoma patients. We assessed various histological features associated with nodal metastasis in patients with grade I, stage I endometrial endometrioid carcinoma (EEC). METHODS AND RESULTS: Eighteen stage I EECs with occult positive lymph nodes and 36 controls were assessed for depth of myoinvasion; microcystic, elongated and fragmented (MELF) pattern of myometrial invasion; lymphovascular invasion (LVI); and epithelial metaplasia. Nodal metastases were subclassified as isolated tumour cells (ITCs; ≤0.2 mm), micrometastasis (>0.2 mm and <2 mm), or macrometastasis (≥2 mm). Node-positive cases had significantly higher rates of LVI (P < 0.001) and MELF invasion (P = 0.003) on univariate analysis. Only LVI was associated significantly with nodal metastasis on multivariate analysis (P = 0.002). Tumours with MELF invasion demonstrated reduced E-cadherin expression. Macrometastases were identified in seven cases (39%) with or without micrometastasis/ITCs. Eight (44%) contained only ITCs. Eleven (61%) had histiocyte-like nodal metastases. Biopsy material from four of six (67%) and five of 17 (29%) cases with and without nodal metastasis showed detached eosinophilic tumour cell buds. Of the former, three were associated with histiocyte-like nodal metastases - a feature absent in biopsies without tumour budding. CONCLUSIONS: Lymph nodes from grade I EEC exhibiting cellular budding or LVI should be examined for occult metastases, especially in the form of histiocyte-like cells.

Esophageal epithelial and mesenchymal cross-talk leads to features of epithelial to mesenchymal transition in vitro.

BACKGROUND: Esophageal fibrosis is a complication of eosinophilic esophagitis (EoE) which has been attributed to both subepithelial fibrosis and to epithelial to mesenchymal transition (EMT), a process by which epithelial cells acquire mesenchymal features. Common to both causes of EoE-fibrosis is the notion that granulocyte-derived TGF-ß, induces myofibroblast differentiation of the target cell. To date, the role of esophageal epithelial cells as effector cells in esophageal fibrosis has never been explored. Herein, we investigated consequences of cross-talk between esophageal epithelial cells and fibroblasts, and identified profibrotic cytokines which influence the development of EMT in vitro. METHODS AND RESULTS: Stimulation of primary fetal esophageal fibroblasts (FEF3) with conditioned media (CEM) from esophageal epithelial cells (EPC2-hTERT), primed FEF3 cells to secrete IL-1ß and TNFα, but not TGFß. To determine whether these cytokines signaled in a paracrine fashion to esophageal epithelial cells, FEF3 cells were stimulated with CEM, followed by transfer of this fibroblast conditioned media (FCM) to EPC2-hTERT cells. Epithelial FCM stimulation increased expression of mesenchymal markers and reduced E-cadherin expression, features of EMT which were TNFα and IL-1ß-dependent. Using organotypic culture models, primary EoE epithelial cells exhibited features of EMT compared to non-EoE cells, corresponding to patterns of EMT in native biopsies. CONCLUSIONS: Esophageal epithelial cell and fibroblast cross-talk contributes to esophageal fibrosis. Our results suggest that features of EMT can develop independent of TGF-ß and granulocytes, which may have important implications in treatment of EoE.

Comprehensive characterization of genomic features and clinical outcomes following targeted therapy and secondary cytoreductive surgery in OCCC: a single center experience.

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) is associated with chemoresistance. Limited data exists regarding the efficacy of targeted therapies such as immune checkpoint inhibitors (ICI) and bevacizumab, and the role of secondary cytoreductive surgery (SCS). METHODS: We retrospectively analyzed genomic features and treatment outcomes of 172 OCCC patients treated at our institution from January 2000 to May 2022. Next-generation sequencing (NGS) was performed where sufficient archival tissue was available. RESULTS: 64.0% of patients were diagnosed at an early stage, and 36.0% at an advanced stage. Patients with advanced/relapsed OCCC who received platinum-based chemotherapy plus bevacizumab followed by maintenance bevacizumab had a median first-line progression-free survival (PFS) of 12.2 months, compared with 9.3 months for chemotherapy alone (hazard ratio=0.69; 95% confidence interval [CI]=0.33, 1.45). In 27 patients who received an ICI, the overall response rate was 18.5% and median duration of response was 7.4 months (95% CI=6.5, 8.3). In 17 carefully selected patients with fewer than 3 sites of relapse, median PFS was 35 months (95% CI=0, 73.5) and median overall survival was 96.8 months (95% CI=44.6, 149.0) after SCS. NGS on 58 tumors revealed common mutations in ARID1A (48.3%), PIK3CA (46.6%), and KRAS (20.7%). Pathogenic alterations in PIK3CA, FGFR2, and NBN were associated with worse survival outcomes. Median tumor mutational burden was 3.78 (range, 0-16). All 26 patients with available loss of heterozygosity (LOH) scores had LOH <16%. CONCLUSION: Our study demonstrates encouraging outcomes with bevacizumab and ICI, and SCS in select relapsed OCCC patients. Prospective trials are warranted.

Endocervical involvement in endometrial adenocarcinoma is not prognostically significant and the pathologic assessment of the pattern of involvement is not reproducible.

OBJECTIVES: Since 1988, cervical gland involvement and stromal invasion defined stage IIA and stage IIB endometrial carcinoma. In 2009, FIGO changed the criteria for stage II disease to include only those with cervical stromal invasion. We wished to: 1) assess the reproducibility of pathologists to distinguish patterns of cervical spread, and 2) determine the prognostic significance of cervical involvement. METHODS: Slides from 46 women with cervical involvement by endometrial adenocarcinoma were scored for 5 patterns of involvement by 6 experienced pathologists to determine reproducibility. To assess prognostic significance, 206 patients with FIGO 1988 stage II adenocarcinoma formed the study population with matched FIGO stage I controls. RESULTS: At least 5 of the 6 pathologists agreed that the cervix was involved in the 46 cases. The reproducibility for cervical gland involvement and endocervical stromal invasion was slight (kappas of 0.15 and 0.28). The survival with any type of cervical involvement was not significantly different from that of matched stage I controls (p=0.18). The 5year recurrence-free survival rates were 84% for FIGO 1988 stage I, 73% for stage IIA, and 82% for stage IIB (FIGO 2009 stage II). CONCLUSIONS: Pathologists reliably recognize cervical involvement by endometrial carcinoma. However, reproducibility for the determination of pattern of cervical spread by experienced pathologists is too low to be of clinical utility. Women with spread of carcinoma to the cervix do not have a significantly lower survival than matched stage I controls. Cervical spread should not be the basis for determination of stage II disease.

Photodynamic activity of plant extracts from Sarawak, Borneo.

Photodynamic therapy (PDT) is a medical treatment that involves the irradiation of an administered photosensitizing drug with light of a particular wavelength to activate the photosensitizer to kill abnormal cells. To date, only a small number of photosensitizers have been clinically approved for PDT, and researchers continue to look for new molecules that have more desirable properties for clinical applications. Natural products have long been important sources of pharmaceuticals, and there is a great potential for discovery of novel chemotypes from under-explored biodiversities in the world. The objective of this study is to mine the terrestrial plants in Sarawak, Borneo Island, for new photosensitizers for PDT. In a screening program from 2004 to 2008, we prepared and studied 2,400 extracts from 888 plants for their photosensitizing activities. This report details the bioprospecting process, preparation and testing of extracts, analysis of the active samples, fractionation of four samples, and isolation and characterization of photosensitizers.

Prevalence, exposure and the public knowledge of keloids on four continents.

INTRODUCTION: Keloid scars are associated with physical and psychological sequelae. No studies have investigated the general public's understanding of keloids. Targeted, short educational interventions in susceptible individuals may aid understanding of the condition and compliance with treatment. We aimed to identify the population with the highest prevalence and lowest knowledge. METHODS: We surveyed four countries to determine the public's understanding of keloids. A quantitative, subjective and cross-sectional street survey was designed using the knowledge, attitudes and practice model principles. The target populations were cities in Ghana, Australia, Canada and England. Surveyors used a hybrid stratified/convenience sampling method. Primary outcomes were prevalence, exposure to keloids as an entity and overall keloid knowledge score compared across demographic groups. Study data have been made fully available for reproducibility and education (https://doi.org/10.17605/OSF.IO/3KZ5E). RESULTS: There were 402 respondents, with a median age of 32 (interquartile range 25-45.25) years, of which 193 were females. The survey was carried out between June 2015 and October 2017. The prevalence of self-identified keloids was 11% in Ghana, 6% in Australia, 2% in Canada and 7% in England. Prevalence, exposure and knowledge were higher in the Ghanaian population. CONCLUSIONS: There was association between knowledge, prevalence and the exposure to keloids as an entity. Findings may suggest targeting public health campaigns towards populations where knowledge is lowest, and exposure to and prevalence of keloids are the highest.

MicroRNA Landscape in Endometrial Carcinomas in an Asian population: Unraveling Subtype-Specific Signatures.

MicroRNAs (MiRNAs) are small, non-coding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression. We analyzed the differential expression of miRNAs in 119 endometrial carcinomas, measuring their expression in histological subtypes, molecular subtypes, and tumors with CTNNB1 mutations. Tumors were subdivided into histological and molecular subtypes as defined by The Cancer Genome Atlas. The expression levels of 352 miRNAs were quantified using the PanoramiR panel. Mir-449a, mir-449b-5p, and mir-449c-5p were the top three miRNAs showing increased expression in both endometrioid and de-differentiated carcinomas but were not significantly increased in serous and clear cell carcinomas. The miRNAs with the most increased expression in serous and clear cell carcinomas were miR-9-3p and miR-375, respectively. We also identified 62 differentially expressed miRNAs among different molecular subtypes. Using sequential forward selection, we built subtype classification models for some molecular subtypes of endometrial carcinoma, comprising 5 miRNAs for MMR-deficient tumors, 10 miRNAs for p53-mutated tumors, and 3 miRNAs for CTNNB1-mutated tumors, with areas under curves of 0.75, 0.85, and 0.78, respectively. Our findings confirm the differential expression of miRNAs between various endometrial carcinoma subtypes and may have implications for the development of diagnostic and prognostic tools.

A decoy mutant ACE2 designed to reduce COVID-19.

The need for new coronavirus disease 2019 (COVID-19) therapeutic strategies continues, especially as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants emerge. Zhang and colleagues elegantly engineered a mutant angiotensin-converting enzyme 2 (ACE2) that competitively binds SARS-CoV-2 spike protein, reduces viral uptake by human lung cells, and ameliorates SARS-CoV-2-induced lung injury in mice expressing human ACE2.

Bioreactor design and validation for manufacturing strategies in tissue engineering.

The fields of regenerative medicine and tissue engineering offer new therapeutic options to restore, maintain or improve tissue function following disease or injury. To maximize the biological function of a tissue-engineered clinical product, specific conditions must be maintained within a bioreactor to allow the maturation of the product in preparation for implantation. Specifically, the bioreactor should be designed to mimic the mechanical, electrochemical and biochemical environment that the product will be exposed to in vivo. Real-time monitoring of the functional capacity of tissue-engineered products during manufacturing is a critical component of the quality management process. The present review provides a brief overview of bioreactor engineering considerations. In addition, strategies for bioreactor automation, in-line product monitoring and quality assurance are discussed.