Depletion of mitochondrial protease OMA1 alters proliferative properties and promotes metastatic growth of breast cancer cells

Metastatic competence of cancer cells is influenced by many factors including metabolic alterations and changes in mitochondrial biogenesis and protein homeostasis. While it is generally accepted that mitochondria play important roles in tumorigenesis, the respective molecular events that regulate aberrant cancer cell proliferation remain to be clarified. Therefore, understanding the mechanisms underlying the role of mitochondria in cancer progression has potential implications in the development of new therapeutic strategies. We show that low expression of mitochondrial quality control protease OMA1 correlates with poor overall survival in breast cancer patients. Silencing OMA1 in vitro in patientderived metastatic breast cancer cells isolated from the metastatic pleural effusion and atypical ductal hyperplasia mammary tumor specimens (21MT-1 and 21PT) enhances the formation of filopodia, increases cell proliferation (Ki67 expression), and induces epithelial-mesenchymal transition (EMT). Mechanistically, loss of OMA1 results in alterations in the mitochondrial protein homeostasis, as reflected by enhanced expression of canonic mitochondrial unfolded protein response genes. These changes significantly increase migratory properties in metastatic breast cancer cells, indicating that OMA1 plays a critical role in suppressing metastatic competence of breast tumors. Interestingly, these results were not observed in OMA1-depleted non-tumorigenic MCF10A mammary epithelial cells. This newly identified reduced activity/levels of OMA1 provides insights into the mechanisms leading to breast cancer development, promoting malignant progression of cancer cells and unfavorable clinical outcomes, which may represent possible prognostic markers and therapeutic targets for breast cancer treatment

How do engineers do that?—An interactive introduction to the engineering design process for secondary age school pupils

It is widely accepted that the United Kingdom (UK) needs more engineers and professionals with skills in science, technology, engineering and maths (STEM) to benefit the economy and keep up with technological change and innovation. However, the true nature of engineering and STEM careers is often misunderstood, with secondary school pupils unable to identify where engineering benefits their everyday lives. This suggests that the societal impacts of engineering are not well-defined within secondary education, causing a lack of diversity in pupils pursuing STEM careers. The authors have developed an activity that demonstrates the true problem-solving nature of engineering, and the numerous ways in which these skills can be applied to everyday life. While most practical ‘design, build and test’ (DBT) exercises aim to foster student engagement with STEM, this activity also emphasises how the engineering design process is a crucial tool for reaching an optimum solution. Pupils work in teams generating ideas and learning from failure, gaining a greater appreciation of how engineers work and the truly exciting nature of engineering. They achieve this by using the engineering design process to help them complete a DBT activity involving building a bridge from limited materials and testing how much weight it can hold. To ensure all pupils have the same opportunities for engagement, the method of delivery, activity design, key learning outcomes, discussion points, and activity relevance have been carefully considered for pupils across a range of age groups, backgrounds, and subject interests. This makes the designed activity ideal for integration into various subject lessons in secondary school classrooms to expose pupils to engineering. The authors have successfully delivered this activity during numerous outreach schemes for pupils visiting the University of Bath, especially noting pupils’ engagement and enthusiasm

Depletion of mitochondrial protease OMA1 alters proliferative properties and promotes metastatic growth of breast cancer cells

Metastatic competence of cancer cells is influenced by many factors including metabolic alterations and changes in mitochondrial biogenesis and protein homeostasis. While it is generally accepted that mitochondria play important roles in tumorigenesis, the respective molecular events that regulate aberrant cancer cell proliferation remain to be clarified. Therefore, understanding the mechanisms underlying the role of mitochondria in cancer progression has potential implications in the development of new therapeutic strategies. We show that low expression of mitochondrial quality control protease OMA1 correlates with poor overall survival in breast cancer patients. Silencing OMA1 in vitro in patientderived metastatic breast cancer cells isolated from the metastatic pleural effusion and atypical ductal hyperplasia mammary tumor specimens (21MT-1 and 21PT) enhances the formation of filopodia, increases cell proliferation (Ki67 expression), and induces epithelial-mesenchymal transition (EMT). Mechanistically, loss of OMA1 results in alterations in the mitochondrial protein homeostasis, as reflected by enhanced expression of canonic mitochondrial unfolded protein response genes. These changes significantly increase migratory properties in metastatic breast cancer cells, indicating that OMA1 plays a critical role in suppressing metastatic competence of breast tumors. Interestingly, these results were not observed in OMA1-depleted non-tumorigenic MCF10A mammary epithelial cells. This newly identified reduced activity/levels of OMA1 provides insights into the mechanisms leading to breast cancer development, promoting malignant progression of cancer cells and unfavorable clinical outcomes, which may represent possible prognostic markers and therapeutic targets for breast cancer treatment

Time periods of altered risk for severe injection drug use-associated skin and soft-tissue infections: protocol for a self-controlled case series in New South Wales, Australia, 2001-2018

Injection drug use-associated bacterial and fungal infections (e.g., skin and soft-tissue infections, endocarditis, osteomyelitis, etc.) are common health problems among people who inject drugs, associated with pain, disability, and death. The incidence of these infections is rising, and better understanding of the social and environmental factors that shape individual injecting practices and risk for injecting-related infections is urgently needed. Using a self-controlled study design, the aim of this proposed study is to quantify the risks of injecting-related skin and soft-tissue infections associated with initiation of, exposure to, and discontinuation of incarceration and OAT among a sample of people with opioid use disorder

Converting from face-to-face to postal follow-up and its effects on participant retention, response rates and errors:lessons from the EQUAL study in the UK

Background: Prospective cohort studies are challenging to deliver, with one of the main difficulties lying in retention of participants. The need to socially distance during the COVID-19 pandemic has added to this challenge. The pre-COVID-19 adaptation of the European Quality (EQUAL) study in the UK to a remote form of follow-up for efficiency provides lessons for those who are considering changing their study design. Methods: The EQUAL study is an international prospective cohort study of patients ≥65 years of age with advanced chronic kidney disease. Initially, patients were invited to complete a questionnaire (SF-36, Dialysis Symptom Index and Renal Treatment Satisfaction Questionnaire) at research clinics every 3–6 months, known as “traditional follow-up” (TFU). In 2018, all living patients were invited to switch to “efficient follow-up” (EFU), which used an abbreviated questionnaire consisting of SF-12 and Dialysis Symptom Index. These were administered centrally by post. Response rates were calculated using returned questionnaires as a proportion of surviving invitees, and error rates presented as the average percentage of unanswered questions or unclear answers, of total questions in returned questionnaires. Response and error rates were calculated 6-monthly in TFU to allow comparisons with EFU. Results: Of the 504 patients initially recruited, 236 were still alive at the time of conversion to EFU; 111 of these (47%) consented to the change in follow-up. In those who consented, median TFU was 34 months, ranging from 0 to 42 months. Their response rates fell steadily from 88% (98/111) at month 0 of TFU, to 20% (3/15) at month 42. The response rate for the first EFU questionnaire was 60% (59/99) of those alive from TFU. With this improvement in response rates, the first EFU also lowered errors to baseline levels seen in early follow-up, after having almost trebled throughout traditional follow-up. Conclusions: Overall, this study demonstrates that administration of shorter follow-up questionnaires by post rather than in person does not negatively impact patient response or error rates. These results may be reassuring for researchers who are trying to limit face-to-face contact with patients during the COVID-19 pandemic

Robust SARS-CoV-2-specific and heterologous immune responses in vaccine-naïve residents of long-term care facilities who survive natural infection

We studied humoral and cellular immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 152 long-term care facility staff and 124 residents over a prospective 4-month period shortly after the first wave of infection in England. We show that residents of long-term care facilities developed high and stable levels of antibodies against spike protein and receptor-binding domain. Nucleocapsid-specific responses were also elevated but waned over time. Antibodies showed stable and equivalent levels of functional inhibition against spike-angiotensin-converting enzyme 2 binding in all age groups with comparable activity against viral variants of concern. SARS-CoV-2 seropositive donors showed high levels of antibodies to other beta-coronaviruses but serostatus did not impact humoral immunity to influenza or other respiratory syncytial viruses. SARS-CoV-2-specific cellular responses were similar across all ages but virus-specific populations showed elevated levels of activation in older donors. Thus, survivors of SARS-CoV-2 infection show a robust and stable immunity against the virus that does not negatively impact responses to other seasonal viruses

Ethnic Variation in the Prevalence of Visual Impairment in People Attending Diabetic Retinopathy Screening in the United Kingdom (DRIVE UK)

PURPOSE: To provide estimates of visual impairment in people with diabetes attending screening in a multi-ethnic population in England (United Kingdom). METHODS: The Diabetic Retinopathy In Various Ethnic groups in UK (DRIVE UK) Study is a cross-sectional study on the ethnic variations of the prevalence of DR and visual impairment in two multi-racial cohorts in the UK. People on the diabetes register in West Yorkshire and South East London who were screened, treated or monitored between April 2008 to July 2009 (London) or August 2009 (West Yorkshire) were included in the study. Data on age, gender, ethnic group, visual acuity and diabetic retinopathy were collected. Ethnic group was defined according to the 2011 census classification. The two main ethnic minority groups represented here are Blacks ("Black/African/Caribbean/Black British") and South Asians ("Asians originating from the Indian subcontinent"). We examined the prevalence of visual impairment in the better eye using three cut-off points (a) loss of vision sufficient for driving (approximately <6/9) (b) visual impairment (<6/12) and (c) severe visual impairment (<6/60), standardising the prevalence of visual impairment in the minority ethnic groups to the age-structure of the white population. RESULTS: Data on visual acuity and were available on 50,331 individuals 3.4% of people diagnosed with diabetes and attending screening were visually impaired (95% confidence intervals (CI) 3.2% to 3.5%) and 0.39% severely visually impaired (0.33% to 0.44%). Blacks and South Asians had a higher prevalence of visual impairment (directly age standardised prevalence 4.6%, 95% CI 4.0% to 5.1% and 6.9%, 95% CI 5.8% to 8.0% respectively) compared to white people (3.3%, 95% CI 3.1% to 3.5%). Visual loss was also more prevalent with increasing age, type 1 diabetes and in people living in Yorkshire. CONCLUSIONS: Visual impairment remains an important public health problem in people with diabetes, and is more prevalent in the minority ethnic groups in the UK

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN