Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Conserving resources in the diagnosis of intraoral fibroepithelial polyps

Fibroepithelial polyps (FEPs) are common, benign intraoral lesions that tend to develop slowly at predictable sites, often in response to local irritation or trauma. Historical precedent often results in referral to oral and maxillofacial surgery (OMFS) departments for biopsy, often irrespective of symptoms, and histological assessment. OMFS and pathology services are struggling to cope with an increasing workload that will potentially lead to widespread delays to diagnosis and treatment. Over the past 20 years, clinical pathways and guidance have been developed to ensure that healthcare interventions, such as the removal of third molars, tonsils, skin tags, and benign moles, are evidence-based, have a net patient benefit, and ensure the best use of finite NHS resources. However, no such guidance exists for intraoral lesions and we regard this as an oversight. We analysed the removal of 682 FEPs over a seven-year period and report sensitivities of 92.4% for a “confirmed clinical suspicion of an FEP” and 99.7% for a “confirmed clinical suspicion of a benign diagnosis”. The incidence of non-benign disease was 0.3%. Primary care dentists should be able to diagnose and monitor FEPs and refer only if symptoms are serious or in high-risk patients or sites. Adopting this practice across the UK could free up to 1825 four-hour OMFS clinics, 405 hours of consultant histopathologists’ time, and recurring savings to the NHS estimated to be in the region of £620 000/annum. We believe that the removal of FEPs should be reclassified as an “intervention not normally funded”, and the time and resources put to better use treating patients with lesions of questionable pathology.     

Food-grade titanium dioxide decreases hematocrit and hemoglobin and increases compulsive-like behavior in male mice

Food-grade titanium dioxide (E171) is widely used as a food additive, and it is known that after oral consumption, E171 is translocated into the bloodstream reaching the highest titanium level at 6 h. E171 is accumulated in some organs triggering toxicity, but the effects on the blood parameters after oral consumption have been less studied. Recently, evidence shows that oral exposure to E171 induces behavioral signs of anxiety and depression. The relation between blood alterations and psychiatric disorders has been previously demonstrated. However, the oral exposure to E171 effects on alterations in blood parameters and effects linked to alterations in animal behavior has not been explored. In this short communication, we aimed to investigate the effects of E171 on specific blood parameters (hematocrit, hemoglobin, number of erythrocytes, and leukocytes) and anxiety and compulsive-like behavior in males and females orally exposed to ~5 mg/kg for 4 weeks. The results showed that E171 decreased hematocrit and hemoglobin in male but not in female mice while leukocyte and erythrocyte count remained unaltered. Oral consumption of E171 decreased the levels of anxiety-like behavior in females but not in male mice, while compulsive-like behavior was increased in both male and female mice.     

Rural barriers to early lung cancer detection: Exploring access to lung cancer screening programs in New Hampshire and Vermont

BackgroundRural populations face many health disadvantages compared to urban areas. There is a critical need to better understand the current lung cancer screening landscape in these communities to identify targeted areas to improve the impact of this proven tool.MethodsData from the County Health Rankings of New Hampshire and Vermont was reviewed for population density, distribution of adult smokers, and level of education compared to the distribution of Lung Cancer Screening Facilities throughout these two states.ResultsScreening programs in southern counties of Vermont with lower levels of education have decreased access. In New Hampshire, there are no programs within 30 miles of the areas with the largest distribution of smokers, and decreased access in some areas with the lowest levels of education.ConclusionsImproving equitable access to high-quality screening services in rural regions and the creation of targeted interventions to address decreased access in areas of high tobacco use and low education is vital to decreasing the incidence of latestage presentations of lung cancer within these populations.     

Detrended fluctuation analysis detects altered coordination of running gait in athletes following a heavy period of training

Objectives

To investigate whether functional overreaching affects locomotor system behaviour when running at fixed relative intensities and if any effects were associated with changes in running performance.