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.     

Work hazards and workers’ mental health: an investigation based on the fifth European Working Conditions Survey

Background:Workplace hazards are a significant source of health impairment for workers and of financial losses for firms. EU directives on workers’ health and safety standards significantly contributed to reduce reported occupational injuries, yet the incidence and prevalence of work-related mental illness is still very high.Objectives:We investigated the association between work-related hazards and individuals’ perceived mental health. We reviewed the existing evidence on the channels through which task-related factors, adverse agents and psychosocial factors are expected to affect workers’ health, with specific regard to mental health.Methods:We used data from the fifth wave of the European Working Conditions Survey, covering over 40,000 face-to-face interviews with workers in 34 countries, which includes information on socio-demographic characteristics, firms and jobs attributes, employment status, as well as working conditions and health status. We carried out an empirical analysis with multivariate regression models in order to estimate the relationship between workers’ mental health problems and workplace risk factors.Results:21,020 interviews were used in the multivariate analysis. We found strong correlations between hazards and various indicators of mental health. Among hazardous agents, low temperatures (β=0.0287) and contact with infectious materials (β=0.0394) were positively associated with mental health outcomes. Among task/sequence-related factors, tiring or painful positions (β=0.0713), repetitive hand/arm movements (β=0.0255), working with VDUs (β=0.0301), repetitive tasks <10 min (β=0.0859) and working in evenings (β=0.00754) were positively associated with mental health. Various psychosocial risk factors related to both the content of the job (for example, frequent disruptive interruptions: β=0.219, working in free time: β=0.0759, poor work-life balance: β=0.228) as well as the job context (for example, bad employment prospects: β=0.177, low decisional autonomy: β=0.245, bad social relations: β=0.186, workplace violence: β=0.411) were positively associated with mental health. The main results of the decomposition show that an important contribution to workers’ overall mental distress at work is associated with psychosocial risk factors (up to 60% for depression/anxiety symptoms and sleep disorders), while the contribution of somatic factors is on average lower (up to 20% for overall fatigue).Conclusions:We argue that action is needed to improve workers’ mental well-being, and reduce the economic costs for both the national health system and employers. Regulations and traditional economic measures are unlikely to prove successful in providing adequate standards of primary and secondary preventive measures in the work place without an appropriate and reliable Risk Assessment Procedure.Key words: Work hazards, risk assessment, job content, mental health     

Cataract Surgery in HIV Seropositive Patients: Long-Term Follow-Up

Purpose: To study epidemiology and clinical findings of cataract in HIV+ patients.

Methods: A total of 32 HIV+ patients, 11 with uveitis/retinitis before surgery and 21 without, mean follow-up 44.9 ± 36.6 months, and 114 HIV- patients, 57 with uveitis/retinitis before surgery and 57 without, were retrospectively compared.

Results: Visual acuity improved in all HIV+ patients (p < 0.001), who were younger (p = 0.01) and more frequently males (p = 0.027). HIV+ patients with uveitis prior surgery improved less (p = 0.046) than HIV- (p < 0.001); their anterior chamber inflammation was similar to baseline. Male sex (p = 0.005), younger age (p < 0.001), dyslipidaemia (p = 0.058), HBV+ (p = 0.037), and unilateral cataract (p = 0.001) were more frequent in HIV+ patients with senile cataract, but they showed the same postoperative course as HIV- patients.

Conclusion: Cataract surgery in HIV+ patients is safe and effective. Uveitis prior to surgery did not significantly affect the postoperative course. Systemic comorbidities are more frequent in HIV+ patients with senile cataract than in HIV- subjects.     

Adherence to the Mediterranean diet and weight status in children: the role of parental feeding practices

Abstract

The study examines Parental Feeding Practices (PFP) in relation to adherence to the Mediterranean Diet (MD) and children’s weight status. It’s a cross-sectional study of 402 parents (68.4% mothers), with children aged 2–12 years. Parents completed the Comprehensive Parental Feeding Questionnaire and the Mediterranean Diet Quality Index for children and adolescents (KIDMED), evaluating children’s adherence to the MD. Logistic regression showed that in children aged 2–<6 years, “emotion regulation/food as reward” and “pressure” decrease MD adherence (OR?=?0.186, p?<?0.0001 and OR?=?0.496, p?=?0.004), and “monitoring” decrease excess body weight (OR?=?0.284, p?=?0.009). In older children (6–12 years), “healthy eating guidance” and “monitoring” increase MD adherence (OR?=?3.262, p?=?0.001 and OR?=?3.147, p?<?0.0001), “child control” decreases MD adherence (OR?=?0.587, p?=?0.049), “pressure” decrease excess body weight (OR?=?0.495, p?<?0.0001) and “restriction” increase excess body weight (OR?=?1.784, p?=?0.015). “Healthy eating guidance” and “monitoring” seem to be the best PFP employed, in terms of children’s MD adherence and weight status.     

The roles of basic psychological needs,self-compassion,and self-efficacy in the development of mastery goals among medical students

Abstract

Aim: Competency-based medical education aims to foster mastery goals in learners. We examined medical students’ mastery approach (beneficial) and mastery avoidance (maladaptive) goals and their associations with students’ basic psychological needs, self-compassion, and self-efficacy.

Methods: This was a cross-sectional study employing an online questionnaire. Two hundred medical students in all four years of the medical program completed the questionnaire, containing measures of mastery goals, basic psychological needs (autonomy, competence, relatedness), self-compassion, and self-efficacy. Regression analyses were performed.

Results: Of the three basic psychological needs, the need for competence was significant in explaining both types of mastery goals. Self-efficacy and self-compassion were significant in explaining mastery approach and mastery avoidance goals, respectively.

Conclusions: Creating learning environments that are supportive of students’ need for competence, raising students’ awareness of the value of learning from mistakes in competency acquisition, and providing opportunities for students to experience self-efficacy may foster beneficial mastery approach goals in medical students.     

Detection of recombinant and endogenous mouse melatonin receptors by monoclonal antibodies targeting the C‐terminal domain

Melatonin receptors play important roles in the regulation of circadian and seasonal rhythms, sleep, retinal functions, the immune system, depression, and type 2 diabetes development. Melatonin receptors are approved drug targets for insomnia, non‐24‐hour sleep‐wake disorders, and major depressive disorders. In mammals, two melatonin receptors (MTRs) exist, MT₁ and MT₂, belonging to the G protein‐coupled receptor (GPCR) superfamily. Similar to most other GPCRs, reliable antibodies recognizing melatonin receptors proved to be difficult to obtain. Here, we describe the development of the first monoclonal antibodies (mABs) for mouse MT₁ and MT₂. Purified antibodies were extensively characterized for specific reactivity with mouse, rat, and human MT₁ and MT₂ by Western blot, immunoprecipitation, immunofluorescence, and proximity ligation assay. Several mABs were specific for either mouse MT₁ or MT₂. None of the mABs cross‐reacted with rat MTRs, and some were able to react with human MTRs. The specificity of the selected mABs was validated by immunofluorescence microscopy in three established locations (retina, suprachiasmatic nuclei, pituitary gland) for MTR expression in mice using MTR‐KO mice as control. MT₂ expression was not detected in mouse insulinoma MIN6 cells or pancreatic beta‐cells. Collectively, we report the first monoclonal antibodies recognizing recombinant and native mouse melatonin receptors that will be valuable tools for future studies.     

Neural plasticity and adult neurogenesis: the deep biology perspective

The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.