Endoplasmic reticulum Ca2+-homeostasis is altered in small and non-small cell lung cancer cell lines

<p>Abstract</p> <p>Background</p> <p>Knowledge of differences in the cellular physiology of malignant and non-malignant cells is a prerequisite for the development of cancer treatments that effectively kill cancer without damaging normal cells. Calcium is a ubiquitous signal molecule that is involved in the control of proliferation and apoptosis. We aimed to investigate if the endoplasmic reticulum (ER) Ca²⁺-homeostasis is different in lung cancer and normal human bronchial epithelial (NHBE) cells.</p> <p>Methods</p> <p>The intracellular Ca²⁺-signaling was investigated using fluorescence microscopy and the expression of Ca²⁺-regulating proteins was assessed using Western Blot analysis.</p> <p>Results</p> <p>In a Small Cell Lung Cancer (H1339) and an Adeno Carcinoma Lung Cancer (HCC) cell line but not in a Squamous Cell Lung Cancer (EPLC) and a Large Cell Lung Cancer (LCLC) cell line the ER Ca²⁺-content was reduced compared to NHBE. The reduced Ca²⁺-content correlated with a reduced expression of SERCA 2 pumping calcium into the ER, an increased expression of IP₃R releasing calcium from the ER, and a reduced expression of calreticulin buffering calcium within the ER. Lowering the ER Ca²⁺-content with CPA led to increased proliferation NHBE and lung cancer cells.</p> <p>Conclusion</p> <p>The significant differences in Ca²⁺-homeostasis between lung cancer and NHBE cells could represent a new target for cancer treatments.</p

2013 Review and Update of the Genetic Counseling Practice Based Competencies by a Task Force of the Accreditation Council for Genetic Counseling

The first practice based competencies (PBCs) for the field of genetic counseling were adopted by the American Board of Genetic Counseling (ABGC), 1996. Since that time, there has been significant growth in established and new work settings (clinical and non‐clinical) and changes in service delivery models and the roles of genetic counselors. These changes prompted the ABGC to appoint a PBC Task Force in 2011 to review the PBCs with respect to their current relevance and to revise and update them as necessary. There are four domains in the revised PBCs: (I) Genetics Expertise and Analysis (II) Interpersonal, Psychosocial and Counseling Skills (III) Education and (IV) Professional Development and Practice. There are 22 competencies, each clarified with learning objectives or samples of activities and skills; a glossary is included. New competencies were added that address genomics, genetic testing and genetic counselors’ roles in risk assessment, education, supervision, conducting research and presenting research options to patients. With PBCs serving as the pre‐defined abilities or outcomes of training, graduating genetic counselors will be well prepared to enter the field with a minimum level of skills and abilities. A description of the Task Force’s work, key changes and the 2013 PBCs are presented herein.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147172/1/jgc40868.pd

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS

Metanephric Stromal Tumor Arising in a Patient With Neurofibromatosis Type 1 Syndrome

Metanephric stromal tumor (MST) is a recently recognized benign renal stromal tumor. MST is thought to be part of a spectrum of benign metanephric renal lesions, which also includes the epithelial lesion metanephric adenoma and the mixed stromal-epithelial lesion metanephric adenofibroma. Metanephric lesions may represent hyperdifferentiated counterparts to Wilms' tumor (WT). MST characteristically shows renovascular angiodysplasia and juxtaglomerular (JG) cell hyperplasia. This is remarkably similar to the renal pathology described in neurofibromatosis-1 (NF-1) syndrome, a condition which is also associated with WT. Here, we report the first case of MST arising in a patient with NF-1. The patient presented with hypertension, and the MST was associated with florid angiodysplasia and JG cell hyperplasia. This case tightens the link between NF-1, WT, and MST

Health-related Quality of Life of Individuals With Neurofibromatosis Type 2

Objective: To explore health-related quality of life (HRQoL) reported by individuals with neurofibromatosis type 2 (NF2) and to assess for correlations between HRQoL and objective measures of disease manifestations. Study Design: Prospective observational study. Setting: Seven international NF2 centers. Subjects: Eighty-one individuals with NF2, 73 adults (>18 years) and 8 children/adolescents (10–17 years). Outcome Measures: Quality of life was measured by Short Form-36 (SF-36) norm-based scores. Objective clinical measures were hearing (categorized by word-recognition scores), facial function (categorized by the House–Brackmann scale) and the volume of subjects’ larger vestibular schwannoma (VS). Results: At baseline, adults showed significant deficits in all but two subscales of the SF-36 compared with age- and gender-adjusted United States population norms. In linear regression models including age, gender, inheritance status, hearing, facial weakness and VS volume, demographic and functional measures showed no relationship to any SF-36 subscale. Larger baseline VS volume was significantly related to reduced physical role performance, reduced mental health, and increased pain (p < 0.05). In bivariate analysis, previous VS surgery was not significantly associated with baseline HRQoL; receipt of VS surgery or tumor growth during the observation period was not significantly associated with changes in HRQoL. Conclusion: NF2 patients report reduced HRQoL in physical, social, and mental domains, but this was not significantly related to objective measures of hearing or facial functioning. Larger baseline VS volume negatively impacted patient-reported HRQoL whereas VS surgery or tumor growth did not. Future studies should explore the relationship between tumor volume and HRQoL and psychosocial factors that may moderate this relationship

A report of the AGCPD task force to evaluate associations between select admissions requirements, demographics, and performance on ABGC certification examination

Graduation from a genetic counseling graduate program accredited by the Accreditation Council of Genetic Counseling and certification obtained by passing the American Board of Genetic Counseling (ABGC) certification examination are increasingly required to practice as a genetic counselor in the USA. Despite the ABGC certification examination serving as a gateway to the genetic counseling career, there have been no research studies to date that have examined what variables are associated with examination performance. Therefore, the Association of Genetic Counseling Program Directors established a Task Force to assess whether trainee demographics, Grade point average (GPA) and Graduate Record Exam (GRE®) percentile scores are associated with passing the ABGC certification examination on the first attempt. We surveyed accredited genetic counseling graduate programs in North America and gathered demographic data, admissions variables, and certification examination outcome data for 1,494 trainees from 24 training programs, representing approximately 60.5% of matriculants between 2007 and 2016. Univariable analysis was performed to assess associations between admissions variables and categorical outcome (pass vs. fail) on the certification examination using Wilcoxon rank‐sum or Fisher’s exact test. Variables significantly associated with the categorical board outcome were then entered in a stepwise model selection procedure. In stepwise logistic regression, trainees with higher GPA (OR = 3.41; 95% CI = 1.99, 5.83), higher verbal (OR = 1.02; 95% CI = 1.01, 1.03) and quantitative (OR = 1.02; 95% CI = 1.01, 1.03) GRE® scores, female trainees (OR = 2.95; 95% CI = 1.70, 5.12), and White trainees (OR 3.37; 95% CI = 2.14, 5.30) had higher odds of passing the certification examination on the first attempt. As programs move to a holistic approach to graduate admissions in order to improve access to the genetic counseling profession, our results may influence programs to provide additional preparation for the certification examination for all trainees. In addition, genetic counseling professional organizations should continue to work together to assess and eliminate outcome disparities in admissions, training, and certification processes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171994/1/jgc41537.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171994/2/jgc41537_am.pd

A novel predicted bromodomain-related protein affects coordination between meiosis and spermiogenesis in drosophila and is required for male meiotic cytokinesis

Temporal coordination of meiosis with spermatid morphogenesis is crucial for successful generation of mature sperm cells. We identified a recessive male sterile Drosophila melanogaster mutant, mitoshell, in which events of spermatid morphogenesis are initiated too early, before meiotic onset. Premature mitochondrial aggregation and fusion lead to an aberrant mitochondrial shell around premeiotic nuclei. Despite successful meiotic karyokinesis, improper mitochondrial localization in mitoshell testes is associated with defective astral central spindles and a lack of contractile rings, leading to meiotic cytokinesis failure. We mapped and cloned the mitoshell gene and found that it encodes a novel protein with a bromodomain-related region. It is conserved in some insect lineages. Bromodomains typically bind to histone acetyl-lysine residues and therefore are often associated with chromatin. The Mitoshell bromodomain-related region is predicted to have an alpha helical structure similar to that of bromodomains, but not all the crucial residues in the ligand-binding loops are conserved. We speculate that Mitoshell may participate in transcriptional regulation of spermatogenesis-specific genes, though perhaps with different ligand specificity compared to traditional bromodomains

Dystrophic spinal deformities in a neurofibromatosis type 1 murine model.

Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36-60% of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population