Enculturation,perceived stress,and physical activity: implications for metabolic risk among the Yup'ik – The Center for Alaska Native Health Research Study

Objectives. American Indians and Alaska Natives (ANs) report among the lowest levels of physical activity in the USA, but there is very little systematic research examining the determinants of physical activity patterns in these populations. This study investigated the relationships between enculturation (or cultural traditionality), psychosocial stress, and physical activity in a community-based sample of Yup'ik women and men living in rural AN communities. Associations between these variables and several metabolic risk factors were also examined.

Design. A sample of 488 Yup'ik participants (284 women and 204 men) from six villages in the Yukon-Kuskokwim Delta region completed a wellness survey and an array of physiological assessments [e.g., body mass index (BMI), blood pressure]. A subset of 179 participants also completed a 3-day pedometer assessment of physical activity.

Results. Multivariate linear regression models indicated that participants who were more enculturated (i.e., living more of a traditional lifestyle) and who experienced lower levels of psychosocial stress were significantly more physically active. In turn, both lower levels of psychosocial stress and higher levels of physical activity were associated with lower BMI, lower percent body fat, and lower waist circumference.

Conclusions. Findings underscore the importance of gaining a culturally specific understanding of physical activity patterns in indigenous groups in order to inform effective health promotion strategies.     

BRAFV600E immunopositive Melanomas Show Low Frequency of Heterogeneity and Association With Epithelioid Tumor Cells: A STROBE-Compliant article

Treatment of BRAF^V600E-mutant melanoma by small molecule inhibitors that target BRAF or MEK kinases is increasingly used in clinical practice and significantly improve patient outcome. However, patients eventually become resistant and therapeutic improvement is required. Molecular diversity within individual tumors (intratumor heterogeneity) and between tumors within a single patient (intrapatient heterogeneity) poses a significant challenge to precision medicine.Using immunohistochemistry, we determined the extent of BRAF^V600E intratumor and intrapatient heterogeneity and the influence of morphological heterogeneity in a large series of 171 melanomas of 81 patients.The BRAF^V600E mutation rate found in our melanoma series is 44%, with none of 22 (0%) melanoma in situ, 23 of 56 (41%) primary tumors, 28 of 59 (48%) regional metastases, and 24 of 34 (71%) distant metastases harboring the mutation. In general, a diffuse homogeneous immunostaining was seen, even in tumors consisting of more than one cell type, that is, epithelioid, spindle, and/or small cell types. Nevertheless, BRAF^V600E-mutant melanomas more often had a purely epithelioid cell population (P = 0.063), that is more evident among distant metastases (P = 0.014). Only two of 75 (3%) mutated specimens (one primary and one metastasis) displayed heterogeneous BRAF^V600E expression. The primary tumor was also morphologically heterogeneous and exclusively displayed BRAF^V600E in the epithelioid component, confirming an association between BRAF^V600E and epithelioid cells. Twenty-eight of 30 patients (93%) had concordant BRAF mutation status between their tumors.Taken together, BRAF^V600E intratumor and intrapatient heterogeneity in melanoma is diminutive, nevertheless, the identified exceptions will have important implications for the clinical management of this disease.     

Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia

Background

C-type lectin-like molecule-1 is a transmembrane receptor expressed on myeloid cells, acute myeloid leukemia blasts and leukemic stem cells. To validate the potential of this receptor as a therapeutic target in acute myeloid leukemia, we generated a series of monoclonal antibodies against the extracellular domain of C-type lectin-like molecule-1 and used them to extend the expression profile analysis of acute myeloid leukemia cells and to select cytotoxic monoclonal antibodies against acute myeloid leukemia cells in preclinical models.

Design and Methods

C-type lectin-like molecule-1 expression was analyzed in acute myeloid leukemia cell lines, and in myeloid derived cells from patients with acute myeloid leukemia and healthy donors. Anti-C-type lectin-like molecule-1 antibody-mediated in vitro cytotoxic activity against acute myeloid leukemia blasts/cell lines and in vivo anti-cancer activity in a mouse xenograft model were assessed. Internalization of C-type lectin-like molecule-1 monoclonal antibodies upon receptor ligation was also investigated.

Results

C-type lectin-like molecule-1 was expressed in 86.5% (45/52) of cases of acute myeloid leukemia, in 54.5% (12/22) of acute myeloid leukemia CD34⁺/CD38⁻ stem cells, but not in acute lymphoblastic leukemia blasts (n=5). Selected anti-C-type lectin-like molecule-1 monoclonal antibodies mediated dose-dependent complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity specifically against acute myeloid leukemia-derived cell lines. Exogenous expression of the transmembrane receptor in HEK293 cells rendered the cells susceptible to antibody-mediated killing by monoclonal antibodies to the receptor. Furthermore, these monoclonal antibodies demonstrated strong complement-dependent cytotoxicity against freshly isolated acute myeloid leukemia blasts (15/16 cases; 94%). The monoclonal antibodies were efficiently internalized upon binding to C-type lectin-like molecule-1 in HL-60 cells. Moreover, a lead chimeric C-type lectin-like molecule-1 monoclonal antibody reduced the tumor size in xenograft mice implanted with HL-60 cells.

Conclusions

Our results demonstrate that targeting C-type lectin-like molecule-1 with specific cytotoxic monoclonal antibodies is an attractive approach which could lead to novel therapies for acute myeloid leukemia.     

Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET

Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BP_ND) in patients with ADHD and to assess associations of SERT BP_ND between the brain regions. 25 medication‐free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [¹¹C]DASB. SERT BP_ND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BP_ND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BP_ND and age in the ADHD and the healthy control group, we confirmed an age‐related decline in brain SERT binding in the thalamus and insula (R² = 0.284, R² = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792–802, 2017. © 2016 Wiley Periodicals, Inc.     

Bariatric Surgery Outcomes in Sarcopenic Obesity

Background

Sarcopenic obesity is the combination of low muscle mass and strength with increased fat mass. This condition is associated with negative health outcomes. We hypothesized that sarcopenia could be a pejorative factor on surgical weight loss.

Objective

The objectives of the study are to determine the influence of sarcopenic obesity on gastric bypass and sleeve gastrectomy results regarding weight loss and comorbidities resolution at 3, 6, and 12 months.

Setting

The study was conducted at the University Hospital.

Methods

Sixty-nine obese patients who benefited from bariatric surgery were included. Skeletal muscle mass was determined by the Janssen’s equation. Physical performance and muscle strength were determined using the 6-min walk test and the wall sit test. Obese subjects from the lowest tertile of the Skeletal Muscle mass Index (SMI) of Baumgartner were set as sarcopenic.

Results

Weight loss outcomes and rate of weight loss failure were not influenced by sarcopenia. At 1 year, mean EBMIL% was 75.4 %?±?5 in sarcopenic subjects vs 67.8 % ±4 in the non-sarcopenic subjects (p?=?0.242). Improvement rates of co-morbidities were similar between groups. Skeletal muscle mass was no more different between groups at 1 year after surgery. There was no patient lost to follow-up.

Conclusions

Bariatric surgery remains effective in achieving weight loss target in sarcopenic patients, with similar remission rates of main comorbidities and similar safety profile than in the non-sarcopenic group. Whether bariatric surgery could result in improvement or deterioration of daily living activities disabilities and functional autonomy in sarcopenic obese patients still have to be evaluated.