Phenotypic Type 2 Diabetes in Obese Youth: Insulin Sensitivity and Secretion in Islet Cell Antibody–Negative Versus –Positive Patients

OBJECTIVE— Some obese youth with a clinical diagnosis of type 2 diabetes have evidence of islet cell autoimmunity with positive autoantibodies. In this study, we investigated the differences in insulin sensitivity and secretion between autoantibody-negative (Ab−) and -positive (Ab+) youth with clinically diagnosed type 2 diabetes in comparison with control subjects

Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach

Endoxifen is the most important metabolite of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing breast cancer patients that do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at higher recurrence risk. In this investigation, 10 clinical tamoxifen studies were pooled (nPatients=1388) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modelling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared to post-menopausal patients, pre-menopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared to elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for pre-menopausal patients, this subpopulation may benefit most from individualised tamoxifen dosing

Atlas of Palliative Care in the Eastern Mediterranean Region

BACKGROUND Information on the state of palliative care development in Eastern Mediterranean countries is scant. This study is the first of its kind in conducting a systematic descriptive analysis of palliative care development in the region. AIMS To describe the current status of palliative care in the Eastern Mediterranean Region according to the World Health Organization (WHO) public health strategy for integrating palliative care: policies, opioid accessibility, services availability, and educational programs plus palliative care professional activity. METHODS Surveys were sent by email to two leaders of palliative care in each country. A follow-up telephone interview was conducted with one leader from each available country. A scoping review of the state of palliative care in Eastern Mediterranean countries using the WHO palliative care public health strategy was conducted using PubMed, CINAHL, Embase, and Google Scholar. RESULTS Sixty eight percent (15/22) of countries in the EMRO region responded to the survey. Of the fifteen participating countries, Saudi Arabia had the highest number of total palliative care programs across the Eastern Mediterranean region, followed by Egypt and Jordan, while Iraq and the Occupied Palestinian Territories reported no palliative care programs. Saudi Arabia, Iran, and Lebanon have official licensing programs in palliative care for physicians, and a further four countries (Egypt, Jordan, Oman, and Qatar) have developed other advanced training programs (such as Masters or Diploma). In terms of education, Jordan, Oman, and Lebanon report having at least one medical school teaching palliative care as an independent subject, though four additional countries (Egypt, Kuwait, Pakistan, and Tunisia) report teaching palliative care integrated into other subjects. There are no nursing schools in the region that teach palliative care as an independent course. In terms of policies, only Tunisia has a stand-alone national palliative care plan. However, 73% (11/15) of participating countries reported having a section for palliative care within their national cancer plan/strategy. In terms of medicine availability, Saudi Arabia reported the highest opioid consumption in morphine equivalence, excluding methadone, at 33.55 mg/capita/year in 2015, with the next highest being Kuwait at 5.59 mg/capita/year. Finally, in terms of professional activity, Morocco, Tunisia, Lebanon, Jordan, Saudi Arabia, Kuwait, and Iran reported having national palliative care associations, though not all are currently active. CONCLUSION Palliative care remains underdeveloped in most countries. Efforts and resources should be mobilized to address the gaps identified to ensure that palliative care becomes accessible across the region.The Atlas of Palliative Care in the Eastern Mediterranean Region is a joint project between the Lebanese Center for Palliative Care – Balsam and the ATLANTES Research Program at the Institute for Culture and Society, University of Navarra, Spain. The World Health Organization (WHO EMRO) contributed to the project offering financial support for the printed version of this Atlas. The International Association for Hospice and Palliative Care (IAHPC) provided funding for design and printing

Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, P<10?77). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P=0.013). Low (<14?nM) compared with high (>35?nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS

3, 3′5 Triiodo L Thyronine Induces Apoptosis in Human Breast Cancer MCF-7cells, Repressing SMP30 Expression through Negative Thyroid Response Elements

Thyroid hormones regulate cell proliferation, differentiation as well as apoptosis. However molecular mechanism underlying apoptosis as a result of thyroid hormone signaling is poorly understood. The antiapoptotic role of Senescence Marker Protein-30 (SMP30) has been characterized in response to varieties of stimuli as well as in knock out model. Our earlier data suggest that thyroid hormone 3, 3'5 Triiodo L Thyronine (T(3)), represses SMP30 in rat liver.In highly metastatic MCF-7, human breast cancer cell line T3 treatment repressed SMP30 expression leading to enhanced apoptosis. Analysis by flow cytometry and other techniques revealed that overexpression and silencing of SMP30 in MCF-7 resulted in decelerated and accelerated apoptosis respectively. In order to identify the cis-acting elements involved in this regulation, we have analyzed hormone responsiveness of transiently transfected hSMP30 promoter deletion reporter vectors in MCF-7 cells. As opposed to the expected epigenetic outcome, thyroid hormone down regulated hSMP30 promoter activity despite enhanced recruitment of acetylated H3 on thyroid response elements (TREs). From the stand point of established epigenetic concept we have categorised these two TREs as negative response elements. Our attempt of siRNA mediated silencing of TRβ, reduced the fold of repression of SMP30 gene expression. In presence of thyroid hormone, Trichostatin- A (TSA), which is a Histone deacetylase (HDAC) inhibitor further inhibited SMP30 promoter activity. The above findings are in support of categorisation of both the thyroid response element as negative response elements as usually TSA should have reversed the repressions.This is the first report of novel mechanistic insights into the remarkable downregulation of SMP30 gene expression by thyroid hormone which in turn induces apoptosis in MCF-7 human breast cancer cells. We believe that our study represents a good ground for future effort to develop new therapeutic approaches to challenge the progression of breast cancer