Structural features and mechanism of crystallization of nanocomposites based on maleinated high density polyethylene and carbon black.

The results of studying the structural features of nanocomposites by electron microscopy, X-ray diffraction analysis, derivatography and stepwise dilatometry are presented. The kinetic regularities of crystallization of nanocomposites based on Exxelor PE 1040-modified high density polyethylene HDPE* and carbon black (CB) are considered by the method of stepwise dilatometry: the dependence of specific volume on temperature. Dilatometric studies were carried out in the temperature range of 20-210 °C. The concentration of nanoparticles was varied within 1.0, 3.0, 5.0, 10, and 20 wt%. In the process of studying the temperature dependence of the specific volume of nanocomposites, it was found that a first-order phase transition occurs for HDPE* samples with 1.0-10 wt% CB content at 119 °C, and for a sample with 20 wt% CB at 115 °C. The study of the process kinetics of nanocomposites isothermal crystallization showed that, for nanocomposites with 1.0-10 wt% CB content, the mechanism of the process is characterized by the formation of a three-dimensional spherulite structure with continuously formed homogeneous and heterogeneous nucleation centers. A substantiated theoretical analysis and interpretation of the discovered regularities of the crystallization process and the growth mechanism of crystalline formations is given. Derivatographic studies of nanocomposites were carried out, according to which the features of changes in the thermal-physical properties of nanocomposites depending on the content of carbon black were established. The results of X-ray diffraction analysis of nanocomposites with 20 wt% carbon black content are presented, according to which there is a slight decrease in their degree of crystallinity.

Medullary Thyroid Carcinoma Associated with Germline RETK666N Mutation.

BACKGROUND: Multiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RETK666N DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown. METHODS: The clinical features, genetic data, and family information of eight index MTC patients with a germline RETK666N variant were assessed. RESULTS: Four probands presented with MTC and extensive nodal metastasis, one with biopsy-confirmed distant metastasis. Two additional probands presented with localized disease. However, nodal status was not available. Of the final two probands, one had an incidental 1.5 mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3 cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5-90 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma. CONCLUSIONS: From this case series, the largest such experience to date, it is concluded that the RETK666N variant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, "at risk" individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.

Bone Metastases and Skeletal-Related Events in Medullary Thyroid Carcinoma.

CONTEXT: Bone metastases (BM) can lead to devastating skeletal-related events (SREs) in cancer patients. Data regarding medullary thyroid carcinoma (MTC) with BM are lacking. OBJECTIVE: We evaluated the natural history of BM and SREs in MTC patients identified by a cancer center tumor registry. SETTING: The study was conducted at a tertiary cancer center. PATIENTS AND MAIN OUTCOME MEASURES: We retrospectively reviewed the charts of MTC patients with BM who received care from 1991 to 2014 to characterize BM and SREs. RESULTS: Of 1008 MTC patients treated, 188 were confirmed to have BM (19%), of whom 89% (168 of 188) had nonosseous distant metastases. Median time from MTC to BM diagnosis was 30.9 months (range 0-533 mo); 25% (45 of 180) had BM identified within 3 months of MTC diagnosis. Median follow-up after detecting BM was 1.6 years (range 0-23.2 y). Most patients (77%) had six or more BM lesions, most often affecting the spine (92%) and pelvis (69%). Many patients (90 of 188, 48%) experienced one or more SREs, most commonly radiotherapy (67 of 90, 74%) followed by pathological fracture (21 of 90, 23%). Only three patients had spinal cord compression. Patients with more than 10 BM lesions were more likely to experience SREs (odds ratio 2.4; P = .007), with no difference in 5-year mortality after MTC diagnosis between patients with (31%) and without SREs (23%) (P = .11). CONCLUSIONS: In this large retrospective series, BM in MTC was multifocal, primarily involving the spine and pelvis, supporting screening these regions for metastases in at-risk patients. SREs were common but spinal cord compression was rare. Antiresorptive therapies in this population should be investigated further with prospective trials.

Role of salvage targeted therapy in differentiated thyroid cancer patients who failed first-line sorafenib.

CONTEXT: Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem. OBJECTIVE: The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure. DESIGN: This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013. PATIENTS: The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). PATIENTS who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS). OUTCOME MEASURES: Progression-free survival, best response, and median OS were measured. RESULTS: Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P = .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n = 4), pazopanib (n = 3), cabozantinib (n = 4), lenvatinib (n = 3), and vemurafenib (n = 3). CONCLUSIONS: Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy.

Expression and transcriptional regulation of individual pregnancy-specific glycoprotein genes in differentiating trophoblast cells.

Human pregnancy-specific glycoproteins (PSGs), encoded by eleven highly conserved genes, are the major placental polypeptides. Low PSG levels in maternal circulation have been associated with complicated pregnancies. However, expression of each PSG gene and their regulation during cytotrophoblast cell differentiation remain poorly explored. Herein, we analyze the expression of five PSG genes and demonstrate that they are almost undetectable in undifferentiated trophoblast, but are all transcribed in differentiated cells. Among them, PSG1, PSG3 and PSG5 genes achieve high mRNA levels while PSG7 and PSG9 are poorly expressed. In addition, total PSG proteins and transcripts markedly increase during trophoblast differentiation, preceding morphological syncytialization and betahCG expression. The 5' regulatory region contributes to the transcriptional control of PSG gene induction in trophoblast cells undergoing differentiation. This responsive region in PSG3 maps within a 130 bp promoter sequence, which overlaps the transcription start site and requires a functional Retinoic Acid Responsive Element (RARE) and a GA-binding protein (GABP) consensus site for basal and differentiation-dependent promoter activity, respectively. Present findings provide novel data for understanding the control of PSG gene expression and demonstrate that their proteins and transcripts represent early markers of trophoblast differentiation.

Activation of beta-catenin signalling increases StarD7 gene expression in JEG-3 cells.

StarD7 gene encodes a protein that belongs to the StAR-related lipid transfer proteins involved in intracellular transport and metabolism of lipids. It has been previously documented that StarD7 has a wide-spread mRNA expression in trophoblastic tissues and several tumour cell lines with highest levels in both choriocarcinoma JEG-3 and JAR cells, hepatocellular carcinoma HepG2, and colorectal adenocarcinoma HT-29 cells. To understand the molecular mechanisms that regulate the expression of the human StarD7 gene, we have cloned and characterized the 5'-flanking region of the gene. Transient transfections of several 5'deleted StarD7-promoter-firefly luciferase constructs into JEG-3 cells indicated that the -312/+157 region contains the gene minimal promoter. In addition, sequence analysis of a 1.6kb gene fragment revealed the presence of a TATA-less promoter as well as multiple regulatory motifs, including one regulatory element corresponding to the T-cell factor 4 (TCF4) binding site. Inhibition of glycogen synthase kinase-3beta (GSK3beta), a component of Wnt/beta-catenin signalling, increased both StarD7 mRNA and protein expression as well as its promoter activity. Co-transfection experiments in JEG-3 cell line revealed that the StarD7 promoter is activated by TCF4 transcription factor and by its beta-catenin coactivator. Moreover, site-directed mutagenesis of the TCF4 site located -614/-608bp relative to the transcription start site markedly diminished StarD7 promoter activity. Chromatin immunoprecipitation analysis demonstrated that beta-catenin and TCF4 are bound in vivo to the StarD7 gene promoter in JEG-3 cells treated with lithium chloride. Collectively, these studies show that beta-catenin and TCF4 activate the human StarD7 gene interacting with its promoter region through Wnt/beta-catenin signalling.

Approach and safety of comprehensive central compartment dissection in patients with recurrent papillary thyroid carcinoma.

BACKGROUND: Despite the generally favorable prognosis of patients with papillary thyroid cancers, 10-year recurrence rates for patients with stage I to III disease is greater than 20%, with central compartment recurrences common among these recurrent sites. METHODS: This study is a retrospective analysis of consecutive patients treated by a single surgeon over an 18-month period of time terminating in 2003. RESULTS: Sixty-three patients underwent a comprehensive dissection of levels VI and VII for papillary thyroid carcinoma during this period. There was a female predominance of 2:1, with 48% of patients being greater than 45 years of age. The median number of lymph nodes identified was 16 (range, 3-52), with 7 (1-20) lymph nodes pathologically involved. Permanent hypoparathyroidism was present on presentation in 13% of patients and developed in an additional 5% following surgery. Although recurrent laryngeal paralysis was present on presentation among 8 (13%) of patients, no patients experienced paralysis of documented functioning recurrent laryngeal nerves or necessitated tracheotomy. Postoperative thyroglobulin levels were reduced to nondetectable in 71% of the informative cases. Over 60% of patients were discharged on their first postoperative day. CONCLUSION: Bilateral paratracheal and superior mediastinal dissection is an oncologically safe procedure exhibiting minimal morbidity when performed among experienced individuals despite multiple prior surgical procedures or existing vocal cord paralysis.

Expression and localization of StarD7 in trophoblast cells.

The StAR-related lipid transfer (START) domain is defined as a motif of around 200 amino acids implicated in lipid/sterol binding. In a previous study, we identified the StarD7 transcript encoding one of the 15 family members with START domain present in the human genome. This transcript was found to be overexpressed in choriocarcinoma JEG-3 cells. In addition, we demonstrated that the recombinant StarD7 protein forms stable Gibbs and Langmuir monolayers at the air-buffer interface, showing marked surface activity and interaction with phospholipid monolayers, mainly with phosphatidylserine, cholesterol and phosphatidylglycerol. This study was undertaken to evaluate the expression and localization of StarD7 protein in trophoblastic samples. Here, we show for the first time the presence of StarD7 protein in human trophoblast cells. Western blot assays revealed a unique specific 34 kDa protein in JEG-3 cell line, choriocarcinoma tissue, complete hydatidiform mole, early and normal term placenta. Immunohistochemical data from early and normal term placentas and complete hydatidiform moles showed that this protein is abundant in the syncytiotrophoblasts, mainly at the apical side of the syncytium, with a weak and focal reaction in the cytotrophoblast cells. Furthermore, an increased StarD7 mRNA and protein expression, as well as a change in its sub-cellular localization was observed in in vitro differentiating cytotrophoblast isolated from normal term placenta. Taken together, these findings support and allow future studies to explore the possibility that StarD7 protein mediates transplacental lipid transport and/or is involved in syncytialization.

Breast cancer: relationship between menopausal symptoms, physiologic health effects of cancer treatment and physical constraints on quality of life in long-term survivors.

AIMS AND OBJECTIVES: The purpose of this study is to describe the relationship between menopausal symptoms, physiologic health effects of cancer treatment and the physical contributors to quality of life in long-term survivors of breast cancer. BACKGROUND: The treatment of menopausal symptoms is hotly debated, especially for women with breast cancer. Common treatments for menopausal symptoms are considered to be contraindicated in women with breast cancer. DESIGN: This is a descriptive, cross-sectional study of long-term breast cancer survivors; a subset of a study that responded to a mailed survey targeting long-term cancer survivors treated at The University of Texas M.D. Anderson Cancer Center. METHODS: In 291 breast cancer patients information was available that included items that commonly relate to menopausal symptoms including hot flushes, painful sexual intercourse, inability to concentrate, fatigue and sleep disturbances. RESULTS: Ninety per cent were Caucasian American and the mean time since diagnosis was 16 +/- 8 years. All patients had been treated with surgery, (60%) with radiotherapy, (68%) with chemotherapy and (37%) with hormonal therapy. Forty-six per cent of the breast cancer survivors indicated that having breast cancer affected their overall health. Self-reported health effects were more common in those survivors who had received a combination of chemotherapy and radiotherapy. A menopausal quality of life score was determined using the items about hot flushes, ability to concentrate, painful sexual intercourse, fatigue, unhappiness and sleep disturbances. CONCLUSIONS: This study reminds us that breast cancer and menopause are independent issues. Quality of life parameters need to be rigidly defined and time sensitive. There are complex interactions between quality of life indicators and specific physiologic consequences of treatment. However, menopausal signs and symptoms may not be different for the breast cancer survivor and they should not be confused with the quality of life/psychosocial issues of the cancer survivor. RELEVANCE TO CLINICAL PRACTICE: Menopause is not a disease process but a normal developmental stage for women. It is important for nurses not only to understand the client needs of the menopausal woman, but also to be able to differentiate between quality of life issues related to menopause and to cancer treatment in order to provide holistic nursing care.

Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship.

HYPOTHESIS: Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC. DESIGN: Review of endocrine surgery database from 1951 through 2002. SETTING: Tertiary referral center. PATIENTS: Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918). MAIN OUTCOME MEASURES: Stage of MTC at diagnosis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism. RESULTS: RET analysis was complete for 71 patients from 39 kindreds. Multivariate analysis identified an increased likelihood of stage III or IV MTC at diagnosis with increasing age (odds ratio, 1.12 per year of age at thyroidectomy; 95% confidence interval, 1.07-1.17; P<.001) and increasing risk group (odds ratio, 14.23 per incremental increase in MTC risk group from 1 to 3; 95% confidence interval, 3.05-66.55; P<.001). Pheochromocytomas were found in 21 patients from 12 kindreds; 20 of 21 patients had codon 634 or 918 mutations. Hyperparathyroidism was found in 10 patients from 7 kindreds; 7 of 10 patients had codon 634 mutations. CONCLUSION: Specific RET mutations predict the phenotypic expression of disease and the MTC aggressiveness in patients with MEN 2, guiding the timing of thyroidectomy and screening for pheochromocytoma.

Genotype-phenotype analysis in multiple endocrine neoplasia type 1.

HYPOTHESIS: Multiple endocrine neoplasia type 1 (MEN 1) syndrome is an autosomal dominant disorder caused by germline mutations in the MEN1 gene and characterized by multiple endocrine tumors, most notably in the parathyroid glands, pituitary, and pancreas. The syndrome demonstrates variable expressivity and considerable genetic heterogeneity. Patient data were examined for possible associations between genotype and phenotype. DESIGN: We reviewed recorded medical data from 1975 to 2001 on patients with MEN 1 and compared specific types and locations of MEN1 gene mutations with manifestations of the syndrome. PATIENTS AND RESULTS: We identified 109 affected patients from 24 MEN 1 kindreds. The phenotypic expression of MEN 1 in affected individuals included hyperparathyroidism in 74%, pancreatic endocrine tumors in 51%, and pituitary tumors in 35%. Twelve of 14 insulinomas occurred in patients with pituitary tumors. Mutation analysis was completed in 14 of 24 kindreds (80 of the 109 patients). Mutations were most common in exons 2 (31%), 9 (15%), and 10 (23%). All 21 patients with frameshift mutations (and known pancreatic endocrine tumor status) had such tumors. Pituitary tumors were associated with frameshift mutations in exon 2. CONCLUSIONS: The type and location of MEN1 mutations may be associated with the phenotypic expression of specific tumors. Such information may assist in the genetic counseling and surveillance of at-risk patients. A specific genotype-phenotype correlation is unlikely because of the heterogeneity of the mutations in the MEN1 gene.

Cancer survivors. Work related issues.

New and more effective treatments for cancer have resulted in individuals living longer with a better quality of life. Many more survivors are employed in the workplace. Cancer is no longer only an issue for survivors and their families; it has become an issue for the employer and the workplace. This article describes survey results of 4,364 long term cancer survivors in which they were asked to respond to items describing their ability to work, job discrimination, and quality of life. Thirty-five percent of survivors were working at the time they completed the survey, and 8.5% considered themselves unable to work. This research has shown that age, gender, ethnic group, and cancer type affected the working status of the survivors. Of survivors continuing to work, 7.3% indicated they had experienced job discrimination. The results indicate most cancer survivors do not perceive employment related problems, and are readily assimilated into the work force. Job discrimination and the ability to work is a quality of life issue.