The expression profile of integrin receptors and osteopontin in thyroid malignancies varies depending on the tumor progression rate and presence of BRAF V600E mutation

Thyroid cancer (TC) is one of the most common malignancy of the human endocrine system. BRAF V600E mutation is the most frequent genetic alteration of papillary carcinoma, the most frequent TC, which effects RAS-RAF-MEK intracellular signaling pathway. These alterations in RAS-RAF-MEK pathway lead to changes in expression levels of cell membrane integrin receptors and their ligand - extracellular matrix protein osteopontin, which in turn increases the metastatic potential of tumor cells. Thus, integrins and their ligand osteopontin can be considered as potential biomarkers of tumor progression and aggressive tumor phenotypes.The aim of the study was to evaluate the expression levels of integrin receptors ITGA2, ITGA3, ITGAV, ITGA6, ITGA9, ITGB1, ITGB3 and their ligands OPNa, OPNb in the thyroid cancer with different BRAF V600E mutation status.

PINX1 promotes malignant transformation of thyroid cancer through the activation of the AKT/MAPK/β-catenin signaling pathway

Although thyroid cancer is the most prevalent endocrine malignancy, overall patients with thyroid cancer have a good long-term survival. However, a small percentage of patients with progressive thyroid cancer have poor outcomes, and the genetic drivers playing a key role thyroid cancer progression are mostly unknown. Here, we investigated the role of the PINX1 in thyroid cancer progression. Interestingly, PINX1 expression was significantly higher in ATC than in PTC in both patients and cell lines. When PINX1 was knockdown in ATC cells, cell proliferation rates, colony formation capacity, and cell cycle progression were significantly reduced. Furthermore, cell motility and the expression of EMT drivers were reduced by PINX1 downregulation. In contrast, the overexpression of PINX1 in PTC cells significantly increased those phenotypes of tumor progression, which demonstrates that PINX1 could promote tumor proliferation and malignant transformation in both PTC and ATC cells. To further understand whether PINX1 is also involved in the progression of PTC to ATC, we examined PI3K/AKT, MAPK, and β-catenin signaling activation after PINX1 modulation. Decreased PINX1 expression reduced the levels of p-AKT, p-ERK, p-p38, and β-catenin in ATC cells, but the increase of PINX1 expression upregulated the phosphorylation of AKT, ERK, and p38 and the levels of β-catenin in PTC cells. These results were all confirmed in xenograft mouse tumors. Our findings suggest that PINX1 regulates thyroid cancer progression by promoting cell proliferation, EMT, and signaling activation, and support the hypothesis that PINX1 could be a prognostic marker and a therapeutic target of thyroid cancer.     

Drug-inducing gynaecomastia--a critical review

Gynaecomastia has been associated with a large variety of drugs in the literature. However, a causal relation of the incidence of gynaecomastia to a certain drug should be considered only if sufficient and significant evidence can be obtained from the studies published. In this review, studies quoted in Medline were evaluated according to the Scottish Intercollegiate Guidelines Network (SIGN) grading system for clinical studies. Reports on 92 drugs were found in Medline in combination with gynaecomastia. An imbalance of the oestrogen/androgen ratio causes gynaecomastia. Also, prolactin has gynaecomastia-inducing properties. In 14 of the drugs quoted, the studies lead to a level of recommendation 'A'. All these drugs have been designed to interfere with the production and action of sexual hormones or of prolactin. In 25 of the drugs, the level of recommendation was 'B'. Besides those drugs in this group that have been designed for interference with the metabolism of steroid hormones or of prolactin, in drugs for acid-related disorders, diuretics, antiretroviral drugs, antimycotics, psychoanaleptics, alcohol gynaecomastia was described as an unexpected adverse effect. Studies on the association of drugs and gynaecomastia do not share a generally accepted definition of gynaecomastia; in this way, the informational value is limited.     

益气平悬饮对艾氏腹水癌小鼠肿瘤浸润淋巴细胞杀伤活性的影响

目的　探讨益气平悬饮对肿瘤浸润淋巴细胞 (tumor- infiltrating lym phocytes,TIL )杀伤自体肿瘤细胞(anto- tumor cells,ATC)活性的影响。方法　取昆明种小鼠 4 0只 ,腹腔接种艾氏腹水癌瘤株 (EAC)瘤液建立移植瘤模型 ,接种次日随机分为 4组 :益气平悬饮大、小剂量 (37.0 ,18.5 g/ kg)组、环磷酰胺对照组、模型对照组。益气平悬饮大、小剂量组当日 ig给药 ,共给药 9d,环磷酰胺组 ip环磷酰胺 75 m g/ kg,自接种第 3日起 ,隔日给药 ,共4次。末次给药次日 ,无菌抽取 EAC小鼠腹水 ,用不连续密度梯度离心收集 TIL 作为效应细胞 ,分离出 ATC作为靶细胞 ,培养液中培养 ,效靶比为 10∶ 1,以 MTT法计算细胞杀伤活性。并在光镜下观察混合培养 2 ,4 ,10 ,14 ,2 4 h细胞形态学变化。结果　益气平悬饮大、小剂量组 TIL杀伤活性均高于模型对照组 ,差异显著 (P<0 .0 5 )。结论益气平悬饮能提高 TIL 杀伤 ATC的活性。     

Patterns and determinants of new first-line antihyperglycaemic drug use in patients with type 2 diabetes mellitus

Aims

We evaluated the patterns and determinants that influence the selection, timing and duration of first-line antihyperglycaemic drug (AHD) treatment in patients with type 2 diabetes in Germany, focusing specifically on treatment-naive AHD initiators.

Methods

Pharmacy dispensing claims data were linked with a cohort of patients newly enrolled in a German Disease Management Program for type 2 diabetes (DMP-DM2) between 2003 and 2009. We examined uptake of first-line pharmacotherapy in previously unmedicated patients and identified predictors of receiving AHD therapy in general and metformin in particular using multivariable regression analyses.

Results

There were 27,138 unmedicated patients with type 2 diabetes and 47.0% of them were started on AHD treatment within 5 years after enrollment. Initial severity of diabetes was the major predictor of receiving first-line pharmacotherapy. Metformin accounted for 63% of newly prescribed AHD in 2003 and more than 80% in 2009 while sulfonylureas accounted for only 10%. Initiating metformin as first-line AHD was associated with younger age, higher BMI, lower HbA1c, and shorter diabetes duration (multivariate p < 0.001 for all). Therapy switch or step-up was less frequent among metformin initiators than sulfonylurea initiators.

Conclusions

The majority of patients were not started on AHD therapy within 5 years after enrollment. In line with recent therapy guidelines, current first-line antihyperglycaemic treatment was increasingly based on metformin. AHD initiators started on sulfonylurea were generally more advanced in their disease and were started later on primary pharmacotherapy.     

Second-Line Chemotherapy with Bleomycin,Methotrexate, and Vinorelbine (BMV) for Patients with Squamous Cell Carcinoma of the Head,Neck and Esophagus (SCC-HN&E) Pretreated with a Cisplatin-Containing Regimen: A Phase II Study

Abstract

We evaluated the toxicity and activity of bleomycin, methotrexate and vinorelbine (BMV) combination chemotherapy in cisplatin-pretreated patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) with the aim of identifying a second-line therapy combination and schedule that might offer an improved therapeutic index. BMV (bleomycin 15 I.U., total dose, methotrexate 30 mg/m², and vinorelbine 30 mg/m²) was administered intravenously every 2 weeks until disease progression, to 26 consecutive patients. Clinical and CT-scan evaluations revealed 7 partial responses (PR) [27%, 95% confidence interval: 9.6%-44.4%], and 13 patients with stable disease (SD) [50%]. The mean progression-free survival for patients who achieved a PR or SD was 6.47 months (range 4-13 months), with 75% of these patients experiencing partial relief of symptoms, mainly pain and dysphagia. BMV, administered second-line in an outpatient setting, has activity similar to that of the taxanes, but with a more acceptable toxicity profile including an absence of alopecia.     

Dutch hospital drug formularies: pharmacotherapeutic variation and conservatism, but concurrence with national pharmacotherapeutic guidelines

AIMS: This research examines current hospital drug formularies (HDFs) of all Dutch general hospitals. It assesses the extent to which they recommend the same drugs, the breadth of their coverage in terms of therapeutic areas, drug groups incorporated and individuals drugs included, and their extent of conservatism by considering the year of introduction of the drugs included within groups. Furthermore, it considers the extent to which their recommendations concur and comply with those of national pharmacotherapeutic guidelines and the WHO Essential Drugs List (EDL). METHODS: Seventy-eight (81%) out of all 96 current Dutch HDFs were received of which 62 were suitable for study. Differences between HDFs and eventual associations with hospital characteristics were researched by statistical testing and case-control studies. To evaluate HDFs' concurrence with national guidelines and compliance with the WHO EDL, nine drug groups were studied in detail: benzodiazepines, calcium channel blockers, beta-adrenoceptor blocking agents, ACE-inhibitors, angiotensin-II inhibitors, NSAIDs, H2-receptor antagonists, 5HT3-antagonists, and H+-pump inhibitors. Concurrence and compliance with national guidelines and the WHO EDL was defined as inclusion of recommended drugs. Non-concurrence was defined as inclusion of nonrecommended drugs. RESULTS: The total number of indications addressed and drug groups incorporated within HDFs varied from 28 to 72 (median 56) and from 30 to 123 (median 97), respectively. The total number of individual drug entities (pharmacological substances) included ranged from 239 to 658 (median 430) and the total number of drug products, including all different dosage forms, from 412 to 1121 (median 655). Within drug groups, drug entities first marketed were most frequently included. Teaching hospitals were most likely to include recently marketed drugs. Depending on the drug group, HDFs' concurrence and compliance with national guidelines and the WHO EDL ranged from 35% to 100%. CONCLUSIONS: Findings indicate that Dutch HDFs are rather uniform in the indications addressed and the drug groups incorporated. However, the number of individual drug entities and drug products included within groups varies considerably. Furthermore, Dutch HDFs are considered rather conservative, as older drugs are favoured over more recent drugs. Generally, with some drug exceptions, Dutch HDFs concur and comply with recommendations in national pharmacotherapeutic guidelines and with the WHO EDL over 90%.