A rare coexistence of parathyroid adenoma and medullary and papillary thyroid carcinoma.

The combination of parathyroid adenoma, medullary thyroid carcinoma (MTC), and papillary thyroid carcinoma (PTC) has been reported occasionally, but it has now been recognized more often through effective evaluations. However, the etiology and risk factors remain unclear, so we discuss them in this article. Here, we report the case of a 64-year-old woman with parathyroid adenoma, MTC, and PTC diagnosed incidentally. This woman was admitted to the Xingtai People's Hospital affiliated to Hebei Medical University for an apparently aggravating symptom of hypodynamia. Her past medical history included diabetes and a left nephrolith. Upon admission, her bloodwork showed hypercalcemia, hypophosphatemia, and elevated serum parathyroid hormone. Subsequently, the sonographic findings revealed dominant nodules in both the right and left lobes with a left inferior suspected parathyroid adenoma. The patient underwent fine needle aspiration (FNA) of the bilateral thyroid lobes, the results of which were both thyroid carcinoma. Therefore, a thyroidectomy, a neck dissection, and the excision of a suspected parathyroid adenoma were performed. A histological examination revealed a combination of parathyroid adenoma, MTC, and PTC. Her serum calcium and parathyroid hormone levels returned to the normal range after the surgery. Our case highlighted the fact that even though the concurrent existence of parathyroid adenoma, MTC, and PTC is rare, the diagnosis of this coexistence should be considered in primary hyperparathyroidism (PHPT). To avoid repeat surgeries, patients with coexisting diseases should be screened cautiously. Therefore, we recommend a preoperative check of the calcium levels in patients with thyroid cancer and a preoperative thyroid check in all patients with PHPT.

miR-452-5p and miR-215-5p expression levels in colorectal cancer tissues and their relationship with clinicopathological features.

The aim of the study was to investigate the expression levels of miR-452-5p and miR-215-5p in colorectal cancer tissues and their relationship with clinicopathological features. A total of 50 specimens of cancerous and adjacent normal tissues were collected from patients with colorectal cancer who underwent surgical resection at the Xingtai People's Hospital from March 2012 to February 2014. All specimens were confirmed by the Department of Pathology. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression levels of miR-452-5p and miR-215-5p in cancerous and adjacent normal tissues. Moreover, the relationship of the expression levels of miR-452-5p and miR-215-5p with the clinicopathological features of patients with colorectal cancer was explored. The expression levels of both miR-452-5p and miR-215-5p in colorectal cancer tissues were significantly lower than those in adjacent normal tissues (P<0.05). miR-452-5p expression was related to tumor-node-metastasis (TNM) staging and differentiation degree in colorectal cancer tissues, and the expression of miR-215-5p was associated with TNM staging, lymph node metastasis and infiltration depth (P<0.05). The 5-year overall survival (OS) rate in the miR-452-5p high-expression group was significantly higher than that in the low-expression group (P<0.05). The 5-year OS rates in the miR-215-5p high- and low-expression groups were 53.57% (15/28) and 40.91% (9/22), respectively, indicating that the 5-year OS rate in the miR-215-5p high-expression group was significantly higher than that in the low-expression group. Cox proportional hazards regression model showed that TNM staging, lymph node metastasis, as well as miR-452-5p and miR-215-5p expression levels were independent risk factors affecting colorectal cancer prognosis (P<0.05), whereas the differentiation degree and infiltration depth were not (P>0.05). In conclusion, the expression levels of miR-452-5p and miR-215-5p were significantly downregulated in colorectal cancer tissues promoting the occurrence, progression, invasion and metastasis of colorectal cancer, which suggests that miR-452-5p and miR-215-5p could be used as prognostic indicators for patients with colorectal cancer.

Copper-catalyzed synthesis of indolyl diketones via C-H oxidation/diacylation of indoles with arylglyoxal hydrates.

An expedient protocol for Cu-catalyzed C-H oxidation/diacylation of indoles with arylglyoxal hydrates to construct indolyl diketones is developed. This methodology exhibits the synthetic utility of the synthesis of an indole-alkaloid 1,2-di(1H-indol-3-yl)ethane-1,2-dione and offers a straightforward means to produce different indolyl nitrogen-containing heterocycles such as indolyl quinoxaline, indolyl hydantoin and indolyl imidazole in high yields. Preliminary mechanistic studies indicate that two proposed pathways are involved in this process.

Expression of Rab5a correlates with tumor progression in pancreatic carcinoma.

Rab family protein Rab5a has been implicated in cancer progression. To date, its expression pattern in human pancreatic cancer has not been investigated. This study aims to examine clinical significance, biological role, and potential mechanism of action of mRab5a in human pancreatic cancer. We analyzed Rab5a protein in cancer tissue of 111 cases of pancreatic cancer using immunohistochemistry. The results show that Rab5a overexpression correlates with high T stage, positive nodal status, and advanced TNM stage. We performed knockdown of Rab5a through transfection of Rab5a-specific siRNA in the Capan-2 cell line, which shows high endogenous expression, and of Rab5a plasmid in the CFPAC-1 cell line, which shows low endogenous expression. Rab5a knockdown inhibited cell proliferation and invasion while its overexpression promoted cell proliferation and invasion. In addition, overexpression of Rab5a induced resistance to 5-FU and gemcitabine while its knockdown reduced resistance to 5-FU and gemcitabine. Furthermore, our results show that Rab5a overexpression upregulates Wnt signaling and expression of Wnt target genes including c-myc and MMP7. Blocking Wnt signaling abolished the effects of Rab5a on Wnt targets and on cancer cell proliferation. In summary, our results show that Rab5a is overexpressed in pancreatic cancer and promotes aggressive biological behavior through regulation of the Wnt/ß-catenin signaling pathway.

Extranodal Rosai-Dorfman disease involving the right atrium in a 60-year-old male.

Rosai-Dorfman disease (RDD) involving the cardiovascular system is extremely rare; to our knowledge, there are only 9 cases in the literature. Here, a case of a 60-year-old male with RDD involving the right atrium is presented. A comprehensive literature review was undertaken to summarize the clinical and pathologic features of this disorder. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2143194139120169.

Gremlin 2 promotes differentiation of embryonic stem cells to atrial fate by activation of the JNK signaling pathway.

The bone morphogenetic protein antagonist Gremlin 2 (Grem2) is required for atrial differentiation and establishment of cardiac rhythm during embryonic development. A human Grem2 variant has been associated with familial atrial fibrillation, suggesting that abnormal Grem2 activity causes arrhythmias. However, it is not known how Grem2 integrates into signaling pathways to direct atrial cardiomyocyte differentiation. Here, we demonstrate that Grem2 expression is induced concurrently with the emergence of cardiovascular progenitor cells during differentiation of mouse embryonic stem cells (ESCs). Grem2 exposure enhances the cardiogenic potential of ESCs by 20-120-fold, preferentially inducing genes expressed in atrial myocytes such as Myl7, Nppa, and Sarcolipin. We show that Grem2 acts upstream to upregulate proatrial transcription factors CoupTFII and Hey1 and downregulate atrial fate repressors Irx4 and Hey2. The molecular phenotype of Grem2-induced atrial cardiomyocytes was further supported by induction of ion channels encoded by Kcnj3, Kcnj5, and Cacna1d genes and establishment of atrial-like action potentials shown by electrophysiological recordings. We show that promotion of atrial-like cardiomyocytes is specific to the Gremlin subfamily of BMP antagonists. Grem2 proatrial differentiation activity is conveyed by noncanonical BMP signaling through phosphorylation of JNK and can be reversed by specific JNK inhibitors, but not by dorsomorphin, an inhibitor of canonical BMP signaling. Taken together, our data provide novel mechanistic insights into atrial cardiomyocyte differentiation from pluripotent stem cells and will assist the development of future approaches to study and treat arrhythmias.

Copper-catalyzed decarboxylative C3-acylation of free (N-H) indoles with α-oxocarboxylic acids.

An efficient Cu-catalyzed decarboxylative C3-acylation of free (N-H) indoles using α-oxocarboxylic acids as acylating agents has been developed. This method was compatible with a variety of functional groups and provided an attractive alternative access to 3-acylindoles in moderate to high yields.

Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1.

The prototypic second messenger cyclic AMP (cAMP) is essential for controlling cellular metabolism, including glucose and lipid homeostasis. In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs). To explore the physiological functions of Epac1, we generated Epac1 knockout mice. Here we report that Epac1 null mutants have reduced white adipose tissue and reduced plasma leptin levels but display heightened leptin sensitivity. Epac1-deficient mice are more resistant to high-fat diet-induced obesity, hyperleptinemia, and glucose intolerance. Furthermore, pharmacological inhibition of Epac by use of an Epac-specific inhibitor reduces plasma leptin levels in vivo and enhances leptin signaling in organotypic hypothalamic slices. Taken together, our results demonstrate that Epac1 plays an important role in regulating adiposity and energy balance.

2-(4-Fluoro-phen-yl)quinoxaline.

In the title compound, C(14)H(9)FN(2), the dihedral angle between the benzene ring and the quinoxaline ring system is 22.2 (3)°. Any aromatic π-π stacking in the crystal must be very weak, with a minimum centroid-centroid separation of 3.995 (2) Å.

Pharmacovigilance practice and risk control of Traditional Chinese Medicine drugs in China: current status and future perspective.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicine (TCM), including Traditional Chinese Medicine drugs (TCM drugs), has been playing a very important role in health protection and disease control for thousands of years in China. Relying on natural products, mainly of herbal origin, used either as raw materials for decoction, as prepared herbal medicines or as formulated traditional medicines, TCM is still widely accepted by Chinese people, especially for chronic diseases treatment. This extensive use warrants safety measures and so TCM drug safety monitoring and risk management are becoming increasingly important tasks for the Chinese State Food and Drug Administration (SFDA). METHODS: The Adverse Drug Reaction (ADR) monitoring system in China was established both for western and TCM drugs in 1989 as a voluntary reporting system with a National Center collecting and compiling reports. Serious or multi-case reports on individual TCM drug or formulated products are detailed in the Chinese ADR Information Bulletin to inform the public and Drug Administrative authorities for risk management. RESULTS: About 10-15% of the ADR reports received by the National Center are related to TCM drugs and mainly pertaining to the formulated products. In certain cases, the suspension of a particular TCM preparation is decided by SFDA China. CONCLUSION: The model of safety monitoring and risk management of TCM drugs is still under exploration. Indeed, the characteristics and risk factors associated with these drugs require both proper understanding and control of the risk by strengthening standardization of clinical applications, basic science research, quality control in manufacturing, exploration of the actives monitoring methodology and enhancement of international communication and cooperation.

Methyl 4-(5-meth-oxy-1H-indol-3-yl)benzoate.

In the title compound, C(17)H(15)NO(3), the dihedral angle between the benzene ring and the indole ring system is 22.5 (3)°. In the crystal, mol-ecules are linked by N-H⋯π and C-H⋯O inter-actions.

Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model.

Activating mutations in the Kras gene are commonly found in some but not all epithelial cancers. In order to understand the susceptibility of different epithelial tissues to Kras-induced tumorigenesis, we introduced one of the most common Kras mutations, Kras(G12D), broadly in epithelial tissues. We used a mouse model in which the G12D mutation is placed in the endogenous Kras locus controlled by inducible, Cre-mediated recombination in tissues expressing cytokeratin 19 including the oral cavity, GI tract, lungs, and ducts of the liver, kidney, and the pancreas. Introduction of the Kras(G12D) mutation in adult mouse tissues led to neoplastic changes in some but not all of these tissues. Notably, many hyperplasias, metaplasias and adenomas were observed in the oral cavity, stomach, colon and lungs, suggesting that exposure to products of the outside environment promotes Kras(G12D)-initiated tumorigenesis. However, environmental exposure did not consistently correlate with tumor formation, such as in the small intestine, suggesting that there are also intrinsic differences in susceptibility to Kras activation. The pancreas developed small numbers of mucinous metaplasias with characteristics of early stage pancreatic intraepithelial neoplasms (PanINs), supporting the hypothesis that pancreatic ducts have the potential to give rise pancreatic cancer.

New anti-fibrotic mechanisms of n-acetyl-seryl-aspartyl-lysyl-proline in silicon dioxide-induced silicosis.

AIMS: We previously reported that tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibited pulmonary inflammation and fibrosis in SiO(2)-induced silicosis. This study aimed to explore the precise mechanism involved. MAIN METHODS: Rats were divided into 3 groups: 1) sham (saline), 2) silicosis+vehicle, and 3) silicosis+Ac-SDKP [800 microg/(kgd)]. SiO(2) particles or saline were administered by tracheal instillation and Ac-SDKP or vehicle (saline) via a mini-osmotic pump planted into the abdominal cavity 48 h before instillation. Animals were observed for 4 weeks. Silicotic nodule fraction (SNF) and macrophage infiltration (ED-1 positive cells) were measured by hematoxylin and eosin (H.E.) and immunohistochemical staining respectively. Collagen I and III, transforming growth factor-beta1 (TGF-beta1) proteins and monocyte chemotactic protein-1 (MCP-1) mRNA were detected by Western Blot (WB) and real-time RT-PCR respectively. In vitro, pulmonary fibroblasts were stimulated by TGF-beta1 (5 microg/ml) with or without Ac-SDKP. Phosphorylated c-Jun N-terminal Kinase (p-JNK) was detected by WB and p-JNK nuclear translocation by confocal analysis. KEY FINDINGS: SiO(2) significantly increased the SNF, collagen I and III proteins, TGF-beta1, MCP-1 mRNA and macrophage infiltration. All these pathological changes were inhibited by Ac-SDKP. TGF-beta1 resulted in fibroblast proliferation, increased expression of collagen I and III proteins, p-JNK and its subsequent nuclear translocation. Addition of Ac-SDKP markedly suppressed these changes. SIGNIFICANCE: These data indicate that the anti-fibrotic effect of Ac-SDKP in silicosis is mediated by inhibiting chronic inflammation, TGF-beta1 production, and TGF-beta1-induced pulmonary fibroblast proliferation and collagen synthesis.

3-(4-Meth-oxy-phen-yl)pyrido[2,3-b]pyrazine.

In the title mol-ecule, C(14)H(11)N(3)O, the benzene ring is twisted by 14.0 (2)° from the plane through the fused ring system. In the crystal, π-π inter-actions [centroid-centroid distances = 3.609 (1), 3.639 (1) and 3.735 (1) Å] form stacks of mol-ecules propagating along the b axis. The crystal packing is further stabilized by weak inter-molecular C-H⋯O and C-H⋯N hydrogen bonds.

Neurog3 gene dosage regulates allocation of endocrine and exocrine cell fates in the developing mouse pancreas.

The basic helix-loop-helix transcription factor Neurog3 (Neurogenin3 or Ngn3) actively drives endodermal progenitor cells towards endocrine islet cell differentiation during embryogenesis. Here, we manipulate Neurog3 expression levels in endocrine progenitor cells without altering its expression pattern using heterozygosity and a hypomorph. Lowered Neurog3 gene dosage in the developing pancreatic epithelium reduces the overall production of endocrine islet cells without significantly affecting the proportions of various islet cell types that do form. A reduced Neurog3 production level in the endocrine-directed pancreatic progenitor population activates the expression of Neurog3 in an increased number of epithelial progenitors. Yet a significant number of these Neurog3+ cells detected in heterozygous and hypomorphic pancreata, possibly those that express low levels of Neurog3, move on to adopt pancreatic ductal or acinar fates. These data directly demonstrate that achieving high levels of Neurog3 expression is a critical step for endocrine commitment from multipotent pancreatic progenitors. These findings also suggest that a high level of Neurog3 expression could mediate lateral inhibition or other unknown feedback mechanisms to regulate the number of cells that initiate Neurog3 transcription and protein production. The control of Neurog3+ cell number and the Neurog3 threshold-dependent endocrine differentiation mechanism combine to select a specific proportion of pancreatic progenitor cells to adopt the islet cell fate.

[Antifibrotic effects of N-acetyl-seryl-aspartyl-lysyl-proline mediated by regulation of transforming growth factor beta and connective tissue growth factor expression on rats with silicosis].

OBJECTIVE: To investigate whether the effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) on transforming growth factor beta (TGF-beta1) and connective tissues growth factor (CTGF) was involved in AcSDKP's antifibrotic effect on the rats with silicosis. METHODS: Rats were divided into 6 groups randomly, 10 rats in each group: Control of silicotic model: 1.0 ml normal sodium and was killed after 4 or 8 weeks; Silicotic model 1: 50 mg/ml silica suspension and was killed after 4 weeks; Silicotic model 2: 50 mg/ml silica suspension and was killed after 8 weeks; Anti-fibrosis treatment of AcSDKP: after each rat was intratracheally instilled with 50 mg/ml silica suspension for 4 weeks, AcSDKP 800 microg/(kg x d) was administered into every rat and rats were killed at the 8 weeks; Preventing fibrosis treatment of AcSDKP: after AcSDKP [800 microg/(kg x d)] was administered into every rat for 48 hours, each rat was intratracheally instilled with 50 mg/ml silica suspension and rats were killed at the 8 weeks. Lung fibrosis in morphology was observed by HE staining. The expressions of TGF-beta1 and CTGF in lung were observed by immunohistochemistry. The mRNA expressions of TGF-beta1 and CTGF in lung were observed by real-time PCR. RESULTS: In anti-fibrosis treatment of AcSDKP group, protein expression of TGF-beta1 and CTGF were (0.244 +/- 0.016) and (0.241 +/- 0.017) respectively, and significantly lower that those in the silicotic model 1 and 2 groups; mRNA expressions of TGF-beta1 and CTGF decreased, mRNA expressions of CTGF were significantly lower that those in the silicotic model 1 and 2 groups (P < 0.05); In preventing fibrosis treatment of AcSDKP group, protein expression and mRNA expression of TGF-beta1 were significantly lower that those in the silicotic model 2 group (P < 0.05). CONCLUSION: AcSDKP can decrease the expressions of TGF-beta1 and CTGF in lung tissues of the rats with experimentally induced pulmonary fibrosis.

[Anti-fibrotic effect of N-acetyl-seryl-aspartyl-lysyl-proline in lung of rat with silicosis].

OBJECTIVE: To investigate the effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) on the collagen synthesis and expression in lung of rats with silicosis. METHODS: Rats were divided into 6 groups randomly, 10 rats in each group: Control 1 of silicotic model: each rat was intratracheally instilled with 1 ml normal sodium and was killed at the fourth week; Control 2 of silicotic model: each rat was intratracheally instilled with 1 ml normal sodium and was killed at the eighth week; Silicotic model 1: each rat was intratracheally instilled with 1 ml silica suspension and was killed at the fourth week; Silicotic model 2: each rat was intratracheally instilled with 1 ml silica suspension and was killed at the eighth week; Anti-fibrosis treatment of AcSDKP: after each rat was intratracheally instilled with 1 ml silica suspension for 4 weeks, AcSDKP 800 microg/(kgxd) was administered into every rat and rats were killed at the eighth week; Preventing fibrosis treatment of AcSDKP: after AcSDKP 800 microg/(kgxd) was administered into every rat for 48 hours, each rat was intratracheally instilled with 1 ml silica suspension and rats were killed at the eighth week. Lung fibrosis in morphology was observed by HE and VG staining. Collagen content was detected by hydroxyproline assay. The expression of type I and III collagen was evaluated by western blot. RESULTS: Compared with those of silicotic model 1 and silicotic model 2 group, in anti-fibrosis treatment of AcSDKP group, the area of silicosis nodules decreased to 84.28% and 67.93%, the content of hydroxyproline decreased to 70.89% and 58.18%, the expression of type I collagen decreased to 71.08% and 58.13%, and expression of type III collagen decreased to 80.13% and 70.70%. Compared with those of silicotic model 2 group, in preventing fibrosis treatment of AcSDKP group, area of silicosis nodules decreased to 61.13%, content of hydroxyproline decreased to 60.27%, and expression of type I and type III collagen decreased to 40.13% and 65.77%. CONCLUSION: AcSDKP could obviously inhibit the synthesis and expression of collagen in lung of rats with silicosis, which is possibly related with anti-fibrosis effect of AcSDKP.

[AcSDKP attenuates PDGF-induced cardiac fibroblasts proliferation and collagen expression: role of extracellular regulated protein kinase 1/2 pathway].

OBJECTIVE: To investigate the effects of AcSDKP on platelet-derived growth factor (PDGF)-induced rat cardiac fibroblasts proliferation and collagen expression and explore the role of extracellular regulated protein kinase 1/2 (ERK1/2) pathway on this process. METHODS: Metabolic activity of fibroblasts was determined by CCK-8. Cell cycle was detected by flow cytometry. Expressions of type I and type III collagen were measured by immunocytochemistry and Western blot. Expressions of phospho-ERK1/2 and ERK1/2 were detected by Western blot. RESULT: 10(-9) mol/L AcSDKP could significantly inhibit PDGF-induced cardiac fibroblasts proliferation, collagen expression and expressions of phospho-ERK1/2, while the protein levels of ERK1/2 were not significantly affected by AcSDKP. CONCLUSION: AcSDKP could inhibit PDGF-induced cardiac fibroblasts proliferation and collagen expression through activation of phosphor-ERK1/2 pathway.

[Antifibrotic effects of N-acetyl-seryl-aspartyl-lysyl-proline mediated by the regulation of MCP-1 and ED-1 expression on rats with silicosis].

OBJECTIVE: To investigate whether the effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) on macrophage infiltration was involved in AcSDKP's antifibrotic effect on the rats with silicosis. METHODS: Rats were intratracheally instilled with silica as silicotic models in the experiment. Wistar rats were divided into 6 groups randomly: control 1, control 2, silicotic model 1, silicotic model 2, anti-fibrosis treatment of AcSDKP, Preventing fibrosis treatment of AcSDKP. Lung fibrosis in morphology was observed by H.E staining. Collage content was detected by Hydroxyproline assy. The expressions of MCP-1 and ED-1 in lung were observed by immunohistochemistry. RESULTS: In anti-fibrosis treatment of AcSDKP group, area of of silicosis nodules decreased to 84.28% and 67.93%, content of hydroxyproline decreased to 70.89% and 58.18%, protein expression of MCP-1 decreased to 82.3% and 84.1%, cell numbers of MCP-1 decreased to 67.4% and 72.5%, protein expression of ED-1 decreased to 78.7% and 79.3%, cell numbers of ED-1 decreased to 54.4% and 66.8%. In Preventing fibrosis treatment of AcSDKP group, area of silicosis nodules decreased to 61.13%, content of hydroxyproline decreased to 60.27%, protein expression and cell numbers of MCP-1 decreased to 85.2% and 86.3%, protein expression and cell numbers of ED-1 decreased to 87.2% and 74.9%. CONCLUSION: AcSDKP can decrease and reverse pulmonary fibrosis in rats with silicosis which may be mediated in part by inhibition of the infiltration and aggregation of macrophage and the severity of silicotic alveolitis.

In vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules.

Endoplasmic reticulum (ER)-associated aminopeptidase (ERAP)1 has been implicated in the final proteolytic processing of peptides presented by major histocompatibility complex (MHC) class I molecules. To evaluate the in vivo role of ERAP1, we have generated ERAP1-deficient mice. Cell surface expression of the class Ia molecules H-2Kb and H-2Db and of the class Ib molecule Qa-2 was significantly reduced in these animals. Although cells from mutant animals exhibited reduced capacity to present several self- and foreign antigens to Kb-, Db-, or Qa-1b-restricted CD8+ cytotoxic T cells, presentation of some antigens was unaffected or significantly enhanced. Consistent with these findings, mice generated defective CD8+ T cell responses against class I-presented antigens. These findings reveal an important in vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules.