Autonomic Dysfunction of the β-Cell and the Pathogenesis of Obesity

Reviews in Endocrine and Metabolic Disorders -     

Diagnosis and treatment of solid-pseudopapillary tumor of the pancreas

BACKGROUND: Solid-pseudopapillary tumor (SPT) of the pancreas is a rare exocrine pancreatic tumor. Despite the increasing recognition of the tumor in recent years, its pathogenesis and apparent therapeutic algorithm remain unclear. This study was designed to define the clinical, imaging, and pathologic features and to improve the diagnosis and treatment of this rare disease. METHOD: The clinical, imaging, and pathologic findings of 9 SPT patients managed in our hospital between 2001 and 2005 were retrospectively analyzed, and related literatures were reviewed. RESULTS: In the 9 patients aged from 14 to 68 years, 8 were female and 1 male. The mean age of these patients at diagnosis was 30 years. Initially, 8 patients complained of vague abdominal pain and one patient had pancreatic mass detected incidentally by abdominal CT. The levels of blood and urine amylase and tumor markers were all within the normal range. B-US, CT and MRI demonstrated that tumors were well encapsulated and contained some degree of internal hemorrhage or cystic degeneration. The mean transverse diameter of these tumors was 5.4 cm (range, 2-10.5 cm). The tumors were located at the head (2 patients), body (2), body and tail junction (4), and tail (1) of the pancreas. Surgical procedures included pancreaticoduodenectomy, distal pancreatectomy, distal pancreatectomy with splenectomy, and enucleation. Histological examination showed solidified cystic areas and papillary protrusions. Two malignant tumors demonstrated retroperitoneal metastases and vascular invasion. Follow-up for 2.5 years on average showed that one patient died of tumor recurrence at 10 months and the rest were alive. CONCLUSIONS: SPT exhibits unique clinical and pathologic features and is readily diagnosed by its characteristic imaging and histological appearance. Surgical resection of the primary tumor and metastases is the treatment of choice.     

Depressive Effect of the Antisense Oligonucleotides of C-myc and PCNA on the Proliferation of VSMC

Objectives To study the depressive effect of the antisense oligonuceotides (ASODN) of c-myc and proliferating cell nuclear antigen (PCNA) on the proliferation of VSMC. Methods Taking the VSMC obtained from rat aorta thoracalis cultured 4～8 generation as research object. The objects were divided into three groups to carry out control study: control group, PCNA ASODN group and c-myc ASODN group. The ASODNs' working concentration all were 1:50. The depressive effect of ASODN on VSMC proliferation was investigated by cell counting, MTT and 3H-TdR incorporation assay; PCNA and c-myc expression were detected by immunohistochemical method after transferring PCNA and c-myc ASODN into VSMC. Results PCNA and c-myc ASODN could inhibit the proliferation of VSMC significantly, compared with control group (P<0.05). ② Transferring PCNA and c-myc ASODN into VSMC obtained successfully; the corresponding gene was inhibited obviously; compared with control group (P<0.05). Conclusions PCNA and c-myc might play a considerable role in the VSMC proliferation process. The corresponding gene could be depressed successfully after transferring PCNA and c-myc ASODN into VSMC, and then the proliferation of VSMC was slowed down. This study presented a beneficial proposal and theoretical fundament for atherosclerotic treatment.     

What is the role of radiotherapy in the treatment of mucosal melanoma of the head and neck?

Mucosal melanoma of the head and neck is a rare, poor prognosis tumour with a high tendency to recur locally and regionally after surgical resection. A number of centres have used radiotherapy to sterilize positive and close margins after non-radical surgery or to treat inoperable cases. The present article discusses the literature data to analyze the possible indications for radiotherapy in terms of patient selection and treatment strategy. In the majority of the available retrospective series, postoperative radiotherapy improves the local control of mucosal melanomas, but its effect on survival has not yet been sufficiently investigated. Radiobiological studies show a high heterogeneity in behaviour of irradiated melanoma cells and the clinical implications of this will be illustrated. In the future, a better understanding of the radiosensitivity of this rare tumour and the availability of new technical modalities might allow for a more profitable incorporation of radiotherapy into a multidisciplinary strategy.     

Carcinosarcoma of the stomach： A case report and review of the literature

Carcinosarcomas are rare, malignant, biphasic tumors. We report the case of a 62-year-old man with gastric carcinosarcoma, along with its clinical, macroscopic and histopathological features. Macroscopically, a specimen of deformed stomach was obtained that measured 200 mm × 150 mm × 100 mm. A 150 mm × 100 mm × 50 mm exophytic tumoral mass （Borrmann type Ⅰ ） was found, which involved the posterior wall from the cardia to the antrum. Histopathologically, a mixed type of malignancy was revealed： an adenocarcinoma with intestinal metaplasia, with interposed fascicles of fusiform atypical cells and numerous large, rounded and oval cells. The tumor showed positive histochemistry for cytokeratin 18, epithelial membrane antigen, carcinoembryonic antigen, chromogranin A and vimentin. Liver metastases were diagnosed 8 mo postoperatively, and the patient died 4 mo later. A review of the available literature is also presented.     

What is the role and significance of serum and stool biomarkers in the diagnosis of IBD?

Biomarkers hold promise for identifying high-risk individuals who may go on to develop IBD as well as prognosticate disease behavior. Stool markers have not been readily accepted but may be more sensitive and specific than our serum biomarkers for evaluating disease activity. Ultimately, genomic and proteomic approaches will be used to identify novel biomarkers in IBD.     

Parasitofauna of the nine-spined stickleback from the Gulf of Gdańsk and the mouth of Dead Vistula

Four species, one subspecies and one parasite marked to the genus were collected from the nine-spined stickleback Pungitius pungitius L. from the Gulf of Gdańsk and the mouth of Dead Vistula. Nine-spined stickleback was noted as a new host in Polish coastal water for five parasites: Glugea anomala (Microsporidia), Diplostomum spathaceum (Digenea-metacercariae) and Apatemon sp. (Digenea-incysted metacercariae), Hysterothylacium aduncum (Nematoda-third stage larvae) and Thersitina gasterostci (Copepoda). Earlier in this area have been obserwd only ciliates Tnchodina domerguei.     

Obesity and the risk of cardiovascular disease and diabetes mellitus

The increasing prevalence of obesity worldwide has many experts concerned about the worsening health of a large proportion of the population. It is well recognized that obesity is associated with a higher mortality, an increased risk of hypertension and hyperlipidemia, cardiovascular disease, diabetes mellitus, osteoarthritis, gall bladder disease and possibly some cancers. Currently it is estimated that over two thirds of adults in the United States are overweight and nearly one third are clinically obese. Of special concern is the rapid increase     

Molecular biology and the diagnosis and treatment of liver diseases

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Effects of Exercise on the Flow of Blood and Lymph

One of the greatest benefits derived fromexerciser is the improved circulation of bloodand lymph to all parts of the body,whichitbrings about.The blood has several important functions,namely,(1) to absorb nutrient material fromthe intestine and distribute it throughout thebody,(2)to take oxygen from the lungs andconvey it to the tissues,(3)toremove wasteproducts from the tissues,and (4) to distri-bute and equalize body heat. To perform thesefunctions effectively the circulatory systemrequires the stimuli of muscular activity.Exercise causes the heart to beat more for     

What are the risks and the benefits of current and emerging weight-loss medications?

Obesity is epidemic; new medications and therapeutic options are urgently needed to reduce the associated health care burden. The initial clinical strategy for weight loss is lifestyle modification involving a combination of diet, exercise, and behavior change. However, it is difficult for many to achieve and maintain weight loss solely through this approach. Only two drugs, orlistat and sibutramine, have been approved by the US Food and Drug Administration (FDA) to treat obesity long term, and both medications have undesirable side effects, leaving an enormous unmet need for efficacious and safe therapy for obesity. Other medications with weight-loss effects have been approved by the FDA for short-term treatment of obesity or for disorders other than obesity, but these also have potential adverse effects. This article discusses the perceived benefits and risks of these approved medications along with emerging drugs that have shown weight-loss effects.     

Analysis of the levels of endotoxin and β-d-glucan in the synovial fluid of hemodialysis patients

Abstract

We analyzed the levels of endotoxin and β-d-glucan, which possibly induce cytokine production, in the synovial fluid of patients on long-term hemodialysis and compared the results to those in patients with osteoarthritis and rheumatoid arthritis. We studied 42 knees in 42 hemodialysis patients, 21 in 21 osteoarthritis patients, and 26 in 26 rheumatoid arthritis patients. The mean ages were 60.7, 63.2, and 59.7 years, respectively. The duration of hemodialysis in the long-term hemodialysis group averaged 14.0 years. The concentrations of endotoxin and β-d-glucan in the synovial fluid of these three groups were measured. The concentration of endotoxin was the same in the three groups. However, the concentration of β-d-glucan was significantly higher in long-term hemodialysis patients. This finding suggests that β-d-glucan may have some relation to the pathogenesis of the synovitis which exists in the hydrarthrosis of long-term hemodialysis patients.     

The molecular and cellular mechanisms of itch and the involvement of TRP channels in the peripheral sensory nervous system and skin

Itch is an unpleasant cutaneous sensation that can arise following insect bites, exposure to plant ingredients, and some diseases. Itch can also have idiopathic causes. Itch sensations are thought to protect against external insults and toxic substances. Although itch is not directly lethal, chronic and long lasting itch in certain diseases can worsen quality of life. Therefore, the mechanisms responsible for chronic itch require careful investigation. There is a significant amount of basic research concerning itch, and the effect of various itch mediators on primary sensory neurons have been studied. Interestingly, many mediators of itch involve signaling related to transient receptor potential (TRP) channels. TRP channels, especially thermosensitive TRP channels, are expressed by primary sensory neurons and skin keratinocytes, which receive multimodal stimuli, including those that cause itch sensations. Here we review the molecular and cellular mechanisms of itch and the involvement of TRP channels in mediating itch sensations.     

Two-state dynamics of the SH3–SH2 tandem of Abl kinase and the allosteric role of the N-cap

The regulation and localization of signaling enzymes is often mediated by accessory modular domains, which frequently function in tandems. The ability of these tandems to adopt multiple conformations is as important for proper regulation as the individual domain specificity. A paradigmatic example is Abl, a ubiquitous tyrosine kinase of significant pharmacological interest. SH3 and SH2 domains inhibit Abl by assembling onto the catalytic domain, allosterically clamping it in an inactive state. We investigate the dynamics of this SH3–SH2 tandem, using microsecond all-atom simulations and differential scanning calorimetry. Our results indicate that the Abl tandem is a two-state switch, alternating between the conformation observed in the structure of the autoinhibited enzyme and another configuration that is consistent with existing scattering data for an activated form. Intriguingly, we find that the latter is the most probable when the tandem is disengaged from the catalytic domain. Nevertheless, an amino acid stretch preceding the SH3 domain, the so-called N-cap, reshapes the free-energy landscape of the tandem and favors the interaction of this domain with the SH2-kinase linker, an intermediate step necessary for assembly of the autoinhibited complex. This allosteric effect arises from interactions between N-cap and the SH2 domain and SH3–SH2 connector, which involve a phosphorylation site. We also show that the SH3–SH2 connector plays a determinant role in the assembly equilibrium of Abl, because mutations thereof hinder the engagement of the SH2-kinase linker. These results provide a thermodynamic rationale for the involvement of N-cap and SH3–SH2 connector in Abl regulation and expand our understanding of the principles of modular domain organization.Tyrosine kinases are involved in a wide variety of key signaling processes and are therefore tightly regulated by the cell. Indeed, numerous pathologies, ranging from cancer to neurodegeneration, result from or are associated with deficiencies in kinase regulation. Consequently, these enzymes are a prominent target for novel pharmacological strategies against human disease.This study focuses on Abelson murine-leukemia viral-oncogene homolog-1 (Abl), which is one of the most ubiquitously conserved tyrosine kinases. Abl is present in all metazoa, where it plays an essential role in processes as diverse as cytoskeleton reorganization, DNA repair, and regulation of apoptosis (1, 2). Accordingly, when constitutively active forms of Abl are present in normal cells, these are transformed into cancer cells (3). For example, in human white blood cells, a chromosomal abnormality leads to the fusion of the bcr and abl genes, which together encode for a cytoplasm-targeted deregulated form of Abl; Bcr-Abl interferes with the cell cycle, resulting in uncontrolled cell proliferation, and is the principal cause of chronic myeloid leukemia (CML) (4).The architecture of Abl kinases resembles that of other tyrosine kinase families such as Src and Tec (5). It consists of a Src-homology-3 (SH3) module, which is an interaction domain specialized for recognition of xPxxP sequence motifs; a Src-homology-2 (SH2) module, which recognizes phosphorylated tyrosines; and the catalytic domain, which binds and cleaves ATP, and mediates tyrosine phosphorylation in protein targets. Additional elements in Abl are not conserved in Src or Tec and vary among isoforms. The Abl-1b splice variant, which is our focus, features a long, seemingly unstructured N-terminal extension preceding the SH3 domain, known as the N-cap, which becomes myristoylated posttranslationally. Following the catalytic domain is another long stretch, containing various sequence motifs for DNA or cytoskeleton recognition, among others.The SH3 and SH2 domains not only function as interaction modules, but also as allosteric inhibitors of the catalytic domain. In autoinhibited Abl, the three domains are assembled into a compact arrangement, in which the SH3–SH2 tandem appears to mechanically clamp the N- and C-lobes of the catalytic domain in an inactive configuration (Fig. 1A) (6, 7), without directly occluding the active site. The domain-domain linkers appear to be key elements in this assembly. The SH2 domain docks directly onto the C-lobe of the catalytic domain, whereas its linker to the N-lobe engages the SH3 domain. Simultaneously, the portion of N-cap most proximal to the SH3 domain binds to the short SH3–SH2 connector, while the myristoyl group, at the very N terminus, inserts itself into a hydrophobic cavity within the C-lobe of the catalytic domain. Interestingly, Src-family kinases adopt the same compact domain organization in their down-regulated form (8), although their equivalent to N-cap serves as a membrane anchor and is not involved in autoinhibition. Instead, a C-terminal extension from the catalytic domain containing a phosphorylated tyrosine associates with the SH2 module and seemingly locks the complex in the autoinhibited state. Reversible phosphorylation of this C-terminal tail is a major regulatory mechanism of Src family kinases (9, 10).Open in a separate windowFig. 1.(A) Crystal structure of Abl in the autoinhibited state (PDB ID code 2FO0). The SH2 domain docks onto the C-lobe of the catalytic domain, whereas the SH3 domain engages the SH2-kinase linker. This inhibitory configuration of the SH3–SH2 tandem is referred to as the on conformer throughout the text. (B) Pseudodihedral angles used to describe the relative orientation of the regulatory domains during the simulations, encompassing residues in the C-terminal β-strand of the SH3 domain, the SH3–SH2 connector, and the N-terminal β-strand of the SH2 domain (Methods).Activation of both Src and Abl is enabled by the disengagement or reconfiguration of the intramolecular interactions just described (7, 11, 12). Regulation can therefore be thought as a reversible equilibrium whereby the SH3, SH2, and catalytic domains are either dissociated or self-assembled in one or more configurations. External factors, such as competing interactions involving one or both regulatory domains, will bias this equilibrium in one or the other direction (13). For Abl in particular, the significance of this mechanism is underscored by the fact that mutations that impair the correct assembly of the autoinhibited complex, either in the SH3–SH2 tandem or in the domain-domain linkers, confer CML cells with resistance against inhibitory drugs designed to target the catalytic domain of the Bcr-Abl oncogene (14). This outcome has prompted considerable interest in the mechanisms of allosteric regulation of Abl and other tyrosine kinases and in the development of compounds designed to interfere with these mechanisms (15–19).In this paper, we use molecular simulations, free energy calculations, and differential scanning calorimetry (DSC) to study the determining factors of a necessary step in the assembly of the autoinhibited form of Abl, namely the organization of the SH3 and SH2 domains into a conformation conducive to its association with the SH2–kinase linker (KL). Our results show that the conformational dynamics of the Abl SH3–SH2 tandem are clearly distinct from those of Src and related kinases. This finding enables us to reconcile seemingly contradictory structural and biophysical data on the mechanism of Abl regulation. Our analysis also enables us to formulate a mechanistic hypothesis for the role of the N-cap. Finally, we also examine the impact of activating mutations within the SH3–SH2 unit, particularly in the short connector between the domains.