Current topics in mutations in the cancer genome

Several oncogenes and tumor suppressor genes are involved in the multistep process of carcinogenesis in many cancer types. Recently, global mutational analyses have revealed that the cancer genome has far greater numbers of mutations than previously thought. Furthermore, the next-generation sequencing method, which has a different principle from conventional Sanger sequencing, has provided more information on the cancer genome such as new cancer-related genes and the existence of many rearrangements in solid cancers. Somatic mutations occurring in cancer cells are divided into "driver" and "passenger" mutations. Driver mutations confer a growth advantage upon the neoplastic clone and are crucial for carcinogenesis. The remaining large majority of mutations are passengers, which, by definition, do not confer a growth advantage. Driver genes with low-frequency mutation rates (less than 10%) are also involved in carcinogenesis along with well-known drivers with high-frequency mutations. There are now several celebrated examples of anticancer drugs of which the efficacy in cancer patients can be predicted based on the genotype of several driver genes, such as EGFR, KRAS, and BRAF on the EGFR signaling pathway. The complete catalogs of somatic mutations provided by the sequencing of the cancer genome are expected to prompt new approaches to diagnosis, therapy, and potentially prevention.     

Characterization of contraction-mediating prostanoid receptors in human penile erectile tissues

The effects of the thromboxane-receptor antagonist L-636,499 were studied on contractions induced by the thromboxane A2 mimic U44069 and by prostaglandin F2 alpha in isolated preparations of the human corpus cavernosum and corpus spongiosum. The objectives were to characterize prostanoid receptors and, in particular, to elucidate whether more than one receptor was involved in prostanoid-induced contraction of penile erectile tissues. L-636,499 at concentrations 10(-6) M to 3 x 10(-5) M induced a parallel shift to the right of the concentration-response curve to U44069 in both corpus cavernosum and corpus spongiosum suggesting competitive antagonism. Schild plots using U44069 as the agonist and L-636,499 as the antagonist revealed slope indexes near unity in both tissues, and the pA2 values were almost identical. In contrast, L-636,499 concentration-dependently reduced the maximum response to prostaglandin F2 alpha, indicating a non-competitive action. The results suggest that the main contraction-mediating prostanoid receptor in human penile erectile tissues is a thromboxane A2 sensitive receptor. However, the presence of more than one contraction-mediating prostanoid receptor cannot be excluded.     

Current topics in the epidemiology of oral cavity and oropharyngeal cancers

Oral cancer incidence rates rose dramatically during the twentieth century in the United States and Europe, especially among individuals under the age of 60 years. Although influenced by age, sex, and country of origin, incidence trends were most strongly affected by elevated risk among individuals born after approximately 1915. This cohort effect was indicative of strong behavioral influences on oral cancer risk. In this article, associations between oral cancer risk and established behavioral risk factors including alcohol and tobacco use are reviewed. Additionally, possible associations between oral cancer risk and oral hygiene, diet, nutritional status, and sexual behavior as well as the influence of genetic factors on oral cancer risk are considered. Special emphasis is placed on evaluating possible risk differences in individuals above and below the age of 45 and in users and nonusers of alcohol and tobacco.     

Current topics review: Charcot neuroarthropathy of the foot and ankle

Charcot arthropathy is a destructive process, most commonly affecting joints of the foot and ankle in diabetics with peripheral neuropathy. Affected individuals present with swelling, warmth, and erythema, often without history of trauma. Bony fragmentation, fracture, and dislocation progress to foot deformity, bony prominence, and instability. This often causes ulceration and deep infection that may necessitate amputation. Instability or deformity may limit the ability to use standard footwear. Treatment is focused on providing a stable and plantigrade foot for functional ambulation with accommodative footwear and orthoses. Historically, treatment had included nonweightbearing immobilization for the acute phase, and surgery had been reserved only for infection, unresolved skin ulceration, or deformity that precluded the use of therapeutic footwear. Current controversies include weightbearing in the acute or reparative phases and early surgical stabilization. Foot-specific patient education and continued periodic monitoring may reduce the morbidity and associated expense of treating the complications of this disorder and may improve the quality of life in this complex patient population.     

Current topics of endoscopic surgery for thyroid cancer

Endoscopic surgery has been introduced in the field of thyroid disease. Endoscopic thyroid surgery is divided into complete endoscopic surgery using CO2 gas, which is approached from the axilla, mammary areola, and anterior chest; and video-assisted thyroid surgery without CO2 gas, approached from the neck or anterior chest under the clavicula through a small incision. Many thyroid tumors are benign, and cases of thyroid cancer are few. Only 7.9% of patients who underwent endoscopic thyroid surgery in the English and Japanese literature had papillary thyroid cancer. Most of these underwent video-assisted thyroidectomy without gas. The indications for endoscopic surgery in papillary thyroid cancer is microcancer or small tumor without lympnode metastasis before surgery. In follicular thyroid cancer, minimally invasive thyroid cancer of less than 5cm is recommended for endoscopic thyroid surgery. Furthermore, in medullary carcinoma with multiple endocrine neoplasia, prophylactic thyroidectomy can be performed using these endoscopic techniques. At present, it is still controversial whether endoscopic surgery should be performed to treat thyroid cancer.     

Expression, roles, receptors, and regulation of osteopontin in the kidney.

Osteopontin (OPN) is a secreted glycoprotein in both phosphorylated and non-phosphorylated forms. It contains an Arg-Gly-Asp cell-binding sequence and a thrombin-cleavage site. OPN is mainly present in the loop of Henle and distal nephrons in normal kidneys in animals and humans. After renal damage, OPN expression may be significantly up-regulated in all tubule segments and glomeruli. Studies utilizing OPN gene-deficient mice, antisense-treated or anti-OPN-treated animals have demonstrated that OPN promotes accumulation of macrophages, and may play a role in macrophage-mediated renal injury, but that the effect may be mild and short-lived. On the other hand, OPN has some renoprotective actions in renal injury, such as increasing tolerance to acute ischemia, inhibiting inducible nitric oxide synthase and suppressing nitric oxide synthesis, reducing cell peroxide levels and promoting the survival of cells exposed to hypoxia, decreasing cell apoptosis and participating in the regeneration of cells. In addition, OPN is associated with renal stones, but whether it acts as a promoter or inhibitor of stone formation is controversial. It has been demonstrated that OPN receptors include two families: integrin and CD44. The OPN integrin receptors include alpha(v)beta(3), alpha(v)beta(1), alpha(v)beta(5) and alpha(9)beta(1), and alpha(4)beta(1). In normal human kidneys, standard CD44 is expressed most dominantly. Different OPN functions are mediated via distinct receptors. Parathyroid hormone, vitamin D(3), calcium, phosphate and some cytokines increase OPN expression in vitro or in vivo, whereas female sex hormones and angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists decrease OPN expression in some renal damage states.     

Differential regulation of bladder beta-adrenergic and muscarinic cholinergic receptors in experimental diabetes.

To determine the contribution of diuresis-induced bladder hypertrophy, which accompanies the diabetic state, on the biochemical and functional alterations observed in the diabetic bladder, we compared three experimental groups: 8-wk streptozocin (STZ)-induced diabetic rats, 8-wk sucrose-fed diuretic rats, and age-matched controls. Diabetic and sucrose-fed rats had higher water intake, higher urine output, and larger bladders than controls. Diabetic rats had lower serum insulin levels, lower body weights, and higher serum glucose levels than either control or sucrose-fed animals. Receptor binding studies with [3H]quinuclidinyl benzilate in bladder dome demonstrated an upregulation of muscarinic receptors in diabetic and sucrose-fed rats compared with controls. Parallel binding studies with [3H]dihydroalprenolol and [125I]iodopindolol showed an upregulation of beta-adrenergic receptors in diabetic but not in sucrose-fed bladder domes. Carbachol induced larger contractile responses in diabetic and sucrose-fed than in control bladder dome muscle strips. isoproterenol relaxed KCl-contracted detrusor strips from both diabetic and sucrose-fed rats to a greater degree and with a higher affinity than detrusor strips from controls. Our data show that overdistension and increased workload per se contributed to the upregulation of muscarinic but not to the upregulation of beta-adrenergic receptors in STZ-induced diabetes. Furthermore, the magnitude of carbachol-induced contractions correlated with muscarinic receptor upregulation, whereas the magnitude of isoproterenol-induced relaxation did not correlate with changes in the density of the beta-adrenergic receptors. Thus, it appears that different regulatory mechanisms are involved in diabetes-induced alterations in muscarinic and beta-adrenergic receptors in bladder dome.     

Current topics in surgery for isolated total anomalous pulmonary venous connection

Surgical correction of total anomalous pulmonary venous connection (TAPVC) remains a challenge, with reported early mortality rates of up to 20 %. In this review article, we describe several topics, including surgery for neonates, diagnoses with multidetector computed tomography (MDCT), and primary sutureless repair. Several studies have reported mortality rates of around 10 %, and demonstrated unchanged hospital mortality in neonates, despite improvement of the overall mortality of cohorts including older patients. Previous reports identified a low body weight at the time of the operation, preoperative pulmonary venous obstruction (PVO), and a prolonged cardiopulmonary bypass time as risk factors for hospital mortality. With the development of new technologies, MDCT has become a good diagnostic modality for use in the pre- and post-operative evaluation. MDCT delineates the drainage site of the vertical vein and the atypical vessel into the systemic vein, and it can also evaluate the existence of obstruction in the vertical vein. Following favorable experiences with post-repair PVO, the indications for sutureless repair as a primary operation have been expanded for infants, including those at risk of developing PVO after the repair of TAPVC. Primary sutureless repair has proven especially useful for difficult patient groups, such as those with congenital PVO, infracardiac TAPVC with small pulmonary veins, or mixed-type TAPVC.     

核受体信号在脂类代谢中的调控作用

核受体是配体依赖性转录因子超家族,对脂类代谢基因有重要的转录调控作用,与许多代谢性疾病密切相关,近年来,国内外对核受体在脂类代谢中调控作用的广泛研究,有助于进一步加深对胆固醇结石病等与脂类代谢相关疾病的发病机制认识.     

Role of histamine receptors in the regulation of edema and circulation postburn

Despite histamine being a potent endogenous vasoactive agent released in increasing amounts postburn, its role in postburn oedema formation has been controversial and its effect on burn circulation poorly investigated. The present study investigated the involvement of H₁, H₂ and H₃ receptors in postburn edema in rats exposed to skin and muscle burns and their influence on skin circulation postburn. We used the selective antagonists clemastine (H₁), ranitidine (H₂), thioperamide (H₃) and the selective H₃ receptor agonist, imetit. Results showed that none of the antagonists or the H₃ agonist had significant effect on postburn edema measured by quantitative spectrophotometric analysis of extravasated Evans blue-albumin in the full-thickness burned skin or muscle. Clemastine and thioperamide failed to induce significant effect on blood flow in the partial- or full-thickness skin burn injury as measured by laser Doppler flowmetry, while ranitidine significantly (P<0.01) reduced blood flow in the full-thickness burn. In contrast, the H₃ receptor agonist, imetit, significantly increased blood flow, both in the partial-thickness burn injury (P<0.05) and in the full-thickness burn (P<0.01). Moreover, imetit significantly (P<0.01) increased mean arterial pressure while thioperamide significantly (P<0.01) reduced systemic pressure. In conclusion, H₁, H₂ and H₃ receptors are not important actors in the regulation of vascular patency permeability, whereas H₃ receptors play an important role by increasing skin circulation postburn, presumably by relaxation of vascular smooth muscle and/or by interacting with other inflammatory neurotransmitters. Data also suggest that H₂ receptor blockers may not be best choice for stress ulcer prophylaxis in burn patients.     

Up-and-down regulation of skeletal muscle acetylcholine receptors. Effects on neuromuscular blockers.

Multiple factors alter the interaction of muscle relaxants with the NMJ. This review has focused on the aberrant responses caused principally by alterations in AChRs (table 1). Many pathologic states increase (up-regulate) AChR number. These include upper and lower motor neuron lesions, muscle trauma, burns, and immobilization. Pre- or postjunctional inhibition of neurotransmission by drugs or toxins also up-regulate AChRs. These include alpha- and beta-BT, NDMR, anticonvulsants, and clostridial toxins. We speculate that other bacterial toxins also up-regulate AChR. With proliferation of AChRs, agonist drug dose-response curves are shifted to the left. The exaggerated release of potassium when depolarization occurs with the use of agonists such as SCh and decamethonium can be attributed to the increased number of AChR. Thus, SCh should be avoided in patients who are in the susceptible phase (see section V). In the presence of increased AChR, the requirement for NDMR is markedly increased. Thus, the response to NDMR may be used as an indirect estimator of increased sensitivity to SCh (table 1). The most extensively studied pathologic state in which there is a decrease in AChRs is myasthenia gravis; there is immunologically mediated destruction and/or functional blockade of AChRs. The pathophysiologic and pharmacologic changes in LEMS are quite distinct from those of myasthenia gravis. Decreased AChRs in myasthenia gravis result in resistance to agonists and increased sensitivity to competitive antagonists. In conditioning exercise, the perturbed muscles show sensitivity to NDMR that may be due to decreased AChRs. Chronic elevations of ACh observed with organophosphorus poisoning or chronic use of reversible cholinesterase inhibitors results in down-regulation of AChRs. In this condition, SCh should be avoided because its metabolic breakdown would be impaired; the requirement for NDMR may be decreased. All of the varied responses to SCh and NDMR, which are associated with concomitant changes in AChRs, are analogous to drug-receptor interactions observed in other biologic systems.