Clinical significance of CDC25A and CDC25B expression in squamous cell carcinomas of the oesophagus

CDC25A, CDC25B and CDC25C belong to a family of protein phosphatases which activate the cyclin-dependent kinase at different points of the cell cycle. According to accumulating evidence, CDC25A and CDC25B seem to possess oncogenic properties. We have analysed these expressions by immunohistochemistry, western blot and RT-PCR in a series of 100 patients with squamous cell carcinoma of the oesophagus. When compared with non-cancerous cells, CDC25A and CDC25B were strongly expressed in the cytoplasm of cancer cells, with positive (+) classification in 46% (46 cases) and 48% (48 cases), respectively. There was no significant correlation between CDC25A and CDC25B expression, nor was there any association with the expression of other cell cycle-regulating molecules, including cyclin D1, Rb, p16(INK4), p27(KIP1)and PCNA (proliferating cell nuclear antigen). CDC25A (+), as well as CDC25B (+), was more frequently found in patients with deeper tumour invasion and lymph node metastasis, while tumour size was correlated only with CDC25A expression. Postoperative survival was significantly poorer for CDC25A (+) patients than CDC25A (-) patients, but was not affected by the CDC25B status. Nuclear localization of CDC25A was observed in 51 cases (51%), regardless of its cytoplasmic expression, and was not associated with clinico-pathological factors or prognosis. Multivariate analysis revealed only the CDC25A status to be an independent significant prognostic factor among these biological and clinico-pathological factors. CDC25A but not CDC25B may be a new prognostic factor for squamous cell carcinoma of the oesophagus. Thus, regulation of the G1 checkpoint in the cell cycle may be important in oesophageal carcinogenesis, which may also involve many other oncogenes.     

Comparison of cerebral activation between motor execution and motor imagery of self-feeding activity

Motor imagery is defined as an act wherein an individual contemplates a mental action of motor execution without apparent action. Mental practice executed by repetitive motor imagery can improve motor performance without simultaneous sensory input or overt output. We aimed to investigate cerebral hemodynamics during motor imagery and motor execution of a self-feeding activity using chopsticks. This study included 21 healthy right-handed volunteers. The self-feeding activity task comprised either motor imagery or motor execution of eating sliced cucumber pickles with chopsticks to examine eight regions of interest: pre-supplementary motor area, supplementary motor area, bilateral prefrontal cortex, premotor area, and sensorimotor cortex. The mean oxyhemoglobin levels were detected using near-infrared spectroscopy to reflect cerebral activation. The mean oxyhemoglobin levels during motor execution were significantly higher in the left sensorimotor cortex than in the supplementary motor area and the left premotor area. Moreover, significantly higher oxyhemoglobin levels were detected in the supplementary motor area and the left premotor area during motor imagery, compared to motor execution. Supplementary motor area and premotor area had important roles in the motor imagery of self-feeding activity. Moreover, the activation levels of the supplementary motor area and the premotor area during motor execution and motor imagery are likely affected by intentional cognitive processes. Levels of cerebral activation differed in some areas during motor execution and motor imagery of a self-feeding activity. This study was approved by the Ethical Review Committee of Nagasaki University(approval No. 18110801) on December 10, 2018.     

Intrahepatic arterial chemotherapy with 5-fluorouracil and intramuscular interferon-alpha for a patient with diffuse type of hepatocellular carcinoma

We report a case of diffuse type advanced hepatocellular carcinoma (HCC), which was successfully treated by a combination therapy of interferon-alpha (IFN) and 5-fluorouracil (5-FU). A 74-year-old man underwent distal gastrectomy 6 years ago for gastric cancer. In April 2002, an increased serum alpha-feto-protein (AFP) level was noted and a computed tomography (CT) of the abdomen revealed a diffuse type of HCC. He was treated with a combination therapy of IFN (5x10(6) units/body i.m., days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26) and 5-FU (500 mg/body/day i.a., days 1-5, 8-12 continuously). The treatment was repeated every 4 weeks with a maximum of five cycles. After 5 cycles, serum AFP levels fell from 665 ng/ml to a normal level. CT showed a reduced size of the tumor. He has been well and continue to receive IFN (3x10(6) units/body i.m., two times a week) and 5-FU (500 mg/body/day i.a., once a week) at the outpatient clinic for the last 16 months.     

Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN™), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors

Purpose  To evaluate safety and tolerability of cediranib, a highly potent and selective vascular endothelial growth factor signaling inhibitor, in Japanese patients with advanced solid tumors refractory to standard therapies. Methods  In part A (n = 16), patients received once-daily oral cediranib (10–45 mg) to identify the maximum tolerated dose (MTD). In part B (n = 24), patients with non-small-cell lung cancer or colorectal cancer received multiple daily doses at the MTD. Results  Cediranib 30 mg/day was considered the MTD since 50% of evaluable patients receiving 45 mg/day experienced dose-limiting toxicities in part A (proteinuria and diarrhea n = 1, proteinuria n = 1, thrombocytopenia n = 1). The most common adverse events were diarrhea (n = 34) and hypertension (n = 32). Pharmacokinetic analysis confirmed cediranib as suitable for once-daily oral dosing. Of 32 evaluable patients, two had partial RECIST responses and 24 had stable disease ≥8 weeks. Conclusions  Cediranib was generally well tolerated at ≤30 mg/day in these Japanese patients and showed encouraging antitumor activity.     

Increased concentrations of soluble tumour necrosis factor receptor (sTNFR) I and II in peritoneal fluid from women with endometriosis

Tumour necrosis factor alpha (TNFalpha), a proapoptotic cytokine, is known to be present in peritoneal fluid from women with endometriosis. An emerging view is that soluble TNF receptors (sTNFR) can modulate the effects of TNFalpha by acting as TNFalpha antagonists. To assess the relevance of sTNFRs in the pathophysiology of endometriosis, concentrations of sTNFR I, sTNFR II and TNFalpha in peritoneal fluid from women with endometriosis (n = 53) and without endometriosis (n = 40) were measured. Concentrations of both sTNFR I and sTNFR II in peritoneal fluid from women with endometriosis were significantly higher than in peritoneal fluid from women without endometriosis, both in the follicular and the luteal phases. TNFalpha concentrations did not differ in patients with and without endometriosis in both phases. When stratified by the stage of the disease, women with both stages I/II and stages III/IV exhibited significantly higher concentrations of sTNFR I and sTNFR II in peritoneal fluid, compared with women without endometriosis, whereas no appreciable difference in the concentrations was detected between stages I/II and stages III/IV. A significant correlation was found between the concentrations of sTNFR I and sTNFR II; while the correlations between TNFalpha and sTNFR I or sTNFR II, were either not significant or were very weak. Furthermore, mRNA for the membrane-associated TNF receptor type 1 and TNF receptor type 2, both of which convey the effects of TNFalpha, were shown to be expressed in endometriotic tissues as well as eutopic endometrium. Together, these findings suggest a possible involvement of sTNFRs in the pathophysiology of endometriosis.     

Complete genome sequence of the hyperthermophilic archaeon Thermococcus kodakaraensis KOD1 and comparison with Pyrococcus genomes

The genus Thermococcus, comprised of sulfur-reducing hyperthermophilic archaea, belongs to the order Thermococcales in Euryarchaeota along with the closely related genus Pyrococcus. The members of Thermococcus are ubiquitously present in natural high-temperature environments, and are therefore considered to play a major role in the ecology and metabolic activity of microbial consortia within hot-water ecosystems. To obtain insight into this important genus, we have determined and annotated the complete 2,088,737-base genome of Thermococcus kodakaraensis strain KOD1, followed by a comparison with the three complete genomes of Pyrococcus spp. A total of 2306 coding DNA sequences (CDSs) have been identified, among which half (1165 CDSs) are annotatable, whereas the functions of 41% (936 CDSs) cannot be predicted from the primary structures. The genome contains seven genes for probable transposases and four virus-related regions. Several proteins within these genetic elements show high similarities to those in Pyrococcus spp., implying the natural occurrence of horizontal gene transfer of such mobile elements among the order Thermococcales. Comparative genomics clarified that 1204 proteins, including those for information processing and basic metabolisms, are shared among T. kodakaraensis and the three Pyrococcus spp. On the other hand, among the set of 689 proteins unique to T. kodakaraensis, there are several intriguing proteins that might be responsible for the specific trait of the genus Thermococcus, such as proteins involved in additional pyruvate oxidation, nucleotide metabolisms, unique or additional metal ion transporters, improved stress response system, and a distinct restriction system.     

Effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone on carbon tetrachloride‐induced hepatic cirrhosis in rats

Aim: The present study was undertaken to evaluate the effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone (HTHQ), a synthesized vitamin E derivative, on carbon tetrachloride (CCl₄)‐induced cirrhosis. Methods: Rats were treated with hypodermic injections of CCl₄ twice a week to induce the hepatic cirrhosis, and given drinking water containing HTHQ or solvent. Primary cultures of rat hepatocytes were performed to evaluate the effects of HTHQ on the expression of inducible nitric oxide synthase (iNOS). Results: Masson's staining of rat livers showed fibrosis around pseudo‐lobules in the CCl₄ group, the lesions being reduced in the CCl₄ HTHQ group. Increases in liver tissue hydroxyproline and α₁(I) collagen, α‐smooth muscle actin and iNOS induced by CCl₄, were also markedly diminished by HTHQ. Furthermore, both HTHQ and vitamin E attenuated interleukin‐1β‐induced iNOS protein expression in cultured hepatocytes, the potency of HTHQ being 10‐times higher than that of vitamin E. Conclusion: HTHQ may inhibit development of hepatic cirrhosis in rats, more potently than vitamin E, by inhibiting the iNOS expression in hepatocytes. Because vitamin E has a radical scavenging action, roles of NO and peroxynitrite will be discussed in the effects of HTHQ on the fibrosis.