Hiroaki Nozawa

Type I interferons are essential mediators of apoptotic death in virally infected cells

The interferons (IFNs) have been extensively studied in the context of host defence against viral infection. In the established model of IFN action, virally infected cells secrete type I IFNs (IFN‐α/β) which induce an antiviral state in uninfected cells. However, it is not clear how IFNs function on the infected cells. It has been reported that cells infected by some viruses die by apoptosis.

Functionally inactivating point mutation in the tumor‐suppressor IRF‐1 gene identified in human gastric cancer

Loss of heterozygosity (LOH) observed in human tumors strongly suggests the existence of (a) tumor‐suppressor gene(s) at the concerned locus. A series of studies has revealed that LOH on the long arm of chromosome 5 (5q) frequently occurs in differentiated gastric adenocarcinomas. Furthermore, it has been shown that the interferon regulatory factor‐1 (IRF‐1) locus on chromosome 5q31.1 is one of the common minimal regions of LOH in these cancers. IRF‐1 is a transcriptional activator that shows tumor‐suppressor activity in the mouse. In the present study, we examined the sequence of the IRF‐1 gene in 9 cases of histologically differentiated gastric adenocarcinomas, all of which exhibited LOH at the IRF‐1 locus. We identified a mis‐sense mutation in the residual allele in one case. This mutated form of IRF‐1 showed markedly reduced transcriptional activity. In addition, over‐expression of wild‐type IRF‐1 induced cell‐cycle arrest, whereas such activity was attenuated in the mutant IRF‐1. These results suggest that the loss of functional IRF‐1 is critical for the development of human gastric cancers. Int. J. Cancer 77:522–527, 1998.

Elevated Neutrophil to Lymphocyte Ratio Predicts Poor Prognosis in Advanced Colorectal Cancer Patients Receiving Oxaliplatin-Based Chemotherapy

Background: The aim of this study was to assess whether the neutrophil to lymphocyte ratio (NLR) and other laboratory markers may predict the prognosis of advanced colorectal cancer (CRC) patients receiving palliative chemotherapy. Methods: The study population included 50 patients with far advanced or recurrent unresectable CRC who received oxaliplatin-based combination chemotherapy as first-line treatment in our hospital between June 2005 and November 2010. Seven clinical variables and 7 laboratory indices before chemotherapy were evaluated retrospectively as the possible prognostic factors of overall and progression-free survival. Results: During the study period, 27 patients (54%) died of CRC. Elevated NLR (≥4.0) was observed in 15 patients (30%). By univariate analysis, elevated NLR, performance status and hypoalbuminemia were significantly associated with both poor overall and progression-free survivals. Multivariate analysis showed that elevated NLR (hazard ratio 4.39, 95% confidence interval 1.82–10.7; p = 0.0013) and thrombocytosis (hazard ratio 5.02, 95% confidence interval 1.69–13.4; p = 0.0066) were independently associated with overall survival. Conclusion: Elevated NLR is a powerful predictor of poor response to oxaliplatin-based chemotherapy in patients with unresectable CRC. The ratio is a simply accessible and inexpensive but useful biomarker in CRC patients receiving chemotherapy.

Critical role for constitutive type I interferon signaling in the prevention of cellular transformation

Interferons‐α/β, which are produced upon viral infection, are key soluble factors for the establishment of an antiviral state, but are also produced at low levels in the absence of infection. Herein, we demonstrate that a weak signal by these constitutively produced IFN‐α/β show a preventive role in cellular transformation. Ifnar1‐deficient (Ifnar1−/–) MEF, which are devoid of IFN‐α/β signal, undergo a spontaneous transformation during long‐term cell culture. Similar to Irf1−/– MEF, primary Ifnar1−/– MEF become tumorigenic in nude mice by the expression of activated c‐Ha‐Ras oncoprotein. However, Ifnar1−/– MEF do not show any abnormal growth properties. A similar observation is made in Ifnb−/– MEF that fail to produce constitutive IFN‐α/β, whereas such a transforming property is not found in MEF that lack any of the IFN receptor downstream molecules including Stat1, IRF9 and IRF1. Furthermore, Ifnar1−/– mice develop chemically‐induced skin papilloma more severely than wild‐type mice. In addition, the expression levels of IFNAR1 mRNA are significantly decreased in human gastric cancer tissues. These results suggest a cell‐intrinsic role of the weak signal by constitutively produced IFN‐α/β to prevent cells from transformation, which may be mediated by a hitherto‐unknown pathway(s) downstream of the IFN‐α/β receptor. (Cancer Sci 2009; 100: 449–456)

Laparoscopic surgery for ulcerative colitis: a review of the literature

Despite the development of new therapies, including anti-TNF alpha antibodies and immunosuppressants, a substantial proportion of patients with ulcerative colitis (UC) still require surgery. Restorative proctocolectomy with ileal-pouch anal anastomosis is the standard surgical treatment of choice for UC. With the advent of laparoscopic techniques for colorectal surgery, ileal-pouch anal anastomosis has also been performed laparoscopically. This paper reviews the history and current trends in laparoscopic surgery for UC. The accumulation of experience and improvement of laparoscopic devices have shifted the paradigm of UC surgery towards laparoscopic surgery over the past decade. Although laparoscopic surgery requires a longer operation, it provides significantly better short and long-term outcomes. The short-term benefits of laparoscopic surgery over open surgery include shorter hospital stays and fasting times, as well as better cosmesis. The long-term benefits of laparoscopy include better fecundity in young females. Some surgeons favor laparoscopic surgery even for severe acute colitis. More efforts are being made to develop newer laparoscopic methods, such as reduced port surgery, including single incision laparoscopic surgery and robotic surgery.

Can total artificial heart animals control their TAH by themselves? One year survival of a TAH goat using a new automatic control method (1/R control).

A total artificial heart (TAH) goat survived for 360 days on the new automatic control method (1/R control), in which the cardiac output of the TAH can be controlled through the cardiovascular center by making it function by reflecting the beta-adrenergic reaction in peripheral vascular resistance. This is thought to be the only long-term, real-time, measurable parameter by which information on the activity of the cardiovascular center can be received directly by the TAH system. In this goat, the hemodynamic parameters (RAP, AoP, and so forth) were kept within physiologic limits when control was stable, and the cardiac output was automatically increased in response to exercise, not unlike that in the natural heart. There were no abnormal blood chemical or hormone data except at end stage. Based on these results 1/R can be considered a physiologic control method for a TAH.

Fabrication of a jellyfish valve for use in an artificial heart

For a valve to be fabricated seamlessly into an artificial heart (AH) blood pump, a jellyfish valve has been developed, in which a thin membrane is fixed at the center of a valve seat having several spokes to protect against prolapse of the membrane. The valve is superior in performances to a Björk-Shiley valve, and reveals good blood compatibility. The valve would be very useful not only for AH animal study, but for future clinical use in infants to adults. Several institutions are already trying the valve. In this paper, the fabrication of the jellyfish valve is introduced, and in vitro and in vivo results summarized. A computer aided design (CAD) system was developed to cut a male wax mold of the valve seat. The input parameters to the CAD are diameter, height, thickness of rim, number of spokes, width and thickness of spokes, etc. Jellyfish valves with diameters of 4 to 27 mm have already been fabricated for many types of AHs and assist pumps.

Pelvic actinomycosis presenting with a large abscess and bowel stenosis with marked response to conservative treatment: a case report

Pelvic actinomycosis is a rare disease that can result in abscess formation, bowel obstruction, and other serious complications. Moreover, the correct diagnosis can seldom be established before radical surgery because the disease often mimics pelvic neoplasms. It has been recently recognized that pelvic actinomycosis is associated with long-term use of an intrauterine contraceptive device.We report a woman with a long-standing intrauterine contraceptive device who visited our hospital complaining of symptoms mimicking large bowel ileus with a subacute course. X-ray fluorography and sigmoidoscopy showed marked stenosis in the sigmoid colon but rejected the possibility of colon cancers. Abdomino-pelvic CT and MRI revealed a huge abscess lying over the urinary bladder and anterior to the uterus. Furthermore, a cervical Papanicolaou smear disclosed Actinomyces species. We removed the intrauterine device from the patient. Subsequent high-dose ampicillin administration led to dramatic shrinkage of the abscess and improved the management of the bowel movement quickly. This is a successful case of symptomatic pelvic actinomycosis that was correctly diagnosed and treated without unnecessary surgical intervention.

Level of arterial ligation in sigmoid colon and rectal cancer surgery.

BackgroundCurative resection of sigmoid colon and rectal cancer includes “high tie” of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the leakage rate, and it is unclear whether this confers a survival advantage. Accordingly, the IMA may be ligated at a point just below the origin of the left colic artery (LCA) “low tie” combined with lymph node dissection (LND) around the origin of the IMA (low tie with LND). However, no study has investigated the detailed prognostic results between “high tie” and “low tie with LND.” The aim of this study was to assess the utility of “low tie with LND” on survival in patients with sigmoid colon or rectal cancer.MethodsA total of 189 sigmoid colon or rectal cancer patients who underwent curative operation from 1997 to 2007 were enrolled in this study. The patient’s medical records were reviewed to obtain clinicopathological information. Overall survival (OS) and relapse-free survival (RFS) rates were calculated using the Kaplan-Meier method, with differences assessed using log-rank test.ResultsForty-two and 147 patients were ligated at the origin of the IMA (high tie) and just below the origin of the LCA combined with LND around the origin of the IMA (low tie with LND), respectively. No significant differences were observed in the complication rate and OS and RFS rates in the two groups. Further, no significant difference was observed in the OS and RFS rates in the lymph node-positive cases in the two groups.Conclusions“Low tie with LND” is anatomically less invasive and is not inferior to “high tie” with prognostic point of view.

The Jellyfish Valve: A Polymer Membrane Valve for the Artificial Heart

The development of a polymer membrane valve for artificial heart blood pumps is very much required, since the mechanical valves, such as the Bjork-Shiley (BS) and Hall valves, used in the present artificial heart (AH) blood pumps have the following problems: 1. A ring thrombus is often formed at the interface between the valve ring and pump housing, because these cannot be fixed seamlessly. 2. Valve failure sometimes occurs at the disc and stent due to a water-hammer effect. 3. Regurgitant and leakage flow generated in the mechanical valve induces hemolysis and the AH patient becomes mildly anemic. 4. The valves are too expensive to popularize the AH as a therapeutic method.