Nondomain biopolymers: Flexible molecular strategies to acquire biological functions

A long-standing assumption in molecular biology posits that the conservation of protein and nucleic acid sequences emphasizes the functional significance of biomolecules. These conserved sequences fold into distinct secondary and tertiary structures, enable highly specific molecular interactions, and regulate complex yet organized molecular processes within living cells. However, recent evidence suggests that biomolecules can also function through primary sequence regions that lack conservation across species or gene families. These regions typically do not form rigid structures, and their inherent flexibility is critical for their functional roles. This review examines the emerging roles and molecular mechanisms of “nondomain biomolecules,” whose functions are not easily predicted due to the absence of conserved functional domains. We propose the hypothesis that both domain- and nondomain-type molecules work together to enable flexible and efficient molecular processes within the highly crowded intracellular environment.     

Therapeutic effect of a CDDP-epirubicin-Lipiodol emulsion on advanced hepatocellular carcinoma

Prior injection of an anticancer agent and Lipiodol mixture is a key point for the treatment of hepatocellular carcinoma (HCC). We therefore prepared a new, improved emulsion of Lipiodol containing a high dose ofcis-diamminedichloroplatinum (CDDP) and epirubicin by replacing the ionic contrast medium (Urografin 67) with a nonionic contrast medium (Iopamidol; Iopamiron 300) and adding phosphatidyl choline. This CDDP-epirubicin-Lipiodol emulsion (CELE) was examined pharmacologically and chemically with the following results. The size of these particles is less than 10 m (diameter) for up to 24 h; the release of 28%–34% of the CDDP and 80%–90% of the epirubicin was estimated in the dissolution test, and 85% of the CDDP and 35% of the epirubicin was retained in the organs in the moment calculation. CELE was injected into 58 HCC patients via a celiac angiographic catheter. In 36 of these patients, the CELE injection was followed by transcatheter arterial embolization (TAE) therapy. Following the administration of CELE as one-shot injection therapy for stage IV HCC, the 1-year survival rate was 59% and the 2-year survival rate was 27%. Moreover, in patients (stage II, 12; stage III, 8; stage IV, 16) who received CELE and subsequently underwent TAE therapy, the 1-year survival rate was 90% and the 2-year survival rate was 67%. The nonionic contrast medium with Lipiodol forms finer emulsified particles, and these particles are more capable of penetrating into the tumor. In addition, the greater pharmacological stability of these particles provides a slow-release effect and prolonged stability of their shape. Finally, theoretically, the use of two major anticancer agents such as CDDP and epirubicin showed a greater clinical effect in the treatment of HCC than either our earlier suspension or a single anticancer agent.Work presented at the Third International Symposium on Treatment of Liver Cancer, Seoul, Korea, 12–13 February 1993     

Role of reactive oxygen in phospholipase A2 activation by ischemia/reperfusion of the rat kidney

Purpose. To investigate the role of phospholipase A₂ (PLA₂) in reperfusion injury of the kidney in an in vivo animal model, renal mitochondrial PLA₂ activity was measured under three different conditions. Methods. Male Wistar rats (n = 72) anesthetized with pentobarbital underwent renal ischemia surgically for 45 min and were reperfused for the indicated time (renal ischemia/reperfusion). Treatments included reperfusion for various predetermined periods (phase 1), exposure to hyperbaric oxygen (phase 2), and administration of reactive oxygen species (ROS) scavenger (phase 3). Thereafter, each kidney was harvested, and mitochondrial PLA₂ activity was measured by a radioisotope technique. Results. Ischemia/reperfusion resulted in time-related PLA₂ activation in the renal mitochondria up to 48 h of reperfusion after renal ischemia. Renal mitochondrial PLA₂ activity was further augmented by hyperbaric oxygen exposure prior to reperfusion, whereas administration of the ROS scavengers suppressed mitochondrial PLA₂ activity. Conclusion. These data suggest that ROS may play an important role in the in vivo activation of PLA₂ associated with renal ischemia/reperfusion. Received for publication on July 6, 1998; accepted on November 30, 1998     

Metastatic seeding of bile duct carcinoma in the transhepatic catheter tract: Report of a case

We describe herein the case of a 51-year-old woman in whom metastatic tumor seeding of the percutaneous transhepatic biliary drainage tract occurred following a pancreatoduodenectomy for carcinoma of the distal common bile, duct. An abdominal computed tomography scan done 6 months after the initial operation detected a hepatic lesion located at the site of the previous percutaneous transhepatic biliary drainage tract. Implantation of bile duct carcinoma in the drainage tract was diagnosed, and the recurrent tumor was successfully resected by performing a subsegmentectomy of segment 3 and removal of the adjacent abdominal wall. At present, 5 years and 4 months after the second resection, the patient is in good health without any signs of recurrence. This case report demonstrates that an aggressive surgical approach should be performed for tumor seeding of a transhepatic biliary catheter tract.     

Antinociceptive effects of ONO-9902, an enkephalinase inhibitor,after visceral stress condition in rats

Purpose

The present study was designed to examine the antinociceptive effects of orally administered ONO-9902, an enkephalinase inhibitor, on both somatic and visceral pain after visceral stress conditions.

Methods

Twenty six male rats were examined. Tail-flick (TF) and colorectal distension (CD) tests were used to determine somatic and visceral antinociceptive effects, respectively. Measurements were performed in rats under immediate post-stress conditions (group ST; n = 14) and in rats nor under stress conditions (group NST; n = 12). In the stressed group, the same device, CD, for visceral antinociceptive effects was used for visceral stress and was applied with an intracolonic pressure of 60 mmHg for 20 min after drug administration. The TF latency and CD threshold were measured before and at 30, 40, 50, 60 and 90 min after administration of ONO-9902 300 mg · kg^?1 or distilled water.

Results

Orally administered ONO-9902 did not produce any changes in the % maximum possible effect (%MPE) in either TF or CD tests in the unstressed group. In the stressed group, %MPE in the CD test increased 18% and 31% at 30 and 40 min, respectively, after oral administration of ONO-9902 compared with the control group (P < 0.05). However, %MPE to TF test did not alter even after the CD-induced stress condition.

Conclusion

These results suggest that ONO-9902 may have analgesic effects on visceral pain but not on somatic pain under immediate post-stress conditions.     

Report on the Computer Software Contest at 38th Congress of the Japan Society of Anesthesiology

We held a computer software contest at 38th Congress of the JSA, held in March, 1991. The aim is to encourage the members of the Society to write softwares and to help distribute them, especially as Freewares. We received 25 entries for the contest; two-thirds of these are for computers of NEC PC9801 series and a third are for Macintosh. We received donations 3 million yen worth of instruments and goods for prizes plus some cash, which as prizes were distributed to those who made entries for the contest.Most of these programs have been registered as freewares at various computer networks, including our Ether-Net, one of the common computer network SIGBBSs among Japanese anesthesiologists.(Suwa K, Miyasaka K, Tanaka Y, et al.: Report on the computer software contest at 38th congress of the Japan society of anesthesiology. J Anesth 5: 441–444, 1991)Executive Committee of the Computer Software Contest at 38th Congress of the Japan Society of Anesthesiology     

Additional Hepatocellular Carcinomas Undetectable before Surgery

The presence of small additional hepatocellular carcinomas (HCCs) undetectable before hepatic resection is a crucial topic for hepatic surgeons. We assessed the incidence of pathologically diagnosed multiple HCCs in 267 patients who underwent hepatic resection for HCC. Ninety-five additional HCC nodules were detected in 72 of the patients (27%). The survival rate of these 72 patients was significant worse than for the 195 with single nodular HCC (p= 0.0013). Twenty-one (22%) were detected before surgery, 29 (31%) during surgery, and 45 (47%) on pathologic examination after surgery. The mean nodule diameters for each group were 2.1, 1.0, and 0.9 cm, respectively (p < 0.0001). None of the 21 nodules detected before surgery was well differentiated, whereas 30 of the 74 nodules in the other two groups were well-differentiated. Although the mean nodule diameter of the well-differentiated HCC group was the smallest, there was no significant difference among the three groups assigned according to tumor differentiation (p= 0.2355). Altogether, 9 of 16 patients with additional nodules detected before surgery (56%) and 49 of 59 with additional nodules detected during or after surgery (88%) had cirrhosis of the liver. The odds ratio for detecting a new HCC nodule during or after surgery in the presence of cirrhosis was 5.444 (p= 0.0087). Improvement in the detection of small additional HCC nodules before and during surgery and meticulous follow-up after surgery are necessary for patients with cirrhosis. For patients without cirrhosis, surgical treatment may be performed according to the results of preoperative imaging studies.     

A cancer-prone case with a background of methylation of p16 tumor suppressor gene.

PURPOSE AND EXPERIMENTAL DESIGN: To date, the presence of p16 gene promoter methylation associated with loss of protein expression has been demonstrated frequently in digestive tract cancers. In this study, we tested for the methylation status of p16 promoter in normal tissue specimens using the methylation-specific PCR technique to examine whether p16 methylation already existed in the background of tumors. RESULTS: Aberrant promoter methylation of p16 gene was detected in 1 of 40 esophageal and 1 of 69 gastric and no colorectal epithelium specimens, and these 2 specimens were derived from the same patient. We also found the same methylation change in both tumor and blood cell DNA. CONCLUSION: These results suggested that the p16 gene was inactivated by methylation in normal background cells of this patient and that other additional factors may promote tumor development in his esophageal and gastric tissues.     

Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo rituximab resistance.

PURPOSE: Rituximab has clinical activity in patients with chronic lymphocytic leukemia (CLL) and has a variety of proposed mechanisms, including apoptosis, complement-dependent cell lysis (CDC), and antibody-dependent cellular cytotoxicity (ADCC). Here we examine pretreatment biologic features that promote resistance to apoptosis and CDC in CLL patients and correlate it with clinical outcome to rituximab-based therapy. PATIENTS AND METHODS: Pretreatment samples from 21 CLL patients treated on a prospective, single-agent rituximab trial were examined for quantitative expression of apoptotic and CDC regulatory proteins, and the level of expression of these proteins was correlated with clinical outcome. RESULTS: Of the 21 patents for whom samples were available, 10 attained a partial response and 11 failed to respond to rituximab therapy. The mean pretreatment expression of Bcl-2, Mcl-1, XIAP, and the ratio of Bcl-2/Bax were higher but not statistically increased in nonresponding patients versus those responding to treatment. In contrast, the pretreatment Mcl-1/Bax ratio was significantly elevated (0.82 +/- 0.28 v 0.39 +/- 0.29, P <.016) in nonresponding patients compared with patients responding to rituximab therapy. Although pretreatment expression of CD55 and CD59 was not associated with response to rituximab therapy, significantly higher levels of CD59 were observed in the CLL cells that were not cleared from the blood at completion of therapy than the level observed at baseline levels (P =.02). CONCLUSION: These data indicate that baseline expression of the Mcl-1/Bax ratio, but not CD55 and CD59, predict for clinical response to rituximab therapy in CLL patients. Further study of disrupted apoptosis in CLL as a potential mechanism of resistance to rituximab appears warranted.