SAPPHIRE: a randomised phase II study of planned discontinuation or continuous treatment of oxaliplatin after six cycles of modified FOLFOX6 plus panitumumab in patients with colorectal cancer.

BACKGROUND: Fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) plus panitumumab therapy is a commonly used first-line chemotherapy for metastatic colorectal cancer (mCRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). We investigated whether the planned discontinuation of oxaliplatin after FOLFOX plus panitumumab therapy can maintain efficacy and reduce PN incidence. PATIENTS AND METHODS: Chemotherapy-naive patients with RAS wild-type mCRC, aged ≥20 years, were enrolled and received six cycles of modified FOLFOX6 (mFOLFOX6) plus panitumumab as induction therapy. Patients who completed induction therapy without progression were randomised to mFOLFOX6 plus panitumumab (group A) or to 5-FU/LV plus panitumumab (group B). The primary end-point was the progression-free survival (PFS) rate at 9 months after randomisation. The secondary end-points were PFS, overall survival (OS), time to treatment failure (TTF), response rate (RR) and safety. RESULTS: In total, 164 patients were enrolled; of whom, 113 patients were then randomised (group A, n = 56; group B, n = 57). The median follow-up after randomisation was 19.6 months. The PFS rates at 9 months and median PFS were 46.4% (80% confidence interval [CI], 38.1-54.9) and 9.1 months (95% CI, 8.6-11.1) in group A, compared with 47.4% (80% CI, 39.1-55.8) and 9.3 months (95% CI, 6.0-13.0) in group B, respectively. RR, OS and TTF were also similar in both groups. Grade ≥2 PN incidence was lower in group B (9.3%) than in group A (35.7%). CONCLUSION: Planned discontinuation of oxaliplatin after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC, achieving similar efficacy while reducing oxaliplatin-associated PN compared with mFOLFOX6 plus panitumumab. TRIAL REGISTRATION NUMBER: NCT02337946.

Wall Enhancement of the Intracranial Aneurysms Revealed by Magnetic Resonance Vessel Wall Imaging Using Three-Dimensional Turbo Spin-Echo Sequence with Motion-Sensitized Driven-Equilibrium: A Sign of Ruptured Aneurysm?

PURPOSE: Wall enhancement of saccular cerebral aneurysms has not been researched sufficiently. Our purpose of this study was to investigate the incidence of aneurysmal wall enhancement by the three-dimensional turbo spin-echo sequence with motion-sensitized driven equilibrium (MSDE-3D-TSE) imaging after gadolinium injection. METHODS: We retrospectively reviewed the pre- and postcontrast MSDE-3D-TSE images of 117 consecutive patients with intracranial aneurysms from September 2011 to July 2013. A total of 61 ruptured and 83 unruptured aneurysms of 61 patients with subarachnoid hemorrhage (SAH) and 56 non-SAH patients were enrolled in this study. We evaluated the wall enhancement of each aneurysm on postcontrast MSDE-3D-TSE images compared with precontrast images. We classified the aneurysmal wall enhancement into three groups as "Strong enhancement," "Faint enhancement," and "No enhancement." RESULTS: "Strong/Faint enhancement" of the aneurysm was detected in 73.8/24.6 % of the ruptured aneurysms and 4.8/13.3 % of the unruptured aneurysms. "No enhancement" was found in 1.6 % of the ruptured aneurysms and 81.9 % of the unruptured aneurysms. CONCLUSIONS: By magnetic resonance vessel wall imaging using the MSDE-3D-TSE sequence, wall enhancement was frequently observed on ruptured aneurysms. Therefore, aneurysmal wall enhancement may be an indicator of the ruptured condition, which is useful information for managing patients with SAH.

Molecular cloning of cDNA for antimycin A-inducible mRNA and its role in cyanide-resistant respiration in Hansenula anomala.

A cDNA for mRNA induced by antimycin A in Hansenula anomala was cloned. The mRNA for the cDNA was expressed in the yeast under the conditions expressing the cyanide-resistant respiration activity. The nucleotide sequence revealed a long open reading frame of 342 codons encoding a protein with a molecular weight of 40,282 in the cDNA. An antibody recognizing the protein encoded by the open reading frame was produced. Immunoblotting of H. anomala proteins with this antibody showed that a 36 kDa protein localized in mitochondria was a mature form of the protein encoded by the cDNA. It is suggested that the cloned cDNA encodes a protein involved in the cyanide-resistant respiratory pathway.

Characterization of the alternative oxidase protein in the yeast Hansenula anomala.

The cyanide-resistant respiratory pathway is induced by respiratory inhibitors in the yeast Hansenula anomala. A monoclonal antibody against the alternative oxidase in the higher plant Sauromatum guttatum cross-reacted with a 36-kDa mitochondrial protein induced by antimycin A in H. anomala and with a protein encoded by a cDNA which was previously cloned for an antimycin A-inducible mRNA in the yeast. There was a similarity in the amino acid sequence between the cDNA-encoded protein and the plant alternative oxidase protein. We propose that the 36-kDa mitochondrial protein encoded by the cDNA is a component of alternative oxidase in H. anomala.

Essential role of ferrous iron in cyanide-resistant respiration in Hansenula anomala.

Antimycin A-dependent induction of cyanide-resistant respiration in Hansenula anomala was completely blocked by o-phenanthroline, alpha,alpha'-dipyridyl, or 8-hydroxyquinoline. Pulse-labeling of the cells with [35S]methionine in the presence of both antimycin A and o-phenanthroline indicated that the 36-kDa protein previously reported to be involved in cyanide-resistant respiration [(1989) J. Biochem. 105, 864-866] was formed in mitochondria even under these conditions. The addition of Fe2+, but not Fe3+, ions to these cells in the presence of cycloheximide resulted in the rapid expression of cyanide-resistant respiration activity. These results suggest that in the presence of both antimycin A and o-phenanthroline an inactive form of the 36-kDa protein was formed and Fe2+ ions converted it to the active form. It is also likely that Fe2+ ions are involved in the reaction mechanism of cyanide-resistant respiration.

A 36-kDa mitochondrial protein is responsible for cyanide-resistant respiration in Hansenula anomala.

Antimycin A-dependent induction of cyanide-resistant respiration in Hansenula anomala was reversibly blocked by carbonylcyanide-m-chlorophenylhydrazone (CCCP). When the cells were pulse-labeled with [35S]methionine in the presence of both antimycin A and CCCP, the radioactivity was incorporated into a 39 kDa mitochondrial protein. Upon removal of CCCP, this protein was processed into a 36 kDa form. The increase in the 36 kDa protein completely paralleled that in cyanide-resistant respiration activity, suggesting that the 39 kDa protein is the precursor of the 36 kDa protein, which is responsible for cyanide-resistant respiration.

Possible involvement of superoxide anion in the induction of cyanide-resistant respiration in Hansenula anomala.

A chemiluminescence study showed that Qi site inhibitors such as antimycin A induce O2- generation in respiring cyanide-sensitive mitochondria from the yeast, Hansenula anomala. The O2- generation was suppressed by radical scavengers such as flavone, butylated hydroxyanisole, and Co0. Induction of cyanide-resistant respiration in H. anomala cells by Qi site inhibitors was also inhibited by these radical scavengers. Furthermore, antimycin A-induced synthesis of the mitochondrial 36-kDa protein, which is thought to be the alternative oxidase functional in the cyanide-resistant respiratory pathway, was abolished by the addition of flavone. These observations suggest that O2- is somehow involved in the induction of cyanide-resistant respiration.

An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei.

Ascofuranone, a prenylphenol antibiotic isolated from a phytopathogenic fungus, Ascochyta visiae, strongly inhibited both glucose-dependent cellular respiration and glycerol-3-phosphate-dependent mitochondrial O2 consumption of long slender bloodstream forms of Trypanosoma brucei brucei. This inhibition was suggested to be due to inhibition of the mitochondriai electron-transport system, composed of glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) and plant-like alternative oxidase. Ascofuranone noncompetitively inhibited the reduced coenzyme Q1-dependent O2 uptake of the mitochondria with respect to ubiquinol (Ki = 2.38 nM). Therefore, the susceptible site is deduced to be the ubiquinone redox machinery which links the two enzyme activities. Further, ascofuranone in combination with glycerol completely blocked energy production, and potently inhibited the in vitro growth of the parasite. Our findings suggest that ascofuranone might be a promising candidate for the chemotherapeutic agents of African trypanosomiasis.

An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei.

Ascofuranone, a prenylphenol antibiotic isolated from a phytopathogenic fungus, Ascochyta visiae, strongly inhibited both glucose-dependent cellular respiration and glycerol-3-phosphate-dependent mitochondrial O2 consumption of long slender bloodstream forms of Trypanosoma brucei brucei. This inhibition was suggested to be due to inhibition of the mitochondrial electron-transport system, composed of glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) and plant-like alternative oxidase. Ascofuranone noncompetitively inhibited the reduced coenzyme Q1-dependent O2 uptake of the mitochondria with respect to ubiquinol (Ki = 2.38 nM). Therefore, the susceptible site is deduced to be the ubiquinone redox machinery which links the two enzyme activities. Further, ascofuranone in combination with glycerol completely blocked energy production, and potently inhibited the in vitro growth of the parasite. Our findings suggest that ascofuranone might be a promising candidate for the chemotherapeutic agents of African trypanosomiasis.

The induction of cyanide-resistant respiration in Hansenula anomala.

Cyanide-resistant respiration was induced in the yeast, Hansenula anomala in the presence of cyanide or antimycin A, which blocks the electron transport after ubiquinone. The de novo protein synthesis in cytosol and oxygen were deduced to be involved in this induction process. The period required for the induction varied during the growth stage, suggesting that involvement of additional physiological factor(s) in this induction process. The organism could multiply in the presence of antimycin A by developing cyanide-resistant respiration despite a decreased growth rate.

Purification and characterization of the assimilatory NADPH-nitrate reductase of Aspergillus nidulans.

NADPH-nitrate reductase [NADPH : nitrate oxidoreductase, EC 1.6.6.3] was purified 500-fold from Aspergillus nidulans with an overall yield of about 20%. The purified enzyme catalyzed NADPH-nitrate, NADPH-cytochrome c, FADH2-nitrate and reduced methyl viologen-nitrate reductase activities. Its molecular weight was estimated to be 180,000 from the Stokes radius and sedimentation coefficient. The oxidized enzyme exhibited an absorption spectrum having a peak at 412 nm and a broad shoulder at about 450 nm. When reduced with NADPH, absorption peaks appeared at 423 (Soret), 527 (beta) and 557 (alpha) nm, and absorption in the 450 nm region decreased. Upon treatment of the reduced enzyme with KNO3, the spectrum returned to that of the oxidized enzyme. The presence of protoheme in the enzyme was confirmed by the absorption spectrum of reduced pyridine hemochromogen. It was concluded that a b-type cytochrome ("cytochrome b-557") is present in the enzyme and is involved in the intramolecular electron transport from NADPH to nitrate. The NADPH-nitrate and NADPH-cytochrome c reductase activities, but not the other two activities, were significantly decreased by incubation of the enzyme at 37 degrees C in the absence of FAD. Analysis by SDS slab gel electrophoresis suggested that the nitrate reductase consists of two each of two subunits of 59,000 and 38,000 daltons and that a dissociation of 38,000 subunits from the native enzyme occurs during heat treatment, resulting in alteration of the catalytic activity.

Possible role of a 36 kDa protein induced by respiratory inhibitors in cyanide-resistant respiration in Hansenula anomala.

The antimycin A or cyanide-dependent appearance of a 36 kDa protein in the particulate fraction was observed in L-[35S]methionine pulse-labeling experiments on cells of Hansenula anomala, in which cyanide-resistant respiration was induced. The combined addition of cycloheximide or anaerobiosis, which block the induction of cyanide-resistant respiration, repressed the synthesis of this protein. These results suggest the involvement of the particulate 36 kDa protein in cyanide-resistant respiration.

Characterization of cyanide-resistant respiration and appearance of a 36 kDa protein in mitochondria isolated from antimycin A-treated Hansenula anomala.

Mitochondria exhibiting cyanide-resistant respiration were isolated from Hansenula anomala which had been incubated in the presence of antimycin A to induce cyanide-resistant respiration. The cyanide-resistant respiration in isolated mitochondria was not inhibited by antimycin A or myxothiazol, suggesting that the branching of the pathway from the normal cyanide-sensitive pathway takes place at the coenzyme Q level. Analysis of mitochondrial proteins by sodium dodecyl sulfate gel electrophoresis indicated that a 36 kDa protein was induced by antimycin A treatment of the yeast. It is suggested that this protein is a component of the cyanide-resistant respiratory pathway.

Functional expression of the ascofuranone-sensitive Trypanosoma brucei brucei alternative oxidase in the cytoplasmic membrane of Escherichia coli.

Trypanosome alternative oxidase (TAO) is the terminal oxidase of the respiratory chain of long slender bloodstream forms (LS forms) of African trypanosoma, which causes sleeping sickness in human and nagana in cattle. TAO is a cytochrome-independent, cyanide-insensitive quinol oxidase and these properties are quite different from those of the bacterial quinol oxidase which belongs to the heme-copper terminal oxidase superfamily. Only little information concerning the molecular structure and enzymatic features of TAO have been available, whereas the bacterial enzyme has been well characterized. In this study, a cDNA encoding TAO from Trypanosoma brucei brucei was cloned into the expression vector pET15b (pTAO) and recombinant TAO was expressed in Escherichia coli. The growth of the transformant carrying pTAO was cyanide-resistant. A peptide with a molecular mass of 37 kDa was found in the cytoplasmic membrane of E. coli, and was recognized by antibodies against plant-type alternative oxidases from Sauromatum guttatum and Hansenula anomala. Both the ubiquinol oxidase and succinate oxidase activities found in the membrane of the transformant were insensitive to cyanide, while those of the control strain, which contained vector alone, were inhibited. This cyanide-insensitive growth of the E. coli carrying pTAO was inhibited by the addition of ascofuranone, a potent and specific inhibitor of TAO ubiquinol oxidase. The ubiquinol oxidase activity of the membrane from the transformant was sensitive to ascofuranone. These results clearly show the functional expression of TAO in E. coli and indicate that ubiquinol-8 in the E. coli membrane is able to serve as an electron donor to the recombinant enzyme and confer cyanide-resistant and ascofuranone-sensitive growth to E. coli. This system will facilitate the biochemical characterization of the novel terminal oxidase, TAO, and the understanding on the mechanism of the trypanocidal effect of ascofuranone.

Influence of cognitive style and interstimulus interval on the hemispheric processing of tactile stimuli.

16 adult subjects performed a tactile recognition task. According to our 1984 study, half of the subjects were classified as having a left hemispheric preference for the processing of visual stimuli, while the other half were classified as having a right hemispheric preference for the processing of visual stimuli. The present task was conducted according to the S1-S2 matching paradigm. The standard stimulus was a readily recognizable object and was presented tactually to either the left or right hand of each subject. The comparison stimulus was an object-picture and was presented visually by slide in a tachistoscope. The interstimulus interval was .05 sec. or 2.5 sec. Analysis indicated that the left-preference group showed right-hand superiority, and the right-preference group showed left-hand superiority. The notion of individual hemisphericity was supported in tactile processing.

[Testicular malignant lymphoma: report of two cases].

One patient was a 79-year-old man, who exhibited right scrotal swelling and the other patient was a 73-year-old man, who exhibited left scrotal swelling. Both patients received high orchiectomy under the diagnosis of testicular tumor and the histopathological diagnosis in both patients was non-Hodgkin's lymphoma. Case 1 was diffuse, medium-sized B cell type, and case 2 was diffuse, mixed B cell type. Several examinations revealed no apparent additional involvement. Neither patient received any adjuvant chemotherapy nor postoperative irradiation. In case 1, for a period of 4 years following high orchiectomy, the patient has been doing well. In case 2, 2 years and 6 months postoperatively, para-aortic lymph node swelling occurred, and chemotherapy was initiated with THP-COP but the patient died at 3 years and 3 months after high orchiectomy.

[A case of 47XYY syndrome presenting with male infertility].

A 32-year-old man was referred to our hospital for primary infertility of a 4.5-year duration. Neither character nor intelligence disorders were observed. Bilateral testes measured 16 ml each. Sperm density was 0-0.1 x 10(6)/ml on 3 separate occasions. Endocrine examinations were all within normal limits. Maturation arrest was found on testicular biopsy. Karyotyping showed 47, XYY inversion. Polymerase chain reaction revealed no deletion of the azoospermic factor (AZF) gene on the Y chromosome. This is the 6th case reported in the Japanese literature of the 47XYY syndrome presenting with male infertility.

[Intracavernous injection of lipo prostaglandin E1 for the diagnosis of impotence: a comparative study with prostaglandin E1-CD].

Intracavernous injection of 20 micrograms prostaglandin E1-CD (PGE1-CD, 8 cases), 5 micrograms lipo prostaglandin E1 (Lipo PG-E1, 8 cases) or 10 micrograms Lipo PGE1 (9 cases) was performed in patients with functional impotence in order to comparatively analyze the diagnostic efficacy of these drugs. Full erection was observed in all patients who received intracavernous injection of 20 micrograms PGE1-CD or 10 micrograms Lipo PGE1. However, full erection was observed in 4 out of 8 patients administered 5 micrograms Lipo PGE1. RigiScan was used on all patients, and latency until erection (achievement of maximum rigidity of the base) after injection, maximum rigidity of the penile tip and base and circumferential expansion rate of the penile tip and base were measured. With regard to these RigiScan data and duration of erection, there were no significant differences among the 3 groups. There were no severe side effects in any of the patients. These findings indicate that 10 micrograms Lipo PGE1 and 20 micrograms PGE1-CD have similar effects and that Lipo PGE1 may be an effective drug for the diagnosis and treatment of impotence.

[A case report: reversible male infertility due to congenital adrenal hyperplasia].

We have studied a 32-year-old patient who was infertile because of azoospermia, We made the final diagnosis of non-classical congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency with adrenal rest tumor of bilateral testes and bilateral adrenal myelolipoma. The patient was given 1.5 mg/day dexamethasone. Decreases in the levels of 17 OHP and adrenal androgen were rapidly observed. After 5 months of treatment, semen analysis showed a sperm density of 2 x 10(4)/ml with 50% motile spermatozoa. His wife became pregnant and delivered of a healthy daughter. We conclude that chronic suppression of gonadotropins secretion caused by overproduction of adrenal androgens in CAH would appear to be the cause for the failure of testicular development and spermatogenesis.

A comparison between intraductal papillary neoplasms of the biliary tract (BT-IPMNs) and intraductal papillary mucinous neoplasms of the pancreas (P-IPMNs) reveals distinct clinical manifestations and outcomes.

BACKGROUND: Intraductal papillary mucinous neoplasm of the biliary tract (BT-IPMN) has been increasingly recognized as a biliary counterpart of intraductal papillary mucinous neoplasm of the pancreas (P-IPMN). However, there is limited information regarding whether BT-IPMNs and P-IPMNs behave in a similar fashion. METHODS: We retrospectively compared clinicopathological variables between 9 patients with BT-IPMN and 44 patients with P-IPMN. RESULTS: There was no significant difference in age between patients with BT-IPMN and those with P-IPMN. The male/female ratio was significantly higher in patients with P-IPMN than in those with BT-IPMN (P = 0.012). Clinical presentation with jaundice was more common in patients with BT-IPMN (67%) than in those with P-IPMN (4.5%, P = 0.002). In addition, serum levels of CEA and CA19-9 were higher in patients with BT-IPMN than in those with P-IPMN (P = 0.019 and P = 0.002, respectively). The pathological diagnosis of malignancy was significantly more common in patients with BT-IPMN (89%) than in those with P-IPMN (23%, P = 0.002). The association with invasive carcinoma was significantly more frequent in patients with BT-IPMN (44.4%) than in those with P-IPMN (6.8%, P = 0.008). Furthermore, survival time after surgical resection was significantly shorter in patients with BT-IPMN than in those with P-IPMN (P = 0.002). CONCLUSION: These findings reveal differences in clinicopathological features and prognosis between BT-IPMN and P-IPMN, thereby suggesting distinct biological pathways underlying the pathogenesis of these neoplasms.