Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer.

The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and is involved in Mixed Lineage Leukemia (MLL) fusion leukemogenesis; however, its role in prostate cancer (PCa) is undefined. Here we show that DOT1L is overexpressed in PCa and is associated with poor outcome. Genetic and chemical inhibition of DOT1L selectively impaired the viability of androgen receptor (AR)-positive PCa cells and organoids, including castration-resistant and enzalutamide-resistant cells. The sensitivity of AR-positive cells is due to a distal K79 methylation-marked enhancer in the MYC gene bound by AR and DOT1L not present in AR-negative cells. DOT1L inhibition leads to reduced MYC expression and upregulation of MYC-regulated E3 ubiquitin ligases HECTD4 and MYCBP2, which promote AR and MYC degradation. This leads to further repression of MYC in a negative feed forward manner. Thus DOT1L selectively regulates the tumorigenicity of AR-positive prostate cancer cells and is a promising therapeutic target for PCa.

Chloroplast development in Arabidopsis thaliana requires the nuclear-encoded transcription factor sigma B.

Development of plastids into chloroplasts, the organelles of photosynthesis, is triggered by light. However, little is known of the factors involved in the complex coordination of light-induced plastid gene expression, which must be directed by both nuclear and plastid genomes. We have isolated an Arabidopsis mutant, abc1, with impaired chloroplast development, which results in a pale green leaf phenotype. The mutated nuclear gene encodes a sigma factor, SigB, presumably for the eubacterial-like plastid RNA polymerase. Our results provide direct evidence that a nuclear-derived prokaryotic-like SigB protein, plays a critical role in the coordination of the two genomes for chloroplast development.

The effect of cyclosporin A on Angiostrongylus cantonensis infection and eosinophilia in mice.

Male BALB/c mice were infected with Angiostrongylus cantonensis and at various times p.i. treated with cyclosporin A (CsA) either for 5 days continuously or intermittently, or for 12-16 days on alternate days. They were monitored for peripheral blood eosinophilia and at necropsy examined for CSF and bone marrow eosinophilia, and worm recovery. CsA treatment provoked a transient inhibition of peripheral blood eosinophilia in all groups examined, followed by rebounding eosinophilia. There was no significant difference in bone marrow and CSF eosinophilia between CsA- and vehicle-treated groups. Mice treated with CsA on alternate days yielded lower intracranial worm recovery with small-sized worms at days 7, 21 and 30 p.i. than vehicle-treated groups did. No significant reduction in worm recovery was noted in mice treated for 5 days either continuously or intermittently, although worms, especially female ones, harvested from groups treated with CsA from days--1 to 3 or from days 13 to 17 were significantly smaller than those from vehicle-treated groups. CsA-treatment suppressed blastogenic responses of spleen cells against Con A or worm antigen at days 7 and 21 p.i. In vitro treatment of the 3rd stage larvae with CsA did not adversely influence survival of A. cantonensis in mice. These data indicate that CsA exerts anti-parasitic effects against A. cantonensis in mice.

Increase in basal level of Hsp70, consisting chiefly of constitutively expressed Hsp70 (Hsc70) in aged rat brain.

Alteration of proteins in the function and higher structure has been observed in aged organisms. Stress proteins, which have a role to protect proteins from denaturation, may respond to the protein denaturation with aging. We found that the basal level of Hsp70, consisting chiefly of constitutively expressed Hsp70 (Hsc70), in 24-month-old Wistar rats was significantly higher in some parts of the brain than that in 6-month-old rats. On the other hand, the basal level of Hsp70 was significantly lower in 24-month-old rats after restricted feeding, which is known to suppress aging, than those fed the diet ad libitum. In the pons, medulla, striatum, and thalamus of 24-month-old rat brain, the level of Hsp70 increased and the denaturation of the cytosol proteins was suppressed. These results suggest that the expression of Hsp70, mostly Hsc70, increases with aging and may have a role to suppress protein denaturation.

Morphogenesis and origin of fibrous long-spacing collagen fibers in collagenase-treated mouse skin tissues.

Morphogenesis and origin of fibrous long-spacing collagen (FLS) fibers in newborn mouse skin tissues treated with collagenase were examined using ultrastructural observation, morphometry, histochemical methods, and immunoelectron microscopy. The enzyme caused both the partial destruction of basal laminae and the formation of abundant FLS fibers in the dermal matrix. The fibers were usually distributed in the vicinity of basal laminae in the capillaries or basal layer cells. The fibers were characterized by the cross-striated dark bands with about 91 nm periodicity and longitudinally aligned filaments with a diameter of about 6.5 nm. The dark bands of FLS fibers were often continuous with the basal laminae. Histochemical results showed that the dark bands contained the similar mucopolysaccharides which were involved in the basal laminae. Immunoelectron microscopic results showed that laminin was present in the dark bands as well as in the basal laminae, and that type VI collagen was located in the filaments of FLS fibers. These results suggest that the dark bands are formed by products similar to basal laminae and that the products were precipitated on type VI collagen-contained filaments with periodic intervals of about 91 nm. Morphometric examination revealed that there was no differences in ultrastructure between FLS fibers of a collagenase-treated mouse and those of a human neural tumor.

Magnetic microcapsules for targeted delivery of anticancer drugs.

To achieve targeted distribution of anticancer drugs with sustained activity, ferromagnetic ethylcellulose microcapsules containing an anticancer drug, mitomycin C (FM-MMC-mc), were prepared by a method based on phase separation principles. Two prototypes of FM-MMC-mc were made: one with the drug as the core and zinc ferrite on its capsular surface (outer type); the other with both the drug and zinc ferrite as the core (inner type). Both preparations provided a sustained-release property and a sensitive response to conventional magnetic force, although certain differences in the release rate of drug, magnetic responsiveness, and particle size were found between the two dosage forms. Animal studies showed that the magnetic microcapsules could be magnetically controlled in the artery and urinary bladder. VX2 tumors in the rabbit hind limb and urinary bladder were successfully treated with magnetic control of FM-MMC-mc. Pharmacokinetic study revealed that the targeting of the microcapsules markedly enhanced the drug absorption into the surrounding tissues for a prolonged period of time. The results indicate the feasibility and effectiveness of the magnetic microcapsules as a targeted drug delivery system.

[Topical treatment of onychomycosis by occlusive dressing using bifonazole cream containing 40% urea].

Topical treatment with an antifungal agent was performed in 70 cases of onychomycosis (69 cases of tinea unguium and 1 case of Candida onychomycosis). The patients were treated every night by occlusive dressing using bifonazole cream containing 40% urea, and then by simple application of 1% bifonazole solution in the morning. During the treatment period, the softened affected nails were removed as completely as possible with nail clippers and files. The nails were observed every two weeks, and the efficacy was evaluated after 12 weeks. Two cases were excluded and 28 cases dropped out leaving 40 cases for efficacy evaluation. Among the 40 patients, 20 appeared to be mycologically negative (mycological cure rate: 50.0%). Clinical response was judged by the changes in opacity and thickness of the nails. Nine patients were evaluated as showing "marked improvement" and 16 as showing "improvement" (improvement rate: 62.5%). Erosion was noted as an adverse reaction in 2 patients. In one patient, treatment was stopped and the lesion was improved by antibiotic ointment, and in another, treatment was resumed when erosion was cured by discontinuation of the treatment. These results suggest that the topical treatment of onychomycosis by occlusive dressing is a useful method for those patients who have difficulties in or do not wish to be treated with oral antifungal agents.

[Expanded indication of percutaneous transluminal coronary angioplasty to the infarcted zone--using thallium-201 exercise scintigram after rehabilitation].

In some cases of old myocardial infarction (OMI), left ventricular wall motion was improved after revascularization, though viability of the infarcted myocardium was not detected by left ventriculography (LVG) and exercise thallium-201 myocardial scintigraphy (EX-Tl). So to obtain more correct information of the viability, EX-Tl was performed again after ergometer rehabilitation for an OMI patient whose myocardial viability of the infarcted zone could not detected by LVG and EX-Tl. Incomplete fill in was showed in the EX-Tl after rehabilitation. So percutaneous transluminal coronary angioplasty (PTCA) was performed. Left ventricular wall motion was improved after three months. EX-Tl after rehabilitation is useful to evaluate the viability that could not detected by LVG and EX-Tl.

[Studies on HLA typing in a family line with spontaneous pneumothorax].

Our patient with spontaneous pneumothorax is the oldest brother of 3 siblings. Pneumothorax had occurred in his younger sister and in 3 of his mother's 4 siblings also. Namely, pneumothorax had occurred in 5 (including our patient) of 7 persons, family line on mother's side, and thoracotomy had been performed in 3 of them. Two cases in which operative findings were obtained were introduced. Next, HLA and alpha 1-antitrypsin (alpha 1-AT) were determined in this family line. As the result, the alpha 1-AT all remained in the normal range and HLA typing was not in a special relation to the occurrence of pneumothorax in this family line.

[Chondrosarcoma of the ribs: report of two cases].

Chondrosarcoma of rib origin is relatively rare in Japan. Two patients with chondrosarcoma of rib origin were treated surgically. Case 1: A 79-year-old male, 4 years ago, he noticed a tumor in the left anteroinferior part of the chest. The histological examination of the specimen obtained by incisional biopsy showed osteochondroma in another hospital and he had been under observation. Since the tumor has recently increased in size, he was referred to our department. Radical resection of the chest wall was performed. As expected, the tumor was found to be a secondary chondrosarcoma by postoperative histological examination. Case 2: A 49-year-old female. In the follow up studies after radical nephrectomy, Tc-MDP scintigram revealed an accumulation in the left second rib. Under the diagnosis of rib metastasis, radical resection was performed. The histological examination showed chondrosarcoma of rib origin postoperatively. This lesion was a primary central type, and is considered to have been resected in the earliest stage of all cases we have found in the Japanese literature.

[Traumatic diaphragmatic hernia].

Five cases of traumatic diaphragmatic hernia were reported and 495 cases reported in Japan were reviewed. Analysis of cases of hernia following blunt trauma in the present study provided a simple classification of fissure of the diaphragm, i.e., "tension type (indirect type)" and "impact type (direct type)". In the former type, the fissure occurs in the central tendon or its vicinity in the diaphragm as a result of distortion of the bony thorax without direct force on the diaphragm, while in the latter type, the fissure occurs in the diaphragm close to the struck bony thorax as a result of blunt force on the bony thorax to which the diaphragm is attached.

[Angiographic findings in a patient with spontaneous hemopneumothorax].

We experienced one patient with spontaneous hemopneumothorax in whom angiography was performed preoperatively. The patient was a 23-year-old female and her plain chest X-ray revealed an index-finger-tip-sized bulla at the left apex and a narrow restiform shadow connecting the pleural cupola with the bulla. Left subclavian arteriography revealed preoperatively that the restiform shadow consisted of aberrant vessels branched from the left costocervical trunk and distributed in and around the bulla at the apex. In the present study very rare angiographic findings and excised specimens obtained from the patient are shown, with reference to surgical indication of spontaneous pneumothorax.

[Chemo-embolization with mitomycin C microcapsules for hepatoma].

Mitomycin C microcapsules (MMC-mc), which were developed as a novel drug carrier, have proved to exert a potential therapeutic effect due to both microinfarction and sustained drug action (chemo-embolization), when infused into a tumor supplying arteries. Experimental studies have demonstrated that chemo-embolization with MMC-mc produces a definitely marked and extensive cytotoxicity in target tissues as compared with traditional arterial chemotherapy, embolization or combination of both. Sixty-seven patients with advanced hepatoma were treated with intra-arterial MMC-mc during the period from 1978 to 1982. Since the majority of patients were in far advanced stages, 56 patients received only single or two infusions of an average dose of 20 mg MMC-mc. Objective tumor reduction greater than 25% in area was observed in 22 (40%) of measurable 55 tumors. Elevated serum alpha-fetoprotein in 26 patients improved in 22 (85%). Relative survival rates of 59 patients without distant metastasis were 64% at 3 months, 49% at 6 months and 26% at 12 months. Side effects such as bone marrow depression, decreased liver function, fever, anorexia, pain and infection were experienced in 9 to 39%, but the majority of them were mild and controllable. Our preliminary experience suggests that MMC-mc can be effectively used in treatment of liver tumors as a palliative but also as a preoperative measure. Further clinical trials including controlled study may well demonstrate the advantages of MMC-mc.