The histogenesis of DMH-induced colonic carcinoma in rats

Twenty-one Donryu male rats of six weeks old were injected with 1,2-dimethyl-hydrazine hydrochloride (DMH), once a week, for 4 to 20 weeks, and sacrificed at intervals of two weeks since a lapse of four weeks after the commencement of the injections. The DMH induced 320 atypia lesions, from 0.03 through 20 mm in size, of grade II or higher. The rate of benign lesions was higher in the group receiving less than 20 injections than in the group of 20 injections of DMH, while in the latter group, the rates of the benign, borderline and malignant lesions were stable, suggesting that benign lesions mainly develop in the earlier period of the DMH treatment, and thereafter various grades of lesions develop at a constant rate. All the benign lesions were less than 1 mm in size, and all lesions greater than 1 mm were malignant. In addition, the size of the lesion was significantly greater when it was occupied by malignant crypts in a greater rate. These results indicate that the benign lesions become cancerous before they reach a certain size (adenoma-carcinoma sequence). Twenty-seven minute lesions (less than 1 mm) were mixed lesions of malignant and benign atypia, suggesting that the adenoma-carcinoma sequence is elicited in any size of lesion. On the other hand, there were 41 minute malignant-only lesions, which constituted 27.7% of the overall minute lesions and included three "single crypt" cancers. In addition, malignant-only lesions were smaller when compared to the malignant-dominant mixed lesions. These results indicate that about 30% of colon cancers develop de-novo.     

Immunohistochemistry of γ‐H2AX as a method of early detection of urinary bladder carcinogenicity in mice

Phosphorylated histone H2AX (γ‐H2AX) has been demonstrated as a DNA damage marker both in vitro and in vivo. We previously reported the effects of genotoxic carcinogens in the urinary bladder of rats by immunohistochemical analysis of γ‐H2AX using samples from 28‐day repeated‐dose tests. To evaluate the application of γ‐H2AX as a biomarker of carcinogenicity in the bladder, we examined species differences in γ‐H2AX formation in the urinary bladder of mice. Six‐week‐old male B6C3F₁ mice were treated orally with 12 chemicals for 4 weeks. Immunohistochemical analysis demonstrated that N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine, p‐cresidine and 2‐acetylaminofluorene (2‐AAF), classified as genotoxic bladder carcinogens, induced significant increases in γ‐H2AX levels in the bladder urothelium. In contrast, genotoxic (2‐nitroanisole, glycidol, N‐nitrosodiethylamine and acrylamide) and non‐genotoxic (dimethylarsinic acid and melamine) non‐bladder carcinogens did not upregulate γ‐H2AX. Importantly, 2‐nitroanisole, a potent genotoxic bladder carcinogen in rats, significantly increased the proportion of γ‐H2AX‐positive cells in rats only, reflecting differences in carcinogenicity in the urinary bladder between rats and mice. Significant upregulation of γ‐H2AX was also induced by uracil, a non‐genotoxic bladder carcinogen that may be associated with cell proliferation, as demonstrated by increased Ki67 expression. 2‐AAF caused γ‐H2AX formation mainly in the superficial layer, together with reduced and disorganized expression of uroplakin III, unlike in rats, suggesting the mouse‐specific cytotoxicity of 2‐AAF in umbrella cells. These results suggest γ‐H2AX is a useful biomarker reflecting species differences in carcinogenicity in the urinary bladder.     

The serum vaspin levels are reduced in Japanese chronic hemodialysis patients

Background

Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified in genetically obese rats that correlates with insulin resistance and obesity in humans. Recently, we found that 7% of the Japanese population with the minor allele sequence (A) of rs77060950 exhibit higher levels of serum vaspin. We therefore evaluated the serum vaspin levels in Japanese chronic hemodialysis patients.

Methods

Healthy Japanese control volunteers (control; n?=?95, 49.9±6.91?years) and Japanese patients undergoing hemodialysis therapy (HD; n?=?138, 51.4±10.5?years) were enrolled in this study, and serum samples were subjected to the human vaspin RIA system.

Results

The measurement of the serum vaspin levels demonstrated that a fraction of control subjects (n?=?5) and HD patients (n?=?11) exhibited much higher levels (> 10?ng/ml; Vaspin_High group), while the rest of the population exhibited lower levels (< 3?ng/ml; Vaspin_Low group). By comparing the patients in the Vaspin_Low group, the serum vaspin levels were found to be significantly higher in the control subjects (0.87±0.24?ng/ml) than in the HD patients (0.32±0.15?ng/ml) (p?<?0.0001). In the stepwise regression analyses, the serum creatinine and triglyceride levels were found to be independently and significantly associated with the vaspin concentrations in all subjects.

Conclusions

The creatinine levels are negatively correlated with the serum vaspin levels and were significantly reduced in the Japanese HD patients in the Vaspin_Low group.

     

Synthetic and biochemical studies on the effect of persulfidation on disulfide dimer models of amyloid β42 at position 35 in Alzheimer's etiology

Protein persulfidation plays a role in redox signaling as an anti-oxidant. Dimers of amyloid β42 (Aβ42), which induces oxidative stress-associated neurotoxicity as a causative agent of Alzheimer''s disease (AD), are minimum units of oligomers in AD pathology. Met35 can be susceptible to persulfidation through its substitution to homoCys residue under the condition of oxidative stress. In order to verify whether persulfidation has an effect in AD, herein we report a chemical approach by synthesizing disulfide dimers of Aβ42 and their evaluation of biochemical properties. A homoCys-disulfide dimer model at position 35 of Aβ42 formed a partial β-sheet structure, but its neurotoxicity was much weaker than that of the corresponding monomer. In contrast, the congener with an alkyl linker generated β-sheet-rich 8–16-mer oligomers with potent neurotoxicity. The length of protofibrils generated from the homoCys-disulfide dimer model was shorter than that of its congener with an alkyl linker. Therefore, the current data do not support the involvement of Aβ42 persulfidation in Alzheimer''s disease.

Our data do not support the Aβ42 persulfidation hypothesis in Alzheimer''s etiology because the neurotoxicity of the homoCys-disulfide-Aβ42 dimer was very weak.     

Intersphincteric resection for very low rectal cancer: a systematic review

Radical surgical treatment for very low rectal cancer near the anus has generally involved abdominoperineal resection. Various sphincter-saving operations have been developed for such tumors to optimize the patients’ postoperative quality of life. Current protocols focus on intersphincteric resection (ISR), which differs from conventional hand-sewn coloanal anastomosis (CAA) after low anterior resection. However, the efficacy of ISR remains unclear. The surgical, oncologic, and functional outcomes after intersphincteric resection (ISR) were reviewed. This review of the current literature was conducted by searching the PubMed online database. Articles focusing specifically on conventional hand-sewn CAA were excluded from this study. The mean mortality rate is <2 %, and the mean morbidity rate ranges from 7.7 to 38.3 %. The mean local recurrence rate varies widely from 0 to 22.7 %, with a mean follow-up duration of 40–94 months. The mean disease-free and overall 5-year survival rates are 69–86 and 79–97 months, respectively. Functional outcomes are generally acceptable, but accurate evaluation is extremely difficult due to the absence of unified appraisal methods. ISR appears surgically, oncologically and functionally acceptable. However, more experience and better understanding of the oncology, anal physiology, and pelvic anatomy are necessary to achieve successful outcomes without complications, and to improve patient survival.     

Localized Neurofibromas in the Bilateral Orbits

Localized neurofibromas are rare in the orbit and, unlike the more common plexiform neurofibromas, are not typically associated with von Recklinghausen neurofibromatosis. We present a rare case of localized neurofibromas in the bilateral orbits.