Clinical significance of programmed death‐1 and programmed death‐ligand 1 expression in the tumor microenvironment of clear cell renal cell carcinoma

Recently, immunotherapy based on blocking immune checkpoints with programmed death‐1 (PD‐1) or PD‐ligand 1 (PD‐L1) Abs has been introduced for the treatment of advanced clear cell renal cell carcinoma (ccRCC), especially tumors resistant to vascular endothelial growth factor‐tyrosine kinase inhibitors (VEGF‐TKIs), but the significance of their expression in the tumor microenvironment is unclear. We investigated these immune checkpoint markers in tumor cells and tumor‐infiltrating immune cells (TIIC) in the tumor microenvironment of 100 untreated and 25 VEGF‐TKI‐treated primary ccRCC tissues. Upregulated expression of PD‐1 and PD‐L1 by TIIC, and PD‐L1 by tumor cells was associated with the histological grade and unfavorable prognosis of RCC patients. High PD‐1 and PD‐L1 expression by TIIC was associated with a poorer response to VEGF‐TKI, whereas PD‐L1 expression by tumor cells did not affect the efficacy of the treatment. Furthermore, increased PD‐1‐positive TIIC and PD‐L1‐positive TIIC were observed in tumors treated with VEGF‐TKIs compared with those in untreated tumors. Our data suggest that PD‐1 and PD‐L1 expression by TIIC in the tumor microenvironment is involved in treatment resistance, and that sequential therapy with immune checkpoint inhibitors could be a promising therapeutic strategy for ccRCC resistant to VEGF‐TKI treatment.     

Brief Report: Bindin is essential for fertilization in the sea urchin

Species-specific sperm−egg interactions are essential for sexual reproduction. Broadcast spawning of marine organisms is under particularly stringent conditions, since eggs released into the water column can be exposed to multiple different sperm. Bindin isolated from the sperm acrosome results in insoluble particles that cause homospecific eggs to aggregate, whereas no aggregation occurs with heterospecific eggs. Therefore, Bindin is concluded to play a critical role in fertilization, yet its function has never been tested. Here we report that Cas9-mediated inactivation of the bindin gene in a sea urchin results in perfectly normal-looking embryos, larvae, adults, and gametes in both males and females. What differed between the genotypes was that the bindin^−/− sperm never fertilized an egg, functionally validating Bindin as an essential gamete interaction protein at the level of sperm–egg cell surface binding.     

Chromosome-specific segmentation revealed by structural analysis of individually isolated chromosomes

Analysis of structural rearrangements at the individual chromosomal level is still technologically challenging. Here we optimized a chromosome isolation method using fluorescent marker-assisted laser-capture and laser-beam microdissection and applied it to structural analysis of two aberrant chromosomes found in a lung cancer cell line. A high-density array-comparative genomic hybridization (array-CGH) analysis of DNA samples prepared from each of the chromosomes revealed that these two chromosomes contained 296 and 263 segments, respectively, ranging from 1.5 kb to 784.3 kb in size, derived from different portions of chromosome 8. Among these segments, 242 were common in both aberrant chromosomes, but 75 were found to be chromosome-specific. Sequences of 263 junction sites connecting the ends of segments were determined using a PCR/Sanger-sequencing procedure. Overlapping microhomologies were found at 169 junction sites. Junction partners came from various portions of chromosome 8 and no biased pattern in the positional distribution of junction partners was detected. These structural characteristics suggested the occurrence of random fragmentation of the entire chromosome 8 followed by random rejoining of these fragments. Based on that, we proposed a model to explain how these aberrant chromosomes are formed. Through these structural analyses, it was demonstrated that the optimized chromosome isolation method described here can provide high-quality chromosomal DNA for high resolution array-CGH analysis and probably for massively parallel sequencing analysis.     

Elevated scrotal temperature, but not varicocele grade, reflects testicular oxidative stress-mediated apoptosis

Purpose  

Elevation of scrotal temperature has been known as a cause of male infertility but the exact mechanism leading to impaired spermatogenesis is unknown. This work aimed to investigate the role of elevated scrotal temperature, oxidative stress, and apoptosis in testes of infertile males associated with varicocele.     

Recent Mortality from Pleural Mesothelioma,Historical Patterns of Asbestos Use,and Adoption of Bans: A Global Assessment

Background

In response to the health risks posed by asbestos exposure, some countries have imposed strict regulations and adopted bans, whereas other countries have intervened less and continue to use varying quantities of asbestos.

Objectives

This study was designed to assess, on a global scale, national experiences of recent mortality from pleural mesothelioma, historical trends in asbestos use, adoption of bans, and their possible interrelationships.

Methods

For 31 countries with available data, we analyzed recent pleural mesothelioma (International Classification of Diseases, 10th Revision) mortality rates (MRs) using age-adjusted period MRs (deaths/million/year) from 1996 to 2005. We calculated annual percent changes (APCs) in age-adjusted MRs to characterize trends during the period. We characterized historical patterns of asbestos use by per capita asbestos use (kilograms per capita/year) and the status of national bans.

Results

Period MRs increased with statistical significance in five countries, with marginal significance in two countries, and were equivocal in 24 countries (five countries in Northern and Western Europe recorded negative APC values). Countries adopting asbestos bans reduced use rates about twice as fast as those not adopting bans. Turning points in use preceded bans. Change in asbestos use during 1970–1985 was a significant predictor of APC in mortality for pleural mesothelioma, with an adjusted R² value of 0.47 (p < 0.0001).

Conclusions

The observed disparities in global mesothelioma trends likely relate to country-to-country disparities in asbestos use trends.     

Role of vitronectin receptor-type integrins and osteopontin in ischemia-induced retinal neovascularization

PURPOSE: It has been reported that vitronectin receptor-type integrins mediate vascular cell proliferation and migration. In this study, we investigated the expression of vitronectin receptor-type integrins and osteopontin in ischemia-induced retinal neovascularization, and examined the role of osteopontin in angiogenesis as a ligand of vitronectin receptor-type integrins. METHODS: Retinal neovascularization was produced by exposing C57BL/6J mice to 75% oxygen from postnatal day (P) 7 to P12. Expression of vitronectin receptor-type integrins and osteopontin was assessed by Northern blot analysis, in situ hybridization, and immunofluorescence. The role of osteopontin in retinal angiogenesis was evaluated by tube formation assay using cultured bovine retinal microcapillary endothelial cells. RESULTS: In the murine model, integrin alpha(v) mRNA was increased from P14 with a 2.6-fold peak response observed on P19, when retinal neovascularization was remarkable. Indirect immunofluorescence for vitronectin receptor-type integrins revealed prominent expression of integrin alpha(v)beta3/beta5 in the neovascular endothelial cells. Osteopontin mRNA was increased from P14, with a 2.0-fold peak response observed on P19. In situ hybridization demonstrated localization of osteopontin mRNA in neovascular tufts. Vascular endothelial growth factor-induced tube formation (8.3 +/- 0.6 mm/field) was inhibited significantly by treatment with anti-osteopontin antibody (4.8 +/- 0.7 mm/field, P <.001). CONCLUSIONS: These data suggest that increased expression of both vitronectin receptor-type integrins and osteopontin in ischemic retina contribute to vascular endothelial cell proliferation and to retinal vascular formation by promoting interaction between endothelial cells and extracellular matrix, which leads to retinal neovascularization.     

Vogt–Koyanagi–Harada disease in elderly Japanese patients

PURPOSE: The purpose of this study was to evaluate the characteristics of Vogt-Koyanagi-Harada (VKH) disease in elderly (age > or =65 years) Japanese patients. METHODS: We reviewed the medical records of all patients diagnosed with VKH disease at the Department of Ophthalmology, Oita University Hospital between October 1982 and March 2005. Data extracted included age, gender, prodromal symptoms, visual acuity, ocular manifestations, extraocular findings, human leukocyte antigen (HLA), ocular complications, treatment, and smoldering inflammation. RESULTS: Of the 68 patients with VKH disease, seven (10%) were classified as elderly at onset. The incidence of optic disk hyperemia, choroidal detachment, and cataract was significantly higher in the elderly patients than the non-elderly patients (<65 years). The total dose of corticosteroid used was higher in the elderly. The incidence of smoldering inflammation was more frequent in the elderly. Final visual acuity was preserved relatively well in the elderly. CONCLUSION: The significantly higher incidence of optic disk hyperemia, choroidal detachment, and cataract, and the more frequent smoldering inflammation in elderly VKH patients indicate that special attention should be paid to these parameters in elderly patients.     

A case of advanced small cell lung cancer complicated by chronic renal failure treated with amrubicin

A 64-year old man first visited our clinic approximately 10 years ago because of diabetic nephropathy that had developed into chronic renal failure. He was hospitalized to examine a left S10 tumor shadow. Based on the results of these examinations, a primary left S10 T2N0M1, ED small cell lung cancer, was diagnosed. During his outpatient visits nephropathy was found. Following admission, he began dialysis(HD). During the detailed examinations, chemotherapy with amrubicin(AMR)was performed and the blood concentration of the drug was measured. The results showed no significant variations in blood concentration before and after the dialysis. While PR was achieved in this patient, a reduction in grade 4 eosinophils was observed as an adverse reaction.