Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis

Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL-6) trans-signaling may be a critical mediator of MNC-MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels compared to matched pre-CLAD samples. Human BAL-derived MCs do not respond to treatment with IL-6 alone but have rapid and prolonged JAK2-mediated STAT3 Tyr705 phosphorylation when exposed to the combination of IL-6 and sIL-6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL-6 and sIL-6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL-6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL-6 and sIL-6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.     

Radiation effects on atherosclerosis in atomic bomb survivors: a cross‐sectional study using structural equation modeling

Past reports indicated that total-body irradiation at low to moderate doses could be responsible for cardiovascular disease risks, but the mechanism remains unclear. The purpose of this study was to investigate the association between radiation exposure and atherosclerosis, an underlying pathology of cardiovascular diseases, in the Japanese atomic bomb survivors. We performed a cross-sectional study measuring 14 clinical-physiological atherosclerosis indicators during clinical exams from 2010 to 2014 in 3274 participants of the Adult Health Study cohort. Multivariable analyses were performed by using a structural equation model with latent factors representing underlying atherosclerotic pathologies: (1) arterial stiffness, (2) calcification, and (3) plaque　as measured with indicators chosen a priori on the basis of clinical-physiological knowledge. Radiation was linearly associated with calcification (standardized coefficient per Gy 0.15, 95?% confidence interval: CI [0.070, 0.23]) and plaque (0.11, 95?% CI [0.029, 0.20]), small associations that were comparable to about 2 years of aging per Gy of radiation exposure, but not with arterial stiffness (0.036, 95?% CI [??0.025, 0.095]). The model fitted better and had narrower confidence intervals than separate ordinary regression models explaining individual indicators independently. The associations were less evident when the dose range was restricted to a maximum of 2 or 1 Gy. By combining individual clinical-physiological indicators that are correlated because of common, underlying atherosclerotic pathologies, we found a small, but significant association of radiation with atherosclerosis.

     

Acute aortic dissection involving an aberrant right subclavian artery

Although the aberrant right subclavian artery is the most common abnormality in aortic arch development, it is unusual to encounter this abnormality when repairing acute aortic dissection. We report a case of Stanford type A acute aortic dissection involving an aberrant right subclavian artery in a 45-year-old man. We used the elephant trunk procedure to surgically manage the intimal tear and aberrant right subclavian artery. This is, to our knowledge, the first report in Japan of surgical reconstruction of an aberrant right subclavian artery in conjunction with acute aortic dissection.     

Comparing the Efficacy and Safety of Gemcitabine plus Nab-Paclitaxel versus Gemcitabine Alone in Older Adults with Unresectable Pancreatic Cancer

BackgroundGemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC.Patients and MethodsIn this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses.ResultsGnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant.ConclusionGnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.     

An mt(+) gamete-specific nuclease that targets mt(-) chloroplasts during sexual reproduction in C. reinhardtii

Although the active digestion of mating-type minus (mt-) chloroplast DNA (cpDNA) in young zygotes is considered to be the basis for the uniparental inheritance of cpDNA in Chlamydomonas reinhardtii, little is known about the underlying molecular mechanism. One model of active digestion proposes that nucleases are either synthesized or activated to digest mt- cpDNA. We used a native-PAGE/in gelo assay to investigate nuclease activities in chloroplasts from young zygotes, and identified a novel Ca(2+)-dependent nuclease activity. The timing of activation (approximately 60-90 min after mating) and the localization of the nuclease activity (in mt- chloroplasts) coincided with the active digestion of mt- cpDNA. Furthermore, the activity of the nuclease was coregulated with the maturation of mating-type plus (mt+) gametes, which would enable the efficient digestion of mt- cpDNA. Based on these observations, we propose that the nuclease (designated as Mt(+)-specific DNase, MDN) is a developmentally controlled nuclease that is activated in mt+ gametes and participates in the destruction of mt- cpDNA in young zygotes, thereby ensuring uniparental inheritance of chloroplast traits.     

Multiple duodeno-jejunal diverticula causing massive intestinal bleeding

A case of massive intestinal blood loss from multiple duodeno-jejunal diverticula is described. A 39-year-old man was referred to our hospital because of recurrent bloody stool and worsening anemia. Upper and lower endoscopy, selective abdominal angiography, and radionuclide scanning were performed to seek the cause of the intestinal bleeding, but none of these studies revealed the source of bleeding. Small-bowel barium follow-through examination showed numerous diverticula in the distal duodenum and proximal jejunum. Excision of the duodenal diverticulum and resection of the involved portion of the jejunum cured the patient. On histopathological examination, an ulcerative lesion with an exposed vessel suggestive of the source of bleeding was seen in the resected duodenal diverticulum. Although duodeno-jejunal diverticula are rare, the importance of a careful search for this malformation in a patient with intestinal blood loss is stressed. Received: September 28, 1998 / Accepted: June 25, 1999     

Inhibition of insulin amyloid fibril formation by cyclodextrins

Localized insulin-derived amyloid masses occasionally form at the site of repeated insulin injections in patients with insulin-dependent diabetes and cause subcutaneous insulin resistance. Various kinds of insulin including porcine insulin, human insulin, and insulin analogues reportedly formed amyloid fibrils in vitro and in vivo, but the impact of the amino acid replacement in insulin molecules on amyloidogenicity is largely unknown. In the present study, we demonstrated the difference in amyloid fibril formation kinetics of human insulin and insulin analogues, which suggests an important role of the C-terminal domain of the insulin B chain in nuclear formation of amyloid fibrils. Furthermore, we determined that cyclodextrins, which are widely used as drug carriers in the pharmaceutical field, had an inhibitory effect on the nuclear formation of insulin amyloid fibrils. These findings have significant implications for the mechanism underlying insulin amyloid fibril formation and for developing optimal additives to prevent this subcutaneous adverse effect.