Aggregation of amyloidogenic proteins into insoluble amyloid fibrils is implicated in various neurodegenerative diseases. This process involves protein assembly into oligomeric intermediates and ...fibrils with highly polymorphic molecular structures. These structural differences may be responsible for different disease presentations. For this reason, elucidation of the structural features and assembly kinetics of amyloidogenic proteins has been an area of intense study. We report here the results of high-speed atomic force microscopy (HS-AFM) studies of fibril formation and elongation by the 42-residue form of the amyloid β-protein (Aβ1–42), a key pathogenetic agent of Alzheimer’s disease. Our data demonstrate two different growth modes of Aβ1–42, one producing straight fibrils and the other producing spiral fibrils. Each mode depends on initial fibril nucleus structure, but switching from one growth mode to another was occasionally observed, suggesting that fibril end structure fluctuated between the two growth modes. This switching phenomenon was affected by buffer salt composition. Our findings indicate that polymorphism in fibril structure can occur after fibril nucleation and is affected by relatively modest changes in environmental conditions.
Construction of a self-assembled supramolecular macroring that has distances and orientations of porphyrin dimer units in close analogy to those of the natural light-harvesting complexes was ...achieved. In natural light-harvesting complexes, bacteriochlorophyll-a's are arranged in macroring structures by coordination from imidazolyl side chains. A structural determination of a light-harvesting antenna complex (LH2) elucidated the arrangement of 18 bacteriochlorophyll-a's in a slipped-cofacial way with C 9 symmetry in B850 in 1995. To obtain such an elegant macroring architecture as an artificial light-harvesting complex, we connected slipped-cofacial dimers of imidazolylporphyrins in a gable-porphyrin orientation. The introduction of zinc assembled by coordination porphyrins with originally a broad molecular weight distribution (MWD). When coordination bonds were cleaved and reorganized under high dilution conditions using chloroform/methanol solution, the MWD was perfectly converged. This crop gave particle images of a uniform height by atomic force microscopy measurements. Further purification was successfully achieved by gel permeation chromatography, and the first eluting component gave a diameter corresponding to the cyclic hexamer of gable-porphyrins from a small-angle X-ray scattering measurement with synchrotron radiation. In summary, porphyrin assemblies in a macroring arrangement were constructed using the gable-porphyrin motif, and their photophysical properties are highly interesting.
To date, a few studies have documented the detailed periodontal conditions of a Japanese population. It is important to know if the awareness of Japanese nationals and dentists regarding oral hygiene ...and prevention of periodontal disease have improved when compared with the past in Japan for the development of future scenarios regarding prevention. The aim of this study was to investigate the severity, prevalence, and extent of periodontal disease in the adult population of the city of Takahagi, Japan. Results were also compared with those of an epidemiological study performed in Japan in the 1980s.
A total of 582 (aged 20 to 89 years) randomly sampled Takahagi residents answered a comprehensive questionnaire and participated in clinical examinations.
The mean percentages of tooth surfaces harboring plaque and exhibiting BOP were 59.5 ± 20.9% and 31.1 ± 21.1%, respectively. The mean PPD and CAL were 2.5 ± 0.5 mm and 2.9 ± 1.0 mm, respectively. Compared with results of the 1980s survey, the mean percentages of plaque and bleeding on probing were lower in the current population. The mean CAL and prevalence of attachment loss of ≥5 mm in some age groups were higher in the present study than in the 1980s study. There were no statistically significant differences with respect to mean probing depth between the 1980s and current age groups.
Periodontal disease was still prevalent in the current Japanese population, even though some improvement occurred. Proper public health programs therefore need to be established.
Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response ...to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18-9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower β
microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/μL), non-deviated κ/λ ratio (0.1-10), lower B2MG (< 5.5 mg/L) and no prior daratumumab use. We proposed a simple scoring system to predict the durability of the elotuzumab treatment effect by classifying the patients into three categories based on their lymphocyte counts (0 points for ≥ 1400/μL and 1 point for < 1400/μL) and κ/λ ratio (0 points for 0.1-10 and 1 point for < 0.1 or ≥ 10) or B2MG (0 points for < 5.5 mg/L and 1 point for ≥ 5.5 mg/L). The patients with a score of 0 showed significantly longer TTNT (p < 0.001) and better survival (p < 0.001) compared to those with a score of 1 or 2. Prospective cohort studies of elotuzumab treatment may be needed to validate the usefulness of our new scoring system.
Carfilzomib (CFZ) constitutes powerful combinatory therapy for relapsed/refractory multiple myeloma (RRMM); however, cardiovascular adverse events (CVAEs) have been shown as major treatment obstacles ...with the use of CFZ. Along with our multi-institutional prospective observational study by the Kyoto Clinical Hematology Study Group on the efficacy and safety of CFZ-based treatments (UMIN000025108), we here performed an ad hoc analysis of CFZ-related CVAEs in 50 patients with RRMM. We analyzed the association between CFZ-related CVAEs and pre-planned examinations, including patients' background, electrocardiographic findings, echocardiographic findings, and serum/plasma levels of 18 potential candidate biomarkers. The common CVAEs were hypertension (42%), arrhythmia (14%), and prolongation of QT corrected interval (10%), whereas no serious CVAEs occurred. The pretreatment serum level of interleukin-6 was identified as a significant risk factor for CFZ-related hypertension. This study revealed hypertension as the most frequent CFZ-related CVAE and suggested that baseline serum interleukin-6 is a useful predictor for CFZ-induced hypertension.
Abstract Objective To evaluate the long-term efficacy and safety of diflunisal in late-onset familial amyloid polyneuropathy (FAP) in a Japanese endemic area. Methods Consecutive six FAP patients ...(mean age: 65.8 ± 7.3 years) with a transthyretin (TTR) Val30Met mutation from an endemic area of late-onset FAP were prospectively recruited to an open label study with oral diflunisal (250 mg twice a day). We evaluated clinical symptoms, Kumamoto FAP score, modified body mass index (mBMI), Medical Research Council sum score, nerve conduction studies (NCS), electrocardiogram (ECG), ECG Holter monitor test, echocardiography, and123 iodine-metaiodobenzylguanidine (123 I-MIBG) myocardial scintigraphy. Results One patient ceased to take diflunisal because of hematuria which was reversible. The other five patients were treated with diflunisal for 3–5 (4.4 ± 0.9 years) years. Autonomic symptoms (orthostatic hypotension and gastrointestinal symptoms) disappeared after treatment in two of the four patients with the symptoms. Delayed heart to mediastinum ratio on123 I-MIBG imaging, a marker of cardiac postganglionic sympathetic nerve function, increased during the three-year treatment. mBMI was maintained through observation period. While, motor and sensory symptoms, Kumamoto FAP scores, and data on NCS gradually deteriorated. Conclusion Diflunisal might be effective especially for autonomic dysfunction in late-onset FAP with a TTR Val30Met mutation.
We conducted a post hoc analysis of our previous pilot observational study on the efficacy and safety of carfilzomib (CFZ)-containing therapy in 50 patients with relapsed/refractory multiple myeloma ...in routine practice to clarify the relationships between three major criteria for vulnerability (frailty, poor performance status PS, and advanced age ≥ 75 years) and their clinical impact on efficacy and adverse events (AEs). Sixteen patients fulfilled at least one and five patients fulfilled all three criteria. The overall response rate was not significantly affected by frailty, poor PS, and/or advanced age; however, frailty and advanced age were significantly associated with shorter progression-free survival (PFS). In contrast, no significant difference in PFS was observed between patients with PS0–1 or PS2–4. The three criteria for vulnerability were associated with more frequent hematologic AEs: frailty, poor PS, and/or advanced age significantly increased the risk of grade 3–4 anemia and lymphopenia. However, these criteria were not associated with increased risk of other non-hematologic AEs except infection. Collectively, these results demonstrate the need to carefully manage severe hematologic AEs in vulnerable patients and perform disease-specific assessment of frailty to predict prognosis.
Background
Primary ocular adnexal mucosa‐associated lymphoid tissue (MALT) lymphoma (POAML) is the most common subtype of indolent ocular adnexal lymphomas. Although radiotherapy (RT) is the standard ...of care for localized POAML, it can occasionally lead to permanent side effects. Other treatment strategies, such as rituximab (R) monotherapy and immunochemotherapy, have been used for POAML treatment, but their long‐term benefits and relative merits remain unclear. While watchful waiting (WW) is a potential option for some indolent lymphomas, the benefits of WW for POAML patients are also unclear.
Methods
We here retrospectively analyzed 75 patients who were diagnosed with POAML between 2008 and 2019 in the institutions of the Kyoto Clinical Hematology Study Group.
Results
Commonly involved sites were conjunctiva (42.7%), orbit (36.0%), and lacrimal gland (12.0%), and most patients (92.0%) presented with Ann Arbor stage IE disease. The treatment strategy was selected at the physicians' discretion. More patients without subjective symptoms by tumor mass were subjected to WW (29 patients), while more patients with tumor‐derived subjective symptoms were treated by tumor‐directed therapy (24 received focal RT, and 19 received R monotherapy). Complete response rates were 79.2% and 42.1% in the RT and R groups, respectively. At 60 months of follow‐up, the estimated proportions of POAML patients not requiring new treatment were 69.4%, 85.2%, and 53.8% in the WW, RT, and R groups, respectively. There were no significant differences in the time to start a new treatment between WW and RT groups (median: both not reached NR, p = 0.187) and between WW and R groups (median: NR vs. 69.0 months, p = 0.554). No specific predictive factor for the future need of treatment was identified in the WW group.
Conclusion
Our results demonstrate WW may be an acceptable treatment option for POAML, especially for asymptomatic patients.
Watchful waiting is expected to produce no inferior time to next treatment (A) and progression free survival (B) compared to radiation or rituximab monotherapy in patients with primary ocular adnexal mucosa‐associated lymphoid tissue lymphoma, especially those without eye‐related symptom.
Abstract The purpose of this research was to clarify the effects of microplasma irradiation on human gingival fibroblasts (HGF). Microplasma irradiation exposure for all HGF samples was limited to 30 ...s at an irradiation distance of 10 mm with a gas flow of 10 L/min. Three experimental groups were used: a 0 V control group (Control); a 650 V (low) microplasma irradiation group (LV); and a 975 V (high) irradiation group (HV). The following cellular characteristics were evaluated in order to analyze the effects of microplasma treatment; morphology, cell count, DNA content, metabolic activity, cell migration, fibroblast growth factor β (FGF-2) production, type I collagen secretion, and cytotoxic analysis. Cell count, DNA content and FGF-2 production have all been linked to wound healing and, interestingly, both the LV and HV groups showed significant (P<0.05) increases in these categories at 72 h after irradiation when compared to the control group. Cytotoxic effects were measured by determining the levels of lactate dehydrogenase, cell death, and DNA damage in HGF cells. In these analyses, the HV and LV groups were not statistically different when compared with the control group at 72 h post-irradiation. These findings suggest that microplasma irradiation activated HGF with no clear cell-damaging effects.
We retrospectively analyzed efficacy and safety of therapy with rabbit antithymocyte globulin (rATG) in combination with cyclosporine A (CsA) in 30 Japanese adult patients with acquired aplastic ...anemia (AA) in the Kyoto Clinical Hematology Study Group. The median observation period was 31 months and the median age of the patients was 54 years. The objective response rates (ORRs) to rATG plus CsA increased over time until 18 months after the start of treatment; the rate of achievement of better than partial response at 18 months was 66.7%. The 2-year overall survival (OS) rate was 79% in all patients. In eight patients aged ≥ 75 years old, the ORR was 62.5% and the 2-year OS rate of 50% was not significantly inferior to that in patients aged ≤ 74 years old. The overall mortality rate was 16.7% in our cohort, while the mortality rate in patients aged ≥ 75 years old was 37.5%, which was higher than that in patients aged ≤ 74 years old (9.1%), although the difference was not statistically significant. Collectively, rATG combined with CsA is an effective and feasible treatment for AA, while patients should be appropriately selected.
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