Prospective study of daily low-dose nedaplatin and continuous 5-fluorouracil infusion combined with radiation for the treatment of esophageal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Protracted low-dose concurrent chemotherapy combined with radiation has been proposed for enhanced treatment results for esophageal cancer. We evaluated the efficacy and the toxicity of a novel regimen of daily low-dose nedaplatin (cis-diammine-glycolatoplatinum) and continuous infusion of 5-fluorouracil (5-FU) with radiation in patients with esophageal squamous cell carcinoma.</p> <p>Methods</p> <p>Between January 2003 and June 2008, 33 patients with clinical stage I to IVB esophageal squamous cell carcinoma were enrolled. Nedaplatin (10 mg/body/day) was administered daily and 5-FU (500 mg/body/day) was administered continuously for 20 days. Fractionated radiotherapy for a total dose of 50.4-66 Gy was administered together with chemotherapy. Additional chemotherapy with nedaplatin and 5-FU was optionally performed for a maximum of 5 courses after chemoradiotherapy. The primary end-point of this study was to evaluate the tumor response, and the secondary end-points were to evaluate the toxicity and the overall survival.</p> <p>Results</p> <p>Twenty-two patients (72.7%) completed the regimen of chemoradiotherapy. Twenty patients (60.6%) achieved a complete response, 10 patients (30.3%) a partial response. One patient (3.0%) had a stable disease, and 2 (6.1%) a progressive disease. The overall response rate was 90.9% (95% confidence interval: 75.7%-98.1%). For grade 3-4 toxicity, leukopenia was observed in 75.8% of the cases, thrombocytopenia in 24.2%, anemia in 9.1%, and esophagitis in 36.4%, while late grade 3-4 cardiac toxicity occurred in 6.1%. Additional chemotherapy was performed for 26 patients (78.8%) and the median number of courses was 3 (range, 1-5). The 1-, 2- and 3-year survival rates were 83.9%, 76.0% and 58.8%, respectively. The 1- and 2-year survival rates were 94.7% and 88.4% in patients with T1-3 M0 disease, and 66.2% and 55.2% in patients with T4/M1 disease.</p> <p>Conclusion</p> <p>The treatment used in our study may yield a high complete response rate and better survival for each stage of esophageal squamous cell carcinoma.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier: NCT00197444</p

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Initial curing characteristics of composite cements under ceramic restorations.

PURPOSE: To assess the degree of conversion (DC) of dual-curing composite cements when cured through ceramic-veneered zirconia disks. METHODS: Portions of mixed cement, either G-CEM LinkForce (GC), Panavia V5 (Kuraray Noritake) or ResiCEM (Shofu), were placed on the ATR crystal of a Fourier Transform Infrared Spectroscope (FTIR; iS50, Thermo Scientific) and squeezed to a 100-µm film thickness using a microscopy cover glass. DC (%) of the composite cements applied in self-curing mode was measured in the dark at 37°C. Following the dual-curing mode, the cements were light-cured directly (positive control) or through a ceramic-veneered zirconia disk (0.5-mm thick zirconia with a 1.0-mm thick veneering ceramic) for 40 sec using two light-curing units (G-Light Prima 2, GC; PenCure, Morita). Per experimental group, 5 tests were conducted to measure DC in self-cure and dual-cure mode (n=5). FTIR spectra of the composite cement films were acquired to determine DC every min up to 30 min. DC of the composite cements was statistically compared using two-way repeated-measures ANOVA (α=0.05). RESULTS: For all cements investigated, the self-curing mode resulted in significantly lower DC at 10, 20 and 30 min than the light-curing mode. When the composite cements were light-cured through the zirconia disk, DC at 30 min dropped significantly for ResiCem (Shofu), while not for Panavia V5 (Kuraray Noritake) and G-CEM LinkForce (GC). CONCLUSIONS: Self-curing slows down polymerization but does not reach for all composite cements the highest (light-cured) DC. Ceramic-veneered zirconia-based restorations may affect DC of some composite cements.status: Published onlin

Multilineage-differentiating stress-enduring (Muse)-like cells exist in synovial tissue

Introduction: Cartilage regeneration is a promising therapy for restoring joint function in patients with cartilage defects. The limited availability of autologous chondrocytes or chondrogenic progenitor cells is an obstacle to its clinical application. We investigated the existence and chondrogenic potential of synovial membrane-derived multilineage-differentiating stress-enduring (Muse)-like cells as an alternative cell source for cartilage regeneration. Methods: Cells positive for stage-specific embryonic antigen-3 (SSEA-3), a marker of Muse cells, were isolated from the synovial membranes of 6 of 8 patients (median age, 53.5 years; range 36–72 years) by fluorescence-activated cell sorting. SSEA-3-positive cells were cultured in methylcellulose to examine their ability to form Muse clusters that are similar to the embryoid bodies formed by human embryonic stem cells. Muse clusters were expanded and chondrogenic potential of M-cluster-derived MSCs examined using a pellet culture system. Chondrogenic differentiation was evaluated by proteoglycan, safranin O, toluidine blue and type II collagen staining. To evaluate the practicality of the procedure for isolating Muse-like cells, we compared chondrogenic potential of M-cluster derived MSCs with expanded cells derived from the clusters formed by unsorted synovial cells. Results: Synovial membranes contained SSEA-3-positive cells that after isolation exhibited Muse-like characteristics such as forming clusters that expressed NANOG, OCT3/4, and SOX2. In the pellet culture system, cell pellets created from the M-cluster-derived MSCs exhibited an increase in wet weight, which implied an increase in extracellular matrix production, displayed metachromasia with toluidine blue and safranin O staining and were aggrecan-positive and type II collagen-positive by immunostaining. Unsorted synovial cells also formed clusters in methylcellulose culture, and the expanded cell population derived from them exhibited chondrogenic potential. The histological and immunohistochemical appearance of chondrogenic pellet created from unsorted synovial cell-derived cells were comparable with that from M-cluster-derived MSCs. Conclusions: Muse-like cells can be isolated from the human synovial membrane, even from older patients, and therefore may provide a source of multipotent cells for regenerative medicine. In addition, the cluster-forming cell population within synovial cells also has excellent chondrogenic potential. These cells may provide a more practical option for cartilage regeneration. Keywords: Cartilage, Regenerative medicine, Chondrogenic potential, Multilineage-differentiating stress-enduring cells, Stage-specific embryonic antigens-

Crystallographic and morphological analysis of sandblasted highly translucent dental zirconia

Objective. To assess the influence of alumina sandblasting on four highly translucent dental zirconia grades. Methods. Fully sintered zirconia disk-shaped specimens (15-mm diameter; 0.5-mm thickness) of four highly translucent yttria partially stabilized zirconia (Y-PSZ) grades (KATANA HT, KATANA STML, KATANA UTML, Kuraray Noritake; Zpex Smile, Tosoh) were sandblasted with 50-m alumina (Al2O3) sand (Kulzer) or left ‘as-sintered’ (control) (n= 5). For each zirconia grade, the translucency was measured using a colorimeter. Surface roughness was assessed using 3D confocal laser microscopy, upon which the zirconia grades were statistically compared for surface roughness using a Kruskal–Wallis test (n= 10). X-ray diffraction (XRD) with Rietveld analysis was used to assess the zirconia-phase composition. Micro-Raman spectroscopy was used to assess the potentially induced residual stress. Results. The translucency of KATANA UTML was the highest (36.7 ± 1.8), whereas that of KATANA HT was the lowest (29.5 ± 0.9). The ‘Al2O3-sandblasted’ and ‘as-sintered’ zirconia revealed comparable surface-roughness Sa values. Regarding zirconia-phase composition, XRD with Rietveld analysis revealed that the ‘as-sintered’ KATANA UTML contained the highest amount of cubic zirconia (c-ZrO2) phase (71 wt%), while KATANA HT had the lowest amount of c-ZrO2 phase (41 wt%). KATANA STML and Zpex Smile had a comparable zirconia-phase composition (60 wt% c-ZrO2 phase). After Al2O3-sandblasting, a significant amount (over 25 wt%) of rhombohedral zirconia (r-ZrO2) phase was detected for all highly translucent zirconia grades. Significance. Al2O3-sandblasting did not affect the surface roughness of the three highly translucent Y-PSZ zirconia grades, but it changed its phase composition.status: publishe

A case of small bowel adenocarcinoma in a patient with Crohn’s disease detected by PET/CT and double-balloon enteroscopy

Small bowel adenocarcinoma (SBA) in patients with Crohn’s disease (CD) is quite rare, difficult to diagnose without surgery, and has a poor prognosis. Here, we report a 48-year-old man with SBA and a 21-year history of CD who was diagnosed by a combination of positron emission tomography/computed tomography (PET/CT) and double-balloon enteroscopy (DBE). Since the age of 27 years, the patient had been treated for ileal CD and was referred to our hospital with persistent melena. Multiple hepatic tumors were found by CT. PET/CT detected an accumulation spot in the small bowel. DBE revealed an ulcerative tumor in the ileum about 100 cm from the ileocecal valve. An endoscopic forceps biopsy specimen showed poorly differentiated adenocarcinoma. There were some longitudinal ulcer scars near the tumor, and the chronic inflammation in the small bowel appeared to be associated with the cancer development. Previous reports suggest the risk of SBA in patients with CD is higher than in the overall population. Since early diagnosis is extremely difficult in these cases, novel techniques, such as PET/CT and DBE, may be expected to help in making a preoperative diagnosis of the development of SBA in CD