A newborn screening program for Pompe disease using dried blood spots (DBSs) was initiated in Japan. Here, we summarized this screening program and described the results of the GAA gene analysis. ...From April 2013 to November 2016, 103,204 newborns were screened; 71 had low acid alpha-glucosidase (AαGlu) activity. GAA sequencing showed that 32 (45.1%) and 37 (52.1%) of these newborns were homozygous and heterozygous for pseudodeficiency alleles c.1726G>A; 2965G>A, respectively. Moreover, 24 of 32 newborns with homozygous c.1726G>A; 2965G>A alleles had no mutations, and the other eight had one mutation each. Thirty-five of 37 newborns with heterozygous c.1726G>A; 2965G>A alleles had one mutation, and the other two had two mutations each. Only one newborn who had two mutations did not harbor c.1726G>A; 2965G>A alleles. Thus, it was difficult to distinguish newborns with c.1726G>A; 2965G>A alleles from newborns with pre-symptomatic Pompe disease using AαGlu assays in DBSs or fibroblasts; GAA gene sequencing was necessary. Seventy-one newborns had 50 variants, including 21 mutations or predictably pathogenic variants, and 29 polymorphisms or predictably non-pathogenic variants. Four of 21 mutations or predictably pathogenic variants and four of 29 polymorphisms or predictably non-pathogenic variants were novel. No infantile-onset Pompe disease was detected, and three newborns were diagnosed with potential late-onset Pompe disease. In the literature, 156 variants have been reported for 296 patients from 277 families in 41 articles from Japan, Korea, Taiwan, and China. Our results provide insights into GAA gene mutation profiles and the relationship between GAA and Pompe disease in Asian populations.
Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells ...from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL.
A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg.
Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, including eight complete responses, with an overall response rate of 50% (95% CI, 30% to 70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The mean half-life period after the eighth infusion was 422 ± 147 hours (± standard deviation). The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases.
KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is warranted.
Fabry disease (FD) is a X-linked inherited disorder caused by mutations in the GLA gene, which results in the deficiency of alpha-galactosidase A (alpha-Gal A). This leads to the progressive ...accumulation of metabolites, which can cause multisystemic dysfunction. A recent screening study among neonates reported an increase in the incidence of FD, and numerous FD patients remain undiagnosed or even misdiagnosed. Therefore, this study aimed to identify patients with FD by performing high-risk screening in 18,135 individuals, enrolled from October 2006 to March 2019, with renal, cardiac, or neurological manifestations from all prefectures in Japan. A total of 601 hospitals participated in this study. Low alpha-Gal A activity was detected in 846 individuals, with 224 of them diagnosed with FD by GLA sequencing. Cases with a family history of FD (n = 64) were also subjected to sequencing, without alpha-Gal A assay, as per individual request, and 12 of them were diagnosed with a variant of FD. A total of 236 patients with FD (97 males and 139 females) were identified from among 18,199 participants. A total of 101 GLA variants, including 26 novel variants, were detected in the 236 patients with FD from 143 families, with 39 amenable variants (39%) and 79 of the 236 patients (33%) suitable for migalastat treatment. From among 18,199 participants, 101 GLA variants, including 26 novel variants, were identified in the 236 patients with FD from 143 families. Migalastat was identified as a suitable treatment option in 33% of the patients with FD and 39% of the GLA variants were detected as amenable. Therefore, the simple screening protocol using dried blood spots that was performed in this study could be useful for early diagnosis and selection of appropriate treatments for FD in high-risk and underdiagnosed patients with various renal, cardiac, or neurological manifestations.
Wnt5a, a non‐canonical Wnt protein, is known to play important roles in several cell functions. However, little is known about the effects of Wnt5a on osteoblastic differentiation of periodontal ...ligament (PDL) cells. Here, we examined the effects of Wnt5a on osteoblastic differentiation and associated intracellular signaling in human PDL stem/progenitor cells (HPDLSCs). We found that Wnt5a suppressed expression of bone‐related genes (ALP, BSP, and Osterix) and alizarin red‐positive mineralized nodule formation in HPDLSCs under osteogenic conditions. Immunohistochemical analysis revealed that a Wnt5a‐related receptor, receptor tyrosine kinase‐like orphan receptor 2 (Ror2), was expressed in rat PDL tissue. Interestingly, knockdown of Ror2 by siRNA inhibited the Wnt5a‐induced downregulation of bone‐related gene expression in HPDLSCs. Moreover, Western blotting analysis showed that phosphorylation of the intracellular signaling molecule, c‐Jun N‐terminal kinase (JNK) was upregulated in HPDLSCs cultured in osteoblast induction medium with Wnt5a, but knockdown of Ror2 by siRNA downregulated the phosphorylation of JNK. We also examined the effects of JNK inhibition on Wnt5a‐induced suppression of osteoblastic differentiation of HPDLSCs. The JNK inhibitor, SP600125 inhibited the Wnt5a‐induced downregulation of bone‐related gene expression in HPDLSCs. Additionally, SP600125 inhibited the Wnt5a‐induced suppression of the alizarin red‐positive reaction in HPDLSCs. These results suggest that Wnt5a suppressed osteoblastic differentiation of HPDLSCs through Ror2/JNK signaling. Non‐canonical Wnt signaling, including Wnt5a/Ror2/JNK signaling, may function as a negative regulator of mineralization, preventing the development of non‐physiological mineralization in PDL tissue.
Wnt5a/Ror2/JNK signaling suppresses osteoblastic differentiation of HPDLSC. Non‐canonical Wnt signaling, including Wnt5a/Ror2/JNK signaling, may function as a negative regulator of mineralization, preventing the development of non‐physiological mineralization in PDL tissue.
We have proposed a scheme to analyze potentially explosive residual silanes (RS) generated in silicon-based semiconductor manufacturing processes in the Yokkaichi Plant, Kioxia Corporation, properly ...under an inert gas atmosphere. Thermal analysis and ballistic mortar tests revealed that the incomplete hydrolyzed RS poses the highest risk. The mass spectrum suggests that the possible structures of the major components of the RS are cyclic polychlorosilanes with the number of silicon atoms less than 16. A combination of instrumental analyses and theoretical calculations suggest that the hydrolyzed products of the RS involve Si–OH, Si–O–Si, and Si–Si moieties. Theoretical calculations predicted the substantial exergonic processes of a model compound (HO)H2Si–SiH2(OH) to form a hydroxylsiloxane and H2.
White mineral trioxide aggregate (WMTA) is a root canal treatment material, which is known to exhibit a dark brown color when in contact with sodium hypochlorite solution (NaOCl). This study aimed to ...investigate the effects of NaOCl on the surface properties of WMTA discs and WMTA-induced osteoblastic differentiation of periodontal ligament stem cells (PDLSCs). Mixed WMTA (ProRoot MTA) was filled into the molds to form WMTA discs. These discs were immersed in distilled water (D-WMTA) or 5% NaOCl (Na-WMTA). Their surface structures and Ca
release level was investigated. Moreover, they were cultured with a clonal human PDLSC line (line 1-17 cells). The main crystal structures of Na-WMTA were identical to the structures of D-WMTA. Globular aggregates with polygonal and needle-like crystals were found on D-WMTA and Na-WMTA, which included Ca, Si, Al, C and O. However, many amorphous structures were also identified on Na-WMTA. These structures consisted of Na and Cl, but did not include Ca. NaOCl immersion also reduced Ca
release level from whole WMTA discs. Line 1-17 cells cultured with D-WMTA formed many mineralized nodules and exhibited high expression levels of osteoblast-related genes. However, cells incubated with Na-WMTA generated a small number of nodules and showed low expression levels of osteoblast-related genes. These results indicated that NaOCl reduced Ca
release from WMTA by generating amorphous structures and changing its elemental distribution. NaOCl may also partially abolish the ability of WMTA to stimulate osteoblastic differentiation of PDLSCs.
Mesenchymal stem cells (MSCs) have the capacity for self-renewal and multilineage differentiation potential, and are considered a promising cell population for cell-based therapy and tissue ...regeneration. MSCs are isolated from various organs including dental pulp, which originates from cranial neural crest-derived ectomesenchyme. Recently, dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHEDs) have been isolated from dental pulp tissue of adult permanent teeth and deciduous teeth, respectively. Because of their MSC-like characteristics such as high growth capacity, multipotency, expression of MSC-related markers, and immunomodulatory effects, they are suggested to be an important cell source for tissue regeneration. Here, we review the features of these cells, their potential to regenerate damaged tissues, and the recently acquired understanding of their potential for clinical application in regenerative medicine.
Background. There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against ...hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). Methods. We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥11 1U/mL. Results. With a median HBV DNA follow-up of 562 days. HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5–12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P<.001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis. Conclusions. Monthly monitoring of HBV DNA is useful for preventing HBV reactivation–related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).
Reconstruction after periacetabular bone tumor resection involves important tradeoffs; large bone grafts or endoprostheses are reported to offer fair walking function in general but can be ...technically demanding and carry a high risk of severe complications. Conversely, hip transposition avoids implant-related risks, but stability and functional return may be less consistent. Fewer studies are available on hip transposition, which is also appealing in more resource-constrained environments, and little is known about the time course from surgery to functional return after hip transposition.
(1) What is the time course of recovery of walking function after hip transposition, especially in the first 6 months? (2) What factors are associated with a greater likelihood of early functional recovery? (3) Is early (2-month) functional recovery associated with a greater likelihood of walking ability and higher Musculoskeletal Tumor Society (MSTS) scores?
Between 2009 and 2019, six tertiary care centers in Japan treated 48 patients with internal hemipelvectomy for malignant tumors. During that time, the preferred reconstructive approach was hip transposition, and 92% (44 of 48) of our patients were treated with this procedure. Among them, 86% (38 of 44) had follow-up of at least 6 months, had no local recurrence during that time, and were included in our retrospective study. We chose 6 months as the minimum follow-up duration because the endpoints in this study pertained to early recovery rather than reconstructive durability. Hip transposition involved moving the proximal end of the femur (femoral head, resection end of the trochanteric area, and spacers such as prostheses) upward to the underside of the resected ilium or the lateral side of the sacrum if sacroiliac joint resection was performed. The end of the proximal femur was stabilized to the remaining ilium or sacrum using polyethylene tape, polyethylene terephthalate mesh, an iliotibial tract graft, or an external fixator, according to the surgeon's preference. The median age at surgery was 46 years (range 9 to 76 years), there were 23 women and 15 men, and the median follow-up duration was 17 months (range 6 to 110 months). The postoperative time course of functional recovery was assessed with a record review, the timing of functional milestones was identified (wheelchair, walker, bilateral crutches, single crutch or cane, and walking without an aid), and the MSTS score at the final follow-up was assessed. Additionally, demographic and surgical factors were reviewed, and their association with short-term functional recovery and the final functional outcome was analyzed.
Patients started using a walker at median postoperative day (POD) 20 (IQR 14 to 36) and with bilateral crutches at median POD 35 (IQR 20 to 57). At POD 60, which was the approximate median date of discharge, 76% (29 of 38) of patients were able to walk using bilateral crutches (the early recovery group) and 24% (nine of 38) of patients were not able to do so (the delayed recovery group). No baseline factors were different between the two groups. The early recovery group had a higher median MSTS score than the delayed recovery group: 57% (range 17% to 90%) versus 45% (13% to 57%) (p = 0.047). Moreover, more patients acquired better function (a single crutch or cane or more) in the early recovery group, with a median of 5 months (95% CI 4 to 11) than did those in the delayed recovery group (median not reached) (p = 0.0006). The HR was 15.2 (95% CI 2.5 to 93). Forty-two percent (16 of 38) underwent additional surgery for wound management.
It took patients a fair amount of time to recover walking function after hip transposition, and patients who could not walk on bilateral crutches at POD 60 seemed less likely to regain walking function and were likely to have lower MSTS scores thereafter. Wound-related complications were frequent. This method may be a realistic alternative for younger patients who have the strength for a long rehabilitation period or those who want to minimize prosthesis-related complications. Future studies with more patients are necessary to understand the risk factors associated with delayed recovery.Level of Evidence Level III, therapeutic study.
The present study sought to elucidate the prognosis of adult T‐cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti‐CCR4 monoclonal antibody. Progression‐free survival ...(PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T‐cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1‐year PFS was 26%, whereas median OS was 14.4 months, and 3‐year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1‐year PFS was zero, with a median OS of 6.0 months, and 3‐year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1‐year PFS was 50%, with a median OS of 25.6 months, and 3‐year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune‐related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab.
Mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune‐related adverse event.
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