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Homosomic mice of the A/J-7SM consomic mouse strain that introduced the entire chromosome 7 (Chr 7) of SM/J into the A/J strain exhibited neonatal lethality. We tentatively maintained segregating inbred strains (A/J-7ASM and A/J-7DSM) in which the central portion of Chr 7 was heterozygous for the A/J and SM/J strains, and the centromeric and telomeric sides of Chr 7 were homozygous for the SM/J strain, instead of the A/J-7SM strain. Based on the chromosomal constitution of Chr 7 in A/J-7ASM and A/J-7DSM mice, the causative gene for neonatal lethality in homosomic mice was suggested to be located within an approximately 1.620 Mb region between D7Mit125 (104.879 Mb) and D7Mit355 (106.499 Mb) on Chr 7. RT-PCR analysis revealed that homosomic mice lacked dachsous cadherin-related 1 (Dchs1), which is located within the D7Mit125 to D7Mit355 region and functions in the regulation of planar cell polarity. Screening for mutations in Dchs1 indicated that homosomic mice possessed an early transposable (ETn)-like sequence in intron 1 of Dchs1. Moreover, an allelism test between Dchs1 ETn-like-insertion alleles detected in homosomic mice and CRISPR/Cas9-induced Dchs1 deletion alleles revealed that Dchs1 is a causative gene for neonatal lethality in homosomic mice. Based on these results, we concluded that in the A/J-7SM strain, ETn-like elements were inserted into intron 1 of SM/J-derived Dchs1 during strain development, which dramatically reduced Dchs1 expression, thus resulting in neonatal lethality in homosomic mice. Additionally, it was suggested that the timing of lethality in Dchs1 mutant mice is influenced by the genetic background.

Various membrane proteins are shed by proteinases, constitutively and/or when stimulated by external signals. While the physiological significance of external signal-induced cleavages has been intensely investigated, relatively little is known about the function of constitutive cleavages. Alcadeinα (Alcα; also called Calsyntenin-1) is an evolutionarily conserved type I single-pass transmembrane protein that binds to kinesin-1 light chain (KLC) to activate kinesin-1's transport of Alcα-containing vesicles. We found that Alcα was constitutively and efficiently cleaved to liberate its ectodomain into the extracellular space, and that full-length Alcα protein was rarely detected on the cell surface. The secretion efficiency of the ectodomain was unaltered by a mutation that both abolished Alcα's KLC-binding activity and attenuated its peripheral transport, suggesting that Alcα's cleavage occurred, at least partly, en route to the cell surface. We further demonstrated that uncleavable mutant Alcα proteins readily accumulated on the cell surface and induced aberrant peripheral recruitment of KLC1 and kinesin heavy chain. Our observations suggest that Alcα is efficiently processed in part to minimize the inappropriate peripheral retention of kinesin-1. This role might exemplify the functional relevance of the constitutive cleavage of single-pass transmembrane proteins.

Various membrane proteins are shed by proteinases, constitutively and/or when stimulated by external signals. While the physiological significance of external signal-induced cleavages has been intensely investigated, relatively little is known about the function of constitutive cleavages. Alcadein[alpha] (Alc[alpha]; also called Calsyntenin-1) is an evolutionarily conserved type I single-pass transmembrane protein that binds to kinesin-1 light chain (KLC) to activate kinesin-1's transport of Alc[alpha]-containing vesicles. We found that Alc[alpha] was constitutively and efficiently cleaved to liberate its ectodomain into the extracellular space, and that full-length Alc[alpha] protein was rarely detected on the cell surface. The secretion efficiency of the ectodomain was unaltered by a mutation that both abolished Alc[alpha]'s KLC-binding activity and attenuated its peripheral transport, suggesting that Alc[alpha]'s cleavage occurred, at least partly, en route to the cell surface. We further demonstrated that uncleavable mutant Alc[alpha] proteins readily accumulated on the cell surface and induced aberrant peripheral recruitment of KLC1 and kinesin heavy chain. Our observations suggest that Alc[alpha] is efficiently processed in part to minimize the inappropriate peripheral retention of kinesin-1. This role might exemplify the functional relevance of the constitutive cleavage of single-pass transmembrane proteins.

BackgroundWe have developed a simple and easy method of estimating the glomerular filtration rate (eGFR) of serum creatinine in Japanese children (eGFRUemura). The eGFR equation is for children aged 2–18 years. Therefore Uemura et al. developed an equation for children younger than 2 years (eGFRunder 2). The aim of the present study was to validate this new equation.MethodsWe collected the data of 13 patients from previous studies and compared the results of eGFRunder 2, eGFRUemura, and updated eGFR developed by Schwartz (eGFRSchwartz) with measured GFR using mean error (ME), root mean square error (RMSE), P30 and Bland–Altman analysis.ResultsThe ME of eGFRunder 2, eGFRUemura and eGFRSchwartz were 2.3 ± 15.9, 7.7 ± 14.5, and 16.0 ± 18.2 ml/min/1.73m2, respectively. The RMSEs were 15.5, 15.9, and 49.6, respectively. The P30 values were 76.9%, 76.9%, and 53.8%, respectively. The graph of Bland–Altman bias analysis showed fan-shape. The eGFRunder 2 equation was the most accurate in the three equations.ConclusionThe eGFRunder 2 equation was useful for Japanese children younger than 2 years.

S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20–80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0–73·3%) in the observation group compared with 77·1% (70·9–82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51–0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1–57·2%) in the observation group compared with 62·4% (55·6–68·4%) in the S-1 group (HR 0·80, 95% CI 0·61–1·04; two-sided p=0·088). The main grade 3–4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Background Renal inulin clearance is the gold standard for evaluation of kidney function, but cannot be measured easily in children. Therefore, we utilize the serum creatinine (Cr)-based estimated GFR (eGFR) measuring serum Cr by the enzymatic method, and we have reported simple serum Cr-based eGFR in Japanese children aged between 2 and 11 years old. Furthermore, we should use serum Cr-based eGFR in Japanese adolescents as well as children with chronic kidney disease for evaluation of renal function. Methods The inulin clearance and serum Cr level determined by an enzymatic method were measured in 131 pediatric chronic kidney disease (CKD) patients between the ages of 2 and 18 years old with no underlying disease affecting renal function except CKD to determine the serum Cr-based eGFR in Japanese children and adolescents. Results We offer the complex estimated GFR equation using polynomial formulae for reference serum creatinine levels with body length in Japanese children except infants, resulting in the following equation: eGFR = 110.2 × ( reference serum Cr / patient's serum Cr ) + 2.93 Reference serum Cr levels ( y ) are shown by the following two equations of body length ( x ): Males : y = − 1.259 x 5 + 7.815 x 4 − 18.57 x 3 + 21.39 x 2 − 11.71 x + 2.628 Females : y = − 4.536 x 5 + 27.16 x 4 − 63.47 x 3 + 72.43 x 2 − 40.06 x + 8.778 Conclusion The new polynomial eGFR formula showing the relationship with body length and serum Cr level may be applicable for clinical screening of renal function in Japanese children and adolescents aged between 2 and 18 years.

BackgroundThe assessment of kidney size is essential for treating kidney disease. However, there are no reliable and sufficiently robust ultrasonographic reference values or prediction formulas for kidney length in Japanese children, based on a sufficient number of participants.MethodsWe retrospectively analyzed kidney measurements by ultrasonography in children aged 18 years or younger from eight facilities throughout Japan between January 1991 and September 2018. Detailed reference values were developed by aggregating the left and right kidneys of boys and girls separately. Simple and practical reference values were developed by combining all the data from left and right kidneys and boys and girls. The estimation formulas for the average value and lower limit of the normal range for kidney length were developed based on regression analysis.ResultsBased on the aggregated kidney length data of 1984 participants (3968 kidneys), detailed reference values and simple reference values for kidney length were determined. From the regression analysis, the formula for calculating the average kidney length was generated as “kidney length (cm) = body height (m) × 5 + 2”, and that for predicting the lower limit of normal kidney length in children under 130 cm was calculated as “lower limit (cm) = 0.85 × [body height (m) × 5 + 2]”.ConclusionDetailed ultrasonographic reference values of kidney length for Japanese children and simple reference values and estimation formulas for daily practice have been established.

In developing a formula for manual use in clinical settings, simplicity is as important as accuracy. Whole-liver (WL) mass is often estimated using demographic and anthropometric information to calculate the standard liver volume or recommended graft volume in liver transplantation. Multiple formulas for estimating WL mass have been reported, including those with multiple independent variables. However, it is unknown whether multivariable models lead to clinically meaningful improvements in accuracy over univariable models. Our goal was to quantitatively define clinically meaningful improvements in accuracy, which justifies an additional independent variable, and to identify an estimation formula for WL graft weight that best balances accuracy and simplicity given the criterion. From the Japanese Liver Transplantation Society registry, which contains data on all liver transplant cases in Japan, 129 WL donor-graft pairs were extracted. Among the candidate models, those with the smallest cross-validation (CV) root-mean-square error (RMSE) were selected, penalizing model complexity by requiring more complex models to yield a ≥5% decrease in CV RMSE. The winning model by voting with random subsets was fitted to the entire dataset to obtain the final formula. External validity was assessed using CV. A simple univariable linear regression formula using body weight (BW) was obtained as follows: WL graft weight [g] = 14.8 × BW [kg] + 439.2. The CV RMSE (g) and coefficient of determination (R 2 ) were 195.2 and 0.548, respectively. In summary, in the development of a simple formula for manually estimating WL weight using demographic and anthropometric variables, a clinically acceptable trade-off between accuracy and simplicity was quantitatively defined, and the best model was selected using this criterion. A univariable linear model using BW achieved a clinically optimal balance between simplicity and accuracy, while one using body surface area performed similarly.

Background Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia rarely transforms into diffuse large B-cell lymphoma, and there have been no reports of cases proving clonal identity when presenting as primary central nervous system lymphoma. There are many unclear aspects regarding the mechanism by which lymphoplasmacytic lymphoma/Waldenström macroglobulinemia infiltrates the central nervous system and transforms, as well as the treatment methods for the transformed lymphoma. Case presentation A 49-year-old Asian Japanese male was emergently transported due to loss of consciousness, revealing a tumorous lesion in the brain. He was diagnosed with primary central nervous system lymphoma following an endoscopic biopsy and treated with immunochemotherapy included high-dose methotrexate. During the second course of immunochemotherapy, a computed tomography scan conducted to investigate bilateral lower leg edema revealed tumorous lesions in both lower legs. A biopsy of the thigh node specimen was diagnosed as lymphoplasmacytic lymphoma. When high-dose methotrexate including immunochemotherapies was finished, the lymphoma lesions in central nervous system had disappeared. However, the symptoms of bilateral lower leg edema were prominent because of remaining the bilateral thigh nodes, so additional immunochemotherapy for lymphoplasmacytic lymphoma/Waldenström macroglobulinemia was administered, resulting in complete remission of the lymphoplasmacytic lymphoma/Waldenström macroglobulinemia as well. primary central nervous system lymphoma, and he has maintained both lymphomas for 4 years. The myeloid differentiation factor 88 ( MYD88 ) gene mutation was detected in primary central nervous system lymphoma and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia lymphoma cells. The same clonal origin of primary central nervous system lymphoma and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia was confirmed according to homology in a region of the immunoglobulin heavy chain V ( IGHV ) gene. On the basis of the characteristics of primary central nervous system lymphoma and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, we speculated that the lymphoplasmacytic lymphoma/Waldenström macroglobulinemia lymphoma cells had already invaded the central nervous system, a condition called Bing-Neel syndrome, and transformed into primary central nervous system lymphoma cells after a certain period. Conclusion It was revealed that the lymphoma cells of both lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and primary central nervous system lymphoma derived from a common cell possessing MYD88 . The utility of adding chemotherapy for low-grade lymphoma in addition to therapy for primary central nervous system lymphoma is not clear. While lymphoplasmacytic lymphoma is a low-grade lymphoma that does not always require chemotherapy, combining treatment for lymphoplasmacytic lymphoma and primary central nervous system lymphoma may contribute to the effectiveness of both treatments.

Alport syndrome-diffuse leiomyomatosis (AS-DL, OMIM: 308940) is a rare variant of the X-linked Alport syndrome that shows overgrowth of visceral smooth muscles in the gastrointestinal, respiratory and female reproductive tracts in addition to renal symptoms. AS-DL results from deletions that encompass the 5' ends of the COL4A5 and COL4A6 genes, but deletion breakpoints between COL4A5 and COL4A6 have been determined in only four cases. Here, we characterize deletion breakpoints in five AS-DL patients and show a contiguous COL4A6/COL4A5 deletion in each case. We also demonstrate that eight out of nine deletion alleles involved sequences homologous between COL4A5 and COL4A6. Most breakpoints took place in recognizable transposed elements, including long and short interspersed repeats, DNA transposons and long-terminal repeat retrotransposons. Because deletions involved the bidirectional promoter region in each case, we suggest that the occurrence of leiomyomatosis in AS-DL requires inactivation of both genes. Altogether, our study highlights the importance of homologous recombination involving multiple transposed elements for the development of this continuous gene syndrome and other atypical loss-of-function phenotypes.