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Phosphorus (P) is an essential element for the metabolism, growth, and development of living organisms, and it often limits primary production in freshwater ecosystems. During flood events, rivers can transport considerable amounts of particulate organic P (org-P) and inorganic P from the basin to the ocean. Understanding the transport mechanisms and changes in P distribution from upstream to downstream areas of rivers is crucial to estimate its flux to the ocean. However, the processes involved in P transformation and cycling among different forms in rivers are not well understood. To better understand P transformation and total P (TP) concentrations in river basins, this study examined various P forms in bottom sediments, river bank sediments, parent rock material, and soil samples along the Tone River, Japan. P forms such as org-P, Ca-bound phosphorus (apatite, Ca-P), P bound with iron oxides/hydroxides (Fe-P), bio unavailable non-apatite inorganic P (NAIP), and TP were analyzed. The results showed an increase in TP concentration in bottom and bank sediment samples along the course of the Tone River. This change in TP was mostly due to the increases in Fe-P and bioavailable org-P, while Ca-P and NAIP decreased toward the downstream area. Analysis of parent rock in three main mountain group areas (Mount Tanigawa, Mount Akagi, and Mount Tsukuba) showed their downstream impacts on TP and the distribution of P forms. Sediment grain size distribution analysis suggested that Fe-P and org-P fractions increased with decreasing sediment particle size, while Ca-P and NAIP were relatively evenly distributed among all grain sizes. The data revealed the transformation of P forms in sediments of the largest river in the Kanto region, Japan, which influence its flux to the Pacific Ocean. The results suggest that Fe-P and org-P may play a more significant role in P transport from river basins to the ocean than previously thought. The findings of this study can be useful for estimating P fluxes to the ocean and for the management of freshwater ecosystems.

Abstract Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with an increased incidence of tumors, such as basal cell carcinomas and medulloblastomas. The PTCH1 gene, responsible for NBCCS, suppresses the hedgehog signaling pathway, which is recognized as one of the important pathways in tumorigenesis and, thus, is a therapeutic target in cancer. In the present study, we generated PTCH1 −/− induced pluripotent stem cells (iPSCs) from NBCCS patient-derived iPSCs (PTCH1 +/−) by gene editing. The proliferation of PTCH1 −/− iPSCs was accelerated due to the activation of the hedgehog signaling pathway. When PTCH1 −/− iPSCs were subcutaneously injected into immunodeficient mice, the resulting teratomas almost exclusively contained immature ectodermal lineage cells expressing medulloblastoma markers, and the percentages of the area occupied by medulloblastoma-like tissue were larger in PTCH1 −/− teratomas than in PTCH1 +/− teratomas. In contrast, in PTCH1 +/+ teratomas, medulloblastoma-like tissue positive for all of these medulloblastoma markers was not observed. The present results indicate the importance of PTCH1 in medulloblastoma formation and the suitability of these gene-edited iPSCs and PTCH1 −/− teratomas as models for the formation of tumors, such as medulloblastomas and Hh-related tumors.

Introduction Our patient treated with pembrolizumab and axitinib is one of the longest survivors in Japan on KEYNOTE 426, despite adverse events, including delayed‐onset hepatitis. We herein present a detailed clinical course and short discussion on the case. Case presentation This was a 49‐year‐old male with clear cell renal cell carcinoma and lung metastases. After cytoreductive nephrectomy, treatment with pembrolizumab plus axitinib was initiated and the patient demonstrated a radiographic partial response as best response. The main adverse event was pembrolizumab‐induced delayed‐onset hepatitis, which was successfully treated with prednisolone. Pembrolizumab was re‐initiated and completed. Conclusion The survival benefit in the present case may be due to the initial potent anti‐cancer effects of axitinib and durable immune effects of pembrolizumab, leading to long‐term treatment‐free survival.

Systematic measurements of atmospheric methane (CH4) mole fractions at the northern high latitudes only began in the early 1980s. Although CH4 measurements from Greenland ice cores consistently covered the period before ∼ 1900, no reliable observational record is available for the intermediate period. We newly report a data set of trace gases from the air trapped in firn (an intermediate stage between snow and glacial ice formation) collected at the NGRIP (North Greenland Ice Core Project) site in 2001. We also use a set of published firn air data at the NEEM (North Greenland Eemian ice Drilling) site. The two Arctic firn air data sets are analysed with a firn air transport model, which translates historical variations to depth profiles of trace gases in firn. We examine a variety of possible firn diffusivity profiles, using a suite of measured trace gases, and reconstruct the CH4 mole fraction by an iterative dating method. Although the reconstructions of the Arctic CH4 mole fraction before the mid-1970s still has large uncertainties (> 30 ppb – parts per billion), we find a relatively narrow range of atmospheric CH4 history that is consistent with both depth profiles of NGRIP and NEEM. The atmospheric CH4 history inferred by this study is more consistent with the atmospheric CH4 scenario prepared for the NEEM firn modelling than that for the CMIP6 (Climate Model Intercomparison Project Phase 6) experiments. Our study shows that the atmospheric CH4 scenario used for the NEEM firn modelling is considered to be the current best choice for the Arctic CH4 history, but it should not be used to tune firn air transport models until being verified by further measurements from sources such as the Arctic ice cores. Given the current difficulty in reconstructing the CH4 history with low uncertainty from the firn air data sets from Greenland, future sampling and measurements of ice cores at a high-accumulation site may be the only way to accurately reconstruct the atmospheric CH4 trend over the 20th century.

Abstract Background Palliative radiotherapy for gastric cancer bleeding has been reported to be a safe and effective treatment, but predictive factors for achievement of hemostasis and overall survival have not been established. Methods In this retrospective study, 120 courses of palliative radiotherapy for gastric cancer bleeding in 117 patients in 4 institutes in Japan were reviewed with approval of the ethical committee in each institute. The rate of achieving hemostasis was evaluated by 50% or more reduction of red blood cell transfusion before and after the start of radiotherapy, elevation of blood hemoglobin concentration in a period of 4 weeks from the start of radiotherapy or improvement of subjective or objective clinical symptoms in a period of 4 weeks from the start of radiotherapy. Predictive factors for overall survival and achieving hemostasis were investigated with the Cox hazards model. Results The median overall survival period was 3.7 months. Multivariate analysis showed that absence of metastatic disease, higher biological effective dose, higher serum albumin level, lower blood urea nitrogen level and lower neutrophil-to-lymphocyte ratio (NLR) were associated with longer overall survival. Elevation of hemoglobin concentration in a period of 4 weeks from the start of radiotherapy (mean concentration: 8.2 g/dL vs. 8.9 g/dL, p = 0.006) and decrease in the amount of red cell transfusion from a 4-week period before to a 4-week period after the start of radiotherapy (mean amount: 716 mL vs. 230 mL, p

Abstract Background The most common gene responsible for autosomal recessive retinitis pigmentosa (RP) is EYS. The manner of decay of genetically defective EYS gene transcripts varies depending on the type of mutation using our cellular model, which consists of induced photoreceptor-directed fibroblasts from EYS-RP patients (EYS-RP cells). However, disease-specific profiles have not been clarified in EYS-RP cells. Herein we investigated comprehensive gene expression patterns and restoration of altered expression by low molecular weight molecules in EYS-RP cells. Methods Using induced photoreceptor-like cells by CRX, RAX, NeuroD, and OTX2, we employed qRT-PCR and DNA microarray analysis to compare expression levels of disease-related genes in EYS-RP cells. We investigated the effect of antiapoptotic or anti-endoplasmic reticulum (ER) stress/antioxidant reagents on the restoration of altered gene expression. Results Expression levels of phototransduction-related genes (blue opsin, rhodopsin, S-antigen, GNAT1, GNAT2) were lower in EYS-RP cells. CRYGD was extracted by global gene expression analysis, as a downregulated, retina-related and apoptosis-, endoplasmic reticulum (ER) stress- or aging-related gene. Pathway enrichment analysis suggested that “complement and coagulation cascades,” “ECM-receptor interaction” and “PI3K-Akt signaling pathway” could be involved in EYS-RP-associated pathogenesis. Among the matching/overlapping genes involved in those pathways, F2R was suggested as an EYS-RP-associated gene. The downregulation of CRYGD and F2R was completely restored by additional 4-PBA, an inhibitor of ER stress, and partially restored by metformin or NAC. In addition, 4-PBA normalized the expression level of cleaved caspase-3. Conclusions Our cellular model may reflect the ER stress-mediated degenerative retina and serve as a pathogenesis-oriented cost-effective rescue strategy for RP patients.

Abstract Background High-dose glucocorticoids (GC) are first-line treatment for adult-onset Still’s disease (AOSD); however, some of the patients remain refractory to initial GC therapy, or rapidly relapse. The aim of this study was to identify prognostic factors for poor treatment response to initial GC therapy for AOSD. Methods Data on newly diagnosed AOSD patients were extracted from our database (n=71, mean age 51.6 years). The primary outcome was a poor treatment outcome at 4 weeks, which was defined as failure to achieve remission or relapse after achieving remission within 4 weeks, followed by administration of two or more rounds of GC pulse therapy or of any other immunosuppressive drugs. Results The initial mean dose ± standard deviation of prednisolone was 0.82 ± 0.23 mg/kg/day, and 34 (47.3%) patients received GC pulse therapy at week 0. Twenty-nine of 71 patients exhibited a poor treatment outcome at 4 weeks (40.8%). The second round of GC pulse therapy or immunosuppressive drugs was added in 17 or 24 of the 29 patients, respectively. These patients had higher baseline white blood cell (WBC) counts, serum ferritin levels, systemic feature score based on clinical symptoms (modified systemic feature score, mSFS), more hemophagocytic syndrome (HPS) over the 4 weeks, and the higher severity score based on modified Pouchot score or severity index of the Japanese Ministry of Health, Labour and Welfare, than the remaining 42 patients. Multivariable logistic regression model identified baseline WBC count as a prognostic factor for poor outcome (odds ratio per 1000/μl increment: 1.12, 95% CI 1.04–1.29), while thrombocytopenia, hyperferritinemia, and mSFS at baseline did not achieve statistical significance. Receiver-operating characteristic curve analysis showed that the optimal cut-off for WBC count was 13,050/μl. The Kaplan-Meier method showed the cumulative rate of poor treatment outcome to be 60.0% in patients with WBC ≥13,050/μl and 23.5% in those with WBC

Abstract Background In clinical practice, the effect of durvalumab and radiation pneumonitis (RP) on survival after intensity-modulated radiotherapy (IMRT) is not fully understood. The purpose of this retrospective study was to investigate factors related to distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS) after IMRT for locally advanced non-small cell lung cancer (LA-NSCLC). Methods All patients who were treated with conventional fractionated IMRT for LA-NSCLC between April 2016 and March 2021 were eligible. Time-to-event data were assessed by using the Kaplan–Meier estimator, and the Cox proportional hazards model was used for prognostic factor analyses. Factors that emerged after the start of IMRT, such as durvalumab administration or the development of RP, were analysed as time-dependent covariates. Results A total of 68 consecutive patients treated with conventional fractionated IMRT for LA-NSCLC were analysed. Sixty-six patients completed radiotherapy, 50 patients received concurrent chemotherapy, and 36 patients received adjuvant durvalumab. During the median follow-up period of 14.3 months, 23 patients died, and tumour progression occurred in 37 patients, including 28 patients with distant metastases. The 1-year DMFS rate, PFS rate and OS rate were 59.9%, 48.7% and 84.2%, respectively. Grade 2 RP occurred in 16 patients, grade 3 in 6 patients and grade 5 in 1 patient. The 1-year cumulative incidences of grade 2 or higher RP and grade 3 or higher RP were 33.8% and 10.3%, respectively. The results of multivariate analyses showed that durvalumab had a significantly lower hazard ratio (HR) for DMFS, PFS and OS (HR 0.31, p

Abstract Background The abscopal effect is a phenomenon in which a tumor located far from irradiated lesions regresses. We have experienced a case in which both intracranial and extracranial lesions showed an abscopal effect after radiotherapy for spinal metastases of unknown primary. We report the differential abscopal effect in extracranial and intracranial lesions. Case presentation A 57-year-old Japanese man was diagnosed with multiple lung nodules, bone metastases, and brain metastases. The results of pathological examination at the previous hospital he visited suggested adenocarcinoma of the lung. However, there was a possibility that the biopsy specimen was inadequate. Radiation therapy was performed on the ninth thoracic vertebra for a total dose of 39 Gy in 13 fractions because the lesion in the ninth thoracic vertebra was destructively extending. After thorough examination, the primary lesion could not be identified, and we made diagnosis of cancer of unknown primary. The patient did not want to receive systemic chemotherapy; however, all of the lesions except for the brain metastases had spontaneously shrunk 2 months after radiation therapy. Although the brain metastases had partially shrunk, whole-brain radiotherapy for a total dose of 36 Gy in 12 fractions was performed. Fifteen months after initial radiation therapy, the brain metastasis recurred, and Gamma Knife radiosurgery was additionally performed. The brain metastases disappeared after the radiosurgery. During a period of 30 months after radiation therapy for the ninth vertebra, the lesions of the trunk all maintained their shrinkage without systemic chemotherapy. Right cervical lymph node metastasis and brain metastases occurred 30 months after the initial radiation therapy. A biopsy of the right cervical lymph node led to the diagnosis of clear cell carcinoma. Although we considered additional radiation therapy or chemotherapy, the patient died 3 months after the progression of recurrence lesions. Discussion and conclusions We report a rare case in which radiotherapy alone for an extracranial metastatic lesion of a vertebra resulted in an abscopal effect on both extracranial and intracranial lesions. Notably, the abscopal effect in the intracranial lesions was weaker than that in the extracranial lesions.

Abstract Background The liver plays an important role in various metabolic processes, including protein synthesis, lipid and drug metabolisms and detoxifications. Primary culture of hepatocytes is used for the understanding of liver physiology as well as for the drug development. Hepatocytes are, however, hardly expandable in vitro making it difficult to secure large numbers of cells from one donor. Alternatively, systems using animal models and hepatocellular carcinoma cells have been established, but interspecies differences, variation between human cell sources and limited hepatic functions are among the challenges faced when using these models. Therefore, there is still a need for a highly stable method to purify human hepatocytes with functional sufficiency. In this study, we aimed to establish an in vitro long-term culture system that enables stable proliferation and maintenance of human hepatocytes to ensure a constant supply. Methods We first established a growth culture system for hepatocytes derived from patients with drug-induced liver injury using fetal mouse fibroblasts and EMUKK-05 medium. We then evaluated the morphology, proliferative capacity, chromosome stability, gene and protein expression profiles, and drug metabolic capacity of hepatocytes in early, middle and late passages with and without puromycin. In addition, hepatic maturation in 3D culture was evaluated from morphological and functional aspects. Results In our culture system, the stable proliferation of human hepatocytes was achieved by co-culturing with mouse fetal fibroblasts, resulting in dedifferentiation into hepatic progenitor-like cells. We purified human hepatocytes by selection with cytocidal puromycin and cultured them for more than 60 population doublings over a span of more than 350 days. Hepatocytes with high expression of cytochrome P450 genes survived after exposure to cytocidal antibiotics because of enhanced drug-metabolizing activity. Conclusions These results show that this simple culture system with usage of the cytocidal antibiotics enables efficient hepatocyte proliferation and is an effective method for generating a stable supply of hepatocytes for drug discovery research at a significant cost reduction.

The molecular arrangement of the extremely uniaxial thin film was determined using X-ray analysis, including grazing incidence wide-angle X-ray scattering. The highly oriented film was obtained by depositing a bisazo dye onto an aligned polytetrafluoroethylene (PTFE) layer via vacuum evaporation, as shown previously. The X-ray analysis indicated that the molecules are arranged in parallel or antiparallel orientations within the unit cell. Moreover, their long axes are parallel to each other within the grains which are uniformly oriented throughout the film. These results confirm the driving force of the orientation reported previously using a molecular dynamics model: dye molecules trapped along the atomic grooves between adjacent PTFE chains serve as nuclei for crystal growth. In addition, the long molecular axes remain parallel to the rubbing direction, although some grains are inclined in the short-axis direction. This molecular arrangement in the film could contribute to a high degree of uniaxial orientation. [ABSTRACT FROM AUTHOR]