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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models.
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Anthropogenic activities have substantially enhanced the loadings of reactive nitrogen (Nr) in the Earth system since pre-industrial times1,2, contributing to widespread eutrophication and air pollution3-6. Increased Nr can also influence global climate through a variety of effects on atmospheric and land processes but the cumulative net climate effect is yet to be unravelled. Here we show that anthropogenic Nr causes a net negative direct radiative forcing of -0.34 [-0.20, -0.50] W m-2 in the year 2019 relative to the year 1850. This net cooling effect is the result of increased aerosol loading, reduced methane lifetime and increased terrestrial carbon sequestration associated with increases in anthropogenic Nr, which are not offset by the warming effects of enhanced atmospheric nitrous oxide and ozone. Future predictions using three representative scenarios show that this cooling effect may be weakened primarily as a result of reduced aerosol loading and increased lifetime of methane, whereas in particular N2O-induced warming will probably continue to increase under all scenarios. Our results indicate that future reductions in anthropogenic Nr to achieve environmental protection goals need to be accompanied by enhanced efforts to reduce anthropogenic greenhouse gas emissions to achieve climate change mitigation in line with the Paris Agreement.
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The uptake of carbon dioxide (CO2) by terrestrial ecosystems is critical for moderating climate change1. To provide a ground-based long-term assessment of the contribution of forests to terrestrial CO2 uptake, we synthesized in situ forest data from boreal, temperate and tropical biomes spanning three decades. We found that the carbon sink in global forests was steady, at 3.6 ± 0.4 Pg C yr-1 in the 1990s and 2000s, and 3.5 ± 0.4 Pg C yr-1 in the 2010s. Despite this global stability, our analysis revealed some major biome-level changes. Carbon sinks have increased in temperate (+30 ± 5%) and tropical regrowth (+29 ± 8%) forests owing to increases in forest area, but they decreased in boreal (-36 ± 6%) and tropical intact (-31 ± 7%) forests, as a result of intensified disturbances and losses in intact forest area, respectively. Mass-balance studies indicate that the global land carbon sink has increased2, implying an increase in the non-forest-land carbon sink. The global forest sink is equivalent to almost half of fossil-fuel emissions (7.8 ± 0.4 Pg C yr-1 in 1990-2019). However, two-thirds of the benefit from the sink has been negated by tropical deforestation (2.2 ± 0.5 Pg C yr-1 in 1990-2019). Although the global forest sink has endured undiminished for three decades, despite regional variations, it could be weakened by ageing forests, continuing deforestation and further intensification of disturbance regimes1. To protect the carbon sink, land management policies are needed to limit deforestation, promote forest restoration and improve timber-harvesting practices1,3.
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Dióxido de Carbono , Secuestro de Carbono , Bosques , Internacionalidad , Árboles , Dióxido de Carbono/metabolismo , Dióxido de Carbono/análisis , Cambio Climático , Conservación de los Recursos Naturales , Ecosistema , Agricultura Forestal/legislación & jurisprudencia , Agricultura Forestal/estadística & datos numéricos , Agricultura Forestal/tendencias , Combustibles Fósiles/efectos adversos , Combustibles Fósiles/provisión & distribución , Taiga , Árboles/metabolismo , Árboles/crecimiento & desarrollo , Clima TropicalRESUMEN
Cell adhesion molecule 1 (CADM1), a single-pass transmembrane protein, is involved in oncogenesis. We previously demonstrated the therapeutic efficacy of anti-CADM1 ectodomain monoclonal antibodies against mesothelioma; however, the underlying mechanism is unclear. In the present study, we explored the molecular behavior of anti-CADM1 antibodies in CADM1-expressing tumor cells. Sequencing analyses revealed that the anti-CADM1 chicken monoclonal antibodies 3E1 and 9D2 are IgY and IgM isotype antibodies, respectively. Co-administration of 3E1 and 9D2 altered the subcellular distribution of CADM1 from the detergent-soluble fraction to the detergent-resistant fraction in tumor cells. Using recombinant chicken-mouse chimeric antibodies that had been isotype-switched from IgG to IgM, we demonstrated that the combination of the variable region of 3E1 and the constant region of IgM was required for CADM1 relocation. Cytochemical studies showed that 3E1 colocalized with late endosomes/lysosomes after co-administration with 9D2, suggesting that the CADM1-antibody complex is internalized from the cell surface to intracellular compartments by lipid-raft mediated endocytosis. Finally, 3E1 was conjugated with the antimitotic agent monomethyl auristatin E (MMAE) via a cathepsin-cleavable linker. Co-administration of 3E1-monomethyl auristatin E and 9D2 suppressed the growth of multiple types of tumor cells, and this anti-tumor activity was confirmed in a syngeneic mouse model of melanoma. 3E1 and 9D2 are promising drug delivery vehicles for CADM1-expressing tumor cells.
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Anticuerpos Monoclonales , Molécula 1 de Adhesión Celular , Sistemas de Liberación de Medicamentos , Inmunoglobulinas , Animales , Humanos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Inmunoglobulinas/administración & dosificación , Inmunoglobulinas/metabolismo , Línea Celular Tumoral , Ratones , Ratones Endogámicos C57BL , Oligopéptidos/administración & dosificación , Oligopéptidos/química , Inmunoglobulina M/inmunología , Inmunoglobulina M/administración & dosificación , Pollos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , FemeninoRESUMEN
Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo-not reached; n = 39) and 23.7 months (95% CI: 14.5-43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29-0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.
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Introduction: Inflammatory myofibroblastic tumors are borderline malignant soft tissue tumors primarily affecting the lungs and pelvic organs. This report presents a rare case of an inflammatory myofibroblastic tumor originating from the prostate gland in a young male. Case presentation: A 20-year-old man developed gross hematuria and dysuria, revealing a prostatic mass. Pathological examination of a biopsy displayed spindle-shaped myofibroblast proliferation and an infiltrate of inflammatory cells, leading to a diagnosis of inflammatory myofibroblastic tumor. Following fertility preservation measures, the patient underwent a robot-assisted laparoscopic total prostatectomy with bilateral nerve sparing, resulting in a postoperative diagnosis of inflammatory myofibroblastic tumor. No recurrence was observed in subsequent imaging, and urinary continence was maintained. Conclusion: Surgical resection appears effective in managing inflammatory myofibroblastic tumors of the prostate. This case underscores the importance of complete tumor resection due to the significant recurrence risk associated with inflammatory myofibroblastic tumors. Radical total prostatectomy emerges as a potential treatment strategy for prostate originating inflammatory myofibroblastic tumors.
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BACKGROUND: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown. METHODS: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid. RESULTS: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration. CONCLUSIONS: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.
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Anticuerpos Monoclonales , Carcinoma de Pulmón de Células no Pequeñas , Quimioradioterapia , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Anciano , Persona de Mediana Edad , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Estudios Prospectivos , Quimioradioterapia/efectos adversos , Estadificación de Neoplasias , Adulto , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Anciano de 80 o más Años , Supervivencia sin ProgresiónRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first infects the host nasal mucosa, where the viral spike protein binds to angiotensin-converting enzyme 2 (ACE2) on the mucosal cells. This study aimed at searching host cell surface molecules that could contribute to the infection in two views; abundance on host cells and affinity to the spike protein. Since the nasal mucosa is lined by respiratory and olfactory epithelia, and both express an immunoglobulin superfamily member cell adhesion molecule 1 (CADM1), whether CADM1 would participate in the spike protein binding was examined. Immunohistochemistry on the mouse nasal cavity detected CADM1 strongly in the olfactory epithelium at cell-cell contacts and on the apical surface but just faintly in the respiratory epithelium. In contrast, ACE2 was detected in the respiratory, not olfactory, epithelium. When mice were administered intranasally with SARS-CoV-2 S1 spike protein and an anti-CADM1 ectodomain antibody separately, both were detected exclusively on the olfactory, not respiratory, epithelium. Then, the antibody and S1 spike protein were administered intranasally to mice in this order with an interval of 1 hour. After 3 hours, S1 spike protein was detected as a protein aggregate floating in the nasal cavity. Next, S1 spike protein labeled with fluorescein was added to the monolayer cultures of epithelial cells exogenously expressing ACE2 or CADM1. Quantitative detection of fluorescein bound to the cells revealed that S1 spike protein bound to CADM1 with affinity half as high as to ACE2. Consistently, docking simulation analyses revealed that S1 spike protein could bind to CADM1 three quarters as strongly as to ACE2 and that the interface of ACE2 was similar in both binding modes. Collectively, intranasal S1 spike protein appeared to prefer to accumulate on the olfactory epithelium, and CADM1 was suggested to contribute to this preference of S1 spike protein based on the molecular abundance and affinity.
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BACKGROUND: An increasing number of women are undergoing breast implantation for cosmetic purposes and for reconstructive purposes after breast excision. The surface morphology of the breast implant is one of the key factors associated with the induction of capsule contraction. The effect of surface morphology on the inflammatory response following implant insertion remains unclear, however. This study conducted comparative analyses to determine the effect of the textured and smooth surface morphology of silicone sheets. METHODS: Each type of silicone sheet was inserted into the subcutaneous pocket below the panniculus carnosus in C57BL/6 mice and mice with genetic disruption of CARD9, Dectin-1, Dectin-2, or Mincle. We also analyzed the collagen fiber capsule thickness, histological findings, and macrophage inflammatory response, including TGF-ß synthesis. RESULTS: We found that textured surface morphology contributed to the formation of collagen fiber capsules and the accumulation of fibroblasts and myofibroblasts, and was accompanied by the accumulation of TGF-ß-expressing macrophages and foreign-body giant cells. CARD9 deficiency attenuated collagen fiber capsule formation, macrophage responses, and TGF-ß synthesis, although the responsible C-type lectin receptors (CLRs) remain to be clarified. CONCLUSIONS: These results suggest that CARD9 may have a strong impact on silicone sheet insertion through the regulation of macrophage responses.
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Termites with symbiotic methanogens are a known source of atmospheric methane (CH4), but large uncertainties remain regarding the flux magnitude. This study estimated global termite CH4 emissions using a framework similar to previous studies but with contemporary datasets and a biogeochemical model. The global termite emission in 2020 was estimated as 14.8 ± 6.7 Tg CH4 year-1, mainly from tropical and subtropical ecosystems, indicating a major natural source from upland regions. Uncertainties associated with estimation methods were assessed. The emission during the historical period 1901-2021 was estimated to have increased gradually (+ 0.7 Tg CH4 year-1) as a result of combined influences of elevated CO2 (via vegetation productivity), climatic warming, and land-use change. Future projections using climate and land-use scenarios (shared socioeconomic pathways [ssp] 126 and 585) also showed increasing trends (+ 0.5 to 5.9 Tg CH4 year-1 by 2100). These results suggest the importance of termite emissions in the global CH4 budget and, thus, in climatic prediction and mitigation.
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INTRODUCTION: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE). METHODS: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers. RESULTS: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocyte density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8+ tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. CONCLUSIONS: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Quimioradioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Estadificación de Neoplasias , Microambiente TumoralRESUMEN
Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.
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Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Hiperaldosteronismo , Hipertensión , Humanos , Aldosterona , Citocromo P-450 CYP11B2 , Uniones Comunicantes , Mutación , Molécula 1 de Adhesión CelularRESUMEN
The recent rise in atmospheric methane (CH4 ) concentrations accelerates climate change and offsets mitigation efforts. Although wetlands are the largest natural CH4 source, estimates of global wetland CH4 emissions vary widely among approaches taken by bottom-up (BU) process-based biogeochemical models and top-down (TD) atmospheric inversion methods. Here, we integrate in situ measurements, multi-model ensembles, and a machine learning upscaling product into the International Land Model Benchmarking system to examine the relationship between wetland CH4 emission estimates and model performance. We find that using better-performing models identified by observational constraints reduces the spread of wetland CH4 emission estimates by 62% and 39% for BU- and TD-based approaches, respectively. However, global BU and TD CH4 emission estimate discrepancies increased by about 15% (from 31 to 36 TgCH4 year-1 ) when the top 20% models were used, although we consider this result moderately uncertain given the unevenly distributed global observations. Our analyses demonstrate that model performance ranking is subject to benchmark selection due to large inter-site variability, highlighting the importance of expanding coverage of benchmark sites to diverse environmental conditions. We encourage future development of wetland CH4 models to move beyond static benchmarking and focus on evaluating site-specific and ecosystem-specific variabilities inferred from observations.
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Ecosistema , Humedales , Metano/análisis , Cambio Climático , Predicción , Dióxido de CarbonoRESUMEN
We developed a near-real-time estimation method for temporal changes in fossil fuel CO2 (FFCO2) emissions from China for 3 months [January, February, March (JFM)] based on atmospheric CO2 and CH4 observations on Hateruma Island (HAT, 24.06° N, 123.81° E) and Yonaguni Island (YON, 24.47° N, 123.01° E), Japan. These two remote islands are in the downwind region of continental East Asia during winter because of the East Asian monsoon. Previous studies have revealed that monthly averages of synoptic-scale variability ratios of atmospheric CO2 and CH4 (ΔCO2/ΔCH4) observed at HAT and YON in JFM are sensitive to changes in continental emissions. From the analysis based on an atmospheric transport model with all components of CO2 and CH4 fluxes, we found that the ΔCO2/ΔCH4 ratio was linearly related to the FFCO2/CH4 emission ratio in China because calculating the variability ratio canceled out the transport influences. Using the simulated linear relationship, we converted the observed ΔCO2/ΔCH4 ratios into FFCO2/CH4 emission ratios in China. The change rates of the emission ratios for 2020-2022 were calculated relative to those for the preceding 9-year period (2011-2019), during which relatively stable ΔCO2/ΔCH4 ratios were observed. These changes in the emission ratios can be read as FFCO2 emission changes under the assumption of no interannual variations in CH4 emissions and biospheric CO2 fluxes for JFM. The resulting average changes in the FFCO2 emissions in January, February, and March 2020 were 17 ± 8%, - 36 ± 7%, and - 12 ± 8%, respectively, (- 10 ± 9% for JFM overall) relative to 2011-2019. These results were generally consistent with previous estimates. The emission changes for January, February, and March were 18 ± 8%, - 2 ± 10%, and 29 ± 12%, respectively, in 2021 (15 ± 10% for JFM overall) and 20 ± 9%, - 3 ± 10%, and - 10 ± 9%, respectively, in 2022 (2 ± 9% for JFM overall). These results suggest that the FFCO2 emissions from China rebounded to the normal level or set a new high record in early 2021 after a reduction during the COVID-19 lockdown. In addition, the estimated reduction in March 2022 might be attributed to the influence of a new wave of COVID-19 infections in Shanghai. Supplementary Information: The online version contains supplementary material available at 10.1186/s40645-023-00542-6.
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AIM: To investigate the effect of ritodrine hydrochloride infusion on fetal movement. METHOD: We gathered 20 pregnant women who received ritodrine hydrochloride infusion as the treated group, and 147 pregnant women who did not as the control group. All women recorded gross fetal movement with the fetal movement acceleration measurement recorder after 28 gestational weeks. The record was divided into epochs of 10 s, and the ratio of movement-positive epochs to all epochs was calculated as the fetal movement index. Furthermore, the mean duration and the mean number per hour of no-fetal movement period, where the fetus did not move for 5 min or more, were calculated as the indexes of no-fetal movement. All indexes were compared between the two groups at 28-31 and 32-35 gestational weeks. RESULTS: The fetal movement indexes (%) were 17.29 ± 7.46 (mean ± SD) in the control group and 13.65 ± 7.13 in the treated group at 28-31 weeks (p = 0.139). At 32-35 weeks, they were 14.55 ± 6.43 and 18.50 ± 5.33, respectively (p = 0.03). Similarly, the no-fetal movement indexes (min, times/h) were 15.03 ± 10.99 and 1.61 ± 0.88, and 18.70 ± 15.80 and 1.75 ± 0.96 (p = 0.824, and 0.673) at 28-31 weeks. At 32-35 weeks, they were 18.13 ± 10.88 and 1.95 ± 0.97, and 9.20 ± 5.51 and 1.14 ± 0.71, respectively (p = 0.003, and 0.003). CONCLUSION: Ritodrine hydrochloride infusion increased the fetal movement and decreased the no-fetal movement period at 32-35 weeks.
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Ritodrina , Embarazo , Femenino , Humanos , Ritodrina/farmacología , Feto , Atención Prenatal , Infusiones Parenterales , AceleraciónRESUMEN
Testicular teratomas are the major histologic type of testicular germ cell tumors and their incidence continues to grow. Moreover, teratomas can develop from undifferentiated cells in induced pluripotent stem (iPS) cell transplantation therapy, seriously hampering the progress of regenerative medicine. Germinal center-associated nuclear protein (GANP) is thought to be important to the biogenetic control of primordial germ cells and is among the genes susceptible to testicular germ cell tumors. Thus, we analyzed the expression of GANP in human testicular postpubertal-type teratomas and established a novel mouse model to reveal the association between GANP and teratomagenesis. We analyzed 31 cases of human testicular postpubertal-type teratomas and, in all cases, GANP was overexpressed. The aberrant expression was also detected in germ cell neoplasia in situ accompanied by the teratoma. GANP expression was particularly high in the epithelia of the epidermis, cutaneous appendages, and trachea-like ciliated epithelium. To further clarify the association between GANP and teratomagenesis, we established a novel teratomagenesis mouse model (CAG-ganpTg mice). In the GANP-teratoma mice, GANP-overexpressing teratomas were more frequent at the testes and the middle portion of the uterus than has been seen in the previously established mouse models. In conclusion, GANP is overexpressed in testicular postpubertal-type teratomas and is an essential teratomagenic factor. We also found that CAG-ganpTg mice are useful mouse models of teratomagenesis that mimics human midline teratomas and that teratomas may originate from the overexpression of GANP in primordial germ cells.
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Neoplasias de Células Germinales y Embrionarias , Teratoma , Neoplasias Testiculares , Masculino , Femenino , Humanos , Ratones , Animales , Testículo/patología , Teratoma/genética , Neoplasias Testiculares/metabolismo , Centro Germinal , Proteínas NuclearesRESUMEN
Estimates of future climate change impacts using numerical impact models are commonly based on a limited selection of projections of climate and other key drivers. However, the availability of large ensembles of such projections offers an opportunity to estimate impact responses probabilistically. This study demonstrates an approach that combines model-based impact response surfaces (IRSs) with probabilistic projections of climate change and population to estimate the likelihood of exceeding pre-specified thresholds of impact. The changing likelihood of exceeding impact thresholds during the 21st century was estimated for selected indicators in three European case study regions (Iberian Peninsula, Scotland and Hungary), comparing simulations that incorporate adaptation to those without adaptation. The results showed high likelihoods of increases in heat-related human mortality and of yield decreases for some crops, whereas a decrease of NPP was estimated to be exceptionally unlikely. For a water reservoir in a Portuguese catchment, increased likelihoods of severe water scarce conditions were estimated for the current rice cultivation. Switching from rice to other crops with lower irrigation demand changes production risks, allowing for expansion of the irrigated areas but introducing a stronger sensitivity to changes in rainfall. The IRS-based risk assessment shown in this paper is of relevance for policy making by addressing the relative sensitivity of impacts to key climate and socio-economic drivers, and the urgency for action expressed as a time series of the likelihood of crossing critical impact thresholds. It also examines options to respond by incorporating alternative adaptation actions in the analysis framework, which may be useful for exploring the types, choice and timing of adaptation responses.
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Radiography is non-destructive imaging for engineering, medical diagnostics, airport security checks, and decontamination activities in nuclear plants. Inorganic scintillators are phosphor materials that convert radiation into visible photons with high luminescence and fast response, and scintillators with a few tens of micrometers thickness can improve sensitivity in radiation detection and imaging. To date, a production method for thick film scintillators is a time and cost consuming way of slicing and poshing bulk single crystals and transparent ceramics. Here, the chemically vapor deposited Ce3+-doped Lu3Al5O12 thick film scintillators (CVD-Ce3+:LuAG) with a thickness of 1-25 µm were produced at deposition time of 1-30 min. Numerical simulations indicated the penetration depth of α-particle in Ce3+:LuAG is 12.8 µm, and the 14-µm-thick CVD-Ce3+:LuAG showed highest light yield (31,000 photons 5.5 MeV-1), superior to the commercial Ce3+:LuAG single crystal scintillator (21,000 photons 5.5 MeV-1). In the X-ray radiograph taken with CVD-Ce3+:LuAG as a scintillation screen, 5-µm-width bar of metal microgrids can be identified. Vapor deposition technique can be a novel high-throughput production way of a thick film scintillator which is in a micrometer-thickness effective to converting radiations into photons for sensitive α-emitter detection and high-resolution X-ray imaging.