A Case of Relapsed/Refractory CD56-Positive Acute Promyelocytic Leukemia, in Which Complete Molecular Remission Was Achieved Following Combination Therapy with Venetoclax and Azacitidine.

An 84-year-old woman was diagnosed as having acute promyelocytic leukemia(APL)in July Year X-3. The test for promyelocytic leukemia- retinoic acid receptor alpha(PML-RARA)mRNA was positive, while that for CD56 was negative. Since her white blood cell( WBC) count was <3,000/µL, with a count of APL cells of <1,000/µL, she was started on monotherapy with all-trans retinoic acid(ATRA). In September Year X-3, complete hematological remission(CHR)was confirmed. she refused to provide consent for receiving consolidation therapy. In February Year X-2, hematological relapse occurred. She was started on re-induction therapy with arsenite(ATO), and in June Year X-2, complete molecular remission(CMR)was achieved. She was started on post-remission therapy with ATO. In August Year X-1, she developed molecular relapse and was started on tamibarotene(Am80). In October Year X-1, hematological relapse was detected, and the test for CD56 was positive. She was started on combined venetoclax(VEN)+azacitidine(AZA)(VEN+AZA). After completion of 1 course of treatment, CMR was achieved, but she developed hematological relapse after 5 courses of treatment. She died of gastrointestinal hemorrhage. This is considered a valuable case for accumulating information on the treatment of CD56-positive APL resistant to ATRA and ATO.

A Case of Immune Thrombocytopenia Occurring after Radiotherapy plus Atezolizumab Treatment for Bladder Cancer.

An 84-year-old female developed gross hematuria. She was diagnosed as urinary bladder carcinoma. She was initiated on concurrent atezolizumab plus radiation(a phase Ⅱ clinical trial)(jRCT2031180060). After 8 cycles of atezolizumab, complete response was confirmed. Maintenance atezolizumab treatment was started. Platelet(Plt)count decreased, there was no rechallenge with atezolizumab. Bone marrow examination revealed normal. Plt count recovered. Plt count decreased again. The serum levels of interleukin-6(IL-6)were elevated. She was diagnosed as having immune thrombocytopenia. She was started on treatment with prednisolone(PSL)at dose of 20 mg/day. Plt count was increased.

[A case of crossed aphasia following infarction in the right anterior cerebral artery territory].

We report a patient presenting with crossed aphasia following infarction in the territory of the right anterior cerebral artery (ACA). A right-handed 68-year-old woman without a history of correction had acute disturbance of consciousness, left hemiparesis predominant in the lower extremity, speech disorder and left unilateral spatial neglect during the admission due to hypertensive emergency. No other family member was left-handed. MRI of the head revealed acute phase infarction in the territory of the right ACA: mesial frontal lobe including the supplementary motor area, anterior cingulate gyrus, and the corpus callosum. Language symptoms in the subacute phase included difficulty in initiation, slow speech rate, loss of intonation and phonetic paraphasia, and accompanying errors in comprehension, repetition, reading, and writing letters. These symptoms suggested "anomalous" type crossed aphasia. No limb apraxia, construction disorder or left unilateral spatial neglect was observed in this period. Only a few cases of crossed aphasia due to infarction in the territory of the ACA have been reported so far. However, language and concomitant symptoms differs, depending on each case, suggesting a difference in individual cerebral lateralization.

Bi-glandular and persistent enterovirus infection and distinct changes of the pancreas in slowly progressive type 1 diabetes mellitus.

In slowly progressive type 1 diabetes mellitus (SPIDDM), the pancreas shows sustained islet inflammation, pancreatitis, pancreatic acinar cell metaplasia/dysplasia (ADM), and intraepithelial neoplasia (PanIN), a precancerous lesion. The mechanisms underlying these changes remain unclear. The presence of enterovirus (EV) encoded-capsid protein 1 (VP1) and -2A protease (2Apro) and the innate immune responses of the pancreas were studied using immunohistochemistry and in situ hybridization in 12 SPIDDM and 19 non-diabetic control pancreases. VP1, 2Apro, and EV-RNA were detected in islets and the exocrine pancreas in all SPIDDM pancreases. Innate immune receptor, melanoma differentiation-associated gene 5 (MDA5), and interferon (IFN)-beta1 were intensified in the islets of SPIDDM patients with short disease duration. However, expressions of MDA5 and IFN-beta1were suppressed in those with longer disease duration. CD3+ T cell infiltration was observed in the VP1- and insulin-positive islets (insulitis) and exocrine acinar cells. CD11c+ dendritic cells (DCs) in islets were scarce in long-term SPIDDM. This study showed the consistent presence of EV, suggesting an association with inflammatory changes in the endocrine and exocrine pancreas in SPIDDM. Suppressed expressions of MDA5 and IFN-beta1, as well as decreased numbers of DCs in the host cells, may contribute to persistent EV infection and induction of ADM/PanIN lesions, which may potentially provide a scaffold for pancreatic neoplasms.

A Case of Diffuse Large B-Cell Lymphoma Complicated by Helicobacter Pylori-Negative Russell Body Gastritis.

A 76-year-old woman with a past history of diabetes mellitus and Hashimoto's disease, in regard to her personal history, she did not smoke or drink alcohol. In March, year X-1, she became aware of cervical lymphadenopathy. Based on the findings of lymph node biopsy, she was diagnosed as having diffuse large B-cell lymphoma(DLBCL). An upper gastrointestinal endoscopy(U-GIE)revealed white granular prominences in the gastric fornix, and biopsy of these lesions revealed the diagnosis of Russell body gastritis(RBG). Neither lymphoma infiltration nor other malignant findings were found. Diagnostic tests for Helicobacter pylori were negative. The clinical stage of the DLBCL was determined as stage ⅢA, and the International Prognostic Index was"high intermediate". She received 6 cycles of R-CHOP therapy, with concomitant use of a proton pump inhibitor. Complete remission was confirmed in November, year X-1. An U-GIE performed again no longer showed the white granular prominences in the gastric fornix. The present report is the first of DLBCL complicated by RBG; our findings suggested that the two diseases were associated with each other.

Ethylenediurea reduces grain chalkiness in hybrid rice cultivars under ambient levels of surface ozone in China.

High concentration of tropospheric ozone (O3) causes crop yield losses, which could be reduced by foliar application of ethylenediurea (EDU). Rice grain appearance is a major quality trait that determines the milling quality, white rice productivity and the market value. Grain chalkiness is one of the common defects that deteriorate the grain appearance in rice due to its negative effects on palatability and milling yield. Whether EDU could reduce grain chalkiness in rice which was usually increased by high concentration of O3 is not clarified. We report the grain chalkiness in 19 rice cultivars (CVs) of three types: indica (6 CVs), japonica (5 CVs) and hybrids (8 CVs), observed in an EDU application experiment in the field in China. The ambient O3 level as expressed by accumulated hourly O3 concentration over the threshold of 40 ppb (AOT40) for 80 days until maturity reached 12.8 ppm h at a near-by monitoring station. Fraction of the chalky grains (FCG) in the hybrid cultivars was 8% lower in EDU than that in the control treatments, whereas no significant effect of EDU on FCG was found in japonica or indica cultivars. The reduction of FCG due to EDU treatment in hybrid cultivars was attributed to the significant reduction of milky white grains followed by that of white belly grains. Thus, the application of EDU could ameliorate the decline of grain appearance quality in hybrid rice by decreasing the FCG and enhancing the fraction of perfect grains (FPG). Moreover, there were significant interactions between the EDU application and rice cultivars, indicating varietal difference in the protection of grain appearance quality by EDU. These results suggest the need for further studies on the mechanisms of the effects of EDU on grain chalkiness.

Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma Associated with Nephrotic Syndrome during Hemodialysis, Treated Successfully with Tirabrutinib.

A 74-year-old woman was diagnosed with Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) in X-18. Fludarabine plus rituximab (FR) was started, and she showed remission. In July X-7, the serum creatinine (Cr) level increased to 1.67 mg/dL, and bendamustine plus rituximab (BR) was started. By November X-7, the Cr level had increased to 8.41 mg/dL, so she was started on hemodialysis (HD). In September X-1, she developed nephrotic syndrome. She was started on tirabrutinib at 480 mg. In July X, her nephrotic syndrome had improved, and a complete response (CR) was achieved. This is the first case of the administration of tirabrutinib in a patient undergoing HD.

Ozone pollution threatens the production of major staple crops in East Asia.

East Asia is a hotspot of surface ozone (O3) pollution, which hinders crop growth and reduces yields. Here, we assess the relative yield loss in rice, wheat and maize due to O3 by combining O3 elevation experiments across Asia and air monitoring at about 3,000 locations in China, Japan and Korea. China shows the highest relative yield loss at 33%, 23% and 9% for wheat, rice and maize, respectively. The relative yield loss is much greater in hybrid than inbred rice, being close to that for wheat. Total O3-induced annual loss of crop production is estimated at US$63 billion. The large impact of O3 on crop production urges us to take mitigation action for O3 emission control and adaptive agronomic measures against the rising surface O3 levels across East Asia.

Ethylenediurea (EDU) protects inbred but not hybrid cultivars of rice from yield losses due to surface ozone.

The rising concentration of ground-level ozone (O3) reduces crop yield via increased oxidative stress. Application of ethylenediurea (EDU) protects plants from O3 and could thereby serve as a means to estimate the crop yield losses due to ambient O3 (AO3). However, no study but a few exceptions has ever compared the yield loss estimates from EDU application with those from O3 elevation experiments. Here, we estimated yield loss to AO3 in rice cultivars across the 3 types, indica, japonica, and hybrid, by an EDU application in the field, and compared the yield losses with those estimated with dose-response relationships based on O3 elevation experiments. Relative yield loss (RYL) in the EDU application was estimated at 16% across the rice types on an assumption of a 100% efficiency for protection of crop yield by EDU. This estimate of RYL was close to the 15% RYL estimated from the O3 elevation experiments when a common sensitivity to O3 is assumed across the cultivars. The rice yield loss due to AO3 was thus consistent between the two approaches supporting the idea of EDU application for the yield loss estimation. When only hybrids are focused, however, the RYL from EDU application (16%) was much lower than the 34% RYL from the O3 elevation experiments, which indicates only a 37% yield protection by EDU in the hybrid rice. The incomplete protection by EDU and its genetic variability indicates the need to quantify the efficiency of protection from AO3-induced yield loss as estimated with O3 manipulating experiments.

Performances of a system for free-air ozone concentration elevation with poplar plantation under increased nitrogen deposition.

The increasing emission of nitrogen oxides exerts large impacts on vegetation by raising surface ozone (O3) concentrations and enhancing atmospheric nitrogen (N) deposition. We established a free-air O3 concentration elevation and enhanced N deposition system (O3-N-FACE) in Beijing, China, to investigate long-term effects of elevated O3 and N deposition on poplar plantation. Eight square plots with a side length of 16 m were randomly allocated to elevated O3 (E-O3) and ambient air (AA) treatments. Ozone generated by electric discharge in pure oxygen is mixed with clean and dry air, and released from small holes on the tubes installed above the plant canopy at a rate controlled to keep O3 concentration in E-O3 plots by 50% higher than that in AA plots. Each O3 treatment plot consisted of four subplots with a factorial combination of 2 lines of poplar clones and 2 levels of N deposition rate. In enhanced N deposition subplots, we sprayed urea solution on the plantation floor at a rate of 60 kg ha-1 year-1. We hereby present the system performances during the growing seasons of 2018 and 2019: the first 2 years of experiment. The mean daytime O3 concentrations of E-O3 plots were 38% and 31% higher than AA plots in 2018 and 2019, respectively. And, in 2019, the accumulated O3 exposure over 40 ppb (AOT40) in E-O3 plots was 70% higher than that in AA plots. The hourly mean O3 concentrations in E-O3 plots were within 20% of the target for 83% of time on average across the four E-O3 plots. Within the E-O3 plots, spatial distribution of the hourly O3 concentration exhibited the maximum deviation at 24% in 2019. We concluded that performance of this system is better than other similar facilities for trees and suitable for a long-term experiment of enhanced O3 and N.

Animal abundance and soil properties affected by long-term organic farming in rice paddies in a typical Japanese yatsuda landscape.

Organic farming was developed to reduce agriculture's negative impacts on the environment and enhance biodiversity for sustainable productivity in agricultural ecosystems, but the long-term effectiveness of its application in Japanese rice paddies is unclear. We sought to understand how long-term organic farming affects the abundance of animals in both the rice growth and fallow seasons, and how soil properties change. We investigated the abundance of fishes, frogs, beetles, and shellfish in the floodwater in summer, and the abundance of earthworms (mainly Enchytraeidae), arthropods (spiders and springtails), and soil properties in aerobic soils in autumn. We examined fields which had been farmed organically for 10 and 18 years in Tochigi, Japan. Fields farmed with conventional management, located close to the selected organic fields, were used as a control. All selected fields were located in a valley, which is the typical landscape of a traditional Japanese farming village, called a yatsuda in Japanese. The results showed an increase in soil organic carbon, total nitrogen, and available phosphorus in plowed soils that had been converted from conventional to organic farming both 10 and 18 years earlier. However, the abundance of various animals were not affected significantly by long-term organic rice farming, other than arthropods in the aerobic soils that had been farmed organically for 18 years. The quantity of most animals in floodwater and fallow season soil was unaffected by long-term organic rice farming in the yatsuda paddy fields, probably due to the circumstances and similar irrigation systems for both conventional and organic rice farming, as well as lighter doses of agrochemical application for conventional rice cultivation.

Metalloelastase-12 is involved in the temporomandibular joint inflammatory response as well as cartilage degradation by aggrecanases in STR/Ort mice.

Temporomandibular joint dysfunction (TMJD) is characterised by clinical symptoms involving both the masticatory muscles and the temporomandibular joint (TMJ). Disc internal derangement and osteoarthritis (OA) are the most common forms of TMJD. Currently, the molecular process associated with degenerative changes in the TMJ is unclear. Our previous study showed that elastin-digested peptides act on human TMJ synovial cells and lead to upregulation of interleukin-6 (IL-6) and metalloelastase-12 (MMP-12; an elastin-degrading enzyme) in vitro. However, there is limited information regarding the involvement of elastin-degradation by MMP-12 in the processes of inflammatory responses and cartilage degradation in vivo. STR/Ort mice were used as a model of TMJ OA in the present study. Significant articular cartilage degeneration was observed starting at 20 weeks of age in the STR/Ort mice and this progressed gradually until 40 weeks, compared with the age-matched CBA mice. Immunostaining analysis showed that MMP-12 and IL-6 were expressed in the chondrocytes in the superficial zones of the cartilage. Immunostaining also showed that aggrecanases [a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5] were expressed in the chondrocytes in the superficial zones of the cartilage. These findings suggest that an inflammatory and degradative process was initiated in the TMJ. Harmful mechanical stimuli, particularly pressure, may cause damage to the elastin fibres in the most elastin-rich superficial layer of the articular cartilage. Elastin-digested peptides are then generated as endogenous warning signals and they initiate a pro-inflammatory cascade. This leads to upregulation of pro-inflammatory mediators, such as IL-6 and MMP-12, which further trigger tissue damage resulting in elevated levels of elastin-digested peptides. IL-6 increases expression of the aggrecanases ADAMTS-4 and ADAMTS-5, following cartilage degradation. This leads to the establishment of a positive feedback loop and may result in chronic inflammation and cartilage degradation of the TMJ in vivo.

Kasumi leukemia cell lines: characterization of tumor genomes with ethnic origin and scales of genomic alterations.

Kasumi-1 has played an important role in an experimental model with t(8;21) translocation, which is a representative example of leukemia cell lines. However, previous studies using Kasumi-1 show discrepancies in the genome profile. The wide use of leukemia cell lines is limited to lines that are well-characterized. The use of additional cell lines extends research to various types of leukemia, and to further explore leukemia pathogenesis, which can be achieved by uncovering the fundamental features of each cell line with accurate data. In this study, ten Kasumi cell lines established in Japan, including five that were previously unknown, have been characterized by SNP microarray and targeted sequencing. SNP genotyping suggested that the genetic ancestry in four of the ten Kasumi cell lines was not classified as Japanese but covered several different east-Asian ethnicities, suggesting that patients in Japan are genetically diverse. TP53 mutations were detected in two cell lines with complex array profiles, indicating chromosomal instability (CIN). A quantitative assessment of tumor genomes at the chromosomal level was newly introduced to reveal total DNA sizes and Scales of Genomic Alterations (SGA) for each cell line. Kasumi-1 and 6 derived from relapsed phases demonstrated high levels of SGA, implying that the level of SGA would reflect on the tumor progression and could serve as an index of CIN. Our results extend the leukemia cellular resources with an additional five cell lines and provide reference genome data with ethnic identities for the ten Kasumi cell lines.

Quantifying determinants of ozone detoxification by apoplastic ascorbate in peach (Prunus persica) leaves using a model of ozone transport and reaction.

Ascorbate in leaf apoplast (ASCapo ) reacts with ozone (O3 ) and thereby reduces O3 flux reaching plasmalemma (Fpl ). Some studies have shown significant protection of cells from O3 by ASCapo , while others have questioned its efficacy. Hypothesizing that the protection by ASCapo depends on other variables, we quantified determinants of O3 detoxification with a model of O3 transport and reaction in apoplast. The model determines ascorbic acid concentration in apoplast (AAapo ) using measured values of O3 concentration (co ), leaf tissue ascorbic acid concentration (AAleaf ), cell wall thickness (L3 ), apoplastic pH (pHapo ), and stomatal conductance (Gsw ). We compared the measured and model-estimated AAapo in leaves of peach (Prunus persica) grown in open-top chambers under non-filtered air (NF) and elevated (EO3 : NF + 80 ppb) O3 concentrations. The estimated AAapo in individual leaves agreed well with the measured values (R2  = .91). Analyses of the simulation results yielded the following findings: (a) The efficacy of O3 reduction with ASCapo as quantified by fractional reduction (ϕ3 ) of O3 flux at the surface of plasmalemma (Fpl ) was lowered from 70% in NF to 40% in EO3 due to the reduction of L3 . The EO3 reduced AAapo , but the lower Gsw and L3 in EO3 increased AAapo resulting in no significant change in AAapo due to EO3 . ϕ3 can be calculated with measured values of AAapo and L3 , and Fpl can be estimated with the measurement-based ϕ3 . (b) When c0 is increased, Fpl increased curvilinearly with the increase of Fst : nominal O3 flux via stomatal diffusion, exhibiting apparent threshold on Fst . The deviation of Fpl from Fst became greater when L3 , pHapo , and AAleaf were increased. The quantification of ϕ3 and Fpl using leaf traits shall facilitate the understanding of the mechanisms of differential plant sensitivity to O3 and improve quantification of the O3 impacts on plants.

Water stress rather than N addition mitigates impacts of elevated O3 on foliar chemical profiles in poplar saplings.

Tropospheric ozone (O3) pollution can alter tree chemical profiles, and in turn, affect forest ecosystem function. However, the magnitude of these effects may be modified by variations in soil water and nutrient availability, which makes it difficult to predict the impacts of O3 in reality. Here we assessed the effects of elevated O3 alone, and in combination with soil water deficit and N addition, on the phytochemical composition of hybrid poplar (Populus deltoides cv. '55/56' × P. deltoides cv. 'Imperial'). Potted trees were grown in open-top chambers (OTCs) under either charcoal-filtered air or elevated O3 (non-filtered air +40 ppb of O3), and trees within each OTC were grown with four combinations of water (well-watered or water deficit) and nitrogen (with or without N addition) levels. We found that elevated O3 alone stimulated the accumulation of foliar nitrogen, soluble sugar, and lignin while inhibiting the accumulation of starch, but had limited impacts on condensed tannins and salicinoids in poplar saplings. Graphical vector analysis revealed that these changes in concentrations of nitrogen, starch and lignin were due largely to altered metabolic processes, while increased soluble sugar concentration related mainly to decreased leaf biomass in most cases. The effects of O3 on poplar foliar chemical profiles depended on soil water, but not soil N, availability. Specifically, O3-mediated changes in carbohydrates and lignin were mitigated by decreased soil water content. Taken together, these results suggested that nitrogen acquisition, carbohydrates mobilization and lignification play a role in poplar tolerance to O3. Moreover, the impacts of elevated O3 on phytochemistry of poplar leaves can be context-dependent, with potential consequences for ecosystem processes under future global change scenarios. Our results highlight the needs to consider multi-factors environments to optimize the management of plantations under changing environments.

Selectively high efficacy of eribulin against high-grade invasive recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have a poor prognosis. Over the past decade, a major development in the first-line treatment of R/M SCCHN was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy. Currently, a promising novel treatment option in R/M SCCHN has emerged, termed immune checkpoint inhibitors. However, only a few patients presenting with R/M SCCHN have exhibited meaningful tumor regression with these agents. Therefore, novel agents are required to order improve the overall survival of patients with R/M SCCHN. Recently, we demonstrated that R/M SCCHN cells are highly sensitive to eribulin. In the present study, the effects of eribulin, paclitaxel and vinblastine were investigated in R/M SCCHN (OLC-01 and OSC-19) and locally advanced SCCHN (OSC-20) cells. Tumour-inhibitory activities of eribulin against R/M SCCHN were evaluated in orthotopic xenograft models. The data revealed that eribulin has sub-nM growth inhibitory activities in vitro against OLC-01 cells, and that it is more potent than paclitaxel and vinblastine. The reduced expression of Tubulin Beta 3 Class III (TUBB3) following treatment was correlated with a high sensitivity to eribulin. Histological analysis of OLC-01 cells in NOD-SCID mice demonstrated that they had a higher invasiveness in the tissue around the alveolar cancer when compared with the histology of OSC-19 cells, which has been reported in our previous study. Treatment with eribulin revealed marked inhibitory activities in vivo at 0.125 mg/kg against OLC-01 cells orthotopic xenografts. In conclusion, the results highlight the existence of invasive-type heterogeneity in R/M SCCHN with respect to eribulin sensitivity. Eribulin is already an approved clinical agent; therefore, the continued investigation of its preclinical antitumor attributes may contribute significantly to the future process of identifying novel uses of eribulin against R/M SCCHN.