GVHD targets organoid-forming bile duct stem cells in a TGF-ß-dependent manner.

ABSTRACT: Graft-versus-host disease (GVHD) is a major life-threatening complication that occurs after allogeneic hematopoietic cell transplantation (HCT). Although adult tissue stem cells have been identified as targets of GVHD in the skin and gut, their role in hepatic GVHD is yet to be clarified. In the current study, we explored the fate of bile duct stem cells (BDSCs), capable of generating liver organoids in vitro, during hepatic GVHD after allogeneic HCT. We observed a significant expansion of biliary epithelial cells (BECs) on injury early after allogeneic HCT. Organoid-forming efficiency from the bile duct was also significantly increased early after allogeneic HCT. Subsequently, the organoid-forming efficiency from bile ducts was markedly decreased in association with the reduction of BECs and the elevation of plasma concentrations of bilirubin, suggesting that GVHD targets BDSCs and impairs the resilience of BECs. The growth of liver organoids in the presence of liver-infiltrating mononuclear cells from allogeneic recipients, but not from syngeneic recipients, was significantly reduced in a transforming growth factor-ß (TGF-ß)-dependent manner. Administration of SB-431542, an inhibitor of TGF-ß signaling, from day 14 to day 28, protected organoid-forming BDSCs against GVHD and mitigated biliary dysfunction after allogeneic HCT, suggesting that BDSCs are a promising therapeutic target for hepatic GVHD.

Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT.

Calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis is standard in allogeneic hematopoietic stem cell transplantation (HCT) but fails to induce long-term tolerance without chronic GVHD (cGVHD) in a considerable number of patients. In this study, we addressed this long-standing question in mouse models of HCT. After HCT, alloreactive donor T cells rapidly differentiated into PD-1+ TIGIT+ terminally exhausted T cells (terminal Tex). GVHD prophylaxis with cyclosporine (CSP) suppressed donor T-cell expression of TOX, a master regulator to promote differentiation of transitory exhausted T cells (transitory Tex), expressing both inhibitory receptors and effector molecules, into terminal Tex, and inhibited tolerance induction. Adoptive transfer of transitory Tex, but not terminal Tex, into secondary recipients developed cGVHD. Transitory Tex maintained alloreactivity and thus PD-1 blockade restored graft-versus-leukemia (GVL) activity of transitory Tex and not terminal Tex. In conclusion, CSP inhibits tolerance induction by suppressing the terminal exhaustion of donor T cells, while maintaining GVL effects to suppress leukemia relapse.

Features of Duration Mismatch Negativity Around the Onset of Overt Psychotic Disorders: A Longitudinal Study.

Reduced amplitude of duration mismatch negativity (dMMN) has been reported in psychotic disorders and at-risk mental state (ARMS); however, few longitudinal MMN studies have examined the amplitude changes during the course of psychosis. We compared dMMN amplitude between ARMS individuals with later psychosis onset and those without, and we longitudinally examined potential dMMN changes around psychosis onset. Thirty-nine ARMS subjects and 22 healthy controls participated in this study. Of the 39 ARMS subjects, 11 transitioned to psychosis (at-risk mental state with later psychosis onset [ARMS-P]) during follow-up and 28 did not (at-risk mental state without later psychosis onset [ARMS-NP]). dMMN was measured twice using an auditory oddball paradigm with a mean interval of 2 years. Follow-up dMMN data were available for all but four ARMS-P subjects. dMMN amplitude at baseline was smaller in ARMS-P subjects compared with control and ARMS-NP subjects. Additionally, ARMS-P subjects displayed a longitudinal decline in dMMN amplitude, which was not present in control and ARMS-P subjects. We also observed a progressive decline in dMMN amplitude during the transition period, suggesting dynamic brain changes associated with the psychosis onset. Our findings implicate dMMN amplitude as a biological predictor of future psychosis onset in high-risk individuals, which may be used for early detection and intervention of psychosis.

Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease.

Myeloid differentiation factor 88 (MyD88) signaling has a crucial role in activation of both innate and adoptive immunity. MyD88 transduces signals via Toll-like receptor and interleukin-1 receptor superfamily to the NFκB pathway and inflammasome by forming a molecular complex with interleukin-1 receptor-associated kinase 4. The MyD88/interleukin-1 receptor-associated kinase 4 pathway plays an important role, not only in innate immunity, but also T-cell immunity; however, its role in donor T cells on the pathophysiology of graft-versus-host disease (GvHD) remains to be elucidated. We addressed this issue by using MyD88-deficient T cells in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-SCT). While MyD88-deficient and wild-type T cells proliferated equivalently after transplantation, MyD88-deficient T cells demonstrated impaired survival and differentiation toward Th1, Tc1, and Th17, and induced less severe GvHD compared to wild-type T cells. Administration of interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 significantly ameliorated GvHD after allo-SCT. These results thus demonstrate that donor T-cell MyD88/interleukin-1 receptor-associated kinase 4 pathway is a novel therapeutic target against GvHD after allo-SCT.

Hematogones Predict Better Outcome in Allogeneic Hematopoietic Stem Cell Transplantation Irrespective of Graft Sources.

Benign precursors of B lymphocytes, termed hematogones, are observed in the regenerative state of hematopoiesis following chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have demonstrated that expansion of hematogones correlates with better clinical outcomes after allo-HSCT. We retrospectively analyzed the association between hematogones and clinical outcomes in 309 consecutive patients who underwent allo-HSCT, which is the largest population-based cohort reported so far. The incidence of hematogones was significantly higher in complete remission (CR) patients at the time of transplantation than in non-CR patients, after myeloablative conditioning than after reduced-intensity conditioning, with tacrolimus-based graft-versus-host disease (GVHD) prophylaxis than with cyclosporine-based prophylaxis, and with disease other than malignant lymphoma (all P < .05). Patients with hematogones developed less acute GVHD and infections than did those without them (P < .05). Emergence of hematogones was associated with superior GVHD-free relapse-free survival and lower nonrelapse mortality, and was an independent prognostic factor for overall survival, irrespective of donor sources.

The association between the incidence of intestinal graft-vs-host disease and antibiotic use after allogeneic hematopoietic stem cell transplantation.

Intestinal microbiota plays an important role in the regulation of allogeneic immune reaction after allogeneic hematopoietic stem cell transplantation (allo-SCT). Intestinal graft-vs-host disease (GVHD) is one of the major causes of mortality after allo-SCT and often complicated with intestinal dysbiosis. Recent studies suggest that antibiotic-induced dysbiosis is a risk factor for intestinal GVHD. We retrospectively evaluated the impacts of antibiotic use on the incidence of intestinal GVHD occurring before day 100 after allo-SCT. Among 213 patients who underwent allo-SCT, 200 patients achieving engraftment were analyzed. Antibiotics were classified into carbapenem, quinolone, penicillin, cephem, and glycopeptide. Among 128 patients who developed acute GVHD, intestinal GVHD developed in 36 patients. Patients with intestinal GVHD received significantly longer administration of carbapenem and glycopeptide compared to those without it in periengraftment period. In multivariate analysis, use of carbapenem for greater than 7 days was associated with an increased risk of intestinal GVHD. However, use of antibiotics for greater than 7 days was not associated with poor overall survival and high nonrelapse mortality. Long use of carbapenem in periengraftment period may be a risk for intestinal GVHD. Prospective studies are required to validate our findings.

Disseminated toxoplasmosis after hematopoietic stem cell transplantation showing unusual magnetic resonance images.

We herein report a patient who had disseminated toxoplasmosis after hematopoietic stem cell transplantation showing atypical clinical presentation and neuroimaging. Parkinsonism symptoms such as muscle rigidity, bradykinesia, tremor, and postural instability were initial manifestations. Magnetic resonance imaging showed diffuse symmetrical lesions of bilateral basal ganglia lacking ringed enhancement. Post-mortem analysis revealed multiple tachyzoites of Toxoplasma gondii in the basal ganglia, mid brain, cerebellum, and cardiac muscle.

[Clinical impact of addition of bevacizumab to the first-line chemotherapy regimen in the treatment of patients with metastatic colorectal cancer].

BACKGROUND: Combination regimens containing bevacizumab(BV)are regarded as one of the standard first-line chemotherapy (1stCTx) regimens in the treatment of metastatic colorectal cancer (mCRC). However, some patients cannot be treated with BV because of the short interval from the palliative operation or other reasons. We present a study of some patients who were treated with add-on BV in the middle of the 1stCTx before disease progression(referred to as "midway BV" regimen hereafter), and here, we report the efficacy of the midway BV regimen as observed in our patients. RESULTS: We retrospectively analyzed the data of 74 mCRC patients, who were undergoing 1stCTx treatment at our hospital from January 2010 to September 2012. We divided the patients into 3 groups, depending on when BV was introduced in their regimen: 40, 25, and 9 patients were respectively included in the "no-BV" group (patients who were treated without BV in the 1stCTx), BV group(patients treated with BV from the 1st cycle in the 1stCTx), and the midway-BV group (patients who were initially treated without BV and then received add-on BV). The response rates of patients in the no-BV, BV, and midway-BV groups were 27.5%, 44.0%, and 55.6%, respectively. The median progression-free survival (PFS) and median survival time of patients in the no-BV, BV, and midway-BV groups were, respectively, 9.7 months, 9.3 months, and 12.8 months, and 20.3 months, 22.2 months, and N. R. CONCLUSION: Although few cases were analyzed and there might be many confounding factors, our study suggests that midway BV is potentially useful for patients with metastatic colorectal cancer who are not initially treated with BV in the first cycle of the 1stCTx regimen.

Resting-state electroencephalogram in drug-free subjects with at-risk mental states who later developed psychosis: a low-resolution electromagnetic tomography analysis.

Background and objectives: Several studies have reported on the resting-state electroencephalogram (EEG) power in patients with schizophrenia, with a decrease in α (especially α2) and an increase in δ and ß1 power compared with healthy control; however, reports on at-risk mental states (ARMS) are few. In this study, we measured the resting-state EEG power in ARMS, and investigated its features and the relationship between the power of the frequency bands and their diagnostic outcomes. Methods: Patients with ARMS who were not on any psychotropic medication and met the Comprehensive Assessment of At-Risk Mental State criteria were included. Patients who developed psychotic disorders were labeled as the ARMS-P group, while patients with ARMS who were followed up prospectively for more than 2 years and did not develop psychotic disorders were classified as the ARMS-NP group. EEGs were measured in the resting state, and frequencies were analyzed using standardized low-resolution brain electromagnetic tomography (sLORETA). Seven bands (δ, θ, α1, α2, ß1-3) underwent analysis. The sLORETA values (current source density [CSD]) were compared between the ARMS-P and ARMS-NP groups. Clinical symptoms were assessed at the time of EEG measurements using the Positive and Negative Syndrome Scale (PANSS). Results: Of the 39 patients included (25 males, 14 females, 18.8 ± 4.5 years old), eight developed psychotic disorders (ARMS-P). The ARMS-P group exhibited significantly higher CSD in the ß1 power within areas of the left middle frontal gyrus (MFG) compared with the ARMS-NP group (best match: X = -35, Y = 25, Z = 50 [MNI coordinates], Area 8, CSD = 2.33, p < 0.05). There was a significant positive correlation between the ß1/α ratio of the CSD at left MFG and the Somatic concern score measured by the PANSS. Discussion: Increased ß1 power was observed in the resting EEG before the onset of psychosis and correlated with a symptom. This suggests that resting EEG power may be a useful marker for predicting future conversion to psychosis and clinical symptoms in patients with ARMS.

[Successful treatment of an HIV-positive multiple myeloma patient with high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation and maintenance therapy with lenalidomide].

A 45-year-old HIV positive male who had previously been administered anti-retrovirus therapy (ART) resulting in a good virological response and with a CD4 count of more than 1,000/µl, complained of general fatigue during a periodic examination. Laboratory data showed decreased Hb (10.8 g/dl) and increased T.P (12.0 g/dl) and IgG (9,077 mg/dl). Monoclonal gammopathy (IgG-λ) was identified and bone marrow aspiration revealed 37.6% atypical plasma cells, leading to the diagnosis of symptomatic multiple myeloma (MM) (ISS clinical staging III).Four courses of VD (bortezomib+dexamethasone) therapy were administered with concurrent ART resulting in VGPR (very good partial response), followed by peripheral blood stem cell collection (the mobilizing chemotherapy was cyclophosphamide). Then, together with ART, high-dose chemotherapy (Mel-200; L-PAM) was administered with autologous peripheral blood stem cell transplantation (PBSCT). Reconstitution of white blood cells was achieved at 10 days after PBSCT. There were no adverse effects of ART and the viral load of HIV was well controlled during the period of these treatments. The final assessment was VGPR and 10 mg/day of lenalidomide has since been administered as maintenance therapy. Standard treatment combined with PBSCT for juvenile-onset MM is also effective and safe for HIV-positive patients receiving ART.

Convulsive Seizure Due to Hypomagnesemia Caused by Short-term Vonoprazan Intake.

A 71-year-old woman was admitted for the treatment of diffuse large B-cell lymphoma of the ileum. She had been taking lansoprazole but was switched to vonoprazan due to epigastric discomfort. Three weeks after starting vonoprazan intake, she had a convulsive seizure, and a blood test showed hypomagnesiemia. The cause of hypomagnesemia was considered to be malabsorption of magnesium from the intestinal tract associated with vonoprazan. After discontinuation of vonoprazan, the magnesium level quickly recovered, and the seizures did not relapse. It is important to consider the risk of hypomagnesemia in patients taking vonoprazan, even for a short period of time.

Patients with marginal zone dural lymphoma successfully treated with rituximab and bendamustine: A report of two cases.

Primary dural low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a rare disease whose main treatment has been local surgery or radiotherapy. Until now, there have been no cases of dural MALT lymphoma treatment of a patient with several relapses or systemic disease. The present study included two patients with dural MALT lymphoma who had several relapses or systemic disease. Since local therapy was not enough to control the disease for these patients, they were treated with systemic chemotherapy. The patients were administered rituximab (375 mg/m2) and two days of bendamustine (90 mg/m2). Both patients recovered from their clinical symptoms immediately, and their tumors were reduced. During and after rituximab and bendamustine therapy, no central nervous system (CNS) metastasis or cerebrospinal fluid invasion of MALT were observed. The current approach using rituximab and bendamustine treatment was effective against dural MALT lymphoma and may prevent its invasion of the CNS.

Prolonged P300 Latency in Antipsychotic-Free Subjects with At-Risk Mental States Who Later Developed Schizophrenia.

We measured P300, an event-related potential, in subjects with at-risk mental states (ARMS) and aimed to determine whether P300 parameter can predict progression to overt schizophrenia. Thirty-three subjects with ARMS, 39 with schizophrenia, and 28 healthy controls participated in the study. All subjects were antipsychotic-free. Subjects with ARMS were followed-up for more than two years. Cognitive function was measured by the Brief assessment of Cognition in Schizophrenia (BACS) and Schizophrenia Cognition Rating Scale (SCoRS), while the modified Global Assessment of Functioning (mGAF) was used to assess global function. Patients with schizophrenia showed smaller P300 amplitudes and prolonged latency at Pz compared to those of healthy controls and subjects with ARMS. During the follow-up period, eight out of 33 subjects with ARMS developed overt psychosis (ARMS-P) while 25 did not (ARMS-NP). P300 latency of ARMS-P was significantly longer than that of ARMS-NP. At baseline, ARMS-P elicited worse cognitive functions, as measured by the BACS and SCoRS compared to ARMS-NP. We also detected a significant relationship between P300 amplitudes and mGAF scores in ARMS subjects. Our results suggest the usefulness of prolonged P300 latency and cognitive impairment as a predictive marker of later development of schizophrenia in vulnerable individuals.

Duration Mismatch Negativity Predicts Remission in First-Episode Schizophrenia Patients.

Objective: Remission in schizophrenia patients is associated with neurocognitive, social, and role functioning during both the early and chronic stages of schizophrenia. It is well-established that the amplitudes of duration mismatch negativity (dMMN) and frequency MMN (fMMN) are reduced in schizophrenia patients. However, the potential link between MMN and remission has not been established. In this study, we investigated the relationship between MMNs and remission in first-episode schizophrenia (FES) and their association with neurocognitive and social functioning. Method: dMMN and fMMN were measured in 30 patients with FES and 22 healthy controls at baseline and after a mean of 3 years. Clinical symptoms and cognitive and social functioning in the patients were assessed at the time of MMN measurements by using the Positive and Negative Syndrome Scale (PANSS), modified Global Assessment of Functioning (mGAF), Schizophrenia Cognition Rating Scale (SCoRS), and the Brief Assessment of Cognition in Schizophrenia (BACS). Remission of the patients was defined using the criteria by the Remission in Schizophrenia Working Group; of the 30 patients with FES, 14 achieved remission and 16 did not. Results: Baseline dMMN amplitude was reduced in FES compared to healthy controls. Further, baseline dMMN in the non-remitters had decreased amplitude and prolonged latency compared to the remitters. MMN did not change during follow-up period regardless of parameters, diagnosis, or remission status. Baseline dMMN amplitude in FES was correlated with future SCoRS and PANSS total scores. Logistic regression analysis revealed that dMMN amplitude at baseline was a significant predictor of remission. Conclusions: Our findings suggest that dMMN amplitude may be a useful biomarker for predicting symptomatic remission and improvement of cognitive and social functions in FES.

FTY720 Attenuates Neuropathic Pain after Spinal Cord Injury by Decreasing Systemic and Local Inflammation in a Rat Spinal Cord Compression Model.

Neuropathic pain severely impairs rehabilitation and quality of life after spinal cord injury (SCI). The sphingosine-1-phosphate receptor agonist, FTY720, plays an important protective role in neuronal injury. This study aims to examine the effects of FTY720 in a rat acute SCI model, focusing on neuropathic pain. Female rats with SCI induced by 1-min clip compression were administered vehicle or 1.5 mg/kg of FTY720 24 h after the injury. Using the mechanical nociceptive threshold test, we monitored neuropathic pain and performed histological analysis of the pain pathway, including the µ opioid receptor (MOR), hydroxytryptamine transporter (HTT), and calcitonin gene-related peptide (CGRP). Motor score, SCI lesion volume, residual motor axons, inflammatory response, glial scar, and microvascular endothelial dysfunction were also compared between the two groups. FTY720 treatment resulted in significant attenuation of post-traumatic neuropathic pain. It also decreased systemic and local inflammation, thereby reducing the damaged areas and astrogliosis and resulting in motor functional recovery. Whereas there was no difference in the CGRP expression between the two groups, FTY720 significantly preserved the MOR in both the caudal and rostral areas of the spinal dorsal horn. Whereas HTT was preserved in the FTY720 group, it was significantly increased in the rostral side and decreased in the caudal side of the injury in the vehicle group. These results suggest that FTY720 ameliorates post-traumatic allodynia through regulation of neuroinflammation, maintenance of the blood-brain barrier, and inhibition of glial scar formation, thereby preserving the connectivity of the descending inhibitory pathway and reducing neuropathic pain.

Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis.

Posttransplant high-dose cyclophosphamide (PTCY) has been increasingly used as graft-versus-host disease (GVHD) prophylaxis after HLA-haploidentical or matched hematopoietic stem cell transplantation (SCT). However, PTCY alone is insufficient and requires additional immunosuppressants such as calcineurin inhibitors. In the current study, we evaluated effects of a novel GVHD prophylaxis with PTCY in combination with short-term KRP203, a selective agonist of sphingosine-1-phosphate receptor 1 that regulates egress of lymphocytes from the secondary lymphoid organs (SLOs) in mice. Short-term oral administration of KRP203 alone induced apoptosis of donor T cells in the SLOs and ameliorated GVHD. Administration of KRP203 significantly preserved graft-versus-leukemia effects compared to cyclosporin. A combination of KRP203 on days 0 to +4 and PTCY on day +3 synergistically suppressed donor T-cell migration into the intestine and skin, and ameliorated GVHD more potently than PTCY alone. A combination of short-term KRP203 and PTCY is a promising novel calcineurin-free GVHD prophylaxis in HLA-haploidentical SCT.

Association between olfactory sulcus morphology and olfactory functioning in schizophrenia and psychosis high-risk status.

Olfactory impairment has been reported in patients with schizophrenia and individuals with a high risk of psychosis, but its neural basis is largely unknown. We used magnetic resonance imaging to investigate the morphology of the olfactory sulcus (an indicator of olfactory system development) and its relation to olfactory function in 38 persons with an at-risk mental state (ARMS), 62 patients with schizophrenia, and 61 healthy controls. Odor detection and identification were examined with a T & T olfactometer. Compared with the controls, the olfactory sulcus was significantly shallower and odor identification was inferior among the ARMS and schizophrenia subjects. Across all subjects, but not within each group, the olfactory sulcus depth was significantly related to better identification of odors. Our results support the concept that olfactory sulcus morphology reflects the neurodevelopmental process of the olfactory system.

Intestinal Lymphatic Endothelial Cells Produce R-Spondin3.

The R-Spondin (R-Spo) family regulates WNT signaling and stimulates the proliferation and differentiation of intestinal stem cells (ISCs). R-Spo plays a critical role in maintaining intestinal homeostasis, but endogenous producers of R-Spo in the intestine remain to be investigated. We found that R-Spo3 was the major R-Spo family member produced in the intestine and it was predominantly produced by CD45-CD90+CD31+ lymphatic endothelial cells (LECs) in the lamina propria of the intestinal mucosa. Transcriptome analysis demonstrated that LECs highly expressed R-Spo receptor, Lgr5, suggesting an autocrine stimulatory loop in LECs. LECs were significantly reduced in number, and their R-Spo3 production was impaired in intestinal graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. The impaired production of R-Spo3 in the intestine may be a novel mechanism of delayed tissue repair and defective mucosal defense in intestinal GVHD. We demonstrate a novel role of intestinal LECs in producing R-Spondin3 to maintain intestinal homeostasis.

Self-assembly of concentric quantum double rings.

We demonstrate the self-assembled formation of concentric quantum double rings with high uniformity and excellent rotational symmetry using the droplet epitaxy technique. Varying the growth process conditions can control each ring's size. Photoluminescence spectra emitted from an individual quantum ring complex show peculiar quantized levels that are specified by the carriers' orbital trajectories.