Immunology and targeted therapy in Castleman disease.

INTRODUCTION: Castleman disease (CD) is a benign lymphoproliferative disease causing severe systemic inflammation. Interleukin-6 (IL-6) is a major pathogenesis of multicentric CD (MCD), but only 30-60% of patients respond to IL-6 inhibitors. Novel agents for IL-6 inhibitor-refractory cases are needed. Clinical data and samples are being collected on a large scale and the clinical, pathological, and pathogenetic aspects are being elucidated. AREAS COVERED: The pathological and clinical classification of CD is outlined. Focusing on idiopathic MCD (iMCD), this review identifies therapeutic targets and summarizes currently recommended drugs and promising therapeutic candidates. EXPERT OPINION: The pathogenesis of MCD has been implicated in the activation of the Janus kinase (JAK)-transcriptional signaling activator (STAT) 3 pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mechanical target of rapamycin (mTOR) signaling pathway. iMCD-TAFRO (thrombocytopenia, anasarca, fever/elevated CRP, reticulin myelofibrosis/renal dysfunction, organ enlargement) is resistant to IL-6 inhibitors, and cyclosporine and mTOR inhibitors are sometimes effective. JAK inhibitors and mTOR inhibitors may be therapeutic agents for iMCD. Recently, we have shown that peripheral helper T (Tph) cell abnormalities are at the core of iMCD pathogenesis. Therapies targeting chemokine (C-X-C motif) ligand 13 (CXCL13) produced by Tph cells and blocking the Tph-CXCL13-B cell pathway may satisfy unmet need in refractory cases.

TCF1highPD-1+Ly108+CD8+ T Cells Are Associated with Graft Preservation in Sensitized Mice Treated with Non-Fc Receptor-Binding CD3 Antibodies.

The non-Fc-binding anti-CD3 Ab [anti-CD3F(ab')2] can induce graft acceptance depending on the therapeutic window in a rodent heart transplant model. The delayed protocol allows for early graft infiltration of lymphocytes, which may behave in an inhibitory manner. We investigated the most effective protocol for anti-CD3F(ab')2 in sensitized conditions to confirm the evidence for clinical application. C57BL/6 mice were sensitized with BALB/c tail skin grafts and transplanted with BALB/c heart grafts at 8-12 wk after sensitization. Fifty micrograms of anti-CD3F(ab')2 was administered daily for 5 consecutive days on days 1-5 (day 1 protocol) or days 3-7 (delayed protocol). In nonsensitized mice, the delayed protocol significantly prolonged graft survival after transplantation from BALB/c to naive B6 (median survival time [MST], >100 d). In contrast, the delayed protocol was unable to prevent graft rejection in sensitized mice (MST, 5 d). A significantly increased percentage of granzyme B+ CD8+ T cells was observed in the graft on day 3 posttransplantation in sensitized conditions. Further, the day 1 protocol significantly prolonged graft survival (MST, 18 d), even in sensitized conditions. Day 1 treatment significantly increased the percentage of Foxp3+CD25+CD4+ T cells and phenotypically changed CD8+ T cells in the graft (i.e., caused a significant increase in the proportion of Ly108+TCF1highPD-1+CD8+ T cells). In conclusion, different timings of delayed anti-CD3F(ab')2 treatment promoted allograft preservation in association with phenotypic changes in CD4+ and CD8+ T cells in the graft under sensitized conditions.

Wetting Kinetics of Lithium-Sodium Orthoborate on Nickel and Stainless Steel under CO2-Lean and Saturated Conditions.

Contact angle measurements were conducted on lithium-sodium orthoborate, an alkali-metal borate-based high-temperature carbon capture sorbent, in contact with nickel and stainless steel under air, N2, and CO2 atmospheres at 600 °C in order to assess the compatibility of this innovative sorbent with packed-bed reactors, typically used in the commercial carbon capture industry. On nickel, the results reveal the melt to be wetting (contact angle θ ≤ 90°), albeit with a contact angle reaching an apparent equilibrium over the experimental time considered. It was found that θ was lower under N2 than under CO2, which was explained as a consequence of the oxide-ion activity difference between the CO2-lean and saturated melts. On stainless steel, however, the melt rapidly spreads, tending toward complete wetting of the metal sheet (θ = 0°) in all atmospheres. For the two metals investigated, the results indicate high to very high wettability, hence the adequacy of using lithium-sodium orthoborate in conventional gas-liquid contactors, further backing this sorbent as a potential alternative to existing sorbents for CO2 capture.

A retrospective study describing the effective exchange of total blood plasma for disease control in the exacerbation of serpiginous choroiditis.

INTRODUCTION: Serpiginous choroiditis presents with large yellow-white exudative lesions that occur near the optic nerve papillae, that progresses slowly with repeated relapses and cures. Although infection and autoimmunity have been implicated, the cause is unknown. METHODS: A man was diagnosed with serpiginous choroiditis on clinical and other examinations. He started treatment with oral corticosteroids, cyclophosphamide, adalimumab, azathioprine, rituximab, and mycophenolate mofetil. Only the steroids and cyclophosphamide had a therapeutic effect. Plasma exchange was initiated, and the lesions quickly resolved. RESULTS: Disease control has been maintained by plasma exchange and cyclophosphamide during flare-ups in the fall and winter, suggesting that plasma exchange is effective in the treatment of serpiginous choroiditis. CONCLUSION: The reproducible response with each recurrence suggests a strong association between the disease and autoimmunity. Furthermore, that some, as yet unknown, autoantibodies are involved in the pathogenesis of serpiginous choroiditis.

Perturbed collagen metabolism underlies lymphatic recanalization failure in Gata2 heterozygous deficient mice.

Lymphedema has become a global health issue following the growing number of cancer surgeries. Curative or supportive therapeutics have long been awaited for this refractory condition. Transcription factor GATA2 is crucial in lymphatic development and maintenance, as GATA2 haploinsufficient disease often manifests as lymphedema. We recently demonstrated that Gata2 heterozygous deficient mice displayed delayed lymphatic recanalization upon lymph node resection. However, whether GATA2 contributes to lymphatic regeneration by functioning in the damaged lymph vessels' microenvironment remains explored. In this study, our integrated analysis demonstrated that dermal collagen fibers were more densely accumulated in the Gata2 heterozygous deficient mice. The collagen metabolism-related transcriptome was perturbed, and collagen matrix contractile activity was aberrantly increased in Gata2 heterozygous embryonic fibroblasts. Notably, soluble collagen placement ameliorated delayed lymphatic recanalization, presumably by modulating the stiffness of the extracellular matrix around the resection site of Gata2 heterozygous deficient mice. Our results provide valuable insights into mechanisms underlying GATA2-haploinsufficiency-mediated lymphedema and shed light on potential therapeutic avenues for this intractable disease.

Carbonate-Induced Structural Transformation of Lithium-Sodium Orthoborate to a Low-Viscosity Metaborate via CO2 Capture.

This paper reports on the structural changes occurring within the lithium-sodium orthoborate crystal lattice during the solid-state absorption of CO2. Results derived from Fourier transform infrared measurements indicate that the CO2-saturated mixed-alkali metal orthoborate and its CO2-lean metaborate counterpart essentially present the same spectral profile, suggesting that CO2 capture results in a fundamental shift of the orthoborate composition to the metaborate one. The implications of such a structural transformation were examined in the molten state at elevated temperatures through rheological measurements, and although confirming that the CO2-lean metaborate exhibits a higher viscosity than the CO2-lean orthoborate, the results suggest that incorporation of CO2 in the orthoborate ionic lattice dilutes the melt, leading to a remarkable reduction in its overall viscosity, despite causing a structural transformation from the less viscous orthoborate form to the more viscous metaborate one.

Peripheral helper-T-cell-derived CXCL13 is a crucial pathogenic factor in idiopathic multicentric Castleman disease.

Castleman disease (CD) is a rare lymphoproliferative disorder. Among subtypes of CD, idiopathic multicentric CD-not otherwise specified (iMCD-NOS) has a poor prognosis and its pathogenesis is largely unknown. Here we present a xenotransplantation model of iMCD-NOS pathogenesis. Immunodeficient mice, transplanted with lymph node (LN) cells from iMCD-NOS patients, develop iMCD-like lethal inflammation, while mice transplanted with LN cells from non-iMCD patients without inflammation serve as negative control. Grafts depleted of human CD3+ T cells fail to induce inflammation in vivo. Upon engraftment, peripheral helper T (Tph) cells expand and levels of human CXCL13 substantially increase in the sera of mice. A neutralizing antibody against human CXCL13 blocks development of inflammation and improves survival in the recipient mice. Our study thus indicates that Tph cells, producing CXCL13 play a critical role in the pathogenesis of iMCD-NOS, and establishes iMCD-NOS as an immunoregulatory disorder.

Weight Loss Improves Liver Dysfunction and Dipstick Proteinuria in Obesity: The Japan Specific Health Checkups Study.

Introduction: Obesity and inappropriate lifestyle is the major risk factors for liver dysfunction and proteinuria. Nevertheless, previous studies have not described the differential impacts of body weight changes and lifestyle modification on already developed liver dysfunction and proteinuria. Methods: The original cohort was 933,490 individuals from the Japanese general population. In this investigation, we included 36,256 obese individuals with elevated levels of aspartate aminotransferase and/or alanine aminotransferase (≥31 IU/L) or positive proteinuria (+/- or more) in both the first and second years. Outcomes were the first normalization of these data defined as improvement in liver dysfunction and proteinuria. Times to outcomes were assessed using the Cox proportional hazards modeling for -1 kg/m2/year change in body mass index (BMI) changes in exercise and alcohol intake. Results: The multivariable-adjusted hazard ratio (HR) for incident improvement in liver dysfunction with BMI change -1.0 kg/m2/year was 1.07 (95% confidence interval [CI] 1.05-1.09) in obesity and that with improved proteinuria was 1.04 (95%CI 1.02-1.07). Compared to subjects without exercise habits, subjects who gained exercise habits exhibited a higher rate of improvement in liver dysfunction (HR 1.08; 95%CI 1.01-1.15) but not in proteinuria (HR 0.98; 95%CI 0.88-1.08). Compared to subjects with continuous alcohol intake habits, subjects who quit alcohol intake also showed a higher rate of improvement in liver dysfunction (HR 1.20; 95%CI 1.09-1.32). Conclusions: This study suggested that weight loss greater than 1 kg/m2/year improves liver dysfunction and dipstick proteinuria in obesity. Particularly, liver dysfunction can be remedied by acquiring an exercise habit and quitting alcohol intake.

TIM-3 signaling hijacks the canonical Wnt/ß-catenin pathway to maintain cancer stemness in acute myeloid leukemia.

The activation of ß-catenin plays critical roles in normal stem cell function, and, when aberrantly activated, the maintenance and enhancement of cancer stemness in many solid cancers. Aberrant ß-catenin activation is also observed in acute myeloid leukemia (AML), and crucially contributes to self-renewal and propagation of leukemic stem cells (LSCs) regardless of mutations in contrast with such solid tumors. In this study, we showed that the AML-specific autocrine loop comprised of T-cell immunoglobulin mucin-3 (TIM-3) and its ligand, galectin-9 (Gal-9), drives the canonical Wnt pathway to stimulate self-renewal and propagation of LSCs, independent of Wnt ligands. Gal-9 ligation activates the cytoplasmic Src homology 2 domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a Src family kinase highly expressed in LSCs but not in HSCs, and HCK phosphorylates p120-catenin to promote formation of the LDL receptor-related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis is principally active in immature LSCs compared with TIM-3-expressed differentiated AML blasts and exhausted T cells. These data suggest that human AML LSCs constitutively activates ß-catenin via autocrine TIM-3/HCK/p120-catenin signaling, and that molecules related to this signaling axis should be critical targets for selective eradication of LSCs without impairing normal HSCs.

Accuracy verification of dental cone-beam computed tomography of mandibular incisor root canals and assessment of its morphology and aging-related changes.

The root canal morphology undergoes aging-related changes, and relevant quantitative analyses have not yet been reported. We compared the cone beam computed tomography (CBCT) and micro-computed tomography (micro-CT) scans of extracted mandibular incisors to check the accuracy of morphological measurements. Thereafter, the root canal morphology and aging-related changes in the mandibular incisors of Japanese individuals were assessed using CBCT. Six extracted teeth were fixed in a phantom head and imaged using CBCT and micro-CT. The correlation between the findings of the two imaging modalities was examined. Further, CBCT reconstructed images of the mandibular incisors of 81 individuals were observed. Age-related changes of the root canals were compared between participants aged <30 years and those aged ≥30 years. The CBCT and micro-CT findings regarding the root canals of the extracted teeth coincided in 94.4% of the cases. Mandibular incisors exhibiting two root canals in either cross-section accounted for 9.9% of central incisors and 12.4% of lateral incisors. Mandibular central incisors with two root canals were observed in two (6.3%) individuals aged <30 years and six (12.2%) aged ≥30 years. Mandibular lateral incisors with two root canals were observed in one (3.1%) individual aged <30 years and nine (18.4%) aged ≥30 years. CBCT allows accurate evaluation of complex root canal morphologies and is useful for endodontic preoperative assessment. Mandibular incisors have more frequent occurrence of two root canals with aging.

Elevated Crude Mortality in Obese Chronic Kidney Disease Patients with Loss of Exercise Habit: A Cohort Study of the Japanese General Population.

Objective The relationship between obesity and risk of death in chronic kidney disease (CKD) patients remains controversial. In addition, no clear evidence has been accumulated regarding whether or not exercise improves mortality in CKD patients. Methods The original cohort was based on a Japanese general population of 685,889 people from 40 to 74 years old who had undergone annual specific health checkups. The number of all-cause deaths during follow-up (mean, 4.7 years) in this study was 1,490. Information on walking and exercise habits was obtained by questionnaires. The study population was divided into 4 categories by the combination of CKD and obesity [body mass index (BMI) ≥25.0 kg/m2]. Changes in the BMI and walking and exercise habits were determined by results for the first year and following year. Results Obese CKD patients with weight gain (BMI increase by more than +1.0 kg/m2/year) showed a higher crude mortality (1.32%) than those with a stable BMI (within ±1.0 kg/m2/year; 0.69%). In the obese CKD population, mortality was higher with loss of exercise habits (0.96%) than in those continuously maintaining exercise habits (0.52%). The age- and sex-adjusted hazard ratio for all-cause death was 2.23 in the group with weight gain compared to the group with stable weight (p<0.01) and 2.08 in the group with loss of exercise habits compared to those who maintained exercise habits (p<0.01). Conclusion This observational cohort study suggested that loss of exercise habits as well as weight gain of more than 1 kg/m2/year might worsen all-cause mortality in the obese CKD population.

Predictors of impaired antibody response after SARS-CoV-2 mRNA vaccination in hematopoietic cell transplant recipients: A Japanese multicenter observational study.

HCT recipients reportedly have a high mortality rate after developing COVID-19. SARS-CoV-2 vaccination is generally useful to prevent COVID-19. However, its safety and efficacy among HCT recipients remain elusive. This large-scale prospective observational study including 543 HCT recipients with 37-months interval from transplant demonstrated high safety profiles of mRNA vaccine: only 0.9% of patients avoided the second dose due to adverse event or GVHD aggravation following the first dose. Regarding the efficacy, serological response with a clinically relevant titer (≥250 BAU/mL) was obtained in 397 (73.1%) patients. We classified the remaining 146 patients as impaired responders and compared the clinical and immunological parameters between two groups. In allogeneic HCT recipients, multivariable analysis revealed the risk factors for impaired serological response as follows: age (≥60, 1 points), HLA-mismatched donor (1 points), use of systemic steroids (1 points), absolute lymphocyte counts (<1000/µL, 1 points), absolute B-cell counts (<100/µL, 1 points), and serum IgG level (<500 mg/dL, 2 points). Notably, the incidence of impaired serological response increased along with the risk scores: patients with 0, 1-3, and 4-7 points were 3.9%, 21.8%, and 74.6%, respectively. In autologous HCT recipients, a shorter interval from transplant to vaccination was the only risk factor for impaired serological response. Our findings indicate that two doses of SARS-CoV-2 vaccine are safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic.

Risk factors for late cytomegalovirus infection after completing letermovir prophylaxis.

Prophylactic use of letermovir (LMV) markedly reduces the incidence of early clinically significant cytomegalovirus (csCMV) infection within the first 100 days after allogeneic hematopoietic cell transplantation (allo-HCT), which improves transplant outcomes. However, some patients eventually develop late-csCMV infection (beyond day 100) after completing LMV prophylaxis. To assess the incidence of late-csCMV infection as well as its risk factors and impacts on transplant outcome, a total of 81 allo-HCT recipients who had not developed early csCMV infection during LMV prophylaxis were retrospectively analyzed. Among them, 23 (28.4%) patients developed late-csCMV infection (until day 180) at a median time of 131 days after transplantation and 30 days after LMV discontinuation, respectively. Late-csCMV infection was correlated with apparent delayed immune reconstitution: patients transplanted from HLA-mismatched donors (hazard ratio [HR] = 13.0, p = 0.011) or CMV-IgG-negative donors (HR = 2.39, p = 0.043) had a significantly higher risk. In this study, transplant outcomes did not differ between patients with and without late-csCMV infection. This suggests a need to clarify the efficacy of extended administration of LMV for preventing late-csCMV infection in a larger number of allo-HCT recipients, especially those with "high-risk" donors.

A Novel Method for Triggering the Swallowing Reflex in Patients with Amyotrophic Lateral Sclerosis: the Ishizaki Press Method.

This study describes the identification of specific maxillofacial points triggering the swallowing reflex by finger pressure in a patient with severe amyotrophic lateral sclerosis. This method has been named as the "Ishizaki Press Method." The first point was identified in a serendipitous encounter during training sessions to aid communication. This led to the search for such additional points, after obtaining informed consent from the patient and his relatives. Seven effective points were identified: the depressions in front of the left and right tragus (Ting gong points), bilateral points over the parotid and submandibular glands, and a point over the mentum in the midline of the face. The efficacy of these trigger points was noted to be ≥ 70%. The mean time taken for swallowing to occur in response to the stimulation at each of these points was less than 10 s, and the induction of a rapid swallowing reflex was recognized. Alternating left and right stimulations of the Ting gong points and the parotid points triggered the swallowing reflex significantly faster than unilateral stimulations alone. The Ishizaki Press Method may improve the management of dysphagia in patients with amyotrophic lateral sclerosis.

Cone-beam computed tomography observation of maxillary first premolar canal shapes.

A variety of shapes has been reported for the roots and root canals of maxillary first premolars. The purposes of the present study were to determine branching and shapes of the roots of maxillary first premolars, as well as age-related changes using slice images obtained with cone-beam computed tomography (CBCT) for dental use. CBCT-reconstructed images of 125 cases that included maxillary first premolars were used as subjects. Slice images at the cervical one-third, center, and apical one-third positions of the root were prepared. Root branching and number of root canals was determined at each measurement position in the images. The subjects were divided into three groups: younger than 30 years, 30 to 50 years, and over 50 years. The root canal morphology was compared among these age groups. Single-rooted premolars were the most frequent. As for number of root canals, a single-canal premolar was observed at the position of the cervical one-third in 33.6%, at the center in 35.2%, and at the apical one-third in 56.0%. Thereafter the subjects were divided into groups by age, namely, younger than 30 years, 30 to 50 years, and over 50 years old, and it was revealed that the ratio of the two-canal type increased with age. In regard to tooth morphology, it was confirmed that the two-canal type shows more frequent occurrence with aging in maxillary first premolar. Based on our findings, we consider that CBCT can be useful for determining the root canal morphology with complicated shapes.

Portal Annular Pancreas With Common Hepatic Artery Trajectory Abnormality: A Case Report and Review of the Literature.

ABSTRACT: Portal annular pancreas (PAP) is a rare congenital pancreatic anomaly, in which the uncinate process of the pancreas fuses to the body of pancreas behind the portal vein. Here, we report a case of PAP with common hepatic arterial anomaly, which was identified during surgery. A 57-year-old man who had branch type intraductal papillary mucinous neoplasm in the head of the pancreas developed a nodule in the cystic lesion. We planned pylorus preserving pancreaticoduodenectomy. The common hepatic artery from the celiac artery passing behind the portal vein was revealed in preoperative examinations. During surgery, we discovered that the uncinate process of the pancreas was fused with the body of the pancreas behind the portal vein. We divided the pancreas at the anterior and posterior of the portal vein. The main pancreatic duct was present in the anterior pancreatic stump. We performed pancreaticojejunostomy in the anterior stump and closed the posterior stump by interrupted suture. Forty-four surgical cases of PAP have been reported in the English medical literature. There are few previous reports of PAP which involved an arterial anomaly. Clinicians should consider PAP preoperatively to ensure that the surgeon can appropriately plan pancreatic resection to avoid postoperative complications.

Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.