Development of TCR-T cell therapy targeting mismatched HLA-DPB1 for relapsed leukemia after allogeneic transplantation.

Relapsed leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a significant challenge, with the re-emergence of the primary disease being the most frequent cause of death. Human leukocyte antigen (HLA)-DPB1 mismatch occurs in approximately 70% of unrelated allo-HSCT cases, and targeting mismatched HLA-DPB1 is considered reasonable for treating relapsed leukemia following allo-HSCT if performed under proper conditions. In this study, we established several clones restricted to HLA-DPB1*02:01, -DPB1*04:02, and -DPB1*09:01 from three patients who underwent HLA-DPB1 mismatched allo-HSCT using donor-derived alloreactive T cells primed to mismatched HLA-DPB1 in the recipient's body after transplantation. A detailed analysis of the DPB1*09:01-restricted clone 2A9 showed reactivity against various leukemia cell lines and primary myeloid leukemia blasts, even with low HLA-DP expression. T cell receptor (TCR)-T cells derived from clone 2A9 retained the ability to trigger HLA-DPB1*09:01-restricted recognition and lysis of various leukemia cell lines in vitro. Our study demonstrated that the induction of mismatched HLA-DPB1 specific T cell clones from physiologically primed post-allo-HSCT alloreactive CD4+ T cells and the redirection of T cells with cloned TCR cDNA by gene transfer are feasible as techniques for future adoptive immunotherapy.

Autologous peripheral blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia is safe but poses challenges for long-term maintenance of molecular remission: Results of the Auto-Ph17 study.

Autologous hematopoietic stem cell transplantation (SCT) is not a standard treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL); however, its position has been reassessed since the introduction of tyrosine kinase inhibitors (TKIs). We prospectively analyzed the efficacy and safety of autologous peripheral blood SCT (auto-PBSCT) for Ph+ALL patients aged between 55 and 70 years who had achieved complete molecular remission. Melphalan, cyclophosphamide, etoposide, and dexamethasone were used for conditioning. A total of 12 courses of maintenance therapy, including dasatinib, were performed. The required number of CD34+ cells was harvested in all five patients. No patient died within 100 days after auto-PBSCT, and no unexpected serious adverse events were observed. Although 1-year event-free survival was 100%, hematological relapse was observed in three patients at a median of 801 days (range, 389-1088 days) after auto-PBSCT. Molecular progressive disease was observed in the other two patients, although they maintained their first hematological remission at the last visit. Auto-PBSCT can be safely performed for Ph+ALL with TKIs. A limitation of auto-PBSCT was suggested, despite the increase in the intensity of a single treatment. The development of long-term therapeutic strategies by including new molecular targeted drugs is warranted to maintain long-term molecular remission.

Collective bending motion of a two-dimensionally correlated bowl-stacked columnar liquid crystalline assembly under a shear force.

Stacked teacups inspired the idea that columnar assemblies of stacked bowl-shaped molecules may exhibit a unique dynamic behavior, unlike usual assemblies of planar disc- and rod-shaped molecules. On the basis of the molecular design concept for creating higher-order discotic liquid crystals, found in our group, we synthesized a sumanene derivative with octyloxycarbonyl side chains. This molecule forms an ordered hexagonal columnar mesophase, but unexpectedly, the columnar assembly is very soft, similar to sugar syrup. It displays, upon application of a shear force on solid substrates, a flexible bending motion with continuous angle variations of bowl-stacked columns while preserving the two-dimensional hexagonal order. In general, alignment control of higher-order liquid crystals is difficult to achieve due to their high viscosity. The present system that brings together higher structural order and mechanical softness will spark interest in bowl-shaped molecules as a component for developing higher-order liquid crystals with unique mechanical and stimuli-responsive properties.

A case of traumatic intrapleural foreign body with progressive supranuclear palsy removed by thoracoscopic surgery.

Traumatic intrathoracic foreign bodies are said to occur in many cases when the patient himself/herself is aware of the trauma. However, at the time of injury, the patient may sometimes be accompanied by loss of consciousness. We report a case of traumatic intrathoracic foreign body that was difficult to diagnose due to loss of consciousness at the time of injury. A 51-year-old female was brought to our emergency department with a fall trauma due to loss of consciousness while bathing. The head computed tomography and electrocardiogram showed no abnormalities, and the laceration of approximately 3 cm in length was found on the left side thorax, and it was sutured and the patient was sent home. Four days later, she returned to our hospital with a complaint of left anterior chest pain, and chest X-ray showed a left degree pneumothorax and mediastinal emphysema. She underwent semi-emergency thoracoscopic removal of the foreign body, and was discharged from the hospital on the fourth postoperative day. She had progressive supranuclear palsy, and her memory at the time of injury was not clear due to loss of consciousness caused by central autonomic neuropathy, and she also had dementia, making it difficult to interview her. She had no thoracic symptoms, and the glass fragment that had strayed into the thoracic cavity was not exposed outside the body, making the diagnosis difficult at the time of initial examination. When a patient with loss of consciousness is difficult to interview at the time of injury, it is advisable to perform an imaging examination appropriate for the site of injury, taking into consideration the presence of foreign bodies.

Characterizing Small-Scale Dynamics of Navier-Stokes Turbulence with Transverse Lyapunov Exponents: A Data Assimilation Approach.

Data assimilation (DA) of turbulence, which involves reconstructing small-scale turbulent structures based on observational data from large-scale ones, is crucial not only for practical forecasting but also for gaining a deeper understanding of turbulent dynamics. We propose a theoretical framework for DA of turbulence based on the transverse Lyapunov exponents (TLEs) in synchronization theory. Through stability analysis using TLEs, we identify a critical length scale as a key condition for DA; turbulent dynamics smaller than this scale are synchronized with larger-scale turbulent dynamics. Furthermore, considering recent findings for the maximal Lyapunov exponent and its relation with the TLEs, we clarify the Reynolds number dependence of the critical length scale.

Design of discotic liquid crystal enabling complete switching along with memory of homeotropic and homogeneous alignment over a large area.

The alignment control of discotic columnar liquid crystals (LCs), featuring a low motility of the constituent molecules and thus having a large viscosity, is a challenging task. Here we show that triphenylene hexacarboxylic ester, when functionalized with hybrid side chains consisting of alkyl and perfluoroalkyl groups in an appropriate ratio, gives a hexagonal columnar (Colh) LC capable of selectively forming large-area uniform homeotropic or homogeneous alignments, upon cooling from its isotropic melt or upon application of a shear force at its LC temperature, respectively. In addition to the alignment switching ability, each alignment state remains persistent unless the LC is heated to its melting temperature. In situ X-ray diffraction analysis under the application of a shear force, together with polarized optical microscopy observations, revealed how the columnar assembly is changed during the alignment-switching process. The remarkable behavior of the discotic LC is discussed in terms of its rheological properties.

A pitfall in hemoglobin A1c measurement with high performance liquid chromatography method in the diagnosis of onset of fulminant type 1 diabetes mellitus.

We showed a case with the onset of fulminant type 1 diabetes mellitus (FT1DM) whose HbA1c could not be measured with HPLC method. We think that the reason why his HbA1c was not be detected was associated with the presence of labile hemoglobin A1c (LHbA1c). These result mean that it is possible that LHbA1c can bring about a pitfall on HPLC method in diagnosis of onset of FT1DM.

Dynamical system analysis of a data-driven model constructed by reservoir computing.

This study evaluates data-driven models from a dynamical system perspective, such as unstable fixed points, periodic orbits, chaotic saddle, Lyapunov exponents, manifold structures, and statistical values. We find that these dynamical characteristics can be reconstructed much more precisely by a data-driven model than by computing directly from training data. With this idea, we predict the laminar lasting time distribution of a particular macroscopic variable of chaotic fluid flow, which cannot be calculated from a direct numerical simulation of the Navier-Stokes equation because of its high computational cost.

Single response assessment of transplant-ineligible multiple myeloma: a supplementary analysis of JCOG1105 (JCOG1105S1).

BACKGROUND: The International Myeloma Working Group response criteria require two consecutive assessments of paraprotein levels. We conducted an exploratory analysis to evaluate whether a single response assessment could be a substitute for the International Myeloma Working Group criteria using data from JCOG1105, a randomized phase II study on melphalan, prednisolone and bortezomib. METHODS: Of 91 patients with transplant-ineligible newly diagnosed multiple myeloma, 79 patients were included. We calculated the kappa coefficient to evaluate the degree of agreement between the International Myeloma Working Group criteria and the single response assessment. RESULTS: Based on the International Myeloma Working Group criteria, 11 (13.9%), 20 (25.3%), 36 (45.6%) and 12 (15.2%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. Based on the single response assessment, 17 (21.5%), 19 (24.1%), 35 (44.3%) and 8 (10.1%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. The kappa coefficient was 0.76 (95% confidence interval, 0.65-0.88), demonstrating good agreement. The single response assessment was not inferior to the International Myeloma Working Group criteria in the median progression-free survival (3.8 and 2.9 years) in stringent complete response/complete response patients, suggesting that the single response assessment was not an overestimation. CONCLUSIONS: The single response assessment could be a substitute for the current International Myeloma Working Group criteria for transplant-ineligible newly diagnosed multiple myeloma.

Effect of levocarnitine administration in patients with chronic liver disease.

L-carnitine administration was reported to improve sarcopenia in patients with cirrhosis. However, the amount of evidence from previous studies is not sufficient. The present study aimed to clarify the effect of levocarnitine (L-carnitine) administration on body composition in patients with chronic liver disease (CLD). In the present study, 85 patients with L-carnitine administration and 87 control patients were enrolled and divided them into two groups, the L-carnitine administration group (LAG, n=44) and the without L-carnitine administration (controls, n=44) group, by using propensity score matching for age, sex, body mass index (BMI) and serum albumin. Δ skeletal muscle mass index (SMI)/year, Δ intramuscular adipose tissue content (IMAC)/year and Δ bone mineral density (BMD)/year were examined during L-carnitine administration. Each parameter was measured by computed tomography (CT) or dual-energy X-ray absorptiometry. The median age overall was 69 years (IQR, 64.0, 75.0); 36 were men and 52 were women. The median SMI was 37.4 cm2/m2 (IQR, 34.01, 44.34). The initial CT scans showed similar median values of SMI for the two groups [37.74 (34.17, 43.58) and 37.16 (33.83, 44.34), P=0.67]. However, the median ΔSMI/year for the LAG and controls were 0.95% (-3.07, 6.10) and -2.34% (-5.34, 0.53), respectively (P=0.003). The median Δ whole body BMD/year for the LAG and controls were -0.24% (-1.20, 0.91) and -1.04% (-2.16, 0.47), respectively (P=0.038). The median ΔIMAC/year and Δ lumbar spine BMD were not significantly different between the LAG and controls. L-carnitine administration may prevent the loss of skeletal muscle mass and BMD; therefore, it may be used as a new treatment option for osteoporosis and sarcopenia in patients with CLD.

Barriers to inpatient palliative care consultation among patients with newly diagnosed cancer after emergency admission.

BACKGROUND: Many patients with advanced cancer diagnosed following emergency presentation will likely benefit from palliative care (PC) interventions. This study assessed the potential patient-related barriers to inpatient PC consultation among patients who were newly diagnosed with cancer after emergency admission (EA) and received only supportive care. METHODS: This observational study retrospectively obtained data on all patients who were admitted to our hospital after emergency transfer between January 2012 and November 2016. We identified patients for whom cancer was listed as the primary disease in the post-hospitalization discharge summary. Out of these patients, we selected those with newly diagnosed cancer and determined whether they were referred for inpatient PC consultation. RESULTS: This study recruited 141 patients with newly diagnosed cancer after EA (1.2% of all emergency transfer cases). Following diagnosis, the PC team intervened in 29.8% of all the patients enrolled in this study and in 53.3% of patients who received only supportive care. In patients who received only supportive care, the patients who were not referred for PC consultation were significantly more likely to have shorter survival time and less likely to receive disclosure about their cancer diagnosis than patients who were referred. CONCLUSIONS: According to this study, short survival time and no disclosure of cancer diagnosis are potential patient-related barriers to inpatient PC consultation among patients with newly diagnosed cancer after EA.

Allogeneic hematopoietic stem cell transplantation at the first remission for younger adults with FLT3-internal tandem duplication AML: The JALSG AML209-FLT3-SCT study.

In this phase II multicenter study (JALSG AML209-FLT3-SCT), we aimed to prospectively elucidate the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) for FLT3-internal tandem duplication (ITD)-positive AML. Newly diagnosed de novo AML patients with FLT3-ITD were enrolled at the achievement of CR1 and received allo-HSCT as soon as possible after the first consolidation therapy. Mutations of 57 genes in AML cells at diagnosis were also analyzed. Among 48 eligible patients with a median age of 38.5 (17-49) years, 36 (75%) received allo-HSCT at a median of 108 days after CR1. The median follow-up was 1726 days. The primary end-point, 3-year disease-free survival (DFS) based on an intent to treat analysis, was 43.8% (95% confidence interval [CI], 30%-57%), suggesting the efficacy of this treatment because the lower limit of the 95% CI exceeded the threshold response rate of 20%. The 3-year overall survival, post-transplant DFS, and non-relapse mortality rates were 54.2% (95% CI, 39%-67%), 58.3% (95% CI, 41%-72%), and 25.0% (95% CI, 12%-40%), respectively. The median ITD allelic ratio (AR) was 0.344 (0.006-4.099). Neither FLT3-ITD AR nor cooccurring genetic alterations was associated with a poor DFS. This prospective study indicated the efficacy and safety of allo-HSCT for FLT3-ITD AML patients in CR1. This study was registered at: www.umin.ac.jp/ctr/ as #UMIN000003433.

Relationship between pre-sarcopenia and quality of life in patients with chronic liver disease: a cross-sectional study.

AIM: This study aimed to clarify the relationship between pre-sarcopenia (PS) and quality of life (QOL) in patients with chronic liver disease (CLD). PATIENTS AND METHODS: This cross-sectional study evaluated 335 patients with CLD. PS was diagnosed on the basis of the assessment criteria by the Japan Society of Hepatology. QOL was evaluated using the short form-36. RESULTS: Patients' mean age was 69.52 ± 10.17 years, and 169 (50.4%) participants were men. The prevalence of PS was 53.7%. Patients were divided into the PS and non-pre-sarcopenia (NPS) groups. Patients in the PS group were older (71.84 ± 9.78 vs. 66.81 ± 9.97, P < 0.01) and mostly women (65.2 vs. 37.8%, P < 0.01) compared with those in the NPS group. QOL, physical function (38.30 ± 17.63 vs. 44.02 ± 14.76, P < 0.01), physical role functioning (RP) (40.63 ± 15.38 vs. 44.88 ± 13.89, P < 0.01), and bodily pain (BP) (48.42 ± 11.45 vs. 51.24 ± 10.19, P = 0.02) were significantly lower in the PS group than in the NPS group. Logistic regression analyses identified that the independent predictive factors for PS were female sex (odds ratio: 3.16, 95% confidence interval: 2.01-4.98; P < 0.01) and RP (odds ratio: 1.97, 95% confidence interval: 1.24-3.12; P < 0.01). CONCLUSION: QOL characteristics of PS patients with CLD were low physical function, RP, and BP in short form-36. In addition, social role functioning was low in the PS patients aged 65-74 years, whereas RP and BP were low in those aged at least 75 years. Female sex and RP were independent predictors of PS according to the multivariate analysis. Maintaining and increasing muscle mass in patients with CLD may contribute toward improving physical QOL.

A multicenter phase I study of inebilizumab, a humanized anti-CD19 monoclonal antibody, in Japanese patients with relapsed or refractory B-cell lymphoma and multiple myeloma.

This multicenter, phase I, open-label dose escalation study evaluated safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of inebilizumab in Japanese patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), or multiple myeloma (MM) who were ineligible for hematopoietic stem cell transplantation. Patients received inebilizumab 2, 4, or 8 mg/kg intravenously on days 1 and 8 of the first 28-day cycle, and once every 28 days thereafter, with a 12 mg/kg cohort added. Twenty patients (11 FL, six DLBCL, two CLL, and one MM) received inebilizumab at four dose levels (2 mg/kg cohort, n = 3; 4 mg/kg cohort, n = 7; 8 mg/kg cohort, n = 4; 12 mg/kg cohort, n = 6). Three patients experienced dose-limiting toxicities: grade 4 neutropenia/grade 3 leukopenia (n = 1, 12 mg/kg) and grade 3 infusion reaction (n = 1 each, 4 mg/kg and 12 mg/kg); the maximum tolerated dose was 8 mg/kg. Four (three FL and one DLBCL) patients achieved complete response; eight (six FL and two DLBCL) achieved partial response. Overall response rate was 60%. Over the dose ranges evaluated, the pharmacokinetic profile of inebilizumab in Japanese patients was generally dose proportional. This phase I study showed acceptable toxicity and preliminary and promising efficacy of inebilizumab in patients with relapsed/refractory FL and DLBCL.

Long-Term Effect of Promoting In-Hospital Physical Activity on Postdischarge Patients with Mild Ischemic Stroke.

BACKGROUND: Although there are reports on the promotion of physical activity during hospitalization, there is no evidence that promoting in-hospital physical activity continues over time after discharge. The purpose of this study was to evaluate the long-term effect of promoting in-hospital physical activity on postdischarge physical activity and self-efficacy for physical activity in patients with mild ischemic stroke. METHODS: This was a cross-sectional study of a post hoc analysis of a previous randomized controlled trial. Patients with mild ischemic stroke were divided into the intervention group (in which physical activity was promoted during hospitalization) and a control group. To promote in-hospital physical activity, patients in the intervention group were instructed in the self-monitoring approach. After discharge, we measured physical activity and self-efficacy for physical activity by mailing a questionnaire to the patients. The average number of steps taken was used the index of postdischarge physical activity. RESULTS: The study sample comprised 30 patients, with 13 patients in the intervention group and 17 patients in the control group. There were no significant differences in physical activity values (6176.8 versus 6112.8 steps/day, P = .932) and self-efficacy for physical activity score (66.0 versus 76.0 points, P = .801) between the 2 groups. CONCLUSIONS: This study showed that the promotion of in-hospital physical activity did not appear to increase physical activity and self-efficacy for physical activity in patients with mild ischemic stroke after discharge. Additional study is needed to establish a more specific approach to promote physical activity during hospitalization that will carry over during long-term follow-up.

Physical Activity, Physical Function, and Quadriceps Muscle Thickness in Male Patients with Sub-Acute Stroke during Hospitalization: A Pilot Study.

Increasing physical activity (PA) is an important rehabilitation target for patients with sub-acute stroke during hospitalization in order to recover physical function and prevent stroke recurrence. However, the characteristics of low PA in stroke patients during hospitalization who were targets for increased intervention have not been reported. The purpose of this study was to investigate the relationship between the daily number of steps and physical function and quadriceps muscle thickness (QMT) in patients with sub-acute stroke during hospitalization for convalescence rehabilitation. Twenty-nine patients with ischemic or haemorrhagic stroke (mean age, 69 ± 11 years) hospitalized for inpatient convalescent rehabilitation were included. PA was measured using a three-dimensional accelerometer that calculates the daily number of steps taken. Physical function was measured by a short physical performance battery (SPPB; 0-12 points) and the leg motor selectivity score (6 motor stages defined by Brunnstrom), and the QMT of both legs was measured using ultrasonography. PA was significantly correlated with the SPPB score (r = 0.63, p = 0.0002), QMT on the paretic side (r = 0.41, p = 0.02), and QMT on non-paretic side (r = 0.56, p = 0.002). There were no significant effects of the leg motor selectivity score on daily PA (F = 1.37, p = 0.27). In the multiple regression analysis, only the SPPB score showed significant linear regression (ß = 0.44, p = 0.02). PA in male patients with sub-acute stroke during hospitalization was related to physical function and QMT and not with the severity of paresis.

Zinc deficiency causes delayed ATP clearance and adenosine generation in rats and cell culture models.

Zinc deficiency causes myriad pathophysiological symptoms, but why distinct phenotypes are generated by zinc deficiency remains unclear. Considering that several ectoenzymes involved in purinergic signaling through extracellular adenine-nucleotide hydrolysis possess zinc ions in their active sites, and disorders in purinergic signaling result in diverse diseases that are frequently similar to those caused by zinc deficiency, herein we examine whether zinc deficiency affects extracellular adenine-nucleotide metabolism. Zinc deficiency severely impairs the activities of major ectoenzymes (ENPP1, ENPP3, NT5E/CD73, and TNAP), and also strongly suppresses adenine-nucleotide hydrolysis in cell-membrane preparations or rat plasma, thereby increasing ATP and ADP levels and decreasing adenosine levels. Thus, zinc deficiency delays both extracellular ATP clearance and adenosine generation, and zinc modulates extracellular adenine-nucleotide metabolism. Since the finely tuned balance between extracellular adenine nucleotides and adenosine is critical for purinergic signaling, these findings provide a novel insight into why zinc deficiency results in diverse symptoms.

Heart Rate Variability During Early Mobilization in Patients with Acute Ischemic Stroke.

Autonomic dysfunction is one of the predictors of poor outcome in patients with acute ischemic stroke. We compared the heart rate variability (HRV) during early mobilization in patients with or without neurological deterioration (ND). We enrolled 7 acute ischemic patients with ND and 14 without ND and measured their HRV in the rest and mobilization by electrocardiography. There was a significant difference in sympathetic nervous activity during mobilization between the 2 groups. However, no significant differences in blood pressure, heart rate, and parasympathetic nerve activity were observed. In patients with acute ischemic stroke, it is likely that the increase in sympathetic nervous activity during mobilization is associated with ND.

Oral lactoferrin influences psychological stress in humans: A single-dose administration crossover study.

Lactoferrin is a secretory protein with various physiological functions. Bovine lactoferrin has been demonstrated to alleviate psychological stresses in rats, but this effect in humans has not yet been assessed. The present study aimed to investigate the changes in psychological stress markers following a calculation task, with either lactoferrin or a placebo orally administered prior to the task. A total of 16 healthy female college students visited Juntendo University, Inzai, Japan following an overnight fast. Subjects were quietly seated for 15 min to stabilize the respiratory rate at 0.25 Hz (one breath every 4 sec). Then, subjects provided saliva, ingested either lactoferrin (800 mg of lactoferrin + soy milk) or a placebo (soy milk), remained seated for another 15 min with respiration rate at 0.25 Hz, and performed a calculation task. The task comprised two sets of 15-min calculations, with a 5-min interval between sets. Each calculation set consisted of various multiplications and divisions using pairs of three-digit numbers. Following the calculation task, saliva was collected again. Heart rate was also monitored to identify the frequency domain of heart-rate variability. The calculation task resulted in increased activity of salivary amylase, and decreased concentration of chromogranin A for both lactoferrin (P=0.028 and P<0.001, respectively) and placebo (P=0.003 and P<0.001, respectively) treatments. The degrees of changes in these salivary markers were similar between the two treatments. Heart rate variability exhibited an increase in the high-frequency (HF) component (P=0.022) and a decrease in low-frequency (LF)/HF and LF/(LF+HF) ratios (both P<0.001) following the calculation task under the placebo condition, demonstrating an upregulation of parasympathetic and a downregulation of sympathetic nervous activities. These changes in parasympathetic (HF) and sympathetic (LF/HF) activities, however, were alleviated by lactoferrin compared with the placebo (P=0.007 and P=0.026, respectively). Collectively these results suggest that oral lactoferrin may mitigate psychological stress in humans.