Real-world outcomes of ponatinib treatment in 724 patients with CML and Ph+ ALL: a post-marketing surveillance study with a special interest in arterial occlusive events in Japan.

BACKGROUND: In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. METHODS: We conducted a post-marketing all-case surveillance to study the safety and efficacy of ponatinib in clinical practice, focusing on arterial occlusive events. RESULTS: Data from 724 patients were collected for 2 years from the initiation of ponatinib. The arterial occlusive events were reported in 6.49% (47/724) with an exposure-adjusted incidence rate of 6.8/100 person-years. The risks associated with arterial occlusive events were age and comorbidities including hypertension and diabetes. At 104 weeks, the cumulative major molecular response rate in patients with chronic-phase chronic myeloid leukemia was 67.2% and the complete cytogenetic response in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was 80.0%. Furthermore, the estimated 1-year overall survival rate was 98.5% for chronic-phase chronic myeloid leukemia and 68.6% for Philadelphia chromosome-positive acute lymphoblastic leukemia. CONCLUSIONS: This surveillance demonstrated that ponatinib has a favorable safety and efficacy profile in Japanese patients and also showed the necessity of closely monitoring arterial occlusive events in older adults and patients with predisposing factors for atherosclerosis.

Neuroimmune modulation by tryptophan derivatives in neurological and inflammatory disorders.

The nervous and immune systems are highly developed, and each performs specialized physiological functions. However, they work together, and their dysfunction is associated with various diseases. Specialized molecules, such as neurotransmitters, cytokines, and more general metabolites, are essential for the appropriate regulation of both systems. Tryptophan, an essential amino acid, is converted into functional molecules such as serotonin and kynurenine, both of which play important roles in the nervous and immune systems. The role of kynurenine metabolites in neurodegenerative and psychiatric diseases has recently received particular attention. Recently, we found that hyperactivity of the kynurenine pathway is a critical risk factor for septic shock. In this review, we first outline neuroimmune interactions and tryptophan derivatives and then summarized the changes in tryptophan metabolism in neurological disorders. Finally, we discuss the potential of tryptophan derivatives as therapeutic targets for neuroimmune disorders.

Broken Screw Rotational Symmetry in the Near-Surface Electronic Structure of AB-Stacked Crystals.

We investigate the electronic structure of 2H-NbS_{2} and h-BN by angle-resolved photoemission spectroscopy (ARPES) and photoemission intensity calculations. Although in bulk form, these materials are expected to exhibit band degeneracy in the k_{z}=π/c plane due to screw rotation and time-reversal symmetries, we observe gapped band dispersion near the surface. We extract from first-principles calculations the near-surface electronic structure probed by ARPES and find that the calculated photoemission spectra from the near-surface region reproduce the gapped ARPES spectra. Our results show that the near-surface electronic structure can be qualitatively different from the bulk electronic structure due to partially broken nonsymmorphic symmetries.

Relative impact of THPO mutation causing hereditary thrombocythemia.

Germline mutations of THPO were reported as causes of hereditary thrombocythemia. Six previously reported distinct sites of the mutation were clustered at the 5`-untranslated region or the exon 3 splicing donor site of the THPO gene. Each mutation was identified in an independent pedigree, and the differences between the mutations were not compared. We cloned six distinct THPO mutations (THPO c.-47delG, THPO c.-31G>T, THPO c.13G>A, THPO c.13+1G>A, THPO c.13+2T>C, and THPO c.13+5G>A) and compared the molecular mechanisms that underlie the increased production of THPO protein. At the transcript level, all of the mutations except THPO c.-47delG showed an exon 3 skipping transcript, including two mutations (THPO c.-31G>T and THPO c.13+5G>A) that were distant from the splicing donor site. THPO c.-47delG showed the same full-length transcript as that of the wild-type transcript. At the protein level, all mutations resulted in a higher level of production of thrombopoietin (THPO) protein compared with wild-type THPO. There are only two distinct patterns of mechanisms for increased production of THPO: exon 3 skipping that deleted upstream suppressive open reading frame (ORF)7 and one base deletion that shifted ORF7 to connect to the initial codon of THPO in-frame. The common mechanisms of hereditary thrombocytosis due to THPO mutations are unleashed THPO translations, which are usually suppressed by upstream out-of-frame ORF7.

Initial Efficacy of the COVID-19 mRNA Vaccine Booster and Subsequent Breakthrough Omicron Variant Infection in Patients with B-Cell Non-Hodgkin's Lymphoma: A Single-Center Cohort Study.

It has been suggested that the effect of coronavirus disease 2019 (COVID-19) booster vaccination in patients with B-cell non-Hodgkin's lymphoma (B-NHL) is inferior to that in healthy individuals. However, differences according to histological subtype or treatment status are unclear. In addition, there has been less research on patients who subsequently develop breakthrough infections. We investigated the effects of the first COVID-19 booster vaccination for patients with B-NHL and the clinical features of breakthrough infections in the Omicron variant era. In this study, B-NHL was classified into two histological subtypes: aggressive lymphoma and indolent lymphoma. Next, patients were subdivided according to treatment with anticancer drugs at the start of the first vaccination. We also examined the clinical characteristics and outcomes of patients who had breakthrough infections after a booster vaccination. The booster effect of the COVID-19 mRNA vaccine in patients with B-NHL varied considerably depending on treatment status at the initial vaccination. In the patient group at more than 1 year after the last anticancer drug treatment, regardless of the histological subtype, the booster effect was comparable to that in the healthy control group. In contrast, the booster effect was significantly poorer in the other patient groups. However, of the 213 patients who received the booster vaccine, 22 patients (10.3%) were infected with COVID-19, and 18 patients (81.8%) had mild disease; these cases included the patients who remained seronegative. Thus, we believe that booster vaccinations may help in reducing the severity of Omicron variant COVID-19 infection in patients with B-NHL.

Familial cases with adult-onset FGF23-related hypophosphatemic osteomalacia -A PHEX 3'-UTR change as a possible cause.

Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. It is possible that there still remain unknown causes or mechanisms for FGF23-related hypophosphatemic diseases. We report two male cousins who had been suffering form FGF23-related hypophosphatemic osteomalacia. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases and whole genome sequencing were conducted. Luciferase assay was used to evaluate the effect of a detected nucleotide change on mRNA stability. Two cousins showed hypophosphatemia with impaired proximal tubular phosphate reabsorption and high FGF23. Serum phosphate of their mothers was within the reference range. Exome sequencing of the proband detected no mutations. Whole genome sequencing of the patients and their mothers identified a nucleotide change in the 3'-UTR of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene (c.*1280_*1287dupGTGTGTGT) which is heterozygous in the mothers and hemizygous in the patients. While sixteen is the most prevalent number of GT repeats, this family had twenty repeats. Luciferase assay indicated that mRNA with 3'-UTR of PHEX with 20 GT repeats was more unstable than that with 16 repeats. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases cannot identify all the genetic causes. Our results strongly suggest that changes of PHEX expression by a nucleotide change in the 3'-UTR is a novel mechanism of FGF23-related hypophosphatemic osteomalacia.

Association study of a single nucleotide polymorphism in the hypoxia response element of the macrophage migration inhibitory factor gene promoter with suicide completers in the Japanese population.

BACKGROUND: More than 800 000 people die by suicide annually. The heritability of suicide is 30%-50%. We focused on the hypoxia response element (HRE), which promotes the expression of macrophage migration inhibitory factor (MIF) via the hypoxia-inducible factor (HIF) pathway, important in neurogenesis and neuroprotection. We examined a genetic polymorphism of rs17004038, a single-nucleotide polymorphism (SNP), in suicide completers and controls. METHODS: The study population included 1336 suicide completers and 814 unrelated healthy controls. All participants were Japanese. We obtained peripheral blood, extracted DNA, and genotyped the patients for SNP rs17004038 (C > A). RESULTS: No significant differences were observed between the two groups in either the allele or genotype analyses. Subgroup analyses by sex, age (<40 or ≥40), and suicide method (violent or nonviolent suicide) were performed with similar results. CONCLUSION: No association was observed between SNP rs17004038 and suicide completion. Although it is challenging to collect a large number of samples from suicide completers, further MIF-related genetic studies, including those of rs17004038, are necessary with larger sample sizes.

Hereditary thrombocythemia due to splicing donor site mutation of THPO in a Japanese family.

Thrombopoietin (THPO) is an essential factor for platelet production. Hereditary thrombocythemia (HT) is caused by a germline mutation of THPO, MPL, or JAK2 and is inherited in an autosomal-dominant manner. We identified a Japanese family with HT due to a point mutation of the splicing donor site of the THPO gene (THPO c.13 + 1G > A). Bone marrow biopsy showed increased megakaryocytes mimicking essential thrombocythemia. One affected family member developed chronic myeloid leukemia. We cloned the mutation and developed mutated and wild type THPO expression vectors. Molecular analysis showed that the mutation causes an exon 3 skipping transcript of THPO that abrogates a suppressive untranslated upstream open reading frame. Although the transcript levels of THPO mRNA were comparable, mutated transcripts were more efficiently translated and THPO protein expression was significantly higher than that of the wild type.

Development and evaluation of a rapid one-step high sensitivity real-time quantitative PCR system for minor BCR-ABL (e1a2) test in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

OBJECTIVE: Minimal residual disease assessment of BCR-ABL messenger ribonucleic acid levels is crucial in Philadelphia chromosome-positive acute lymphoblastic leukemia for prognosis and treatment planning. However, accurately quantifying minor BCR-ABL transcripts, which comprise 70% of Philadelphia chromosome-positive acute lymphoblastic leukemia cases, lacks a national-approved method. METHODS: We developed the "Otsuka" minor BCR-ABLmessenger ribonucleic acid assay kit with exceptional precision (0.00151%). Minor BCR-ABL messenger ribonucleic acid levels were analyzed in 175 adults, 36 children with acute lymphoblastic leukemia and 25 healthy individuals to evaluate the kit's performance. RESULTS: The "Otsuka" kit showed high concordance with a commonly used chimeric gene screening method, indicating reliable detection of positive cases. Quantitative results demonstrated a robust correlation with both a laboratory-developed test and a diagnostic research product. The "Otsuka" kit performs comparably or even surpass to conventional products, providing valuable insights into Philadelphia chromosome-positive acute lymphoblastic leukemia pathology. CONCLUSIONS: The 'Otsuka" minor BCR-ABL messenger ribonucleic acid assay kit exhibits excellent performance in quantifying minor BCR-ABL transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia patients. Our results align well with established screening methods and show a strong correlation with laboratory-developed tests and diagnostic research products. The "Otsuka" kit holds great promise as a valuable tool for understanding Philadelphia chromosome-positive acute lymphoblastic leukemia pathology and guiding effective treatment strategies.

Oxidation-treated carbon nanotube yarns accelerate neurite outgrowth and induce axonal regeneration in peripheral nerve defect.

Carbon nanotubes (CNTs) have the potential to promote peripheral nerve regeneration, although with limited capacity and foreign body reaction. This study investigated whether CNTs hydrophilized by oxidation can improve peripheral nerve regeneration and reduce foreign body reactions and inflammation. Three different artificial nerve conduit models were created using CNTs treated with ozone (O group), strong acid (SA group), and untreated (P group). They were implanted into a rat sciatic nerve defect model and evaluated after 8 and 16 weeks. At 16 weeks, the SA group showed significant recovery in functional and electrophysiological evaluations compared with the others. At 8 weeks, histological examination revealed a significant increase in the density of regenerated neurofilament and decreased foreign body giant cells in the SA group compared with the others. Oxidation-treated CNTs improved biocompatibility, induced nerve regeneration, and inhibited foreign-body reactions.

Diagnosis and Prognostic Value of the Underlying Cause of Acute Coronary Syndrome in Optical Coherence Tomography-Guided Emergency Percutaneous Coronary Intervention.

Background The prognostic impact of optical coherence tomography-diagnosed culprit lesion morphology in acute coronary syndrome (ACS) has not been systematically examined in real-world settings. Methods and Results This investigator-initiated, prospective, multicenter, observational study was conducted at 22 Japanese hospitals to identify the prevalence of underlying ACS causes (plaque rupture [PR], plaque erosion [PE], and calcified nodules [CN]) and their impact on clinical outcomes. Patients with ACS diagnosed within 24 hours of symptom onset undergoing emergency percutaneous coronary intervention were enrolled. Optical coherence tomography-guided percutaneous coronary intervention recipients were assessed for underlying ACS causes and followed up for major adverse cardiac events (cardiovascular death, myocardial infarction, heart failure, or ischemia-driven revascularization) at 1 year. Of 1702 patients with ACS, 702 (40.7%) underwent optical coherence tomography-guided percutaneous coronary intervention for analysis. PR, PE, and CN prevalence was 59.1%, 25.6%, and 4.0%, respectively. One-year major adverse cardiac events occurred most frequently in patients with CN (32.1%), followed by PR (12.4%) and PE (6.2%) (log-rank P<0.0001), primarily driven by increased cardiovascular death (CN, 25.0%; PR, 0.7%; PE, 1.1%; log-rank P<0.0001) and heart failure trend (CN, 7.1%; PR, 6.8%; PE, 2.2%; log-rank P<0.075). On multivariate Cox regression analysis, the underlying ACS cause was associated with 1-year major adverse cardiac events (CN [hazard ratio (HR), 4.49 [95% CI, 1.35-14.89], P=0.014]; PR (HR, 2.18 [95% CI, 1.05-4.53], P=0.036]; PE as reference). Conclusions Despite being the least common, CN was a clinically significant underlying ACS cause, associated with the highest future major adverse cardiac events risk, followed by PR and PE. Future studies should evaluate the possibility of ACS underlying cause-based optical coherence tomography-guided optimization.

Helicobacter pylori eradication treatment for primary gastric diffuse large B-cell lymphoma: A single-center analysis.

BACKGROUND: Unlike the already established effect of Helicobacter pylori (H. pylori) eradication on gastric mucosa-associated lymphoid tissue (MALT) lymphoma, its therapeutic effect on primary gastric diffuse large B-cell lymphoma (DLBCL) is still unclear. AIM: To clarify the efficacy of H. pylori eradication treatment for primary gastric DLBCL. METHODS: We reported on 3 new cases, and added them to 3 previously reported cases. We analyzed the usefulness of H. pylori eradication treatment for gastric DLBCL for a total of 6 cases at our center. RESULTS: Of the 6 patients (27-90 years old, 3 males and 3 females), all 3 patients with single lesions (one transformed from MALT lymphoma) achieved complete remission (CR) after H. pylori eradication. Regarding the 2 newly reported cases, CR was maintained for more than 6 years with eradication treatment alone. In contrast, none of the 3 patients with 2 lesions achieved CR. In 1 newly reported case, endoscopic CR was achieved in one lesion, while stable disease was obtained in the other lesion. Two patients with progressive disease responded to standard chemotherapy ± radiation and remained in CR for more than 6 years. CONCLUSION: We believe it is worthwhile to attempt H. pylori eradication for elderly patients with primary gastric DLBCL in a single lesion with a small tumor burden.

An Electrochemical Sensor of Theophylline on a Boron-Doped Diamond Electrode Modified with Nickel Nanoparticles.

Theophylline is a drug with a narrow therapeutic range. Electrochemical sensors are a potentially effective method for detecting theophylline concentration to prevent toxicity. In this work, a simple modification of a boron-doped diamond electrode using nickel nanoparticles was successfully performed for a theophylline electrochemical sensor. The modified electrode was characterized using a scanning electron microscope and X-ray photoelectron spectroscopy. Square wave voltammetry and cyclic voltammetry methods were used to study the electrochemical behavior of theophylline. The modified nickel nanoparticles on the boron-doped diamond electrode exhibited an electrochemically active surface area of 0.0081 cm2, which is larger than the unmodified boron-doped diamond's area of 0.0011 cm2. This modified electrode demonstrated a low limit of detection of 2.79 µM within the linear concentration range from 30 to 100 µM. Moreover, the modified boron-doped diamond electrode also showed selective properties against D-glucose, ammonium sulfate, and urea. In the real sample analysis using artificial urine, the boron-doped diamond electrode with nickel nanoparticle modifications achieved a %recovery of 105.10%, with a good precision of less than 5%. The results of this work indicate that the developed method using nickel nanoparticles on a boron-doped diamond electrode is promising for the determination of theophylline.

Conceptual study on extraction of formic acid from the electrolyte after electroreduction of CO2: Desalination and dehydration using a high-silica chabazite zeolite membrane.

Here, we propose a two-step pervaporation system with a high-silica CHA (chabazite) membrane, which has sufficient resistance to water and acid, to demonstrate the extraction and condensation of the formic acid formed by electroreduction of CO2. The kinetic diameters of water and formic acid are similar and smaller than the pore size of CHA, while the hydrated electrolyte ions (e.g., K+ and Cl-) are larger than the pore size of CHA. Consequently, the electrolyte ions are separated from the mixture of water and formic acid in the first desalination process, and then water molecules are easily removed from the mixture in the second dehydration process. From 300 ml of an approximately 3 wt% formic acid aqueous solution containing 0.5 M KCl, 10 ml of 18.2 wt% formic acid was obtained.

[Brentuximab Vedotin, Doxorubicin, Vinblastine, Dacarbazine(A+AVD)Therapy for Classical Hodgkin Lymphoma- A Single-Institution Experience].

The JSH Practical Guidelines for Hematological Malignancies, 2018 expanded edition, newly adopted brentuximab vedotin, doxorubicin, vinblastine, dacarbazine(A+AVD)protocol as a standard treatment for advanced-stage classical Hodgkin lymphoma(CHL). Therefore, this retrospective analysis compared 15 patients who received A+AVD therapy with 21 patients who received doxorubicin, bleomycin, vinblastine, dacarbazine(ABVD)therapy. All patients were newly diagnosed with CHL and received induction therapy between April 2015 and June 2022 in our hospital. All except 1 patient of the A+AVD group had advanced-stage CHL. The median age was 63(23-85)years. The estimated 2-year overall survival of the A+AVD group was better than that of the ABVD group which included 6 patients with clinical stage Ⅲ or higher CHL (100% vs 66.7%, p=0.047). In contrast, there was no significant difference in the complete response rate(53.8% vs 100%, p=0.109)between the 2 groups. The overall response rate after first-line treatment(69.2% vs 100%, p=0.255), and the estimated 2-year progression-free survival(70.1% vs 66.7%, p=0.321)between the A+AVD and the ABVD groups were similar.

Time-, spin-, and angle-resolved photoemission spectroscopy with a 1-MHz 10.7-eV pulse laser.

We describe a setup of time-, spin-, and angle-resolved photoemission spectroscopy (tr-SARPES) employing a 10.7 eV (λ = 115.6 nm) pulse laser at a 1 MHz repetition rate as a probe photon source. This equipment effectively combines the technologies of a high-power Yb:fiber laser, ultraviolet-driven harmonic generation in Xe gas, and a SARPES apparatus equipped with very-low-energy-electron-diffraction spin detectors. A high repetition rate (1 MHz) of the probe laser allows experiments with the photoemission space-charge effects significantly reduced, despite a high flux of 1013 photons/s on the sample. The relatively high photon energy (10.7 eV) also brings the capability of observing a wide momentum range that covers the entire Brillouin zone of many materials while ensuring high momentum resolution. The experimental setup overcomes the low efficiency of spin-resolved measurements, which gets even more severe for the pump-probed unoccupied states, and affords the opportunity to investigate ultrafast electron and spin dynamics of modern quantum materials with energy and time resolutions of 25 meV and 360 fs, respectively.

Dominant-negative type of IKZF1 deletion showed a favorable prognosis in adult B-cell acute lymphoblastic leukemia.

IKZF1 deletion is a recurrent genomic alteration in B-cell acute lymphoblastic leukemia (B-ALL) and is divided into dominant-negative (DN) and loss of function (LOF) deletions. The prognostic impact of each deletion has not been fully elucidated. We retrospectively analyzed 117 patients with adult B-ALL including 60 patients with BCR::ABL1-positive B-ALL and 57 patients with BCR::ABL1-negative B-ALL by the fluorescence in situ hybridization (FISH) method for IKZF1 deletion and multiplex PCR for the 4 most common IKZF1 deletions (∆4-7, ∆2-7, ∆2-8, and ∆4-8). Samples, in which IKZF1 deletion was detected by FISH but a specific type of deletion was not identified by the PCR, were categorized as "other." Patients were classified into a DN group that had at least 1 allele of ∆4-7 (n = 23), LOF and other group (n = 40), and wildtype group (n = 54). DN type IKZF1 deletions were found in 33.3% of BCR::ABL1-positive cases and 5.2% of BCR::ABL1-negative cases. LOF and other type IKZF1 deletions were found in 43.4% of BCR::ABL1-positive cases and 24.6% of BCR::ABL1-negative cases. Patients with the DN group showed significantly higher overall survival (OS) than that of the LOF and other and WT groups (P = 0.011). Multivariate analysis including age, WBC counts, complex karyotype, and DN type IKZF1 deletion showed that the DN type of IKZF1 deletion (HR = 0.22, P = 0.013) had a positive impact and age ≥ 65 (HR = 1.92, P = 0.029) had a negative impact on OS. The prognostic impact of IKZF1 deletion depends on the type of deletion and DN type of IKZF1 deletion showed better prognosis in adult B-ALL patients.Clinical trial registration This study was part of a prospective observational study (Hokkaido Leukemia Net, UMIN000048611). It was conducted in compliance with ethical principles based on the Helsinki Declaration and was approved by the institutional review board of Hokkaido University Hospital (#015-0344).

Permeation behavior of porphyrin derivatives with different functional group positions across cancer cell membranes.

Porphyrin, which shows selective accumulation in cancer cells, has attracted attention as a drug carrier. The influences of the functional porphyrin positions (ß- and meso-positions) on porphyrin accumulation must be understood. In this work, we focused on the investigation of the phenyl functional group whose ß-position influences cancer cell accumulation through direct membrane permeation and endocytosis. The endocytic pathway, in particular, is influenced by both clathrin-dependent and caveolae-dependent endocytosis.

Booster effect of a third mRNA-based COVID-19 vaccine dose in patients with myeloid malignancies.

BACKGROUND: We have reported that seroconversion rates after the second dose of mRNA-based COVID-19 vaccines for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were 100% and 95% respectively, with no significant difference from healthy controls (HCs).However, there are very limited data for the response to a third vaccine dose in those patients. AIMS: In this complementary study, we investigated the booster effect of a third mRNA-based COVID-19 vaccine dose in patients with myeloid malignancies. MATERIALS & METHODS: A total 58 patients including 20 patients with MDS and 38 patients with AML were enrolled. Anti-SARS-CoV-2S immunoassays were performed at 3, 6, and 9 months after the second vaccine dose. RESULTS: Seventy-five percent of the MDS patients and 37% of the AML patients were receiving active treatment at the time of the third vaccination. Both the initial and third vaccine response in AML patients were comparable to those in HCs. In MDS patients, although the initial vaccine immunogenicity was inferior to that in HCs and AML patients, the third vaccine improved the response to a level not inferior to those in HCs and AML patients. Of note, the third vaccine resulted in a significant increase of antibodies in actively treated MDS patients who had shown a response inferior to that in untreated patients after two doses of vaccination. DISCUSSION: In patients with myeloid malignancies, the third vaccine dose showed a booster effect, and disease- and therapy-related factors associated with the booster response have been identified. CONCLUSION: The third dose of an mRNA-based COVID-19 vaccine showed a booster effect in patients with myeloid malignancies. Such a good booster response has not been reported in other haematological malignancies.