RUNX1 expression is regulated by a super-enhancer and is a therapeutic target in adult T-cell leukemia/lymphoma.

Super-enhancers (SEs) play an important role in regulating tumor-specific gene expression. JQ1, a Bromodomain-containing protein 4 (BRD4) inhibitor, exerts antitumor effects by disrupting SE-mediated regulation of gene expression. We investigated the anti-adult T-cell leukemia/lymphoma (ATL) effects of JQ1. JQ1 induced apoptosis and inhibited ATL cell proliferation. JQ1 suppressed RUNX1expression through the disruption of SE-mediated gene regulation. In the previous reports, it was shown that IC50s of AI-10-104 and Ro5-3335, RUNX1 inhibitors were 1-10 µM for lymphoblastic leukemia cell lines carrying RUNX1 mutations. In the present study, we demonstrated that IC50s of AI-10-104 and Ro5-3335 were also 1-10 µM or lower for ATL cell lines. Simultaneously, AI-10-104 suppressed MYC proto-oncogene (c-MYC) expression. RUNX1 is a potential therapeutic target for ATL that promotes c-MYC expression. We showed that RUNX1 expression is regulated via SEs in ATL and that RUNX1 may be a novel therapeutic target for ATL.

Safety of cricotracheostomy with skin and tracheal membrane flaps for severe COVID-19 patients.

OBJECTIVE: Airway surgery is performed for COVID-19 patients who require long-term tracheal intubation and mechanical ventilation. Tracheostomy sometimes causes postoperative complications represented by bleeding at a relatively high rate in COVID-19 patients. As an alternative surgical procedure to tracheostomy, cricotracheostomy may reduce these complications, but few studies have examined its safety. METHODS: Data were retrospectively collected for sixteen COVID-19 patients (11 underwent tracheostomy, 5 underwent modified cricotracheostomy). In addition to patients' backgrounds and blood test data, the frequency of complications and additional care required for postoperative complications were collected. Statistical analysis was conducted by the univariate analysis of Fischer analysis and Mann-Whitney U test. RESULTS: Five cases experienced postoperative bleeding, four cases experienced peristomal infection, and one case experienced subcutaneous emphysema in the tracheostomy patients. These complications were not observed in the cricotracheostomy patients. The number of additional cares for postoperative complications was significantly lower in cricotracheostomy than in tracheostomy patients (p < 0.05). CONCLUSIONS: Modified cricotracheostomy could be a safe procedure in airway surgery for patients with COVID-19 from the point of fewer postoperative complications and additional care. It might be necessary to select the cricotracheostomy depending on patients' background to reduce postoperative complications.

Direct observation of crystal degradation behaviour in porous crystals under low-dose electron diffraction conditions.

The quantification of electron beam damage in crystalline porous materials has been investigated under low-dose electron irradiation conditions. As a result of the systematic quantitative analysis of time-course changes in electron diffraction patterns, it was found that the unoccupied volume in the MOF crystal is a crucial factor for electron beam resistance.

Characteristics of Nasal Foreign Bodies and Equipment on Complications During Removal Procedures.

OBJECTIVE: The treatment of nasal foreign bodies involves safe and reliable removal. Few reports have investigated the relationship between equipment and the incidence of complications. METHODS: This retrospective study included 300 patients with nasal foreign bodies (average: 3.28 years, interquartile range: 2-4 years). Patients' background, characteristics of nasal foreign body, equipment to remove the nasal foreign body, and complications were obtained from medical records. Statistical analysis was performed using Pearson's chi-square test for associated factors and the incidence of epistaxis among the complications. RESULTS: Nasal foreign bodies were found and removed in 256 patients. Forceps, hooks, suction, modified paper clips, and cotton swabs were mainly used to remove the nasal foreign bodies. Epistaxis due to the removal procedure was observed in 26 patients. The occurrence of epistaxis differed depending on the equipment (p = 0.077) and was less frequent in suction and paper clips than in forceps (p < 0.05 and p = 0.077). Epistaxis was not observed when a cotton swab was used. Aspiration and septal perforation were not observed. A statistical relationship was not detected between the hardness of foreign bodies and the occurrence of epistaxis (p = 0.251). The incidence of epistaxis was higher in cases nasal foreign bodies remained for 1 day and over than in cases foreign bodies were removed within 1 day (p < 0.05). CONCLUSIONS: This study revealed that suction, modified paper clips, and cotton swabs could be beneficial options for minimizing complications in the removal of nasal foreign bodies. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2553-2557, 2023.

Antibody responses after BNT162b2 vaccination in Japanese geriatric intermediate care facilities.

Background: To evaluate antibody responses against the primary series of vaccination of severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2] vaccines in the staff and residents of Japanese geriatric intermediate care facilities. Methods: All subjects (159 staff and 96 residents) received two doses of the BNT162b2 mRNA vaccine 3 weeks apart. Baseline data of subject were collected using a structured form. Serum samples were collected three times: before vaccination, 3 weeks after the first dose, and 4 weeks after the second dose, and anti-receptor binding domain of the spike protein of SARS-CoV-2 [anti-RBD] IgG was measured using two immunoassays. Results: After the second dose, geometric mean titers [GMT] of anti-RBD with both the Abbott and Roche assay were significantly lower in residents than staff (2282 AU/mL vs. 8505 AU/mL, and 258 U/mL vs. 948 U/mL, respectively). Multivariate analysis of characteristics affecting antibody responses (≥1280 AU/mL for Abbott and > 210 U/mL for Roche) showed lower odds ratios [ORs] for older age (adjusted OR per 10 year increase [aOR] = 0.62, 95 % confidence interval [95 %CI]; 0.38-1.02), steroid usage (aOR = 0.09, 95 %CI; 0.01-0.60) and regular nonsteroidal anti-inflammatory drugs [NSAIDs] usage (aOR = 0.16, 95 %CI; 0.03-0.88). Conclusions: Elderly people and steroid and NSAID users had lower antibody responses following the second vaccine dose.

General Synthesis of MOF Nanotubes via Hydrogen-Bonded Organic Frameworks toward Efficient Hydrogen Evolution Electrocatalysts.

The application scope of metal-organic frameworks (MOFs) can be extended by rationally designing the architecture and components of MOFs, which can be achieved via a metal-containing solid templated strategy. However, this strategy suffers from low efficiency and provides only one specific MOF from one template. Herein, we present a versatile templated strategy in which organic ligands are weaved into hydrogen-bonded organic frameworks (HOFs) for the controllable and scalable synthesis of MOF nanotubes. HOF nanowires assembled from benzene-1,3,5-tricarboxylic acid and melamine via a simple sonochemical approach serve as both the template and precursor to produce MOF nanotubes with varied metal compositions. Hybrid nanotubes containing nanometal crystals and N-doped graphene prepared through a carbonization process show that the optimized NiRuIr alloy@NG nanotube exhibits excellent electrocatalytic HER activity and durability in alkaline media, outperforming most reported catalysts. The strategy proposed here demonstrates a pioneering study of combination of HOF and MOF, which shows great potential in the design of other nanosized MOFs with various architectures and compositions for potential applications.

Alvocidib inhibits IRF4 expression via super-enhancer suppression and adult T-cell leukemia/lymphoma cell growth.

Adult T-cell leukemia/lymphoma (ATL) is an intractable hematological malignancy with extremely poor prognosis. Recent studies have revealed that super-enhancers (SE) play important roles in controlling tumor-specific gene expression and are potential therapeutic targets for neoplastic diseases including ATL. Cyclin-dependent protein kinase (CDK) 9 is a component of a complex comprising transcription factors (TFs) that bind the SE region. Alvocidib is a CDK9 inhibitor that exerts antitumor activity by inhibiting RNA polymerase (Pol) II phosphorylation and suppressing SE-mediated, tumor-specific gene expression. The present study demonstrated that alvocidib inhibited the proliferation of ATL cell lines and tumor cells from patients with ATL. RNA sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) disclosed that SE regulated IRF4 in the ATL cell lines. Previous studies showed that IRF4 suppression inhibited ATL cell proliferation. Hence, IRF4 is a putative alvocidib target in ATL therapy. The present study revealed that SE-mediated IRF4 downregulation is a possible mechanism by which alvocidib inhibits ATL proliferation. Alvocidib also suppressed ATL in a mouse xenograft model. Hence, the present work demonstrated that alvocidib has therapeutic efficacy against ATL and partially elucidated its mode of action. It also showed that alvocidib is promising for the clinical treatment of ATL and perhaps other malignancies and neoplasms as well.

Clinical features of non-infectious pulmonary complications after donor lymphocyte infusion in post-transplant patients: The Nagasaki Transplant Group Experience.

Donor lymphocyte infusion (DLI) is a therapeutic modality for relapsed hematological malignancies after allogeneic hematopoietic stem cell transplantation. We retrospectively analyzed non-infectious pulmonary complications (non-IPCs) following DLI therapy in 41 post-transplant patients with hematological malignancies, and found that 7 developed post-DLI non-IPCs. The 6-year cumulative incidence of non-IPCs was 18.0%. In these patients, non-IPCs were classified into three subtypes: acute respiratory distress syndrome (ARDS), nonspecific interstitial pneumonia (NSIP), and bronchiolitis obliterans syndrome (BOS). The median intervals from the last date of DLI to the development of ARDS and BOS were 12 days (range, 12-14) and 9.4 months (range, 2.6-61.8), respectively; the intervals between DLI and the development of NSIP were 3.5 and 24.7 in 2 patients. Regarding the status of GVHD before the diagnosis with ARDS, 2 out of 3 patients showed the progression of acute GVHD following DLI therapy. One out of 2 patients with NSIP and all 3 patients with BO had chronic GVHD symptoms prior to the development of non-IPCs. In our cohort, 1 patient died of the progression of NSIP. In conclusion, the present study showed the clinical features of non-IPCs following DLI, suggesting the importance of careful follow-ups for non-IPCs in post-DLI patients.

Thermal crystal phase transition in zeolitic imidazolate frameworks induced by nanosizing the crystal.

An unusual crystal phase transition was demonstrated in a zeolitic imidazolate framework with a rigid coordination network. Differential scanning calorimetry and powder X-ray diffraction revealed that nanosizing the crystal structure was crucial for the phase transition at low temperature. The thermodynamic parameters of the phase transition were determined by calorimetry.

The response-guided ATG treatment provides a survival benefit and KPS recovery for patients with steroid refractory acute GVHD: The Nagasaki Transplant Group Experience.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) is a serious complication that negatively affects the prognosis and quality of life of patients who receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Antithymocyte globulin (ATG) is one of the second-line treatments for SR-aGVHD. We retrospectively evaluated Karnofsky Performance Status (KPS) recovery and clinical response in 11 patients who received the response-guided low-dose ATG treatment for SR-aGVHD after allo-HSCT using alternative donors. The median dose of ATG per cycle was 1.0 mg/kg (range, 1.0-1.25 mg/kg) and the median number of cycles of ATG was 2 (range, 1-4). The overall response rate was 63.6%, and the estimated overall survival rate at 1 year was 63.6%. Two out of seven patients who survived 1 year after the response-guided ATG treatment had KPS of 80 or higher. The remaining 5 patients had KPS of lower than 80 due to moderate chronic GVHD (cGVHD) and/or ≥grade 3 infectious complications. Based on the poor prognosis of patients with SR-aGVHD, the response-guided ATG treatment represents one therapeutic option. The present results also suggest that chronic GVHD and infectious complications after the response-guided ATG treatment were associated with decreased KPS recovery and impaired social function.

Efficacy and Cardiovascular Adverse Events of Long-term Treatment with Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia: A Report from the Nagasaki CML Study Group.

Objective The standard treatment for chronic myeloid leukemia (CML) is the continuous use of tyrosine kinase inhibitors (TKIs), which results in a favorable prognosis for the majority of patients. Recent studies have identified cardiovascular diseases (CVDs) as late adverse events (AEs) related to TKIs. In this study, we evaluated the long-term efficacy and AEs of TKIs, focusing on CVDs. Methods We performed a retrospective survey of CML patients (diagnosed from 2001 to 2016) treated with TKIs in Nagasaki Prefecture. Clinical data were obtained from their medical records. We analyzed the survival, estimated cumulative incidence of CVDs, and risk factors for CVD among CML patients treated with TKIs. Results The overall survival rate of 264 CML patients treated with TKIs (median age 58 years old) was 89.6% [95% confidence interval (CI), 84.9-92.9%], and 80.5% (95% CI, 73.4-85.9%) at 5 and 10 years after the CML diagnosis, respectively. CVD events occurred in 26 patients (9.8%, median age 67.5 years old) with a median 65.5 months of TKI treatment. The cumulative incidences at 2 and 5 years was 2.4% (95% CI, 1.0-4.8%) and 5.2% (95% CI, 2.8-8.6%), respectively. Hypertension and a high SCORE chart risk at the diagnosis of CML were associated with CVD events during TKI treatment. Conclusion TKI treatment contributed to the long-term survival of CML patients in Nagasaki Prefecture in a "real-world" setting, but the incidence of CVDs seemed to be increased in these patients. A proper approach to managing risk factors for CVD is warranted to reduce CVD events during TKI treatment.

Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma with HTLV-1-associated myelopathy.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for adult T-cell leukemia/lymphoma (ATL), but comorbidities increase transplant-related mortality. Here we report the outcome of allo-HSCT in a patient with ATL with human T-cell leukemia virus type I (HTLV-1)-associated myelopathy-tropical spastic paraparesis (HAM/TSP). A 48-year-old man was diagnosed with HAM/TSP and started prednisolone therapy. Ten years later, he developed lymphoma-type ATL. At the diagnosis of ATL, Osame's Motor Disability Score (OMDS) was 4. When prednisolone was gradually tapered and stopped following chemotherapy for ATL, HAM/TSP symptoms recurred (OMDS 7). Bone marrow transplantation from a human leukocyte antigen allele 8/8 matched unrelated donor was performed while ATL was in partial remission. Neutrophil engraftment with complete donor chimerism was achieved on day 19 after allo-HSCT. Mild gait improvement (OMDS 5) was observed on day 30. Although ATL relapsed on day 275, progression of HAM/TSP symptoms was not observed. Furthermore, there was no clear progression of HAM/TSP symptoms after donor lymphocyte infusions. The outcome of this case suggests that ATL patients with HAM/TSP tolerate allo-HSCT and donor lymphocyte infusions.

Correction: Islam, S., et al. Impaired Expression of Chloroplast HSP90C Chaperone Activates Plant Defense Responses with a Possible Link to a Disease-Symptom-Like Phenotype. International Journal of Molecular Science 2020, 21, 4202.

The authors wish to make the following corrections to this paper [...].

Comparative Analysis of Bacterial Diversity and Community Structure in the Rhizosphere and Root Endosphere of Two Halophytes, Salicornia europaea and Glaux maritima, Collected from Two Brackish Lakes in Japan.

Microbial community structures associated with halophytes and their compositions among different habitats, particularly natural saline sites, have not yet been investigated in detail. In the present study, we examined the diversity and composition of the rhizosphere and root endosphere bacteria of two halophytes, Salicornia europaea L. and Glaux maritima L., collected from two adjacent brackish lakes, Lake Notoro and Lake Tofutsu, in Japan. The bacterial species richness and diversity indices of the two halophytes collected from both lakes showed no significant differences in the rhizosphere or root endosphere. In contrast, beta diversity and taxonomic analyses revealed significant differences in the bacterial communities from each halophyte between the two lakes even though the two locations were natural saline sites, indicating that the bacterial communities for S. europaea and G. maritima both fluctuated in a manner that depended on the geographical location. Common and abundant genera associated with each halophyte across the two lakes were then identified to verify the bacterial genera specifically inhabiting each plant species. The results obtained showed that the composition of abundant genera inhabiting each halophyte across two lakes was distinct from that reported previously in other saline soil areas. These results suggest that each halophyte in different geographical sites had an individual complex bacterial community.

Transcriptome Analysis Shows Activation of Stress and Defense Responses by Silencing of Chlorophyll Biosynthetic Enzyme CHLI in Transgenic Tobacco.

In the present study, we have shown the transcriptional changes in a chlorosis model transgenic tobacco plant, i-amiCHLI, in which an artificial micro RNA is expressed in a chemically inducible manner to silence the expression of CHLI genes encoding a subunit of a chlorophyll biosynthetic enzyme. Comparison to the inducer-treated and untreated control non-transformants and untreated i-amiCHLI revealed that 3568 and 3582 genes were up- and down-regulated, respectively, in the inducer-treated i-amiCHLI plants. Gene Ontology enrichment analysis of these differentially expressed genes indicated the upregulation of the genes related to innate immune responses, and cell death pathways, and the downregulation of genes for photosynthesis, plastid organization, and primary and secondary metabolic pathways in the inducer-treated i-amiCHLI plants. The cell death in the chlorotic tissues with a preceding H2O2 production was observed in the inducer-treated i-amiCHLI plants, confirming the activation of the immune response. The involvement of activated innate immune response in the chlorosis development was supported by the comparative expression analysis between the two transgenic chlorosis model systems, i-amiCHLI and i-hpHSP90C, in which nuclear genes encoding different chloroplast proteins were similarly silenced.

Impaired Expression of Chloroplast HSP90C Chaperone Activates Plant Defense Responses with a Possible Link to a Disease-Symptom-Like Phenotype.

RNA-seq analysis of a transgenic tobacco plant, i-hpHSP90C, in which chloroplast HSP90C genes can be silenced in an artificially inducible manner resulting in the development of chlorosis, revealed the up- and downregulation of 2746 and 3490 genes, respectively. Gene ontology analysis of these differentially expressed genes indicated the upregulation of ROS-responsive genes; the activation of the innate immunity and cell death pathways; and the downregulation of genes involved in photosynthesis, plastid organization, and cell cycle. Cell death was confirmed by trypan blue staining and electrolyte leakage assay, and the H2O2 production was confirmed by diaminobenzidine staining. The results collectively suggest that the reduced levels of HSP90C chaperone lead the plant to develop chlorosis primarily through the global downregulation of chloroplast- and photosynthesis-related genes and additionally through the light-dependent production of ROS, followed by the activation of immune responses, including cell death.

[Composite adult T-cell leukemia/lymphoma and Epstein-Barr virus-positive diffuse large B-cell lymphoma].

Human T-cell leukemia virus type I (HTLV-1) infection and adult T-cell leukemia-lymphoma (ATL) have been shown to cause immunodeficiency. However, only a few cases have been reported on the development of Epstein-Barr virus positive-diffuse large B-cell lymphoma (EBV-DLBCL) in HTLV-1 carriers or in patients with ATL. Here we report a case of a female HTLV-1 carrier who developed cytomegalovirus (CMV) retinitis. During the CMV retinitis treatment, she developed a liver tumor. The diagnosis of composite ATL and EBV-DLBCL was made by tumor biopsy. The patient also suffered from pulmonary cryptococcosis and invasive pulmonary aspergillosis at the time of chemotherapy initiation. She had repeated CMV antigenemia and bacterial sepsis during the course of chemotherapy, and she died of bacterial sepsis. HTLV-1 carriers who are complicated with opportunistic infections should be carefully observed not only for ATL development but also for the development of EBV-DLBCL and associated infectious complications.

Treatment with mogamulizumab or lenalidomide for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: The Nagasaki transplant group experience.

Mogamulizumab (Mog) and lenalidomide (Len) are new therapeutic candidates for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present study, we retrospectively analyzed 12 patients who received Mog or Len monotherapy for relapsed ATL after allo-HSCT. Eight and three patients received Mog and Len, respectively. The remaining patient received Mog for the first relapse and Len for the third relapse. A complete response was achieved by three and two patients who received Mog and Len, respectively, two and one of whom remained alive with a complete response for more than 20 months. In terms of adverse events, the emergence or progression of graft-versus-host disease was observed in three out of four patients treated with Len and in none of the patients treated with Mog. The development or progression of cytomegalovirus reactivation was detected in four out of eight patients treated with Mog and in none of those treated with Len. The present results suggest that Mog and Len would be promising treatment options for relapsed ATL after allo-HSCT and need to be selected based on adverse event profiles.

[Ectopic pulmonary calcification after parathyroidectomy in multiple myeloma].

Ectopic soft tissue calcification (ESTC), a rare clinical condition, causes tissue and organ damage. It is associated with chronic renal failure, hyperparathyroidism, and malignant neoplasms, including multiple myeloma, and it is reportedly resistant to treatment. Here, we present the case of a 71-year-old male with multiple myeloma who had rapid ESTC in the lung. He had developed hypoparathyroidism secondary to thyroidectomy. During the course of our observation, he rapidly developed ectopic pulmonary calcification approximately 2 weeks after acquiring an infection. There was no evidence of further progression of multiple myeloma after the onset of ESTC, and treatment with ferric citrate hydrate and precipitated calcium resulted in immediate improvement of his pulmonary signs. We recommend cautious monitoring for patients with multiple myeloma and hypoparathyroidism to detect the onset of ectopic calcification. In addition, low blood phosphorus levels should be effectively treated.