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1.
Intern Med ; 2024 Jun 06.
Article En | MEDLINE | ID: mdl-38839334

Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation (LP/L-IDD) are rare entities associated with the use of immunosuppressive drugs (ISD) for autoimmune conditions. Composite lymphomas, featuring both B-cell and T-cell lymphomas, are infrequent, and their occurrence as LP/L-IDD is rare. We herein report the case of a 70-year-old man with right pleural effusion and lymphadenopathy, who was treated with infliximab for sarcoidosis and ankylosing spondylitis. A biopsy revealed a composite lymphoma of DLBCL and PTCL-NOS. CHOP chemotherapy led to significant remission. This case report emphasizes the need to consider lymphoma in patients with autoimmune diseases such as sarcoidosis and ankylosing spondylitis, especially those treated with ISDs.

2.
J Clin Immunol ; 44(6): 126, 2024 May 22.
Article En | MEDLINE | ID: mdl-38773000

Alemtuzumab is used with reduced-toxicity conditioning (RTC) in allogeneic hematopoietic cell transplantation (HCT), demonstrating efficacy and feasibility for patients with inborn errors of immunity (IEI) in Western countries; however, the clinical experience in Asian patients with IEI is limited. We retrospectively analyzed patients with IEI who underwent the first allogeneic HCT with alemtuzumab combined with RTC regimens in Japan. A total of 19 patients were included and followed up for a median of 18 months. The donors were haploidentical parents (n = 10), matched siblings (n = 2), and unrelated bone marrow donors (n = 7). Most patients received RTC regimens containing fludarabine and busulfan and were treated with 0.8 mg/kg alemtuzumab with intermediate timing. Eighteen patients survived and achieved stable engraftment, and no grade 3-4 acute graft-versus-host disease was observed. Viral infections were observed in 11 patients (58%) and 6 of them presented symptomatic. The median CD4+ T cell count was low at 6 months (241/µL) but improved at 1 year (577/µL) after HCT. Whole blood cells continued to exhibit > 80% donor type in most cases; however, 3/10 patients exhibited poor donor chimerism only among T cells and also showed undetectable levels of T-cell receptor recombination excision circles (TRECs) at 1 year post-HCT. This study demonstrated the efficacy and safety of alemtuzumab; however, patients frequently developed viral infections and slow reconstitution or low donor chimerism in T cells, emphasizing the importance of monitoring viral status and T-cell-specific chimerism. (238 < 250 words).


Alemtuzumab , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Transplantation Conditioning , Transplantation, Homologous , Humans , Alemtuzumab/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Male , Female , Transplantation Conditioning/methods , Child, Preschool , Child , Infant , Graft vs Host Disease/etiology , Retrospective Studies , Asian People , Treatment Outcome , Adolescent
3.
Rinsho Ketsueki ; 65(3): 158-163, 2024.
Article Ja | MEDLINE | ID: mdl-38569859

Although alectinib is effective for relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL) and has a favorable safety profile, its role as a bridging therapy for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the role of allo-HSCT itself in this setting are unknown. A 35-year-old man with ALK-positive ALCL experienced relapse after first-line therapy with CHOP. Brentuximab vedotin led to partial response and high-dose chemotherapy combined with autologous HSCT was performed. However, disease progressed 15 months after transplantation, and alectinib was initiated. Complete response (CR) was achieved after three months of treatment, and alectinib was continued for 5 months. After cessation of alectinib, allogeneic bone marrow transplantation from an HLA 1-locus mismatched unrelated donor was performed after conditioning with fludarabine, busulfan, and total body irradiation. GVHD prophylaxis consisted of tacrolimus and short-term methotrexate. The post-transplant course was unremarkable except for grade I acute GVHD. The lymphoma has not recurred for 2 years after allo-HSCT without resuming alectinib. The clinical course of our case suggests that alectinib bridging therapy and allo-HSCT are effective in relapsed/refractory ALK-positive ALCL.


Carbazoles , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Lymphoma, Large-Cell, Anaplastic , Piperidines , Male , Humans , Adult , Lymphoma, Large-Cell, Anaplastic/therapy , Neoplasm Recurrence, Local , Receptor Protein-Tyrosine Kinases/therapeutic use
4.
Ann Hematol ; 103(5): 1737-1744, 2024 May.
Article En | MEDLINE | ID: mdl-38509389

Although it is known that BK polyomavirus (BKPyV) causes hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of BKPyV viremia has not been fully evaluated. We retrospectively analyzed the results of quantitative polymerase chain reaction (PCR) evaluations for detecting BKPyV in the whole blood samples of patients undergoing allogeneic HSCT during the period from January 2010 to June 2020 at a single institute, Tokyo Medical and Dental University. BKPyV was detected in the blood of 28 of the 107 evaluated patients, and the cumulative incidence of was 27.9% (95%CI: 20.2-37.9%). HC due to BKPyV developed in four of the 28 patients with BKPyV viremia (14.3%) and in two of the 79 patients without it (2.5%; P < 0.05). BKPyV viremia itself did not affect the patients' post-transplant estimated glomerular filtration rate (eGFR), but BKPyV viremia with a high viral load was significantly associated with decreased eGFR values (P < 0.05). BKPyV viremia was also associated with significantly lower progression-free survival at 3 years (35.1% [95%CI: 17.8-53.1%] vs. 60.4% [95%CI: 48.4-70.5], P < 0.05). Our findings demonstrated that BKPyV viremia was associated with onset of HC, an early decline of renal function, and poorer survival after allogeneic HSCT. Further studies are needed to test these results and elucidate the mechanisms of renal dysfunction associated with BKPyV viremia.


BK Virus , Cystitis, Hemorrhagic , Cystitis , Hematopoietic Stem Cell Transplantation , Polyomavirus Infections , Tumor Virus Infections , Humans , Retrospective Studies , Viremia/complications , Polyomavirus Infections/complications , Hematopoietic Stem Cell Transplantation/adverse effects , Tumor Virus Infections/epidemiology
5.
PLoS One ; 19(2): e0296675, 2024.
Article En | MEDLINE | ID: mdl-38394294

Although spinach is predominantly dioecious, monoecious plants with varying proportions of female and male flowers are also present. Recently, monoecious inbred lines with highly female and male conditions have been preferentially used as parents for F1-hybrids, rather than dioecious lines. Accordingly, identifying the loci for monoecism is an important issue for spinach breeding. We here used long-read sequencing and Hi-C technology to construct SOL_r2.0_pseudomolecule, a set of six pseudomolecules of spinach chromosomes (total length: 879.2 Mb; BUSCO complete 97.0%) that are longer and more genetically complete than our previous version of pseudomolecules (688.0 Mb; 81.5%). Three QTLs, qFem2.1, qFem3.1, and qFem6.1, responsible for monoecism were mapped to SOL_r2.0_pseudomolecule. qFem3.1 had the highest LOD score and corresponded to the M locus, which was previously identified as a determinant of monoecious expression, by genetic analysis of progeny from female and monoecious plants. The other QTLs were shown to modulate the ratio of female to male flowers in monoecious plants harboring a dominant allele of the M gene. Our findings will enable breeders to efficiently produce highly female- and male-monoecious parental lines for F1-hybrids by pyramiding the three QTLs. Through fine-mapping, we narrowed the candidate region for the M locus to a 19.5 kb interval containing three protein-coding genes and one long non-coding RNA gene. Among them, only RADIALIS-like-2a showed a higher expression in the reproductive organs, suggesting that it might play a role in reproductive organogenesis. However, there is no evidence that it is involved in the regulation of stamen and pistil initiation, which are directly related to the floral sex differentiation system in spinach. Given that auxin is involved in reproductive organ formation in many plant species, genes related to auxin transport/response, in addition to floral organ formation, were identified as candidates for regulators of floral sex-differentiation from qFem2.1 and qFem6.1.


Plant Breeding , Spinacia oleracea , Spinacia oleracea/genetics , Quantitative Trait Loci/genetics , Chromosomes, Plant/genetics , Indoleacetic Acids
6.
Front Plant Sci ; 15: 1304366, 2024.
Article En | MEDLINE | ID: mdl-38318497

We have previously reported a wide variation in salt tolerance among Arabidopsis thaliana accessions and identified ACQOS, encoding a nucleotide-binding leucine-rich repeat (NLR) protein, as the causal gene responsible for the disturbance of acquired osmotolerance induced after mild salt stress. ACQOS is conserved among Arabidopsis osmosensitive accessions, including Col-0. In response to osmotic stress, it induces detrimental autoimmunity, resulting in suppression of osmotolerance, but how ACQOS triggers autoimmunity remains unclear. Here, we screened acquired osmotolerance (aot) mutants from EMS-mutagenized Col-0 seeds and isolated the aot19 mutant. In comparison with the wild type (WT), this mutant had acquired osmotolerance and decreased expression levels of pathogenesis-related genes. It had a mutation in a splicing acceptor site in NUCLEOPORIN 85 (NUP85), which encodes a component of the nuclear pore complex. A mutant with a T-DNA insertion in NUP85 acquired osmotolerance similar to aot19. The WT gene complemented the osmotolerant phenotype of aot19. We evaluated the acquired osmotolerance of five nup mutants of outer-ring NUPs and found that nup96, nup107, and aot19/nup85, but not nup43 or nup133, showed acquired osmotolerance. We examined the subcellular localization of the GFP-ACQOS protein and found that its nuclear translocation in response to osmotic stress was suppressed in aot19. We suggest that NUP85 is essential for the nuclear translocation of ACQOS, and the loss-of-function mutation of NUP85 results in acquired osmotolerance by suppressing ACQOS-induced autoimmunity in response to osmotic stress.

7.
Plant Physiol ; 194(2): 1166-1180, 2024 Jan 31.
Article En | MEDLINE | ID: mdl-37878763

Calcium (Ca2+) is a major ion in living organisms, where it acts as a second messenger for various biological phenomena. The Golgi apparatus retains a higher Ca2+ concentration than the cytosol and returns cytosolic Ca2+ to basal levels after transient elevation in response to environmental stimuli such as osmotic stress. However, the Ca2+ transporters localized in the Golgi apparatus of plants have not been clarified. We previously found that a wild-type (WT) salt-tolerant Arabidopsis (Arabidopsis thaliana) accession, Bu-5, showed osmotic tolerance after salt acclimatization, whereas the Col-0 WT did not. Here, we isolated a Bu-5 background mutant gene, acquired osmotolerance-defective 6 (aod6), which reduces tolerance to osmotic, salt, and oxidative stresses, with a smaller plant size than the WT. The causal gene of the aod6 mutant encodes CATION CALCIUM EXCHANGER4 (CCX4). The aod6 mutant was more sensitive than the WT to both deficient and excessive Ca2+. In addition, aod6 accumulated higher Ca2+ than the WT in the shoots, suggesting that Ca2+ homeostasis is disturbed in aod6. CCX4 expression suppressed the Ca2+ hypersensitivity of the csg2 (calcium sensitive growth 2) yeast (Saccharomyces cerevisiae) mutant under excess CaCl2 conditions. We also found that aod6 enhanced MAP kinase 3/6 (MPK3/6)-mediated immune responses under osmotic stress. Subcellular localization analysis of mGFP-CCX4 showed GFP signals adjacent to the trans-Golgi apparatus network and co-localization with Golgi apparatus-localized markers, suggesting that CCX4 localizes in the Golgi apparatus. These results suggest that CCX4 is a Golgi apparatus-localized transporter involved in the Ca2+ response and plays important roles in osmotic tolerance, shoot Ca2+ content, and normal growth of Arabidopsis.


Arabidopsis Proteins , Arabidopsis , Arabidopsis/metabolism , Calcium/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Golgi Apparatus/metabolism , trans-Golgi Network/metabolism , Membrane Transport Proteins/metabolism , Saccharomyces cerevisiae/metabolism
8.
Br J Haematol ; 204(4): 1279-1287, 2024 Apr.
Article En | MEDLINE | ID: mdl-38131400

Primary vitreoretinal lymphoma (PVRL) is a rare subtype of malignant lymphoma with a poor prognosis because of high frequency of central nervous system (CNS) progression. Identification of factors associated with CNS progression is essential to improve the prognosis of patients with PVRL. We conducted a retrospective study of 54 patients diagnosed with PVRL and treated at our hospital to identify factors associated with CNS progression and prognosis. All patients were treated with intravitreal methotrexate (MTX) injections in the affected eyes until lesion resolution. Twenty-four patients were treated with systemic administration of high-dose MTX (systemic HD-MTX) every other week for a total of five cycles following intravitreal MTX injection. Of 24 patients, 20 completed five cycles of systemic HD-MTX. The 5-year cumulative incidence of CNS progression and overall survival (OS) rate were 78.0% and 69.0% respectively. By univariate and multivariate analyses, bilateral disease and the detection of B-cell clonality confirmed by flow cytometric analysis were risk factors associated with CNS progression. Moreover, systemic HD-MTX completion reduced the risk of CNS progression and was identified as a factor affecting OS. In this study, factors for CNS progression identified may potentially contribute to the optimized therapeutic stratification to improve the survival of patients with PVRL.


Central Nervous System Neoplasms , Lymphoma , Retinal Neoplasms , Humans , Retinal Neoplasms/drug therapy , Retinal Neoplasms/pathology , Retrospective Studies , Vitreous Body/pathology , Lymphoma/drug therapy , Central Nervous System/pathology , Methotrexate
9.
Asian Cardiovasc Thorac Ann ; 32(2-3): 133-135, 2024 Mar.
Article En | MEDLINE | ID: mdl-38146143

Tetralogy of Fallot was repaired previously in a preschooler through right ventriculotomy, providing excellent exposure for ventricular septal defect closure and right ventricular outflow tract obstruction relief. Herein, we describe the preschooler as a 50-year-old man with untreated atrial septal defect found at pulmonary valve replacement in the remote period after tetralogy of Fallot repair. It was inferred intraoperatively that the previous tetralogy of Fallot was repaired only through right ventriculotomy, and atrial septal defect closure was performed together with pulmonary valve replacement.


Cardiac Surgical Procedures , Heart Septal Defects, Atrial , Heart Septal Defects, Ventricular , Tetralogy of Fallot , Male , Humans , Middle Aged , Tetralogy of Fallot/surgery , Treatment Outcome , Heart Septal Defects, Atrial/surgery , Heart Septal Defects, Ventricular/surgery
10.
Rinsho Ketsueki ; 64(11): 1426-1430, 2023.
Article Ja | MEDLINE | ID: mdl-38072429

A 43-year-old man presenting with oral bleeding was diagnosed with acute promyelocytic leukemia (APL). Induction chemotherapy consisting of all-trans retinoic acid and idarubicin was initiated, and disseminated intravascular coagulation (DIC) was treated with fresh frozen plasma and recombinant thrombomodulin infusions. The patient was free from neurological symptoms throughout the clinical course. However, cerebral hemorrhagic lesions were detected incidentally on magnetic resonance imaging performed to screen for leukemic central nervous system invasion at 2 weeks after treatment initiation. Imaging findings suggested subacute or later-phase cerebral hemorrhage. Platelet transfusions and other supportive care was provided. Serial imaging evaluations confirmed reduction of the hemorrhagic lesions. Hematological remission was achieved after induction chemotherapy, and no symptoms due to cerebral hemorrhage developed during the subsequent consolidation therapy. As patients with APL characteristically experience hemorrhagic events due to bleeding tendency caused by DIC, physicians should be aware of the possibility of asymptomatic cerebral hemorrhage in these patients.


Disseminated Intravascular Coagulation , Hemorrhagic Disorders , Leukemia, Promyelocytic, Acute , Male , Humans , Adult , Leukemia, Promyelocytic, Acute/complications , Leukemia, Promyelocytic, Acute/drug therapy , Disseminated Intravascular Coagulation/etiology , Tretinoin/therapeutic use , Cerebral Hemorrhage/complications , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
11.
Gels ; 9(12)2023 Nov 25.
Article En | MEDLINE | ID: mdl-38131914

α-Form hydrated crystals form a lamellar gel in which the alkyl chains of the amphiphilic molecules are hexagonally arranged within bilayers below the gel-liquid crystal phase transition temperature. In practice, the lamellar gel network with excess water is called an "α-gel", particularly in the cosmetics industry. In this study, the hydration or water sorption of amphiphilic materials in water vapor was assessed using a humidity-controlled quartz crystal microbalance with dissipation monitoring (QCM-D) technique. The amphiphilic materials used in this study were hexadecyl phosphate salts neutralized with L-arginine (C16P-Arg), CsOH (C16P-Cs), KOH (C16P-K), and NaOH (C16P-Na). Small- and wide-angle X-ray scattering measurements revealed that C16P-Arg and C16P-Cs yielded α-form hydrated crystals. Humidity-controlled QCM-D measurements demonstrated that C16P-Arg and C16P-Cs more readily underwent hydration or water sorption than C16P-K and C16P-Na. The key conclusion is that the significant hydration ability of C16P-Arg and C16P-Cs promotes the formation of the corresponding α-form hydrated crystals.

12.
PNAS Nexus ; 2(11): pgad329, 2023 Nov.
Article En | MEDLINE | ID: mdl-38024402

Plants are often exposed not only to short-term (S-) but also to long-term (L-)heat stress over several consecutive days. A few Arabidopsis mutants defective in L-heat tolerance have been identified, but the molecular mechanisms are less understood for this tolerance than for S-heat stress tolerance. To elucidate the mechanisms of the former, we used a forward genetic screen for sensitive to long-term heat (sloh) mutants and isolated sloh3 and sloh63. The mutants were hypersensitive to L- but not to S-heat stress, and sloh63 was also hypersensitive to salt stress. We identified the causal genes, SLOH3 and SLOH63, both of which encoded splicing-related components of the MOS4-associated complex (MAC). This complex is widely conserved in eukaryotes and has been suggested to interact with spliceosomes. Both genes were induced by L-heat stress in a time-dependent manner, and some abnormal splicing events were observed in both mutants under L-heat stress. In addition, endoplasmic reticulum (ER) stress and subsequent unfolded protein response occurred in both mutants under L-heat stress and were especially prominent in sloh63, suggesting that enhanced ER stress is due to the salt hypersensitivity of sloh63. Splicing inhibitor pladienolide B led to concentration-dependent disturbance of splicing, decreased L-heat tolerance, and enhanced ER stress. These findings suggest that maintenance of precise mRNA splicing under L-heat stress by the MAC is important for L-heat tolerance and suppressing ER stress in Arabidopsis.

13.
PNAS Nexus ; 2(11): pgad348, 2023 Nov.
Article En | MEDLINE | ID: mdl-38024403

Natural genetic variation has facilitated the identification of genes underlying complex traits such as stress tolerances. We here evaluated the long-term (L-) heat tolerance (37°C for 5 days) of 174 Arabidopsis thaliana accessions and short-term (S-) heat tolerance (42°C, 50 min) of 88 accessions and found extensive variation, respectively. Interestingly, L-heat-tolerant accessions are not necessarily S-heat tolerant, suggesting that the tolerance mechanisms are different. To elucidate the mechanisms underlying the variation, we performed a chromosomal mapping using the F2 progeny of a cross between Ms-0 (a hypersensitive accession) and Col-0 (a tolerant accession) and found a single locus responsible for the difference in L-heat tolerance between them, which we named Long-term Heat Tolerance 1 (LHT1). LHT1 is identical to MAC7, which encodes a putative RNA helicase involved in mRNA splicing as a component of the MOS4 complex. We found one amino acid deletion in LHT1 of Ms-0 that causes a loss of function. Arabidopsis mutants of other core components of the MOS4 complex-mos4-2, cdc5-1, mac3a mac3b, and prl1 prl2-also showed hypersensitivity to L-heat stress, suggesting that the MOS4 complex plays an important role in L-heat stress responses. L-heat stress induced mRNA processing-related genes and compromised alternative splicing. Loss of LHT1 function caused genome-wide detrimental splicing events, which are thought to produce nonfunctional mRNAs that include retained introns under L-heat stress. These findings suggest that maintaining proper alternative splicing under L-heat stress is important in the heat tolerance of A. thaliana.

14.
FEBS Lett ; 597(19): 2473-2483, 2023 Oct.
Article En | MEDLINE | ID: mdl-37698340

Grimontia hollisae collagenase (Ghcol) exhibits high collagen-degrading activity. To explore its catalytic mechanism, its substrate (Gly-Pro-Hyp-Gly-Pro-Hyp, GPOGPO)-complexed crystal structure was determined at 2.0 Å resolution. A water molecule was observed near the active-site zinc ion. Since this water was not observed in the product (GPO)-complexed Ghcol, it was hypothesized that the GPOGPO-complexed Ghcol structure reflects a Michaelis complex, providing a structural basis for understanding the catalytic mechanism. Analyses of the active-site geometry and site-directed mutagenesis of the active-site tyrosine residues revealed that Glu493 and Tyr564 were essential for catalysis, suggesting that Glu493 functions as an acid and base catalyst while Tyr564 stabilizes the tetrahedral complex in the transition state. These results shed light on the catalytic mechanism of bacterial collagenase.

15.
Sci Rep ; 13(1): 13762, 2023 08 23.
Article En | MEDLINE | ID: mdl-37612373

Recently, TNF receptor type 2 (TNFR2) signaling was found to be involved in the proliferation and activation of regulatory T cells (Tregs), a subpopulation of lymphocytes that suppress immune responses. Tregs mediate peripheral immune tolerance, and the disruption of their functions causes autoimmune diseases or allergy. Therefore, cell expanders or regulators of Tregs that control immunosuppressive activity can be used to treat these diseases. We focused on TNFR2, which is preferentially expressed on Tregs, and created tumor necrosis factor-α (TNF-α) muteins that selectively activate TNFR2 signaling in mice and humans, termed R2agoTNF and R2-7, respectively. In this study, we attempted to optimize the structure of muteins to enhance their TNFR2 agonistic activity and stability in vivo by IgG-Fc fusion following single-chain homo-trimerization. The fusion protein, scR2agoTNF-Fc, enhanced the expansion of CD4+CD25+ Tregs and CD4+Foxp3+ Tregs and contributed to their immunosuppressive activity ex vivo and in vivo in mice. The prophylactic administration of scR2agoTNF-Fc suppressed inflammation in contact hypersensitivity and arthritis mouse models. Furthermore, scR2-7-Fc preferentially expanded Tregs in human peripheral blood mononuclear cells via TNFR2. These TNFR2 agonist-Fc fusion proteins, which have bivalent structures, are novel Treg expanders.


Arthritis , T-Lymphocytes, Regulatory , Animals , Humans , Mice , Immunosuppressive Agents , Leukocytes, Mononuclear , Receptors, Tumor Necrosis Factor, Type II/genetics , Tumor Necrosis Factor-alpha
16.
Nihon Shokakibyo Gakkai Zasshi ; 120(7): 610-614, 2023.
Article Ja | MEDLINE | ID: mdl-37423732

A 79-year-old woman underwent colonoscopy that revealed a 30-mm-sized nodular, mixed-type, lateral spreading tumor-granular in the lower rectum. Endoscopic submucosal dissection was performed, and the pathological findings indicated a mostly adenoma-type tumor with synaptophysin, cluster of differentiation 56-positive, and chromogranin A-negative associated with neuroendocrine carcinoma. Surgical resection was performed owing to vascular invasion, and the lymph node metastasis of the endocrine carcinoma component was observed. Thus, we reported a rare case of the coexistence of adenoma and neuroendocrine carcinoma.


Adenoma , Carcinoma, Neuroendocrine , Rectal Neoplasms , Aged , Female , Humans , Adenoma/pathology , Adenoma/surgery , Carcinoma, Neuroendocrine/pathology , Carcinoma, Neuroendocrine/surgery , Lymphatic Metastasis , Rectal Neoplasms/pathology , Rectal Neoplasms/surgery , Colonoscopy
17.
Biomaterials ; 299: 122174, 2023 08.
Article En | MEDLINE | ID: mdl-37285642

Although the extracellular matrix (ECM) plays essential roles in heart tissue engineering, the optimal ECM components for heart tissue organization have not previously been elucidated. Here, we focused on the main ECM component, fibrillar collagen, and analyzed the effects of collagens on heart tissue engineering, by comparing the use of porcine heart-derived collagen and other organ-derived collagens in generating engineered heart tissue (EHT). We demonstrate that heart-derived collagen induces better contraction and relaxation of human induced pluripotent stem cell-derived EHT (hiPSC-EHT) and that hiPSC-EHT with heart-derived collagen exhibit more mature profiles than those with collagens from other organs. Further, we found that collagen fibril formation and gel stiffness influence the contraction, relaxation, and maturation of hiPSC-EHT, suggesting the importance of collagen types III and type V, which are relatively abundant in the heart. Thus, we demonstrate the effectiveness of organ-specific collagens in tissue engineering and drug discovery.


Induced Pluripotent Stem Cells , Tissue Engineering , Animals , Swine , Humans , Myocytes, Cardiac , Collagen/pharmacology , Extracellular Matrix
18.
Cancer Sci ; 114(9): 3719-3727, 2023 Sep.
Article En | MEDLINE | ID: mdl-37365854

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a troublesome problem in patients receiving MTX for rheumatoid arthritis (RA). However, its incidence, prognosis, and risk factors remain unclear. In this retrospective study, we evaluated the actual incidence, prognostic impact, and risk factors of MTX-LPD. Of the 986 patients with RA treated with MTX, 90 patients experienced 95 new malignancies (NMs), with LPD as the most frequent in 26 patients. The cumulative LPD incidences were 1.3% and 4.7% at 5 and 10 years after MTX initiation, respectively. Among the 24 patients who discontinued MTX after developing LPD, 15 showed sustained regression, without difference in overall survival between patients with LPD and without NM. Inflammatory markers and absolute lymphocyte counts were not useful for early LPD development detection, but most of the patients with LPD had persistently elevated erythrocyte sedimentation ratios. Regarding concomitant drugs, tacrolimus increased the risk only if patients were not receiving biological disease-modifying antirheumatic drugs (bDMARDs). bDMARDs did not increase the risk for any of the drugs or the number of classes used. The number of LPD cases was lower in patients with IL-6A even after a long period after MTX, although with no statistically significant difference. Thus, approximately 1 in 20 patients with RA developed MTX-LPD over the 10 years of MTX treatment, but it did not affect the survival of patients with RA. Tacrolimus increased the risk of developing LPD for certain patients and should be used with caution.


Antirheumatic Agents , Arthritis, Rheumatoid , Lymphoproliferative Disorders , Humans , Methotrexate/adverse effects , Retrospective Studies , Tacrolimus/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/complications , Antirheumatic Agents/adverse effects , Lymphoproliferative Disorders/chemically induced , Lymphoproliferative Disorders/epidemiology
19.
Genome Biol Evol ; 15(8)2023 08 01.
Article En | MEDLINE | ID: mdl-37348049

Genome sizes are known to vary within and among closely related species, but the knowledge about genomic factors contributing to the variation and their impacts on gene functions is limited to only a small number of species. This study identified a more than 2-fold heritable genome size variation among the unicellular Zygnematophycean alga, Closterium peracerosum-strigosum-littorale (C. psl.) complex, based on short-read sequencing analysis of 22 natural strains and F1 segregation analysis. Six de novo assembled genomes revealed that genome size variation is largely attributable to genome-wide copy number variation (CNV) among strains rather than mating type-linked genomic regions or specific repeat sequences such as rDNA. Notably, about 30% of genes showed CNV even between strains that can mate with each other. Transcriptome and gene ontology analysis demonstrated that CNV is distributed nonrandomly in terms of gene functions, such that CNV was more often observed in the gene set with stage-specific expression. Furthermore, in about 30% of these genes with CNV, the expression level does not increase proportionally with the gene copy number, suggesting presence of dosage compensation, which was overrepresented in genes involved in basic biological functions, such as translation. Nonrandom patterns in gene duplications and corresponding expression changes in terms of gene functions may contribute to maintaining the high level of CNV associated with extensive genome size variation in the C. psl. complex, despite its possible detrimental effects.


Closterium , Closterium/genetics , Genome Size , DNA Copy Number Variations , Plants/genetics , Reproduction/genetics
20.
Metabolites ; 13(5)2023 May 11.
Article En | MEDLINE | ID: mdl-37233692

Volatile organic compounds (VOCs) play an important role in the biological activities of the medicinal Zingiberaceae species. In commercial preparations of VOCs from Kaempferia parviflora rhizomes, its leaves are wasted as by-products. The foliage could be an alternative source to rhizome, but its VOCs composition has not been explored previously. In this study, the VOCs in the leaves and rhizomes of K. parviflora plants grown in a growth room and in the field were analyzed using the headspace solid-phase microextraction (HS-SPME) method coupled with gas chromatography and time-of-flight mass spectrometry (GC-TOF-MS). The results showed a total of 75 and 78 VOCs identified from the leaves and rhizomes, respectively, of plants grown in the growth room. In the field samples, 96 VOCs were detected from the leaves and 98 from the rhizomes. These numbers are higher compared to the previous reports, which can be attributed to the analytical techniques used. It was also observed that monoterpenes were dominant in leaves, whereas sesquiterpenes were more abundant in rhizomes. Principal component analysis (PCA) revealed significantly higher abundance and diversity of VOCs in plants grown in the field than in the growth room. A high level of similarity of identified VOCs between the two tissues was also observed, as they shared 68 and 94 VOCs in the growth room and field samples, respectively. The difference lies in the relative abundance of VOCs, as most of them are abundant in rhizomes. Overall, the current study showed that the leaves of K. parviflora, grown in any growth conditions, can be further utilized as an alternative source of VOCs for rhizomes.

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