Publications by authors named "Takashi Ishida"

355 Publications

Multipotent progenitors and hematopoietic stem cells arise independently from hemogenic endothelium in the mouse embryo.

Cell Rep 2021 Sep;36(11):109675

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98105, USA. Electronic address:

During embryogenesis, waves of hematopoietic progenitors develop from hemogenic endothelium (HE) prior to the emergence of self-renewing hematopoietic stem cells (HSCs). Although previous studies have shown that yolk-sac-derived erythromyeloid progenitors and HSCs emerge from distinct populations of HE, it remains unknown whether the earliest lymphoid-competent progenitors, multipotent progenitors, and HSCs originate from common HE. In this study, we demonstrate by clonal assays and single-cell transcriptomics that rare HE with functional HSC potential in the early murine embryo are distinct from more abundant HE with multilineage hematopoietic potential that fail to generate HSCs. Specifically, HSC-competent HE are characterized by expression of CXCR4 surface marker and by higher expression of genes tied to arterial programs regulating HSC dormancy and self-renewal. Taken together, these findings suggest a revised model of developmental hematopoiesis in which the initial populations of multipotent progenitors and HSCs arise independently from HE with distinct phenotypic and transcriptional properties.
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http://dx.doi.org/10.1016/j.celrep.2021.109675DOI Listing
September 2021

[A Case of Mucinous Adenocarcinoma Extending to Bladder Neck and Prostate].

Hinyokika Kiyo 2021 Aug;67(8):395-398

The Department of Pathology, Aichi Medecal University Hospital.

A 56-year-old man visited a clinic with the chief complaint of frequent micturition and residual sensation of urine. He was referred to our hospital for close examination. Cystoscopy showed a tumor protruding toward the bladder neck from the prostate with stones and debris on the surface. Magnetic resonance imaging showed an encapsulated tumor of iso-intensity in the prostate in T2-weighed images. Prostate specific antigen was 0.88 mg/dl. Transurethral resection of prostate was performed under the diagnosis of benign prostate hyperplasia. During the operation, a solid tumor with mucus deposit was observed. Intraoperative rapid pathological diagnosis was mucinous adenocarcinoma. A radical cystectomy was performed. Pathologically, mucinous adenocarcinoma was distributed in the bladder neck, the prostate and surrounding tissue, but the prostatic urethra was intact. The surgery was assessed to be curative. Neither neoadjuvant nor adjuvant chemotherapy was performed, since the effectiveness of chemotherapy for mucinous adenocarcinoma arising from urothelial epithelium has not been established.
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http://dx.doi.org/10.14989/ActaUrolJap_67_8_395DOI Listing
August 2021

Subsequent systemic therapy for non-small cell lung cancer patients with immune checkpoint inhibitor-related interstitial lung disease.

Transl Lung Cancer Res 2021 Jul;10(7):3132-3143

Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Although immune checkpoint inhibitors (ICIs) are effective for advanced non-small cell lung cancer (NSCLC), ICIs may cause interstitial lung disease (ILD), which results in treatment discontinuation and is sometimes fatal. Despite the high incidence of ICI-related ILD, there are few cancer treatment options for patients. This study aimed to evaluate the safety and efficacy of subsequent systemic cancer therapy in NSCLC patients with ICI-related ILD.

Methods: We retrospectively assessed NSCLC patients who received programmed cell death-1 (PD-1) inhibitors as first- to third-line therapy at participating institutions of the Niigata Lung Cancer Treatment Group from January 2016 to October 2017.

Results: This analysis included 231 patients, 32 (14%) of whom developed ICI-related ILD. Of these patients, 16 (7%) received subsequent systemic cancer treatments. The median overall survival (OS) tended to be longer in the systemic cancer therapy group than in the no systemic cancer therapy group [22.2 months (95% CI: 1-NE) 4.5 months (95% CI: 1-NE); P=0.067]. ICI-related ILD recurred in half of the patients who received systemic cancer therapy, and the median OS tended to be shorter in patients with recurrent ICI-related ILD [22.0 months (95% CI: 1-NE) 7.0 months (95% CI: 1-NE); P=0.3154].

Conclusions: According to the current study, systemic cancer treatment is effective in patients with ICI-related ILD; however, its safety is uncertain because of the high risk of ICI-related ILD recurrence and poor survival outcome following ILD recurrence.
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http://dx.doi.org/10.21037/tlcr-21-198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350095PMC
July 2021

Clinical significance of TP53 mutations in adult T-cell leukemia/lymphoma.

Br J Haematol 2021 Aug 17. Epub 2021 Aug 17.

Department of Pathology and Molecular Diagnostics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion-deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required.
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http://dx.doi.org/10.1111/bjh.17749DOI Listing
August 2021

Surgical glove perforation during laparoscopic colorectal procedures.

Surg Endosc 2021 Aug 11. Epub 2021 Aug 11.

Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: It has been reported that in conventional open surgery, approximately 10% of surgical gloves are perforated during surgery without being noticed. To protect both the patient and medical staff from harm, double gloving or changing gloves routinely at certain intervals during surgery is recommended. However, whether these protective measures are also necessary for laparoscopic colorectal surgery is unknown because the actual perforation rate during laparoscopic procedures is unclear.

Methods: Seventy-seven laparoscopic colorectal surgeries were evaluated, and a total of 616 surgical gloves used in the surgeries were collected for analysis. The presence of glove perforation was tested by the standard water-leak test method (EN455-1).

Results: Seven perforations were detected (1.1%). The duration of the laparoscopic procedure was not a statistically significant risk factor for glove perforation (p = 0.41). Postoperative surgical site infections (SSIs) were observed in 12 cases (15.6%), but there was no significant correlation between the presence of glove perforation and SSI (p = 0.92). According to the bacterial cultivation results, the majority of causative agents of SSI were enterobacteria, which belong to the major gut flora.

Conclusion: Although the perforation rate was considerably lower than that in open surgery, surgical glove perforation occurred during laparoscopic procedures. Double gloving in laparoscopic colorectal surgery is recommended not to prevent SSI but to protect medical workers from harmful infections after direct contact with the patient.
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http://dx.doi.org/10.1007/s00464-021-08670-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356683PMC
August 2021

Another route of CO gas excretion independent of red blood cells in human lungs.

Pflugers Arch 2021 Oct 12;473(10):1657-1666. Epub 2021 Jul 12.

Department of Innovation of Medical and Health Sciences Research, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.

We demonstrated pulmonary arteriolar blood flow-mediated CO gas excretion in rabbit lungs. The shear stress stimulation produced CO gas in cultured human endothelial cells of pulmonary arterioles via the activation of F/F ATP synthase. To confirm the findings in human subjects undergoing the operation with heart-lung machines, we aimed to evaluate the effects of a stepwise switch, from a partial to a complete cardiopulmonary bypass, of the circulatory blood volume (BV, 100% = 2.4 × cardiac index), on the end-expiratory CO pressure (PetCO), maximal flow velocity in the pulmonary artery (Max Vp), the inner diameter (ID) of pulmonary artery, pulmonary arterial CO pressure (P mix v CO), pulmonary arterial O pressure (P mix v O), hematocrit (Hct), pH, the concentration of HCO, and base excess (BE) in mixed venous blood in 9 patients with a mean age of 72.3 ± 3.4 years. In addition, the effects of the decrease in Hct infused with physiological saline solution (PSS) on PetCO were investigated in the human subjects. An approximately linear relationship between the PetCO and Max Vp was observed. The pumping out of 100% BV produced little or no change in the Hct, pH, P mix v CO, and P mix v O, respectively. The hemodilution produced by intravenous infusion of PSS caused a significant decrease in the Hct, but not in the PetCO. In conclusion, another route of CO gas excretion, independent of red blood cells, may be involved in human lungs.
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http://dx.doi.org/10.1007/s00424-021-02586-3DOI Listing
October 2021

Impact of intraoperative hypocapnia on postoperative complications in laparoscopic surgery for colorectal cancer.

Surg Today 2021 Jun 29. Epub 2021 Jun 29.

Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Purpose: In laparoscopic surgery (LS) for colorectal cancer (CRC), the relationship between intraoperative end-tidal carbon dioxide concentration (EtCO) and surgery-related complications remains unexplored. This study assessed the impact of intraoperative EtCO on postoperative complications in LS for CRC.

Methods: In total, 909 patients who underwent LS for CRC were enrolled. Hypocapnia and hypercapnia were defined as EtCO < 35 mmHg and > 40 mmHg, respectively, and the relationships between hypocapnia or hypercapnia duration and postoperative complications were analyzed.

Results: The median (range) durations of hypocapnia and hypercapnia were 2.0 (0-8.3) h and 0.3 (0-5.8) h, respectively. Complications were observed in 208 cases (23.0%), which included 37 (4.1%) instances of anastomotic leakage and 86 (9.5%) of superficial surgical site infection (SSI). While the hypercapnia duration was not associated with the short-term outcomes, prolonged hypocapnia was significantly correlated with complications (p = 0.02), specifically superficial SSI (p = 0.005). Multivariate analyses adjusted for confounding factors confirmed that hypocapnia prolongation was an independent risk factor for postoperative superficial SSI [OR 1.19; 95% confidence interval (Cl) 1.03-1.36, p = 0.01].

Conclusion: Intraoperative hypocapnia may be a risk factor for postoperative complications, in particular superficial SSI, in LS for CRC.
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http://dx.doi.org/10.1007/s00595-021-02315-4DOI Listing
June 2021

Identification of genes involved in -induced gall formation processes in .

Plant Biotechnol (Tokyo) 2021 Mar;38(1):1-8

Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto, Kumamoto 860-8555, Japan.

Root-knot nematodes (RKN; ) are phytoparasitic nematodes that cause significant damage to crop plants worldwide. Recent studies have revealed that RKNs disrupt various physiological processes in host plant cells to induce gall formation. However, little is known about the molecular mechanisms of gall formation induced by nematodes. We have previously found that RNA expression levels of some of genes related to micro-RNA, cell division, membrane traffic, vascular formation, and meristem maintenance system were modified by nematode infection. Here we evaluated these genes importance during nematode infection by using Arabidopsis mutants and/or β-glucronidase (GUS) marker genes, particularly after inoculation with nematodes, to identify the genes involved in successful nematode infection. Our results provide new insights not only for the basic biology of plant-nematode interactions but also to improve nematode control in an agricultural setting.
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http://dx.doi.org/10.5511/plantbiotechnology.20.0716aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215457PMC
March 2021

Taxonomic and Gene Category Analyses of Subgingival Plaques from a Group of Japanese Individuals with and without Periodontitis.

Int J Mol Sci 2021 May 18;22(10). Epub 2021 May 18.

Department of Microbiology, Tokyo Dental College, Chiyoda-ku, Tokyo 101-0061, Japan.

Periodontitis is an inflammation of tooth-supporting tissues, which is caused by bacteria in the subgingival plaque (biofilm) and the host immune response. Traditionally, subgingival pathogens have been investigated using methods such as culturing, DNA probes, or PCR. The development of next-generation sequencing made it possible to investigate the whole microbiome in the subgingival plaque. Previous studies have implicated dysbiosis of the subgingival microbiome in the etiology of periodontitis. However, details are still lacking. In this study, we conducted a metagenomic analysis of subgingival plaque samples from a group of Japanese individuals with and without periodontitis. In the taxonomic composition analysis, genus and demonstrated significantly different compositions between healthy sites and sites with periodontal pockets. The results from the relative abundance of functional gene categories, carbohydrate metabolism, glycan biosynthesis and metabolism, amino acid metabolism, replication and repair showed significant differences between healthy sites and sites with periodontal pockets. These results provide important insights into the shift in the taxonomic and functional gene category abundance caused by dysbiosis, which occurs during the progression of periodontal disease.
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http://dx.doi.org/10.3390/ijms22105298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157553PMC
May 2021

Efficacy and Safety of Nivolumab and Ipilimumab for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Cohort Study.

Curr Oncol 2021 04 3;28(2):1402-1411. Epub 2021 Apr 3.

Department of Urology, Graduate School of Medicine, Gifu University, Gifu 5011194, Japan.

We conducted a multicenter, retrospective study to evaluate the efficacy and safety of combination nivolumab plus ipilimumab (NIVO+IPI) in 35 patients with advanced or metastatic renal cell carcinoma (mRCC). In this study, we focused on patients who received NIVO+IPI and were stratified into intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium model at five institutions in Japan. The primary endpoint was overall survival (OS). Secondary endpoints were disease control rate (DCR), best overall response (BOR), objective response rate (ORR), and progression-free survival (PFS). In addition, we evaluated the role of inflammatory cell ratios, namely neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as predictive biomarkers in patients with mRCC. The median follow-up period was 1 year, and the 1-year OS rate was 95.8%. The ORR and DCR were 34.3% and 80.0%, respectively. According to BOR, four patients (11.4%) achieved complete response. According to NLR stratification, the 1-year PFS rates were 82.6% and 23.7% when the NLR was ≤4.6 and >4.6, respectively ( = 0.04). Based on PLR stratification, the 1-year PFS rates were 81.7% and 34.3% when the PLR was ≤188.1 and >188.1, respectively ( = 0.033). Although 71.4% of the patients experienced treatment-related adverse events (TRAEs) with NIVO+IPI, only four patients discontinued NIVO+IPI due to grade 3/4 TRAEs. Patients treated with NIVO+IPI as a first-line therapy for advanced or mRCC achieved relatively better oncological outcomes. Therefore, NIVO+IPI may have potential advantages and may lead to a treatment effect compared to those receiving targeted therapies. In addition, PLR >188.1 may be a useful predictive marker for mRCC patients who received NIVO+IPI.
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http://dx.doi.org/10.3390/curroncol28020133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167798PMC
April 2021

Computer aided drug discovery review for infectious diseases with case study of anti-Chagas project.

Parasitol Int 2021 Aug 27;83:102366. Epub 2021 Apr 27.

Department of Computer Science, School of Computing, Tokyo Institute of Technology, 4259-J3-23, Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan. Electronic address:

Neglected tropical diseases (NTDs) are parasitic and bacterial infections that are widespread, especially in the tropics, and cause health problems for about one billion people over 149 countries worldwide. However, in terms of therapeutic agents, for example, nifurtimox and benznidazole were developed in the 1960s to treat Chagas disease, but new drugs are desirable because of their side effects. Drug discovery takes 12 to 14 years and costs $2.6 billon dollars, and hence, computer aided drug discovery (CADD) technology is expected to reduce the time and cost. This paper describes our methods and results based on CADD, mainly for NTDs. An overview of databases, molecular simulation and pharmacophore modeling, contest-based drug discovery, and machine learning and their results are presented herein.
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http://dx.doi.org/10.1016/j.parint.2021.102366DOI Listing
August 2021

P3CMQA: Single-Model Quality Assessment Using 3DCNN with Profile-Based Features.

Bioengineering (Basel) 2021 Mar 19;8(3). Epub 2021 Mar 19.

Department of Computer Science, School of Computing, Tokyo Institute of Technology, Ookayama, Meguro-ku, Tokyo 152-8550, Japan.

Model quality assessment (MQA), which selects near-native structures from structure models, is an important process in protein tertiary structure prediction. The three-dimensional convolution neural network (3DCNN) was applied to the task, but the performance was comparable to existing methods because it used only atom-type features as the input. Thus, we added sequence profile-based features, which are also used in other methods, to improve the performance. We developed a single-model MQA method for protein structures based on 3DCNN using sequence profile-based features, namely, P3CMQA. Performance evaluation using a CASP13 dataset showed that profile-based features improved the assessment performance, and the proposed method was better than currently available single-model MQA methods, including the previous 3DCNN-based method. We also implemented a web-interface of the method to make it more user-friendly.
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http://dx.doi.org/10.3390/bioengineering8030040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003382PMC
March 2021

Inhibition of Heat-shock Protein 27 Reduces 5-Fluorouracil-acquired Resistance in Human Colon Cancer Cells.

Anticancer Res 2021 Mar;41(3):1283-1290

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Background/aim: In previous work we showed that expression of heat-shock protein 27 (HSP27; encoded by HSPB1) was associated with inherent resistance to 5-fluorouracil (5-FU). However, the relationship between HSP27 and acquired resistance remains unknown.

Materials And Methods: We generated an acquired resistance model (WiDr-R) of a colon cancer cell line by exposing WiDr cells to 5-FU. Cell viability assays under treatment with 5-FU, as well as down-regulation of HSP27 using small interfering HSP27 RNA, were performed. HSP27 mRNA and protein expression was analyzed using real-time polymerase chain reaction and western blotting.

Results: 5-FU-acquired resistance induced overexpression of HSP27 mRNA and protein levels in WiDr-R cells. Furthermore, siRNA knockdown of HSP27 in WiDr-R cells reduced 5-FU-acquired resistance.

Conclusion: These findings demonstrate that HSP27 is associated with 5-FU resistance in human colon cancer cell cells and suggest that HSP27 regulation represents a novel approach to overcoming chemoresistance in colorectal cancer.
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http://dx.doi.org/10.21873/anticanres.14885DOI Listing
March 2021

Discovery, characterization and functional improvement of kumamonamide as a novel plant growth inhibitor that disturbs plant microtubules.

Sci Rep 2021 03 23;11(1):6077. Epub 2021 Mar 23.

Graduate School of Science and Technology, Kumamoto University, Kurokami 2-39-1, Kumamoto, 860-8555, Japan.

The discovery and useful application of natural products can help improve human life. Chemicals that inhibit plant growth are broadly utilized as herbicides to control weeds. As various types of herbicides are required, the identification of compounds with novel modes of action is desirable. In the present study, we discovered a novel N-alkoxypyrrole compound, kumamonamide from Streptomyces werraensis MK493-CF1 and established a total synthesis procedure. Resulted in the bioactivity assays, we found that kumamonamic acid, a synthetic intermediate of kumamonamide, is a potential plant growth inhibitor. Further, we developed various derivatives of kumamonamic acid, including a kumamonamic acid nonyloxy derivative (KAND), which displayed high herbicidal activity without adverse effects on HeLa cell growth. We also detected that kumamonamic acid derivatives disturb plant microtubules; and additionally, that KAND affected actin filaments and induced cell death. These multifaceted effects differ from those of known microtubule inhibitors, suggesting a novel mode of action of kumamonamic acid, which represents an important lead for the development of new herbicides.
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http://dx.doi.org/10.1038/s41598-021-85501-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988157PMC
March 2021

Sequence Alignment Using Machine Learning for Accurate Template-based Protein Structure Prediction.

Bio Protoc 2020 May 5;10(9):e3600. Epub 2020 May 5.

School of Computing, Tokyo Institute of Technology, Tokyo, Japan.

Template-based modeling, the process of predicting the tertiary structure of a protein by using homologous protein structures, is useful when good templates can be available. Indeed, modern homology detection methods can find remote homologs with high sensitivity. However, the accuracy of template-based models generated from the homology-detection-based alignments is often lower than that from ideal alignments. In this study, we propose a new method that generates pairwise sequence alignments for more accurate template-based modeling. Our method trains a machine learning model using the structural alignment of known homologs. When calculating sequence alignments, instead of a fixed substitution matrix, this method dynamically predicts a substitution score from the trained model.
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http://dx.doi.org/10.21769/BioProtoc.3600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842780PMC
May 2020

LocalDrop: A Hybrid Regularization for Deep Neural Networks.

IEEE Trans Pattern Anal Mach Intell 2021 Feb 23;PP. Epub 2021 Feb 23.

In neural networks, developing regularization algorithms to settle overfitting is one of the major study areas. We propose a new approach for the regularization of neural networks by the local Rademacher complexity called LocalDrop. A new regularization function for both fully-connected networks (FCNs) and convolutional neural networks (CNNs), including drop rates and weight matrices, has been developed based on the proposed upper bound of the local Rademacher complexity by the strict mathematical deduction. The analyses of dropout in FCNs and DropBlock in CNNs with keep rate matrices in different layers are also included in the complexity analyses. With the new regularization function, we establish a two-stage procedure to obtain the optimal keep rate matrix and weight matrix to realize the whole training model. Extensive experiments have been conducted to demonstrate the effectiveness of LocalDrop in different models by comparing it with several algorithms and the influences of different hyperparameters on the final performances.
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http://dx.doi.org/10.1109/TPAMI.2021.3061463DOI Listing
February 2021

A prospective phase II study of multimodal prophylactic treatment for afatinib-induced adverse events in advanced non-small cell lung cancer (Niigata Lung Cancer Treatment Group 1401).

Transl Lung Cancer Res 2021 Jan;10(1):252-260

Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Afatinib has shown clinical benefits in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor () mutations. Many patients treated with afatinib experience skin or gastrointestinal toxicity. However, an effective management strategy has not been established. This prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity.

Methods: This single-arm prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity in patients with mutation positive advanced NSCLC who planned to receive a 40 mg dose of afatinib. Eligible patients were treated with oral loperamide (2 mg twice per day), prophylactic minocycline (100 mg once per day), topical medium-class steroids, and gargling with sodium azulene. The primary endpoint was the ability of prophylactic loperamide to prevent severe or intolerable diarrhea during the 4 weeks after the initial administration of afatinib. The incidence, severity and time to occurrence of diarrhea, rash, oral mucositis and paronychia were evaluated based on a daily patient questionnaire.

Results: Forty-six patients were enrolled. The primary endpoint analysis was performed in 35 patients as the per-protocol (PP) population. The 4-week successful prophylaxis rate for severe or intolerable diarrhea was 82.9% (90% confidence interval: 70.1-91.9%). In the total population, the incidences of grade 3 or higher rash, oral mucositis and paronychia within 4 weeks were 4%, 2% and 4%, respectively.

Conclusions: Prophylactic loperamide administration was not effective in preventing severe or intolerable diarrhea during afatinib treatment. Adequate dose reduction will be a better approach to manage afatinib-induced diarrhea. Multimodal prevention using minocycline, topical steroids and gargling with sodium azulene may be helpful to maintain compliance with afatinib treatment (UMIN000016167).
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http://dx.doi.org/10.21037/tlcr-20-649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867768PMC
January 2021

Single-Step Retrosynthesis Prediction Based on the Identification of Potential Disconnection Sites Using Molecular Substructure Fingerprints.

J Chem Inf Model 2021 02 3;61(2):641-652. Epub 2021 Feb 3.

Department of Computer Science, School of Computing, Tokyo Institute of Technology, W8-85, 2-12-1, Ookayama, Meguro 152-8552, Tokyo, Japan.

The proper application of retrosynthesis to identify possible transformations for a given target compound requires a lot of chemistry knowledge and experience. However, because the complexity of this technique scales together with the complexity of the target, efficient application on compounds with intricate molecular structures becomes almost impossible for human chemists. The idea of using computers in such situations has existed for a long time, but the accuracy was not sufficient for practical applications. Nevertheless, with the steady improvement of machine learning and artificial intelligence in recent years, computer-assisted retrosynthesis has been gaining research attention again. Because of the overall lack of chemical reaction data, the main challenge for the recent retrosynthesis methods is low exploration ability during the analysis of target and intermediate compounds. The main goal of this research is to develop a novel, template-free approach to address this issue. Only individual molecular substructures of the target are used to determine potential disconnection sites, without relying on additional information such as chemical reaction class. The model for the identification of potential disconnection sites is trained on novel molecular substructure fingerprint representations. For each of the disconnections suggested using the model, a simple structural similarity-based reactant retrieval and scoring method is applied, and the suggestions are completed. This method achieves 47.2% top-1 accuracy for the single-step retrosynthesis task on the processed United States Patent Office dataset. Furthermore, if the predicted reaction class is used to narrow down the reactant candidate search space, the performance is improved to 61.4% top-1 accuracy.
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http://dx.doi.org/10.1021/acs.jcim.0c01100DOI Listing
February 2021

A ClearSee-Based Clearing Protocol for 3D Visualization of Embryos.

Plants (Basel) 2021 Jan 20;10(2). Epub 2021 Jan 20.

International Research Organization for Advanced Science and Technology (IROAST), Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan.

Tissue clearing methods combined with confocal microscopy have been widely used for studying developmental biology. In plants, ClearSee is a reliable clearing method that is applicable to a wide range of tissues and is suitable for gene expression analysis using fluorescent reporters, but its application to the embryo, a model system to study morphogenesis and pattern formation, has not been described in the original literature. Here, we describe a ClearSee-based clearing protocol which is suitable for obtaining 3D images of embryos. The method consists of embryo dissection, fixation, washing, clearing, and cell wall staining and enables high-quality 3D imaging of embryo morphology and expression of fluorescent reporters with the cellular resolution. Our protocol provides a reliable method that is applicable to the analysis of morphogenesis and gene expression patterns in embryos.
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http://dx.doi.org/10.3390/plants10020190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909245PMC
January 2021

Phospholipase Cβ3 Expressed in Mouse DRGs is Involved in Inflammatory and Postoperative Pain.

J Pain Res 2020 10;13:3371-3384. Epub 2020 Dec 10.

Department of Anesthesiology and Resuscitology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.

Background: Previous studies suggested that phospholipase Cβ3 (PLCβ3), which is a common downstream component in the signaling cascade, plays an important role in peripheral mechanisms of perception including nociception. However, detailed profiles of PLCβ3-expressing dorsal root ganglion (DRG) neurons and involvement of PLCβ3 in inflammatory and postoperative pain have not been fully investigated.

Purpose: We evaluated neurochemical char0acteristics of PLCβ3-expressing DRG neurons in mice and then we examined the effects of selective knockdown of PLCβ3 expression in DRGs on inflammatory and postoperative pain.

Methods: Male C57BL/6-strain mice were used. For the inflammatory model, each mouse received subcutaneous injection of complete Freund's adjuvant (CFA) in the left hindpaw. For the postoperative pain model, a plantar incision was made in the left hindpaw. PLCβ3 antisense oligodeoxynucleotide or PLCβ3 mismatch oligodeoxynucleotide was intrathecally administered once a day for three consecutive days in each model. The time courses of thermal hyperalgesia and mechanical hyperalgesia were investigated. Changes in PLCβ3 protein levels in DRGs were evaluated by Western blotting.

Results: Immunohistochemical analysis showed that high proportion of the PLCβ3-positive profiles were biotinylated isolectin B4-positive or transient receptor potential vanilloid subfamily 1-positive. PLCβ3 protein level in DRGs during CFA-induced inflammation was comparable to that at baseline. Intrathecal administration of PLCβ3 antisense oligodeoxynucleotide, which significantly suppressed PLCβ3 expression in DRGs, did not affect pain thresholds in normal conditions but inhibited CFA-induced thermal and mechanical hyperalgesia both at the early and late phases compared to that in mismatch oligodeoxynucleotide-treated mice. Intrathecal administration of PLCβ3 antisense oligodeoxynucleotide also inhibited surgical incision-induced thermal and mechanical hyperalgesia.

Conclusion: Our results uncover a unique role of PLCβ3 in the development and maintenance of inflammatory pain induced by CFA application and in those of surgical incision-induced pain, although PLCβ3 does not play a major role in thermal nociception or mechanical nociception in normal conditions.
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http://dx.doi.org/10.2147/JPR.S280565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737028PMC
December 2020

Location, Location, Location: How Vascular Specialization Influences Hematopoietic Fates During Development.

Front Cell Dev Biol 2020 13;8:602617. Epub 2020 Nov 13.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

During embryonic development, sequential waves of hematopoiesis give rise to blood-forming cells with diverse lineage potentials and self-renewal properties. This process must accomplish two important yet divergent goals: the rapid generation of differentiated blood cells to meet the needs of the developing embryo and the production of a reservoir of hematopoietic stem cells to provide for life-long hematopoiesis in the adult. Vascular beds in distinct anatomical sites of extraembryonic tissues and the embryo proper provide the necessary conditions to support these divergent objectives, suggesting a critical role for specialized vascular niche cells in regulating disparate blood cell fates during development. In this review, we will examine the current understanding of how organ- and stage-specific vascular niche specialization contributes to the development of the hematopoietic system.
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http://dx.doi.org/10.3389/fcell.2020.602617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691428PMC
November 2020

Clinical significance of CD28 gene-related activating alterations in adult T-cell leukaemia/lymphoma.

Br J Haematol 2021 01 18;192(2):281-291. Epub 2020 Nov 18.

Department of Pathology and Molecular Diagnostics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Multiple oncogenic events are involved in the development of adult T-cell leukaemia/lymphoma (ATL). Because CD28 plays a pivotal role in T-cell activation, we focused on alterations of the CD28 gene in ATL. We found multiple genetic abnormalities related to CD28 among the 144 patients enrolled in the present study. These involved gene fusions with the cytotoxic T-lymphocyte-associated antigen 4 or the inducible T-cell co-stimulator in 14 patients (10%), CD28-activating mutations in 3 (2%), and CD28 copy number variations in 34 (24%). Patients with such CD28 gene alterations were significantly younger than those without. In patients not receiving allogeneic haematopoietic stem cell transplantation, those with CD28 gene alterations tended to have a worse prognosis than those without. Finally, patients with chronic or smouldering ATL subtypes with CD28 gene alterations had a significantly worse prognosis than those without. These findings indicate that ATL, especially chronic or smouldering subtypes, have a more aggressive clinical course and are more refractory to conventional chemotherapies or mogamulizumab if they harbour CD28 gene alterations, likely because of continuous, prolonged, and enhanced CD28 activatory signalling. Novel treatment strategies to overcome the effects of these CD28 gene alterations are warranted.
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http://dx.doi.org/10.1111/bjh.17211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894310PMC
January 2021

Association of surfactant protein D with pulmonary metastases from colon cancer.

Oncol Lett 2020 Dec 5;20(6):322. Epub 2020 Oct 5.

Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.

Surfactant protein D (SP-D) is a member of the collectin family of proteins, which is secreted by airway epithelial cells. SP-D serves an important role in the immune system and in the inflammatory regulation of the lung. SP-D was recently found to suppress lung cancer progression by downregulating epidermal growth factor signaling. However, the relationship between SP-D and pulmonary metastases from colon cancer remains unknown. The present study aimed to determine whether SP-D may suppress the development of the mouse rectal carcinoma cell line, CMT93, . The present study investigated the effect of SP-D on pulmonary metastases from colon cancer using SP-D knockout mice. A wound healing assay and cell invasion assay revealed that SP-D suppressed the proliferation, migration and invasion of CMT-93 cells. After injection of CMT-93 cells into the tail vein, SP-D knockout mice were significantly more susceptible to developing pulmonary metastases than C57/BL6 mice (control). Moreover, a novel cell line (CMT-93 pulmonary metastasis; CMT-93 PM) was established from the lesions of pulmonary metastases in C57/BL6 mice following injection of CMT93 into the tail vein. CMT-93 PM exhibited more robust invasion and proliferation compared to CMT93, which was unaffected by exposure to SP-D. A higher incidence of pulmonary metastases was detected following injection of CMT93 PM into the tail vein of C57/BL6 mice compared with CMT-93. Consequently, SP-D may be involved in the pathogenesis of pulmonary metastases from colon cancer.
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http://dx.doi.org/10.3892/ol.2020.12185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583848PMC
December 2020

Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study.

Blood Adv 2020 10;4(20):5133-5145

Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Monitoring of Immune Responses Following Mogamulizumab-Containing Treatment in Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (MIMOGA) is a multicenter prospective observational study to establish the most effective and safe treatment strategy using mogamulizumab for ATL patients (UMIN000008696). Mogamulizumab-naive patients were enrolled (n = 102), of whom 101 received mogamulizumab-containing treatment (68 acute, 18 lymphoma, 12 chronic, and 3 smoldering subtypes). At enrollment, there was a significant inverse correlation between serum soluble interleukin-2 receptor (sIL-2R) levels and percentages of Tax-specific cytotoxic T lymphocytes (Tax-CTLs) in the entire lymphocyte population or in the CD8+ T cell subset, but there was not a correlation with cytomegalovirus pp65-specific cytotoxic T lymphocytes (CMV-CTLs). The overall response rate was 65%, and median progression-free survival and overall survival (OS) were 7.4 and 16.0 months, respectively. A higher percentage of Tax-CTLs, but not CMV-CTLs, within the entire lymphocyte population or in the CD8+ T cell subset was significantly associated with longer survival. Multivariate analysis identified the clinical subtype (acute or lymphoma type), a higher sIL-2R level, and a lower percentage of CD2-CD19+ B cells in peripheral blood mononuclear cells as significant independent unfavorable prognostic factors for OS. This indicates that a higher percentage of B cells might reflect some aspect of a favorable immune status leading to a good outcome with mogamulizumab treatment. In conclusion, the MIMOGA study has demonstrated that mogamulizumab exerts clinically meaningful antitumor activity in ATL. The patient's immunological status before mogamulizumab was significantly associated with treatment outcome. Further time series immunological analyses, in addition to comprehensive genomic analyses, are warranted.
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http://dx.doi.org/10.1182/bloodadvances.2020003053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594399PMC
October 2020

The Impact of Smoking on Pulmonary Metastasis in Colorectal Cancer.

Onco Targets Ther 2020 30;13:9623-9629. Epub 2020 Sep 30.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Introduction: Recently, clinical studies have revealed that smoking can contribute to the poor prognosis of colorectal cancer (CRC) and, additionally, can be a risk factor for pulmonary metastasis of CRC. However, there has been no basic research regarding the underlying molecular mechanism. The purpose of this study was to clarify the mechanism by which smoking causes pulmonary metastasis of CRC.

Methods: First, pulmonary metastasis model mice inhaled cigarette smoke or air (control) for 1 h once a day for 3 weeks. We attempted to clarify the effect of smoking on the incidence of pulmonary metastasis. On the 15th day, CMT-93 cells were injected into the tail vein. At 6 and 8 weeks following injection, the extent of pulmonary metastasis was evaluated using in vivo micro CT. After the last CT examination, the mice were sacrificed, and the lungs were extracted for pathological examination.

Results: The number of mice with pulmonary metastases in the smoking group was significantly higher than in the control group. Three weeks of smoking induced mild inflammation in the lungs, as evidenced by increases in the levels of IL-6 and TNF-α in bronchoalveolar lavage. Moreover, the adhesion-related molecule ICAM-1 was overexpressed in pulmonary tissue, which allowed drained cancer cells to remain in the lung and contribute to the formation of pulmonary metastasis.

Conclusion: Collectively, cigarette smoking may contribute to the pathogenesis and development of pulmonary metastasis in CRC through enhancement of adhesion and inflammation.
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http://dx.doi.org/10.2147/OTT.S263250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533240PMC
September 2020

Immunohistochemistry for CCR4 C-terminus predicts CCR4 mutations and mogamulizumab efficacy in adult T-cell leukemia/lymphoma.

J Pathol Clin Res 2021 01 6;7(1):52-60. Epub 2020 Oct 6.

Department of Pathology and Molecular Diagnostics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Mogamulizumab targets extracellular N-terminal domain of CCR4, which is expressed in most adult T-cell leukemia/lymphoma (ATL) cases. Recently, we reported that CCR4 C-terminal gain-of-function mutations were frequent in ATL cases, and a subgroup with these mutations who were treated without allogenic hematopoietic stem cell transplantation (HSCT) and with mogamulizumab-containing [HSCT (-) and mogamulizumab (+)] regimens had a superior survival rate. Although these mutations are most likely a biomarker for predicting a strong response to mogamulizumab, their detection is time-consuming and costly. A more convenient screening tool may be necessary in the clinical setting. In this study, the clinicopathological importance of immunohistochemistry for the CCR4 N-terminus (CCR4-N-IHC) and C-terminus (CCR4-C-IHC) was examined in a large ATL cohort (n = 92). We found that CCR4-C-IHC, but not CCR4-N-IHC, was inversely correlated with the CCR4 mutation status. In ATL patients negative for CCR4-C-IHC, a subgroup treated with HSCT (-) and mogamulizumab (+) regimens showed a significantly better prognosis. In addition, CCR4-C-IHC was found to be a useful marker for high-sensitivity screening of the CCR4 mutational status (87%). The present study suggests that CCR4-C-IHC may be useful for identifying ATL patients harboring mutated CCR4 who may benefit from the superior efficacy of mogamulizumab-containing regimens and that CCR4-C-IHC may be a rapid and cost-efficient tool for screening for CCR4 mutation status.
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http://dx.doi.org/10.1002/cjp2.180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737778PMC
January 2021

Cerebrospinal fluid drainage to prevent postoperative spinal cord injury in thoracic aortic repair.

J Anesth 2021 02 26;35(1):43-50. Epub 2020 Sep 26.

Department of Anesthesiology, School of Medicine, The Jikei University, Minato Ku, Japan.

Background: Cerebrospinal fluid drainage (CSFD) is recommended as a spinal cord protective strategy in open and endovascular thoracic aortic repair. Although small studies support the use of CSFD, systematic reviews have not suggested definite conclusion and a large-scale study is needed. Therefore, we reviewed medical records of patients who had undergone descending and thoracoabdominal aortic repair (both open and endovascular repair) at multiple institutions to assess the association between CSFD and postoperative motor deficits.

Methods: Patients included in this study underwent descending or thoracoabdominal aortic repair between 2000 and 2013 at 12 hospitals belonging to the Japanese Association of Spinal Cord Protection in Aortic Surgery. We conducted a retrospective study to investigate whether motor-evoked potential monitoring is effective in reducing motor deficits in thoracic aortic aneurysm repair. We use the same dataset to examine whether CSFD reduces motor deficits after propensity score matching.

Results: We reviewed data from 1214 patients [open surgery, 601 (49.5%); endovascular repair, 613 (50.5%)]. CSFD was performed in 417 patients and not performed in the remaining 797 patients. Postoperative motor deficits were observed in 75 (6.2%) patients at discharge. After propensity score matching (n = 700), mixed-effects logistic regression performed revealed that CSFD is associated with postoperative motor deficits at discharge [adjusted odds ratio (OR), 3.87; 95% confidence interval (CI), 2.30-6.51].

Conclusion: CSFD may not be effective for postoperative motor deficits at discharge.
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http://dx.doi.org/10.1007/s00540-020-02857-wDOI Listing
February 2021

Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study.

Cancer Sci 2020 Dec 21;111(12):4567-4580. Epub 2020 Oct 21.

Department of Hematology, International Medical Center, Saitama Medical University, Saitama, Japan.

Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983-1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010-2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow-up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016-2017. Of 770 evaluable patients, 391 (50.8%) had acute-type, 192 (24.9%) had lymphoma-type, 106 (13.8%) had chronic-type, and 81 (10.5%) had smoldering-type ATL. The initial therapy regimens used for acute/lymphoma-type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP)-like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma-type ATL patients. The 4-year survival rates (the median survival time, days) for acute-, lymphoma-, unfavorable chronic-, favorable chronic-, and smoldering-type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4-year survival rates for acute- and lymphoma-type ATL improved compared with those reported in 1991, but those for chronic- and smoldering-type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan.
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http://dx.doi.org/10.1111/cas.14658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734015PMC
December 2020

Efficacy of cabazitaxel and the influence of clinical factors on the overall survival of patients with castration-resistant prostate cancer: A local experience of a multicenter retrospective study.

Asia Pac J Clin Oncol 2021 Jun 24;17(3):238-244. Epub 2020 Sep 24.

Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.

Aim: To date, the optimal sequencing of life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unclear owing to a lack of prospective trials. This study aimed to evaluate the efficacy and safety of cabazitaxel (CBZ) treatment and examine the prognostic factors for oncological outcomes in patients with mCRPC who received CBZ after docetaxel (DOC).

Methods: This multi-institutional retrospective study included 44 patients with mCRPC who received CBZ. All enrolled patients had histologically confirmed prostate cancer (PCa) with distant metastases and had received DOC before CBZ administration. The primary endpoint was the oncological outcomes, including the overall (OS) and progression-free survival (PFS). The secondary endpoints were adverse events due to CBZ and rates of ≥30% reduction in prostate-specific antigen (PSA) levels.

Results: The median follow-up period was 9.2 months (range, 0.2-34 months). During this time, 34 patients (77%) died of PCa. The median OS and PFS were 12.2 (range, 0.2-34 months) and 1.4 months (range, 0.4-17 months), respectively. According to the PSA decline rate, patients who achieved a ≥30% reduction in PSA levels had significantly longer OS than those who showed a <30% reduction in PSA levels (P = 0.002). Regarding the number of cycles of CBZ, patients who received ≥4 cycles of CBZ showed significantly longer OS than those who received <4 cycles of CBZ (P < 0.001). Patients who had visceral metastasis showed significantly shorter OS than those without visceral metastasis (P = 0.012).

Conclusion: This study demonstrated that CBZ was effective and safe in Japanese local patients in a real-world setting. Patients with mCRPC who received ≥4 cycles of CBZ showed a ≥30% reduction in the serum PSA levels, and did not have visceral metastasis might achieve longer OS.
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http://dx.doi.org/10.1111/ajco.13441DOI Listing
June 2021

Clinical significance of tryptophan catabolism in follicular lymphoma.

Hematol Oncol 2020 Dec 29;38(5):742-753. Epub 2020 Sep 29.

Department of Hematology & Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

The enzyme, indoleamine 2,3-dioxygenase 1 (IDO), catabolizes tryptophan (Trp) in the kynurenine (Kyn) pathway, and is important in suppressing antitumor immune responses in the tumor microenvironment. With regard to previously untreated patients with follicular lymphoma (FL), we sought to establish the prognostic significance of Trp catabolism in this disease. Serum Trp and Kyn levels in 110 patients with FL were quantified, and their relationship to different clinical parameters studied. IDO expression in the lymph nodes of affected patients was studied. Study participants included 54 males and 56 females (age range 39-86, median 62 years), showing a 5-year overall survival (OS) rate of 78.5%. Patients with a high Kyn level (5-year OS, 65.0% vs. 81.7%; p = 0.026), high Kyn/Trp ratio (71.1% vs. 81.7%; p = 0.002), and low hemoglobin (Hb) level (<12.0 g/dL; p = 0.001; a component of FL international prognostic indexes) demonstrated a significantly shorter OS. Multivariate analysis included the following 10 variables: age, sex, serum β2-microglobulin, Hb, longest diameter of the largest involved node, Ann Arbor stage, serum lactate dehydrogenase, histologic grading, B symptoms, and serum Kyn/Trp ratio; a lower Hb level and a high Kyn/Trp ratio (HR, 3.239; 95% CI, 1.296-8.096) led to a significantly inferior OS. In the microenvironment, some CD11c-positive myeloid dendritic cells but not FL tumor cells were found to produce IDO. Overall, measuring levels of serum Kyn and Trp in individual patients with FL contributed to predicting their prognosis.
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http://dx.doi.org/10.1002/hon.2804DOI Listing
December 2020
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