Publications by authors named "Naoki Takahashi"

469 Publications

Diagnostic utility of the aberrant immunohistochemical expression of CD3 molecules for peripheral T-cell lymphomas.

Ann Diagn Pathol 2022 Jul 22;60:152013. Epub 2022 Jul 22.

Department of Pathology, Saitama Medical University, International Medical Center, 1397-1, Yamane, Hidaka-shi, Saitama 350-1298, Japan.

The histological diagnosis of peripheral T-cell lymphomas (PTCLs) is often challenging. Flow cytometry (FCM) sometimes shows the loss of pan-T-cell markers for PTCLs, suggesting the neoplastic nature of these cells. Immunohistochemically, the total loss of pan-T-cell markers has been demonstrated in PTCLs. Furthermore, except for the total loss, the aberrant immunohistochemical expressions of pan-T-cell markers have also been empirically observed in PTCLs, but the details remain unexamined. Therefore, the present study semi-quantitatively evaluated the aberrant expression of cytoplasmic CD3ε (cCD3ε), the most common immunohistochemical pan-T-cell marker, in 91 PTCL cases. The expressions of the other CD3 molecules, CD3δ, CD3γ, and CD3ζ were also examined. Frequencies of the total immunohistochemical loss of CD3 molecules and loss of surface CD3ε (sCD3ε) in FCM were analyzed for comparison. The results showed atypical, aberrant expression patterns for immunohistochemical CD3 molecules: perinuclear, cytoplasmic, membranous, and partial negative. The frequency of each molecule was as follows: cCD3ε 40.7 %, CD3δ 26.4 %, CD3γ 53.8 %, and CD3ζ 54.9 %, especially the latter two showed high frequency in peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and adult T-cell lymphoma/leukemia. Immunohistochemical total loss was less than aberrant expression in all CD3 molecules, with the frequency of cCD3ε being the lowest (6.6 %). The loss of sCD3ε in FCM was observed in 43.3 % of cases, with a similar frequency to the aberrant expression of cCD3ε. In conclusion, the aberrant immunohistochemical expression of cCD3ε was a useful finding as is sCD3ε loss in FCM, but CD3γ and CD3ζ were more useful, facilitating the diagnosis of PTCLs.
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http://dx.doi.org/10.1016/j.anndiagpath.2022.152013DOI Listing
July 2022

Metachronous lesions in the orbit, retroperitoneum, and pleura of mucosa-associated lymphoid tissue lymphoma: A case report.

Cancer Rep (Hoboken) 2022 Jul 28:e1689. Epub 2022 Jul 28.

Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Hidaka, Japan.

Background: Mucosa associated lymphoid tissue (MALT) lymphoma of the orbit is rare, often indolent, but can recur, and spread to extra-nodal sites. Pleural and retroperitoneum recurrences of MALT lymphoma are rare.

Case: A 65-year-old man was referred to our hospital due to right pleural effusion and difficulty in breathing. He had a medical history of having undergone surgery for MALT lymphoma of the left orbit. A chest computed tomography (CT) scan showed right pleural thickness, pleural effusion, and a retroperitoneal mass, spreading from the muscular layer to the subcutaneous layer. The thickened pleural lesion was surgically biopsied and diagnosed as a recurrence of MALT lymphoma.

Conclusion: Pleural effusion should be carefully examined and monitored for the possibility of recurrence in MALT lymphoma patients.
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http://dx.doi.org/10.1002/cnr2.1689DOI Listing
July 2022

T1 signal intensity ratio of the pancreas as an imaging biomarker for the staging of chronic pancreatitis.

Abdom Radiol (NY) 2022 Jul 20. Epub 2022 Jul 20.

Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Purpose: Our purpose was to validate the T1 SIR (T1 score) as an imaging biomarker for the staging of CP in a large, multi-institutional, prospective study.

Methods: The prospective study population included 820 participants enrolled in the PROCEED study from nine clinical centers between June 2017 and December 2021. A radiologist at each institution used a standardized method to measure the T1 signal intensity of the pancreas and the reference organs (spleen, paraspinal muscle, liver), which was used to derive respective T1 scores. Participants were stratified according to the seven mechanistic stages of chronic pancreatitis (MSCP 0-6) based on their clinical history, MRCP, and CT findings.

Results: The mean pancreas-to-spleen T1 score was 1.30 in participants with chronic abdominal pain, 1.22 in those with acute or recurrent acute pancreatitis, and 1.03 in definite CP. After adjusting for covariates, we observed a linear, progressive decline in the pancreas-to-spleen T1 score with increasing MSCP from 0 to 6. The mean pancreas-to-spleen T1 scores were 1.34 (MSCP 0), 1.27 (MSCP 1), 1.21 (MSCP 2), 1.16 (MSCP 3), 1.18 (MSCP 4), 1.12 (MSCP 5), and 1.05 (MSCP 6) (p < 0.0001). The pancreas-to-liver and pancreas-to-muscle T1 scores showed less linear trends and wider confidence intervals.

Conclusion: The T1 score calculated by SIR of the pancreas-to-spleen shows a negative linear correlation with the progression of chronic pancreatitis. It holds promise as a practical imaging biomarker in evaluating disease severity in clinical research and practice.
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http://dx.doi.org/10.1007/s00261-022-03611-4DOI Listing
July 2022

Soybean peptide inhibits the biofilm of periodontopathic bacteria via bactericidal activity.

Arch Oral Biol 2022 Jul 9;142:105497. Epub 2022 Jul 9.

Division of Periodontology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, 951-8514 Niigata, Japan. Electronic address:

Objective: This study aimed to clarify the antibacterial mechanism and antibiofilm effect of soybean-derived peptide BCBS-11 against periodontopathic bacteria.

Design: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of BCBS-11 against Porphyromonas gingivalis (P. gingivalis), Fusobacterium nucleatum (F. nucleatum), and Streptococcus mitis (S. mitis) were determined for the antibacterial mechanism. The effect of BCBS-11 on membrane permeability and depolarization activity were investigated using propidium iodide (PI) staining and 3, 3'-dipropylthiadicarbocyanine iodide (DiSC-(5)) analysis. Monospecies and multispecies biofilms were cultured on 96-well plates. The amount of biofilm was determined using crystal violet staining to determine the inhibition of biofilm formation and the eradication of established biofilm using BCBS-11. The cytotoxicity of BCBS-11 was evaluated using 3-(4, 5-Dimethylthiazol-2-yl)- 2, 5-diphenyltetrazolium bromide (MTT) assay.

Results: The MIC and MBC indicated the bactericidal activity of BCBS-11 against P. gingivalis and F. nucleatum. The PI staining revealed that BCBS-11 disrupted the bacterial membrane integrity. The DiSC-(5) analysis indicated that BCBS-11 depolarized the bacterial cytoplasmic membrane. These results indicate the antimicrobial action of BCBS-11 through membrane disruption and the collapse of membrane electrochemical gradient. BCBS-11 significantly inhibited the monospecies biofilm formation of P. gingivalis and F. nucleatum and also inhibited dual-species biofilm. BCBS-11 was not cytotoxic toward human oral epithelial cells.

Conclusions: BCBS-11 inhibits the monospecies and multispecies biofilm formation of P. gingivalis and F. nucleatum, and their bactericidal activity results from membrane disruption.
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http://dx.doi.org/10.1016/j.archoralbio.2022.105497DOI Listing
July 2022

Brassinosteroids are required for efficient root tip regeneration in .

Plant Biotechnol (Tokyo) 2022 Mar;39(1):73-78

Graduate School of Science and Technology, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.

Compared with other organisms, plants have an extraordinary capacity for self-repair. Even if the entire tissues, including the stem cells, are resected, most plant species are able to completely regenerate whole tissues. However, the mechanism by which plants efficiently regenerate the stem cell niche during tissue reorganization is still largely unknown. Here, we found that the signaling mediated by plant steroid hormones brassinosteroids is activated during stem cell formation after root tip excision in . Treatment with brassinazole, an inhibitor of brassinosteroid biosynthesis, delayed the recovery of stem cell niche after root tip excision. Regeneration of root tip after resection was also delayed in a brassinosteroid receptor mutant. Therefore, we propose that brassinosteroids participate in efficient root tip regeneration, thereby enabling efficient tissue regeneration to ensure continuous root growth after resection.
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http://dx.doi.org/10.5511/plantbiotechnology.21.1103aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9200090PMC
March 2022

Association between computerized tomography (CT) study of body composition and severity of acute pancreatitis: Use of a novel Z-score supports obesity paradox.

Clin Nutr 2022 Aug 18;41(8):1676-1679. Epub 2022 Jun 18.

Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. Electronic address:

Background & Aims: The association between body composition parameters measured on computed tomography (CT) and severity of acute pancreatitis (AP) is conflicting because these composition parameters vary considerably by sex and age. We previously developed normative body composition data, in healthy subjects. Z-score calculated from the normative data gives age and sex adjusted body composition parameters. We studied the above association using this novel Z-score in a large cohort of patients with AP.

Methods: Between January 2014 and March 2018, patients admitted with AP and had CT scans within a week of admission, were enrolled. Body composition data including skeletal muscle (SM), subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were calculated from the CT scan using deep learning automated algorithm. Then we converted the value to Z-score, and then compared the same score between mild AP, moderately severe AP and severe AP defined by revised Atlanta criteria.

Results: Out of 514 patients, 336 (65.4%) are mild AP, 130 (25.3%) moderately severe AP, and 48 (9.3%) severe AP. Patients with moderately severe AP had significantly lower SM-z-score than those with mild AP (1.21 vs1.73, p = 0.048) and patients with severe AP had significantly lower SAT-z-score than those with mild AP (0.70 vs.1.29, p = 0.016). VAT-z-score was not significantly different between three groups. (p = 0.76).

Conclusion: Lower SM-z-score and SAT-z-score were associated with moderately severe and severe types of AP, respectively. Future prospective studies in patients with AP using Z-scores, may define the association between body composition and severity of AP, and explain the inconsistencies reported in previous studies.
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http://dx.doi.org/10.1016/j.clnu.2022.06.010DOI Listing
August 2022

Fanconi syndrome in an elderly patient with membranous nephropathy during treatment with the immunosuppressant mizoribine.

CEN Case Rep 2022 Jun 24. Epub 2022 Jun 24.

Department of Nephrology, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.

We report on an 80-year-old man diagnosed with Fanconi syndrome induced by mizoribine after 4 weeks of administration to treat membranous nephropathy. Mizoribine is an oral immunosuppressant that inhibits inosine monophosphate dehydrogenase and is widely used in Japan for the treatment of autoimmune diseases and nephrotic syndrome, as well as after renal transplantation. Acquired Fanconi syndrome is often caused by drugs (antibacterial, antiviral, anticancer, and anticonvulsant drugs) and is sometimes caused by autoimmune diseases, monoclonal light chain-associated diseases, or heavy metal poisoning. In our patient, hypokalemia, hypophosphatemia, glucosuria, hypouricemia, and severe proteinuria resolved gradually after discontinuation of mizoribine administration, despite oral administration of prednisolone followed by a single intravenous injection of rituximab. The patient was ultimately diagnosed with Fanconi syndrome induced by mizoribine based on his clinical course and his typical laboratory data with the absence of proximal tubular acidosis. To our knowledge, this is the first report of Fanconi syndrome possibly induced by mizoribine. Although the precise mechanism by which mizoribine induces proximal tubular dysfunction is unknown, we suggest that nephrologists should be aware of the onset of Fanconi syndrome, a rare complication during mizoribine treatment.
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http://dx.doi.org/10.1007/s13730-022-00715-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243880PMC
June 2022

Quality is more important than quantity: pre-operative sarcopenia is associated with poor survival in advanced ovarian cancer.

Int J Gynecol Cancer 2022 Jun 9. Epub 2022 Jun 9.

Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, USA

Background: Sarcopenia is prevalent among older patients with cancer and is associated with poor outcomes.

Objective: To explore the relationship between muscle mass, quality, and patient age with overall survival after surgery for advanced ovarian cancer.

Methods: Patients with advanced stage (IIIC/IV) ovarian cancer who underwent primary cytoreductive surgery between January 2006 and July 2016 were included. Body composition measures were calculated from pre-operative CT imaging: skeletal muscle index (skeletal muscle index=skeletal muscle area normalized for height), skeletal muscle density, and skeletal muscle gauge (product of skeletal muscle index and skeletal muscle density). Each measure was transformed to a z-score and evaluated for association with risk of death using Cox proportional hazards models. Recursive partitioning was used to classify patients into homogeneous subgroups considering age and skeletal muscle gauge as predictors of overall survival.

Results: The study included 429 patients (mean age 64.2 years). Increased age moderately correlated with decreased skeletal muscle gauge (r=-0.45). Decreasing skeletal muscle density and skeletal muscle gauge were significantly associated with increased risk of death; HR (95% CI) per 1-unit decrease in z-score of 1.24 (1.10 to 1.39) for skeletal muscle density and 1.27 (1.12 to 1.44) for skeletal muscle gauge. Associations were diluted after adjusting for age (1.13 (1.00 to 1.29) skeletal muscle density and 1.14 (0.99 to 1.30) skeletal muscle gauge). Recursive partitioning identified three subgroups: <60 years old, ≥60 years old with skeletal muscle gauge ≥937.3, and ≥60 years old with skeletal muscle gauge <937.3; median overall survival was 5.8, 3.3, and 2.3 years, respectively (p<0.001).

Conclusions: Skeletal muscle gauge, a novel sarcopenia measure incorporating quantity and quality, was associated with poorer survival in patients with advanced ovarian cancer, particularly among patients older than 60. Expanding our knowledge of how sarcopenia relates to solid tumor outcomes among high-risk patients can modify our treatment approach.
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http://dx.doi.org/10.1136/ijgc-2022-003387DOI Listing
June 2022

Updated efficacy outcomes of anti-PD-1 antibodies plus multikinase inhibitors for advanced gastric cancer patients with or without liver metastases in clinical trials.

Clin Cancer Res 2022 Jun 9. Epub 2022 Jun 9.

National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Purpose: We previously reported preliminary activity of regorafenib plus nivolumab or lenvatinib plus pembrolizumab in advanced gastric cancer (AGC). Meanwhile, several studies demonstrated liver metastases are less responsive to immunotherapy.

Patients And Methods: Combined efficacy outcomes with a longer follow-up in a phase Ib trial of regorafenib plus nivolumab (REGONIVO) and a phase II trial of lenvatinib plus pembrolizumab (LENPEM) were examined in AGC with or without liver metastases (REGONIVO plus LENPEM cohort). We also investigated the efficacy of anti-PD-1 monotherapies (anti-PD-1 monotherapy cohort). A comparison of the immune microenvironment between gastric primary tumors and liver metastases was also conducted by multiplex immunohistochemistry.

Results: In the REGONIVO plus LENPEM cohort, with a median follow-up of 14.0 months, objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were 46%, 7.8 months, and 15.6 months in patients with liver metastases, while 69%, 6.9 months, and 15.5 months in those without. In the anti-PD-1 monotherapy cohort, with a median follow-up of 27.6 months, ORR, mPFS, and mOS were 9%, 1.4 months, and 6.4 months in patients with liver metastases, while 22%, 2.3 months, and 9.0 months in those without. Multiplex IHC revealed liver metastases were associated with an abundance of immune suppressive cells, such as tumor-associated macrophages and regulatory T cells, with fewer CD8+ T cells compared with gastric primary tumors.

Conclusions: Anti-PD-1 antibodies plus regorafenib or lenvatinib for AGC showed promising antitumor activity with a longer follow-up, irrespective of liver metastases status, despite a more immune suppressive tumor microenvironment in liver metastases.
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http://dx.doi.org/10.1158/1078-0432.CCR-22-0630DOI Listing
June 2022

Correlation Between Enlargement of Retinal Nerve Fiber Defect Angle in En Face Imaging and Visual Field Progression.

Transl Vis Sci Technol 2022 06;11(6)

Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Purpose: Retinal nerve fiber layer defects (RNFLDs) become enlarged with glaucoma progression. We measured the RNFLD angle and investigated whether it was correlated with deterioration of the visual field in patients with glaucoma.

Methods: This study included 84 eyes of 84 patients with open-angle glaucoma (mean deviation [MD] = -6.51 ± 5.91 dB, follow-up period = 2.82 ± 0.74 years) with the RNFLDs, who underwent en face swept-source optical coherence tomography (SS-OCT) wide scans (12 × 9 mm) at least 6 times. The RNFLD angle was measured as the intersection between the RNFLD and a circle centered on the disc with a radius half the distance between the disc and the fovea. Slopes for the RNFLD angle, macular ganglion cell layer thickness (GCCT), and circumpapillary RNFL thickness (cpRNFLT) were compared with the MD slope, as measured with the Humphrey field analyzer 24-2 program.

Results: The correlation coefficients with MD slope were -0.67 for the RNFLD angle slope (P < 0.001), 0.15 for the macular GCCT slope (P = 0.163), and 0.04 for the cpRNFLT slope (P = 0.719). The RNFLD angle tended to increase as the number of disc hemorrhage occurrences increased (rs = 0.31, P = 0.004). The RNFLD angle slope also had good predictive power for glaucoma progression (area under the receiver operating characteristic curve = 0.88, 95% confidence interval = 0.81-0.95).

Conclusions: We found that the RNFLD angle slope was more closely associated with the MD slope than were other OCT parameters. This suggests that measurement of the RNFLD angle with en face OCT images could be effective in evaluating glaucoma progression.

Translational Relevance: Our study provides a method for monitoring glaucoma progression with SS-OCT.
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http://dx.doi.org/10.1167/tvst.11.6.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187958PMC
June 2022

Impact of measurement method on interobserver variability of apparent diffusion coefficient of lesions in prostate MRI.

PLoS One 2022 23;17(5):e0268829. Epub 2022 May 23.

Department of Radiology, Mayo Clinic, Rochester, Minnesota, United States of America.

Purpose: To compare the inter-observer variability of apparent diffusion coefficient (ADC) values of prostate lesions measured by 2D-region of interest (ROI) with and without specific measurement instruction.

Methods: Forty lesions in 40 patients who underwent prostate MR followed by targeted prostate biopsy were evaluated. A multi-reader study (10 readers) was performed to assess the agreement of ADC values between 2D-ROI without specific instruction and 2D-ROI with specific instruction to place a 9-pixel size 2D-ROI covering the lowest ADC area. The computer script generated multiple overlapping 9-pixel 2D-ROIs within a 3D-ROI encompassing the entire lesion placed by a single reader. The lowest mean ADC values from each 2D-small-ROI were used as reference values. Inter-observer agreement was assessed using the Bland-Altman plot. Intraclass correlation coefficient (ICC) was assessed between ADC values measured by 10 readers and the computer-calculated reference values.

Results: Ten lesions were benign, 6 were Gleason score 6 prostate carcinoma (PCa), and 24 were clinically significant PCa. The mean±SD ADC reference value by 9-pixel-ROI was 733 ± 186 (10-6 mm2/s). The 95% limits of agreement of ADC values among readers were better with specific instruction (±112) than those without (±205). ICC between reader-measured ADC values and computer-calculated reference values ranged from 0.736-0.949 with specific instruction and 0.349-0.919 without specific instruction.

Conclusion: Interobserver agreement of ADC values can be improved by indicating a measurement method (use of a specific ROI size covering the lowest ADC area).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0268829PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9126398PMC
May 2022

A lightweight deep learning model for automatic segmentation and analysis of ophthalmic images.

Sci Rep 2022 05 20;12(1):8508. Epub 2022 May 20.

Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Detection, diagnosis, and treatment of ophthalmic diseases depend on extraction of information (features and/or their dimensions) from the images. Deep learning (DL) model are crucial for the automation of it. Here, we report on the development of a lightweight DL model, which can precisely segment/detect the required features automatically. The model utilizes dimensionality reduction of image to extract important features, and channel contraction to allow only the required high-level features necessary for reconstruction of segmented feature image. Performance of present model in detection of glaucoma from optical coherence tomography angiography (OCTA) images of retina is high (area under the receiver-operator characteristic curve AUC ~ 0.81). Bland-Altman analysis gave exceptionally low bias (~ 0.00185), and high Pearson's correlation coefficient (p = 0.9969) between the parameters determined from manual and DL based segmentation. On the same dataset, bias is an order of magnitude higher (~ 0.0694, p = 0.8534) for commercial software. Present model is 10 times lighter than Unet (popular for biomedical image segmentation) and have a better segmentation accuracy and model training reproducibility (based on the analysis of 3670 OCTA images). High dice similarity coefficient (D) for variety of ophthalmic images suggested it's wider scope in precise segmentation of images even from other fields. Our concept of channel narrowing is not only important for the segmentation problems, but it can also reduce number of parameters significantly in object classification models. Enhanced disease diagnostic accuracy can be achieved for the resource limited devices (such as mobile phone, Nvidia's Jetson, Raspberry pi) used in self-monitoring, and tele-screening (memory size of trained model ~ 35 MB).
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http://dx.doi.org/10.1038/s41598-022-12486-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122907PMC
May 2022

Effects of Metastatic Sites on Circulating Tumor DNA in Patients With Metastatic Colorectal Cancer.

JCO Precis Oncol 2022 04;6:e2100535

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Purpose: Low concordance between plasma-based and tissue-based tests for determining the mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology.

Materials And Methods: We investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315).

Results: Of 1,187 patients with mCRC enrolled in GOZILA, 138 were eligible (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only metastases). The concordance of / status between Guaradant360 and tissue in vitro diagnostic tests was 95.9% in patients with liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only metastases. ctDNA fraction, as measured by the median maximum variant allelic fraction (max VAF), and median number of detected variants were 23.1% and five in liver-only, 6.0% and five in lymph node-only, 0.4% and three in peritoneum-only, and 0.4% and three in lung-only metastases, respectively (all < .001, Kruskal-Wallis test). Few patients with liver-only (2.0%) and lymph node-only metastasis (13.3%) had a max VAF < 0.2%, which is required to ensure a detection limit of 95%, but max VAF was more frequently < 0.2% in patients with lung-only (27.7%) or peritoneum-only metastasis (29.6%).

Conclusion: Patients with lung-only and peritoneum-only metastatic disease have significantly lower levels of ctDNA, suggesting decreased clinical sensitivity for subclonal variants. This observation suggests that such patients may benefit from concurrent tissue and plasma testing to provide optimal genotyping for subsequent therapy selection.
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http://dx.doi.org/10.1200/PO.21.00535DOI Listing
April 2022

Efficacy and Safety of Difelikefalin in Japanese Patients With Moderate to Severe Pruritus Receiving Hemodialysis: A Randomized Clinical Trial.

JAMA Netw Open 2022 05 2;5(5):e2210339. Epub 2022 May 2.

Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.

Importance: Patients with pruritus receiving hemodialysis frequently experience oppressive physical and psychiatric symptoms that directly affect their quality of life and increase mortality. However, treatment options are limited.

Objective: To determine the clinically recommended dose of difelikefalin, a κ-opioid receptor agonist, based on the efficacy, dose response, safety, and pharmacokinetics.

Design, Setting, And Participants: This randomized, double-blind, placebo-controlled, 4-arm phase 2 trial was conducted from February 1, 2019, to October 22, 2019, at 94 sites in Japan. Patients with moderate to severe pruritus receiving hemodialysis were enrolled.

Interventions: Difelikefalin (0.25, 0.5, and 1.0 μg/kg) and placebo were intravenously administered 3 times a week at the end of each hemodialysis session for 8 weeks.

Main Outcome And Measures: The primary end point was the change from baseline in the weekly mean Worst Itching Intensity Numerical Rating Scale (NRS) score at week 8. Secondary outcomes measured changes in itch-related quality-of-life score using the Skindex-16 and 5-D itch scale. Safety was assessed according to adverse events, laboratory tests, vital signs, body weight, and 12-lead electrocardiogram.

Results: A total of 247 Japanese patients (186 male [75%]; mean [SD] age, 64.5 [11.7] years) were randomized to placebo (n = 63), 0.25 μg/kg of difelikefalin (n = 61), 0.5 μg/kg of difelikefalin (n = 61), or 1.0 μg/kg of difelikefalin (n = 62). The changes from baseline in the adjusted mean (SE) of the 24-hour Worst Itching Intensity NRS score at week 8 were -2.86 (0.29) in the placebo group, -2.97 (0.29) in the 0.25 μg/kg of difelikefalin group, -3.65 (0.30) in the 0.5 μg/kg of difelikefalin group, and -3.64 (0.30) in the 1.0 μg/kg of difelikefalin group. Significant differences were found in the 0.5 μg/kg of difelikefalin group (adjusted mean difference, -0.80; 95% CI, -1.55 to -0.04; P = .04) and the 1.0 μg/kg of difelikefalin group (adjusted mean difference, -0.78; 95% CI, -1.54 to -0.03; P = .04) compared with placebo. The Skindex-16 overall score and 5-D itch scale total score indicated an improvement with treatment with 0.5 and 1.0 μg/kg of difelikefalin (adjusted weekly mean [SE] Skindex-16 overall score at week 8, -27.79 [2.05]; 95% CI, -31.83 to -23.74 for 0.5 μg/kg of difelikefalin and -22.69 [2.04]; 95% CI, -26.71 to -18.68 for 1.0 μg/kg of difelikefalin; adjusted weekly mean [SE] 5-D itch scale total score at week 8, -6.5 [0.4]; 95% CI, -7.2 to -5.8 for 0.5 μg/kg of difelikefalin and -6.8 [0.3]; 95% CI, -7.5 to -6.2 for 1.0 μg/kg of difelikefalin). The incidence of adverse events was 67% (42 of 63 patients) in the placebo group, 72% (44 of 61 patients) in the 0.25 μg/kg of difelikefalin group, 77% (47 of 61 patients) in the 0.5 μg/kg of difelikefalin group, and 85% (53 of 62 patients) in the 1.0 μg/kg of difelikefalin group. No dependency was reported.

Conclusions And Relevance: The findings of this phase 2 randomized clinical trial of difelikefalin suggest that 0.5 μg/kg of difelikefalin should be the clinically recommended dose as a new option for treating moderate to severe pruritus in patients undergoing hemodialysis because of its efficacy, acceptable tolerability, and manageable safety profile.

Trial Registration: ClinicalTrials.gov Identifier: NCT03802617.
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http://dx.doi.org/10.1001/jamanetworkopen.2022.10339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9073569PMC
May 2022

Three-dimensional structural analysis of mitochondria composing each subtype of fast-twitch muscle fibers in chicken.

J Vet Med Sci 2022 Jun 14;84(6):809-816. Epub 2022 Apr 14.

Department of Veterinary Anatomy, School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan.

In a previous study, the three-dimensional structures of mitochondria in type I and type IIb muscle fibers of chicken were analyzed. The study reported differences in the shape of the mitochondria and the distribution of lipid droplets. In this study, we three-dimensionally analyzed mitochondria and lipid droplets of type II muscle fiber subtypes IIa, IIb, and IIc of chicken lateral iliotibial muscle in the same field of view using correlative light electron microscopy (CLEM) and array tomography methods. The reconstructed images showed that the mitochondria of type IIa muscle fiber were thick and aligned along the myofibrils, and many lipid droplets were embedded in the mitochondria. The mitochondria of type IIb muscle fibers were intermittent, aligned along the myofibrils, and showed contact between adjacent horizontal mitochondria. No lipid droplets were observed in type IIb muscle fiber. In type IIc muscle fiber, we observed irregularly shaped mitochondria with small diameters aligned along the myofibrils. Lipid droplets not only were embedded in the mitochondria but also existed independently in some cases. The combination of array tomography and CLEM methods enabled three-dimensional electron microscopic observation of mitochondria in different subtypes of type II muscle fibers. The subtypes of type II muscle fibers differed in mitochondrial occupancy and morphology and in lipid droplet distribution, and characteristics that had been demonstrated biochemically were also demonstrated ultrastructurally.
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http://dx.doi.org/10.1292/jvms.22-0080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246695PMC
June 2022

Clinical features and prognosis of patients with and without diabetes mellitus undergoing endovascular aortic aneurysm repair.

BMC Endocr Disord 2022 Apr 7;22(1):92. Epub 2022 Apr 7.

Department of Vascular Surgery, Saiseikai Yahata General Hospital, 5-9-27 Harunomachi, Yahatahigashi-ku, Kitakyushu City, Fukuoka, 805-0050, Japan.

Background: This study aimed to compare the clinical features and prognoses of patients with and without diabetes mellitus (DM) who underwent endovascular repair for aortic aneurysm (AA).

Methods: We analyzed the clinical database of a prospective multicenter study, registering 929 patients who underwent their first endovascular AA repair in Japan between January 2016 and June 2018. The baseline characteristics and prognoses (including all-cause mortality and cardiovascular events) after repair were compared between the DM and non-DM groups. Prognoses were also compared between the groups after propensity score matching.

Results: In total, 226 patients (24.3%) had DM. Compared with non-DM patients, DM patients had higher pack-years of smoking (P = 0.011), higher body mass index (P = 0.009), lower high-density lipoprotein cholesterol levels (P = 0.038), higher triglyceride levels (P = 0.025), and lower left ventricular ejection fraction (P = 0.005). Meanwhile, the low-density lipoprotein cholesterol and blood pressure levels showed no significant intergroup difference (all P > 0.05). DM patients had a higher prevalence of myocardial infarction (P = 0.016), history of coronary revascularization (P = 0.015), and lower extremity artery disease (P = 0.019). Lesion characteristics and procedures were similar between the groups (all P > 0.05). DM patients had a higher risk of all-cause mortality and cardiovascular events than non-DM patients (both P < 0.001). Subsequent propensity score matching also demonstrated that DM patients had a significantly lower rate of overall survival (P = 0.001) and freedom from cardiovascular events (P = 0.010). The Kaplan-Meier estimates at 1 year for the overall survival were 85.6% (95% confidence interval [CI], 80.9% to 90.5%) and 94.3% (95% CI, 91.7% to 97.0%) for patients with and without DM, respectively. The corresponding estimates for freedom from cardiovascular events were 79.8% (95% CI, 74.5% to 85.5%) and 87.7% (95% CI, 84.2% to 91.3%), respectively.

Conclusions: Among patients undergoing endovascular AA repair, those with DM had more cardiovascular risk factors. DM patients had a higher incidence rate of all-cause mortality and cardiovascular events. Matching analysis indicated that DM per se would be a risk factor for poor prognoses after AA repair.
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http://dx.doi.org/10.1186/s12902-022-01008-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8988424PMC
April 2022

Magnetic resonance imaging (MRI) helps differentiate renal cell carcinoma with sarcomatoid differentiation from renal cell carcinoma without sarcomatoid differentiation.

Abdom Radiol (NY) 2022 06 5;47(6):2168-2177. Epub 2022 Apr 5.

Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Purpose: The aim of the present study is to identify predictive imaging findings and construct a diagnostic model for differentiating renal cell carcinoma (RCC) with and without sarcomatoid dedifferentiation (sRCC and non-sRCC).

Methods: This study is a single-center retrospective study. All patients had magnetic resonance imaging (MRI) with gradient-echo T1-weighted images, single-shot T2-weighted images (T2WI), and enhanced nephrographic phase images. Forty pathologically confirmed sRCCs and 80 non-sRCCs were included in this study. Control cases were selected by matching the tumor diameter and the year of MRI. Two radiologists independently evaluated the following findings: growth pattern, presence of low-intensity area on T2WI in the tumor (T2LIA), presence of non-enhancing area, local tumor stage, and presence of regional lymphadenopathy. Two radiologists measured the diameter of the tumor, T2LIA, and the non-enhancing area. Multivariable logistic regression analysis was used to identify independent predictive factors for differentiating sRCC from non-sRCC. Selected variables were entered in the logistic regression model, and the area under the curve (AUC) was calculated for each reader with 95% confidence intervals (CIs).

Results: Larger T2LIA-to-tumor diameter ratio, regional lymphadenopathy, and local tumor stage 4 were associated with sRCC, and selected for the subsequent construction of a logistic regression model. With this model, the AUCs were 0.76 (95% CI, 0.66-0.85) and 0.70 (95% CI, 0.59-0.81) for prediction of sRCC.

Conclusion: In conclusion, larger T2LIA-to-tumor diameter ratio, regional lymphadenopathy, and local tumor stage 4 are predictive findings of sRCC. As a result, the model constructed using these findings demonstrated a moderate degree of diagnostic accuracy.
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http://dx.doi.org/10.1007/s00261-022-03501-9DOI Listing
June 2022

An exploration of trifluridine/tipiracil in combination with irinotecan in patients with pretreated advanced gastric cancer.

Invest New Drugs 2022 06 12;40(3):614-621. Epub 2022 Mar 12.

Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.

Background: Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer, but their efficacies are limited. We investigated the combination of FTD/TPI and irinotecan for such patients.

Methods: Patients who were refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) and treated with irinotecan (100 [Level 1] or 125 [Level 2] mg/m on days 1 and 15) and FTD/TPI (35 mg/m/dose, twice daily, on days 1-5 and 8-12 [Level A] or on days 1-5 and days 15-19 [Level B]) of a 28-day cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D); the secondary endpoint was the disease control rate (DCR).

Results: Eleven patients were enrolled: 2 at Level 1A, 3 at Level 1B, and 6 at Level 2B. DLTs occurred in 2/2 patients at Level 1A and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved a partial response, and the DCR was 72.7% (95% CI, 39.0%-94.0%). The median progression-free survival and overall survival periods were 3.0 months (95% CI, 0.92-not reached) and 10.2 months (95% CI, 2.2-not reached), respectively.

Conclusion: The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B; this level was associated with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation of the efficacy of RP2D treatment is necessary.
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http://dx.doi.org/10.1007/s10637-022-01223-9DOI Listing
June 2022

Fenofibrate reduces cisplatin-induced apoptosis by inhibiting the p53/Puma/Caspase-9 pathway and the MAPK/Caspase-8 pathway rather than by promoting autophagy in murine renal proximal tubular cells.

Biochem Biophys Rep 2022 Jul 28;30:101237. Epub 2022 Feb 28.

Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

The main lesion of cisplatin nephrotoxicity is damage to proximal tubular cells due to increased apoptosis via the mitochondrial and death receptor pathways, which may be alleviated by appropriate promotion of autophagy. Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-α) activator, is recently reported to promote autophagy as well as protect against cisplatin nephrotoxicity, although the mechanisms were only partially analyzed. Here, the detailed mechanisms of these putative protective effects were investigated in a murine renal proximal tubular (mProx) cell line. Fenofibrate attenuated cisplatin-induced apoptosis of mProx cells based on flow cytometry. As for the mitochondrial apoptotic pathway, the reagent reduced cisplatin-stimulated caspase-3 activation by decreasing the phosphorylation of p53, JNK, and 14-3-3, cytosolic and mitochondrial Puma accumulation, cytochrome C release to the cytosol, and resulting cytosolic caspase-9 activation. Fenofibrate also decreased cisplatin-stimulated activation of caspases-8 by suppressing MAPK and NFkB pathways and reducing the gene expression of TNF-α, TL1A, and Fas, main mediators of the death receptor apoptotic pathway. Autophagy defined by p62 reduction and an increase in LC3 II/I was promoted by fenofibrate in mProx cells under starvation. Autophagy inhibition using 3-MA further increased basal and cisplatin-induced caspase-3 and -8 activation, but had no influence on the inhibitory effects of fenofibrate on caspase activation. In conclusion, our study suggests fenofibrate to be a candidate agent to mitigate cisplatin nephrotoxicity by inhibiting the mitochondrial and death apoptotic pathways rather than by promoting autophagy.
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http://dx.doi.org/10.1016/j.bbrep.2022.101237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8889369PMC
July 2022

Novel Oleanane-Type Triterpene Glycosides from the L. Seeds and Apoptosis-Inducing Activity via Mitochondria.

Int J Mol Sci 2022 Feb 12;23(4). Epub 2022 Feb 12.

School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1, Horinouchi, Hachioji, Tokyo 192-0392, Japan.

L., commonly known as "Soapwort", is a rich source of triterpene glycosides; however, the chemical constituents of seeds have not been fully identified. In this study, we conducted a systematic phytochemical investigation of the seeds of and obtained 17 oleanane-type triterpene glycosides (-), including seven new glycosides (-). The structures of - were determined based on a detailed analysis of NMR spectroscopic data and chromatographic and spectroscopic analyses following specific chemical transformation. The cytotoxicities of the isolated compounds were evaluated against HL-60 human promyelocytic leukemia cells, A549 human adenocarcinoma lung cancer cells, and SBC-3 human small-cell lung cancer cells. The cytotoxicities of , , and toward HL-60 cells and SBC-3 cells were nearly as potent as that of cisplatin. Compound , a bisdesmosidic triterpene glycoside obtained in good yield, arrested the cell cycle of SBC-3 cells at the G/M phase, and induced apoptosis through an intrinsic pathway, accompanied by ROS generation. As a result of the mitochondrial dysfunction induced by , mitochondria selective autophagy, termed mitophagy, occurred in SBC-3 cells.
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http://dx.doi.org/10.3390/ijms23042047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877789PMC
February 2022

Combined Drainage and Protocolized Necrosectomy Through a Co-axial Lumen-Apposing Metal Stent for Pancreatic Walled-off Necrosis: A Prospective Multicenter Trial.

Ann Surg 2021 Nov 2. Epub 2021 Nov 2.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, USA Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia, USA Endoscopy Division, Boston Scientific Corporation, Marlborough, Massachusetts, USA.

Objective: We evaluated a protocolized endoscopic necrosectomy approach with a lumen-apposing metal stent (LAMS) in patients with large symptomatic walled-off pancreatic necrosis (WON) comprising significant necrotic content, with or without infection.

Summary Background Data: Randomized trials have shown similar efficacy of endoscopic treatment compared to surgery for infected WON.

Design: We conducted a regulatory, prospective, multicenter single-arm clinical trial examining the efficacy and safety of endoscopic ultrasound (EUS)-guided LAMS with protocolized necrosectomy to treat symptomatic WON ≥ 6 cm in diameter with > 30% solid necrosis. After LAMS placement, protocolized WON assessment was conducted and endoscopic necrosectomy was performed for insufficient WON size reduction and persistent symptoms. Patients with radiographic WON resolution to ≤ 3 cm and/or 60-day LAMS indwell had LAMS removal, then 6-month follow-up. Primary endpoints were probability of radiographic resolution by 60 days and procedure-related serious adverse events (SAEs).

Results: Forty consecutive patients were enrolled September 2018 - March 2020, of whom 27 (67.5%) were inpatients and 19 (47.5%) had clinical evidence of infection at their index procedure. Mean WON size was 15.0 ± 5.6 cm with mean 53.2% ± 16.7% solid necrosis. Radiographic WON resolution was seen in 97.5% (95% CI, 86.8%, 99.9%) by 60 days, without recurrence in 34 patients with 6-month follow-up data. Mean time to radiographic WON resolution was 34.1 ± 16.8 days. SAEs occurred in 3 patients (7.5%), including sepsis, vancomycin-resistant enterococcal bacteremia and shock, and upper gastrointestinal bleeding. There were no procedure-related deaths.

Conclusions: EUS-guided drainage with protocolized endoscopic necrosectomy to treat large symptomatic or infected walled-off necrotic pancreatic collections was highly effective and safe. Clinicaltrials.gov no: NCT03525808.
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http://dx.doi.org/10.1097/SLA.0000000000005274DOI Listing
November 2021

Paravertebral extramedullary hematopoiesis in a case of myelodysplastic syndrome with ring sideroblasts and an SF3B1 mutation.

Int J Hematol 2022 Jun 28;115(6):898-901. Epub 2022 Jan 28.

Department of Hematology, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.

We present the case of a 56-year-old male patient with paravertebral extramedullary hematopoiesis (EMH) secondary to myelodysplastic syndrome with ring sideroblasts and multilineage dysplasia. In a routine health checkup over 5 years prior, he presented with asymptomatic mild anemia and a posterior mediastinal mass. Pathological and cytomorphological findings of the resected paravertebral mass were similar to those of his bone marrow specimen, and included cellularity with erythroid hyperplasia, multilineage dysplastic changes, and the presence of ring sideroblasts. A concordant SF3B1 mutation was detected in both bone marrow and paravertebral mass samples, suggesting that the EMH cells were derived from the bone marrow.
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http://dx.doi.org/10.1007/s12185-022-03291-2DOI Listing
June 2022

CT findings and diagnostic performance of upper urinary tract carcinoma in situ.

Eur Radiol 2022 May 22;32(5):3269-3279. Epub 2022 Jan 22.

Department of Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Objectives: To evaluate the CT characteristics and detectability of carcinoma in situ (CIS) of the upper urinary tract.

Methods: Between January 2007 and March 2020, 28 patients (mean age: 73 years, 25 male and 3 female) with 29 pure CIS lesions of the upper urinary tract (i.e., without concomitant non-CIS lesion) who underwent nephroureterectomy were identified. The most recent CT scan performed before ureteroscopy, systemic neoadjuvant chemotherapy, or nephroureterectomy was selected for analysis. Twenty-eight patients without upper tract malignancy were selected as a control group. All images were evaluated for presence of upper urinary tract CIS using confidence levels ranging from 1 to 100 by two radiologists. The confidence level of 75 was used as a cutoff threshold for calculating sensitivity and specificity.

Results: The median interval between CT scan and nephroureterectomy was 96 days. The number of true-positive lesions (per-lesion sensitivity) was 41% (12/29) and 52% (15/29) by readers 1 and 2. The true-positive lesion appeared as wall thickening in 83% (10/12) by reader 1 and 80% (12/15) by reader 2, and as a mass in 17% (2/12) by reader 1 and 20% (3/15) by reader 2. All mass-forming lesions were located in the renal collecting system. The per-patient sensitivity and specificity were 42% and 100% in reader 1, and 54% and 96% in reader 2.

Conclusions: The common abnormal finding of pure CIS in the upper urinary tract was wall thickening. Pure CIS could also appear as a mass-forming lesion when it is located in the renal collecting system.

Key Points: • The common abnormal finding of pure CIS in the upper urinary tract is wall thickening. Gradually progressive urothelial wall thickening and/or worsening symptoms should raise the suspicion of CIS. • Pure CIS in the upper urinary tract also appears as a mass-forming lesion when it is located in the renal collecting system. • Hydronephrosis and fat stranding play an auxiliary role in detecting pure CIS in the upper urinary tract.
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http://dx.doi.org/10.1007/s00330-021-08445-0DOI Listing
May 2022

CFI 25 Subunit of Cleavage Factor I is Important for Maintaining the Diversity of 3' UTR Lengths in Arabidopsis thaliana (L.) Heynh.

Plant Cell Physiol 2022 Mar;63(3):369-383

Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011 Japan.

Cleavage and polyadenylation at the 3' end of the pre-mRNA is essential for mRNA function, by regulating its translatability, stability and translocation to the cytoplasm. Cleavage factor I (CFI) is a multi-subunit component of the pre-mRNA 3' end processing machinery in eukaryotes. Here, we report that plant CFI 25 subunit of CFI plays an important role in maintaining the diversity of the 3' ends of mRNA. The genome of Arabidopsis thaliana (L.) Heynh. contained four genes encoding three putative CFI subunits (AtCFI 25, AtCFI 59 and AtCFI 68), orthologous to the mammalian CFI subunits. There were two CFI 25 paralogs (AtCFI 25a and AtCFI 25b) that shared homology with human CFI 25. Two null alleles of AtCFI 25a displayed smaller rosette leaves, longer stigmatic papilla, smaller anther, earlier flowering and lower fertility compared to wild-type plants. Null alleles of AtCFI 25b, as well as, plants ectopically expressing full-length cDNA of AtCFI 25a, displayed no obvious morphological defects. AtCFI 25a was shown to interact with AtCFI 25b, AtCFI 68 and itself, suggesting various forms of CFI in plants. Furthermore, we show that AtCFI 25a function was essential for maintaining proper diversity of the 3' end lengths of transcripts coding for CFI subunits, suggesting a self-regulation of the CFI machinery in plants. AtCFI 25a was also important to maintain 3' ends for other genes to different extent. Collectively, AtCFI 25a, but not AtCFI 25b, seemed to play important roles during Arabidopsis development by maintaining proper diversity of the 3' UTR lengths.
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http://dx.doi.org/10.1093/pcp/pcac002DOI Listing
March 2022

Bendamustine-induced rash is associated with a favorable prognosis in patients with indolent B-cell lymphoma.

J Clin Exp Hematop 2022 Mar 28;62(1):18-24. Epub 2021 Dec 28.

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

Bendamustine is now recognized as a key drug for indolent B-cell lymphoma (iBCL), mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Skin toxicity associated with bendamustine is one of the characteristic adverse effects. We retrospectively examined the relationship between bendamustine-associated drug rashes and disease prognosis of iBCL and MCL at our institution. Between January 2011 and August 2019, 65 patients (39 men and 26 women, median age 68, range 41-84 years) were treated with bendamustine alone (n=11, 120 mg/m on days 1 and 2) or a combination of rituximab and bendamustine (n=54, 90 mg/m on days 1 and 2). Of these patients, 47 had follicular lymphoma (FL), 10 had MCL and 8 had other iBCLs. Drug rash occurred in 27 (41.5%). Eight cases (29.6%) were grade 1, 5 (18.5%) were grade 2 and 14 (51.9%) were grade 3. The onset was in the first course in 17 (63.0%), 2nd course in 5 (18.5%), 3rd course in 2 (7.4%), 4th course in 1 (3.7%) and 5th course in 2 (7.4%). No treatment was administered in 1 case (3.7%), topical steroid was applied in 10 (37.0%), antiallergic drug was administered in 2 (7.4%), topical steroid and antiallergic drug were administered in 5 (18.5%), and oral and topical steroid and antiallergic drug were administered in 9 (33.3%). The 3-year progression-free survival (PFS) and overall survival (OS) in patients with rash development were 80.0% and 85.5%, respectively, and those in patients without development were 36.4% and 54.0%, respectively (p=0.009 and 0.02, respectively). By multivariate analysis, the development of rash was associated with a better PFS and a diagnosis of iBCL was associated with a better OS. This study revealed that bendamustine-induced rash is associated with a favorable prognosis among patients with iBCL.
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http://dx.doi.org/10.3960/jslrt.21018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010495PMC
March 2022

Laminin Isoforms in Human Dental Pulp: Lymphatic Vessels Express Laminin-332, and Schwann Cell-Associated Laminin-211 Modulates CD163 Expression of M2-like Macrophages.

Immunohorizons 2021 12 29;5(12):1008-1020. Epub 2021 Dec 29.

Division of Oral Science for Health Promotion, Department of Oral Health and Welfare, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Laminin, a basement membrane heterotrimeric glycoprotein composed of α/β/γ subunits, has important tissue-specific functions in the control of cellular behavior. Our recent study showed the colocalization of CD163 M2-like macrophages with Schwann cells in human dental pulp, leading us to hypothesize that the laminin isoform of Schwann cells is associated with CD163 expression. The present study investigated the distribution of laminin isoforms in human dental pulp and the underlying mechanisms that affect macrophage phenotypes. Immunofluorescence analysis indicated that blood vessels were exclusively positive for laminin α4 and α5, whereas laminin α2 was associated with Schwann cells. Unexpectedly, laminin α3/laminin-332 (α3β3γ2) was detected on lymphatic vessels. In intact and carious teeth, CD163 cells were associated with laminin α2, whereas CD206 single-positive cells were present inside, outside, and along blood vessels. In vitro incubation of THP-1 macrophages in plates coated with laminin-211/511 or its functionally analogous E8 fragments of α-chain (E8-α) indicated that cell shapes differed between macrophages grown on laminin-211/E8-α2 and macrophages grown on laminin-511/E8-α5. Laminin-211/E8-α2-coated plates upregulated CD163 expression, compared with laminin-511/E8-α5-coated plates. Integrin α3- and integrin α6-neutralizing Abs altered the shape of THP-1 macrophages and upregulated mRNA levels of CD206 and CD163 in macrophages grown on laminin-511; the neutralizing Abs did not affect macrophages grown on laminin-211. These findings suggest that laminin isoforms differentially regulate macrophage behavior via distinct integrin-laminin affinities. Of note, laminin-332 is expressed by pulpal lymphatic vessels, the existence of which has been debated; laminin-211 might have a role in maintaining CD163 expression on macrophages.
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http://dx.doi.org/10.4049/immunohorizons.2100110DOI Listing
December 2021

Effects of intra-articular inoculation with Mycoplasma bovis on immunological responses in calf joints.

Vet Immunol Immunopathol 2022 Feb 16;244:110364. Epub 2021 Dec 16.

Animal Health Laboratory, Department of Veterinary Science, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan. Electronic address:

Mycoplasma arthritis that caused by Mycoplasma bovis exhibit severe lameness. This disease is difficult to cure with antibiotics, but the detailed pathological mechanisms have not been fully clarified. In this study, we examined the effects of intra-articular inoculation with M. bovis on immunological responses in calf joints. We inoculated three calves each with M. bovis or phosphate buffer saline (control) into the right stifle joint and dissected them at 15 days postinoculation. Mycoplasma bovis-inoculated calves exhibited swelling of the stifle joint, increases in synovial fluid, fibrin deposition, and cartilage thinning. Intracellular M. bovis was detected in synovial tissues analyzed by immunohistochemistry and transmission electron microscopy. Messenger RNA expressions of interleukin (IL)-1β, IL-6, IL-8, IL-12p40, and IL-17A in synovial fluid cells and synovial tissues from M. bovis-inoculated calves were significantly higher than those from control calves. Protein levels of these cytokines in synovial fluid from M. bovis-inoculated calves were markedly higher than those from control calves. Our study clarified that inoculation with M. bovis into the stifle joint induced the production of inflammatory cytokines by synovial fluid cells and synovial tissues, causing a severe inflammatory response in joints. Additionally, M. bovis could invade cells in synovial tissues, which may have aided it in evading antibiotics and host immune surveillance.
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http://dx.doi.org/10.1016/j.vetimm.2021.110364DOI Listing
February 2022

[Tubulointerstitial nephritis with IgM-positive plasma cells in an elderly woman diagnosed by a renal biopsy and treated with corticosteroid therapy].

Nihon Ronen Igakkai Zasshi 2021 ;58(4):630-636

Department of Nephrology and Dialysis, Nagoya City West Medical Center.

An 81-year-old female was referred to our department 1 year ago due to a worsening renal function. Her manifestations met the criteria of Sjögren syndrome, suggesting renal failure likely resulting from tubulointerstitial nephritis (TIN) due to Sjögren syndrome. However, at her request, she was followed up with no further investigation or treatment. The following July, since her renal function deteriorated again, a renal biopsy was performed. Using IgM-CD138 dual staining, the renal pathology showed the infiltration of accumulated IgM-positive plasma cells within the renal insterstitium, so she was diagnosed with tubulointerstitial nephritis with IgM-positive plasma cells (IgMPC-TIN).IgMPC-TIN, proposed by Takahashi et al. in 2017, as a type of TIN, is characterized by the pathological infiltrations of IgM-positive plasma cells within the renal insterstitium and is effectively treated with corticosteroid therapy. Despite her old age, corticosteroid therapy was performed, resulting in the improvement in her renal function according to blood and urine tests and an improved pulmonary involvement, although renal dysfunction remained.Elderly patients often have multiple underlying medical conditions and take numerous medications, so differentiating renal disorders is challenging. However, a renal biopsy, even in an elderly patient, can aid in identifying the cause of renal disorders and predicting the prognosis. IgMPC-TIN is a condition in which renal function can be expected to improve if treated. It is thus important to make a diagnosis of IgMPC-TIN without overlooking and to consider proper treatment.
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http://dx.doi.org/10.3143/geriatrics.58.630DOI Listing
December 2021

Muscle fat index is associated with frailty and length of hospital stay following transcatheter aortic valve replacement in high-risk patients.

Int J Cardiol 2022 Feb 3;348:33-38. Epub 2021 Dec 3.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of America. Electronic address:

Background: Aging is associated with progressive loss of muscle mass, as well as replacement of muscle with fat and fibrous tissue. We studied the contribution of muscle fat content, a surrogate marker of biological aging, to frailty and Length of Hospital Stay (LOS) following Transcatheter Aortic Valve Replacement (TAVR).

Methods: We evaluated 415 patients who underwent TAVR from February 2012 to December 2016 at Mayo Clinic, MN, USA. Densities between -190 to -30 Hounsfield Units within the abdominal muscle area were determined as muscle fat. Muscle Fat Index (MFI) was defined as muscle fat mass divided by height squared. LOS was considered as the primary outcome. Stepwise multivariable linear regression was used to identify the predictors of LOS.

Results: Mean age ± SD of the study population was 81.2 ± 9.6 years and 58.07% were male. Seventy-two patients (17.35%) had frailty. Median (IQR) LOS was 4 (3-6) days. MFI was higher in patients with frailty (median (IQR); 18.1 [13.8-24.2] vs 14.4 [10.6-18.7], p < 0.001) and was positively correlated with LOS (r = 0.129, p = 0.009). In multivariable analysis of predictors of LOS, MFI (β = 0.06, p = 0.022), pre-TAVR atrial fibrillation/flutter (β = 0.5, p = 0.015), and post-TAVR complications (β = 0.91, p < 0.001) were directly, and femoral access route (β = -1.13, p < 0.001) and pre-TAVR hemoglobin (β = -0.35, p = 0.002) were inversely associated with LOS.

Conclusions: MFI can be determined from pre-TAVR CT scans and is a novel predictor of LOS following TAVR. This objective indicator can potentially be used in a pre-TAVR clinic to plan for rehabilitation programs in selected patients.
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http://dx.doi.org/10.1016/j.ijcard.2021.11.087DOI Listing
February 2022
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