Publications by authors named "Hiroyuki Yamaguchi"

257 Publications

Early discontinuation of induction therapy in chemoimmunotherapy as an effective alternative to the standard regimen in patients with non-small cell lung cancer: a retrospective study.

J Cancer Res Clin Oncol 2021 Sep 12. Epub 2021 Sep 12.

Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.

Purpose: We aimed to investigate whether induction chemotherapy with less than four courses is as effective as induction chemotherapy with more than four courses in non-small cell lung cancer (NSCLC) patients receiving chemoimmunotherapy.

Methods: We retrospectively enrolled 249 patients with NSCLC who received chemoimmunotherapy at 12 centers in Japan between January and December 2019. The patient group that completed less than four courses owing to adverse events (AEs), and received subsequent maintenance therapy was compared to the group that received at least four courses of induction chemotherapy followed by maintenance therapy.

Results: On univariate and multivariate analyses, the patient group that transitioned to maintenance therapy after completing less than four courses of induction chemotherapy had significantly shorter progression-free survival (PFS) than those who completed at least four courses (hazard ratio [HR] 2.15, 95% confidence interval: 1.38-3.37, p < 0.001 and HR 2.32, 95% confidence interval: 1.40-3.84, p = 0.001, respectively). There was no obvious difference in PFS between the group in which induction chemotherapy ended in two or three courses leading to partial or complete response, and the group that continued at least four courses of induction chemotherapy (log-rank test p = 0.53).

Conclusion: Treatment efficacy may be maintained if induction chemotherapy is completed in less than four courses owing to development of AEs, and is administered for more than two courses with partial or complete response; efficacy is maintained even on transitioning to maintenance therapy.
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http://dx.doi.org/10.1007/s00432-021-03782-5DOI Listing
September 2021

Clinical impact of pembrolizumab combined with chemotherapy in elderly patients with advanced non-small-cell lung cancer.

Lung Cancer 2021 Aug 31;161:26-33. Epub 2021 Aug 31.

Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto, Japan.

Objectives: Combination therapy of immune checkpoint inhibitors and chemotherapy is considered to be one of the standard treatment options for patients with advanced non-small-cell lung cancer (NSCLC). However, the clinical significance of immune checkpoint inhibitors combined with chemotherapy in elderly patients with NSCLC has not yet been fully understood. Therefore, this study aimed to evaluate how aging affects the therapeutic impact of chemotherapy combine with immune checkpoint inhibitors in elderly patients.

Materials And Methods: We retrospectively analyzed 203 patients with advanced NSCLC who were treated with the combination therapy of pembrolizumab and chemotherapy between January 2019 and December 2019 at 12 institutions in Japan. We analyzed the clinical impacts of age on the following two groups: those who received pembrolizumab with platinum and pemetrexed (pemetrexed regimen) and those who received pembrolizumab with carboplatin and nab-paclitaxel/paclitaxel (paclitaxel regimen). Progression-free and overall survival were assessed via the Kaplan-Meier method.

Results: Multivariate analysis demonstrated that progression-free and overall survival were significantly shorter in elderly patients (aged ≥75 years) with NSCLC than in non-elderly patients (aged <75 years) with NSCLC in the pemetrexed regimen group. In contrast, there were no significant differences in progression-free and overall survival between elderly patients and non-elderly patients with NSCLC in the paclitaxel regimen group. In elderly patients with NSCLC, a programmed death-ligand 1 tumor proportion score of ≥50% was significantly associated with progression-free survival, and performance status of ≥2 was significantly associated with overall survival. Low albumin level (<3.5 g/dL) was significantly associated with both progression-free and overall survival.

Conclusion: The results of this retrospective study show that the pemetrexed regimen, but not the paclitaxel regimen, was related to poor clinical outcomes in elderly patients with NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.08.015DOI Listing
August 2021

A Phase II Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis From NSCLC: Results for the T790M Cohort of the OCEAN Study (LOGIK1603/WJOG9116L).

J Thorac Oncol 2021 Aug 19. Epub 2021 Aug 19.

Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Oita, Japan; Lung Oncology Group in Kyushu (LOGiK), Fukuoka, Japan.

Objectives: Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC.

Methods: The OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA.

Results: The median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%-79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively.

Conclusions: This study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.
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http://dx.doi.org/10.1016/j.jtho.2021.07.026DOI Listing
August 2021

Wild ciliates differ in susceptibility to JR32.

Microbiology (Reading) 2021 08;167(8)

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

We investigated how (Lp) JR32 interacts with CS11A and E6, two ciliates that we isolated from sewage and sink trap sludge, respectively, using a handmade maze device containing a 96-well crafting plate. Our 18S rDNA-based phylogenetic analysis showed that CS11A and E6 formed distinct clades. Scanning electron microscopy showed that CS11A had a bigger-sized body than E6 and, unlike IB (the reference strain), neither ciliate produced pellets, which are extracellular vacuoles. Fluorescence microscopic observations revealed that although the intake amounts differed, all three ciliates rapidly ingested LpJR32 regardless of the presence or absence of the virulence genes, indicating that they all interacted with LpJR32. In co-cultures with CS11A, the LpJR32 levels were maintained but fell dramatically when the co-culture contained the LpJR32 deletion mutant instead. CS11A died within 2 days of co-culture with LpJR32, but survived co-culture with the deletion mutant. In co-cultures with E6, LpJR32 levels were maintained but temporarily decreased independently of the virulence gene. Concurrently, the E6 ciliates survived by forming cysts, which may enable them to resist harsh environments, and by diminishing the sensitivity of trophozoites to Lp. In the IB co-cultures with LpJR32 or Δ, the Lp levels were maintained, albeit with temporal decreases, and the IB levels were also maintained. We conclude that unlike IB with pellet production, CS11A can be killed by LpJR32 infection, and E6 can resist LpJR32 infection through cyst formation and the low sensitivity of trophozoites to Lp. Thus, the two ciliates that we isolated had different susceptibilities to LpJR32 infection.
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http://dx.doi.org/10.1099/mic.0.001078DOI Listing
August 2021

Bilateral Adrenal Infarctions as an Initial Manifestation of TAFRO Syndrome: A Case Report and Review of the Literature.

Intern Med 2021 Aug 13. Epub 2021 Aug 13.

Department of Internal Medicine, Mito Kyodo General Hospital, University of Tsukuba, Japan.

TAFRO syndrome is a systemic inflammatory disorder resembling multicentric Castleman disease; it is characterized by thrombocytopenia, anasarca, a fever, reticulin fibrosis, and organomegaly. Involvement of the adrenal glands, including adrenal infarction, hemorrhaging, and adrenomegaly, has recently been reported in several cases and been considered a characteristic early-stage symptom. We herein report a case of TAFRO syndrome initially presenting with bilateral adrenal infarctions and review the literature on TAFRO syndrome related to adrenal involvement. This case suggests that adrenal abnormalities as an early clinical feature of TAFRO syndrome may be useful for the early diagnosis.
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http://dx.doi.org/10.2169/internalmedicine.7976-21DOI Listing
August 2021

Transanal approach after preoperative imatinib treatment of a rectal gastrointestinal stromal tumors with external anal sphincter invasion: A case report.

Int J Surg Case Rep 2021 Aug 19;85:106217. Epub 2021 Jul 19.

Department of Surgery, Japan Community Health Care Organization Isahaya General Hospital, Nagasaki, Japan.

Introduction And Importance: Rectal gastrointestinal stromal tumors (GISTs) are rare, and preserving anorectal function can be challenging. We report the case of a patient with rectal GIST with external anal sphincter invasion, treated via the laparoscopic and transanal approaches.

Case Presentation: A 61-year-old man with locally advanced GIST in the right anterolateral wall of the lower rectum was examined. Lower endoscopy revealed a 50-mm submucosal tumor located 4 cm from the anal verge. On immunohistochemistry, the biopsy specimen tested positive for CD34 and C-KIT, and the patient was diagnosed with GIST. Abdominal magnetic resonance imaging (MRI) revealed external anal sphincter infiltration. Because of the large tumor size and proximity to the anal verge, preserving the anus was challenging, and colorectal resection was avoided. Instead, neoadjuvant therapy with imatinib was administered to facilitate local resection of the tumor. Post-treatment MRI showed a reduction in tumor size (30 × 20 × 30 mm), and surgery was performed. We identified an appropriate resection line for diplomatic sphincter resection of the infiltrated area by laparoscopy alone. Thus, we performed a hybrid surgery using the laparoscopic and transanal approaches. The patient had an unremarkable postoperative course and was discharged on postoperative day 23.

Clinical Discussion: No study has reported cases of rectal GIST with external anal sphincter invasion wherein anal function was preserved. Here, imatinib was administered preoperatively, and hybrid surgery was performed using the transanal and laparoscopic approaches.

Conclusion: Preoperative treatment and surgery preserved anorectal function in a patient with a massive rectal GIST.
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http://dx.doi.org/10.1016/j.ijscr.2021.106217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335625PMC
August 2021

Nuclear factor-kappa B decoy oligodeoxynucleotide-loaded poly lactic-co-glycolic acid nanospheres promote periodontal tissue healing after tooth replantation in rats.

J Periodontol 2021 Jul 28. Epub 2021 Jul 28.

Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Background: Excessive inflammation in the periodontal tissue after tooth replantation can lead to inflammatory root resorption and interrupt periodontal tissue regeneration. We tested the hypothesis that nuclear factor-κB decoy oligodeoxynucleotide-loaded poly lactic-co-glycolic acid nanospheres (NF-PLGA) inhibit excessive inflammation and promote healing of periodontal tissue after replantation in rats.

Methods: The upper right incisors of rats were extracted, immersed in different specific solutions, and replanted. The rats were euthanized at 7, 14, and 28 days after replantation. Morphological evaluation with micro-CT and histological assessment with hematoxylin and eosin and tartrate-resistant acid phosphatase (TRAP) staining was performed. Additionally, we examined the expression of interleukin (IL)-1β, IL-6, transforming growth factor-β1 (TGF-β1), and fibroblast growth factor-2 (FGF-2) in the periodontal ligament (PDL) by performing immunohistological assessment.

Results: The NF-PLGA group showed significantly greater dental root thickness than the other experimental groups. Root resorption was not observed after the application of NF-PLGA on day 7. The application of NF-PLGA also resulted in a significantly lower number of TRAP-positive osteoclasts on days 7 and 14 after replantation. Significantly lower expression of IL-1β and IL-6 and higher expression of TGF-β1 and FGF-2 were observed under the application of NF-PLGA in the PDL.

Conclusions: NF-PLGA promoted the healing process by inhibiting the initial excessive inflammatory response in the PDL, preventing root resorption, and promoting periodontal tissue regeneration. The findings also suggested that the PLGA nanospheres-mediated transfection of the decoy oligodeoxynucleotides can be useful for the clinical application of replanted tooth root surfaces.
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http://dx.doi.org/10.1002/JPER.21-0134DOI Listing
July 2021

Three-Dimensional Convolutional Autoencoder Extracts Features of Structural Brain Images With a "Diagnostic Label-Free" Approach: Application to Schizophrenia Datasets.

Front Neurosci 2021 7;15:652987. Epub 2021 Jul 7.

Department of Information Medicine, National Center of Neurology and Psychiatry, National Institute of Neuroscience, Tokyo, Japan.

There has been increasing interest in performing psychiatric brain imaging studies using deep learning. However, most studies in this field disregard three-dimensional (3D) spatial information and targeted disease discrimination, without considering the genetic and clinical heterogeneity of psychiatric disorders. The purpose of this study was to investigate the efficacy of a 3D convolutional autoencoder (3D-CAE) for extracting features related to psychiatric disorders without diagnostic labels. The network was trained using a Kyoto University dataset including 82 patients with schizophrenia (SZ) and 90 healthy subjects (HS) and was evaluated using Center for Biomedical Research Excellence (COBRE) datasets, including 71 SZ patients and 71 HS. We created 16 3D-CAE models with different channels and convolutions to explore the effective range of hyperparameters for psychiatric brain imaging. The number of blocks containing two convolutional layers and one pooling layer was set, ranging from 1 block to 4 blocks. The number of channels in the extraction layer varied from 1, 4, 16, and 32 channels. The proposed 3D-CAEs were successfully reproduced into 3D structural magnetic resonance imaging (MRI) scans with sufficiently low errors. In addition, the features extracted using 3D-CAE retained the relation to clinical information. We explored the appropriate hyperparameter range of 3D-CAE, and it was suggested that a model with 3 blocks may be related to extracting features for predicting the dose of medication and symptom severity in schizophrenia.
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http://dx.doi.org/10.3389/fnins.2021.652987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294943PMC
July 2021

Impact of cancer cachexia on the therapeutic outcome of combined chemoimmunotherapy in patients with non-small cell lung cancer: a retrospective study.

Oncoimmunology 2021 8;10(1):1950411. Epub 2021 Jul 8.

Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Although previous studies suggest that cancer cachexia is a poor prognostic factor for immune checkpoint inhibitor monotherapy, the impact of cancer cachexia on chemoimmunotherapy is unclear. We investigated the impact of cancer cachexia on the therapeutic outcomes of chemoimmunotherapy for non-small cell lung cancer (NSCLC). We retrospectively analyzed patients' medical records with NSCLC who received chemoimmunotherapy in 12 institutions in Japan between January and November 2019. We defined cancer cachexia as weight loss exceeding 5% of the total body weight or a body mass index of < 20 kg/m and weight loss of more than 2% of the total body weight within 6 months before chemoimmunotherapy initiation, with laboratory results exceeding reference values. This study enrolled 235 patients with NSCLC, among whom 196 were eligible for analysis, and 50 (25.5%) met the criteria for cachexia diagnosis. Patients with cancer cachexia had a significantly higher frequency of a programmed death-ligand 1 (PD-L1) expression of ≥ 50% (48%, = .01) and shorter progression-free survival (PFS; log-rank test: = .04) than patients without cachexia. There was no significant difference in overall survival (OS) between the cachexia and no-cachexia groups (log-rank test: = .14). In the PD-L1 ≥ 50% population, there was no significant difference in PFS and OS (log-rank test: = .19 and = .79, respectively) between patients with NSCLC in the cachexia or no-cachexia groups. Cancer cachexia might be a poor prognostic factor in patients with NSCLC receiving chemoimmunotherapy.
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http://dx.doi.org/10.1080/2162402X.2021.1950411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274442PMC
August 2021

Usefulness of a 3D-printing air sampler for capturing live airborne bacteria and exploring the environmental factors that can influence bacterial dynamics.

Res Microbiol 2021 Jul 14:103864. Epub 2021 Jul 14.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Kita 12 Nishi 5, Kita-ku, Sapporo, Hokkaido 060-0812, Japan. Electronic address:

We created a handmade 3D-printed air sampler to effectively collect live airborne bacteria, and determined which environmental factors influenced the bacteria. Bacterial colony forming units (CFUs) in the air samples (n=37) were monitored by recording the environmental changes occurring over time, then determining the presence/absence of correlations among such changes. The bacterial CFUs changed sharply and were significantly correlated with the DNA concentrations, indicating that the captured bacteria made up most of the airborne bacteria. Spearman's rank correlation analysis revealed significant correlations between the bacterial CFU values and some environmental factors (humidity, wind speed, insolation, and 24-h rainfall). Similarly the significant associations of CFU with humidity and wind speed were also found by multiple regression analysis with box-cox transformation. Among our panel of airborne bacteria (952 strains), 70 strains were identified as soil-derived Bacillus via the production of Escherichia coli- and Staphylococcus aureus-growth inhibiting antibiotics and by 16S rDNA typing. Soil-derived protozoa were also isolated from the air samples. We conclude that the airborne bacteria mainly derived from soil can alter in number according to environmental changes. Our sampler, which was created by easy-to-customize 3D printing, is a useful device for understanding the dynamics of live airborne bacteria.
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http://dx.doi.org/10.1016/j.resmic.2021.103864DOI Listing
July 2021

Efficacy of S-1 after pemetrexed in patients with non-small cell lung cancer: A retrospective multi-institutional analysis.

Thorac Cancer 2021 Sep 13;12(17):2300-2306. Epub 2021 Jul 13.

Department of Respiratory Medicine, Nagasaki University Graduate, School of Biomedical Sciences, Nagasaki, Japan.

Background: S-1 and pemetrexed (PEM) are key treatments for non-small cell lung cancer (NSCLC). However, the mechanism of anticancer activity of S-1 and PEM is similar. Cross-resistance between S-1 and PEM is of concern. This exploratory study was designed to evaluate the treatment effect of S-1 following PEM-containing treatment.

Methods: This retrospective study included patients with advanced (c-stage III or IV, UICC seventh edition) or recurrent NSCLC who received S-1 monotherapy following the failure of previous PEM-containing chemotherapy at six hospitals in Japan. The primary endpoint of the study was the overall response rate (ORR). The secondary endpoint was the disease control rate (DCR), time to treatment failure (TTF), progression-free survival (PFS), and overall survival (OS).

Results: A total of 53 NSCLC patients met the criteria for inclusion in the study. Forty-six patients had adenocarcinoma (88.7%) and no patients had squamous cell carcinoma. Thirty-one patients (58.5%) received the standard S-1 regimen and 18 patients (34.0%) received the modified S-1 regimen. ORR was 1.9% (95% confidence interval [CI]: 0.00%-10.1%). Median TTF, PFS, and OS were 65, 84, and 385 days, respectively.

Conclusions: Although there were several limitations in this study, the ORR of S-1 after PEM in patients with nonsquamous (non-SQ) NSCLC was low compared to the historical control. One of the options in the future might be to avoid S-1 treatment in PEM-treated patients who need tumor shrinkage.
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http://dx.doi.org/10.1111/1759-7714.14055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410557PMC
September 2021

The molecular complex of ciliary and golgin protein is crucial for skull development.

Development 2021 07 1;148(13). Epub 2021 Jul 1.

Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Intramembranous ossification, which consists of direct conversion of mesenchymal cells to osteoblasts, is a characteristic process in skull development. One crucial role of these osteoblasts is to secrete collagen-containing bone matrix. However, it remains unclear how the dynamics of collagen trafficking is regulated during skull development. Here, we reveal the regulatory mechanisms of ciliary and golgin proteins required for intramembranous ossification. During normal skull formation, osteoblasts residing on the osteogenic front actively secreted collagen. Mass spectrometry and proteomic analysis determined endogenous binding between ciliary protein IFT20 and golgin protein GMAP210 in these osteoblasts. As seen in Ift20 mutant mice, disruption of neural crest-specific GMAP210 in mice caused osteopenia-like phenotypes due to dysfunctional collagen trafficking. Mice lacking both IFT20 and GMAP210 displayed more severe skull defects compared with either IFT20 or GMAP210 mutants. These results demonstrate that the molecular complex of IFT20 and GMAP210 is essential for the intramembranous ossification during skull development.
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http://dx.doi.org/10.1242/dev.199559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276989PMC
July 2021

X-ray adaptive zoom condenser utilizing an intermediate virtual focus.

Opt Express 2021 May;29(10):15604-15615

We propose an extended X-ray adaptive zoom condenser that can form an intermediate virtual focus. The system comprises two deformable mirrors for focusing within a single dimension and can vary its numerical aperture (NA) without changing the positions of the light source, mirrors, or final focus. The desired system NA is achieved simply by controlling the mirror surfaces, which enables conversion between convex and concave forms, by varying the position of the intermediate virtual focus. A feasibility test at SPring-8 under a photon energy of 10 keV demonstrated that the beam size can be varied between 134 and 1010 nm.
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http://dx.doi.org/10.1364/OE.422723DOI Listing
May 2021

Alteration of DNA Damage Response Causes Cleft Palate.

Front Physiol 2021 29;12:649492. Epub 2021 Mar 29.

Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, United States.

Cleft palate is one of the most common craniofacial birth defects, however, little is known about how changes in the DNA damage response (DDR) cause cleft palate. To determine the role of DDR during palatogenesis, the DDR process was altered using a pharmacological intervention approach. A compromised DDR caused by a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor resulted in cleft palate in wild-type mouse embryos, with increased DNA damage and apoptosis. In addition, a mouse genetic approach was employed to disrupt breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2), known as key players in DDR. An ectomesenchymal-specific deletion of or resulted in cleft palate due to attenuation of cell survival. This was supported by the phenotypes of the ectomesenchymal-specific / double-knockout mice. The cleft palate phenotype was rescued by superimposing p53 null alleles, demonstrating that the BRCA1/2-p53 DDR pathway is critical for palatogenesis. Our study highlights the importance of DDR in palatogenesis.
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http://dx.doi.org/10.3389/fphys.2021.649492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039291PMC
March 2021

A randomized phase II study of S-1 monotherapy versus cisplatin with vinorelbine for completely resected stage II/IIIA non-small cell lung cancer: rationale and study protocol design for the LOGIK1702 study.

BMC Cancer 2021 Mar 8;21(1):249. Epub 2021 Mar 8.

Department of Thoracic and Breast Surgery, Oita University, Oita, Japan.

Background: The current standard postoperative treatment for stage II-IIIA non-small cell lung cancer (NSCLC) is a regimen of platinum doublet adjuvant chemotherapy. These regimens, which are the same as for solid NSCLC tumors, often cause severe adverse reactions in the treated patients. Therefore, an effective treatment regimen with fewer side effects is needed.

Methods/design: The purpose of this study is to evaluate the effectiveness and safety of S-1 monotherapy (80 mg/m orally administrated twice daily, at day 1-14, 16 cycles) and cisplatin with vinorelbine combination therapy (cisplatin 80 mg/m at day 1,vinorelbine 25 mg/m at day 1, 8, 4 cycles) in patients with II/IIIA stage non-small-cell lung cancer who underwent a total resection. In addition, we will also evaluate the level of treatment side effects by assessing quality of life (QOL), work productivity and activity performance. The primary endpoint is a 2-year relapse free survival (RFS) and the second primary endpoints are 2-year overall survival (OS), rate of treatment completion, safety, work productivity and activity, and quality of adjusted life years (QALY). At the same time, we aim to obtain precise information required to perform future phase 3 randomized controlled trials. The study is designed to estimate the primary endpoint with accuracy determined as the width of its 95% confidence interval to be less than 20%. Recruitment started in May 2017 and is ongoing.

Discussion: This study has been conceived to establish a superior regimen for completely resected NSCLC based on efficacy, safety and QOL.

Trial Registration: Registry number: UMIN000027435 . Registered May 22, 2017.
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http://dx.doi.org/10.1186/s12885-021-07945-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941711PMC
March 2021

Remarkable response to pembrolizumab with platinum-doublet in PD-L1-low pulmonary sarcomatoid carcinoma: A case report.

Thorac Cancer 2021 04 19;12(7):1126-1130. Epub 2021 Feb 19.

Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Pulmonary sarcomatoid carcinoma (SC) is an aggressive subtype of lung cancer that exhibits resistance to cytotoxic chemotherapy. Although programmed cell death 1 (PD-1) inhibitors have been reported to show antitumor effects in patients with high programmed death-ligand 1 (PD-L1) expressing SC, the efficacy of combined therapy with PD-1 inhibitor plus cytotoxic chemotherapy has not previously been clarified. We herein report a case of SC with low expression of PD-L1 and few pre-existing tumor-infiltrating lymphocytes which showed a remarkable response to pembrolizumab plus cytotoxic chemotherapy as first-line treatment. Our findings suggest that combined treatment might enhance the immunogenic response, even in immunologically ignored SCs.
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http://dx.doi.org/10.1111/1759-7714.13890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017259PMC
April 2021

Duration of antifungal therapy for septic pulmonary embolism caused by from a central venous catheter: A case report.

Clin Case Rep 2021 Feb 4;9(2):707-710. Epub 2020 Dec 4.

Department of Respiratory Medicine Nagasaki University Graduate School of Biomedical Sciences Nagasaki Japan.

The treatment duration for candidemia with septic pulmonary embolism should be determined based on the clearance of fungus from the bloodstream and improvement of symptoms. The remaining lung nodules may not necessarily indicate persistent infection.
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http://dx.doi.org/10.1002/ccr3.3628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869368PMC
February 2021

Impact of Corticosteroid Administration within 7 Days of the Hospitalization for Influenza Pneumonia with Respiratory Failure: A Propensity Score Analysis Using a Nationwide Administrative Database.

J Clin Med 2021 Jan 31;10(3). Epub 2021 Jan 31.

Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.

Influenza pneumonia, which causes acute respiratory distress syndrome and multiple organ failure, has no established management protocol. Recently, corticosteroid therapy was used to treat coronavirus disease 2019 with respiratory failure; however, its effectiveness as a treatment for influenza pneumonia remains controversial. To investigate the impact of corticosteroid therapy for the early phase of severe influenza pneumonia, we compared influenza pneumonia patients with respiratory failure treated with or without corticosteroids within 7 days after hospital admission using a Japanese nationwide administrative database. The primary endpoint was the mortality rate. The secondary endpoints were duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. The inverse probability weighting method with estimated propensity scores was used to minimize the data collection bias. We included 3519 patients with influenza pneumonia with respiratory failure. Of these, 875 were treated with corticosteroids. There was no significant difference between the groups regarding 30-day and 90-day mortality, duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. However, the in-hospital mortality rate was higher in the corticosteroid group. The use of systematic corticosteroid therapy in patients with influenza pneumonia was associated with a higher in-hospital mortality rate.
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http://dx.doi.org/10.3390/jcm10030494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866855PMC
January 2021

Distribution of amoebal endosymbiotic environmental chlamydia Neochlamydia S13 via amoebal cytokinesis.

Microbiol Immunol 2021 Mar 16;65(3):115-124. Epub 2021 Feb 16.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

We previously isolated a symbiotic environmental amoeba, harboring an environmental chlamydia, Neochlamydia S13. Interestingly, this bacterium failed to survive outside of host cells and was immediately digested inside other amoebae, indicating bacterial distribution via cytokinesis. This may provide a model for understanding organelle development and chlamydial pathogenesis and evolution; therefore, we assessed our hypothesis of Neochlamydia S13 distribution via cytokinesis by comparative analysis with other environmental Chlamydiae (Protochlamydia R18 and Parachlamydia Bn ). Dual staining with 4',6-diamidino-2-phenylindole and phalloidin revealed that the progeny of Neochlamydia S13 and Protochlamydia R18 existed in both daughter cells with a contractile ring on the verge of separation. However, in contrast to other environmental Chlamydiae, little Neochlamydia S13 16S ribosomal DNA was amplified from the culture supernatant. Interestingly, Neochlamydia S13 failed to infect aposymbiotic amoebae, indicating an intimate interaction with the host cells. Furthermore, its infectious rates in cultures expanded from a single amoeba were always maintained at 100%, indicating distribution via cytokinesis. We concluded that unlike other environmental Chlamydiae, Neochlamydia S13 has a unique ability to divide its progeny only via host amoebal cytokinesis. This may be a suitable model to elucidate the mechanism of cell organelle distribution and of chlamydial pathogenesis and evolution.
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http://dx.doi.org/10.1111/1348-0421.12871DOI Listing
March 2021

Pneumoconiosis with a Sarcoid-Like Reaction Other than Beryllium Exposure: A Case Report and Literature Review.

Medicina (Kaunas) 2020 Nov 22;56(11). Epub 2020 Nov 22.

Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.

Chronic beryllium disease (CBD) is a granulomatous disease that resembles sarcoidosis but is caused by beryllium. Clinical manifestations similar to those observed in CBD have occasionally been reported in exposure to dusts of other metals. However, reports describing the clinical, radiographic, and pathological findings in conditions other than beryllium-induced granulomatous lung diseases, and detailed information on mineralogical analyses of metal dusts, are limited. A 51-year-old Japanese man with rapidly progressing nodular shadows on chest radiography, and a 10-year occupation history of underground construction without beryllium exposure, was referred to our hospital. High-resolution computed tomography showed well-defined multiple centrilobular and perilobular nodules, and thickening of the intralobular septa in the middle and lower zones of both lungs. No extrathoracic manifestations were observed. Pathologically, the lung specimens showed 5-12 mm nodules with dust deposition and several non-necrotizing granulomas along the lymphatic routes. X-ray analytical electron microscopy of the same specimens revealed aluminum, iron, titanium, and silica deposition in the lung tissues. The patient stopped smoking and changed his occupation to avoid further dust exposure; the chest radiography shadows decreased 5 years later. The radiological appearances of CBD and sarcoidosis are similar, although mediastinal or hilar lymphadenopathy is less common in CBD and is usually seen in the presence of parenchymal opacities. Extrathoracic manifestations are also rare. Despite limited evidence, these findings are similar to those observed in pneumoconiosis with a sarcoid-like reaction due to exposure to dust other than of beryllium. Aluminum is frequently detected in patients with pneumoconiosis with a sarcoid-like reaction and is listed as an inorganic agent in the etiology of sarcoidosis. It was also detected in our patient and may have contributed to the etiology. Additionally, our case suggests that cessation of dust exposure may contribute to improvement under the aforementioned conditions.
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http://dx.doi.org/10.3390/medicina56110630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700418PMC
November 2020

Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.

Thorac Cancer 2021 01 20;12(2):272-276. Epub 2020 Nov 20.

Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
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http://dx.doi.org/10.1111/1759-7714.13756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812073PMC
January 2021

[Trends in Outpatient Chemotherapy for Thoracic Oncology].

Gan To Kagaku Ryoho 2020 Oct;47(10):1461-1464

Clinical Oncology Center, Nagasaki University Hospital.

We conducted a survey of the outpatient pharmacotherapy we administered from April 2016 to March 2019 to understand trends in chemotherapy for respiratory thoracic malignancies, such as lung cancer. Over the 3-year period, 19,408 were treated in the outpatient chemotherapy department. Of these, 1,270(6.5%)had respiratory thoracic malignancies. The total number of patients and the number of patients with thoracic malignancies(%) were 5,815 and 320(5.5%); 6,344 and 434(6.8%); and 7,247 and 516(7.1%)in FY2016, FY2017 and FY2018, respectively. This shows that both increased during the study period. Each patient was treated in the chemotherapy department multiple times, and treatment for thoracic malignancies was initiated in 161 patients. The female:male ratio was 27%:73%, and the patients' median age(range)was 68 years(range: 36-84 years). Lung cancer was the most common disease(91%), followed by malignant pleural mesothelioma(5%), thymoma(2%), thymic carcinoma(1%), and synovial sarcoma(1%). The most common histological type of lung cancer was adenocarcinoma(67%), followed by squamous cell carcinoma(17%), small cell carcinoma( 7%), and others(9%). Outpatient chemotherapy was introduced as a first-line, second-line, and third-line or later treatment in 46%, 28%, and 22% of cases, respectively. While the number of patients increased, the number of new patients with thoracic malignancies decreased from 58 in FY2016 to 52 in FY2017 and 51 in FY2018. Conversely, the number of visits to the chemotherapy department by each new patient almost doubled from 5.5 in FY2016 to 8.5 in FY2017 and 10.1 in FY2018. The proportion of patients for which immunotherapy was included in the induction treatment regimen increased from 28% and 24% in FY2016 and FY2017, respectively, to 39% in FY2018. The increase in the use of outpatient chemotherapy for respiratory thoracic malignancies was due to the increase in the proportion of patients undergoing immunotherapy and the number of visits to the chemotherapy department per patient. It is important to implement measures to help prolong and increase the use of outpatient pharmacotherapy for respiratory thoracic malignancies by cooperating with surrounding medical institutions and increasing the number of beds available.
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October 2020

Novel and potent antimicrobial effects of caspofungin on drug-resistant Candida and bacteria.

Sci Rep 2020 10 20;10(1):17745. Epub 2020 Oct 20.

Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.

Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis. They exhibit fungicidal activity by inhibiting the synthesis of β-1,3-D-glucan, an essential component of the fungal cell wall. However, they are active only against proliferating fungal cells and unable to completely eradicate fungal cells even after a 24 h drug exposure in standard time-kill assays. Surprisingly, we found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) Candida and bacteria cells even in non-growth conditions. This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Furthermore, caspofungin dissolved in low ionic solutions drastically reduced mature biofilm cells of MDR Candida auris in only 5 min, as well as Candida-bacterial polymicrobial biofilms in a catheter-lock therapy model. Caspofungin displayed ion concentration-dependent conformational changes and intracellular accumulation with increased reactive oxygen species production, indicating a novel mechanism of action in low ionic conditions. Importantly, caspofungin dissolved in 5% glucose water did not exhibit increased toxicity to human cells. This study facilitates the development of new therapeutic strategies in the management of catheter-related biofilm infections.
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http://dx.doi.org/10.1038/s41598-020-74749-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576149PMC
October 2020

IFT20 is critical for collagen biosynthesis in craniofacial bone formation.

Biochem Biophys Res Commun 2020 12 28;533(4):739-744. Epub 2020 Sep 28.

Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, 77030, USA; Graduate Program in Genetics and Epigenetics, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, 77030, USA. Electronic address:

Intraflagellar transport (IFT) is essential for assembling primary cilia required for bone formation. Disruption of IFT frequently leads to bone defects in humans. While it has been well studied about the function of IFT in osteogenic cell proliferation and differentiation, little is known about its role in collagen biosynthesis during bone formation. Here we show that IFT20, the smallest IFT protein in the IFT-B complex, is important for collagen biosynthesis in mice. Deletion of Ift20 in craniofacial osteoblasts displayed bone defects in the face. While collagen protein levels are unaffected by loss of Ift20, collagen cross-linking was significantly altered. In both Ift20:Wnt1-Cre and Ift20:Ocn-Cre mice the bones exhibit increased hydroxylysine-aldehyde deived cross-linking, and decreased lysine-aldehyde derived cross-linking. To obtain insight into the molecular mechanisms, we examined the expression levels of telopeptidyl lysyl hydroxylase 2 (LH2), and associated chaperone complexes. The results demonstrated that, while LH2 levels were unaffected by loss of Ift20, its chaperone, FKBP65, was significantly increased in Ift20:Wnt1-Cre and Ift20:Ocn-Cre mouse calvaria as well as femurs. These results suggest that IFT20 plays a pivotal role in collagen biosynthesis by regulating, in part, telopeptidyl lysine hydroxylation and cross-linking in bone. To the best of our knowledge, this is the first to demonstrate that the IFT components control collagen post-translational modifications. This provides a novel insight into the craniofacial bone defects associated with craniofacial skeletal ciliopathies.
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http://dx.doi.org/10.1016/j.bbrc.2020.09.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744399PMC
December 2020

Presence of heat shock protein 47-positive fibroblasts in cancer stroma is associated with increased risk of postoperative recurrence in patients with lung cancer.

Respir Res 2020 Sep 14;21(1):234. Epub 2020 Sep 14.

Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.

Background: Heat shock protein 47 (HSP47), a collagen-binding protein, has a specific role in the intracellular processing of procollagen production. HSP47 expression is associated with cancer growth and metastasis in several types of cancers. However, none of the studies have assessed whether HSP47 expression is associated with the risk of postoperative recurrence of lung cancer until now. Therefore, we aimed to assess this association.

Methods: The study population consisted of a cohort of consecutive patients who underwent surgery for lung cancer at Nagasaki University Hospital, Nagasaki, Japan, from January 2009 to December 2010. Patient characteristics, survival and disease-free survival (DFS), and laboratory findings were compared between patients who tested positive and negative for HSP47 expression in lung cancer cells and between those who showed high and low numbers of HSP47-positive fibroblasts in cancer stroma.

Results: A total of 133 patients underwent surgery for lung cancer. Sixty-seven patients (50.4%) had HSP47-positive cancer cells, and 91 patients (68.4%) had a higher number of HSP47-positive fibroblasts. The patients with a high number of HSP47-positive fibroblasts had a shorter DFS than those with a low number of HSP47-positive fibroblasts. Multivariate analysis identified only the presence of a high number of HSP47-positive fibroblasts as an independent risk factor for recurrence of lung cancer after surgery (odds ratio, 4.371; 95% confidence interval, 1.054-29.83; P = 0.042).

Conclusion: The present study demonstrated that the presence of a high number of HSP47-positive fibroblasts in the cancer stroma was a risk factor for recurrence of lung cancer after surgery.
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http://dx.doi.org/10.1186/s12931-020-01490-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488681PMC
September 2020

Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells.

Front Immunol 2020 21;11:1405. Epub 2020 Jul 21.

Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Increasing attention has been paid to human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) in the field of cancer immunotherapy. We have previously demonstrated that a novel bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA), efficiently expands peripheral blood Vγ2Vδ2 T cells to purities up to 95-99% in 10-11 days. In the present study, we first examined the effect of PTA on farnesyl diphosphate synthase (FDPS) using liquid chromatography mass spectrometry (LC-MS) to analyze the mechanism underlying the PTA-mediated expansion of Vγ2Vδ2 T cells. We find that the prodrug induced the accumulation of both isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), direct upstream metabolites of FDPS. This indicates that not only IPP but also DMAPP plays an important role in PTA-mediated stimulation of Vγ2Vδ2 T cells. We next analyzed TCR-independent cytotoxicity of Vγ2Vδ2 T cells. When human lung cancer cell lines were challenged by Vγ2Vδ2 T cells, no detectable cytotoxicity was observed in 40 min. The lung cancer cell lines were, however, significantly killed by Vγ2Vδ2 T cells after 4-16 h in an effector-to-target ratio-dependent manner, demonstrating that Vγ2Vδ2 T cell-based cell therapy required a large number of cells and longer time when tumor cells were not sensitized. By contrast, pulsing tumor cell lines with 10-30 nM of PTA induced significant lysis of tumor cells by Vγ2Vδ2 T cells even in 40 min. Similar levels of cytotoxicity were elicited by ZOL at concentrations of 100-300 μM, which were much higher than blood levels of ZOL after infusion (1-2 μM), suggesting that standard 4 mg infusion of ZOL was not enough to sensitize lung cancer cells in clinical settings. In addition, Vγ2Vδ2 T cells secreted interferon-γ (IFN-γ) when challenged by lung cancer cell lines pulsed with PTA in a dose-dependent manner. Taken together, PTA could be utilized for both expansion of Vγ2Vδ2 T cells and sensitization of tumor cells in Vγ2Vδ2 T cell-based cancer immunotherapy. For use in patients, further studies on drug delivery are essential because of the hydrophobic nature of the prodrug.
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http://dx.doi.org/10.3389/fimmu.2020.01405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385076PMC
April 2021

Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in vitro.

Biochem Biophys Res Commun 2020 09 1;530(3):561-565. Epub 2020 Aug 1.

Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.

Excessive extracellular matrix deposition, in particular collagen, is an important cause of lung fibrosis. Heat shock protein 47 (HSP47), a collagen-binding protein, plays an important role in the intracellular processing of procollagen. A small molecule that blocks the collagen chaperone function of HSP47 has been reported as an HSP47 inhibitor. The aim of this study was to assess the effect of the HSP47 inhibitor on collagen synthesis and other fibrotic process in vitro. We evaluated collagen expression by western blot, and determined cell viability and migration by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and scratch test, respectively, in human and mouse lung fibroblasts. Treatment of lung fibroblasts with HSP47 siRNA decreased collagen type I expression. Similarly, the HSP47 inhibitor decreased collagen type I expression in transforming growth factor beta 1 (TGF-β1)-treated lung fibroblasts in a dose-dependent manner. The inhibitor also decreased the viability and cell migration ability of TGF-β1-treated lung fibroblasts. Overall, we demonstrated that HSP47 is a potential therapeutic target for pulmonary fibrosis. The small molecule HSP47 inhibitor may mediate antifibrotic effects by suppressing the overexpression of collagen, and inhibiting the viability and migration of fibroblasts. Further research is needed to clarify the therapeutic potential of this HSP47 inhibitor for pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.bbrc.2020.07.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387976PMC
September 2020

Amrubicin in previously treated patients with malignant pleural mesothelioma: A phase II study.

Thorac Cancer 2020 07 28;11(7):1972-1978. Epub 2020 May 28.

Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Background: The aim of this study was to assess the efficacy and safety of amrubicin for previously treated malignant pleural mesothelioma.

Methods: The eligibility criteria were: previously treated unresectable malignant pleural mesothelioma; performance status 0-1; age ≤ 75; adequate hematological, hepatic, and renal function. The patients were injected with 35 mg/m amrubicin on days one, two, and three every 3-4 weeks. The planned number of patients was 32.

Results: The study was terminated due to delay in enrollment and 10 patients were subsequently enrolled (nine males and one female; median age 67 [range 49-73]), of which four had epithelioid tumors, three had sarcomatoid tumors and three had biphasic tumors, respectively. According to the International Mesothelioma Interest Group (IMIG), one, four, and four patients had stage II, III, and IV, respectively, and one had postoperative recurrence. There was one (10%) partial response, four (40%) had stable disease, and five (50%) patients exhibited disease progression. The overall response and disease control rates were 10% (95% CI: 0.3-44.5%) and 60% (95% CI: 26.2-87.8%), respectively. The median progression-free survival time was 1.6 months. The median overall survival time was 6.6 months, and the one-, two-, and three-year survival rates were 23%, 23%, and 0%, respectively. The observed grade 3 or 4 toxicities included neutropenia in six (60%) patients; leukopenia in five (50%) patients; and febrile neutropenia, thrombocytopenia, anemia, and pneumonia in one (10%) patient each.

Conclusions: There was not enough data to evaluate the efficacy because the study was terminated early. However, amrubicin showed limited activity and acceptable toxicities when used in previously treated malignant pleural mesothelioma patients.
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http://dx.doi.org/10.1111/1759-7714.13490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327919PMC
July 2020

Hypoxia promotes Chlamydia trachomatis L2/434/Bu growth in immortal human epithelial cells via activation of the PI3K-AKT pathway and maintenance of a balanced NAD/NADH ratio.

Microbes Infect 2020 10 19;22(9):441-450. Epub 2020 May 19.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, North-12, West-5, Kita-ku, Sapporo 060-0812, Japan. Electronic address:

Chlamydia trachomatis LGV (CtL2) causes systemic infection and proliferates in lymph nodes as well as genital tract or rectum producing a robust inflammatory response, presumably leading to a low oxygen environment. We therefore assessed how CtL2 growth in immortal human epithelial cells adapts to hypoxic conditions. Assessment of inclusion forming units, the quantity of chlamydial 16S rDNA, and inclusion size showed that hypoxia promotes CtL2 growth. Under hypoxia, HIF-1α was stabilized and p53 was degraded in infected cells. Moreover, AKT was strongly phosphorylated at S473 by CtL2 infection. This activation was significantly diminished by LY-294002, a PI3K-AKT inhibitor, which decreased the number of CtL2 progeny. HIF-1α stabilizers (CoCl, desferrioxamine) had no effect on increasing CtL2 growth, indicating no autocrine impact of growth factors produced by HIF-1α stabilization. Furthermore, in normoxia, CtL2 infection changed the NAD/NADH ratio of cells with increased gapdh expression; in contrast, under hypoxia, the NAD/NADH ratio was the same in infected and uninfected cells with high and stable expression of gapdh, suggesting that CtL2-infected cells adapted better to hypoxia. Together, these data indicate that hypoxia promotes CtL2 growth in immortal human epithelial cells by activating the PI3K-AKT pathway and maintaining the NAD/NADH ratio with stably activated glycolysis.
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http://dx.doi.org/10.1016/j.micinf.2020.04.010DOI Listing
October 2020
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