Impact of the COVID-19 pandemic on COPD exacerbations in Japanese patients: a retrospective study.

Various infection control measures implemented during the coronavirus disease (COVID-19) pandemic have reduced the number of respiratory infections, which are the most common cause of chronic obstructive pulmonary disease (COPD) exacerbations. Here, we investigated whether infectious disease prevention during the COVID-19 pandemic reduced COPD exacerbations and the characteristics of patients exhibiting exacerbations before and during the COVID-19 pandemic. We included outpatients and inpatients with moderate or severe COPD exacerbations who required systemic steroids between April 1, 2018 and March 31, 2022. Their medical records were retrospectively compared and analyzed in 2-year intervals (before and during the COVID-19 pandemic). During the 4-year observation period, 70,847 outpatients and 2,772 inpatients were enrolled; 55 COPD exacerbations were recorded. The number of COPD exacerbations decreased from 36 before to 19 during the COVID-19 pandemic. Regarding the characteristics of patients with exacerbations, the % forced expiratory volume in one second (52.3% vs. 38.6%, P = 0.0224) and body mass index (BMI) (22.5 vs. 19.3, P = 0.0127) were significantly lower during the COVID-19 pandemic than before the pandemic. The number of COPD exacerbations during the pandemic decreased. Additionally, the tendency for a reduction in COPD exacerbation was greatest in patients with preserved lung function or above-standard BMI patients.

miR-146a regulates emphysema formation and abnormal inflammation in the lungs of two mouse models.

miR-146a, a microRNA (miRNA) that regulates inflammatory responses, plays an important role in many inflammatory diseases. Although an in vitro study had suggested that miR-146a is involved in abnormal inflammatory response, being a critical factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), in vivo evidence of its pathogenic role in COPD remains limited. Eight-week-old male B6(FVB)-Mir146tm1.1Bal/J [miR-146a knockout (KO)] and C57BL/6J mice were intratracheally administered elastase and evaluated after 28 days or exposed to cigarette smoke (CS) and evaluated after 5 mo. miR-146a expression was significantly increased in C57BL/6J mouse lungs due to elastase administration (P = 0.027) or CS exposure (P = 0.019) compared with that in the control group. Compared with C57BL/6J mice, elastase-administered miR-146a-KO mice had lower average computed tomography (CT) values (P = 0.017) and increased lung volume-to-weight ratio (P = 0.016), mean linear intercept (P < 0.001), and destructive index (P < 0.001). Moreover, total cell (P = 0.006), macrophage (P = 0.001), neutrophil (P = 0.026), chemokine (C-X-C motif) ligand 2/macrophage inflammatory protein-2 [P = 0.045; in bronchoalveolar lavage fluid (BALF)], cyclooxygenase-2, and matrix metalloproteinase-2 levels were all increased (in the lungs). Following long-term CS exposure, miR-146a-KO mice showed a greater degree of emphysema formation in their lungs and inflammatory response in the BALF and lungs than C57BL/6J mice. Collectively, miR-146a protected against emphysema formation and the associated abnormal inflammatory response in two murine models.NEW & NOTEWORTHY This study demonstrates that miR-146a expression is upregulated in mouse lungs because of elastase- and CS-induced emphysema and that the inflammatory response by elastase or CS is enhanced in the lungs of miR-146a-KO mice than in those of control mice, resulting in the promotion of emphysema. This is the first study to evaluate the protective role of miR-146a in emphysema formation and the associated abnormal inflammatory response in different in vivo models.

A unique genetic variation with respect to blast (Pyricularia oryzae Cavara) resistance in rice (Oryza sativa L.) varieties in Vietnam.

A unique genetic variation with respect to blast resistance was clarified in 201 rice accessions from Vietnam. These accessions were classified into three clusters-A, B1, and B2-based on their reactions to 26 standard differential blast isolates selected in Vietnam. Cluster A was the dominant cultivar group in Vietnam and the most susceptible of the three clusters. Cluster B1 was the smallest group and the most resistant. Cluster B2 was the second-most dominant group and of intermediate resistance between clusters A and B1. The percentages of accessions comprising each cluster varied by region and area. Accessions in cluster A were distributed widely throughout Vietnam and had the highest frequencies in both the Central and North regions. Accessions in cluster B2 were found with highest frequencies in the mountainous and intermediate areas of the North region. Accessions in cluster B1 were found with highest frequencies in the Central region and Red River Delta area (North region). These results suggest that rice accessions in Vietnam were basically susceptible (cluster A) or of intermediate resistance (cluster B2), and that high-resistance cultivars were mainly distributed in the low altitude areas, such as the Red River Delta area and Central region.

Blood Eosinophil Count as a Predictive Biomarker of Chronic Obstructive Pulmonary Disease Exacerbation in a Real-World Setting.

Introduction: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death, and COPD exacerbation worsens the prognosis. Eosinophilic airway inflammation is a COPD phenotype that causes COPD exacerbation and is correlated with peripheral blood eosinophil count. We analyzed real-world data of COPD patients to assess the risk factors of COPD exacerbation focusing on blood eosinophils. Materials and Methods: Patients with COPD who visited our hospital between January 1, 2018, and December 31, 2018, were recruited, and their background information, spirometry data, laboratory test results, and moderate-to-severe exacerbation events during the one-year follow-up period were collected from the electronic medical records and analyzed. The COPD exacerbation risk factors were assessed using univariate and multivariate logistic regression analyses. Results: Twenty-two of 271 (8.1%) patients experienced moderate-to-severe exacerbation. Patients with exacerbation showed worse pulmonary function, and we found that a high blood eosinophil count (≥350 cells/µL; p=0.014), low % FEV1 (<50%; p=0.002), increase in white blood cell (≥9000 cells/µL; p=0.039), and use of home oxygen therapy (p=0.005) were risk factors for future exacerbations. We also found a strong correlation between eosinophil count cut-offs and exacerbation risk (r = 0.89, p < 0.001). On the other hand, there was no relation between exacerbation risk and inhalation therapy for COPD. Conclusion: In a real-world setting, peripheral blood eosinophil count could be a predictor of future COPD exacerbation.

[Malignant lymphoma diagnosed by gallbladder wall thickness in an autoimmune hepatitis patient].

A 77-year-old female patient was undergoing steroid treatment for cirrhosis with autoimmune hepatitis. Periodic imaging acquisitions revealed both irregular gallbladder wall thickness and an isovascular tumor in segment one of the liver. After cholecystectomy and segmental hepatectomy, the pathological diagnosis was diffuse large B-cell lymphoma in both organs. Accordingly, she received chemotherapy but the disease rapidly spread;she died five months after surgery. Malignant lymphoma of the gallbladder is an uncommon disease;we consider that autoimmunity factors were associated with this pathogenesis.

Carcinoembryonic antigen levels in pancreatic juice are associated with histological subtypes of intraductal papillary mucinous neoplasm of the pancreas.

Background: The present study aimed to examine the correlation between preoperative carcinoembryonic antigen levels in pancreatic juice (PJ-CEA) and the histological subtype of intraductal papillary mucinous neoplasm (IPMN). Methods: We enrolled IPMN patients who underwent endoscopic retrograde pancreatography between March 2002 and March 2018. Clinical factors associated with IPMN histological subtypes of 67 patients who underwent surgery were analyzed. Furthermore, the relationship between CEA immunohistochemistry findings and histological subtypes was investigated. Results: Median PJ-CEA were 15 ng/ml in the gastric type, 150 ng/ml in the intestinal type, and 175 ng/ml in the pancreatobiliary type. Both intestinal and pancreatobiliary types had significantly higher PJ-CEA than the gastric type (p = 0.001). In the analysis of histological subtype predictors, high PJ-CEA (≥63 ng/ml) only showed a significant difference in multivariate analyses (95% confidence interval 4.8-70.2; p < 0.001). Immunohistochemistry findings revealed significantly higher CEA expression in the non-gastric type than in the gastric type (p < 0.001). The non-gastric type showed a significantly worse prognosis than the gastric type (p = 0.017). Conclusion: PJ-CEA was an independent predictor of IPMN histological subtypes in a preoperative setting. High PJ-CEA predict the non-gastric type, while low PJ-CEA predict the gastric type.

Propylene glycol, a component of electronic cigarette liquid, damages epithelial cells in human small airways.

BACKGROUND: Electronic cigarettes (e-cigarettes) are used worldwide as a substitute for conventional cigarettes. Although they are primarily intended to support smoking cessation, e-cigarettes have been identified as a gateway to smoking habits for young people. Multiple recent reports have described the health effects of inhaling e-cigarettes. E-cigarette liquid (e-liquid) is mainly composed of propylene glycol (PG) and glycerol (Gly), and the aerosol generated by these devices primarily contains these two components. Thus, this study aimed to evaluate the effects of PG and Gly on human small airway epithelial cells (SAECs). METHODS: SAECs were exposed to PG or Gly, and cell proliferation, cell viability, lactate dehydrogenase (LDH) release, DNA damage, cell cycle, and apoptosis were evaluated. Additionally, SAECs derived from chronic obstructive pulmonary disease (COPD) patients (COPD-SAECs) were investigated. RESULTS: Exposure of SAECs to PG significantly inhibited proliferation (1%, PG, p = 0.021; 2-4% PG, p < 0.0001) and decreased cell viability (1-4% PG, p < 0.0001) in a concentration-dependent manner. Gly elicited similar effects but to a reduced degree as compared to the same concentration of PG. PG also increased LDH release in a concentration-dependent manner (3% PG, p = 0.0055; 4% PG, p < 0.0001), whereas Gly did not show a significant effect on LDH release. SAECs exposed to 4% PG contained more cells that were positive for phosphorylated histone H2AX (p < 0.0001), a marker of DNA damage, and an increased proportion of cells in the G1 phase (p < 0.0001) and increased p21 expression (p = 0.0005). Moreover, caspase 3/7-activated cells and cleaved poly (ADP-ribose) polymerase 1 expression were increased in SAECs exposed to 4% PG (p = 0.0054). Furthermore, comparing COPD-SAECs to SAECs without COPD in PG exposure, cell proliferation, cell viability, DNA damage and apoptosis were significantly greater in COPD-SAECs. CONCLUSION: PG damaged SAECs more than Gly. In addition, COPD-SAECs were more susceptible to PG than SAECs without COPD. Usage of e-cigarettes may be harmful to the respiratory system, especially in patients with COPD.

Long-term safety of Prolastin®-C, an alpha1-proteinase inhibitor, in Japanese patients with alpha1-antitrypsin deficiency.

BACKGROUND: Safety and pharmacokinetics (PK) of alpha1-proteinase inhibitor, modified process (Alpha-1 MP), was evaluated in a clinical trial of Japanese patients with alpha1-antitrypsin deficiency (AATD). The present study aimed to evaluate the long-term safety of weekly intravenous infusions of 60 mg/kg Alpha-1 MP in Japanese patients with AATD. METHODS: This was a multi-center, open-label extension (OLE) study that enrolled adult patients with AATD, who had completed the preceding safety and PK clinical trial. Patients were administered with Alpha-1 MP (60 mg/kg) weekly, for 52 weeks, and this could be renewed annually. Alpha1-MP trough levels (Cmin) were evaluated, and safety endpoints include: treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs potentially related to Alpha-1 MP, chronic obstructive pulmonary disease (COPD) exacerbations, laboratory parameters, vital signs, and pulmonary function tests (forced expiration volume in 1 s [FEV1] and forced vital capacity [FVC]). RESULTS: Four patients underwent Alpha-1 MP intravenous infusions at a mean (SD) of 210.8 (9.54) for 213 weeks (four years), with a Cmin of 55.73 (4.99) mg/dL. A total of fifty-four TEAEs were reported in four patients, in which most of them were mild (n = 52, 96.3%). Two patients had five SAEs, and all were unrelated to treatment. Three mild TEAEs were potentially related to treatment with Alpha-1 MP. No clinically significant findings in laboratory parameters, COPD exacerbations, or vital signs were observed. There were no identifiable differences in FEV1 and FVC throughout the study period. CONCLUSIONS: Long-term weekly intravenous infusions of 60 mg/kg Alpha-1 MP are generally safe and well-tolerated in Japanese patients with AATD. CLINICALTRIALS: GOV: NCT02870348; JAPIC CTI: JapicCTI-163194.

Complemental Diagnosis of IgG4-Related Pancreaticobiliary Diseases by Multiple Hypoechoic Lesions in the Submandibular Glands.

The diagnosis of autoimmune pancreatitis (AIP) and immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) may require a somewhat invasive pathological examination and steroid responsiveness. This retrospective study assessed the complemental diagnosis of AIP and IgG4-SC using submandibular gland (SG) ultrasonography (US) in 69 patients, including 54 patients with AIP, 2 patients with IgG4-SC, and 13 patients with both AIP and IgG4-SC. The data from the physical examination and US of SGs to diagnose AIP (n = 67) and IgG4-SC (n = 15) were analyzed. The steroid therapy efficacy in resolving hypoechoic lesions in SGs was evaluated in 36 cases. The presence of IgG4-related pancreaticobiliary disease with multiple hypoechoic lesions in SGs was reduced from 31 to 11 cases after steroid therapy, suggesting that multiple hypoechoic lesions in SGs are strongly associated with IgG4-positive cell infiltrations. Multiple hypoechoic lesions in SGs were observed in 53 cases, whereas submandibular swelling on palpation was observed in 21 cases of IgG4-related pancreaticobiliary diseases. A complemental diagnosis of IgG4-related pancreaticobiliary diseases without a histological diagnosis and steroid therapy was achieved in 57 and 68 cases without and with multiple hypoechoic lesions in SGs, respectively. In conclusion, multiple hypoechoic lesions in SGs are useful for the complemental diagnosis of IgG4-related pancreaticobiliary diseases.

Quantification of Soil-surface Roots in Seedlings and Mature Rice Plants.

Soil-surface roots (SORs) in rice are primary roots that elongate over or near the soil surface. SORs help avoid excessive reduction of stress that occurs in paddy, such as in saline conditions. SORs may also be beneficial for rice growth in phosphorus-deficient paddy fields. Thus, SOR is a useful trait for crop adaptation to certain environmental stresses. To identify a promising genetic material showing SOR, we established methods for evaluating SOR under different growth conditions. We introduced procedures to evaluate the genetic diversity of SOR in various growth stages and conditions: the Cup method allowed us to quantify SOR at the seedling stage, and the Basket method, using a basket buried in a pot or field, is useful in quantifying SOR at the adult stage. These protocols are expected to contribute not only to the evaluation of the genetic diversity of SOR, but also the isolation of related genes in rice.

Exposure to the heated tobacco product IQOS generates apoptosis-mediated pulmonary emphysema in murine lungs.

Pulmonary emphysema is predominantly caused by chronic exposure to cigarette smoke (CS). Novel tobacco substitutes, such as heated tobacco products (HTPs), have emerged as healthier alternatives to cigarettes. IQOS, the most popular HTP in Japan, is advertised as harmless compared with conventional cigarettes. Although some studies have reported its toxicity, few in vivo studies have been conducted. Here, 12-wk-old C57BL6/J male mice were divided into three groups and exposed to air (as control), IQOS aerosol, or CS for 6 mo. After exposure, the weight gain was significantly suppressed in the IQOS and CS groups compared with the control (-4.93 g; IQOS vs. air and -5.504 g; CS vs. air). The serum cotinine level was significantly higher in the IQOS group than in the control group. The neutrophils and lymphocyte count increased in the bronchoalveolar lavage fluid of the IQOS and CS groups compared with those in the control group. Chronic IQOS exposure induced pulmonary emphysema similar to that observed in the CS group. Furthermore, expression levels of the genes involved in the apoptosis-related pathways were significantly upregulated in the lungs of the IQOS-exposed mice. Cytochrome c, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase-1 were overexpressed in the IQOS group compared with the control. Single-stranded DNA and TdT-mediated dUTP nick-end labeling-positive alveolar septal cell count significantly increased in the IQOS group compared with the control. In conclusion, chronic exposure to IQOS aerosol induces pulmonary emphysema predominantly via apoptosis-related pathways. This suggests that HTPs are not completely safe tobacco products.

New Hybrid Spikelet Sterility Gene Found in Interspecific Cross between Oryza sativa and O. meridionalis.

Various kinds of reproductive barriers have been reported in intraspecific and interspecific crosses between the AA genome Oryza species, to which Asian rice (O. sativa) and African rice (O. glaberrima) belong. A hybrid seed sterility phenomenon was found in the progeny of the cross between O. sativa and O. meridionalis, which is found in Northern Australia and Indonesia and has diverged from the other AA genome species. This phenomenon could be explained by an egg-killer model. Linkage analysis using DNA markers showed that the causal gene was located on the distal end of chromosome 1. Because no known egg-killer gene was located in that chromosomal region, this gene was named HYBRID SPIKELET STERILITY 57 (abbreviated form, S57). In heterozygotes, the eggs carrying the sativa allele are killed, causing semi-sterility. This killer system works incompletely: some eggs carrying the sativa allele survive and can be fertilized. The distribution of alleles in wild populations of O. meridionalis was discussed from the perspective of genetic differentiation of populations.

Protocol for assessing senescence-associated lung pathologies in mice.

Cellular senescence underlies tissue aging and aging-associated pathologies, as well as lung pathology. We and others have shown that elimination of senescent cells alleviates pulmonary diseases such as fibrosis and emphysema in animal models. We herein describe a protocol for assessing senescence-dependent lung phenotypes in mice. This protocol describes the use of ARF-DTR mice for semi-genetic elimination of lung senescent cells, followed by a pulmonary function test and the combination with pulmonary disease models to study lung pathologies. For complete details on the use and execution of this protocol, please refer to Hashimoto et al. (2016), Kawaguchi et al. (2021), and Mikawa et al. (2018).

Role of magnifying endoscopy with narrow-band imaging in the diagnosis of noninvasive gastric neoplasia.

BACKGROUND AND AIM: There are no globally approved, distinguishing criteria enabling the classification of gastric adenomas and intramucosal carcinomas for differential diagnosis of noninvasive neoplasia (NIN). METHODS: Next-generation sequencing of 50 cancer-related genes was undertaken on 68 pathologically diagnosed microdissected gastric neoplasms (25 adenomas, 27 intramucosal carcinomas, and 16 submucosal carcinomas) obtained during endoscopic submucosal dissection. Findings from magnifying endoscopy with narrow-band imaging (M-NBI) of 52 NINs (the 25 adenomas and 27 intramucosal carcinomas) were compared with these data. RESULTS: Among all 68 neoplasms, the most frequently mutated genes were APC (76% in adenoma, 11.1% in intramucosal carcinoma, and 0% in submucosal carcinoma; P < 0.001) and TP53 in intramucosal and submucosal carcinomas (8% in adenoma, 48.1% in intramucosal carcinoma, and 75% in submucosal carcinoma; P < 0.001). Dividing the NIN neoplasms into five groups according to their mutational status (A1: APC mutation, A2: APC + α mutation, B: APC + TP53 mutation, C: TP53 mutation, D: no mutation in either APC or TP53) resulted in almost identical diagnoses by pathology and M-NBI for groups A1 (12/13, 92%), C (12/13, 92%), and D (16/17, 94%) but not for groups A2 (3/7, 43%) or B (0/2, 0%). This finding implies that NINs with the APC + α mutation have carcinoma-like endoscopic features despite most being judged as adenomas by pathology. CONCLUSION: A diagnosis of NINs by pathology or M-NBI in the subset of gastric tumors classified by cancer-related mutations is not completely identical, suggesting the possible additional role of M-NBI in diagnosing NINs. Further studies are needed to confirm this.

Clinical significance of genetic alterations in endoscopically obtained pancreatic cancer specimens.

Although comprehensive gene analyses of pancreatic cancer provide new knowledge on molecular mechanisms, the usefulness and possibility of the analyses in routinely available clinical samples remain unclear. We assessed the possibility and utility of target sequencing of endoscopically obtained pancreatic cancer samples. Fifty-eight pancreatic cancer patients who underwent EUS-FNA or endoscopic biopsy were enrolled. The extracted DNA quantity was assessed and used for next-generation sequencing (NGS) of 50 cancer-related genes from which gene mutations, copy number alterations, and microsatellite instability (MSI) were extracted via secondary analysis. A median of 19.2 ng (3.8-228) of DNA was extracted from formalin-fixed paraffin-embedded samples. Gene alterations were detected in 55 of 58 samples (94.8%), including all samples with a DNA concentration below the detection limit (n = 11). Four frequently altered genes were KRAS (83%), TP53 (66%), SMAD4 (26%), and PTEN (17%), and molecular targetable genes were detected in 13 cases (22.4%). Five samples (8.6%) had many mutations and suspected MSI with impaired mismatch repair genes. A Cox regression analysis revealed that metastasis (p < 0.005, hazard ratio [HR] 10.1), serum CEA >5 ng/ml (p = 0.01, HR 2.86), ≤10 detected hotspot mutations (p = 0.03, HR 9.86), and intact Ras signaling (p < 0.005, HR 5.57) were associated with a poor pancreatic cancer prognosis. We performed small, targeted sequencing of pancreatic cancer using available samples from real clinical practice and determined the relationship between gene alterations and prognosis to help determine treatment choices.

Deep sequencing analysis of serum hepatitis B virus-RNA during nucleot(s)ide analogue therapy.

AIM: Recently, serum hepatitis B virus (HBV)-RNA has been reported to be detectable even when HBV particle production is inhibited by nucleot(s)ide analogues (NAs). However, the dynamics of the HBV-RNA sequence compared with those of HBV-DNA during the emergence of antiviral resistance are yet to be elucidated. METHODS: First, we quantified serum HBV-RNA in 181 infected patients, and its relationships with clinical characteristics as well as HBV markers were investigated. Next, we undertook simultaneous deep sequencing of HBV-RNA/HBV-DNA and their dynamics among four patients receiving NA therapy who were experiencing viral breakthrough. RESULTS: Serum HBV-RNA was detected in 25% (31/123) of cases among patients with HBV without NAs, and the detection rate was significantly high in hepatitis B e antigen-positive cases with high viral activity. In patients with chronic hepatitis, hepatitis B core-related antigen was significantly correlated with serum HBV-RNA irrespective of NA use. In the analysis of the four patients experiencing viral breakthrough, no NA resistance mutation was detected in the serum HBV-RNA immediately before the breakthrough. However, NA-resistant sequences appeared at the rates of 0%, 3%, 14%, and 100%, and the NA-resistant HBV-RNA sequence rate was correlated with the peak HBV-DNA titer multiplied by the HBV-DNA detection duration during the breakthrough (R2 = 0.978) observed before redisappearance of HBV-DNA following the addition of new NA. CONCLUSION: Serum HBV-RNA could reflect the transcriptional activity of covalently closed circular DNA and hepatitis B core-related antigen. The dynamics of HBV-RNA could help understanding of the turnover process of HBV covalently closed circular DNA in the liver.

Tranilast Inhibits Pulmonary Fibrosis by Suppressing TGFß/SMAD2 Pathway.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix (ECM) protein in the lungs. Transforming growth factor (TGF) ß-induced ECM protein synthesis contributes to the development of IPF. Tranilast, an anti-allergy drug, suppresses TGFß expression and inhibits interstitial renal fibrosis in animal models. However, the beneficial effects of tranilast or its mechanism as a therapy for pulmonary fibrosis have not been clarified. METHODS: We investigated the in vitro effect of tranilast on ECM production and TGFß/SMAD2 pathway in TGFß2-stimulated A549 human alveolar epithelial cells, using quantitative polymerase chain reaction, Western blotting, and immunofluorescence. In vitro observations were validated in the lungs of a murine pulmonary fibrosis model, which we developed by intravenous injection of bleomycin. RESULTS: Treatment with tranilast suppressed the expression of ECM proteins, such as fibronectin and type IV collagen, and attenuated SMAD2 phosphorylation in TGFß2-stimulated A549 cells. In addition, based on a wound healing assay in these cells, tranilast significantly inhibited cell motility, with foci formation that comprised of ECM proteins. Histological analyses revealed that the administration of tranilast significantly attenuated lung fibrosis in mice. Furthermore, tranilast treatment significantly reduced levels of TGFß, collagen, fibronectin, and phosphorylated SMAD2 in pulmonary fibrotic tissues in mice. CONCLUSION: These findings suggest that tranilast inhibits pulmonary fibrosis by suppressing TGFß/SMAD2-mediated ECM protein production, presenting tranilast as a promising and novel anti-fibrotic agent for the treatment of IPF.

Hermansky-Pudlak syndrome-associated pneumothorax with rapid progression of respiratory failure: a case report.

BACKGROUND: Hermansky-Pudlak syndrome (HPS) is an extremely rare disease with pulmonary fibrosis (PF), oculocutaneous albinism, induced platelet dysfunction, and granulomatous colitis. Although patients with HPS-associated PF (HPS-PF) often receive treatment with anti-fibrotic agents, including pirfenidone, many HPS-PF cases are progressive. The development of pneumothorax is known to be rare in HPS-PF. Pneumothorax development is generally important for prognosis in patients with interstitial pneumonia. However, there are few reports regarding the development of pneumothorax in patients with HPS-PF. CASE PRESENTATION: A 50-year-old Japanese man with chestnut hair, white skin, and light brown squint eyes visited our hospital for interstitial pneumonia examination. Chest high-resolution computed tomography (HRCT) demonstrated diffuse bilateral reticular opacities along the bronchovascular bundles and traction bronchiectasis predominantly in the upper lung fields. He was definitively diagnosed with HPS because genetic analysis showed that he had a homozygous mutation, c.398 + 5G > A, in the HPS-1 gene. After diagnosis with HPS-PF, he initiated home oxygen therapy due to gradually progressive hypoxemia. Three months after the HPS-PF diagnosis, the patient suddenly developed severe chest pain and dyspnea and was admitted to our hospital on emergency. He was diagnosed with pneumothorax by chest radiological findings. He immediately received chest drainage; however, his pneumothorax did not improve. Therefore, he underwent video-assisted surgery by thoracic surgeons. The leak point was not detected, but multiple bullae were found, mainly in the upper lung lobes. Thus, the surgeons did not perform bullectomy and only covered the apical areas. Fifteen days after the surgery, the patient developed high fever and dyspnea with a new diffuse reticular shadow found through HRCT. We first initiated the patient on broad-spectrum antibiotics; however, the symptoms and radiological findings worsened. Therefore, we started treatment with pirfenidone for inhibition of PF progression. The patient re-developed pneumothorax with severe respiratory failure. Although he re-underwent chest drainage, he died of progressive respiratory failure. CONCLUSIONS: We herein report the case of a rare HPS patient who developed pneumothorax with progressive PF. Pneumothorax may cause rapid progressive respiratory failure and may be associated with PF progression in HPS-PF.

Fractionated small cell-free DNA increases possibility to detect cancer-related gene mutations in advanced colorectal cancer.

BACKGROUND AND AIM: Liquid biopsy is a method that can efficiently detect tumor genetic abnormalities from body fluids such as blood and urine. Detection sensitivity and the available number of mutations in cell-free DNA (cfDNA) are limited. In this study, we develop a highly sensitive and comprehensive method to detect mutations from cfDNA by concentrating tumor fractions of small cfDNA in advanced colorectal cancers. METHODS: Biopsied specimens and 37 serum samples were collected from 27 patients with advanced colorectal carcinoma. A serum-extracted cfDNA was divided into enriched fractionated small cfDNA and unfractionated cfDNA. Both cfDNAs were subjected to digital polymerase chain reaction (PCR) to evaluate their KRAS, BRAF, CDKN2A, and TP53 status. Consequently, their mutant allele frequencies (MAFs) were compared and analyzed by next-generation sequencing (NGS) in conjunction with tissue-derived DNA. RESULTS: NGS analyses revealed mutations in TP53 (63%), KRAS (63%), APC (30%), and PIK3CA (22%). Digital PCR could detect mutations in 25 of 27 samples (93%) of unfractionated cfDNA, a rate that increased to 100% when samples were enriched with fractionated small cfDNA (6.8 vs 10.7%, P < 0.001). NGS also showed increased MAFs in fractionated small cfDNA compared to unfractionated cfDNA (16.3 vs 18.8%, P = 0.012) and a tendency to detect a greater number of cancer-related genes in fractionated cfDNA. CONCLUSIONS: Fractionated small cfDNA increased MAFs of gene mutations and increases the possibilities to detect cancer-related genes even in advanced cancer patients from whom it is difficult to obtain tissue samples.

Root angle modifications by the DRO1 homolog improve rice yields in saline paddy fields.

The root system architecture (RSA) of crops can affect their production, particularly in abiotic stress conditions, such as with drought, waterlogging, and salinity. Salinity is a growing problem worldwide that negatively impacts on crop productivity, and it is believed that yields could be improved if RSAs that enabled plants to avoid saline conditions were identified. Here, we have demonstrated, through the cloning and characterization of qSOR1 (quantitative trait locus for SOIL SURFACE ROOTING 1), that a shallower root growth angle (RGA) could enhance rice yields in saline paddies. qSOR1 is negatively regulated by auxin, predominantly expressed in root columella cells, and involved in the gravitropic responses of roots. qSOR1 was found to be a homolog of DRO1 (DEEPER ROOTING 1), which is known to control RGA. CRISPR-Cas9 assays revealed that other DRO1 homologs were also involved in RGA. Introgression lines with combinations of gain-of-function and loss-of-function alleles in qSOR1 and DRO1 demonstrated four different RSAs (ultra-shallow, shallow, intermediate, and deep rooting), suggesting that natural alleles of the DRO1 homologs could be utilized to control RSA variations in rice. In saline paddies, near-isogenic lines carrying the qSOR1 loss-of-function allele had soil-surface roots (SOR) that enabled rice to avoid the reducing stresses of saline soils, resulting in increased yields compared to the parental cultivars without SOR. Our findings suggest that DRO1 homologs are valuable targets for RSA breeding and could lead to improved rice production in environments characterized by abiotic stress.