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Abstract Purpose Although most pharmaceutical companies and bio-ventures have not yet created a practical business model or a credible exit thus far, most are expecting potential new business to be derived from regenerative medicine. This article discusses and proposes some ideas regarding a patent strategy for regenerative medicine. Methods PubMed literature searches were conducted to identify recent reports relevant to regenerative medicine. Information regarding patents and patent applications were obtained from the database service of the Japan Platform for Patent Information on the website of the National Center for Industrial Property Information and Training at https://www.j-platpat.inpit.go.jp/web/all/top/BTmTopEnglishPage and the Japan Patent Office at https://www.jpo.go.jp/index.htm. Findings The infrastructure of regenerative medicine in Japan is still maturing. Patent protection is important in regenerative medicine considering its special characteristics. Implications Based on the understanding of the special characteristics of regenerative medicine, this article discusses and proposes some ideas regarding a patent strategy for the field, which is different from that of a typical patent strategy as in the case of a small-molecule drug. [ABSTRACT FROM AUTHOR]

Abstract We report a case of recurrent idiopathic pulmonary hemosiderosis after a long-term remission presented with Sjögren's syndrome. The patient was diagnosed with IPH due to repeated pneumonia and blood sputum in his childhood. He was admitted to our hospital due to exertional dyspnea and dry cough with bilateral ground-glass opacity in chest computed tomography at the age of 32. Video-assisted thoracoscopic surgery was performed and the specimens showed nonspecific interstitial pneumonia pattern with diffuse, chronic alveolar hemorrhage, suggesting recurrence of IPH. He was also diagnosed with Sjögren's syndrome. Further immunological studies will reveal the pathogenesis of IPH. [ABSTRACT FROM AUTHOR]

Summary T helper 17 (Th17) cell development is programmed by the orphan nuclear receptor RORγt, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here, we show that steroid receptor coactivator-3 (SRC-3) critically regulates Th17 cell differentiation. Reduced incidence of experimental autoimmune encephalitis (EAE) associated with decreased Th17 cell generation in vivo was observed in mice with SRC-3 deletion specifically in T cells. In vitro , SRC-3 deficiency did not affect TGF-β/IL-6-induced Th17 cell generation but severely impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23. Microarray analysis revealed that SRC-3 not only regulates IL-17A but also IL-1R1 expression. SRC-3 bound to Il17a and Il1r1 loci in a RORγt-dependent manner and was required for recruitment of the p300 acetyltransferase. Thus, SRC-3 is critical for RORγt-dependent gene expression in Th17 cell-driven autoimmune diseases. [ABSTRACT FROM AUTHOR]

A 48-year-old man was admitted for evaluation of abnormal shadows on chest radiograph. Chest computed tomography (CT) showed cysts, nodules, and cervical and axillary lymphadenopathies. Elevated serum levels of IgG4 and interleukin (IL)-6 suggested IgG4-related disease (IgG4-RD) or multicentric Castleman's disease (MCD). Histologic findings of the cervical lymph node and right lung S 6 biopsies revealed numerous IgG4-positive plasma cells. Although CT findings of the lungs were atypical for IgG4-RD, consistent histologic findings, clinical symptoms, and laboratory data made us conclude IgG4-RD. Because histologic findings of IgG4-RD and MCD have similarities, differentiating between the two diseases should consider the clinical presentation. [ABSTRACT FROM AUTHOR]

A 68-year-old woman was admitted to our hospital with a dry cough in 2010. Chest computed tomography showed the appearance of a nonspecific interstitial pneumonia (NSIP) pattern. Video-assisted thoracoscopic surgery (VATS) was performed, and the specimens prominently showed a usual interstitial pneumonia (UIP) pattern. She was diagnosed with bird-related chronic hypersensitivity pneumonitis (BRCHP) on the basis of the detection of antibodies to pigeon dropping extract in her serum and a history of using feather-filled duvets and indirect exposure to birds in her living environment. Even though she was treated with corticosteroids and immunosuppressants and recommended to avoid bird-related antigens, she had a progressive course with repeated acute exacerbation episodes and died of respiratory failure. The autopsy findings showed diffuse alveolar damage superimposed on UIP. Clinicians should be aware that BRCHP patients especially with histopathologically UIP pattern may experience acute exacerbation. [ABSTRACT FROM AUTHOR]

We describe the case of a 73-year-old man who experienced dry cough and exertional dyspnea after dabigatran administration. Chest radiographs revealed the development of bilateral consolidative and ground glass opacity, and transbronchial lung biopsy showed organized materials in the alveolar spaces with moderate inflammatory infiltrate and focal fibrosis. Lung opacity gradually disappeared after discontinuing dabigatran. To date, there has been only one report regarding dabigatran-induced lung injury, except for alveolar hemorrhage and eosinophilic pneumonia. Therefore, we should consider that any drug can cause various types of lung injuries. [ABSTRACT FROM AUTHOR]

Objective: Although positive pleural lavage cytology (PLC) has been demonstrated to be closely associated with a poor prognosis for patients with lung cancer, it has not been incorporated into the TNM staging system of the Union for International Cancer Control. The aim of our study was to retrospectively examine the clinical significance of PLC status and illustrate the recommendations of the International Pleural Lavage Cytology Collaborators (IPLCC) in a large national database. Methods: The Japanese Joint Committee of Lung Cancer Registry database included 11,073 patients with non–small cell lung cancer who underwent resections in 2004. We extracted the clinicopathologic data for 4171 patients (37.3%) who underwent PLC. These patients were staged according to the seventh edition of the Union for International Cancer Control TNM classification and by recommendations of the IPLCC, in which T was singly upgraded up to a maximum of T4 for those who were PLC-positive. Prognoses based on these 2 systems were compared. Results: A total of 217 patients (5.2%) were PLC-positive, which was significantly associated with a higher incidence of adenocarcinoma and advanced disease. The 5-year survival for patients with positive and negative PLC results were 44.5% and 72.8%, respectively, and this difference in survival was statistically significant (P < .001). Multivariate analysis showed that positive PLC status was an independent factor for a poor prognosis (hazard ratio, 1.57; P < .001). Significant differences in survival were also found between patients with positive and negative PLC results in the same T categories and stages, including T2a, T3, stage IB, and stage IIIA. The IPLCC recommendations adjusted the prognostic differences in all T categories and stages. The significant difference in survival disappeared between the 2 groups in all T categories and stages. Conclusions: Our results indicate that a T category upgrade is prognostically adequate for patients who are PLC-positive. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to identify the modern surgical results of pathologic T3 lung cancer and to examine the heterogeneity of this group from the nationwide database. Methods: The registered data of 11,663 cases from the Japanese Joint Committee of Lung Cancer Registry conducted in 2010 were analyzed, which included patients with resected lung cancer during 2004. Of these patients, 531 with invasive T3 lung cancer constituted the study population. Results: Of the 531 patients, 466 were men and 65 women, with a mean age of 65.9 years. The 3- and 5-year survival rates and median survival time was 54.0%, 44.9%, and 46 months, respectively. A multivariate analysis showed incomplete resection, N2 disease, and no adjuvant therapy were independent prognostic factors of a poor outcome. However, pneumonectomy and N1 disease were not significantly associated with the prognosis. In terms of each involved structure, we detected 407 patients with T3 tumors involving the chest wall, 56 involving the mediastinal pleura, 45 with involvement of the bronchus within 2 cm of the carina, 31 involving the diaphragm, and 20 involving the pericardium. The corresponding 5-year survival rates were 43.2%, 40.1%, 55.2%, 42.6%, and 54.2%. Conclusions: The modern 5-year survival rates of patients with T3 lung cancer involving any neighboring structures have been 40% to 55%, and the current pT3 group was proved to have a relatively uniform prognosis. [ABSTRACT FROM AUTHOR]

Abstract: The H+-translocating inorganic pyrophosphatase is a proton pump that hydrolyzes inorganic pyrophosphate. It consists of a single polypeptide with 14–17 transmembrane domains (TMs). We focused on the third quarter region of Streptomyces coelicolor A3(2) H+-pyrophosphatase, which contains a long conserved cytoplasmic loop. We assayed 1520 mutants for pyrophosphate hydrolysis and proton translocation, and selected 34 single-residue substitution mutants with low substrate hydrolysis and proton-pump activities. We also generated 39 site-directed mutant enzymes and assayed their activity. The mutation of 5 residues in TM10 resulted in low energy-coupling efficiencies, and mutation of conserved residues Thr409, Val411, and Gly414 showed neither hydrolysis nor pumping activity. The mutation of six, five, and four residues in TM11, 12, and 13, respectively, gave a negative effect. Phe388, Thr389, and Val396 in cytoplasmic loop i were essential for efficient H+ translocation. Ala436 and Pro560 in the periplasmic loops were critical for coupling efficiency. These low-efficiency mutants showed dysfunction of the energy-conversion and/or proton-translocation activity. The energy efficiency was increased markedly by the mutation of two and six residues in TM9 and 12, respectively. These results suggest that TM10 is involved in enzyme function, and that TM12 regulate the energy-conversion efficiency. H+-pyrophosphatase might involve dynamic linkage between the hydrophilic loops and TMs through the central half region of the enzyme. [Copyright &y& Elsevier]

Abstract: The H+-pyrophosphatase (H+-PPase) consists of a single polypeptide, containing 16 or 17 transmembrane domains. To determine the higher order oligomeric state of Streptomyces coelicolor H+-PPase, we constructed a series of cysteine substitution mutants and expressed them in Escherichia coli. Firstly, we analyzed the formation of disulfide bonds, promoted by copper, in mutants with single cysteine substitutions. 28 of 39 mutants formed disulfide bonds, including S545C, a substitution at the periplasmic side. The formation of intermolecular disulfide bonds suppressed the enzyme activity of several, where the substituted residues were located in the cytosol. Creating disulfide links in the cytosol may interfere with the enzyme''s catalytic function. Secondly, we prepared double mutants by introducing second cysteine substitutions into the S545C mutant. These double-cysteine mutants produced cross-linked complexes, estimated to be at least tetramers and possibly hexamers. Thirdly, we co-expressed epitope-tagged, wild type, and inactive mutant H+-PPases in E. coli and confirmed the formation of oligomers by co-purifying one subunit using the epitope tag used to label the other. The enzyme activity of these oligomers was markedly suppressed. We propose that H+-PPase is present as an oligomer made up of at least two or three sets of dimers. [Copyright &y& Elsevier]

The H+-translocating pyrophosphatase (H+-PPase) is a proton pump that is found in a wide variety of organisms. It consists of a single polypeptide chain that is thought to possess between 14 and 17 transmembrane domains. To determine the topological arrangement of its conserved motifs and transmembrane domains, we carried out a cysteine-scanning analysis by determining the membrane topology of cysteine substitution mutants of Streptomyces coelicolor H+-PPase expressed in Escherichia coli using chemical reagents. First, we prepared a synthetic DNA that encoded the enzyme and constructed a functional cysteine-less mutant by substituting the four cysteine residues. We then introduced cysteine residues individually into 42 sites in its hydrophilic regions and N- and C-terminal segments. Thirty-six of the mutant enzymes retained both pyrophosphatase and H+-translocating activities. Analysis of 29 of these mutant forms using membrane-permeable and -impermeable sulfhydryl reagents revealed that S. coelicolor H+-PPase contains 17 transmembrane domains and that several conserved segments, such as the substrate-binding domains, are exposed to the cytoplasm. Four essential serine residues that were located on the cytoplasmic side were also identified. A marked characteristic of the S. coelicolor enzyme is a long additional sequence that includes a transmembrane domain at the C terminus. We propose that the basic structure of H+-PPases has 16 transmembrane domains with several large cytoplasmic loops containing functional motifs. [ABSTRACT FROM AUTHOR]

In F1-ATPase, the rotation of the central axis subunit relative to the surrounding α3β3 subunits is coupled to ATP hydrolysis. We previously reported that the introduced regulatory region of the γ subunit of chloroplast F1-ATPase can modulate rotation of the γ subunit of the thermophilic bacterial F1-ATPase (Bald, D., Noji, H., Yoshida, M., Hirono-Hara, Y., and Hisabori, T. (2001) J. Biol. Chem. 276, 39505-39507). The attenuated enzyme activity of this chimeric enzyme under oxidizing conditions was characterized by frequent and long pauses of rotation of γ. In this study, we report an inverse regulation of the γ subunit rotation in the newly engineered F1-chimeric complex whose three negatively charged residues Glu210-Asp211-Glu212 adjacent to two cysteine residues of the regulatory region derived from chloroplast F1-ATPase γ were deleted. ATP hydrolysis activity of the mutant complex was stimulated up to 2-fold by the formation of the disulfide bond at the regulatory region by oxidation. We successfully observed inverse redox switching of rotation of γ using this mutant complex. The complex exhibited long and frequent pauses in its rotation when reduced, but the rotation rates between pauses remained unaltered. Hence, the suppression or activation of the redox-sensitive Fl-ATPase can be explained in terms of the change in the rotation behavior at a single molecule level. These results obtained by the single molecule analysis of the redox regulation provide further insights into the regulation mechanism of the rotary enzyme. [ABSTRACT FROM AUTHOR]

Summary: Background:: Thirty-five years after the Yusho incident, some symptoms, signs and laboratory abnormalities are still found in Yusho patients. Objective:: To describe the cardiovascular, respiratory and renal abnormalities caused by Yusho, especially in relation to blood polychlorinated dibenzofuran concentration. Methods:: A total of 358 officially registered patients with Yusho participated in this study. Medical records of the patients obtained from the annual nationwide health examinations held from 2001 to 2003 were used in the study. The symptoms, signs and laboratory findings in cardiac, respiratory and renal systems were compared with blood concentrations of polychlorinated biphenyls (PCBs) and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF). Results:: Airway symptoms such as cough and sputum were frequently seen in Yusho patients, whereas other symptoms, signs and laboratory abnormalities were not remarkable. There were marginal relationships between cough and blood concentration of PCBs, and between sputum and 2,3,4,7,8-PeCDF. Conclusion:: Organs of the respiratory system remain affected by Yusho 35 years after the incident, whereas little effect on cardiac and renal systems is observed. [Copyright &y& Elsevier]

We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. We evaluated the prognostic ability of a "drug score" computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53–0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52–0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54–0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54–0.69). Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted. • Concomitant medications affect clinical outcomes from immune checkpoint inhibitors. • We previously validated a prognostic drug score in European patients with NSCLC. • We explored the prognostic ability of the drug score in Japanese patients with NSCLC. • The use of probiotics might mitigate the deleterious effect of antibiotics. • Racial differences should be considered when investigating this topic. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) mutations are present in ∼3% of patients with non–small cell lung cancer (NSCLC), with exon-20 insertions accounting for ∼90% of such HER2 mutations and having been identified as driver oncogenic alterations. Antibody–cytotoxic drug conjugates including trastuzumab deruxtecan have shown an excellent efficacy for NSCLC with HER2 mutations. We have now performed a phase II study to evaluate the efficacy of ado-trastuzumab emtansine (T-DM1) for NSCLC positive for HER2 exon-20 insertion mutations. Eligible patients with HER2 exon-20 insertion mutations confirmed by next-generation sequencing or multiplex polymerase chain reaction platforms and a history of one or two lines of chemotherapy received T-DM1 (3.6 mg/kg) intravenously every 21 days. The primary end-point of the study was the objective response rate (ORR). Between February 2019 and July 2020, 22 patients were enrolled in the study. A775_G776insYVMA was the most frequent HER2 exon-20 insertion mutation, accounting for 19 (86.4%) of the 22 patients. The ORR was 38.1% (90% confidence interval, 23.0–55.9%), and the disease control rate was 52.4%. The median duration of response was 3.5 months, and the median progression-free survival and median overall survival were 2.8 and 8.1 months, respectively. Toxicity was mild, with the frequency of adverse events of grade ≥3 being low. T-DM1 is a potential treatment option for patients with NSCLC with HER2 exon-20 insertion mutations. Further investigation of biomarkers for T-DM1 is warranted to improve its efficacy for NSCLC with such mutations. JapicCTI-194620 • Ado-trastuzumab emtansine was tested for patients with non-small cell lung cancer. • The objective response rate for T-DM1 in these patients was 38.1%. • Toxicity was mild, with the frequency of adverse events of grade ≥3 being low. [ABSTRACT FROM AUTHOR]