Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2).

The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.

Novel air-liquid interface culture model to investigate stiffness-dependent behaviors of alveolar epithelial cells.

Pulmonary alveoli are functional units in gas exchange in the lung, and their dysfunctions in lung diseases such as interstitial pneumonia are accompanied by fibrotic changes in structure, elevating the stiffness of extracellular matrix components. The present study aimed to test the hypothesis that such changes in alveoli stiffness induce functional alteration of epithelial cell functions, exacerbating lung diseases. For this, we have developed a novel method of culturing alveolar epithelial cells on polyacrylamide gel with different elastic modulus at an air-liquid interface. It was demonstrated that A549 cells on soft gels, mimicking the modulus of a healthy lung, upregulated mRNA expression and protein synthesis of surfactant protein C (SFTPC). By contrast, the cells on stiff gels, mimicking the modulus of the fibrotic lung, exhibited upregulation of SFTPC gene expression but not at the protein level. Cell morphology, as well as cell nucleus volume, were also different between the two types of gels.

Bird-related non-fibrotic hypersensitivity pneumonitis with bronchoalveolar lavage fluid eosinophilia that developed after COVID-19 vaccination: A case report.

A 60-year-old man who had been keeping seven budgerigars and four cockatiels in his house for 2 years developed dyspnea and was admitted to our hospital the day after receiving the second dose of the messenger RNA coronavirus disease 2019 vaccination. Chest high resolution computed tomography (HRCT) showed bilateral ground glass opacities without nodules or mosaic attenuation. IgG specific for budgerigars was positive. Although his respiratory symptoms were resolved without corticosteroid therapy, he developed severe dyspnea soon after the discharge to his home. The results of bronchial alveolar lavage fluid obtained at the initial admission and after the provocation challenge showed elevation of lymphocytes (34%) and eosinophils (37%). We finally diagnosed him with non-fibrotic bird-related hypersensitivity pneumonitis. His condition and HRCT findings were improved by corticosteroid treatment. All his birds were given away. He has not experienced any recurrence or deterioration of respiratory function even after withdrawal of corticosteroid.

A Triply Linked Porphyrin-Norcorrole Hybrid with Singlet Diradical Character.

Norcorrole Ni(II) complexes have recently received considerable attention because they are readily accessible antiaromatic molecules. Their high stability under ambient conditions and ease of synthesis have enabled the exploration of the intrinsic properties of antiaromatic molecules. Here, we report the synthesis and properties of meso-meso singly linked porphyrin-norcorrole hybrids and a triply linked porphyrin-norcorrole hybrid. The singly linked and triply linked porphyrin-norcorrole hybrids were fully characterized, including an X-ray structural analysis. Due to their orthogonal conformation, the singly linked hybrids maintain the individual electronic properties of their porphyrin and norcorrole subunits, while the triply linked hybrid shows a significantly smaller electrochemical HOMO-LUMO gap (0.45 eV) than that of Ni(II) dimesitylnorcorrole (1.08 eV). Furthermore, the triply linked hybrid exhibits singlet diradical characteristics, as confirmed by VT NMR, ESR, and SQUID experiments.

Hepatitis B virus evades the immune system by suppressing the NF-κB signaling pathway with DENND2A.

Overcoming hepatitis B virus (HBV) is a challenging problem because HBV deceives the host immune system. We have found that DENN domain-containing 2A (DENND2A) was essential for HBV maintenance, although its role remains unclear. In this study, we elucidate its function by screening a novel DENND2A-binding peptide, DENP4-3S. DENP4-3S exhibits homology to SAM and SH3 domain-containing protein 1 (SASH1), a scaffold protein involved in Toll-like receptor signaling that promotes proinflammatory cytokine production. We confirmed that DENND2A interacts with SASH1 specifically. Overexpression and knockdown experiments showed that overexpression of DENND2A suppressed the transcriptional activity of NF-κB, and the knockdown of DENND2A promoted it and the production of cytokines and interferons. Here, we constructed a fusion protein (10M-DEN3SN) consisting of an anti-asialoglycoprotein receptor antibody and DENP4-3S to deliver the peptide to hepatocytes specifically. 10M-DEN3SN inhibited the interaction between DENND2A and SASH1, and rescued SASH1 trapped by DENND2A, leading to the upregulation of NF-κB and its downstream signaling. In addition, 10M-DEN3SN suppressed HBV proliferation in PXB chimeric mice. These results with the DENND2A-binding peptide delivered into hepatocytes suggested the involvement of DENND2A, SASH, and NF-κB signaling pathway in the HBV infection and onset of hepatitis. In conclusion, this study indicates that HBV utilizes DENND2A and SASH1 to evade the immune system.IMPORTANCEHepatitis B virus (HBV) is a serious liver infection with no established cure, causing an abnormal host immune response. Here, we identified a novel peptide that interacts with DENN domain-containing 2A (DENND2A), a host factor essential for HBV maintenance. The resulting peptide showed sequence homology, revealing an interaction between DENND2A and the immune system regulator SASH1. This study suggests that DENND2A contributes to HBV infection by suppressing the cellular immune system by inhibiting SASH1. The DENND2A-binding peptide, incorporated into our hepatocyte-specific peptide delivery system, inhibited the DENND2A-SASH1 interaction and promoted the production of cytokines and interferons in cultured hepatocytes. As a consequence, the peptide suppressed HBV proliferation in humanized mice. We report new insights into the role of DENND2A and SASH1 in HBV maintenance and highlight the importance of the immune system.

Pseudocarcinomatous Hyperplasia of the Nose and Necrotic Tracheitis Associated with Acute Myeloid Leukemia: A Case Report.

A 29-year-old woman who had been diagnosed with acute myeloid leukemia presented with persistent grade-4 febrile neutropenia (FN) after initial chemotherapy with idarubicin and cytarabine. Despite intensive treatment, FN persisted. Subsequently, her nose became reddish and swollen, obstructing the nasal cavities. Computed tomography revealed swelling of the nostrils and an irregular tracheal surface. Debridement of the nasal lesion and a bronchoscopic biopsy of the tracheal lesion were also performed. A histopathological examination revealed pseudocarcinomatous hyperplasia (PCH) of the nose and necrotizing tracheitis. Both nasal PCH and necrotizing tracheitis ameliorated when the patient recovered from leukocytopenia.

Functional involvement of endothelial lipase in hepatitis B virus infection.

BACKGROUND: HBV infection causes chronic liver disease and leads to the development of HCC. To identify host factors that support the HBV life cycle, we previously established the HC1 cell line that maintains HBV infection and identified host genes required for HBV persistence. METHODS: The present study focused on endothelial lipase (LIPG), which binds to heparan sulfate proteoglycans (HSPGs) in the cell membrane. RESULTS: We found HBV infection was impaired in humanized liver chimeric mouse-derived hepatocytes that were transduced with lentivirus expressing short hairpin RNA against LIPG. Long-term suppression of LIPG combined with entecavir further suppressed HBV replication. LIPG was shown to be involved in HBV attachment to the cell surface by using 2 sodium taurocholate cotransporting peptide (NTCP)-expressing cell lines, and the direct interaction of LIPG and HBV large surface protein was revealed. Heparin and heparinase almost completely suppressed the LIPG-induced increase of HBV attachment, indicating that LIPG accelerated HBV attachment to HSPGs followed by HBV entry through NTCP. Surprisingly, the attachment of a fluorescently labeled NTCP-binding preS1 probe to NTCP-expressing cells was not impaired by heparin, suggesting the HSPG-independent attachment of the preS1 probe to NTCP. Interestingly, attachment of the preS1 probe was severely impaired in LIPG knockdown or knockout cells. Inhibitors of the lipase activity of LIPG similarly impaired the attachment of the preS1 probe to NTCP-expressing cells. CONCLUSIONS: LIPG participates in HBV infection by upregulating HBV attachment to the cell membrane by means of 2 possible mechanisms: increasing HBV attachment to HSPGs or facilitating HSPG-dependent or HSPG-independent HBV attachment to NTCP by its lipase activity.

[DRUG-INDUCED LUNG INJURY DUE TO OTSU-JI-TO FOLLOWED BY DRUG-INDUCED LIVER INJURY: A CASE REPORT].

A 69-year-old woman who had been treated with Otsu-ji-to for fourteen days developed liver dysfunction. She continued to take Otsu-ji-to and was admitted to our hospital due to respiratory failure with extensive ground-glass opacities on chest computed tomography 22 days after starting to take Otsuji-to. Although she developed severe respiratory failure, her condition was improved by discontinuation of Otsu-ji-to and high-dose corticosteroid pulse therapy. The lymphocyte stimulation test was positive for Otsu-ji-to. Finally, we diagnosed drug-induced lung injury due to Otsu-ji-to. As in this case, severe herbal medicine-induced lung injury may be developed secondary to preceding liver injury. When a patient prescribed ou-gon-containing herbal medicines such as Otsu-ji-to develops liver dysfunction, due to herbal medicines containing ou-gon such as Otsu-ji-to, it is important to evaluate lung injury and discontinue the Kampo drug.

High TLR6 Expression Status Predicts a More Favorable Prognosis after Esophagectomy for Locally Advanced Thoracic Esophageal Squamous Cell Carcinoma.

Most so-called "beneficial bacteria" in gut microbiota are Gram-positive, and TLR6 recognizes the peptidoglycan (PGN) present in their cell walls. We hypothesized that a high TLR6 expression status predicts a more favorable prognosis after esophagectomy. We used an ESCC tissue microarray (TMA) to examine TLR6 expression status in ESCC patients and to determine whether TLR6 expression status correlates with prognosis after curative esophagectomy. We also examined whether PGN influences the cell proliferation activity of ESCC lines. Clinical ESCC samples from 177 patients tested for the expression of TLR6 were categorized as 3+ (n = 17), 2+ (n = 48), 1+ (n = 68), or 0 (n = 44). High TLR6 expression (3+ and 2+) correlated with significantly more favorable 5-year overall survival (OS) and disease-specific survival (DSS) after esophagectomy than a lower TLR6 expression (1+ and 0). Univariate and multivariate analyses showed that TLR6 expression status is an independent prognostic factor that affects 5-year OS. PGN significantly inhibited the cell proliferation activity of ESCC lines. This is the first study to show that high TLR6 expression status predicts a more favorable prognosis in locally advanced thoracic ESCC patients after curative esophagectomy. PGN released from "beneficial bacteria" seems to have potential to inhibit the cell proliferation activity of ESCC.

Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use.

Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1-4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound 1). Compound 5 inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases. Binding site analysis revealed that compound 5 covalently bound to the cysteine 491 highly flexible glycine-rich loop region of the FGFR2 adenosine triphosphate pocket. Futibatinib is currently in Phase I-III trials for patients with oncogenically driven FGFR genomic aberrations. In September 2022, the U.S. Food & Drug Administration granted accelerated approval for futibatinib in the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement.

Budget impact analysis of comprehensive genomic profiling for untreated advanced or recurrent solid cancers in Japan.

AIMS: In Japan, the use of comprehensive genomic profiling (CGP) is only available for cancer patients who have no standard of care (SoC), or those who have completed SoC. This may lead to missed treatment opportunities for patients with druggable alterations. In this study, we evaluated the potential impact of CGP testing before SoC on medical costs and clinical outcome in untreated patients with advanced or recurrent biliary tract cancer (BTC), non-squamous non-small cell lung cancer (NSQ-NSCLC), or colorectal cancer (CRC) in Japan between 2022 and 2026. MATERIALS AND METHODS: We constructed a decision-tree model reflecting the healthcare environment of Japan, to estimate the clinical outcome and medical costs impact of CGP testing by comparing two groups (with vs without CGP testing before SoC). The epidemiological parameters, detection rates of druggable alterations, and overall survival were collected from literature and claims databases in Japan. Treatment options selected based on druggable alterations were set in the model based on clinical experts' opinions. RESULTS: In 2026, the number of untreated patients with advanced or recurrent BTC, NSQ-NSCLC, and CRC was estimated to be 8600, 32,103, and 24,896, respectively. Compared with the group without CGP testing before SoC, CGP testing before SoC increased druggable alteration detection and treatment rate with matched therapies in all three cancer types. The medical costs per patient per month were estimated to increase with CGP testing before SoC in the three cancer types by 19,600, 2900, and 2200 JPY (145, 21, and 16 USD), respectively. LIMITATIONS: Only those druggable alterations with matched therapies were considered in the analysis model, while the potential impact of other genomic alterations provided by CGP testing was not considered. CONCLUSIONS: The present study suggested that CGP testing before SoC may improve patient outcomes in various cancer types with a limited and controllable increase in medical costs.

Subpleural fibrotic interstitial lung abnormalities are implicated in non-small cell lung cancer radiotherapy outcomes.

BACKGROUND: The relationship between interstitial lung abnormalities (ILAs) and the outcomes of lung cancer radiotherapy is unclear. This study investigated whether specific ILA subtypes are risk factors for radiation pneumonitis (RP). PATIENTS AND METHODS: This retrospective study analysed patients with non-small cell lung cancer treated with radical-intent or salvage radiotherapy. Patients were categorised into normal (no abnormalities), ILA, and interstitial lung disease (ILD) groups. The ILA group was further subclassified into non-subpleural (NS), subpleural non-fibrotic (SNF), and subpleural fibrotic (SF) types. The Kaplan-Meier and Cox regression methods were used to determine RP and survival rates and compare these outcomes between groups, respectively. RESULTS: Overall, 175 patients (normal, n = 105; ILA-NS, n = 5; ILA-SNF, n = 28; ILA-SF, n = 31; ILD, n = 6) were enrolled. Grade ≥2 RP was observed in 71 (41%) patients. ILAs (hazard ratio [HR]: 2.33, p = 0.008), intensity-modulated radiotherapy (HR: 0.38, p = 0.03), and lung volume receiving 20 Gy (HR: 54.8, p = 0.03) contributed to the cumulative incidence of RP. Eight patients with grade 5 RP were in the ILA group, seven of whom had ILA-SF. Among radically treated patients, the ILA group had worse 2-year overall survival (OS) than the normal group (35.3% vs 54.6%, p = 0.005). Multivariate analysis revealed that the ILA-SF group contributed to poor OS (HR: 3.07, p =0.02). CONCLUSIONS: ILAs, particularly ILA-SF, may be important risk factors for RP, which can worsen prognosis. These findings may aid in making decisions regarding radiotherapy.

Prognostic implications of prostaglandin E-major urinary metabolite in resected non-small-cell lung cancer.

OBJECTIVES: Cyclooxygenase-2-derived prostaglandin E2 (PGE2) is highly involved in the promotion of cancer progression. The end product of this pathway, PGE-major urinary metabolite (PGE-MUM), is a stable metabolite of PGE2 that can be assessed non-invasively and repeatedly in urine samples. The aim of this study was to assess the dynamic changes in perioperative PGE-MUM levels and their prognostic significance in non-small-cell lung cancer (NSCLC). METHODS: Between December 2012 and March 2017, 211 patients who underwent complete resection for NSCLC were analysed prospectively. PGE-MUM levels in 2 spot urine samples taken 1 or 2 days preoperatively and 3-6 weeks postoperatively were measured using a radioimmunoassay kit. RESULTS: Elevated preoperative PGE-MUM levels were associated with tumour size, pleural invasion and advanced stage. Multivariable analysis revealed that age, pleural invasion, lymph node metastasis and postoperative PGE-MUM levels were independent prognostic factors. In matched pre- and postoperative urine samples obtained from patients who are eligible for adjuvant chemotherapy, an increase in PGE-MUM levels following resection was an independent prognostic factor (hazard ratio 3.017, P = 0.005). Adjuvant chemotherapy improved survival in patients with increased PGE-MUM levels after resection (5-year overall survival, 79.0 vs 50.4%, P = 0.027), whereas survival benefit was not observed in those with decreased PGE-MUM levels (5-year overall survival, 82.1 vs 82.3%, P = 0.442). CONCLUSIONS: Increased preoperative PGE-MUM levels can reflect tumour progression and postoperative PGE-MUM levels are a promising biomarker for survival after complete resection in patients with NSCLC. Perioperative changes in PGE-MUM levels may aid in determining the optimal eligibility for adjuvant chemotherapy.

Overcoming challenges in acute care hospitalizations for patients with opioid use disorder.

BACKGROUND: Hospitalized patients with opioid use disorder (OUD) present unique challenges and opportunities for inpatient medical teams. Having the ability to initiate medications for opioid use disorder (MOUD) and linkage to outpatient treatment are key to improve inpatient care of patients with OUD. OBJECTIVE: This study aimed to describe the process taken by a multidisciplinary work group to improve the acute care management of patients with OUD. PRACTICE DESCRIPTION: In 2018, we identified that inpatient care teams at the University of Chicago Medicine (UCM) lacked a standardized approach to the management of hospitalized patients with OUD and that the care typically did not include evidence-based therapies. Herein, we describe the process taken to develop the OUD workgroup and the work completed by the workgroup. PRACTICE INNOVATION: The OUD workgroup spearheaded the development of an OUD consult service, formulary revisions, education for health care workers (inpatient nurse training and X-waiver training for prescribers), and outpatient partnerships. Pharmacy-led initiatives included formulary management, electronic medication orders, naloxone co-prescribing decision support, and MOUD education. EVALUATION METHODS: The OUD consult service was granted an Institutional Review Board exemption for quality improvement analysis through UCM. A data analytics dashboard was built to track consult service volumes and outcomes. RESULTS: From July 2020 to April 2021, 296 OUD consults occurred. In total, 103 consult patients (35%) received and were discharged with buprenorphine. An additional 118 patients (40%) were managed with methadone and linked to outpatient care. Naloxone dispensing at discharge increased to over 65%, which did not include patients who opted out or were discharged to a facility. CONCLUSION: The ongoing OUD epidemic presents a need for the development of services to improve management of patients with OUD in the acute care setting. The OUD workgroup has improved the management of patients admitted with OUD. Pharmacy-based initiatives are key to the development of safe and effective management of OUD in hospitalized patients.

Outpatient cross-titration to buprenorphine for chronic pain: A retrospective analysis.

OBJECTIVE: To determine the effectiveness and safety of the University of Washington's buprenorphine cross-titration protocol for chronic pain in the outpatient setting. METHODS: Retrospective chart review was performed on 150 patients transitioned from full µ-opioid agonist therapy to buprenorphine using the University of Washington Medical Center Pain Clinic's cross-titration protocol between September 1, 2020, and December 31, 2021, in an outpatient setting. Primary outcome was to determine the percentage of patients who completed the cross-titration and continued buprenorphine without full µ-opioid agonists 4 weeks after completion. Secondary outcomes included final buprenorphine dose, days needed to complete cross-titration, deviation rates from the protocol, and opioid-related adverse events. RESULTS: Fifteen of 31 (48.4 percent) included patients successfully converted to buprenorphine. Median duration of successful cross-titration was 29 days (interquartile range 19-57). Average end-titration dose for patients on buprenorphine/naloxone sublingual films was 7.9 ± 5.7 mg/day, while for buprenorphine transdermal (TD) patches, it was 11.9 ± 4.8 mcg/h. Morphine equivalent daily dose (MEDD) prior to induction varied widely. All patients transitioned to TD buprenorphine were taking ≤30 mg MEDD. Patients previously taking >120 mg MEDD stabilized on 8-16 mg/day buprenorphine. Most common reasons for cross-titration failure were inadequate pain control and intolerable adverse effects. DISCUSSION: The University of Washington's buprenorphine cross-titration protocol for chronic pain was successful in about half of included patients undergoing conversion from chronic full µ-opioid agonist therapy and generally well tolerated. Clinical responses were widely variable, and many required slower taper and higher end-titration buprenorphine dose than anticipated. Although protocols provide structure for cross-titration, each course should be monitored closely and individualized.

Safety and effectiveness of istradefylline as add-on therapy to levodopa in patients with Parkinson's disease: Final report of a post-marketing surveillance study in Japan.

INTRODUCTION: Istradefylline is approved in Japan and the US for treatment of Parkinson's disease (PD) in adult patients who experience the wearing-off phenomenon while receiving levodopa; however, safety and efficacy data for real-world clinical use are lacking. METHODS: We report the final results of a prospective, long-term, post-marketing surveillance study of istradefylline adjunct to levodopa for adults with PD experiencing the wearing-off phenomenon. Patients across 214 study sites initiating treatment with oral istradefylline once-daily 20- or 40-mg were followed-up for 1 year. We collected demographic data, disease and treatment histories, and recorded adverse events and adverse drug reactions (ADRs). The priority survey item was the occurrence of psychiatric ADRs. Effectiveness was evaluated by the physician's global and motor function assessments. RESULTS: Case report forms were collected for 1320 patients, and the safety and effectiveness analysis sets included 1318 and 1284 patients, respectively. The mean age was 71.5 years and 56.2% of patients were women. A total of 274 patients (20.8%) experienced an ADR, 39 patients had a serious ADR, and 7 patients had a fatal ADR that was considered not related to istradefylline. Common ADRs included dyskinesia, hallucination, and visual hallucination. Sixty-five patients (4.9%) experienced a psychiatric ADR. Istradefylline was effective (physician-rated) in 59.8% of patients, and most patients had reduced or unchanged off-time duration, improved or unchanged off-time symptoms, and improved or unchanged motor symptoms. CONCLUSION: Istradefylline safely and effectively improves motor symptoms in PD patients experiencing the wearing-off phenomenon with levodopa therapy in the real-world setting.

The diagnostic yield and characteristics of bronchoalveolar lavage in suspected nontuberculous mycobacterial pulmonary disease.

Background: Bronchoalveolar lavage (BAL) has widely been used to manage respiratory diseases including respiratory infections. The aim of this study was to evaluate the diagnostic yield of BAL for detecting nontuberculous Mycobacterium (NTM). Methods: We retrospectively reviewed the records of 54 patients who underwent bronchoscopy due to suspected NTM pulmonary disease. Positive culture results of respiratory specimens were defined as NTM pulmonary disease. For BAL, two or three aliquots of 50 mL (total 100 or 150 mL) of sterile normal saline were instilled through bronchoscope. Results: NTM was detected in 31 of 54 (57.4%) patients. The detection rates were not different between the patients who underwent bronchoscopy with BAL (24 of 39, 61.5%) and those without (7 of 15, 46.7%) (P = 0.437). BAL fluid was mostly neutrophil dominant in both positive and negative NTM culture groups. In the subgroup analysis of 33 patients who underwent both the BAL and anti- glycopeptidolipid (GPL)-core immunoglobulin A (IgA) antibody measurements, 12 of 19 (63.2%) positive Mycobacterium avium complex (MAC) culture patients and 8 of 14 (57.1%) negative MAC culture patients were positive for anti-GPL-core IgA antibody (seropositive) (P = 0.991). There was no severe complication related to BAL. Conclusions: The diagnostic yield of BAL with ≥100 mL sterile saline was not superior to that of bronchial wash or sputum aspiration in patients with suspected NTM pulmonary disease. Patients with seropositive but negative culture results for MAC suggest pseudonegative for pulmonary MAC disease.

A case of renal cell carcinoma with microscopic pulmonary tumor embolism proven by surgical lung biopsy.

Pulmonary tumor embolism (PTE) is difficult to diagnose before death. We report the case of a 75-year-old man with microscopic PTE of renal cell carcinoma who was diagnosed by surgical lung biopsy. He visited our hospital because of dyspnea on exertion. Chest computed tomography (CT) showed multiple micronodules and ground glass opacities. Steroid therapy was started as therapeutic diagnosis for IgG4-related pulmonary disease. However, he was admitted our hospital due to progressive respiratory failure. Pathological findings of a lung biopsy obtained by video-assisted thoracic surgery showed PTE of renal cell carcinoma without embolization of large pulmonary arteries. He received palliative medicine and died four months after the surgical lung biopsy. In cases of multiple micronodules in chest CT findings and worsened respiratory symptoms, PTE should be considered in the differential diagnosis.

Guanine nucleotide exchange factor DOCK11-binding peptide fused with a single chain antibody inhibits hepatitis B virus infection and replication.

Hepatitis B virus (HBV) infection is a major global health problem with no established cure. Dedicator of cytokinesis 11 (DOCK11), known as a guanine nucleotide exchange factor (GEF) for Cdc42, is reported to be essential for the maintenance of HBV. However, potential therapeutic strategies targeting DOCK11 have not yet been explored. We have previously developed an in vitro virus method as a more efficient tool for the analysis of proteomics and evolutionary protein engineering. In this study, using the in vitro virus method, we screened and identified a novel antiasialoglycoprotein receptor (ASGR) antibody, ASGR3-10M, and a DOCK11-binding peptide, DCS8-42A, for potential use in HBV infection. We further constructed a fusion protein (10M-D42AN) consisting of ASGR3-10M, DCS8-42A, a fusogenic peptide, and a nuclear localization signal to deliver the peptide inside hepatocytes. We show using immunofluorescence staining that 10M-D42AN was endocytosed into early endosomes and released into the cytoplasm and nucleus. Since DCS8-42A shares homology with activated cdc42-associated kinase 1 (Ack1), which promotes EGFR endocytosis required for HBV infection, we also found that 10M-D42AN inhibited endocytosis of EGFR and Ack1. Furthermore, we show 10M-D42AN suppressed the function of DOCK11 in the host DNA repair system required for covalently closed circular DNA synthesis and suppressed HBV proliferation in mice. In conclusion, this study realizes a novel hepatocyte-specific drug delivery system using an anti-ASGR antibody, a fusogenic peptide, and DOCK11-binding peptide to provide a novel treatment for HBV.

Estimation of the Under-Reporting of Suspected Serious Adverse Drug Reactions in Japan Using An Interrupted Time Series Analysis.

OBJECTIVE: Spontaneous reports of adverse drug reactions (ADRs) are an essential data source for pharmacovigilance activities. However, spontaneous reporting is affected by under-reporting, which can lead to bias in statistical signal detection and failure to identify potential drug-associated risks. This study aimed to estimate the degree of under-reporting of suspected serious ADRs (sADRs) in spontaneous reports in Japan. METHODS: The new active ingredients approved in Japan between 2010 and 2016 for which all-case surveillance was conducted were selected for this study. Data of sADR reports were extracted from the Japanese Adverse Drug Event Report database (JADER). An interrupted time series (ITS) analysis was conducted to compare the number of sADR reports (sADR cases) obtained in the all-case surveillance period with that obtained in the spontaneous report period (after all-case surveillance had been completed). RESULTS: The ITS analysis of all sADR cases revealed that 24 (68.6%) of the 35 investigated drugs showed a statistically significant decrease in the intercept (level) in the spontaneous reporting period compared with that in the all-case surveillance period. The median of the reduction rate of the level was 60.1%. The number of drugs with a statistically significant decrease in the level of cases with sADRs in the Important Medical Event list and in that leading to death was 19/35(54.3%) and 6/35 (17.1%), respectively. CONCLUSION: This study demonstrated the existence of sADR under-reporting in spontaneous reports in Japan quantitatively. Meanwhile, it was suggested that information on sADRs was reported appropriately according to their level of severity.