Development of an ATP force field for coarse-grained simulation of ATPases and its application to the maltose transporter.

The biological functions of ATPases, such as myosin, kinesin, and ABC transporter, are due to large conformational motions driven by energy obtained from ATP. Elucidation of the mechanisms underlying these ATP-driven movements is one of the greatest challenges in computational chemistry. It has been shown that the MARTINI coarse-grained method is a promising tool for the investigation of large conformational motions in various proteins. However, this method has not yet been applied to ATPases because of the lack of a force field for the ATP molecule. Here, we developed force field parameters for the ATP molecule and conducted simulations using these parameters for the subunits (MalK2 ) and the full-length structure (MalFGK2 -E) of a maltose transporter. It was found for both targets that the dimerization of the nucleotide binding domains (NBDs) is induced upon ATP binding. Moreover, for the full-length transporter, the conformational transition from the pre-translocation state to the outward-facing state was observed and was accompanied by an initial transport motion of the substrate. It is expected that coarse-grained simulations utilizing the parameters for the ATP molecule developed here will serve as a powerful tool for investigating other ATPases as well. © 2019 Wiley Periodicals, Inc.

Nab-paclitaxel maintenance therapy following carboplatin + nab-paclitaxel combination therapy in chemotherapy naïve patients with advanced non-small cell lung cancer: multicenter, open-label, single-arm phase II trial.

Background A global multicenter study demonstrated superiority of carboplatin + nab-paclitaxel (PTX) therapy compared to carboplatin + PTX in terms of response rate (RR) and non-inferiority in terms of progression free survival (PFS) and overall survival (OS) in untreated patients with stage IIIB/IV non-small cell lung cancer; no clinical findings have so far been reported on maintenance therapies with nab-PTX. The aim of this study was to determine the efficacy and safety of maintenance therapy with nab-PTX following carboplatin + nab-PTX combination therapy. Methods Carboplatin (AUC 6) was administered on Day 1; and nab-PTX 100 mg/m2 on Days 1, 8, and 15, and dosing was repeated in 4 courses of 4 weeks each. In patients with clinical response was observed at the end of the 4th course, nab-PTX maintenance therapy was repeated. Results Out of 39 patients included in the efficacy analysis, 19 (48.7%) patients completed the induction therapy and 15 (38.5%) were transitioned to maintenance therapy. The median PFS in the maintenance phase was 6.5 (90%CI 1.4-11.4) months. The median OS in 15 patients was 12.6 (95%CI: 7.4-not reached). Grade ≥ 3 toxicities observed in more than 5% of patients were neutropenia (55.0%), anemia (15.0%), and febrile neutropenia (5.0%), with no increase during the maintenance phase. Conclusions Although statistically significance was not demonstrated presumably due to a limited transition rate from induction to maintenance phase, nab-PTX was suggested to be a useful treatment option following the induction therapy with nab-PTX in patients with advanced NSCLC.

[Pilot study of intermittent administration of liposomal amphotericin B for chronic pulmonary aspergillosis].

Treatment for chronic pulmonary aspergillosis is difficult and frequently is required for prolong period. In outpatients setting, only voriconazole and itraconazole could be used. Since liposomal amphotericin B (L-AMB) demonstrated prolonged half-time, we have investigated the feasibility of L-AMB in outpatient setting. Three cases of chronic pulmonary aspergillosis were treated with intermittent administration of 2.5 mg/kg of L-AMB twice weekly for one month in outpatient settings. Improve of symptoms was attained in 2 of 3 cases. Improvement of chest images were in 2 of 3, improvement of laboratory test were in 2 of 3. Adverse events were only fatigue and short period of fever. No recurrence of pulmonary aspergillosis has been found after treatment. Intermittent administration of L-AMB in outpatient settings could be an option for pulmonary aspergillosis.

[A case report of pulmonary aspergillosis in lung transplant recipient successfully treated with inhalation administration of liposomal amphotericin B].

We report a case of pulmonary aspergillosis in lung transplant recipient who was successfully treated with inhalation administration of anti-fungal agent. The case was 33-year-old female. Two years ago, she had received lung transplant because of lymphangioleiomyomatosis. One year ago, she had diagnosed of pulmonary aspergillosis and successfully treated with micafungin and itraconazole. Then she had been continuous administered with itraconazole. In June 20xx, she had nausea and vomiting and was diagnosed of viral enteritis. Although abdominal symptoms were relieved, ground glass opacity was discovered in her right lung. Bronchoscopic examination revealed ulceration of bronchus with white necrotic substance. Laboratory culture test demonstrated Aspergillus spp. Finally she was diagnosed of recurrent pulmonary aspergillosis. First, she was treated with intravascular administration of micafungin. Then, inhalation administration of liposomal amphotericin B was changed. Ground glass opacity and bronchial region of pulmonary aspergillosis was improved. Thereafter, inhalation of amphotericin B was continued and no recurrence of pulmonary aspergillosis has been found. Inhalation of anti-fungal agent could be an option for pulmonary aspergillosis.

Real-world Efficacy and Safety of Atezolizumab Plus Bevacizumab, Paclitaxel and Carboplatin for First-line Treatment of Japanese Patients With Metastatic Non-squamous Non-small Cell Lung Cancer.

BACKGROUND/AIM: Platinum-doublet chemotherapy plus either programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) checkpoint inhibitors has been reported to improve the survival of patients with advanced non-small cell lung cancer (NSCLC). The IMpower150 study showed significant improvements in progression-free survival and overall survival with atezolizumab in combination with bevacizumab, a humanized anti-VEGF monoclonal antibody, paclitaxel, and carboplatin (ABCP therapy) in chemotherapy-naïve patients with non-squamous NSCLC. We herein report the efficacy and safety of ABCP therapy in Japanese patients with non-squamous NSCLC in clinical practice. PATIENTS AND METHODS: We retrospectively evaluated the efficacy and safety of ABCP therapy in 30 patients treated at our hospital from February 2019 to December 2021. RESULTS: The median age of patients was 69 years, 24 (80.0%) patients were male, 29 (96.7%) patients had a performance status of 0 or 1, 28 (93.3%) patients had adenocarcinoma histology, and 7 (23.3%) patients had epidermal growth factor receptor mutations. Evaluation of the PD-L1 tumor proportion score (TPS) showed that 12 (40.0%), 8 (26.7%), and 6 (20.0%) patients had a TPS of ≥50%, 1% to 49%, and <1%, respectively. The objective response rate of the intention-to-treat wild-type population was 73.9%, and the median progression-free survival was 8.3 months. Immune checkpoint inhibitor (ICI)-induced pneumonitis occurred in one (3.3%) patient. CONCLUSION: ABCP therapy for Japanese non-squamous NSCLC patients in a clinical setting achieved a high response rate with low incidence of ICI-induced pneumonitis equivalent to those observed in IMpower150 study.

Simultaneous nodular lymphocyte-predominant Hodgkin lymphoma with papillary thyroid carcinoma: a case report.

We herein report the case of a 48-year-old man diagnosed with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL, Stage IA) and papillary thyroid carcinoma (PTC, Stage I). Total thyroidectomy, left modified neck dissection and biopsy of the right cervical lymph node were performed. Postoperatively, NLPHL treatment was prioritized, and external radiation (30.6 Gy) was applied to the right neck. PTC was considered a high-risk category for recurrence due to extranodal invasion of lymph node metastasis, and radioactive iodine therapy (ablative dose, 1110 MBq) was administered. Both PTC and NLPHL showed no recurrence 18 months after surgery.

Incidence and mortality of acute myocardial infarction. A population-based study including patients with out-of-hospital cardiac arrest.

The in-hospital mortality rate of acute myocardial infarction (AMI) is improving. In Japan, little information exists concerning the incidence and mortality of AMI. Therefore, our population-based analysis examined the incidence and mortality rate in AMI cases in individuals that lived in the Matsumoto region in 2002. We studied 169 AMI patients who were admitted within 14 days after a non-out-of-hospital cardiac arrest (non-OHCA group) and 63 patients with an AMI-related out-of-hospital cardiac arrest (OHCA group). The in-hospital mortality rate of the non-OHCA group was 9.5% (reperfusion therapy [+] 3.4%, [-] 22.7%, P < 0.0001). The rate of return of spontaneous circulation and the survival rate were 21% and 1.6%, respectively, in the OHCA group. The incidence of AMI in the non-OHCA and OHCA groups combined was 55.2 to 63.1 events/100,000 people annually and the mean age of AMI patients was 70 ± 13 years. The population-based mortality rate of AMI was 34% to 42%. The mortality rate of AMI remains high, and most deaths occur outside of the hospital. Prehospital care may lower the mortality rate of AMI.

[Relationship between combined emphysema, pulmonary hypertension and %FEV1 in patients with idiopathic interstitial pneumonia].

The prognosis of idiopathic pulmonary fibrosis (IPF) is poor, and it deteriorates when it is complicated with pulmonary hypertension (PH). Forced vital capacity (FVC) is a useful parameter for evaluating the disease status of interstitial pneumonia (IP). However, in patients with IP complicated with emphysema, the disease severity can be overlooked because of relatively well preserved FVC. We investigated the correlation between the maximum pressure gradient (PG) in the tricuspid valve using echocardiographic measurements and pulmonary function tests in patients with IP without emphysema and in those with IP with emphysema. There was an inverse correlation between PG and %FVC in patients with IP without emphysema. However, the above inverse correlation between PG and %FVC mentioned above disappeared when analyzed in the whole cohort of patients (n = 42) consisting of IP without emphysema (n = 35) and IP with emphysema (n = 7). Patients with IP without emphysema did not show a correlation between PG and %FEV1, but when analyzed using the whole cohort of patients an inverse correlation between PG and %FEV1 was observed (p<0.05). In clinical practice, not only FVC, but also %FEV1 is a valuable parameter in investigating the complication of emphysema and PH in patients with chronic idiopathic interstitial pneumonia.

Molecular mechanism underlying the selective attack of trehalose lipids on cancer cells as revealed by coarse-grained molecular dynamics simulations.

The present study indicated that the mixed lipid bilayer of dimyristoylphosphatidylcholine (DMPC) and trehalosemonomyristate (TreC14) interacted strongly with the plasma membrane of cancer cells, and not that of normal cells, when the composition of TreC14 was 70%, as revealed by coarse-grained molecular dynamics simulations. These results were consistent with those of previous experimental studies, indicating that DMPC/TreC14 mixed liposomes (DMTreC14) with TreC14 composition at 70% exhibited a strong anti-cancer effect without affecting normal cells. The simulations also revealed that lipids with highly hydrophilic and bulky head groups, such as TreC14, phosphatidylinositol (PI), and phosphatidylserine (PS), showed the tendency to accumulate. This caused both the DMTreC14 and cancer cell membranes to bend into large positive curvatures, resulting in tight contact between them. In contrast, no apparent interaction between the DMTreC14 and normal cell membranes was observed because PI and PS did not exist in the extracellular monolayer of the normal cell membrane.

Lung squamous cell carcinoma with severe hypomagnesemia due to cisplatin plus gemcitabine in combination with necitumumab therapy: A case report.

A 72-year-old man, diagnosed with advanced lung squamous cell carcinoma, was administered of cisplatin plus gemcitabine with necitumumab, a human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), as a sixth-line treatment. Tumor shrinkage was observed, but asymptomatic grade 4 hypomagnesemia occurred on day 8 of the second cycle. He received magnesium replenishment and hypomagnesemia recovered on day 40, but tumor progression was observed during the period of magnesium correction. Hypomagnesemia is known as a major adverse event of treatment with anti-EGFR antibodies, but there have been no case reports of severe hypomagnesemia or its clinical course.

Prevalence of viral infection in acute exacerbation of interstitial lung diseases in Japan.

BACKGROUND: Fatal acute exacerbation of interstitial lung diseases is often accompanied by indicators of infection such as fever, cough, and sputum. Although viral infection can contribute to acute exacerbation of interstitial lung diseases, few studies have identified a relationship between acute exacerbations and viral infections. The present study aimed to prospectively clarify the role of viral infection in patients showing acute exacerbation of interstitial lung disease in Japan. METHODS: Nasopharyngeal swab specimens were collected from patients with acute exacerbation of interstitial lung disease between May 2017 and February 2019. Respiratory viruses were detected by the Luminex xTAG Respiratory Viral Panel FAST v2 RUO kit and the BioFire FilmArray Respiratory Panel assay. RESULTS: Three of 29 patients demonstrated respiratory viral infection during acute exacerbation of interstitial lung diseases. The infectious agents were identified as respiratory syncytial virus, respiratory syncytial virus and influenza A virus, and influenza A virus and rhino/enterovirus in the three patients, respectively. CONCLUSIONS: These results suggest that viral infection did not frequently induce acute exacerbation of interstitial lung diseases in Japan.

Inhaled corticosteroids might not increase the risk of pneumonia in patients with chronic obstructive pulmonary disease in Japan.

BACKGROUND: The use of inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD) decreases the frequency of COPD exacerbations. Recently, pneumonia was reported as a complication of ICS in patients with COPD. However, there have been few reports concerning the relationship between ICS and pneumonia in Japan. Moreover, there is little information on the types of ICS. PATIENTS AND METHODS: To clarify these issues, we investigated the occurrence of pneumonia in Japanese patients with COPD. We retrospectively investigated the occurrence of pneumonia in patients with COPD in our hospital from January 2009 to August 2013. Morbidity and mortality, ICS use, age, sex, and COPD classification were investigated. A group of patients with COPD who received ICS and a group of patients with COPD who did not receive ICS were compared each other. RESULTS: Fifty-one patients developed pneumonia among 639 (7.98%) patients with COPD. Among 252 ICS-treated patients with COPD, 13 (5.16%) developed pneumonia, and among 387 ICS-untreated patients with COPD, 38 (9.82%) developed pneumonia. The mortality rate in ICS-treated patients with COPD was 7.7%, while that in ICS-untreated patients was 10.5% (P=0.767). Fluticasone/salmeterol use tended to show a higher risk of pneumonia than budesonide/formoterol use. The use of ICS did not increase the risk of pneumonia or mortality due to pneumonia in Japanese patients with COPD. CONCLUSION: ICS might not increase the risk of pneumonia in Japanese patients with COPD. In regard to pneumonia, ICS can be safely used in Japanese patients with COPD. Because there are apparent differences in lung diseases among races, appropriate treatment should be investigated in each country.

Low-dose Epidermal Growth Factor Receptor (EGFR)- Tyrosine Kinase Inhibition of EGFR Mutation-positive Lung Cancer: Therapeutic Benefits and Associations Between Dosage, Efficacy and Body Surface Area.

A key drug for treatment of EGFR mutation-positive non-small cell lung cancer is epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). While the dosage of many general anti-tumor drugs is adjusted according to the patient body surface area, one uniform dose of most TKIs is recommended regardless of body size. In many cases, dose reduction or drug cessation is necessary due to adverse effects. Disease control, however, is frequently still effective, even after dose reduction. In this study, we retrospectively reviewed the characteristics of 26 patients at Fukuoka University Hospital between January 2004 and January 2015 in whom the EGFR-TKI dose was reduced with respect to progression free survival and overall survival. There were 10 and 16 patients in the gefitinib group and the erlotinib group, respectively. The median progression-free survival in the gefitinib group and the erlotinib group was 22.4 months and 14.1 months, respectively, and the median overall survival was 30.5 months and 32.4 months, respectively. After stratification of patients by body surface area, the overall median progression-free survival was significantly more prolonged in the low body surface area (<1.45 m2) group (25.6 months) compared to the high body surface area (>1.45 m2) group (9.7 months) (p=0.0131). These results indicate that low-dose EGFR-TKI may sufficiently control disease without side effects in lung cancer patients with a small body size.

Chronic Pseudomonas aeruginosa infection-induced chronic bronchitis and emphysematous changes in CCSP-deficient mice.

The club cell secretory protein (CCSP) is a regulator of lung inflammation following acute respiratory infection or lung injury. Recently, the relationship between CCSP and COPD has been reported. Since COPD results from an abnormal inflammatory response, we hypothesized that CCSP could have a protective role against chronic inflammation-induced lung damage. To address this issue, the pathophysiology of chronic lung inflammation induced by Pseudomonas aeruginosa in CCSP-deficient mice was determined. A tube of 5 mm in length was soaked in a fluid containing P. aeruginosa (PAO01 strain) for 1 week and inserted into the trachea of CCSP-deficient mice. One week later, P. aeruginosa was administered into the trachea. Five weeks after insertion of tube, the mice were sacrificed. Bronchoalveolar lavage fluids were collected to determine the bacterial growth, and the lung histology and physiology were also examined. P. aeruginosa was continuously detected in bronchoalveolar lavage fluids during the study. Neutrophils were increased in the bronchoalveolar lavage fluids from the CCSP-deficient mice in comparison to wild-type mice. A histological study demonstrated chronic inflammation around bronchus, serious bronchial stenosis, and alveolar enlargement in the CCSP-deficient mice. The lung physiology study demonstrated an increase in the lung compliance of the CCSP-deficient mice. Chronic P. aeruginosa inflammation resulted in chronic bronchitis and emphysematous changes in the CCSP-deficient mice. CCSP could play an important role in protecting the host from the chronic inflammation-induced lung damage.

Adenoid Cystic Carcinoma of the Lung with an EGFR Mutation.

An 80-year-old woman was referred to our hospital due to the presence of a mass that was identified on a chest X-ray. A further investigation demonstrated advanced adenoid cystic carcinoma of the lungs. Anti-cancer chemotherapy with docetaxel was carried out and the lesion remained as stable disease. Subsequently, pleural effusion was detected, and an investigation of the pleural effusion revealed the existence of malignant cells with an epidermal growth factor (EGFR) mutation. Gefitinib was administered and the pleural effusion resolved. This is the first case of a positive EGFR mutation of adenoid cystic carcinoma of the lung with a favorable response to an EGFR-tyrosine kinase inhibitor.

A new cancer cell detection method using an infectivity-enhanced adenoviral vector.

Cytological examination is widely used as a diagnostic tool because of the ease of collecting cells from the involved area. However, the diagnostic yield of cytological examination is unsatisfactory; the reasons include sampling error, poorly prepared samples, small numbers of malignant cells, and low grades of cellular atypia. In this study, we focused on the high infectivity of adenovirus towards epithelial cells and applied the luciferase- expressing adenoviral vector to a new cancer cell detection tool. In addition, adenoviral infectivity was enhanced by modifying viral fiber proteins. The sensitivity of the diagnostic tool was tested using the NCI-H1299 lung cancer cell line, and validated in body fluid samples from cancer patients with a variety of etiology. Results showed that the adenovirus efficiently transfected NCI-H1299 with high sensitivity. Only 10 cancer cells were sufficient for detection of luciferase signals. In body fluid samples, the adenovirus confirmed the diagnosis for malignant and benign cancer, but not in non-epithelial cell derived samples. This study provides proof-of-concept for a more reliable and sensitive diagnostic tool for epithelium-derived cancer.

Efficacy of aprepitant in patients with advanced or recurrent lung cancer receiving moderately emetogenic chemotherapy.

AIMS AND BACKGROUND: To evaluate the efficacy of a combination of aprepitant and conventional antiemetic therapy in patients with advanced or recurrent lung cancer receiving moderately emetogenic chemotherapy (MEC). METHODS: Patients with advanced or recurrent lung cancer who were treated with MEC regimens at the Department of Respiratory Medicine, Fukuoka University Hospital, were included and classified into the following groups: control group (treatment: 5-HT3 receptor antagonists + dexamethasone) and aprepitant group (treatment: 5-HT3 receptor antagonists + dexamethasone + aprepitant). The presence or absence of chemotherapy-induced nausea and vomiting (CINV) was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0; patients with grade 1 or above were considered positive for CINV. Food intake per day, completion of planned chemotherapy, and progression-free survival (PFS) achieved by chemotherapy were investigated. RESULTS: The complete suppression rate of nausea in the aprepitant group was significantly higher than that in the control group (p = 0.0043). Throughout the study, the food intake in the aprepitant group was greater than that in the control group, with the rate being significantly higher, in particular, on day 5 (p = 0.003). The completion rate of planned chemotherapy was also higher in the aprepitant group (p = 0.042). PFS did not differ significantly, but tended to be improved in the aprepitant group. CONCLUSIONS: The aprepitant group showed significantly higher complete suppression of nausea, food intake on day 5, and completion of planned chemotherapy than the control group.