Real-world Prognostic Data on Unresectable Stage III Non-small-cell Lung Cancer Treated with Concurrent Chemoradiation Therapy by Histological Type.

Objective The current standard treatment for locally advanced, unresectable stage III non-small-cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CCRT) and durvalumab administration. Although reports have indicated that the prognosis of squamous cell carcinoma is poorer than that of adenocarcinoma, real-world data are currently inadequate. Methods The present study analyzed patients with stage III NSCLC who received CCRT at the study center between April 2018 and February 2022. These patients were retrospectively classified into adenocarcinoma and squamous cell carcinoma groups for an analysis of the progression-free survival (PFS), overall survival (OS), and patient background factors, including the age, performance status, smoking history, and pre-CCRT laboratory data. Results A total of 109 patients were included for the analysis; 25 were excluded, and 44 and 40 patients were classified into the adenocarcinoma and squamous cell carcinoma groups, respectively. The median PFS was significantly longer in the adenocarcinoma group than in the squamous cell carcinoma group [27.9 (95% confidence interval {CI}: 15.2-not achieved) vs. 9.63 (95% CI: 5.88-13.9) months; p<0.01]. Similarly, the median OS was significantly longer in the adenocarcinoma group than in the squamous cell carcinoma group [not achieved (95% CI: 48.1-not achieved) vs. 23.8 (95% CI; 14.6-not achieved) months; p<0.01]. In the multivariate Cox proportional hazard analysis, the histological type was the only prognostic factor for the PFS (p<0.05) and OS (p<0.05). Conclusion The median PFS and OS were poorer in patients with squamous cell carcinoma than in those with stage III NSCLC treated with CCRT and durvalumab. The histological type was an independent factor affecting the PFS and OS.

Oxygen-evolving photosystem II structures during S1-S2-S3 transitions.

Photosystem II (PSII) catalyses the oxidation of water through a four-step cycle of Si states (i = 0-4) at the Mn4CaO5 cluster1-3, during which an extra oxygen (O6) is incorporated at the S3 state to form a possible dioxygen4-7. Structural changes of the metal cluster and its environment during the S-state transitions have been studied on the microsecond timescale. Here we use pump-probe serial femtosecond crystallography to reveal the structural dynamics of PSII from nanoseconds to milliseconds after illumination with one flash (1F) or two flashes (2F). YZ, a tyrosine residue that connects the reaction centre P680 and the Mn4CaO5 cluster, showed structural changes on a nanosecond timescale, as did its surrounding amino acid residues and water molecules, reflecting the fast transfer of electrons and protons after flash illumination. Notably, one water molecule emerged in the vicinity of Glu189 of the D1 subunit of PSII (D1-E189), and was bound to the Ca2+ ion on a sub-microsecond timescale after 2F illumination. This water molecule disappeared later with the concomitant increase of O6, suggesting that it is the origin of O6. We also observed concerted movements of water molecules in the O1, O4 and Cl-1 channels and their surrounding amino acid residues to complete the sequence of electron transfer, proton release and substrate water delivery. These results provide crucial insights into the structural dynamics of PSII during S-state transitions as well as O-O bond formation.

Do the physical activity questions in the Japanese version of the Cardiovascular Health Study criteria truly reflect a decline in physical activity?

Older participants identified as having decreased physical activity according to the Japanese version of the Cardiovascular Health Study criteria did not show a significant reduction in accelerometer-measured physical activity. Despite its widespread use in Japanese studies, the Japanese version of the Cardiovascular Health Study physical activity questionnaire may not effectively capture declines in physical activity.

First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations: The UNICORN Phase 2 Nonrandomized Clinical Trial.

Importance: Non-small cell lung cancer (NSCLC) with uncommon EGFR mutations is a rare subgroup, composing 14% of all EGFR mutations. Objective: To determine the usefulness of osimertinib in previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations, excluding exon 20 insertion mutations. Design, Setting, and Participants: This multicenter, open-label, single-group, phase 2 nonrandomized clinical trial enrolled patients from April 10, 2020, to May 31, 2022, with a follow-up of 6 months from the date the last patient was enrolled. The study enrolled 42 patients with uncommon EGFR mutations, of whom 40 were eligible. Intervention: Osimertinib, 80 mg once daily, was administered orally to patients. Main Outcomes and Measures: The primary end point was the overall response rate (ORR). The secondary end points were disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), duration of response (DoR), and safety of osimertinib. Patients were included in the study on an intention-to-treat basis. Results: Of the 40 eligible patients, 22 were men (55.0%) and the median age was 72 years (range, 39.0-88.0 years). The most common mutations were G719X (20 [50.0%]), S768I (10 [25.0%]), and L861Q (8 [20.0%]). The ORR was 55.0% (90% CI, 40.9%-68.5%) and the DCR was 90.0% (95% CI, 76.3%-97.2%). The median PFS was 9.4 months (95% CI, 3.7-15.2 months) after a median follow-up of 12.7 months (range, 2.7-30.7 months). The median TTF was 9.5 months (95% CI, 5.6-30.3 months), median OS was not reached (NR; 95% CI, 19.3 months to NR), and median DoR was 22.7 months (95% CI, 9.5 months to NR). The ORR for patients with solitary or compound uncommon EGFR mutations was 45.5% (90% CI, 26.9%-65.3%) and 66.7% (90% CI, 43.7%-83.7%), respectively. Median PFS for patients with solitary or compound uncommon EGFR mutations was 5.4 months (95% CI, 3.6-22.7 months) and 9.8 months (95% CI, 5.1 months to NR), respectively. Median OS for patients with solitary or compound uncommon EGFR mutations was 23.0 months (95% CI, 12.3 months to NR) and NR, respectively. Median DoR for patients with solitary or compound uncommon EGFR mutations was 22.7 months (95% CI, 3.6-22.7 months) or NR (95% CI, 5.7 months to NR), respectively. Grade 3 or 4 adverse events were reported by 11 patients (27.5%), and 5 patients (12.5%) developed interstitial lung disease. All adverse events were manageable, and there were no treatment-related deaths. Conclusions and Relevance: Osimertinib showed clinical activity with manageable toxic effects among previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations other than exon 20 insertion mutations. The results support the use of osimertinib as a treatment option for this patient population. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCTs071200002.

Association Between Timed Up-and-Go Test and Future Changes in the Frailty Status in a Longitudinal Study of Japanese Community-Dwelling Older Adults.

Purpose: This study aimed to evaluate the relationship between timed up-and-go (TUG) test time and changes in frailty status in a longitudinal cohort study of rural Japanese older adults. Patients and Methods: This prospective cohort study included 545 community-dwelling older adults. Initial and 2-year follow-up surveys were conducted. We compared the number of the Japanese version of the Cardiovascular Health Study components during the follow-up period and classified the participants into three groups: the favorable change, unchanged as prefrail, and unfavorable change groups. Associations between changes in frailty status and TUG time in the first survey were examined. The predictive ability of the TUG test was determined using the receiver operating characteristic (ROC) curve. Results: The favorable change group comprised 315 individuals (57.8%), the unchanged as prefrail group 105 (19.2%), and the unfavorable change group 125 (22.9%). TUG time was associated with the favorable and unfavorable changes after adjustment for covariates (OR 0.79, 95% CI 0.68-0.92, P=0.001 and OR 1.27, 95% CI 1.09-1.49, P=0.002). The ROC curve of TUG time as a predictor of unfavorable changes showed an area under the curve of 0.59. A cut-off point of TUG was calculated as 6.3 s with 49.6% sensitivity and 66.0% specificity. Conclusion: TUG time in the first survey was significantly associated with changes in frailty status 2 years later. However, its predictive value as a stand-alone test is limited and has the potential to predict future changes in the frailty status in older adults in combination with other tests.

A Survey of Pharmacy Students' Satisfaction with a Basic Life Support Course and an Exploration of Factors Related to Awareness Change Before and After the Course.

The model core curriculum for pharmacy education and professional standards for pharmacists established by the Japan Pharmaceutical Association aim to inculcate knowledge and skills on basic life support (BLS) and ensure that pharmacy students are well equipped with knowledge on BLS. In this study, pharmacy students were enrolled in the PUSH course, a BLS training course for citizens, and a questionnaire survey was conducted before and after the course to evaluate the change in students awareness about BLS and overall satisfaction with the course. The participants enrolled for the course were fourth-year students from the School of Pharmacy, Hyogo Medical University, who consented to participate in the study. A total of ninety-nine participants were included in this study. After the completion of the course, the participants displayed greater confidence, preparedness, and willingness to teach BLS, and decreased anxiety about BLS. Factor analysis revealed four factors based on the questionnaire answers before the course, while three factors were extracted based on the answers after the course. Lack of confidence in BLS, extracted as one of the factors before the course was inverted and gave rise to a new factor. Some participants displayed increased awareness about BLS after completion of the PUSH course. Hierarchical cluster analysis before and after the course divided respondents into three groups. The results showed that lesser number of participants displayed anxiety over BLS after the course. The results also indicated high levels of satisfaction among the participants after the completion of the PUSH course.

Efficacy of new oral rinse containing sodium hyaluronate in xerostomia: A randomized crossover study.

OBJECTIVES: To evaluate the efficacy of a new oral rinse containing sodium hyaluronate and other functional ingredients in reducing xerostomia-associated symptoms. MATERIALS AND METHODS: In this 8-week, double-blind crossover study, xerostomia subjects used all three of GUM®HYDRAL™ Oral Rinse, placebo rinse, and Biotene® Oral Rinse as active control. Visual Analog Scale, a dry mouth questionnaire, Oral Health Impact Profile-14, unstimulated saliva flow rate (USFR), and Revised Oral Assessment Guide (ROAG) were assessed before and after 2 weeks of treatments. RESULTS: Thirty-seven patients completed all three treatment modalities. Subjective measurements were significantly decreased by test product and active control; however, no significant difference was observed between the treatments. Test product and active control demonstrated a significant increase in USFR over 0.2 ml/min, a normal threshold of hyposalivation. Both test product and active control improved a total score of ROAG, whereas the effectiveness of the test product was significantly better than that of other two treatments. CONCLUSIONS: The new oral rinse may be beneficial to improve the quality of life of xerostomia patients as dry mouth symptoms were reduced for both subjective and objective measurements. Test oral rinse was found to be more effective than placebo or active control for some of the objective measurements.

Toxicity and growth characteristics of epiphytic dinoflagellate Gambierdiscus silvae in Japan.

The genus Gambierdiscus is a marine benthic/epiphytic dinoflagellate that has been investigated worldwide as the causative agent of ciguatera poisoning (CP). In Japan, CP occurs mainly in the subtropical region and sporadically in the temperate region. To understand the mechanism of CP outbreaks in the coastal regions, identifying the species of Gambierdiscus occurring in the regions and determining their toxicity and growth characteristics, such as growth responses to temperature, salinity, and light intensity, are important. Recently, the occurrence of G. silvae in the Japanese temperate and subtropical regions has been revealed through metabarcoding. However, the toxicity and growth characteristics of G. silvae have not yet been investigated. In this study, three strains of Gambierdiscus were isolated from a depth of 30 m in subtropical waters in Japan and were identified as Gambierdiscus silvae based on morphological characteristics and phylogenetic positions. A dichloromethane soluble fraction (DSF) and aqueous methanol soluble fraction (MSF) of the three strains showed high mouse toxicity by intraperitoneal injection, but only the DSF of the three strains showed toxicity by gavage. All strains grew in the range of 17.5-30 °C and salinity range of 25-40, and grew well at 25 °C and salinity 30. The optimal light intensity for growth of the strains was 42.0-83.0 µmol photons/m2/s. These results suggest that G. silvae has the potential to be widely distributed from temperate to subtropical/ regions and in shallow to deep coastal waters of Japan. Understanding the growth characteristics of this species would be useful in predicting the occurrence of this species in Japanese coastal waters. Finally, the results obtained in this study suggest that G. silvae showing high toxicity is one of the causative agents of CP in Japan, and knowledge of this species would be useful in understanding the mechanism of CP outbreaks in Japan.

Association between the baseline tumor size and outcomes of patients with non-small cell lung cancer treated with first-line immune checkpoint inhibitor monotherapy or in combination with chemotherapy.

Background: The baseline tumor size (BTS) is a prognostic factor for patients with non-small cell lung cancer (NSCLC) who received immune checkpoint inhibitor monotherapy (ICI-mono). However, this relationship is not yet known in patients treated with ICI in combination with chemotherapy (ICI-chemo). Methods: This single-center retrospective study evaluated 159 patients with advanced NSCLC who received first-line ICI-mono or ICI-chemo from January 2016 to April 2021. Their BTS values were estimated using the maximum BTS (max BTS) (maximum target lesions' longest diameter) and total BTS (sum of target lesions' longest diameters) in a radiological assessment according to the Response Evaluation Criteria for Solid Tumors. Results: Based on a multivariable analysis, the large max BTS group had worse progression-free survival (PFS) in patients treated with ICI-mono (P=0.009), but it was not associated with worse PFS in patients treated with ICI-chemo (P=0.132). The group treated with ICI-mono had worse PFS compared to the group treated with ICI-chemo in patients with max BTS ≥50 mm (P=0.004), and the group treated with ICI-mono was not associated with worse PFS compared to the group treated with ICI-chemo in patients with max BTS <50 mm (P=0.107). Conclusions: While a large max BTS was identified as a prognostic factor for worse PFS in patients treated with ICI-mono, it was not identified as such in patients treated with ICI-chemo. The max BTS may have different predicting efficacy for patients with NSCLC treated with ICI-mono and ICI-chemo.

Uncommon EGFR mutations conducted with osimertinib in patients with NSCLC: a study protocol of phase 2 study (UNICORN/TCOG1901).

Patients with uncommon EGFR-mutated non-small-cell lung cancer (NSCLC) demonstrated lower clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors compared with patients harboring common EGFR-mutated NSCLC. The US FDA has approved afatinib for uncommon EGFR mutation positive NSCLC based on the pooled analysis in the first- or second-line setting. Osimertinib has limited evidence in the small sample sizes of phase 2 studies in any-line settings. The aim of the present single-arm, multicenter, phase 2 study is to evaluate the efficacy of osimertinib for previously untreated NSCLC. The primary end point is to assess the overall response to osimertinib. The secondary end points include disease control rate, progression-free survival, duration of time-to-treatment failure, overall survival and safety. Clinical trial registration: jRCTs071200002.

Lay abstract Tyrosine kinase inhibitor (TKI) medications are targeting EGFR work on the first-line treatment for patients with common EGFR mutation positive non-small-cell lung cancer (EGFR+ NSCLC) that has spread to other parts of the body and has the EGFR+ NSCLC in tumor testing. Uncommon EGFR mutations and compound EGFR mutations have less activity for first-generation EGFR-TKIs; however, second- or third-generation EGFR-TKIs are broader spectrum than first-generation EGFR-TKIs have activities ideally. The authors describe the need for and design a study of osimertinib in patients with uncommon/compound EGFR+ NSCLC.

An efficient method to screen for the soil bacteria producing therapeutically effective antibiotics.

The discovery of novel therapeutic antimicrobials has become an urgent issue in response to the global crisis of the spread of multi-drug-resistant bacteria. In this report, we propose an efficient screening method for antimicrobial agents with therapeutic potential from soil bacteria. With this method, colonies of the soil bacteria were formed first on agar plates containing only an extract of soil, followed by an overlay of soft agar containing the pathogens, an antibiotic target. Then, we selected the colonies that formed the inhibitory zones on soft agar and evaluated the therapeutic efficacy of their culture supernatants using a silkworm bacterial infection model. Using Staphylococcus aureus as an indicator strain to obtain bacteria that produce therapeutically effective antimicrobials, we succeeded in reducing the screening size by 20-fold compared to the conventional method. An analysis of 86 antibiotics producers identified in this study indicated that the majority belonged to Streptomyces sp. and Lysobacter sp., well-known producers of secondary metabolites. Besides, the presence of eight genera and 37 species among the identified species indicated the diversity of antibiotic producers. Based on the finding of our study, we propose this method as an efficient way to discover novel antimicrobial agents that are therapeutically effective.

Determination of optimal culture conditions for toxin production by a Prorocentrum lima complex strain with high diarrhetic shellfish toxins yield.

Diarrhetic shellfish poisoning (DSP) is caused by the consumption of shellfish contaminated by diarrhetic shellfish toxins (DSTs) such as okadaic acid (OA) and dinophysistoxins (DTXs) produced by some species of dinoflagellates. To prevent the occurrence of human intoxication cases, inspection of DSTs (OA and DTXs) in shellfish is important. An instrumental method using liquid chromatography-tandem mass spectrometry (LC/MS/MS) has been recently employed in Japan for the monitoring of OA and DTXs in shellfish. For such analysis, reference materials (RMs) of OA and DTXs are essential. Demand for the reference materials, especially dinophysistoxin-1 (DTX1), is recently increasing in Japan. Production of the materials has been performed by mass cultivation of a dinoflagellate (Prorocentrum lima) strain that produces DTXs and OA, which indicates that the efficiency of production depends on the toxin production of the strain used. In this study, P. lima complex subclade 1e strain MIO12P was determined to be a high DTX1 producer among the three Japanese strains of the P. lima complex (subclades 1e, 1f, and 1i). It was clarified that the culture medium suitable for toxin production by strain MIO12P was metals mix SWII medium, and the optimal temperature and salinity for toxin production were 25 °C and salinity 30, respectively. The DTX1 yield (1265.3 ng ml-1) of strain MIO12P cultured under the conditions described above was the highest reported worldwide. Prorocentrum lima complex subclade 1e strain MIO12P is expected to be useful for the sustainable production of DTX1 as a source of RMs for chemical and biochemical methods in the future.

A case series on the safety of immunotherapy with reduced blood testing frequency in lung cancer patients.

BACKGROUND: The necessity of regular blood tests with the administration of immune checkpoint inhibitors has not been investigated. This study examined the safety of omitting a blood test every 2 weeks for patients with lung cancer who were injected an immune checkpoint inhibitor. METHODS: We conducted a retrospective review of the medical records of 201 patients diagnosed with lung cancer and administered with nivolumab or durvalumab between December 1, 2015, and February 30, 2020, in a single hospital. We extracted 16 patients who had treatments without blood testing every 2 weeks. RESULTS: Adverse events that resulted in discontinued treatment included two cases of interstitial pneumonia, one case of creatinine increase, and one infection. All four cases were detected by chest X-ray or their symptoms. CONCLUSIONS: Our results indicate that immune checkpoint inhibitor administration without a blood test every 2 weeks did not subject patients to more adverse side effects.

Abundance of the benthic dinoflagellate Prorocentrum and the diversity, distribution, and diarrhetic shellfish toxin production of Prorocentrum lima complex and P. caipirignum in Japan.

In the present study, the abundance of Prorocentrum and the molecular phylogeny, distribution, and DST production of P. lima complex and P. caipirignum in Japan were investigated. First, the cell densities of Prorocentrum were assessed from the temperate to subtropical zones in Japan between 2014 and 2018. The cell density in the subtropical zone [19.0 ± 40.2 cells/g wet weight (ww) algae] was significantly higher than that in the temperate zone (1.4 ± 3.4 cells/g ww algae). A total of 244 clonal strains were established from the temperate and subtropical zones. Phylogenetic analyses based on the large-subunit ribosomal DNA D1/D2 revealed that the strains were separated into four species/species complex/phylotypes (P. lima complex, P. caipirignum, and new phylotypes Prorocentrum spp. types 1 and 2). The strains of P. lima complex could be separated into two clades (1 and 3). Furthermore, the strains of clades 1 and 3 could be separated into nine subclades (1a, 1c, 1d, 1e, 1f, 1g, 1h, 1i, and 1j) and three subclades (3a, 3b, and 3c), respectively. The strains of P. caipirignum were separated into two subclades (b and e). Each phylotype/subclade showed a unique distribution pattern in Japan: P. lima complex subclades 1a, 1c, and 3a and P. caipirignum subclades b and e were widespread from the temperate to subtropical zones. On the other hand, P. lima complex subclades 1e and 1i were restricted to the temperate zone, and P. lima complex subclades 1d, 1f, 1g, 1h, 1j, 3b, and 3c and Prorocentrum spp. types 1 and 2 were restricted to the subtropical zone. Furthermore, the DST production of the 243 clonal strains was assessed by LC/MS/MS analysis. The results revealed that all strains produced okadaic acid (OA) and that the OA contents of P. lima complex subclades 1d and 1f, P. caipirignum subclades b and e, and Prorocentrum sp. type 2 tended to be higher than those of the other subclades. While P. lima complex subclades 1a, 1e, 1f, and 1i produced DTX1, the other phylotype/subclades produced either no or low quantities of DTX1. A strain of P. lima complex subclade 1e showed the highest OA and DTX1 contents (55.27 and 70.73 pg/cell, respectively) in the world. These results suggest that there are potential risks for DST accumulation in benthic animals in Japan.

Impact of Diabetes Perceptions on Medication Adherence in Japan.

Background: Patients' perception of diabetes mellitus is one of the psychosocial factors influencing diabetic behavior. This patients' perception of the disease is a mental image formed from the experience of patients with type 2 diabetes mellitus and reportedly reflects the aspect of recuperation. We investigated the relationship between changes in the patients' perception of the disease and medication adherence, as influenced by the active involvement of community pharmacists. Methods: A prospective cohort study that used patient registry based in community pharmacies was conducted in patients with type 2 diabetes using oral antidiabetic agents at a pharmacy in Ishikawa Prefecture in Japan. Patients responded to the questionnaire at the time of enrollment and at the end of the one-year intervention period. The pharmacist confirmed the patient's medication status and treatment problems via telephone calls at least once every two weeks for one year. Main outcome measures: Type 2 diabetes patients' perception of the disease related to medication adherence. Results: The study enrolled 113 patients. Among the seven diabetes image factors, "Living an orderly life" and "Feeling of fear" were significantly associated with medication adherence. "Feeling of neglect of health" was significantly associated at the subscale level. Conclusion: All the three factors related to medication adherence indicated self-care ability. To enhance the self-care ability of the patient, pharmacists should assist in self-care interventions for the patients.

Correlation between the qualification for bevacizumab use and the survival of patients with non-small cell lung cancer harboring the epidermal growth factor receptor mutation: a retrospective analysis.

PURPOSE: Previously, the combination of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and bevacizumab (BEV) was investigated. A subgroup analysis of the IMpower150 trial, which investigated the combination of atezolizumab, carboplatin, paclitaxel, and bevacizumab (ABCP), demonstrated the benefit of ABCP in patients harboring EGFR mutations. This study aims to assess the prognostic significance of the qualification for BEV use and the proportion of patients who potentially benefit from BEV-containing combination therapy before and after initial EGFR-TKI treatment. METHODS: We retrospectively analyzed the data of 297 patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations who had received EGFR-TKIs. We performed statistical analyses using the Kaplan-Meier method and the Cox regression adjusted for risk factors. RESULTS: Of the 297 patients, 203 (68%) were eligible to receive BEV ("BEV fit") at the time of EGFR-TKI initiation. Among the "BEV unfit" patients at baseline (n = 70), 14 (20%) became eligible to receive ABCP ("ABCP fit") at the time of EGFR-TKI failure. The median overall survival (OS) of the "BEV fit" and "BEV unfit" patients was 26.2 [95% confidence interval (CI) 23.7-31.2] and 19.1 (95% CI 15.0-25.1) months, respectively (P < 0.001). The multivariate analysis revealed a marked correlation between survival and the qualification for BEV use. CONCLUSIONS: The qualification for BEV use at baseline is independently related to the OS. Some patients harboring EGFR mutations, including those who were "BEV unfit" at baseline, could be eligible for the ABCP regimen after EGFR-TKI treatment.

Development of Hepatocellular Carcinoma During Nivolumab Treatment for Recurrent Non-Small Cell Lung Cancer: A Case Report.

Nivolumab, a monoclonal antibody targeting programmed cell death 1 (PD-1), is the standard second-line therapy for advanced non-small cell lung cancer (NSCLC). In the current immunotherapy era, it is often difficult to evaluate the therapeutic effect, disease progression, and pseudo-enlargement of the tumor or the emergence of another etiology. In the present report, we describe a 79-year-old patient with hepatocellular carcinoma (HCC) newly detected during nivolumab treatment for recurrent NSCLC. When the patient was 73 years old, he had suffered from NSCLC and received concurrent chemoradiotherapy comprising cisplatin and docetaxel, achieving a complete response. Six years after the chemoradiotherapy, the patient had multiple lung and hepatic lesions. We thus started the treatment with nivolumab for recurrent NSCLC. All those lesions responded to nivolumab over nine cycles. By contrast, a lesion was newly detected in the medial segment of left hepatic lobe, liver segment 4 (S4), and was gradually getting larger, as judged by computed tomographic scan. Liver biopsy revealed the growing lesion to be a well-differentiated HCC. Consequently, the patient was treated with radiofrequency ablation to HCC, while nivolumab treatment was continued for NSCLC. Immunohistochemical analysis of the HCC specimens revealed nuclear accumulation of ß-catenin compared with normal liver cells and undetectable expression of program death ligand 1 (PD-L1). Such expression profiles of ß-catenin and PD-L1 in HCC may be responsible for the resistance against nivolumab treatment. Immunohistochemical features of the biopsy specimens may be predictive of the effectiveness of the immunotherapy in HCC.

The relationship between patients' perception of type 2 diabetes and medication adherence: a cross-sectional study in Japan.

BACKGROUND: The self-management of type 2 diabetes mellitus (T2DM), which involves adherence to medical instructions on diet and nutritional advice, physical activity, medication regimen, and weight and stress management, is necessary for the treatment of T2DM.In this study, we investigated the relationship between patients' perceptions of their disease and their adherence to their medications. And we attempted to determine whether distinct subphenotypes of behavioral change of medication adherence can be discerned based on a patients' perceptions. METHOD: A cross-sectional study using a questionnaire was conducted among 157 patients with T2DM from October 2015 to September 2017. Questionnaires were administered to assess the participants' demographic and clinical characteristics, medication adherence, diabetes knowledge, and perception of being diabetic. Principal component analysis (PCA) and cluster analyses were performed to classify medication adherence patterns in the total cohort. Multiple regression analyses were performed to identify the determinant factors of medication adherence. RESULTS: PCA showed the interpretable medication adherence of patients with diabetes by using component 1 ("accessibility to medical treatment") and component 2 ("status of taking medicines"). We identified four groups that show significantly different medication adherence by using cluster analysis on the basis of the two components. Multiple regression analysis showed that body mass index (BMI), family history of diabetes, one factor of patient's perception (living an orderly life), and diabetes knowledge were found to be significant predictors of medication adherence in patients with T2DM. CONCLUSIONS: In patients with T2DM, the patient's diabetes perception of "living an orderly life" is associated with medication adherence. A poor adherence group may be able to change their adherence to diabetes treatment by developing the perception of "living an orderly life."

Electrostatic interactions between middle domain motif-1 and the AAA1 module of the bacterial ClpB chaperone are essential for protein disaggregation.

ClpB, a bacterial homologue of heat shock protein 104 (Hsp104), can disentangle aggregated proteins with the help of the DnaK, a bacterial Hsp70, and its co-factors. As a member of the expanded superfamily of ATPases associated with diverse cellular activities (AAA+), ClpB forms a hexameric ring structure, with each protomer containing two AAA+ modules, AAA1 and AAA2. A long coiled-coil middle domain (MD) is present in the C-terminal region of the AAA1 and surrounds the main body of the ring. The MD is subdivided into two oppositely directed short coiled-coils, called motif-1 and motif-2. The MD represses the ATPase activity of ClpB, and this repression is reversed by the binding of DnaK to motif-2. To better understand how the MD regulates ClpB activity, here we investigated the roles of motif-1 in ClpB from Thermus thermophilus (TClpB). Using systematic alanine substitution of the conserved charged residues, we identified functionally important residues in motif-1, and using a photoreactive cross-linker and LC-MS/MS analysis, we further explored potential interacting residues. Moreover, we constructed TClpB mutants in which functionally important residues in motif-1 and in other candidate regions were substituted by oppositely charged residues. These analyses revealed that the intra-subunit pair Glu-401-Arg-532 and the inter-subunit pair Asp-404-Arg-180 are functionally important, electrostatically interacting pairs. Considering these structural findings, we conclude that the Glu-401-Arg-532 interaction shifts the equilibrium of the MD conformation to stabilize the activated form and that the Arg-180-Asp-404 interaction contributes to intersubunit signal transduction, essential for ClpB chaperone activities.

The Traditional Japanese Herbal Medicine Hachimijiogan Elicits Neurite Outgrowth Effects in PC12 Cells and Improves Cognitive in AD Model Rats via Phosphorylation of CREB.

Hachimijiogan (HJG) is a traditional herbal medicine that improves anxiety disorders in patients with dementia. In this study, we tested the hypothesis that HJG exerts neurotrophic factor-like effects to ameliorate memory impairment in Alzheimer disease (AD) model rats. First, we describe that HJG acts to induce neurite outgrowth in PC12 cells (a rat pheochromocytoma cell line) like nerve growth factor (NGF) in a concentration-dependent manner (3 µg/ml HJG, p < 0.05; 10-500 µg/ml HJG, p < 0.001). While six herbal constituents of HJG, Rehmannia root, Dioscorea rhizome, Rhizoma Alismatis, Poria sclerotium, Moutan bark, and Cinnamon bark, could induce neurite outgrowth effects, the effect was strongest with HJG (500 µg/ml). Second, we demonstrated that HJG-induced neurite outgrowth was blocked by an inhibitor of cAMP response element binding protein (CREB), KG-501 (10 µM, p < 0.001). Moreover, HJG was observed to induce CREB phosphorylation 20-90 min after treatment (20 min, 2.50 ± 0.58-fold) and CRE-mediated transcription in cultured PC12 cells (500 µg/ml, p < 0.01; 1000 µg/ml, p < 0.001). These results suggest a CREB-dependent mechanism underlies the neurotrophic effects of HJG. Finally, we examined improvements of memory impairment following HJG treatment using a Morris water maze in AD model animals (CI + Aß rats). Repeated oral administration of HJG improved memory impairment (300 mg/kg, p < 0.05; 1000 mg/kg, p < 0.001) and induced CREB phosphorylation within the hippocampus (1000 mg/kg, p < 0.01). Together, our results suggest that HJG possesses neurotrophic effects similar to those of NGF, and can ameliorate cognitive dysfunction in a rat dementia model via CREB activation. Thus, HJG could potentially be a substitute for neurotrophic factors as a treatment for dementia.