Identification of tryptophanase from Escherichia coli for the synthesis of S-allyl-l-cysteine and related S-substituted cysteine derivatives.

A wide variety of S-substituted cysteine derivatives occur in plant metabolites. For example, S-allyl-l-cysteine (SAC), mainly contained in garlic, gathers huge interest because of its favorable bioactivities for human health. However, conventional methods for preparing SAC suffer from several drawbacks with regard to efficiency and toxicity, which highlights the need for improved processes for SAC synthesis. This study aims to develop a novel bioprocess to produce SAC by microbial enzymes from easily available substrates. We found that Escherichia coli had the ability to synthesize SAC from allyl mercaptan, pyruvic acid, and ammonium sulfate. An enzyme purification through 3-step column chromatography, followed by determination of the N-terminal amino acid sequence revealed that tryptophanase (TnaA) was the enzyme responsible for SAC formation. Although the enzyme catalyzed the reversible reaction for synthesizing and degrading SAC, the degradation proceeded significantly faster than the synthesis. Interestingly, TnaA catalyzed the synthesis of a wide range of S-substituted cysteines with alkyl chains or aromatic rings, some of which are present in Allium and Petiveria plants. Our results showed a novel substrate specificity of TnaA toward various S-substituted cysteine. TnaA is a promising biocatalyst for developing a new process to supply various valuable S-substituted cysteine derivatives for medicinal and health-promoting applications.

Sox17-mediated expression of adherent molecules is required for the maintenance of undifferentiated hematopoietic cluster formation in midgestation mouse embryos.

Hematopoietic stem cell-containing intra-aortic hematopoietic cell clusters (IAHCs) emerge in the dorsal aorta of the aorta-gonad-mesonephros (AGM) region during midgestation mouse embryos. We previously showed that transduction of Sox17 in CD45lowc-Kithigh cells, which are one component of IAHCs, maintained the cluster formation and the undifferentiated state, but the mechanism of the cluster formation by Sox17 has not been clarified. By microarray gene expression analysis, we found that genes for vascular endothelial-cadherin (VE-cad) and endothelial cell-selective adhesion molecule (ESAM) were expressed at high levels in Sox17-transduced c-Kit+ cells. Here we show the functional role of these adhesion molecules in the formation of IAHCs and the maintenance of the undifferentiated state by in vitro experiments. We detected VE-cad and ESAM expression in endothelial cells of dorsal aorta and IAHCs in E10.5 embryos by whole mount immunohistochemistry. Cells with the middle expression level of VE-cad and the low expression level of ESAM had the highest colony-forming ability. Tamoxifen-dependent nuclear translocation of Sox17-ERT fusion protein induced the formation of cell clusters and the expression of Cdh5 (VE-cad) and ESAM genes. We showed the induction of the Cdh5 (VE-cad) and ESAM expression and the direct interaction of Sox17 with their promoter by luciferase assay and chromatin immunoprecipitation assay, respectively. Moreover, shRNA-mediated knockdown of either Cdh5 (VE-cad) or ESAM gene in Sox17-transduced cells decreased the multilineage-colony forming potential. These findings suggest that VE-cad and ESAM play an important role in the high hematopoietic activity of IAHCs and cluster formation.

A phase 2 study of adjuvant carboplatin plus S-1 followed by maintenance S-1 therapy for patients with completely resected stage II/IIIA non-small cell lung cancer-Japanese Northern East Area Thoracic Surgery Study Group JNETS1302 study.

BACKGROUND: The standard adjuvant chemotherapy regimen for completely resected pathological stage II/IIIA non-small cell lung cancer (NSCLC) is four courses of cisplatin plus vinorelbine. However, the continuity and toxicity of cisplatin-based regimens remain problematic. Conversely, carboplatin-based chemotherapy is a less toxic and more tolerable regimen for various stages of NSCLC. In particular, the efficacy and tolerability of carboplatin plus S-1 in advanced NSCLC were confirmed by previous pivotal studies such as the LETS trail. Therefore, this phase II study assessed the feasibility, safety, and usefulness of carboplatin plus S-1 followed by maintenance S-1 as an adjuvant treatment. METHODS: In this single-arm, multicenter phase II study, 40 patients who previously underwent complete resection of NSCLC were enrolled from November 2013 to January 2015. The chemotherapy protocol was four cycles of carboplatin (AUC 5 on day 1) and oral S-1 (80 mg/m2 every other day from days 1 to 21) followed by oral S-1 (80 mg/m2 every other day for 48 weeks). The primary endpoint was the treatment completion rate, and the secondary endpoints were adverse events and 2-year recurrence-free survival. RESULTS: The treatment completion rate of the planned schedule was as low as 30.0% (90% confidence interval: 40.3-63.0%). The reasons for adjuvant chemotherapy discontinuation were adverse events, refusal, tumor recurrence, and other reasons in 13, 6, 10, and 2 patients, respectively. The 2-year progression-free survival rate was 66.7% among patients who completed maintenance chemotherapy. There were no treatment-related deaths, and most adverse events were less than grade 3. CONCLUSIONS: Carboplatin plus S-1 followed by S-1 maintenance for 1 year in the adjuvant treatment of NSCLC was not tolerable, although most adverse events were not severe. However, patients who can fully complete the regimen might experience clinical benefit.

Clinicopathological features of intraoperative pleural lavage cytology for non-small cell lung cancer.

OBJECTIVE: The significance of clinicopathological features of pre- and post-resection pleural lavage cytology (PLC) for non-small cell lung carcinoma (NSCLC) currently remains unknown. METHODS: Between January 2010 and December 2012, pre- and post-resection PLC were performed for NSCLC in 565 patients at Tohoku University, Miyagi Cancer Center, or Sendai Medical Center. The relationship between the clinicopathological features and patient outcomes was analyzed. RESULTS: Twenty-two patients (3.9%) had positive findings from pre- or post-resection PLC. Both PLC were correlated with pT and pl factors, while only post-resection PLC was correlated with pN factor (p < 0.005). The 5-year disease-free survival (DFS) rate of the positive pre-resection PLC was significantly poorer than that of negative (26.7% vs. 76.9%, p < 0.0001). In addition, the 5-year DFS of the positive post-resection PLC was also poorer than that of negative (14.3% vs. 76.0%, p < 0.0001). Multivariate analyses revealed that both PLC were not independent prognostic factors in our study. CONCLUSIONS: A significant association of post-resection PLC with N factor is considered to be characteristics of post-resection PLC different from pre-resection PLC. A prognostic impact of post-resection PLC and its detailed difference from pre-resection PLC should be clarified by further investigations.

CD271 is a negative prognostic factor and essential for cell proliferation in lung squamous cell carcinoma.

Squamous cell carcinoma is a major type of cancer in the lung. While several therapeutic target molecules for lung adenocarcinoma have been identified, little is known about lung squamous cell carcinoma (LSCC). We recently reported that CD271 (p75 neurotrophin receptor) serves as a marker for tumor initiation and is a key regulator of cell proliferation in hypopharyngeal squamous cell carcinoma. In this study, we found that CD271 was also expressed in squamous cell carcinoma, but not in adenocarcinoma, of several tissues, including the lung, and the expression of CD271 was associated with a poor prognosis in LSCC. To examine CD271's role in LSCC, we established xenograft cell lines from LSCC patients. Within the sorted live LSCC cell population, the CD271high cells were primarily cycling through the G2/M phase, while the CD271low cells were mostly in the G0 phase. CD271 knockdown in the LSCC cells completely suppressed their proliferation and tumor-formation capability, and increased their cell-cycle arrest in the G0 phase. In the CD271-knockdown cells, ERK-phosphorylation was decreased, while no change was observed in the IκBα-phosphorylation, p65-phosphorylation, or Akt-phosphorylation. Treatment with the MEK inhibitor U0126 decreased the LSCC cells' proliferation capability. Microarray analysis revealed that CD271 knockdown attenuated the RAS-related pathways. The knockdown of TrkB, which forms a heterodimer with CD271 and accelerates its downstream signaling, partially inhibited the LSCC cell proliferation. These results indicated that LSCC exclusively depends on CD271 for cell proliferation, in part through ERK-signaling activation, and CD271 is a promising target for LSCC therapy.

Association between Family History of Cancer and Lung Cancer Risk among Japanese Men and Women.

Although cigarette smoking is a major risk factor for lung cancer, genetic susceptibility may also affect lung cancer risk. To explore the role of genetic risk, this case-control study investigated the association between family history of cancer at several sites and lung cancer risk. A total of 1,733 lung cancer cases and 6,643 controls were selected from patients aged 30 years and over admitted to a single hospital in Japan between 1997 and 2009. Information on family history of cancer was collected using a self-administered questionnaire and odds ratios (ORs) were estimated by unconditional logistic regression. Family history of lung cancer in first-degree relatives was associated with an increased risk of lung cancer among both sexes. According to histology and type of relatives, a parental history of lung cancer was significantly associated with an increased risk of female adenocarcinoma (OR = 1.72). Stratification by smoking status revealed that this significant positive association in women was limited to ever-smokers (OR = 4.13). In men, a history of lung cancer in siblings was significantly associated with an increased risk of small cell carcinoma (OR = 2.28) and adenocarcinoma (OR = 2.25). Otherwise, positive associations between history of breast (OR = 1.99) and total (OR = 1.71) cancers in siblings and the risk of male adenocarcinoma were observed. These results suggest that inherited genetic susceptibility may contribute to the development of lung cancer. In men, shared exposure to environmental factors among siblings may also be responsible for the increase in lung cancer risk.

Longitudinal Factors Associated With Increased Alcohol and Tobacco Use in Fukushima Nuclear Power Plant Workers 32 Months After the Nuclear Disaster: The Fukushima News Project Study.

OBJECTIVES: The aim of this study was to predict increased alcohol and tobacco use in Fukushima nuclear power plant (NPP) workers 3 years after a nuclear disaster. METHODS: Surveys were conducted in two postdisaster waves (Wave 1: 2 to 3 months; Wave 2: 32 months). Adjusted risk ratio (aRR) was computed to assess the covariates of increased alcohol and tobacco use in Wave 2. RESULTS: Increased alcohol use was associated with age of 29 years or less [aRR (95% confidence interval (95% CI): 1.26 (1.01 to 1.57)], major property loss [1.25 (95% CI 1.02 to 1.55)], and high posttraumatic stress responses (PTSRs) [1.34 (95% CI 1.08 to 1.67)] in Wave 1. Increased tobacco use was associated with age of 29 years or less [1.46 (95% CI 1.12 to 1.90)] and high PTSR [1.62 (95% CI 1.25 to 2.10)] in Wave 1 (P < 0.05). CONCLUSION: The workers' increased alcohol and tobacco use were predicted by major property loss (alcohol), age of 29 years or less, and high PTSR (alcohol/tobacco) in Wave 1.

S100A10 upregulation associates with poor prognosis in lung squamous cell carcinoma.

S100A10 is one of the members of the S100 protein family and is a key plasminogen receptor. Its upregulation has been reported in many types of tumors. In lung cancer, an association between upregulation of S100A10 and poor prognoses has been reported only in adenocarcinoma. We pursued the possibility of significance in lung squamous cell carcinoma (SCC). We first examined S100A10 protein expression by immunohistochemistry in 120 primary resected lung SCCs; 33 (27.5%) tumors showed strong membranous-immunopositivity particularly at the invasive front, i.e., the cancer-cell surface in contact with the stroma. Expression levels were significantly associated with higher pathological TNM stage (P = 0.0119), tumor size (P = 0.0003), lymphatic invasion (P = 0.0005), lymph node metastasis (P = 0.0006), and poorer prognosis (P = 0.0064). Our present results suggest that high S100A10 expression of the lung SCC cells, particularly adjacent to stroma, plays an important role in tumor progression, probably caused by lymphatic invasion and nodal metastasis.

Periostin is a negative prognostic factor and promotes cancer cell proliferation in non-small cell lung cancer.

Periostin is a matricellular protein that is secreted by fibroblasts and interacts with various cell-surface integrin molecules. Although periostin is known to support tumor development in human malignancies, little is known about its effect on lung-cancer progression. We here demonstrate that periostin is a negative prognostic factor that increases tumor proliferation through ERK signaling in non-small cell lung carcinoma. We classified 189 clinical specimens from patients with non-small cell lung-cancer according to high or low periostin expression, and found a better prognosis for patients with low rather than high periostin, even in cases of advanced-stage cancer. In a syngenic implantation model, murine Ex3LL lung-cancer cells formed smaller tumor nodules in periostin-/- mice than in periostin+/+ mice, both at the primary site and at metastatic lung sites. An in vitro proliferation assay showed that stimulation with recombinant periostin increased Ex3LL-cell proliferation. We also found that periostin promotes ERK phosphorylation, but not Akt or FAK activation. These findings suggest that periostin represents a potential target in lung-cancer tumor progression.

Preoperative bronchoscopic cancer confirmation does not increase risk of recurrence in stage1A non-small cell lung cancer.

OBJECTIVE: This study was conducted to evaluate the risk of recurrence possibly caused by preoperative bronchoscopic cancer confirmation in stage1A non-small cell lung cancer. METHODS: One hundred and seventy-nine cases of peripheral non-small cell lung cancer (including 151 adenocarcinoma) with no more than 3 cm in their tumor longer diameter were selected. All patients underwent preoperative diagnostic bronchoscopy followed by lobectomy, and were demonstrated to have pathologically free of lymph node involvement and pleural involvement. Radiological and pathological low-grade adenocarcinomas were excluded. Of 179 cases, 95 were confirmed lung cancer by bronchoscope (Group 1) and rest 84 had failed cancer confirmation by bronchoscope before surgery (Group 2). Forty-eight pairs for non-small cell lung cancer and 41 pairs for adenocarcinoma were identified from each group by propensity caliper matching. Kaplan-Meier method and log-rank test were performed on matched groups, and Cox proportional hazard model analysis was performed on whole matched cases. RESULTS: Log-rank test revealed no significant inferiority of recurrence-free survival of Group 1 in both all-NSCLC and adenocarcinoma subset. Cox proportional hazard model analysis also revealed that the 'presence of preoperative bronchoscopic cancer confirmation' dose not increase risk of recurrence in both NSCLC and adenocarcinoma subset. CONCLUSIONS: It is unlikely that preoperative bronchoscopic cancer confirmation would increase recurrence risk in stage1A non-small cell lung cancer; however, a future prospective study with larger cohorts would be warranted to validate the results.

Relationships among personality traits, metabolic syndrome, and metabolic syndrome scores: The Kakegawa cohort study.

OBJECTIVE: Metabolic syndrome and the presence of metabolic syndrome components are risk factors for cardiovascular disease (CVD). However, the association between personality traits and metabolic syndrome remains controversial, and few studies have been conducted in East Asian populations. METHODS: We measured personality traits using the Japanese version of the Eysenck Personality Questionnaire (Revised Short Form) and five metabolic syndrome components-elevated waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose-in 1322 participants aged 51.1±12.7years old from Kakegawa city, Japan. Metabolic syndrome score (MS score) was defined as the number of metabolic syndrome components present, and metabolic syndrome as having the MS score of 3 or higher. We performed multiple logistic regression analyses to examine the relationship between personality traits and metabolic syndrome components and multiple regression analyses to examine the relationship between personality traits and MS scores adjusted for age, sex, education, income, smoking status, alcohol use, and family history of CVD and diabetes mellitus. We also examine the relationship between personality traits and metabolic syndrome presence by multiple logistic regression analyses. RESULTS: "Extraversion" scores were higher in those with metabolic syndrome components (elevated waist circumference: P=0.001; elevated triglycerides: P=0.01; elevated blood pressure: P=0.004; elevated fasting glucose: P=0.002). "Extraversion" was associated with the MS score (coefficient=0.12, P=0.0003). No personality trait was significantly associated with the presence of metabolic syndrome. CONCLUSIONS: Higher "extraversion" scores were related to higher MS scores, but no personality trait was significantly associated with the presence of metabolic syndrome.

Epidermal Growth Factor Receptor Mutation as a Risk Factor for Recurrence in Lung Adenocarcinoma.

BACKGROUND: The presence of epidermal growth factor receptor (EGFR) mutations is an established prognostic factor for patients with advanced lung adenocarcinoma. Here, we examined whether EGFR mutation status is a prognostic factor for patients who had undergone surgery. METHODS: Clinicopathologic data from 1,463 patients who underwent complete surgical resection for lung adenocarcinoma between 2005 and 2012 were collected. Differences in postoperative recurrence-free survival and overall survival according to EGFR mutation status were evaluated. RESULTS: Of 835 eligible patients, the numbers of patients with wild-type EGFR (WT), exon 19 deletion (Ex19), and exon 21 L858R (Ex21) were 426, 175, and 234, respectively. Patients with Ex19 had a significantly higher incidence of extrathoracic recurrence than patients with Ex21 (p = 0.004). The 5-year recurrence-free survival rates for patients with WT, Ex19, and Ex21 were 63.0%, 67.5%, and 78.2%, respectively. The Ex21 group had a significantly longer recurrence-free survival than the WT group (p < 0.001) and the Ex19 group (p = 0.016). The 5-year overall survival for patients with WT, Ex19, and Ex21 were 76.9%, 86.5%, and 87.5%, respectively. Patients with Ex19 and Ex21 had a significantly longer overall survival than patients with WT (Ex19, p = 0.009; Ex21, p < 0.001). Multivariate analysis for recurrence-free survival showed that Ex19 was significantly associated with a worse prognosis than Ex21 (p = 0.019). CONCLUSIONS: Patients with Ex19 had significantly shorter recurrence-free survival and had extrathoracic recurrence more frequently than patients with Ex21 among patients with resected lung adenocarcinoma, implying that Ex19 could be a worse prognostic factor.

Maintenance of hematopoietic stem and progenitor cells in fetal intra-aortic hematopoietic clusters by the Sox17-Notch1-Hes1 axis.

The aorta-gonad-mesonephros region, from which definitive hematopoiesis first arises in midgestation mouse embryos, has intra-aortic hematopoietic clusters (IAHCs) containing hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). We previously reported expression of the transcription factor Sox17 in IAHCs, and overexpression of Sox17 in CD45lowc-KIThigh cells comprising IAHCs maintains the formation of cell clusters and their multipotency in vitro over multiple passages. Here, we demonstrate the importance of NOTCH1 in IAHC formation and maintenance of the HSC/HPC phenotype. We further show that Notch1 expression is positively regulated by SOX17 via direct binding to its gene promoter. SOX17 and NOTCH1 were both found to be expressed in vivo in cells of IAHCs by whole mount immunostaining. We found that cells transduced with the active form of NOTCH1 or its downstream target, Hes1, maintained their multipotent colony-forming capacity in semisolid medium. Moreover, cells stimulated by NOTCH1 ligand, Jagged1, or Delta-like protein 1, had the capacity to form multilineage colonies. Conversely, knockdown of Notch1 and Hes1 led to a reduction of their multipotent colony-forming capacity. These results suggest that the Sox17-Notch1-Hes1 pathway is critical for maintaining the undifferentiated state of IAHCs.

New nucleoside hydrolase with transribosylation activity from Agromyces sp. MM-1 and its application for enzymatic synthesis of 2'-O-methylribonucleosides.

Microorganisms were screened for transribosylation activity between 2'-O-methyluridine (2'-OMe-UR) and nucleobases, for the purpose of developing a biotransformation process to synthesize 2'-O-methylribonucleosides (2'-OMe-NRs), which are raw materials for nucleic acid drugs. An actinomycete, Agromyces sp. MM-1 was found to produce 2'-O-methyladenosine (2'-OMe-AR) when whole cells were used in a reaction mixture containing 2'-OMe-UR and adenine. The enzyme responsible for the transribosylation was partially purified from Agromyces sp. MM-1 cells through a six-step separation procedure, and identified as a nucleoside hydrolase family enzyme termed AgNH. AgNH was a bi-functional enzyme catalyzing both hydrolysis towards 2'-OMe-NRs and transribosylation between 2'-OMe-UR and various nucleobases as well as adenine. In the hydrolysis reaction, AgNH preferred guanosine analogues as its substrates. In the transribosylation reaction, AgNH showed strong activity towards 6-chloroguanine, with 25-fold relative activity when adenine was used as the acceptor substrate. The transribosylation reaction product from 2'-OMe-UR and 6-chloroguanine was determined to 2'-O-methyl-6-chloroguanosine (2'-OMe-6ClGR). Under the optimal conditions, the maximum molar yield of 2'-OMe-6ClGR reached 2.3% in a 293-h reaction, corresponding to 440 mg/L.

Predição de risco de lesão por pressão em pacientes de unidade de terapia intensiva: revisão integrativa / Predicción de riesgo de lesión por presión en pacientes de unidad de terapia intensiva: revisión integrativa / Pressure injury risk prediction in critical care patients: an integrative review

RESUMO Objetivo: identificar os instrumentos que são utilizados para avaliar o risco de lesão por pressão em pacientes críticos adultos de unidade de terapia intensiva e analisar a capacidade preditiva dos mesmos. Método: revisão integrativa observando-se os critérios para seleção dos estudos: avaliação do risco de lesão por pressão em pacientes internados em unidade de terapia intensiva de adultos por meio de escala ou índice; mensuração da capacidade preditiva do instrumento aplicado; idiomas inglês, português ou espanhol; período entre 1962 e 2016. Os descritores utilizados foram: pressure ulcer ou pressure sores e risk assessment. As variáveis de interesse foram: sensibilidade, especificidade, valor preditivo positivo, valor preditivo negativo e área sob a curva receiver operator characteristic. Resultados: : foram identificadas 1032 publicações e deste total foram selecionados 13 estudos para análise. A predição do risco para lesão por pressão foi mensurada unicamente com escalas genéricas em sete dos 13 estudos. Nos estudos comparativos de escalas específicas de unidade de terapia intensiva com escalas genéricas, o valor preditivo negativo foi elevado e todos com área da curva receiver operator characteristic com valores acima de 0,700. Entre as escalas genéricas predominou a escala de Braden. Foram identificadas seis escalas que apresentaram boa capacidade preditiva para avaliar risco de lesão por pressão em pacientes de unidade de terapia intensiva. Conclusão: : esta revisão revelou uma variedade de escalas preditivas, genéricas e específicas, que são utilizadas para avaliação de risco de lesão por pressão no paciente de unidade de terapia intensiva.

RESUMEN Objetivo identificar los instrumentos que se utilizan para evaluar el riesgo de lesión por presión en pacientes críticos adultos de unidad de terapia intensiva y analizar la capacidad predictiva de los mismos. Método revisión integrativa observándose los criterios para la selección de los estudios: evaluación del riesgo de lesión por presión en pacientes internados en unidad de terapia intensiva de adultos por medio de escala o índice; medición de la capacidad predictiva del instrumento aplicado; idiomas Inglés, portugués o español; período entre 1962 y 2016. Los descriptores utilizados fueron: pressure ulcer o pressure sores y risk assessment. Las variables de interés fueron: sensibilidad, especificidad, valor predictivo positivo, valor predictivo negativo y área bajo la curva receptor operador. Resultados se identificaron 1032 publicaciones y de este total se seleccionaron 13 estudios para análisis. La predicción del riesgo para la lesión por presión se midió únicamente con escalas genéricas en siete de los 13 estudios. En los estudios comparativos de escalas específicas de unidad de terapia intensiva con escalas genéricas, el valor predictivo negativo fue elevado y todos con área de la curva receptor operator con valores por encima de 0,700. Entre las escalas genéricas predominó la escala de Braden. Se identificaron seis escalas que presentaron buena capacidad predictiva para evaluar riesgo de lesión por presión en pacientes de unidad de terapia intensiva. Conclusión esta revisión reveló una variedad de escalas predictivas, genéricas y específicas, que se utilizan para evaluar el riesgo de lesión por presión en el paciente de unidad de terapia intensiva.

ABSTRACT Objective: to identify instruments used to assess pressure injury risk in adult critically ill patients in an intensive care unit and analyze their predictive capacity. Method: an integrative review was carried out, observing the following criteria for study selection: pressure injury risk assessment in patients hospitalized in adult intensive care units by means of a scale or index; predictive capacity measurement of the instrument used; English, Portuguese, or Spanish languages; period between 1962 and 2016. The descriptors used were: pressure ulcer or pressure sores and risk assessment. The variables of interest were: sensitivity; specificity; positive predictive value; negative predictive value; and area under the receiver operating characteristic curve. Results: a total of 1,032 publications were identified, of which 13 studies were selected for analysis. Pressure injury risk prediction was only measured with generic scales in seven of the 13 studies. In the comparative studies of intensive care unit specific scales with generic scales, the negative predictive value was high and they all presented an area of receiver operating characteristic curve with values higher than 0.700. There was a prevalence of the Braden scale among generic scales. Six scales that presented good predictive capacity to assess pressure injury risk in intensive care patients were identified. Conclusion: the present review showed a range of predictive, generic, and specific scales used for pressure injury risk assessment in intensive care unit patients.

Matched-pair analysis of a multi-institutional cohort reveals that epidermal growth factor receptor mutation is not a risk factor for postoperative recurrence of lung adenocarcinoma.

OBJECTIVE: It is unclear whether epidermal growth factor receptor (EGFR) mutation status is a risk factor for postoperative recurrence of surgically resected lung adenocarcinoma (ADC). Therefore, we conducted a multi-institutional study employing matched-pair analysis to compare recurrence-free survival (RFS) and overall survival (OS) of patients with lung ADC according to EGFR mutation status. METHODS: We collected the records of 909 patients who underwent surgical resection for lung ADC between 2005 and 2012 at five participating institutions and were also examined their EGFR mutation status. For each patient with an EGFR mutation, we selected one with the wild-type EGFR sequence and matched them according to institution, age, gender, smoking history, pathological stage (pStage), and adjuvant treatment. We compared RFS and OS of the matched cohort. RESULTS: The patients were allocated into groups (n=181 each) with mutated or wild-type EGFR sequences. Both cohorts had identical characteristics as follows: institution, median age (68 years), men (85, 47%), ever smokers (77, 43%), and pStage (IA, 108, 60%; IB, 48, 27%; II, 14, 8%; III, 11, 6%). The 3- and 5-year RFS rates of patients with mutated or wild-type EGFR sequence were 79%, 68% and 77%, 68%, respectively (p=0.557). The respective OS rates were 92%, 81%, and 89%, 79% (p=0.574). CONCLUSION: Matched-pair and multi-institutional analysis reveals that an EGFR mutation was not a significant risk factor for recurrence of patients with surgically resected lung adenocarcinoma.

Enzymatic synthesis of 2'-O-methylribonucleosides with a nucleoside hydrolase family enzyme from Lactobacillus buchneri LBK78.

2'-O-Methylribonucleosides (2'-OMe-NRs) are promising raw materials for the production of nucleic acid drugs. We previously reported that LbNH, a nucleoside hydrolase from Lactobacillus buchneri LBK78 (NITE P-01581), was the first enzyme found to act on 2'-OMe-NRs. In the present study, we determined that LbNH also has the transribosylation activity between 2'-OMe-NRs and nucleobases, in addition to the hydrolyzing activity towards 2'-OMe-NRs. When 2'-O-methyluridine (2'-OMe-UR) and adenine were reacted with LbNH, 2'-O-methyladenosine (2'-OMe-AR) was produced. LbNH preferred purine nucleobases as its acceptor substrates for the transribosylation with 2'-OMe-UR as a donor substrate. Kinetic analysis of LbNH revealed that adenine behaved as a mixed inhibitor of the hydrolysis of 2'-OMe-UR. Under the optimal reaction conditions, the maximum molar yield of enzymatic 2'-OMe-AR produced reached 0.97% towards 2'-OMe-UR, corresponding to 0.16 g/L.

Ex vivo model of non-small cell lung cancer using mouse lung epithelial cells.

Lung cancer is the most common cause of cancer mortality, however, efficient methods to culture, expand and transform lung epithelial (LE) cells have not been established. In the present study, an efficient ex vivo method was applied to recapitulate lung carcinogenesis using mouse LE cells. A Matrigel-assisted three-dimensional culture was used to isolate and selectively expand LE cells from mouse lungs. Purified LE cells were passaged and expanded for at least 2 to 3 months while maintaining epidermal growth factor-dependence. LE cells were also easily transformed by genetic manipulations using retroviral vectors. A SV40 large-T antigen, suppressing p53 and pRB, plus an activated oncogene, such as KrasG12V or EGFRex19del, were required to transform LE cells. Transformed cells formed tumors resembling non-small cell lung cancer (NSCLC) in allograft models and exhibited strong oncogene addiction. This experimental system provided a unique model system to study lung tumorigenesis and develop novel therapeutics against NSCLC.

Nivolumab-Induced Severe Akathisia in an Advanced Lung Cancer Patient.

BACKGROUND Nivolumab is an anti-PD-1 immune checkpoint inhibitor that was recently developed for cancer immunotherapy. In the clinical trials of nivolumab, its adverse effects were reported to be less likely than those of conventional anti-cancer agents; however, after practical clinical distribution, it has come to be known that nivolumab induces various immune-related adverse events. CASE REPORT A 58-year-old male with a recurrence of lung adenocarcinoma was treated with nivolumab. Only four days after the initial administration of nivolumab, the patient presented with unbearable restlessness and distress that was resistant to all therapeutic agents used, and it gradually became worse. He finally came to need deep sedation despite his cancer status being stable during the course. Clinical tests including magnetic resonance imaging, cerebrospinal fluid cytology, and antibodies of paraneoplastic syndrome exhibited no signs of encephalitis or another possible cause of the neuropathy. The diagnosis of akathisia could be made only by his somatoform presentation. It was uncertain whether or not this complication was correlated with the activation of his immune system. CONCLUSIONS Anti-immune check point inhibitors may induce many unknown adverse events. Severe akathisia induced by nivolumab, as in our case, has not been reported yet. Collecting every adverse event of nivolumab may be important to make a better algorithm to manage its huge variety of complications.

Mixed squamous cell and glandular papilloma of the lung resembling early adenocarcinoma: A case report.

INTRODUCTION: An extremely rare case of mixed squamous cell and glandular papilloma of the lung is reported. The correlation between the radiological and the pathological features as well as the clinical pitfall in making a diagnosis is discussed. PRESENTATION OF CASE: An asymptomatic 68-year-old female with a cigarette smoking habit presented with a small nodule in her peripheral lung. A wedge resection was performed though it failed on-site diagnosis which was instead obtained following pathological scrutiny. The postsurgical course was excellent with no recurrence of disease. DISCUSSION: A small ground glass nodule gradually enlarged and transformed to a partially solid nodule a year and a half later. This transformation falsely made us suspect an early adenocarcinoma development. Eventually, the extremely rare subtype of pulmonary papilloma, with biphasic glandular and squamous cells, had been demonstrated to obstruct the peripheral bronchiole; and the adjoining alveoli had filled with a large volume of mucus. These pathological features seemed to have constituted the inner solid portion and the marginal ground glass portion respectively in the CT images, mimicking invasive lepidic adenocarcinoma. CONCLUSION: Both pre- and intra-operative diagnoses are difficult mainly because of the rareness of the disease, however, mixed squamous cell and glandular papilloma may be considered in case the presence of primary adenocarcinoma is not validated.