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Myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2) proteins are promising targets for cancer therapy. Here, we investigated the structure–activity relationships (SARs) and performed molecular docking analysis of renieramycin T (RT) and its analogues and identified the critical functional groups of Mcl-1 targeting. RT have a potent anti-cancer activity against several lung cancer cells and drug-resistant primary cancer cells. RT mediated apoptosis through Mcl-1 suppression and it also reduced the level of Bcl-2 in primary cells. For SAR study, five analogues of RT were synthesized and tested for their anti-cancer and Mcl-1- and Bcl-2-targeting effects. Only two of them (TM-(–)-18 and TM-(–)-4a) exerted anti-cancer activities with the loss of Mcl-1 and partly reduced Bcl-2, while the other analogues had no such effects. Specific cyanide and benzene ring parts of RT’s structure were identified to be critical for its Mcl-1-targeting activity. Computational molecular docking indicated that RT, TM-(–)-18, and TM-(–)-4a bound to Mcl-1 with high affinity, whereas TM-(–)-45, a compound with a benzene ring but no cyanide for comparison, showed the lowest binding affinity. As Mcl-1 helps cancer cells evading apoptosis, these data encourage further development of RT compounds as well as the design of novel drugs for treating Mcl-1-driven cancers.

In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer‐related oncogenes using next‐generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation. For patients with multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). In this research, we carried out targeted sequencing of 20 lung cancer‐related genes using next‐generation sequencing (NGS) for MLC patients and compared the histopathological diagnosis and the mutational diagnosis. Our results suggest that multiplex mutational analysis of MLC could be a useful complementary tool for distinguishing between MP and IM.

Surgery for intertrochanteric fractures using intramedullary hip nails (IHNs) is among the most common surgical procedures in the orthopedic field. Although IHNs provide good overall outcomes, they sometimes cause complications, such as loss of reduction and cut-out. Here, we investigated the usefulness of IHNs with an anterior offset (Best Fit Nail® [BFN]) in maintaining fragment reduction and ensuring proper lag screw position compared with conventional non-offset nails (Proximal Femoral Nail Antirotation® [PFNA]), using postoperative computed tomography (CT). Fifty consecutive patients with intertrochanteric fractures who underwent surgery with BFNs (BFN group) and 50 patients who underwent surgery with PFNAs (PFNA group) were retrospectively analyzed. Indices evaluated by postoperative CT were displacement distance of proximal fragment relative to distal fragment, reduction status (intramedullary, anatomical, and extramedullary types), lag screw direction, and angle between lag screw and femoral neck axis (deviation angle). Median [interquartile range] displacement distance was significantly smaller in the BFN group (0 [0, 0] mm) compared with the PFNA group (5.2 [3.6, 7.1] mm) (p<0.001). Reduction status was significantly better in the BFN group (anatomical type, 40 cases; intramedullary type, in 9 cases, and extramedullary type in 1 case) than in the PFNA group (anatomical type, 6 cases; intramedullary type, 43 cases; extramedullary type, 1 case) (p<0.001). Deviation of lag screw direction was observed in significantly fewer cases in the BFN group (20 cases; 40%) compared with the PFNA group (36 cases; 72%). Lag screw deviation angle was significantly smaller in the BFN group (-0.71°±4.0°) compared with the PFNA group (6.9°±7.1°). No adverse events related to surgery were observed in either group. Intertrochanteric fracture surgery using offset BFNs exhibited significantly smaller displacement distance, better reduction status, and higher frequency of no deviation with central lag screw position, compared with surgery using non-offset PFNAs.

Oral infections, particularly periodontitis, are a well-established risk factor for cardiovascular diseases, although the molecular mechanisms involved remain elusive. The aims of the present study were to investigate the effects of lipopolysaccharide derived from Porphyromonas gingivalis (PG-LPS) on cardiac function in mice, and to elucidate the underlying mechanisms. Mice (C57BL/6) were injected with PG-LPS (0.8 mg/kg/day) with or without an inhibitor of Toll-like receptor 4 (TLR4) signaling (TAK-242, 0.8 mg/kg/day) for 4 weeks. Left ventricular ejection function was significantly decreased at 1 week (from 67 ± 0.5 to 58 ± 1.2%) and remained low at 4 weeks (57 ± 1.0%). The number of apoptotic myocytes was increased (approximately 7.4-fold), the area of fibrosis was increased (approximately 3.3-fold) and the number of 8-hydroxydeoxyguanosine-positive myocytes, a sensitive indicator of oxidative DNA damage, was increased (approximately 7.6-fold) at 4 weeks in the heart of PG-LPS treated mice. However, levels of various serum pro-inflammatory cytokines in PG-LPS-treated mice were similar to those in control mice. The impairment of cardiac function in PG-LPS-treated mice appears to involve activation of TLR4-NADPH oxidase (NOX) 4 signaling, leading to abundant production of reactive oxygen species and Ca 2+ leakage from sarcoplastic reticulumn induced by calmodulin kinase II (CaMKII)-mediated phosphorylation of phospholamban (at Thr-17) and ryanodine receptor 2 (at Ser-2448). Pharmacological inhibition of TLR4 with TAK-242 attenuated the changes in cardiac function in PG-LPS-treated mice. Our results indicate that TLR4-NOX4 signaling may be a new therapeutic target for treatment of cardiovascular diseases in patients with periodontitis.

A general protocol for the asymmetric synthesis of 3-N-arylmethylated right-half model compounds of renieramycins was developed, which enabled structure–activity relationship (SAR) study of several 3-N-arylmethyl derivatives. The most active compound (6a) showed significant cytotoxic activity against human prostate cancer DU145 and colorectal cancer HCT116 cell lines (IC50 = 11.9, and 12.5 nM, respectively).

Purpose The effect of prehospital epinephrine on neurological outcome in out-of-hospital cardiac arrest (OHCA) is still controversial. We sought to determine whether prehospital epinephrine administration was associated with improved outcomes in adult OHCA. Methods A nationwide, population-based, propensity score-matched study of OHCA patients from January 1, 2011, to December 31, 2012, in Japan was conducted. We included adult OHCA patients treated by emergency medical service personnel without an excessive delay. The primary outcome was neurologically favorable survival 1 month after OHCA. Results A total of 237,068 patients (16,616 with a shockable rhythm and 220,452 with a non-shockable rhythm) were included in the final cohort. A total of 4024 out of the 16,616 shockable OHCAs and 29,393 out of the 220,452 non-shockable OHCAs received prehospital epinephrine. In the propensity score-matched cohort, prehospital epinephrine was associated with a decreased chance of neurologically favorable survival (shockable OHCA 7.6 vs. 17.9 %, OR 0.38 [95%CI 0.33–0.43]; non-shockable OHCA 0.6 vs. 1.2 %, OR 0.47 [95%CI 0.39–0.56]). In the subgroup analyses, prehospital epinephrine was significantly associated with poor neurological outcome in all subgroups. In the ancillary analyses, although the neurological outcome was worse as the number of epinephrine doses increased or the time to epinephrine increased, patients had a greater chance of a favorable neurological outcome only when a single dose of epinephrine was administered within 15 min of the emergency call in shockable OHCA. Conclusions Among adult OHCA patients, prehospital epinephrine was associated with a decreased chance of neurologically favorable survival. Situations in which prehospital epinephrine is effective may be extremely limited.

IntroductionTo develop and validate a new trauma mortality prediction scoring system based on International Statistical Classification of Diseases (ICD)-10 codes, using a Japanese administrative claims and discharge abstract database.MethodsThis retrospective observational study used the Japanese Diagnosis Procedure Combination database. Injuries were categorised into 33 groups with 5 additional groups based on injury sites and types. A multivariable logistic regression analysis was performed for in-hospital mortality in a derivation cohort after adjusting for the 38 groups, patient's sex, age and Charlson Comorbidity Index score. Each variable was assigned a score that was equal to the value of the regression coefficient. The new severity score was defined as the sum of the scores. The new scoring system was tested in a validation cohort.ResultsThe mortality rates were 2.4% (9270/393 395) and 2.5% (8778/349 285) in the derivation and validation cohorts, respectively. The area under the receiver operating curve (AUROC) of the new scoring system was 0.887 (95% CI 0.884 to 0.890) in the validation cohort. Subgroup analyses showed that the scoring system retained high predictive performance both for patients <65 years (AUROC 0.934, 95% CI 0.928 to 0.939) and for elderly patients at the age of ≥65 years (AUROC 0.825, 95% CI 0.820 to 0.829).ConclusionsA new ICD-10-based injury severity scoring system was developed and validated. Further studies are required to validate the scoring system in other databases.

Prerenal acute kidney injury (AKI) is thought to be a reversible loss of renal function without structural damage. Although prerenal and intrinsic AKI frequently coexist in clinical situations, serum creatinine and urine output provide no information to support their differentiation. Recently developed biomarkers reflect tubular epithelial injury; therefore, we evaluated urinary biomarker levels in an adult mixed intensive care unit (ICU) cohort of patients who had been clinically evaluated as having prerenal AKI. Urinary L-type fatty acid–binding protein (L-FABP), neutrophil gelatinase–associated lipocalin (NGAL), interleukin-18 (IL-18), N-acetyl-β-D-glucosaminidase (NAG), and albumin in patients with prerenal AKI showed modest but significantly higher concentrations than in patients with non-AKI. We also conducted a proof-of-concept experiment to measure urinary biomarker excretion in prerenal AKI caused by volume depletion. Compared with cisplatinum and ischemia–reperfusion models in mice, volume depletion in mice caused a modest secretion of L-FABP and NGAL into urine with more sensitive response of L-FABP than that of NGAL. Although no histological evidence of structural damage was identified by light microscopy, partial kidney hypoxia was found by pimonidazole incorporation in the volume depletion model. Thus, our study suggests that new AKI biomarkers can detect mild renal tubular damage in prerenal acute kidney injury.

Techniques for the extraction and use of nucleic acids from formalin-fixed and paraffin-embedded (FFPE) tissues, preserved over long time periods in libraries, have been developed. However, DNA extracted from FFPE tissues is generally damaged, and long-term storage may affect DNA quality. Therefore, it is important to elucidate the effect of long-term storage on FFPE tissues and evaluate the techniques used to extract DNA from them. In the present study, the yield, purity, and integrity of DNA in FFPE tissue samples was evaluated. Two DNA extraction techniques were used: A silica-binding DNA collection method using QIAamp DNA FFPE Tissue kit (QIA) and a total tissue DNA collection method using a WaxFree DNA extraction kit (WAX). A total of 25 FFPE tissues from lung adenocarcinomas were studied, which had been surgically resected and fixed at Okayama University Hospital prior to examination and subsequent storage at room temperature for 0.5, 3, 6, 9 and 12 years. Extracted DNA was quantified using ultraviolet absorbance, fluorescent dye, and quantitative polymerase chain reaction (qPCR). The quality of the DNA was defined by the absorbance ratio of 260 to 280 nm (A260/280) and Q-score, which is the quantitative value of qPCR product size ratio. The results demonstrated that the yield of total DNA extracted using WAX was significantly greater than when QIA was used (P<0.01); however, DNA extracted using WAX included more contaminants and was significantly more fragmented compared with DNA extracted using QIA (P<0.01). Aging had no significant effect on absolute DNA yield or DNA purity, although it did significantly contribute to increased DNA degradation for both QIA and WAX extraction (QIA P=0.02, WAX P=0.03; 0.5 years vs. 3 years, QIA P<0.01, WAX P=0.03; 9 years vs. 12 years). Both extraction methods are viable depending on whether high yield or high quality of extracted DNA is required. However, due to the increased degradation with age, storage time limits the available DNA in FFPE tissues regardless of the extraction method.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although the cure rate of ALL has greatly improved, a considerable number of patients suffer from relapse of leukemia. Therefore, ALL remains the leading cause of death from cancer during childhood. To improve the cure rate of these patients, precisely detecting patients with high risk of relapse and incorporating new targeted therapies are urgently needed. This study investigated inexpensive, rapid, next-generation sequencing of more than 150 cancer-related genes for matched diagnostic, remission, and relapse samples of 17 patients (3 months to 15 years old) with relapsed ALL. In this analysis, we identified 16 single-nucleotide variants (SNVs) and insertion/deletion variants and 19 copy number variants (CNVs) at diagnosis and 28 SNVs and insertion/deletion variants and 22 CNVs at relapse. With these genetic alterations, we could detect several B cell precursor ALL patients with high-risk gene alterations who were not stratified into the highest-risk group (5/8, 62.5%). We also detected potentially actionable genetic variants in about half of the patients (8/17, 47.1%). Among them, we found that one patient harbored germline TP53 mutation as a secondary finding. This inexpensive, rapid method can be immediately applied as clinical sequencing and could lead to better management of these patients and potential improvement in the survival rate in childhood ALL.