Novel single nucleotide polymorphism biomarkers to predict opioid effects for cancer pain.

There have been few studies on predictive biomarkers that may be useful to select the most suitable opioids to optimize therapeutic efficacy in individual patients with cancer pain. We recently investigated the efficacy of morphine and oxycodone using single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) rs4680 gene as a biomarker (RELIEF study). To explore additional biomarkers that may enable the selection of an appropriate opioid for individual patients with cancer pain, three SNPs were examined: C-C motif chemokine ligand 11 (CCL11; rs17809012), histamine N-methyltransferase (HNMT; rs1050891) and transient receptor potential V1 (TRPV1; rs222749), which were screened from 74 pain-related SNPs. These SNPs, which were identified as being significantly associated with the analgesic effect of morphine, were then used to genotype the 135 patients in the RELIEF study who had been randomized into a morphine group (n=69) or an oxycodone group (n=66). The present study then assessed whether the SNPs could also be used as selective biomarkers to predict which opioid(s) might be the most suitable to provide pain relief for patients with cancer. Oxycodone tended to provide superior analgesic effects over morphine in patients carrying the genotype AA for the CCL11 rs17809012 SNP (P=0.012 for interaction), suggesting that it could serve as a potential biomarker for personalized analgesic therapy for patients suffering with cancer pain.

Morphine Versus Oxycodone for Cancer Pain Using a Catechol-O-methyltransferase Genotype Biomarker: A Multicenter, Randomized, Open-Label, Phase III Clinical Trial (RELIEF Study).

BACKGROUND: We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain. METHODS: A randomized, multicenter, open-label trial was conducted at a Japanese hospital's palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reduction ≥ 33% from baseline and up to ≤ 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype. RESULTS: Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; P = .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; P = 0.098). CONCLUSION: Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief.

Safety evaluation of immediate breast reconstruction for locally advanced breast cancer in Japanese patients.

BACKGROUND: While breast reconstruction often improves the quality of life of patients with locally advanced breast cancer, there is still no consensus on its safety. This retrospective report aimed to verify the safety of immediate breast reconstruction for locally advanced breast cancer. METHODS: We retrospectively analyzed 500 breast cancer surgeries performed between January 2005 and December 2019 at our hospital, including 120 immediate breast reconstructions. The following five items were analyzed: the patients' choice of reconstruction method, rate of chemotherapy and radiotherapy, surgical margin positivity rate, complications associated with surgery, overall survival rate, and breast cancer-free survival rate. RESULTS: Sixty-three of the 120 patients underwent autologous breast reconstruction. Of those who underwent reconstruction surgery, 95.8% received chemotherapy and 78.3% underwent post-mastectomy radiation therapy. Reconstruction failed in 8 cases with tissue expander and in 1 case with free TRAM flap. Breast reconstruction surgery was not a factor in delaying adjuvant therapy, but complications requiring intervention tended to increase the duration of adjuvant therapy. There was no statistically significant difference in the rate of surgical margin positivity, overall survival rate, or breast cancer-free survival rate. CONCLUSIONS: Although complications associated with reconstructive surgery occurred, appropriate intervention prevented delays in breast cancer treatment, and the complications did not negatively affect the overall or breast cancer-free survival rates. Our study found no evidence to avoid primary breast reconstruction in patients with locally advanced breast cancer.

Translational recoding by chemical modification of non-AUG start codon ribonucleotide bases.

In contrast to prokaryotes wherein GUG and UUG are permissive start codons, initiation frequencies from non-AUG codons are generally low in eukaryotes, with CUG being considered as strongest. Here, we report that combined 5-cytosine methylation (5mC) and pseudouridylation (Ψ) of near-cognate non-AUG start codons convert GUG and UUG initiation strongly favored over CUG initiation in eukaryotic translation under a certain context. This prokaryotic-like preference is attributed to enhanced NUG initiation by Ψ in the second base and reduced CUG initiation by 5mC in the first base. Molecular dynamics simulation analysis of tRNAiMet anticodon base pairing to the modified codons demonstrates that Ψ universally raises the affinity of codon:anticodon pairing within the ribosomal preinitiation complex through partially mitigating discrimination against non-AUG codons imposed by eukaryotic initiation factor 1. We propose that translational control by chemical modifications of start codon bases can offer a new layer of proteome diversity regulation and therapeutic mRNA technology.

A versatile and robust cell purification system with an RNA-only circuit composed of microRNA-responsive ON and OFF switches.

Human induced pluripotent stem cells (iPSCs) are promising cell resources for cell therapy and drug discovery. However, iPSC-derived differentiated cells are often heterogenous and need purification using a flow cytometer, which has high cost and time consumption for large-scale purification. MicroRNAs (miRNAs) can be used as cell selection markers, because their activity differs between cell types. Here, we show miRNA-responsive ON and OFF switch mRNAs for robust cell purification. The ON switch contains a miRNA-target sequence after the polyadenylate tail, triggering translational activation by sensing the target miRNA. By designing RNA-only circuits with miRNA-ON and -OFF switch mRNAs that encode a lethal ribonuclease, Barnase, and its inhibitor, Barstar, we efficiently purified specific cell types, including human iPSCs and differentiated cardiomyocytes, without flow cytometry. Synthetic mRNA circuits composed of ON and OFF switches provide a safe, versatile, and time-saving method to purify various cell types for biological and clinical applications.

Influences of remote exercise training for community-dwelling older adults in Japan during the COVID-19 pandemic.

[Purpose] The coronavirus disease (COVID-19) pandemic has caused sudden lifestyle changes. This study aimed to determine the limitations in activity and the influences of remote exercise training on community-dwelling older adults during a state of emergency in Japan. [Participants and Methods] In May 2020, during the COVID-19 state of emergency, we carried out a mail survey of community-dwelling older adults who had previously participated in a disability prevention program in Ami town, Ibaraki, Japan. The mail included a brochure on exercises and a DVD. The attached exercise program was comprised of 10 different exercises, which could be conducted in approximately 30 minutes. [Results] Of the 191 older adults, 73 responded to this survey (38.2%), of which 42 (58.5%) participants had decreased outdoor exercise activity, and 50 (68.5%) decreased the amount of time spent on physical activities during the COVID-19 state of emergency. There were significant reductions (19.2-22.5%) in the perceived exercise load for each posture after two weeks of remote exercise training with DVD (n=26). [Conclusion] Our results suggested that the remote exercise training with the brochure and DVD may be effective. Since this study involved a small number of participants, future studies should involve larger populations.

Skeletal Muscle Mass and Higher-Level Functional Capacity in Female Community-Dwelling Older Adults.

PURPOSE: In this study, our purpose was to examine the relationship between skeletal muscle mass and higher-level functional capacity in female community-dwelling older adults. Participant(s) and Methods: In this cross-sectional study, we targeted 55 female community-dwelling older adults aged 65 years and above participating in long-term care prevention classes in Ibaraki Prefecture between 2018 and 2020. We excluded individuals with cognitive impairment and those judged as having sarcopenia. The variables of interest included age, height, weight, body mass index, skeletal muscle mass index (SMI), handgrip strength, step count, and family structure. We calculated the SMI by dividing the extremities' total lean mass by the square of the height (in m), while the number of steps was calculated using the three-axis accelerometer Actigraph GT3X®. We measured skeletal muscle mass via bioelectrical impedance analysis using the InBody270 body composition analyzer and muscular strength as grip strength. RESULTS: We observed significant relationships between skeletal muscle mass and Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) (ß = 0.336, p < 0.01) and handgrip strength (ß = 0.230). CONCLUSION: In this study, a relationship between skeletal muscle mass and higher-level functional capacity was demonstrated among elderly female community residents.

PDZK1 induces resistance to apoptosis in esophageal adenocarcinoma cells.

BACKGROUND: Esophageal cancer is a lethal malignancy with a poor prognosis. The incidence of esophageal adenocarcinoma, which develops from Barrett's esophagus (BE), has recently been increasing. In a previous study, we found that PDZK1 expression is higher in long segment BE compared to that in short-segment BE. However, the function of PDZK1 in the mucosa of BE is unclear. AIMS: Clarify the role of PDZK1 in BE mucosa using PDZK1 overexpressed cells. METHODS: Human adenocarcinoma-derived OE33 cells were used as a parental cell line and transfected to generate PDZK1 overexpressed OE33 cells (PC cells) or transfected with empty vector as control cells (NC cells). Cell growth of NC and PC cells in 10% fetal bovine serum was evaluated by cell counting. The effect of PDZK1 on proteasome inhibitor (PSI)-induced apoptosis was qualified by fluorescence microscopy and quantified by flow cytometry. Expression of apoptosis-related proteins was evaluated by western blotting. RESULTS: There were no significant differences in cell growth between NC and PC cells. PSI significantly increased apoptosis in NC cells, but not in PC cells. In response to PSI, increased levels of cleaved-caspase3 and decreased pro-caspase3 levels were found in NC cells, but not in PC cells. In NC cells, PSI significantly decreased Bcl-2 expression without affecting Bax levels. In contrast, high expression of both Bcl-2 and Bax was observed in PC cells. CONCLUSION: Overexpression of PDZK1 protein induces an apoptosis-resistant phenotype in BE cells, which may be a potential therapeutic target.

Molecular biomarker identification for esophageal adenocarcinoma using endoscopic brushing and magnified endoscopy.

BACKGROUND: Barrett's esophagus (BE) is a predisposing factor for esophageal adenocarcinoma (EAC); however, the precise mechanism underlying this association remains unclear. The identification of biomarkers that are associated with an increased risk of BE progression to EAC would facilitate diagnosis and early treatment. Toward this goal, we aimed to identify biomarkers associated with BE and EAC in patients. METHODS: In conjunction with high-resolution magnified endoscopy with narrow-band imaging (ME-NBI), we obtained brushing samples from the long-segment BE (LSBE) or short-segment BE (SSBE) of patients with EAC or without EAC (control). To identify candidate biomarker genes, microarray analysis was performed for a training set of 28 American samples. To confirm the microarray results, expression levels of the 16 candidate biomarkers were evaluated by real-time polymerase chain reaction analysis, using samples collected from an additional 53 American patients. In addition, we also performed a functional analysis for these genes using Gene Ontology (GO) enrichment analysis. RESULTS: Among the 16 genes identified as differentially expressed by microarray analysis, the GO analysis indicated matrix metalloproteinase (MMP) family associated with 'collagen metabolic process' and 'multicellular organismal macromolecule metabolic process' as the two top biological processes. Brushing samples of patients with EAC showed up-regulated expression of decay-accelerating factors (DAF and CD55) and topoisomerase type Iiα (TOP2A), and down-regulated expression of the sodium channel epithelial 1 beta subunit (SCNN1B). CONCLUSIONS: The up-regulation of CD55 and TOP2A, and the down-regulation of SCNN1B were common to the brushing samples and might serve as molecular biomarkers for identifying EAC in patients with SSBE. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) (000004004).

Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial.

IMPORTANCE: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. OBJECTIVE: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. INTERVENTIONS: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. MAIN OUTCOMES AND MEASURES: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. RESULTS: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. CONCLUSIONS AND RELEVANCE: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. TRIAL REGISTRATION: UMIN Identifier: UMIN000016794.

A Novel Exercise for Enhancing Visuospatial Ability in Older Adults with Frailty: Development, Feasibility, and Effectiveness.

We aimed to develop a novel exercise to improve visuospatial ability and evaluate its feasibility and effectiveness in older adults with frailty. A non-randomized preliminary trial was conducted between June 2014 and March 2015. We recruited 35 adults with frailty (24 women), aged 66-92 years. Participants were assigned to either locomotive- or visuospatial-exercise groups. All participants exercised under the supervision of physiotherapists for 90 min/week for 12 weeks. The visuospatial exercise participants used cubes with six colored patterns and were instructed to "reproduce the same colored pattern as shown in the photo", using the cubes. In the locomotive exercise group, lower extremity functional training was provided. Rates of retention and attendance measured feasibility. Most participants completed the intervention (77.3%, locomotive; 84.6%, visuospatial) and had good attendance (83.8%, locomotive; 90.7%, visuospatial). Mini-mental state examination (MMSE), clock drawing test (CDT), and seven physical performance tests were conducted before and after interventions. The improvement in the MMSE score, qualitative analysis of CDT, grip strength, and sit and reach assessments were significantly greater in the visuospatial exercise group than in the locomotive exercise group. The cube exercise might be a feasible exercise program to potentially improve visuospatial ability and global cognition in older adults with frailty.

A Short-Duration Combined Exercise and Education Program to Improve Physical Function and Social Engagement in Community-Dwelling Elderly Adults.

Exercise is a key intervention for improving older adults' physical function and life expectancy. Here, we investigated a short-term intervention program designed to improve the physical functioning of elderly adults in a community-dwelling setting. We examined the effect of a 5-week combined exercise and education program on the physical function, social engagement, mobility performance, and fear of falling in 42 subjects older than 65 years. Eleven subjects dropped out. There was significant improvement in the 30-second chair stand test (p < .001) and timed up-and-go test (p < .001) between the baseline and the last session. At the end of the intervention, the subjects' social engagement was significantly higher than at baseline (p = .022), but this improvement was not maintained in the follow-up assessment. These results suggest that a combined exercise and education program can improve the physical function and social engagement of elderly individuals living in a community dwelling.

Clinical and immune profiling for cancer of unknown primary site.

BACKGROUND: Immune checkpoint inhibitors (ICIs) confer a survival benefit in many cancer types. Given that the survival outcome for cancer of unknown primary site (CUP) remains poor, we investigated the potential of CUP for immunotherapy. METHODS: A total of 164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients) who were treated between January 2009 and March 2017 was identified from a review of medical records at Kindai University Hospital. They included 92 patients for whom pretreatment tumor tissue was available both for determination of programmed cell death-ligand 1 expression and tumor-infiltrating lymphocyte (TIL) density by immunohistochemistry (IHC) and for immune-related gene expression profiling (irGEP). The results of irGEP for CUP were compared with published data for ICI-treated solid cancers classified into progressive disease (PD) and non-PD subsets according to their best response to ICIs. RESULTS: The median overall survival of all CUP patients was 29.3 months (95% confidence interval [CI], 15.7-not reached) and 7.1 months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P = 0.002-0.067; CUP versus non-PD, P = 0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P = 0.008, false discovery rate = 0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented. CONCLUSIONS: The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.

Cell-Type-Specific CRISPR Activation with MicroRNA-Responsive AcrllA4 Switch.

Anti-CRISPR proteins have the potential to regulate CRISPR-Cas systems in a cell-type-specific manner. To selectively edit the genome in target cells, we controlled the expression of AcrllA4, a Streptococcus pyogenes Cas9 inhibitor, based on endogenous microRNA (miRNA) activity. We designed a miRNA-responsive AcrllA4 switch, which is a synthetic mRNA that contains a completely complementary sequence to an arbitrary miRNA at the 5'-UTR region and encodes AcrllA4. Together with the Cas9- or dCas9-VPR-guide RNA complex, this switch functions as a cell-specific Cas9 or dCas9-VPR activator that induces gene knockout or activation depending on the target miRNA. By sensing intracellular miRNAs, the conditional CRISPR-Cas9 ON system that we report could provide a powerful tool for future therapeutic applications and genome engineering.

Author Correction: Synthetic RNA-based logic computation in mammalian cells.

The original version of this Article contained an error in the fourth sentence of the second paragraph of the 'Improving the performance of miRNA-responsive circuits' section of the Results, which incorrectly read 'We confirmed a significant fold-change between ON and OFF states (from 3.5- to 9.0-fold) in 293FT cells (Supplementary Figure 3).' The correct version states '4.6' in place of '3.5'. This has been corrected in both the PDF and HTML versions of the Article.The original version of the Supplementary Information contained a corresponding error in Supplementary Figure 3. The HTML has been updated to include a corrected version of the Supplementary Information.

Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site.

PURPOSE: Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP. PATIENTS AND METHODS: Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate. RESULTS: One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in the site-specific therapy and empirical PC arms, respectively. Cancer types most commonly predicted were pancreatic (21%), gastric (21%), and lymphoma (20%). The 1-year survival rate was 44.0% and 54.9% for site-specific treatment and empirical PC ( P = .264), respectively. Median overall and progression-free survival were 9.8 and 5.1 months, respectively, for site-specific treatment versus 12.5 and 4.8 months for empirical PC ( P = .896 and .550, respectively). Median overall survival (16.7 v 10.6 months; P = .116) and progression-free survival (5.5 v 3.9 months; P = .018) were better for predicted more-responsive than less-responsive tumor types. CONCLUSION: Site-specific treatment that was based on microarray profiling did not result in a significant improvement in 1-year survival compared with empirical PC, although prediction of the original site seemed to be of prognostic value.

Factors associated with overweight status, obesity, and sedentary behavior in elementary and junior high school students.

BACKGROUND: Sedentary behavior increases the risks of obesity and cardiovascular disease in adults, but these relationships are uncertain in elementary and junior high school students. We investigated whether sedentary behavior is related to overweight status and obesity in high-risk children with lifestyle diseases. METHOD: A cross-sectional study was performed in 115 children and primary caregivers who attended a lecture for preventing child lifestyle diseases in Ibaraki prefecture, Japan. The main outcome measure was excess weight (percent overweight). Factors associated with excess weight in children were evaluated using multiple regression analysis. Basic physical and demographic characteristics, biochemical data (total cholesterol [TC], low and high density lipoprotein cholesterol [LDL-C and HDL-C], alanine aminotransferase [ALT]), blood pressure, child and parental sedentary time, parental BMI, and family environment were evaluated. RESULTS: In total, 107 children were eligible for participation in the study. Excess weight in these children was 28.6 ± 18.4. Sedentary time was 337.2 ± 122.5 min/day in children and 347.0 ± 196.2 min/day in parents. Multiple regression analysis revealed that children's sedentary behavior (ß = 0.02, (95%CI: 0.00 to 0.04)) and HDL-C (ß = -0.59, (95%CI: -0.81 to -0.38)) as independent predictors of children's excess weight. CONCLUSION: Study findings suggest that decreasing children's sedentary behavior in addition to greater physical activity is important for the prevention of overweight status and obesity in high-risk children with lifestyle diseases. Reduction of sedentary time, and engaging in regular exercise are all important for proper weight maintenance in children.

aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer.

BACKGROUND: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC. MATERIALS AND METHODS: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG). RESULTS: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS). CONCLUSION: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC. IMPLICATIONS FOR PRACTICE: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.

Synthetic RNA-based logic computation in mammalian cells.

Synthetic biological circuits are designed to regulate gene expressions to control cell function. To date, these circuits often use DNA-delivery methods, which may lead to random genomic integration. To lower this risk, an all RNA system, in which the circuit and delivery method are constituted of RNA components, is preferred. However, the construction of complexed circuits using RNA-delivered devices in living cells has remained a challenge. Here we show synthetic mRNA-delivered circuits with RNA-binding proteins for logic computation in mammalian cells. We create a set of logic circuits (AND, OR, NAND, NOR, and XOR gates) using microRNA (miRNA)- and protein-responsive mRNAs as decision-making controllers that are used to express transgenes in response to intracellular inputs. Importantly, we demonstrate that an apoptosis-regulatory AND gate that senses two miRNAs can selectively eliminate target cells. Thus, our synthetic RNA circuits with logic operation could provide a powerful tool for future therapeutic applications.

Selection of opioids for cancer-related pain using a biomarker: a randomized, multi-institutional, open-label trial (RELIEF study).

BACKGROUND: Cancer patients experience pain that has physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Opioids are used in treatment of pain in patients with various types of cancer. We previously showed that the catechol-O-methyltransferase (COMT) genotype is related to the plasma level of morphine and the required dose of morphine in an exploratory prospective study. The findings showed that a group of patients with a GG single nucleotide polymorphism (SNP) rs4680 in COMT required a significantly higher dose of morphine than a non-GG group. A biomarker for selection of opioids for cancer pain relief would be particularly useful clinically, and therefore we have planned a randomized comparative study of morphine and oxycodone, using the COMT rs4680 SNP as a biomarker. This study is aimed at verifying the assumption that patients in the GG group require an increased morphine dose for pain relief. METHODS: The RELIEF study is a randomized, multi-institutional, open-label trial with a primary endpoint of the proportion of subjects requiring high-dose opioids, as calculated from the dose of a rescue preparation administered on day 0. Secondary endpoints include the Hospital Anxiety and Depression Scale, Short form McGill Pain Questionnaire-2, European Organization for Research and Treatment of Cancer QLQ-C15-PAL, Pain Catastrophizing Scale, and adverse events, Eligibility criteria are patients with advanced carcinoma with non-daily use of opioids in initial screening for registration; and cancer pain targeted for daily opioid treatment, NSAIDs or acetaminophen, NRS ≥3(average over 24 h), opioid-treatment naive within 30 h, no chemotherapy, radiotherapy, or bisphosphonate administration newly started within 2 weeks, and written informed consent at the time of second registration. Between November 2014 and June 2017, an estimated 110 patients from two sites in Japan were randomized (1:1) to morphine or oxycodone in GG and non-GG groups. DISCUSSION: A method for selection of appropriate opioids in cancer patients is a high unmet medical need. This study was designed to evaluate the efficacy of different opioids in patients with cancer based on gene polymorphism, as the first potential multi-institutional registration trial to be conducted in cancer patients with pain. TRIAL REGISTRATION: UMIN000015579 Date of registration: 4 November 2014. It is updated once every six months, the latest update is 30 June 2017. Trial status. The enrollment started in November 2014. At the time of manuscript submission (July 2017), Three-quarters of patients have participated. We thus expect to complete the recruitment by March 2018.