p53-independent tumor suppression by cell-cycle arrest via CREB/ATF transcription factor OASIS.

CREB/ATF transcription factor OASIS/CREB3L1 is upregulated in long-term-cultured astrocytes undergoing cell-cycle arrest due to loss of DNA integrity by repeated replication. However, the roles of OASIS in the cell cycle remain unexplored. We find that OASIS arrests the cell cycle at G2/M phase after DNA damage via direct induction of p21. Cell-cycle arrest by OASIS is dominant in astrocytes and osteoblasts, but not in fibroblasts, which are dependent on p53. In a brain injury model, Oasis-/- reactive astrocytes surrounding the lesion core show sustained growth and inhibition of cell-cycle arrest, resulting in prolonged gliosis. We find that some glioma patients exhibit low expression of OASIS due to high methylation of its promoter. Specific removal of this hypermethylation in glioblastomas transplanted into nude mice by epigenomic engineering suppresses the tumorigenesis. These findings suggest OASIS as a critical cell-cycle inhibitor with potential to act as a tumor suppressor.

Effect of PARP Inhibitors as Maintenance Treatment on Restricted Mean Survival Time in Platinum-Sensitive Recurrent Ovarian Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Earlier trials on the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors in platinum-sensitive relapsed ovarian cancer used the hazard ratio (HR) as an efficacy parameter. OBJECTIVE: The present meta-analysis was focused on improving the robustness and clinical interpretability of the efficacy evaluation of PARP inhibitors using the restricted mean survival time (RMST). METHODS: A search for relevant studies published up to July 31, 2020, was performed in electronic databases to identify eligible trials comparing PARP inhibitors with placebo. The difference in RMST was used as a PARP inhibitor efficacy parameter. Combined differences in RMST with 95% CIs across studies were calculated using a random-effects model. RESULTS: Four trials (6 articles) were assessed, including 1079 patients treated with PARP inhibitors and 598 with placebo. The combined RMST differences for up to 360 days (PARP inhibitors minus placebo: point estimate and 95% CI) among all patients and the patients of subgroups with BRCA mutations, homologous recombination-deficient (HRD) carcinoma, and BRCA wild-type carcinoma were 87 days (95% CI = 71, 102), 112 days (95% CI = 96, 129), 99 days (95% CI = 80, 119), and 69 days (95% CI = 47, 92), respectively. The combined RMST differences for up to 660 and 720 days were also larger among patients with BRCA mutations than among those with HRD carcinoma. CONCLUSION AND RELEVANCE: Based on using the RMST difference as an alternative measure to the HR, this meta-analysis suggests that PARP inhibitors are the most effective for patients with BRCA mutations, followed by patients with HRD carcinoma.

Factors associated with successful phase III trials for solid tumors: A systematic review.

BACKGROUND: It is known that the success rates of phase III trials for solid cancers are low. The aim of this study was to investigate factors related to trial design and operation that were associated with the probability of the success of phase III trials for solid cancers based on the latest comprehensive data. METHODS: Relevant clinical trials, started between September 2007 and December 2017, were retrieved from ClinicalTrials.gov. Then, variables related to the selected trials such as types of primary endpoint and duration of trial enrollment were collected from the literature and ClinicalTrials.gov. Based on the collected data, a multivariate logistic regression analysis was conducted to find factors associated with the successful results. RESULTS: Four hundred phase III trials were found eligible for the study. Unsuccessful trials were 207 and successful trials were 193. As a result of multivariate logistic regression analysis, factors that presented a statistically significant relationship were primary endpoint (Odds ratio [OR]: 2.79 [95% CI: 1.59-4.89]), control arm (OR: 3.06 [95% CI: 1.39-6.73]), start year of trial (OR: 3.28 [95% CI: 1.87-5.77]), and duration of trial enrollment (OR: 0.77 [95% CI: 0.60-0.99]). CONCLUSION: Type of primary endpoints (time-to-event endpoints other than overall survival), control arm (treatments with lower evidence level, placebo or best supportive care), and duration of trial enrollment (faster enrollment speed) were associated with phase III trial success.

OASIS/CREB3L1 is a factor that responds to nuclear envelope stress.

The nuclear envelope (NE) safeguards the genome and is pivotal for regulating genome activity as the structural scaffold of higher-order chromatin organization. NE had been thought as the stable during the interphase of cell cycle. However, recent studies have revealed that the NE can be damaged by various stresses such as mechanical stress and cellular senescence. These types of stresses are called NE stress. It has been proposed that NE stress is closely related to cellular dysfunctions such as genome instability and cell death. Here, we found that an endoplasmic reticulum (ER)-resident transmembrane transcription factor, OASIS, accumulates at damaged NE. Notably, the major components of nuclear lamina, Lamin proteins were depleted at the NE where OASIS accumulates. We previously demonstrated that OASIS is cleaved at the membrane domain in response to ER stress. In contrast, OASIS accumulates as the full-length form to damaged NE in response to NE stress. The accumulation to damaged NE is specific for OASIS among OASIS family members. Intriguingly, OASIS colocalizes with the components of linker of nucleoskeleton and cytoskeleton complexes, SUN2 and Nesprin-2 at the damaged NE. OASIS partially colocalizes with BAF, LEM domain proteins, and a component of ESCRT III, which are involved in the repair of ruptured NE. Furthermore, OASIS suppresses DNA damage induced by NE stress and restores nuclear deformation under NE stress conditions. Our findings reveal a novel NE stress response pathway mediated by OASIS.

Approval success rates of drug candidates based on target, action, modality, application, and their combinations.

The current success rate of a drug candidate, from the beginning of the clinical trial to receiving marketing approval, is about 10%-20%, and it has not changed during the past few decades. Therefore, pharmaceutical companies are under pressure to select one compound, among many others, with a high probability of success. The differences in drug features affect their probabilities of approval success. In this study, we examined the approval success rates of drug candidates, developed in the United States, the European Union, or Japan, by focusing on four parameters ("drug target," "drug action," "drug modality," and "drug application") and their combinations, and identified factors that conditioned the outcome of the drug development process. We obtained a total success rate of 12.8%, after evaluating 3999 compounds. Moreover, after analyzing the combinations of these parameters, the approval success rates of drugs that corresponded to the following categories-a stimulant in drug action or an enzyme in drug target and biologics (excluding monoclonal antibody) in drug modality-were high (34.1% and 31.3%, respectively). Univariate and multivariate logistic regression analyses revealed that stimulant in drug action, and "B" (blood and blood forming organs), "G" (genito-urinary system and sex), and "J" (anti-infectives for systemic use) in drug application were statistically associated with high approval success rates. We found several parameters and their combinations that affected drug approval success rates. Our results could assist pharmaceutical companies in evaluating the probability of success of their drug candidates and, thus, in efficiently conducting the clinical development process.

Factors Influencing Regulatory Decision-Making in Signal Management: Analysis Based on the Signals Identified from the FAERS.

PURPOSE: This study aimed to identify factors that influence the decision to take safety regulatory actions in routine signal management based on spontaneous reports. For this purpose, we analyzed the safety signals identified from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and related information. METHOD: From the signals that the FDA identified in the FAERS between 2008 1Q and 2014 4Q, we selected 216 signals for which regulatory action was or was not taken. Characteristics of the signals were extracted from the FAERS quarterly reports that give information about what signals were identified from the FAERS and what actions were taken for them, and the FAERS data released in the same quarter when the signal was published. Univariate and multivariable logistic regression analysis was used to assess the relationship between the characteristics of each of the signals and the decision on regulatory action. RESULT: As a result of the univariate logistic regression analysis, we selected 5 factors (positive rechallenge, number of cases accumulated in the last one-year period before the signal indication, previous awareness, serious outcome, risk for special populations) to include in the multivariable logistic regression model (p < 0.2). The multivariate logistic regression analysis showed that the number of cases accumulated in the last one-year period before the signal indication and previous awareness were associated with the regulatory action (p < 0.05). CONCLUSION: The present study showed that number of cases accumulated in the last one-year period before the signal indication and previous awareness potentially associated with the United States regulatory action. When assessing safety signals, we should be careful of the adverse events with a large number of cases accumulated rapidly in a short period. In addition, we should pay attention to new information on not only unknown risks but also previously identified and potential risks.

Predictability of Severe Adverse Events in Phase 3 Trials from Safety Information on Phase 1 Trials in Oncology Drug Development.

PURPOSE: Safety information obtained in phase 1 trials is becoming increasingly important with the recent changes in the development strategy of oncology drugs, including the skipping of phase 2 or 3 trials before regulatory approval. This study aimed to investigate the predictive factors for severe adverse events (AEs) in phase 3 trials based on phase 1 trial data. METHODS: The data on phase 1 and phase 3 trials applied for their marketing approval of the newly approved anticancer drugs in Japan were used for analysis. Regression analyses were performed to investigate factors related to the predictability of the occurrence of severe AEs in phase 3 trials based on phase 1 trial data. RESULTS: Thirty-two drugs (80 phase 1 trials and 40 phase 3 trials) were selected for the analyses. As a result of multivariate regression analyses, immune therapy agents (P = 0.009) and a pair of monotherapy in the phase 1 trials and combination therapy in the phase 3 trials (P = 0.017) were associated with low predictability of severe AEs in the phase 3 trials; signal inhibitor agents (P = 0.002) and large number of subjects in phase 1 trials (P = 0.008) were associated with high predictability. A significant relationship between the actual number of subjects in phase 1 trials and the predictability of severe AEs was observed when trials for immune checkpoint inhibitors were excluded (P < 0.001). CONCLUSION: These results should be effectively utilized for the strategic design of early-stage oncology drug development.

Impact of Advantage in Tumor Response on the Correlation Between Progression-Free Survival and Overall Survival: Meta-Analysis of Clinical Trials in Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) in patients with advanced non-small cell lung cancer. OBJECTIVE: This study aimed to investigate an impact of advantage in tumor response on the correlation between PFS and OS in advanced non-small cell lung cancer. METHODS: Based on a literature search, we identified randomized controlled trials of first-line therapy for advanced non-small cell lung cancer. The impact of absolute difference in objective response rate between treatment arms on the correlation between hazard ratios (HRs) for PFS and OS was evaluated based on Spearman rank correlation coefficients. RESULTS: Sixty trials with a total of 29,134 patients were identified. The HR for PFS showed a relatively higher correlation with HR for OS (rs = 0.75) when the trials were limited to those that demonstrated a larger advantage in objective response rate, compared with the case for trials that demonstrated a smaller advantage (rs = 0.66). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (non-targeted, anti-angiogenic, and immunotherapy) except for the group of epidermal growth factor receptor-targeted agents. CONCLUSIONS: The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS-HR based on PFS-HR in clinical trials in patients with advanced non-small cell lung cancer.

Factors associated with high placebo response in clinical studies of hot flashes: a meta-analysis.

IMPORTANCE: High placebo response can often mask the evaluation of active treatment in clinical studies for women with hot flashes and potentially undermine the evaluation of new treatments. OBJECTIVE: The aim of this meta-analysis was to determine the factors associated with high placebo response (defined as the reduction in the mean number of hot flash frequency from baseline) in randomized, controlled, double-blind studies enrolling women with hot flashes. EVIDENCE REVIEW: To identify eligible studies, Embase, MEDLINE, and BIOSIS Previews were searched for English-language articles published between April 1975 and August 2020. Placebo-controlled, double-blind, randomized studies that assessed changes in hot flash frequency were included if they satisfied the defined criteria. We conducted univariate and multivariate analyses using categorical and numerical data. Categorical data included the following variables and levels in brackets: active treatment type (hormone therapy /non- hormone therapy /complementary and alternative medicine), administration route (oral/non-oral), study region (in/excluded the US), breast cancer population (in/excluded), entry criteria of hot flash severity (moderate to severe only/all included), parallel or crossover study, placebo run-in period before treatment (yes/no), and menopausal status (postmenopausal only/include perimenopausal/include premenopausal). Numerical data included published year, pretreatment period duration, treatment period duration, number of sites, number of total participants, number of placebo participants, number of treatment arms, mean age, BMI, and hot flash frequency at baseline. FINDINGS: Forty-three of the 802 identified publications were included in the review. Multivariate analysis identified three individual factors associated with high placebo response: treatment period duration, number of treatment arms, and BMI. CONCLUSIONS AND RELEVANCE: We identified several factors associated with high placebo response in clinical studies of women with hot flashes. Knowing these factors may enable proactive implementation of operational and analytic strategies that further aid in determining the true treatment effect of an intervention.

Comparison of efficacy outcomes of anticancer drugs between Japanese patients and the overall population.

BACKGROUND: It is important to recognize regional and racial differences in drug efficacy and safety when performing multi-regional clinical trials (MRCTs). To understand regional differences, we compared the efficacy results in Japanese patients and the overall population in the MRCTs of anticancer drugs. METHODS: All new approvals of oncology drugs in Japan from January 2009 to December 2018 were searched using the Pharmaceuticals and Medical Devices Agency web site to find phase 3 MRCTs for the analysis. As the supporting data source, a literature search was performed in PubMed and Google Scholar. Linear regression analysis was performed and Pearson correlation coefficients (r) were calculated to compare the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between Japanese patients and the overall population. RESULTS: Seventy MRCTs were identified. The correlation of hazard ratios (HRs) for OS between Japanese patients and the overall population was moderate (r = 0.45), and OS was 1.31 times longer in Japanese patients than in the overall population, although the correlation of median OS was strong (r = 0.91). The HRs for PFS were moderately correlated (r = 0.70) and the correlation of median PFS was strong (r = 0.90). The correlation of ORR was very strong (r = 0.96). CONCLUSION: The PFS and ORR were consistent between Japanese patients and the overall population. A longer median OS was observed in Japanese patients. Our results would be a useful reference when planning and conducting MRCTs that include Japan for global simultaneous drug development.

Analysis of Pediatric Drug Approval Lag in Japan.

BACKGROUND: Drugs should be made available to all patients in a timely manner regardless of whether they are adults or children. In contrast to the United States (US) and the European Union (EU), no laws mandating pediatric drug development have been established in Japan. The objective of this study was to examine the current status and characteristics of pediatric drug development in Japan using information on the approval lag for pediatric indications between Japan and the EU. METHODS: Drugs approved for pediatric indications between January 2007 and December 2018 in Japan were studied. The approval lag for pediatric indications between Japan and the EU was calculated and analyzed by approval time and the Anatomical Therapeutic Chemical (ATC) classification. Factors potentially affecting the approval lag, such as orphan drug status, company nationality, and clinical data package, were examined. RESULTS: The median approval lag for 105 drugs with pediatric indications in both Japan and the EU was 1017 days (Japan was behind). The lag for ATC category B improved significantly after 2011, and for category L after 2015; the medians were less than half a year. The lag for drugs developed globally via multi-regional clinical trials was significantly shorter compared with drugs developed regionally. CONCLUSION: Global clinical trials are the most effective means of shortening approval lag time in pediatric drug development. Global development is making rapid progress for many adult diseases, thereby creating an environment for proactive participation in global clinical trials even for pediatric drugs. For further improvement, more active drug development for pediatric indication is recommended in tandem with the US and the EU.

Factors Related to Conversion from Accelerated to Full Approval for Drugs Approved in the United States Between 2000 and 2016.

BACKGROUND: Accelerated approval (AA) is a program that grants approval to drugs based on clinical trial data for a surrogate endpoint or an intermediate clinical endpoint. Pharmaceutical companies are required to conduct a confirmatory trial to demonstrate true clinical benefit of the drug to obtain full approval (FA) for the AA. This study aimed at clarifying the points that should be considered by examining the characteristics of AA indications in all disease areas and the factors related to the status of conversion from AA to FA. METHODS: AA indications granted from January 1, 2000, to June 30, 2016, were investigated from the aspects of the characteristics of AAs and the status of conversion from AA to FA. RESULTS: Eighty-nine AAs were examined, of which 65 were converted to FA and 24 were not. A significant association was found between the FA status and period in which AA was granted, disease area, availability of IA data of a confirmatory trial for FA at the time of AA, and sales ranking of the company. CONCLUSIONS: To successfully convert from AA to FA, a development plan that focuses not only on AA but also on future FA needs to be considered and implemented from the early stage of development in line with the FDA guidance. In particular, for companies with insufficient experience in the development of AA indications and for products/indications without an established endpoint, more active discussion with the regulatory authorities from an early stage of development should be encouraged.

Role of the E3 ubiquitin ligase HRD1 in the regulation of serotonin transporter function.

To elucidate the regulation of serotonin transporter (SERT) function via its membrane trafficking, we investigated the involvement of the ubiquitin E3 ligase HRD1 (HMG-CoA reductase degradation protein), which participates in endoplasmic reticulum (ER)-associated degradation (ERAD), in the functional regulation of SERT. Cells transiently expressing wild-type SERT or a SERT C-terminal deletion mutant (SERTΔCT), a SERT protein predicted to be misfolded, were used for experiments. Studies using HRD1-overexpressing or HRD1-knockdown cells demonstrated that HRD1 is involved in SERT proteolysis. Overexpression of HRD1 promoted SERT ubiquitination, the effect of which was augmented by treatment with the proteasome inhibitor MG132. Immunoprecipitation studies revealed that HRD1 interacts with SERT in the presence of MG132. In addition, HRD1 was intracellularly colocalized with SERT, especially with aggregates of SERTΔCT in the ER. HRD1 also affected SERT uptake activity in accordance with the expression levels of the SERT protein. These results suggest that HRD1 contributes to the membrane trafficking and functional regulation of SERT through its involvement in ERAD-mediated SERT degradation.

Pediatric Drug Development in Japan: A Comparison of the Current Situation and Characteristics Between Japan and Europe.

BACKGROUND: In contrast to the European Union and the USA, no laws or regulations mandating pediatric drug development have been established in Japan. Based on the information on drugs approved for pediatric indications in Europe and Japan, we evaluated the recent status of pediatric drug approvals and their characteristics in Japan in comparison with those of Europe. METHODS: Drugs approved for pediatric indications between 2007 and 2015 in both regions were included in the study. The proportion of drugs with pediatric indications was calculated by the Anatomical Therapeutic Chemical (ATC) classification, and the status of pediatric formulation development was examined. The time from adult to pediatric indication approval was determined. RESULTS: A total of 135 drugs were approved for pediatric indications in Europe, with 208 approved in Japan. The proportion of drugs with pediatric indications in Japan among those approved for pediatric indications in Europe was lower among those with ATC classifications of N (Nervous system) and J (Antiinfectives for systemic use) and those with the development of pediatric formulations than among others. Excepting drugs for which adult and pediatric indications were simultaneously approved, the most commonly observed period from the adult indication approval to the pediatric indication approval was more than 12 years in Japan and 3-6 years in Europe. CONCLUSION: The present findings suggested that pediatric development is indeed being promoted in Japan. However, the period from adult to pediatric indication approval was longer in Japan than in Europe, and the development of pediatric drugs for certain diseases has been sluggish, indicating room for further improvement.

Characteristics of Drug Intervention Clinical Trials and Scientific Impact of the Trial Outcome: A Bibliometric Analysis Using the Relative Citation Ratio in Non-small Cell Lung Cancer from 2007 to 2016.

BACKGROUND: Although a large number of clinical trials have been conducted, the types of clinical trials that are scientifically influential, frequently utilized by society, and contribute to the progress of evidence-based medicine (EBM) have not been studied. Thus, we aimed to investigate the relationship between the characteristics of clinical trials and the scientific impact of the outcome in non-small cell lung cancer (NSCLC) by performing a bibliometric analysis using relative citation ratio (RCR), a newly developed bibliometric index by the National Institutes of Health (NIH). METHODS: Primary publications of drug intervention clinical trials for NSCLC between 2007 and 2016 were included in the study. The characteristics of clinical trials were compared among four RCR categories with 50 trials in each [LOW50, 50 NIH percentile (50NIH%ile), 95 NIH percentile (95NIH%ile), and TOP50], totaling to 200 trials. RESULTS: Median RCRs of LOW50, 50NIH%ile, 95NIH%ile, and TOP50 were 0.03, 1.00, 5.76, and 26.89, respectively. Publications of Phase 3, randomized, blinded, for-profit-company supported/sponsored, multi-center trials, and trials with a larger number of subjects were shown to have a higher scientific impact. Publications of clinical trials of newly developed molecular target drugs, including epidermal growth factor receptor-tyrosine kinase inhibitors, anaplastic lymphoma kinase inhibitors, and immune checkpoint inhibitors demonstrated a higher scientific impact than those of traditional chemotherapies. CONCLUSION: Clinical trials designed to have a high evidence level would improve the scientific impact of the outcome, and novel interventions would be another factor to improve the clinical trials' influence.

The Role of Tissue-Specific Ubiquitin Ligases, RNF183, RNF186, RNF182 and RNF152, in Disease and Biological Function.

Ubiquitylation plays multiple roles not only in proteasome-mediated protein degradation but also in various other cellular processes including DNA repair, signal transduction, and endocytosis. Ubiquitylation is mediated by ubiquitin ligases, which are predicted to be encoded by more than 600 genes in humans. RING finger (RNF) proteins form the majority of these ubiquitin ligases. It has also been predicted that there are 49 RNF proteins containing transmembrane regions in humans, several of which are specifically localized to membrane compartments in the secretory and endocytic pathways. Of these, RNF183, RNF186, RNF182, and RNF152 are closely related genes with high homology. These genes share a unique common feature of exhibiting tissue-specific expression patterns, such as in the kidney, nervous system, and colon. The products of these genes are also reported to be involved in various diseases such as cancers, inflammatory bowel disease, Alzheimer's disease, and chronic kidney disease, and in various biological functions such as apoptosis, endoplasmic reticulum stress, osmotic stress, nuclear factor-kappa B (NF-κB), mammalian target of rapamycin (mTOR), and Notch signaling. This review summarizes the current knowledge of these tissue-specific ubiquitin ligases, focusing on their physiological roles and significance in diseases.

Investigation of the Influencing Factors on the Incidence of Vertebral Fracture: A Meta-analysis Based on Placebo Data of Randomized Clinical Trials.

BACKGROUND: The incidence of vertebral fracture is commonly used as a primary endpoint in randomized clinical trials of pharmaceutical agents for osteoporosis. In order to investigate the impact of ethnic/regional difference in osteoporosis clinical trials on the incidence of vertebral fracture, we examined the correlation between the incidence of vertebral fracture in the placebo group and baseline bone mineral density (BMD), ethnic and regional differences, or other factors by meta-regression analysis. METHODS: We studied a total of 21 trials involving 28,425 patients treated with placebo, which were identified through MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. RESULTS: A univariate meta-regression showed a significant correlation between the proportion of subjects experiencing new vertebral fracture and the proportion of Caucasian subjects (coefficient = 0.223, [Formula: see text]), and the proportion of subjects with prevalent vertebral fracture (0.161, [Formula: see text]). Baseline lumbar spine BMD did not show significant correlations. As a result of multivariate meta-regression analysis with the factors with [Formula: see text] by the univariate meta-regression, the proportion of subjects with prevalent vertebral fracture was identified as an influencing factor (0.139, [Formula: see text]). CONCLUSIONS: The multivariate meta-regression showed that prevalent vertebral fracture was the most important factor to predict subsequent vertebral fracture. In addition, considering the results of the univariate meta-regression analysis, we suggest that the ethnic/regional difference should be considered as one of the important factors that influence the incidence of new vertebral fracture, a primary endpoint of osteoporosis study, when the Caucasian reference range is used in clinical trials.

Magnitude of advantage in tumor response contributes to a better correlation between treatment effects on overall survival and progression-free survival: a literature-based meta-analysis of clinical trials in patients with metastatic colorectal cancer.

BACKGROUND: Although it is suggested that the endpoints originated from the concept of tumor shrinkage dynamics, such as early tumor shrinkage and depth of response, are strongly associated with overall survival (OS) in patients with metastatic colorectal cancer (mCRC), they are yet to be validated as a single surrogate endpoint of OS by themselves. This study aimed to investigate the impact of advantage in tumor response on the correlation between treatment effects on progression-free survival (PFS) and OS in mCRC patients. METHODS: Based on an electronic search, we identified randomized controlled trials of first-line therapy for mCRC. The impact of advantage in objective response rate (ORR) on the correlation between treatment effects on PFS and OS was evaluated based on Spearman correlation coefficients (rs). RESULTS: Forty-seven trials with a total of 24,018 patients were identified. The hazard ratio for PFS showed a relatively higher correlation with that for OS (rs = 0.63) when the trials were limited to those that demonstrated a larger difference in ORR, compared to the case for trials that demonstrated a smaller difference (rs = 0.32). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (targeted or non-targeted). CONCLUSIONS: The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS benefit based on PFS in patients with mCRC. The accuracy of OS estimation in mCRC is expected to be improved by considering the degree of tumor shrinkage in conjunction with PFS.

Production of BBF2H7-derived small peptide fragments via endoplasmic reticulum stress-dependent regulated intramembrane proteolysis.

Intramembrane cleavage of transmembrane proteins is a fundamental cellular process to produce important signals that elicit biological responses. These proteolytic events are known as regulated intramembrane proteolysis (RIP). ATF6 and BBF2H7 are transmembrane basic leucine zipper transcription factors and are subjected to RIP by site-1 protease (S1P) and site-2 protease (S2P) sequentially in response to endoplasmic reticulum (ER) stress. However, the detailed mechanisms responsible for RIP of the transcription factors, including the precise cutting sites, are still unknown. In this study, we demonstrated that S1P cleaves BBF2H7 just before the RXXL S1P recognition motif. Conversely, S2P cut at least three different sites in the membrane (next to Leu380, Met381, and Leu385), indicating that S2P cleaves the substrates at variable sites or via a multistep process. Interestingly, we found BBF2H7-derived small peptide (BSP) fragments located between the S1P and S2P cleavage sites in cells exposed to ER stress. Major type of BSP fragments was composed of 45 amino acid including partial transmembrane and luminal regions and easily aggregates like amyloid ß (Aß) protein. These results advance the understanding of poorly characterized ER stress-dependent RIP. Furthermore, the aggregable peptides produced by ER stress could link to the pathophysiology of neurodegenerative disorders.

Influence of Prevalent Vertebral Fracture on the Correlation between Change in Lumbar Spine Bone Mineral Density and Risk of New Vertebral Fracture: A Meta-Analysis of Randomized Clinical Trials.

BACKGROUND AND OBJECTIVE: The correlation between change in bone mineral density (BMD) and the incidence of new vertebral fracture has been drawing attention in regard to evaluation of fracture risk and drug efficacy. We investigated the impact of the prevalence of vertebral fracture on this correlation via a meta-regression analysis with a view to improving evaluation of the correlation. METHODS: A total of 19 postmenopausal osteoporosis clinical studies involving 62,432 patients in 46 placebo or treatment groups were identified through MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. We performed a multivariate meta-regression analysis to examine the correlation between the percentage change in lumbar spine BMD from baseline at 3 years and the proportion of subjects experiencing new vertebral fractures, with or without the proportion of subjects with prevalent vertebral fracture as a covariate. We also analyzed the interaction between the subgroups divided by the proportion of subjects with prevalent vertebral fracture and the percentage change in lumbar spine BMD from baseline at 3 years. RESULTS: A multivariate meta-regression analysis showed a significant correlation between the change in lumbar spine BMD and the proportion of subjects experiencing new vertebral fracture, and a lower Akaike information criterion was obtained when the proportion of subjects with prevalent vertebral fracture was added as an explanatory variable. Significant interaction between the proportion of subjects with prevalent vertebral fracture and the change in lumbar spine BMD was shown. CONCLUSIONS: The change in lumbar spine BMD, not BMD T-score at one timepoint, had a significant correlation with the incidence of vertebral fracture. The prediction of the fracture risk by change in lumbar spine BMD was improved by adjusting the proportion of subjects with prevalent vertebral fracture in the study population. The difference of prevalence of vertebral fracture among populations should be considered when the association between change in lumbar spine BMD and incidence of vertebral fracture is examined.