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.

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.

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.

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.

NFAT5 up-regulates expression of the kidney-specific ubiquitin ligase gene Rnf183 under hypertonic conditions in inner-medullary collecting duct cells.

We previously reported that among the 37 RING finger protein (RNF) family members, RNF183 mRNA is specifically expressed in the kidney under normal conditions. However, the mechanism supporting its kidney-specific expression pattern remains unclear. In this study, we elucidated the mechanism of the transcriptional activation of murine Rnf183 in inner-medullary collecting duct cells. Experiments with anti-RNF183 antibody revealed that RNF183 is predominantly expressed in the renal medulla. Among the 37 RNF family members, Rnf183 mRNA expression was specifically increased in hypertonic conditions, a hallmark of the renal medulla. RNF183 up-regulation was consistent with the activation of nuclear factor of activated T cells 5 (NFAT5), a transcription factor essential for adaptation to hypertonic conditions. Accordingly, siRNA-mediated knockdown of NFAT5 down-regulated RNF183 expression. Furthermore, the -3,466 to -3,136-bp region upstream of the mouse Rnf183 promoter containing the NFAT5-binding motif is conserved among mammals. A luciferase-based reporter vector containing the NFAT5-binding site was activated in response to hypertonic stress, but was inhibited by a mutation at the NFAT5-binding site. ChIP assays revealed that the binding of NFAT5 to this DNA site is enhanced by hypertonic stress. Of note, siRNA-mediated RNF183 knockdown increased hypertonicity-induced caspase-3 activation and decreased viability of mIMCD-3 cells. These results indicate that (i) RNF183 is predominantly expressed in the normal renal medulla, (ii) NFAT5 stimulates transcriptional activation of Rnf183 by binding to its cognate binding motif in the Rnf183 promoter, and (iii) RNF183 protects renal medullary cells from hypertonicity-induced apoptosis.

Hypertonicity-responsive ubiquitin ligase RNF183 promotes Na, K-ATPase lysosomal degradation through ubiquitination of its ß1 subunit.

We previously reported that RNF183, a member of the RING finger (RNF) protein family, is specifically expressed in the renal collecting duct and that RNF183 mRNA is induced by the activity of nuclear factor of activated T cells 5 (NFAT5), which regulates the transcription of essential proteins for adaptation to hypertonic conditions. The renal medulla is the only tissue that is continuously hypertonic; therefore, RNF183 possibly plays an important role in adaptation to continuous hypertonic conditions. However, the mechanism of how cells adapt to long-term hypertonicity via RNF183 remains unclear. In this study, the Na, K-ATPase α1 subunit was identified as a candidate substrate of RNF183 by the BirA proximity-biotinylation technique. The Na, K-ATPase α1 subunit acts as an ion transporter along with the Na, K-ATPase ß1 subunit at the plasma membrane. We confirmed that RNF183 interacted with both α1 and ß1 subunits; however, we found that RNF183 ubiquitinated only the ß1 subunit, not the α1 subunit. Furthermore, RNF183 translocated both α1 and ß1 subunits from the plasma membrane to lysosomes. In addition, the expression levels of α1 and ß1 subunits in HEK293 cells stably expressing RNF183 were significantly decreased compared with mock control cells, and were restored by siRNA-mediated knockdown of RNF183. Moreover, in RNF183-expressing cells, chloroquine treatment increased the protein levels of the α1 and ß1 subunits. Therefore, our results suggest that Na, K-ATPase α1 and ß1 subunits are degraded in lysosomes by RNF183-mediated ubiquitination of ß1 subunit.

STT3B-dependent posttranslational N-glycosylation as a surveillance system for secretory protein.

Nascent secretory proteins are extensively scrutinized at the endoplasmic reticulum (ER). Various signatures of client proteins, including exposure of hydrophobic patches or unpaired sulfhydryls, are coordinately utilized to reduce nonnative proteins in the ER. We report here the cryptic N-glycosylation site as a recognition signal for unfolding of a natively nonglycosylated protein, transthyretin (TTR), involved in familial amyloidosis. Folding and ER-associated degradation (ERAD) perturbation analyses revealed that prolonged TTR unfolding induces externalization of cryptic N-glycosylation site and triggers STT3B-dependent posttranslational N-glycosylation. Inhibition of posttranslational N-glycosylation increases detergent-insoluble TTR aggregates and decreases cell proliferation of mutant TTR-expressing cells. Moreover, this modification provides an alternative pathway for degradation, which is EDEM3-mediated N-glycan-dependent ERAD, distinct from the major pathway of Herp-mediated N-glycan-independent ERAD. Hence we postulate that STT3B-dependent posttranslational N-glycosylation is part of a triage-salvage system recognizing cryptic N-glycosylation sites of secretory proteins to preserve protein homeostasis.

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.

Post-marketing safety-related regulatory actions on first-in-class drugs: A double-cohort study.

WHAT IS KNOWN AND OBJECTIVE: New first-in-class (FIC) drugs with novel mechanisms of action may be highly effective, but lack adequate safety information, and therefore may be associated with crucial post-marketing safety issues. The objective of this study was to evaluate the post-marketing risk of FIC drug with comparison occurrence of Post-marketing safety-related regulatory actions (PSRAs) due to FIC drugs to that due to other new drugs. METHODS: A full list of all new molecular entities and therapeutic biologics, except diagnostic agents and vaccines, which were approved in the United States between 1 January 2003, and 31 December 2013, were included in this study. Drugs with novel mechanisms of action at the time of approval were classified as the FIC cohort and other new drugs as the control cohort. PSRAs were defined as safety-related post-marketing withdrawal, new issuance or the addition of black box warnings. Specifically, we identified PSRAs associated with adverse drug reactions (ADR-PSRAs). Subsequently, we identified drug allergy ADR-PSRAs and class-effect ADR-PSRAs, and also extracted drug-specific ADR-PSRAs. To evaluate the post-marketing safety risk of FIC drugs, we estimated the odds ratio of the occurrence of ADR-PSRAs between the FIC cohort and the control cohort. RESULTS AND DISCUSSION: The odds ratio of the occurrence of all ADR-PSRA in the FIC cohort was 0.96 (95% CI: 0.57-1.61, P = .8758), showing no difference compared to that of the control cohort. However, the odds ratio of the occurrence of drug-specific ADR-PSRAs in the FIC cohort was 2.06 (95% CI: 1.20-3.55, P = .0091). WHAT IS NEW AND CONCLUSION: This study demonstrated that a strong relationship existed between FIC drugs and the occurrence of drug-specific ADR-PSRAs, suggesting that post-marketing safety risk for FIC drugs is higher than that for other new drugs given the same class at approval.

A specific combination of P wave duration and morphology accurately predicts the presence of left atrial low voltage area in patients with atrial fibrillation.

BACKGROUND: Since low voltage area (LVA) impairs not only intra atrial conduction velocity but also intra atrial propagate direction, these alternates may reflect the P wave duration (PWD) and morphology. We examined the relationship between the PWD, morphology and LVA. METHODS: Consecutive 127 AF patients were divided into 2 groups depending on the presence of LVA (35 subjects LVA positive group, 92 subjects LVA negative group). P wave morphologies were divided into 3 categories, normal: P-wave duration<120 ms, partial interatrial block (IAB): P wave duration≥120 ms, advanced IAB: PWD ≥ 120 ms with biphasic P waves in inferior leads. LVA was defined as a voltage amplitude<0.5 mV, and qualitatively assessed to be categorized into three grades (mild<10%, 10% ≤ moderate<30%, 30% ≤ extensive). RESULTS: LVA was significantly highly detected in patients of advanced age, female, comorbidities of hypertension, prior brain infarction, LA enlargement. PWD was correlated with LA volume in the LVA negative group, but not in the LVA positive group. Advanced IAB was significantly accumulated in the LVA positive group while partial IAB was found in both LVA positive and negative groups. Receiver-operating characteristics curve revealed that a combination of IAB and biphasic P wave in any inferior lead identified the presence of LVA with 83% sensitivity and 98% specificity. PWD and the presence of advanced IAB were independent predictors of LVA as determined by multivariate logistic regression analysis. CONCLUSION: Advanced IAB is a favorable parameter for the presence of LVA.

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.

Calnexin promotes the folding of mutant iduronate 2-sulfatase related to mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II) is one of the most common mucopolysaccharidoses, which is caused by mutation of the gene encoding iduronate 2-sulfatase (IDS). The loss of function of IDS leads to the accumulation of heparan sulfate and dermatan sulfate of glycosaminoglycans throughout the body, resulting in skeletal deformities, mental retardation, rigid joints, and thick skin. Recently, enzyme replacement therapy has become a common strategy for treating this condition. However, its effectiveness on the central nervous system (CNS) is limited because intravenously administered recombinant IDS (rIDS) cannot pass through the blood brain barrier. Therefore, several methods for delivering rIDS to the CNS, using anti-human transferrin receptor antibody and adeno-associated virus 9, have been explored. To investigate additional approaches for treatment, more cognition about the intracellular dynamics of mutant IDS is essential. We have already found that mutant IDS accumulated in the endoplasmic reticulum (ER) and was degraded by ER-associated degradation (ERAD). Although the dynamics of degradation of mutant IDS was revealed, the molecular mechanism related to the folding of mutant IDS in the ER remained unclear. In this research, we confirmed that mutant IDS retained in the ER would be folded by binding with calnexin (CNX). Thus, knockdown of CNX reduced the translocation of mutant IDS from ER to lysosome and its enzyme activity, indicating that the correct folding of this protein via interaction with CNX ensures its functional activity. These findings reveal the possibility that modifying the interaction of mutant IDS and CNX could contribute to alternative therapeutic strategies for MPS II.

Renal medullary tonicity regulates RNF183 expression in the collecting ducts via NFAT5.

Nuclear factor of activated T-cells 5 (NFAT5) directly binds to the promoter of the RING finger protein 183 (RNF183) gene and induces its transcription under hypertonic conditions in mouse inner-medullary collecting duct (mIMCD-3) cells. However, there is no specific anti-RNF183 antibody for immunostaining; therefore, it is unclear whether NFAT5 regulates RNF183 expression in vivo and where RNF183 is localized in the kidney. This study investigated NFAT5-regulated in vivo RNF183 expression and localization using CRISPR/Cas9-mediated RNF183-green fluorescent protein (RNF183-GFP) knock-in mice. GFP with linker sequences was introduced upstream of an RNF183 open reading frame in exon 3 by homologous recombination through a donor plasmid. Immunofluorescence staining using GFP antibody revealed that GFP signals gradually increase from the outer medulla down to the inner medulla and colocalize with aquaporin-2. Furosemide treatment dramatically decreased RNF183 expression in the renal medulla, consistent with the decrease in NFAT5 protein and target gene mRNA expression. Furosemide treatment of mIMCD-3 cells did not affect mRNA expression and RNF183 promoter activities. These results indicated that RNF183 is predominantly expressed in the renal medullary collecting ducts, and that decreased renal medullary tonicity by furosemide treatment decreases RNF183 expression by NFAT5 downregulation.

Regulatory characteristics and pivotal study design of US Food and Drug Administration approval of drugs for major vs. minor cancer.

PURPOSE: We aimed to investigate the regulatory approval of drugs for cancers by the US Food and Drug Administration based on the cancer type (major vs. minor), including the use of expedited development programs and duration from Investigational New Drug application (IND) to marketing approval. METHODS: From publicly available records and through a Freedom of Information Act request, we gathered data to evaluate regulatory characteristics and pivotal study design for 115 anticancer drug approvals between 2012 and 2017 and the data were analyzed based on cancer incidence (major vs. minor cancers) and how expedited programs, orphan drug designation, and pivotal study design contribute to expedited approval was studied. RESULTS: Drugs targeting minor cancers more frequently (67%; P = 0.0155) utilized breakthrough therapy designation and/or accelerated approval, both of which significantly contributed to expedited drug approval (median time from IND to approval, 6.4 years; P = 0.0008, 6.2 years; P < 0.0001). Drug approvals for pivotal study design without a comparator arm took significantly less time from IND to approval (median time from IND to approval, 6.2 years; P < 0.0001). CONCLUSIONS: Drugs targeting minor cancers have frequently utilized the expedited development programs; thus, efficiently shortening time to approval. As many of such drugs are approved based on non-comparative pivotal studies, meticulous evaluation and follow-up should be performed for such drugs after their approval.

Neuronal activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived neurotrophic factor in cell soma.

Unfolded protein response (UPR) has roles not only in resolving the accumulation of unfolded proteins owing to endoplasmic reticulum (ER) stress, but also in regulation of cellular physiological functions. ER stress transducers providing the branches of UPR signaling are known to localize in distal dendritic ER of neurons. These reports suggest that local activation of UPR branches may produce integrated outputs for distant communication, and allow regulation of local events in highly polarized neurons. Here, we demonstrated that synaptic activity- and brain-derived neurotrophic factor (BDNF)-dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation by using murine neuroblastoma cell line, Neuro-2A and primary cultured hippocampal neurons derived from postnatal day 0 litter C57BL/6 mice. ER stress transducer, inositol-requiring kinase 1 (IRE1), was activated at postsynapses in response to excitatory synaptic activation. Activated dendritic IRE1 accelerated accumulation of the downstream transcription factor, x-box-binding protein 1 (XBP1), in the nucleus. Interestingly, excitatory synaptic activation-dependent up-regulation of XBP1 directly facilitated transcriptional activation of BDNF. BDNF in turn drove its own expression via IRE1-XBP1 pathway in a protein kinase A-dependent manner. Exogenous treatment with BDNF promoted extension and branching of dendrites through the protein kinase A-IRE1-XBP1 cascade. Taken together, our findings indicate novel mechanisms for communication between soma and distal sites of polarized neurons that are coordinated by local activation of IRE1-XBP1 signaling. Synaptic activity- and BDNF-dependent distinct activation of dendritic IRE1-XBP1 cascade drives BDNF expression in cell soma and may be involved in dendritic extension. Cover Image for this issue: doi. 10.1111/jnc.14159.

Assessment of Cardiovascular Risk With Glucagon-Like Peptide 1 Receptor Agonists in Patients With Type 2 Diabetes Using an Alternative Measure to the Hazard Ratio.

BACKGROUND: Randomized clinical trials with the aim of evaluating the cardiovascular risks associated with glucagon-like peptide 1 (GLP-1) receptor agonists, lixisenatide, liraglutide, semaglutide, and exenatide, have been conducted. They showed different results among the agents, but the reason has not been explained. OBJECTIVE: To evaluate the cardiovascular risks associated with GLP-1 receptor agonists by using an alternative measure to the hazard ratio. METHODS: We used the difference in restricted mean survival time (RMST) as a measure of cardiovascular risks. Four randomized clinical trials with cardiovascular events as a primary endpoint, ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide), were reevaluated by estimating the RMSTs for each of the agents and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information. RESULTS: The differences of RMSTs (GLP-1 receptor agonist minus placebo: point estimate and 95% CI) for primary composite endpoint of cardiovascular events were 0 days [-14, 14] in ELIXA (1080 days follow-up), 20 days [6, 34] in LEADER (1620 days follow-up), 8 days [1, 15] in SUSTAIN-6 (672 days follow-up), and 11 days [-3, 26] in EXSCEL (1825 days follow-up). As for the risk of other cardiovascular outcomes, there were no substantial differences between GLP-1 receptor agonists and placebo. CONCLUSIONS: Liraglutide and semaglutide decrease the risk of major adverse cardiovascular events compared with placebo when using the difference in RMST. The previously reported result that GLP-1 receptor agonists do not increase the risk of cardiovascular outcomes compared with placebo is also confirmed.

Analysis of factors related to the occurrence of important drug-specific postmarketing safety-related regulatory actions: A cohort study focused on first-in-class drugs.

PURPOSE: First-in-class (FIC) drugs with novel modes of action pose concerns regarding important postmarketing safety issues. The purpose of this study was to analyze the factors related to the occurrence of postmarketing safety-related regulatory actions (PSRAs) for drugs approved in the United States (US), with a focus on FIC drugs. METHODS: New molecular entities and new therapeutic biologics approved in the United States between 1 January 2003 and 31 December 2013 were included in the analysis. Important drug-specific PSRAs were defined as market withdrawal or the addition of new black box warnings or warnings due to adverse drug reactions. The relationship between baseline characteristics and the occurrence of important drug-specific PSRAs was investigated using a multivariate logistic regression model. We also defined the event as the first important PSRA and estimated the time-to-event for each factor. RESULTS: ATC category L (antineoplastic and immunomodulating agents) and FIC drug classification were shown to be statistically significant factors, with odds ratios of 2.15 (95% CI: 1.12-4.11; P = 0.0203) and 1.87 (95% CI: 1.06-3.31; P = 0.0309), respectively. ATC category L and FIC drugs were also significant factors for time to occurrence of the first event. CONCLUSION: FIC designation and ATC category L were identified as factors related to important drug-specific PSRAs. These factors were also associated with the time to occurrence of the first important drug-specific PSRAs.

Significance of data mining in routine signal detection: Analysis based on the safety signals identified by the FDA.

PURPOSE: Data mining has been introduced as one of the most useful methods for signal detection by spontaneous reports, but data mining is not always effective in detecting all safety issues. To investigate appropriate situations in which data mining is effective in routine signal detection activities, we analyzed the characteristics of signals that the US Food and Drug Administration (FDA) identified from the FDA Adverse Event Reporting System (FAERS). METHODS: Among the signals that the FDA identified from the FAERS between 2008 1Q and 2014 4Q, we selected 233 signals to evaluate in this study. We conducted a disproportionality analysis and classified these signals into two groups according to the presence or absence of statistical significance in the reporting odds ratio (ROR). Then, we compared the two groups based on the characteristics of the suspected drugs and adverse events (AEs). RESULTS: Safety signals were most frequently identified for new drugs that had been on the market for less than 5 years, but some signals were still identified for old drugs (≥20 years), and most of them were statistically significant. The proportion of the signals for "serious" events was significantly higher in the group of nonsignals by ROR (Fisher's exact test, P = 0.032). CONCLUSIONS: Data mining was shown to be effective in the following situations: (1) early detection of safety issues for newly marketed drugs, (2) continuous monitoring of safety issues for old drugs, and (3) signal detection of nonserious AEs, to which little attention is usually given.

Luman is involved in osteoclastogenesis through the regulation of DC-STAMP expression, stability and localization.

Luman (also known as CREB3) is a type-II transmembrane transcription factor belonging to the OASIS family that localizes to the endoplasmic reticulum (ER) membrane under normal conditions. In response to ER stress, OASIS-family members are subjected to regulated intramembrane proteolysis (RIP), following which the cleaved N-terminal fragments translocate to the nucleus. In this study, we show that treatment of bone marrow macrophages (BMMs) with cytokines - macrophage colony-stimulating factor (M-CSF) and RANKL (also known as TNFSF11) - causes a time-dependent increase in Luman expression, and that Luman undergoes RIP and becomes activated during osteoclast differentiation. Small hairpin (sh)RNA-mediated knockdown of Luman in BMMs prevented the formation of multinucleated osteoclasts, concomitant with the suppression of DC-STAMP, a protein that is essential for cell-cell fusion in osteoclastogenesis. The N-terminus of Luman facilitates promoter activity of DC-STAMP, resulting in upregulation of DC-STAMP expression. Furthermore, Luman interacts with DC-STAMP, and controls its stability and localization. These results suggest that Luman regulates the multinucleation of osteoclasts by promoting cell fusion of mononuclear osteoclasts through DC-STAMP induction and intracellular distribution during osteoclastogenesis.

Assessment of the Risk of Hospitalization for Heart Failure With Dipeptidyl Peptidase-4 Inhibitors, Saxagliptin, Alogliptin, and Sitagliptin in Patients With Type 2 Diabetes, Using an Alternative Measure to the Hazard Ratio.

BACKGROUND: Saxagliptin statistically significantly increased the risk of hospitalization for heart failure compared with placebo in the clinical trial of SAVOR-TIMI 53. Neither the reason why only saxagliptin among several dipeptidyl peptidase-4 (DPP-4) inhibitors increased the risk, nor the clinical implication of the result has been explained. OBJECTIVE: To evaluate the risk of hospitalization for heart failure associated with DPP-4 inhibitors by using an alternative measure to the hazard ratio. METHODS: We used the difference in restricted mean survival time (RMST) between DPP-4 inhibitors and placebo to evaluate the risk of cardiovascular events, including hospitalization for heart failure associated with DPP-4 inhibitors. Three randomized clinical trials with cardiovascular events as a primary end point-EXAMINE (alogliptin), SAVOR-TIMI 53 (saxagliptin), and TECOS (sitagliptin)-were reevaluated by estimating the RMSTs for the DPP-4 inhibitors and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information. RESULTS: The differences of RMSTs (DPP-4 inhibitors minus placebo) for hospitalization for heart failure were -4 days [-6, -2] in the SAVOR-TIMI 53 (720 days follow-up), -3 days [-9, 3] in the EXAMINE (900 days follow-up), and 1 day [-5, 7] in the TECOS (1440 days follow-up). There were no substantial differences in the risk of other cardiovascular outcomes between DPP-4 inhibitors and placebo. CONCLUSIONS: There are no substantial clinically relevant differences in the risk of cardiovascular events, including hospitalization for heart failure, between 3 of the DPP-4 inhibitors and placebo.