A real-world disproportionality analysis of apalutamide: data mining of the FDA adverse event reporting system.

Background: Apalutamide is a new drug class, which is approved to treat prostate cancer (PCa). The aim of our study was to assess the safety profiles of apalutamide in real-world through data mining of the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Method: We included adverse event (AE) reports regarding apalutamide submitted to the FAERS from 2018 quarter 1 (2018Q1) to 2022 quarter 1 (2022Q1). Disproportionality analyses, including reporting odds ratio (ROR), were performed to identify the signals of AEs in patients receiving apalutamide. A signal was detected if the lower limit of the 95% confidence interval (CI) of ROR >1 and at least 3 AEs were reported. Results: The FAERS database documented 4,156 reports regarding apalutamide from 1 January 2018, to 31 March 2022. A total of 100 significant disproportionality preferred terms (PTs) were retained. Frequently observed AEs in patients receiving apalutamide included rash, fatigue, diarrhea, hot flush, fall, weight decreased, hypertension. The most significant system organ class (SOC) was "skin and subcutaneous tissue disorders", which mainly consisted of dermatological adverse events (dAEs). The additional AEs observed with the significantly signal contain lichenoid keratosis, increased eosinophil count, bacterial pneumonia, pulmonary tuberculosis, hydronephrosis. Conclusion: Our findings provide valuable evidence for apalutamide safety profile in the real-world, which could help clinicians and pharmacists to enhance their vigilance and improve the safety of apalutamide in clinical practice.

Adverse event profiles of PCSK9 inhibitors alirocumab and evolocumab: Data mining of the FDA adverse event reporting system.

BACKGROUND: Proprotein convertase subtilisin/kexin type (PCSK9) inhibitor is a new drug class approved for treating dyslipidemias. Herein, we aimed to investigate the safety profiles of PCSK9 inhibitors (alirocumab and evolocumab) using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: We included adverse event (AE) reports regarding alirocumab and evolocumab submitted to the FAERs between 2015Q3 to 2021Q1. Disproportionality analyses, including reporting odds ratio (ROR), were performed to detect risk signals from the FAERs data to identify potential drug-AE associations. A signal was considered when the lower limit of the 95% confidence interval of ROR exceeded 1 and ≥3 AEs were reported. The definition relied on system organ class and preferred terms established by the Medical Dictionary for Regulatory Activities. RESULTS: The FAERS database documented 31 475 reports regarding PCSK9 inhibitors (alirocumab and evolocumab) from July 1, 2015, to March 31, 2021. Although some differences were detected, alirocumab and evolocumab shared considerably similar safety profiles. The most significant RORs and most common reports were injection-site reactions (eg, injection-site pain, bruising, haemorrhage, erythema), muscle-related AEs (eg, myalgia, back pain, arthralgia, muscle spasms), influenza-like illness, pain and headache. CONCLUSION: Data mining of the FAERs is useful for examining PCSK9 inhibitor-induced AEs. Herein, our findings were largely consistent with clinical experience and could help clinicians improve the safety of PCSK9 inhibitors in clinical practice.

RNA-binding protein RNPC1 acts as an oncogene in gastric cancer by stabilizing aurora kinase B mRNA.

BACKGROUND: RNPC1 is reported to act as a tumor suppressor by binding and regulating the expression of target genes in various cancers. However, the role of RNPC1 in gastric cancer and the underlying mechanisms are still unclear. METHODS: Gastric cancer cells were stably transfected with lentivirus. Proliferation, migration, invasion, cell cycle in vitro and tumorigenesis in vivo were used to assess the role of RNPC1. Quantitative real-time PCR, western blotting and immunohistochemistry were used to detect the relationship between RNPC1 and aurora kinase B (AURKB). RNA immunoprecipitation (RIP), RNA electrophoretic mobility shift assays (REMSAs), and dual-luciferase reporter assays were used to identify the direct binding sites of RNPC1 with AURKB mRNA. A CCK-8 assay was conducted to confirm the function of AURKB in RNPC1-induced growth promotion. RESULTS: High RNPC1 expression was found in gastric cancer tissues and cell lines and was associated with high TNM stage. RNPC1 overexpression significantly promoted the proliferation, migration, and invasion of gastric cancer cells. Knockdown of RNPC1 could impede gastric cancer tumorigenesis in nude mice. AURKB expression was positively related to RNPC1. RNPC1 directly binds to the 3'-untranslated region (3'-UTR) of AURKB and enhances AURKB mRNA stability. AURKB reversed the proliferation induced by RNPC1 in gastric cancer cells. RNPC1 resulted in mitotic defects, aneuploidy and chromosomal instability in gastric cancer cells, similar to AURKB. CONCLUSION: RNPC1 acts as an oncogene in gastric cancer by influencing cell mitosis by increasing AURKB mRNA stability, which may provide a potential biomarker and a therapeutic target for gastric cancer.

NKTR-358: A novel regulatory T-cell stimulator that selectively stimulates expansion and suppressive function of regulatory T cells for the treatment of autoimmune and inflammatory diseases.

Impaired interleukin-2 (IL-2) production and regulatory T-cell dysfunction have been implicated as immunological mechanisms central to the pathogenesis of multiple autoimmune and inflammatory diseases. NKTR-358, a novel regulatory T-cell stimulator, is an investigational therapeutic that selectively restores regulatory T-cell homeostasis in these diseases. We investigated NKTR-358's selectivity for regulatory T-cells, receptor-binding properties, ex vivo and in vivo pharmacodynamics, ability to suppress conventional T-cell proliferation in mice and non-human primates, and functional activity in a murine model of systemic lupus erythematosus. In vitro, NKTR-358 demonstrated decreased affinity for IL-2Rα, IL-2Rß, and IL-2Rαß compared with recombinant human IL-2 (rhIL-2). A single dose of NKTR-358 in cynomolgus monkeys produced a greater than 15-fold increase in regulatory T-cells, and the increase lasted until day 14, while daily rhIL-2 administration for 5 days only elicited a 3-fold increase, which lasted until day 7. Repeated dosing of NKTR-358 over 6 months in cynomolgus monkeys elicited cyclical, robust increases in regulatory T-cells with no loss in drug activity over the course of treatment. Regulatory T-cells isolated from NKTR-358-treated mice displayed a sustained, higher suppression of conventional T-cell proliferation than regulatory T-cells isolated from vehicle-treated mice. NKTR-358 treatment in a mouse model (MRL/MpJ-Faslpr) of systemic lupus erythematosus for 12 weeks maintained elevated regulatory T-cells for the treatment duration and ameliorated disease progression. Together, these results suggest that NKTR-358 has the ability to elicit sustained and preferential proliferation and activation of regulatory T-cells without corresponding effects on conventional T-cells, with improved pharmacokinetics compared with rhIL-2.

Efficacy and safety of thrombolysis for acute ischemic stroke with atrial fibrillation: a meta-analysis.

BACKGROUND: The efficacy and safety of intravenous thrombolysis (IVT) for acute ischemic stroke with atrial fibrillation (AF) is still controversial. METHODS: We conducted a meta-analysis of all relevant studies, retrieved through systematic search of PubMed, Embase, and Cochrane databases up to December 31, 2019. Modified Rankin Scale (mRS) scores of 0-1 at 90 days, mRS of 0-2 at 90 days, overall mortality, and incidence of symptomatic intracranial hemorrhage (sICH) were collected as outcome measures. Fixed- and random-effects meta-analytical models were applied, and between-study heterogeneity was assessed. RESULTS: A total of 8509 patients were enrolled in 18 studies. A comparison of IVT treatment in AF versus non-AF patients showed that AF was associated with a significantly lower proportion of patients with mRS of 0-1 (24.1% vs. 34.5%; OR 0.59; 95% CI 0.43-0.81; P < 0.001), mRS of 0-2 (33.6% vs. 47.8%; OR 0.55; 95% CI 0.43-0.70; P < 0.001), as well as significantly higher mortality (19.4% vs. 11.5%; OR 2.05; 95% CI 1.79-2.36; P < 0.001) and higher incidence of sICH (6.4% vs. 4.1%; OR 1.60; 95% CI 1.27-2.01; P < 0.001). A comparison of AF patients who were subjected or not to IVT showed that thrombolysis carried a higher risk of sICH (5.7% vs. 1.6%; OR 3.44; 95% CI 2.04-5.82; P < 0.001) and was not associated with a better prognosis. Subgroup analysis in prospective studies also suggested a poorer functional prognosis and higher mortality in AF patients treated with IVT compared with those who did not receive IVT. Some heterogeneity was present in this meta-analysis. CONCLUSIONS: Acute IS patients with AF had worse outcomes than those without AF after thrombolytic therapy, and had a higher incidence of sICH after thrombolysis than those without thrombolysis. Thrombolysis in ischemic stroke patients with AF should be carefully considered based on clinical factors such as NIHSS score, age, and the type of AF.

Specific knockdown of hippocampal astroglial EphB2 improves synaptic function via inhibition of D-serine secretion in APP/PS1 mice.

Increasing evidence emphasizes the protective role of Eph receptors in synaptic function in the pathological development of Alzheimer's disease (AD); however, their roles in the regulation of hippocampal astrocytes remain largely unknown. Here, we directly investigated the function of astroglial EphB2 on synaptic plasticity in APP/PS1 mice. Using cell isolation and transgene technologies, we first isolated hippocampal astrocytes and evaluated the expression levels of ephrinB ligands and EphB receptors. Then, we stereotaxically injected EphB2-Flox-AAV into the hippocampus of GFAP-cre/APP/PS1 mice and further evaluated hippocampal synaptic plasticity and astroglial function. Interestingly, astrocytic EphB2 expression was significantly increased in APP/PS1 mice in contrast to its expression profile in neurons. Moreover, depressing this astroglial EphB2 upregulation enhanced hippocampal synaptic plasticity, which results from harmful D-serine release. These results provide evidence of the different expression profiles and function of EphB2 between astrocytes and neurons in AD pathology.

Regional Differences in Food Allergies.

The prevalence of food allergies is increasing worldwide. To understand the regional specificities of food allergies and develop effective therapeutic interventions, extensive regional epidemiological studies are necessary. While data regarding incidence, prevalence, regional variation, and treatment in food allergies are available for western countries, such studies may not be available in many Asian countries. China accounts for almost 20% of the world's population and has a vast ethnic diversity, but large-scale meta-analyses of epidemiological studies of food allergy in China are lacking. A literature search revealed 22 publications on the prevalence of food allergy in Chinese populations. A review of these studies showed that the prevalence of food allergies in China is comparable to that in western countries, even though the Chinese diet is vastly different from that of the West and may vary even greatly within China, and finally, specific antigenic triggers of food allergy vary between China and the West and also within China. Current clinical management of food allergy in China includes allergen-specific immunotherapy, Chinese herbal medicine, acupuncture, and Western medicine. This study demonstrates an unmet need in China for a thorough investigation of the prevalence of food allergies in China, the specific foods involved, and characterization of the specific antigenic triggers of food allergy with respect to ethnicity, age, and diet in China.

Serum STLT-1 and bilirubin levels in patients with acute coronary syndrome and correlation with prognosis.

The serum triggering receptor expressed on myeloid cell (TREM)-like transcription factor-1 [soluble TREM-like transcript-1 (STLT-1)] and bilirubin levels were investigated in patients with acute coronary syndrome and the correlation with prognosis. A total of 125 patients of acute coronary syndrome admitted to the Department of Cardiology in People's Hospital of Rizhao were selected, including 45 cases with ST-segment elevation myocardial infarction (STEMI), 36 cases with non-ST-elevation myocardial infarction (NSTEMI) and 44 cases with unstable angina pectoris (UAP), while 48 subjects were enrolled as the normal control. The serum STLT-1 and bilirubin levels on admission and on the 3rd, 7th and 10th day after admission of patients in each group were respectively determined, the level changes of these two indicators in serum during the initial stage of acute coronary syndrome were analyzed, and their effects on prognosis of patients were analyzed. STLT-1 levels in groups STEMI, NSTEMI and UAP were higher than those in the normal control group, and serum levels of STLT-1 in groups STEMI and NSTEMI were higher than those in group UAP. Bilirubin levels in groups STEMI, NSTEMI and UAP were lower than those in the normal control group, and serum levels of bilirubin in groups STEMI and NSTEMI were lower than those in group UAP. The proportions of complications in patients of groups STEMI and NSTEMI were significantly higher than those in group UAP (P<0.05). The results showed that the timely and effective treatment administered to patients with acute coronary syndrome during the initial stage to reduce the level of STLT-1 in serum and enhance bilirubin to a relatively high level is conducive in ameliorating the prognosis of patients, which is of clinical significance.

Clinical and economic impact of pharmacist interventions on sampled outpatient prescriptions in a Chinese teaching hospital.

BACKGROUND: Limited studies have evaluated the effectiveness of pharmacist interventions on outpatient prescription. The goal of this study was to evaluate the clinical and economic impacts of pharmacist interventions on randomly sampled outpatient prescriptions. METHOD: Outpatient prescriptions of our hospital were sampled automatically and reviewed by pharmacists since 2011. Pharmacists intervened in inappropriate prescriptions (IPs) real-timely, and summarized and analyzed the information monthly. Cost-benefit analysis was performed to estimate the economic benefit of the pharmacist intervention. RESULTS: From 2011 to 2016, pharmacists reviewed 101,271 prescriptions and intervened in 5155 prescriptions. With the interventions of pharmacists, the number of IPs decreased from 1845 to 238, while the inappropriate percentage decreased from 12.60 to 1.22%. The inappropriate rates of different departments and the types decreased annually. IPs were mainly from the Department of Medicine and Department of Surgery and category 1 (Non-indicated medications) in all years. The benefit-to-cost ratios of pharmacist interventions were always more than 1. In the same years, the benefit-to-cost ratios in public payments were higher than those with insurance and self-payment. CONCLUSION: This form of pharmacist intervention constitutes a method that showed positive clinical and economic benefits and is worth expanding in large hospitals. Pharmacists should pay more attention on prescriptions in department of surgery or prescriptions with public payments.

Sphingosine kinase inhibitors: A patent review.

Sphingosine kinases (SphKs) catalyze the conversion of the sphingosine to the promitogenic/migratory product, sphingosine-1-phosphate (S1P). SphK/S1P pathway has been linked to the progression of cancer and various other diseases including allergic inflammatory disease, cardiovascular diseases, rejection after transplantation, the central nervous system, and virus infections. Therefore, SphKs represent potential new targets for developing novel therapeutics for these diseases. The history and development of SphK inhibitors are discussed, summarizing SphK inhibitors by their structures, and describing some applications of SphK inhibitors. We concluded: i) initial SphK inhibitors based on sphingosine have low specificity with several important off-targets. Identification the off-targets that would work synergistically with SphKs, and developing compounds that target the unique C4 domain of SphKs should be the focus of future studies. ii) The modifications of SphK inhibitors, which are devoted to increasing the selectivity to one of the two isoforms, now focus on the alkyl length, the spacer between the head and linker rings, and the insertion and the position of lipidic group in tail region. iii) SphK/S1P signaling pathway holds therapeutic values for many diseases. To find the exact function of each isoform of SphKs increasing the number of SphK inhibitor clinical trials is necessary.

Inhibitors targeting the SUMOylation pathway: A patent review 2012­2015 (Review).

Small ubiquitin­related modifier (SUMO) proteins bind to the lysine residue of target proteins to produce functionally mature proteins. The abnormal SUMOylation of certain target proteins is associated with diseases including cancer, heart disease, diabetes, arthritis, degenerative diseases and brain ischemia/stroke. Thus, there has been growing appreciation for the potential importance of the SUMO conjugation pathway as a target for treating these diseases. This review introduces the important steps in the reversible SUMOylation pathway. The SUMO inhibitors disclosed in the patents between 2012 and 2015 are divided into different categories according to their mechanisms of action. Certain compounds disclosed in this review have also been reported in other articles for their inhibition of the SUMOylation pathway following screening in cell lines. Although there are few studies using animal models or clinical trials that have used these compounds, the application of bortezomin, a ubiquitylation inhibitor, for treating cancer indicates that SUMO inhibitors may be clinically successful.

Quercetin alleviates thermal and cold hyperalgesia in a rat neuropathic pain model by inhibiting Toll-like receptor signaling.

Neuropathic pain is caused by lesion or disease of the nervous system, which results in abnormal spontaneous and evoked pain. It's common in clinical practice and greatly impairs the life quality of patients, but the effective treatment is still lacking. In this study, we aimed to explore the effect of quercetin (QUE) on neuropathic pain and the underlying mechanisms. Spinal nerve ligation (SNL) was performed in Sprague Dawley rats to establish the neuropathic pain model. Single or continuous oral administration of QUE after the operation or continuous administration before the operation was applied to evaluate the effects of QUE on SNL-induced thermal and cold hyperalgesia. Dorsal root ganglions from these rats were harvested to analyze the expression levels of some inflammatory mediators. Primary cultured astrocytes and HEK293 cells were used to further explore the downstream signaling pathways of QUE. Both single and continuous oral administration of QUE dose-dependently alleviated SNL-induced thermal and cold hyperalgesia. Pre-administration also attenuated neuropathic pain symptoms. Meanwhile, SNL-induced increase in protein or mRNA levels of some inflammatory mediators could be down-regulated by QUE treatment. Furthermore, QUE reduced the phosphorylation of TAK1, IKK and JNK2 in cultured astrocytes. Moreover, luciferase assay in HEK293 cells showed that QUE dose-dependently inhibited NF-κB activity only via TAK1. QUE exerts anti-inflammatory effects and alleviates neuropathic pain through the inhibition of Toll-like receptor signaling pathway. It could shed some light on the potential applications of QUE in chronic pain therapy.

Expression and purification of a major allergen, Pla a 1, from Platanus acerifolia pollen and the preparation of its monoclonal antibody.

Platanus acerifolia pollen is considered an important source of airborne allergens in numerous cities. Pla a 1 is a major allergen from P. acerifolia pollen. The present study aimed to express and purify Pla a 1, and to prepare its monoclonal antibody. In the present study, the Pla a 1 gene was subcloned into a pET­28a vector and transformed into the ArcticExpress™ (DE3) RP Escherichia coli host strain. The purified Pla a 1 was then used to immunize BALB/c mice. When serum detection was positive, spleen cells were isolated from the mice and fused with SP2/0 myeloma cells at a ratio of 10:1. Hybridoma cells were screened by indirect ELISA and limiting dilution. Positive cells were used to induce the formation of antibody­containing ascites fluid, and the antibodies were purified using protein A­agarose. The results of the present study demonstrated that recombinant Pla a 1 was successfully expressed and purified, and exhibited positive immunoglobulin E­binding to serum from patients allergic to P. acerifolia. A total of 11 hybridomas that steadily secreted anti­Pla a 1 antibody were obtained and an immunoblotting analysis indicated that all of these monoclonal antibodies specifically recognized the Pla a 1 protein. These results suggested that specific anti­Pla a 1 antibodies may be obtained, which can be used for the rapid detection of Pla a 1 allergens and in the preparation of vaccines against P. acerifolia pollen.

miR-93 enhances hepatocellular carcinoma invasion and metastasis by EMT via targeting PDCD4.

OBJECTIVES: To clarify the potential biological function of miR-93 and its related molecular mechanism underlying metastasis in human hepatocellular carcinoma (HCC). RESULTS: miR-93 was significantly up-regulated in HCC tissues and was associated with poor 5-year overall survival in HCC patients. Transwell assays showed that over-expression of miR-93 increased HCC cell migration and invasion in vitro. Programmed cell death 4 (PDCD4) was a target gene of miR-93 and miR-93 could down-regulate the expression of PDCD4 by directly targeting its 3'-UTR. The re-expression of PDCD4 could attenuate the HCC cell invasion and migration induced by miR-93, while the knockdown of PDCD4 would promote HCC cell migration and invasion via the epithelial-mesenchymal transition (EMT) pathway. CONCLUSIONS: miR-93 provides new insight into the molecular mechanisms of pathogenesis and progression in HCC and offer a potential therapeutic target for the treatment of HCC patients.

Expression, purification and epitope analysis of Pla a 3 allergen from Platanus acerifolia pollen.

Platanus acerifolia (P. acerifolia) is an important cause of pollinosis in cities. The use of allergen extracts on patients with allergic diseases is the most commonly applied method to attempt to treat pollinosis. Pla a 3, a non­specific lipid transfer protein, is a major allergen present in P. acerifolia pollen extracts. In the present study, the Pla a 3 gene was sub­cloned into a pSUMO­Mut vector using Stu I and Xho I sites and transformed into the Arctic Express™ (DE3) RP E. coli host strain. The purified Pla a 3 allergen was analyzed by western blotting and the results revealed that the Pla a 3 allergen has the ability to bind IgE in the P. acerifolia pollen of allergic patients' sera. Moreover, the authors predicted the potential B cell epitopes of the Pla a 3 allergen using the DNAStar Protean system, the Bioinformatics Predicted Antigenic Peptides system and the BepiPred 1.0 server. In addition, the T cell epitopes were predicted by the SYFPEITHI database and the NetMHCII­2.2 server. As a result, two B cell epitopes (35­45 and 81­86) and four potential T cell epitopes including 2­15, 45­50, 55­61 and 67­73 were predicted in the present study. The current results can be used to contribute to allergen immunotherapies and useful in peptide­based vaccine designs of pollen allergy.

Selective deletion of apolipoprotein E in astrocytes ameliorates the spatial learning and memory deficits in Alzheimer's disease (APP/PS1) mice by inhibiting TGF-ß/Smad2/STAT3 signaling.

Astrocytes and apolipoprotein E (apoE) play critical roles in cognitive function, not only under physiological conditions but also in some pathological situations, particularly in the pathological progression of Alzheimer's disease (AD). The regulatory mechanisms underlying the effect of apoE, derived from astrocytes, on cognitive deficits during AD pathology development are unclear. In this study, we generated amyloid precursor protein/apoE knockout (APP/apoEKO) and APP/glial fibrillary acidic protein (GFAP)-apoEKO mice (the AD mice model used in this study was based on the APP-familial Alzheimer disease overexpression) to investigate the role of apoE, derived from astrocytes, in AD pathology and cognitive function. To explore the mechanism, we investigated the amyloidogenic process related transforming growth factor ß/mothers against decapentaplegic homolog 2/signal transducer and activator of transcription 3 (TGF-ß/Smad2/STAT3) signaling pathway and further confirmed by administering TGF-ß-overexpression adeno-associated virus (specific to astrocytes) to APP/GFAP-apoEKO mice and TGF-ß-inhibition adeno-associated virus (specific to astrocytes) to APP/WT mice. Whole body deletion of apoE significantly ameliorated the spatial learning and memory impairment, reduced amyloid ß-protein production and inhibited astrogliosis in APP/apoEKO mice, as well as specific deletion apoE in astrocytes in APP/GFAP-apoEKO mice. Moreover, amyloid ß-protein accumulation was increased due to promotion of amyloidogenesis of APP, and astrogliosis was upregulated by activation of TGF-ß/Smad2/STAT3 signaling. Furthermore, the overexpression of TGF-ß in astrocytes in APP/GFAP-apoEKO mice abrogated the effects of apoE knockout. In contrast, repression of TGF-ß in astrocytes of APP/WT mice exerted a therapeutic effect similar to apoE knockout. These data suggested that apoE derived from astrocytes contributes to the risk of AD through TGF-ß/Smad2/STAT3 signaling activation. These findings enhance our understanding of the role of apoE, derived from astrocytes, in AD and suggest it to be a potential biomarker and therapeutic target for AD.

Etirinotecan pegol administration is associated with lower incidences of neutropenia compared to irinotecan administration.

PURPOSE: The relationship between incidences of neutropenia and 10-hydroxy-7-ethyl camptothecin (SN38) exposure was explored using SN38 pharmacokinetic and neutrophil count data from toxicology studies of etirinotecan pegol (EP) and irinotecan in beagle dogs. METHODS: Dogs received four weekly intravenous infusions of either vehicle control (n = 22), EP (6, 15, 20, 25, 40/25 mg/kg; n = 3-9 dogs/dose group/sex; n = 48), or irinotecan (20 or 25 mg/kg n = 3-4 dogs/dose group/sex; n = 14). Blood samples were collected up to 50 days post-dose for characterization of SN38 pharmacokinetics. Two separate models were created describing SN38 concentration time profiles after either irinotecan or EP administrations to project the AUC0-168h after Day 1 and Day 22 doses. The relationship between incidence of neutropenia and SN38 exposure was explored using logistic regression. RESULTS: The incidence of neutropenia in dogs receiving weekly doses of irinotecan or EP was strongly correlated with maximum plasma SN38 concentration (C max), but not SN38 area under the concentration-time curve (AUC). Neutropenia occurred in approximately 80% of dogs receiving irinotecan (mean SN38 C max of 13.5 and 26.3 ng/mL for 20 and 25 mg/kg, respectively). No neutropenia occurred in dogs receiving EP at doses up to and including 25 mg/kg (mean SN38 C max of 3.4 and 4.9 ng/mL for 20 and 25 mg/kg, respectively), despite 2.5-3.6 times greater SN38 AUC after EP compared to irinotecan at equivalent doses. CONCLUSIONS: EP administration avoids both high SN38 C max values and development of dose-limiting neutropenia observed after irinotecan, while maintaining greater and sustained SN38 exposure between doses.

Omalizumab for the treatment of chronic spontaneous urticaria: A meta-analysis of randomized clinical trials.

BACKGROUND: Chronic spontaneous urticaria (CSU) is defined by itchy hives, angioedema, or both for at least 6 weeks. Omalizumab, an anti-IgE antibody that affects mast cell and basophil function, is a promising new treatment option. As of now, however, the efficacy and safety of different doses of omalizumab used in clinical trials for CSU have not been systematically analyzed and summarized. OBJECTIVE: We sought to assess the efficacy and safety of different doses of omalizumab for the treatment of CSU in a meta-analysis of clinical trial results. METHODS: Suitable trials were identified by searching PubMed, Medline, Embase, and Web of Science databases and with the help of omalizumab's manufacturers. Only double-blind, randomized, placebo-controlled studies with omalizumab-treated versus placebo-treated patients with CSU were included in this analysis. RESULTS: We identified 7 randomized, placebo-controlled studies with 1312 patients with CSU. Patients treated with omalizumab (75-600 mg every 4 weeks) had significantly reduced weekly itch and weekly wheal scores compared with the placebo group. Omalizumab's effects were dose dependent, with the strongest reduction in weekly itch and weekly wheal scores observed with 300 mg. Rates of complete response were significantly higher in the omalizumab group (relative risk, 4.55; P < .00001) and dose dependent, with the highest rates in the 300-mg group. Rates of patients with adverse events were similar in the omalizumab and placebo groups. CONCLUSION: This meta-analysis provides high-quality evidence for the efficacy and safety of omalizumab in patients with CSU and for treating these patients with 300 mg of omalizumab every 4 weeks.

NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models.

PURPOSE: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates. EXPERIMENTAL DESIGN: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates. RESULTS: In a murine melanoma tumor model, the ratio of tumor-killing CD8(+) T cells to Foxp3(+) regulatory T cells was greater than 400 for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single agent and provided durable immunity that was resistant to tumor rechallenge in combination with anti-CTLA-4 antibody. NKTR-214 was well tolerated in non-human primates. CONCLUSIONS: These data support further evaluation of NKTR-214 in humans for a variety of tumor types, adding to the repertoire of potent and potentially curative cancer immunotherapies.

Non-use of health care service among empty-nest elderly in Shandong, China: a cross-sectional study.

BACKGROUND: Empty-nest elderly refers to those elderly with no children or whose children have already left home. Few studies have focused on healthcare service use among empty-nest seniors, and no studies have identified the prevalence and profiles of non-use of healthcare services among empty-nest elderly. The purpose of this study is to compare the prevalence of non-use of healthcare services between empty-nest and non-empty-nest elderly and identify risk factors for the non-use of healthcare services among empty-nest seniors. METHODS: Four thousand four hundred sixty nine seniors (60 years and above) were draw from a cross-sectional study conducted in three urban districts and three rural counties of Shandong Province in China. Non-visiting within the past 2 weeks and non-hospitalization in previous year are used to measure non-use of healthcare services. Chi-square test is used to compare the prevalence of non-use between empty-nesters and non-empty-nesters. Multivariate logistic regression analysis is employed to identify the risk factors of non-use among empty-nest seniors. RESULTS: Of 4469 respondents, 2667 (59.7%) are empty-nesters. Overall, 35.5% of the participants had non-visiting and 34.5% had non-hospitalization. Non-visiting rate among empty-nest elderly (37.7%) is significantly higher than that among non-empty-nest ones (32.7%) (P = 0.008). Non-hospitalization rate among empty-nesters (36.1%) is slightly higher than that among non-empty-nesters (31.6%) (P = 0.166). Financial difficulty is the leading cause for both non-visiting and non-hospitalization of the participants, and it exerts a larger negative effect on access to healthcare for empty-nest elderly than non-empty-nest ones. Both non-visiting and non-hospitalization among empty-nest seniors are independently associated with low-income households, health insurance status and non-communicable chronic diseases. The non-visiting rate is also found to be higher among the empty-nesters with lower education and those from rural areas. CONCLUSIONS: Our findings indicate that empty-nest seniors have higher non-use rate of healthcare services than non-empty-nest ones. Financial difficulty is the leading cause of non-use of health services. Healthcare policies should be developed or modified to make them more pro-poor and also pro-empty-nested.