Genexol-PM is a novel Cremophor EL (CrEL)-free polymeric micelle formulation of paclitaxel (Taxol). This multicenter phase II study was designed to evaluate the efficacy and safety of the combination ...of Genexol-PM and cisplatin for the treatment of advanced non-small-cell lung cancer (NSCLC).
Patients with advanced NSCLC received Genexol-PM 230 mg/m2 and cisplatin 60 mg/m2 on day 1 of a 3-week cycle as first-line therapy. Intrapatient dose escalation of Genexol-PM to 300 mg/m2 was carried out from the second cycle if the prespecified toxic effects were not observed after the first cycle.
Sixty-nine patients were enrolled in this study. Overall response rate was 37.7%. The median time to progression was 5.8 months and the median survival period was 21.7 months. The major non-hematologic toxic effects included grade 3 peripheral sensory neuropathy (13.0%) and grade 3/4 arthralgia (7.3%). Four patients (5.8%) experienced grade 3/4 hypersensitivity reactions. The major hematological toxic effects were grade 3/4 neutropenia (29.0% and 17.4%, respectively).
Genexol-PM plus cisplatin combination chemotherapy showed significant antitumor activity. The use of CrEL-free, polymeric micelle formulation of paclitaxel allowed administration of higher doses of paclitaxel compared with the CrEL-based formulation without significant increased toxicity.
Aims/hypothesis
The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the ...susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes.
Methods
Rat insulin promoter (RIP)-
Cre
+
;autophagy-related 7 (
Atg7
)
F/W
mice were bred with
ob/w
mice to derive RIP-
Cre
+
;
Atg7
F/F
-
ob/ob
mice and to induce ER stress in vivo.
GFP-LC3
+
-
ob/ob
mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine.
Results
Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85α and p85β regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with
ob/ob
mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced.
Conclusions/interpretation
These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.
Abstract Non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation shows good and rapid response to EGFR tyrosine kinase inhibitors (TKIs). We ...prospectively evaluated the efficacy of EGFR TKI for metastatic brain tumors in NSCLC patients harboring EGFR mutation. This was an open-label, single-institution, phase II study. Patients diagnosed with NSCLC harboring EGFR mutation and measurable metastatic brain tumors were eligible. They received either erlotinib or gefitinib once a day. Out of total 28 patients enrolled, 23 patients (83%) showed a partial response (PR) and 3 patients (11%) did stable disease (SD), giving a disease control rate of 93%. Median progression free survival (PFS) and overall survival (OS) were 6.6 months (95% CI, 3.8–9.3 months) and 15.9 months (95% CI, 7.2–24.6 months), respectively. There was no difference in PFS and OS according to EGFR TKIs used. After discontinuation of the treatment, 14 patients (50%) received local therapy for metastatic brain tumors during their disease course, either whole brain radiotherapy or radiosurgery, giving a local therapy-free interval of 12.6 months (95% CI, 7.6–17.6 months). EGFR TKI therapy might be the treatment of choice for metastatic brain tumors in NSCLC patients harboring an activating EGFR mutation.
Background
Recent evidence indicates that Staphylococcus aureus, one of the most important human pathogens, secretes vesicles into the extracellular milieu.
Objective
To evaluate whether inhalation ...of S. aureus‐derived extracellular vesicles (EV) is causally related to the pathogenesis of inflammatory pulmonary diseases.
Methods
Staphylococcus aureus EV were prepared by sequential ultrafiltration and ultracentrifugation. The innate immune response was evaluated in vitro after the application of EV to airway epithelial cells and alveolar macrophages. In vivo innate and adaptive immune responses were evaluated after airway exposure to EV. Adjuvant effects of EV on the development of hypersensitivity to inhaled allergens were also evaluated after airway sensitization with S. aureus EV and ovalbumin (OVA).
Results
Staphylococcus aureus and S. aureus EV were detected in house dust. Alveolar macrophages produced both tumor necrosis α (TNF‐α) and interleukin 6 (IL‐6) after in vitro stimulation with S. aureus EV, whereas airway epithelial cells produced only IL‐6. Repeated airway exposure to S. aureus EV induced both Th1 and Th17 cell responses and neutrophilic pulmonary inflammation, mainly via a Toll‐like receptor 2 (TLR2)‐dependent mechanism. In terms of adjuvant effects, airway sensitization with S. aureus EV and OVA resulted in neutrophilic pulmonary inflammation after OVA challenge alone. This phenotype was partly reversed by the absence of interferon γ (IFN‐γ) or IL‐17.
Conclusion
Staphylococcus aureus EV can induce Th1 and Th17 neutrophilic pulmonary inflammation, mainly in a TLR2‐dependent manner. Additionally, S. aureus EV enhance the development of airway hypersensitivity to inhaled allergens.
Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic ...breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 95% CI 0·437–0·994, one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 75% of 92 vs 14 16% of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
To cite this article: Hong S-W, Kim M-R, Lee E-Y, Kim JH, Kim Y-S, Jeon SG, Yang J-M, Lee B-J, Pyun B-Y, Gho YS, Kim Y-K. Extracellular vesicles derived from Staphylococcus aureus induce atopic ...dermatitis-like skin inflammation. Allergy 2011; 66: 351-359. ABSTRACT: Background: Recently, we found that Staphylococcus aureus produces extracellular vesicles (EV) that contain pathogenic proteins. Although S. aureus infection has been linked with atopic dermatitis (AD), the identities of the causative agents from S. aureus are controversial. We evaluated whether S. aureus-derived EV are causally related to the pathogenesis of AD. Methods: Extracellular vesicles were isolated by the ultracentrifugation of S. aureus culture media. The EV were applied three times per week to tape-stripped mouse skin. Inflammation and immune dysfunction were evaluated 48 h after the final application in hairless mice. Extracellular vesicles-specific IgE levels were measured by ELISA in AD patients and healthy subjects. Results: The in vitro application of S. aureus EV increased the production of pro-inflammatory mediators (IL-6, thymic stromal lymphopoietin, macrophage inflammatory protein-1α, and eotaxin) by dermal fibroblasts. The in vivo application of S. aureus EV after tape stripping caused epidermal thickening with infiltration of the dermis by mast cells and eosinophils in mice. These changes were associated with the enhanced cutaneous production of IL-4, IL-5, IFN-γ, and IL-17. Interestingly, the serum levels of S. aureus EV-specific IgE were significantly increased in AD patients relative to healthy subjects. Conclusion: These results indicate that S. aureus EV induce AD-like inflammation in the skin and that S. aureus-derived EV are a novel diagnostic and therapeutic target for the control of AD.
The Himalayas and the Tibetan Plateau region (HTP), despite being a remote and sparsely populated area, is regularly exposed to polluted air masses with significant amounts of aerosols including ...black carbon. These dark, light-absorbing particles are known to exert a great melting potential on mountain cryospheric reservoirs through albedo reduction and radiative forcing. This study combines ground-based and satellite remote sensing data to identify a severe aerosol pollution episode observed simultaneously in central Tibet and on the southern side of the Himalayas during 13-19 March 2009 (pre-monsoon). Trajectory calculations based on the high-resolution numerical weather prediction model COSMO are used to locate the source regions and study the mechanisms of pollution transport in the complex topography of the HTP. We detail how polluted air masses from an atmospheric brown cloud (ABC) over South Asia reach the Tibetan Plateau within a few days. Lifting and advection of polluted air masses over the great mountain range is enabled by a combination of synoptic-scale and local meteorological processes. During the days prior to the event, winds over the Indo-Gangetic Plain (IGP) are generally weak at lower levels, allowing for accumulation of pollutants and thus the formation of ABCs. The subsequent passing of synoptic-scale troughs leads to southwesterly flow in the middle troposphere over northern and central India, carrying the polluted air masses across the Himalayas. As the IGP is known to be a hotspot of ABCs, the cross-Himalayan transport of polluted air masses may have serious implications for the cryosphere in the HTP and impact climate on regional to global scales. Since the current study focuses on one particularly strong pollution episode, quantifying the frequency and magnitude of similar events in a climatological study is required to assess the total impact.
To investigate the influence of pregnancy on patients with neuromyelitis optica spectrum disorder (NMOSD).
A total of 190 women with NMOSD were enrolled from 7 referral hospitals in 4 countries. We ...reviewed medical records and used a structured questionnaire to investigate gravidity, parity, and the number of relapses during the 2 years before pregnancy, during each trimester of pregnancy, during the first and second trimesters after delivery, and for 6 months thereafter. The annualized relapse rate (ARR) was calculated for each period.
Of the 190 women with NMOSD, 40 patients experienced 54 informative pregnancies, and all of them were seropositive for aquaporin-4 antibody. Fourteen patients developed the first symptoms of NMOSD either during the pregnancy (3 patients) or within a year after delivery or abortion (8 and 3 patients, respectively). Twenty-six patients experienced 40 pregnancies after the onset of NMOSD (26 deliveries and 14 abortions 1 spontaneous and 13 elective). There was one preterm delivery with birth defects and no stillbirths. The ARR during pregnancy did not differ from that before pregnancy, but it increased significantly during the first and second trimesters after delivery (5.3 and 3.7 times, respectively). Moreover, 77% of the deliveries were associated with postpartum relapses.
The significantly increased relapse rate and numerous cases of NMOSD onset after pregnancy suggest that delivery adversely affects the course of NMOSD. Prospective studies are needed to confirm our findings.
Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms ...leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3'-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.
KRAS mutations in non-small-cell lung cancer (NSCLC) are associated with poor prognosis. Trametinib, a selective inhibitor of MEK1/MEK2, demonstrated similar efficacy to docetaxel in patients with ...advanced KRAS-mutant NSCLC, with median progression-free survival of 12 and 11 weeks, respectively. With moderate activity as a monotherapy, trametinib-based combination regimens may show improve efficacy.
KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC.
Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m2 i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary.
One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio HR 1.14; 95% CI 0.75–1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52–1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia.
Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC.
NCT01362296.
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