The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II-IIIA non-small cell lung cancer (NSCLC). ...However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy.
ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus ...vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor (
) mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results.
From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and
-activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat ITT population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data.
Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio HR, 0.92; 95% CI, 0.62 to 1.36;
= .674); respective 5-year OS rates were 53.2% and 51.2% (
= .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP (
= .316) and 5y DFS rates were 22. 6% and 23.2% (
= .928), respectively.
Adjuvant therapy with gefitinib in patients with early-stage NSCLC and
mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.
The global incidence of cardiac diseases is expected to increase in the coming years, imposing a substantial socioeconomic burden on healthcare systems. Autophagy is a tightly regulated lysosomal ...degradation mechanism important for cell survival, homeostasis, and function. Accumulating pieces of evidence have indicated a major role of autophagy in the regulation of cardiac homeostasis and function. It is well established that dysregulation of autophagy in cardiomyocytes is involved in cardiac hypertrophy, myocardial infarction, diabetic cardiomyopathy, and heart failure. In this sense, autophagy seems to be an attractive therapeutic target for cardiac diseases. Recently, multiple natural products/phytochemicals, such as resveratrol, berberine, and curcumin have been shown to regulate cardiomyocyte autophagy via different pathways. The autophagy‐modifying capacity of these compounds should be taken into consideration for designing novel therapeutic agents. This review focuses on the role of autophagy in various cardiac diseases and the pharmacological basis and therapeutic potential of reported natural products in cardiac diseases by modifying autophagic processes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II–IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with ...EGFR-mutant stage IB–IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II–IIIA (N1–N2) NSCLC.
We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18–75 years with completely resected (R0), stage II–IIIA (N1–N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079.
Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8–44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months 95% CI 24·9–32·5) than with vinorelbine plus cisplatin (18·0 months 13·6–22·3; hazard ratio HR 0·60, 95% CI 0·42–0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two 2% patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 34% patients vs none with gefitinib), leucopenia (14 16% vs none), and vomiting (eight 9% vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related.
Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II–IIIA (N1–N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature.
Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of People's Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
C‐aryl glycosides are popular basic skeletons in biochemistry and pharmaceutical chemistry. Herein, ruthenium‐catalyzed highly stereo‐ and site‐selective ortho‐ and meta‐CAr−H glycosylation is ...described. A series of C‐aryl pyranosides and furanosides were synthesized by this method. The strategy showed good substrate scope, and various N‐heterocyclic directing groups were compatible with the reaction system. A mechanistic study suggested that the key pathway of ortho‐CAr−H glycosylation might involve oxidative addition/reduction elimination, whereas aryl meta‐C−H glycosylation was mediated by σ‐activation. Density functional theory calculations also showed that the high stereoselectivity of meta‐CAr−H glycosylation was due to steric hindrance.
A series of C‐aryl pyranosides and furanosides were synthesized by ruthenium‐catalyzed ortho‐ and meta‐CAr−H glycosylation. Mechanistic studies suggest that the key pathway of ortho‐CAr−H glycosylation involves an oxidative addition/reductive elimination process, while aryl meta‐C−H glycosylation is mediated by σ‐activation. DFT calculations showed that steric hindrance is responsible for the high stereoselectivity of meta‐CAr−H glycosylation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
IoT is leading a digital revolution in both academia and industry. It brings convenience to people's daily lives; however, the issues of security and privacy of IoT become challenges. Blockchain, a ...decentralized database based on cryptographic techniques, is promising for IoT security, which may influence a variety of areas including manufacture, finance, and trading. The blockchain framework in an IoT system is an intriguing alternative to the traditional centralized model, which is struggling to meet some specified demands in IoT. In this article, we investigate typical security and privacy issues in IoT and develop a framework to integrate blockchain with IoT, which can provide great assurance for IoT data and various functionalities and desirable scalability including authentication, decentralized payment, and so on. We also suggest some possible solutions to these security and privacy issues in IoT based on blockchain and Ethereum to show how blockchain contributes to IoT.
Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development. However, little is known about its anti-tumor mechanism in small cell lung ...cancer (SCLC). In this study, we found that curcumin can inhibit SCLC cell proliferation, cell cycle, migration, invasion and angiogenesis through suppression of the STAT3. SCLC cells were treated with curcumin (15 µmol/L) and the results showed that curcumin was effective in inhibiting STAT3 phosphorylation to downregulate of an array of STAT3 downstream targets ,which contributed to suppression of cell proliferation, loss of colony formation, depression of cell migration and invasion. Curcumin also suppressed the expression of proliferative proteins (Survivin, Bcl-X(L) and Cyclin B1), and invasive proteins (VEGF, MMP-2, MMP-7 and ICAM-1). Knockdown of STAT3 expression by siRNA was able to induce anti-invasive effects in vitro. In contrast, activation of STAT3 upstream of interleukin 6 (IL-6) leads to the increased cell proliferation ,cell survival, angiogenesis, invasion, migration and tumor growth. Our findings illustrate the biologic significance of IL-6/JAK/STAT3 signaling in SCLC progression and provide novel evidence that the pathway may be a new potential target for therapy of SCLC. It was concluded that curcumin is a potent agent in the inhibition of STAT3 with favorable pharmacological activity,and curcumin may have translational potential as an effective cancer therapeutic or preventive agent for SCLC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Early detection and accurate monitoring of chronic kidney disease (CKD) could improve care and retard progression to end-stage renal disease. Here, using untargeted metabolomics in 2155 participants ...including patients with stage 1-5 CKD and healthy controls, we identify five metabolites, including 5-methoxytryptophan (5-MTP), whose levels strongly correlate with clinical markers of kidney disease. 5-MTP levels decrease with progression of CKD, and in mouse kidneys after unilateral ureteral obstruction (UUO). Treatment with 5-MTP ameliorates renal interstitial fibrosis, inhibits IκB/NF-κB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperfusion injury, as well as in cultured human kidney cells. Overexpression of tryptophan hydroxylase-1 (TPH-1), an enzyme involved in 5-MTP synthesis, reduces renal injury by attenuating renal inflammation and fibrosis, whereas TPH-1 deficiency exacerbates renal injury and fibrosis by activating NF-κB and inhibiting Nrf2 pathways. Together, our results suggest that TPH-1 may serve as a target in the treatment of CKD.
Tumor cells adapt to excessive oxidative stress by actuating reactive oxygen species (ROS)‐defensing system, leading to a resistance to oxidation therapy. In this work, self‐delivery photodynamic ...synergists (designated as PhotoSyn) are developed for oxidative damage amplified tumor therapy. Specifically, PhotoSyn are fabricated by the self‐assembly of chlorine e6 (Ce6) and TH588 through π–π stacking and hydrophobic interactions. Without additional carriers, nanoscale PhotoSyn possess an extremely high drug loading rate (up to 100%) and they are found to be fairly stable in aqueous phase with a uniform size distribution. Intravenously injected PhotoSyn prefer to accumulate at tumor sites for effective cellular uptake. More importantly, TH588‐mediated MTH1 inhibition could destroy the ROS‐defensing system of tumor cells by preventing the elimination of 8‐oxo‐2′‐deoxyguanosine triphosphate (8‐oxo‐dG), thereby exacerbating the oxidative DNA damage induced by the photodynamic therapy (PDT) of Ce6 under light irradiation. As a consequence, PhotoSyn exhibit enhanced photo toxicity and a significant antitumor effect. This amplified oxidative damage strategy improves the PDT efficiency with a reduced side effect by increasing the lethality of ROS without generating superabundant ROS, which would provide a new insight for developing self‐delivery nanoplatforms in photodynamic tumor therapy in clinic.
Carrier free photodynamic synergists are developed for oxidative damage amplified tumor therapy by destroying the reactive oxygen species (ROS)‐defensing system without generating excessive ROS, which shed light on the development of self‐delivery nanoplatforms for efficient photodynamic therapy by utilizing the limited oxygen in hypoxic tumors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Being conductive and flexible, 2D transition metal nitrides and carbides (MXenes) can serve in Li–S batteries as sulfur hosts to increase the conductivity and alleviate the volume expansion. However, ...the surface functional groups, such as OH and F, weaken the ability of bare MXenes in the chemisorption of polysulfides. Besides, they create numerous hydrogen bonds which make MXenes liable to restack, resulting in substantial loss of active area and, thus, inaccessibility of ions and electrolyte. Herein, a facile, one‐step strategy is developed for the growth of TiO2 quantum dots (QDs) on ultrathin MXene (Ti3C2Tx) nanosheets by cetyltrimethylammonium bromide‐assisted solvothermal synthesis. These QDs act as spacers to isolate the MXene nanosheets from restacking, and preserve their 2D geometry which guarantees larger electrode–electrolyte contact area and higher sulfur loading. The stronger adsorption energy of polysulfides with TiO2 (than with Ti3C2Tx), as proven by density functional theory calculations, is essential for better on‐site polysulfide retention. The ultrathin nature and protected conductivity ensure rapid ion and electron diffusion, and the excellent flexibility maintains high mechanical integrity. In result, the TiO2 QDs@MXene/S cathode exhibits significantly improved long‐term cyclability and rate capability, disclosing a new opportunity toward fast and stable Li–S batteries.
TiO2 quantum dots (QDs) are grown on ultrathin MXene nanosheets by a facile, one‐step strategy through cetyltrimethylammonium bromide‐assisted solvothermal synthesis, resulting in TiO2 QDs@MXene nanohybrids that serve as a high‐performance sulfur host toward fast and stable Li–S batteries.
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