Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received ...durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.
DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.
Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven 2% of 345 patients) and in the durvalumab plus tremelimumab group (16 5% of 340 patients), and neutropenia in the chemotherapy group (66 21% of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury).
This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.
AstraZeneca.
Identification of patients at risk of death from cancer surgery should aid in preoperative preparation. The purpose of this study is to assess and adjust the age-adjusted Charlson comorbidity index ...(ACCI) to identify cancer patients with increased risk of perioperative mortality.
We identified 156,151 patients undergoing surgery for one of the ten common cancers between 2007 and 2011 in the Taiwan National Health Insurance Research Database. Half of the patients were randomly selected, and a multivariate logistic regression analysis was used to develop an adjusted-ACCI score for estimating the risk of 90-day mortality by variables from the original ACCI. The score was validated. The association between the score and perioperative mortality was analyzed.
The adjusted-ACCI score yield a better discrimination on mortality after cancer surgery than the original ACCI score, with c-statics of 0.75 versus 0.71. Over 80 years of age, 70-80 years, and renal disease had the strongest impact on mortality, hazard ratios 8.40, 3.63, and 3.09 (P < 0.001), respectively. The overall 90-day mortality rates in the entire cohort varied from 0.9%, 2.9%, 7.0%, and 13.2% in four risk groups stratifying by the adjusted-ACCI score; the adjusted hazard ratio for score 4-7, 8-11, and ≥ 12 was 2.84, 6.07, and 11.17 (P < 0.001), respectively, in 90-day mortality compared to score 0-3.
The adjusted-ACCI score helps to identify patients with a higher risk of 90-day mortality after cancer surgery. It might be particularly helpful for preoperative evaluation of patients over 80 years of age.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Coupling charge impurity scattering effects and charge‐carrier modulation by doping can offer intriguing opportunities for atomic‐level control of resistive switching (RS). Nonetheless, such effects ...have remained unexplored for memristive applications based on 2D materials. Here a facile approach is reported to transform an RS‐inactive rhenium disulfide (ReS2) into an effective switching material through interfacial modulation induced by molybdenum‐irradiation (Mo‐i) doping. Using ReS2 as a model system, this study unveils a unique RS mechanism based on the formation/dissolution of metallic β‐ReO2 filament across the defective ReS2 interface during the set/reset process. Through simple interfacial modulation, ReS2 of various thicknesses are switchable by modulating the Mo‐irradiation period. Besides, the Mo‐irradiated ReS2 (Mo‐ReS2) memristor further exhibits a bipolar non‐volatile switching ratio of nearly two orders of magnitude, programmable multilevel resistance states, and long‐term synaptic plasticity. Additionally, the fabricated device can achieve a high MNIST learning accuracy of 91% under a non‐identical pulse train. The study's findings demonstrate the potential for modulating RS in RS‐inactive 2D materials via the unique doping‐induced charged impurity scattering property.
A facile Mo‐irradiation doping is demonstrated for interfacial modulation of resistive switching (RS) in rhenium disulfide (ReS2) memristors, leading to a bipolar non‐volatile switching ratio of nearly two orders of magnitude, programmable multilevel resistance states, and long‐term synaptic plasticity. The device simultaneously achieves a high learning accuracy of 91% in an artificial neural network, demonstrating its potential for neuromorphic computing application.
A suitable clustering algorithm for grouping sensor nodes can increase the energy efficiency of WSNs. However, clustering requires additional overhead, such as cluster head selection and assignment, ...and cluster construction. This paper proposes a new regional energy aware clustering method using isolated nodes for WSNs, called Regional Energy Aware Clustering with Isolated Nodes (REAC-IN). In REAC-IN, CHs are selected based on weight. Weight is determined according to the residual energy of each sensor and the regional average energy of all sensors in each cluster. Improperly designed distributed clustering algorithms can cause nodes to become isolated from CHs. Such isolated nodes communicate with the sink by consuming excess amount of energy. To prolong network lifetime, the regional average energy and the distance between sensors and the sink are used to determine whether the isolated node sends its data to a CH node in the previous round or to the sink. The simulation results of the current study revealed that REAC-IN outperforms other clustering algorithms.
To achieve a sensitive and accurate method in body temperature measurement of cattle, this study explores the uses of infrared thermography (IRT), an anemometer, and a humiture meter as a multiple ...sensors architecture. The influence of environmental factors on IRT, such as wind speed, ambient temperature, and humidity, was considered. The proposed signal processes removed the IRT frames affected by air flow, and also eliminated the IRT frames affected by random body movement of cattle using the frame difference method. In addition, the proposed calibration method reduced the impact of ambient temperature and humidity on IRT results, thereby increasing the accuracy of IRT temperature. The difference of mean value and standard deviation value between recorded rectal reference temperature and IRT temperature were 0.04 °C and 0.10 °C, respectively, and the proposed system substantially improved the measurement consistency of the IRT temperature and reference on cattle body temperature. Moreover, with a relatively small IRT image sensor, the combination of multiple sensors architecture and proper data processing still achieved good temperature accuracy. The result of the root-mean-square error (RMSE) was 0.74 °C, which is quite close to the accurate result of the IRT measurement.
Globally, there are over half a million new patients with head and neck squamous cell carcinomas (HNSCC) every year. The current therapeutic approaches to HNSCC are surgery and adjuvant radiotherapy. ...These approaches carry a high incidence of metastasis or recurrence from HNSCC cells' radioresistance. Recent studies have revealed that a combination with radiosensitizers can be used to improve the radioresistance in HNSCC; however, few agents are approved as radiosensitizers. The constitutive activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a vitally oncogenic type of signaling that promotes tumorigenesis, metastasis, and radiotherapy resistance in HNSCC. Pharmacological targeting of PI3K/AKT/mTOR signaling pathway is considered a promising strategy of radiosensitization in HNSCC. In this review, we summarize the oncogenic significance of PI3K/AKT/mTOR signaling in HNSCC with radiotherapy resistance and highlight the therapeutic potential of small molecule inhibitors against PI3K/AKT/mTOR signaling for the radiosensitization in HNSCC treatment. It provides a mechanistic framework for the development of new drugs for radiosensitization in HNSCC radiotherapy via targeting PI3K/AKT/mTOR signaling pathway.
Approximately 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are reported annually. Radiation therapy is an important treatment for oral squamous cell carcinoma (OSCC). The ...survival rate of patients with HNSCC remained low (50%) in decades because of radiation therapy failure caused by the radioresistance of HNSCC cells. This study aimed to identify PI3K inhibitors that can enhance radiosensitivity. Results showed that pan-Phosphoinositide 3-kinases (PI3K) inhibitor BKM120 and class I α-specific PI3K inhibitor BYL719 dose-dependently reduced the growth of OSCC cells but not that of radioresistant OML1-R cells. The combination treatment of BKM120 or BYL719 with radiation showed an enhanced inhibitory effect on OSCC cells and radioresistant OML1-R cells. Furthermore, the enhanced inhibitory effect of the combination treatment was confirmed in patient-derived OSCC cells. The triple combination treatment of mTOR inhibitor AZD2014 and BKM120 or AZD2014 and BYL719 with radiation showed a significantly enhanced inhibitory effect on radioresistant OML1-R cells. These results suggest that the PI3K inhibitors are potential therapeutic agents with radiosensitivity for patients with OSCC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Semiconductor nanocrystals are widely used as photocatalysts for the degradation of organic dye molecules due to their strong electron transfer ability and high catalytic reactivity. However, as a ...photocatalyst with excellent performance, semiconductor nanocrystals still have some disadvantages, such as aggregation, photocorrosion during the reactions, and loss during recycling that need to be addressed. In response to these problems, it is necessary to improve the using efficiency of “active charges” of the photocatalysts and their stability in the recycling process, which can be achieved by transferring the unreacted “active charges” to other active materials and fixing the photocatalysts in the polymer matrix. Here, we designed nanocrystals with three components, Cu2O–ZnO–AgNC (silver nanocube), as photocatalysts with high stability and high reactivity for the degradation of Congo red molecules under irradiation in the visible light range. The high reactivity of Cu2O–ZnO–AgNC as a photocatalyst can be attributed to the generation of “active charges”, hot electrons from AgNC, and excited electron–hole pairs from Cu2O under visible light irradiation. Moreover, the photocorrosion of Cu2O can be suppressed by transferring the unreacted “active charges” to ZnO and the photocatalytic performance can be further improved. These results enable the design and synthesis of catalysts or photocatalysts with high catalytic performance for various reduction reactions.
Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective ...therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells.
The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells.
Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone.
In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hypogonadism and oxidative stress are occurring commonly in men with diabetes and associated male infertility. This study aimed to investigate the capability of anti-oxidative and anti-inflammatory ...properties of fucoxanthin as well as to evaluate its protective effects on male reproduction in diabetic rats. The RAW 264.7 macrophage cells were used to evaluate the anti-oxidative and anti-inflammatory activity. Thirty male Sprague-Dawley rats were induced by streptozotocin-nicotinamide for a diabetes model and fed either with three different doses of fucoxanthin (13, 26, and 65 mg/kg) or rosiglitazone (0.571 mg/kg) for four weeks. The fucoxanthin significantly inhibited nitric oxide production and reduced reactive oxygen species level in lipopolysaccharide-induced RAW 264.7 cells. In the animal study, fucoxanthin administration improved insulin resistance, restored sperm motility, decreased abnormal sperm number, and inhibited lipid peroxidation. Moreover, it restored GPR54 and SOCS-3 mRNA expression in the hypothalamus and recovered luteinizing hormone level, as well as the testosterone level. In conclusion, fucoxanthin not only possessed antioxidant and anti-inflammatory properties but also decreased the diabetes signs and symptoms as well as improved spermatogenesis and male reproductive function.
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