Summary Background No standard treatments are available for advanced thymic epithelial tumours after failure of platinum-based chemotherapy. We investigated the activity of sunitinib, an orally ...administered tyrosine kinase inhibitor. Methods Between May 15, 2012, and Oct 2, 2013, we did an open-label phase 2 trial in patients with histologically confirmed chemotherapy-refractory thymic epithelial tumours. Patients were eligible if they had disease progression after at least one previous regimen of platinum-containing chemotherapy, an Eastern Cooperative Oncology Group performance status of two or lower, measurable disease, and adequate organ function. Patients received 50 mg of sunitinib orally once a day, in 6-week cycles (ie, 4 weeks of treatment followed by 2 weeks without treatment), until tumour progression or unacceptable toxic effects arose. The primary endpoint was investigator-assessed best tumour response at any point, which we analysed separately in thymoma and thymic carcinoma cohorts. Patients who had received at least one cycle of treatment and had their disease reassessed were included in the analyses of response. The trial was registered with ClinicalTrials.gov , number NCT01621568. Findings 41 patients were enrolled, 25 with thymic carcinoma and 16 with thymoma. One patient with thymic carcinoma was deemed ineligible after enrolment and did not receive protocol treatment. Of patients who received treatment, one individual with thymic carcinoma was not assessable because she died. Median follow-up on trial was 17 months (IQR 14·0–18·4). Of 23 assessable patients with thymic carcinoma, six (26%, 90% CI 12·1–45·3, 95% CI 10·2–48·4) had partial responses, 15 (65%, 95% CI 42·7–83·6) achieved stable disease, and two (9%, 1·1–28·0) had progressive disease. Of 16 patients with thymoma, one (6%, 95% CI 0·2–30·2) had a partial response, 12 (75%, 47·6–92·7) had stable disease, and three (19%, 4·1–45·7) had progressive disease. The most common grade 3 and 4 treatment-related adverse events were lymphocytopenia (eight 20% of 40 patients), fatigue (eight 20%), and oral mucositis (eight 20%). Five (13%) patients had decreases in left-ventricular ejection fraction, of which three (8%) were grade 3 events. Three (8%) patients died during treatment, including one individual who died of cardiac arrest that was possibly treatment-related. Interpretation Sunitinib is active in previously treated patients with thymic carcinoma. Further studies are needed to identify potential biomarkers of activity. Funding National Cancer Institute (Cancer Therapy Evaluation Program).
The western conifer seed bug (WCSB) Leptoglossus occidentalis (Heidemann) (Heteroptera: Coreidae) is a pest insect that causes significant losses of coniferous trees worldwide. In this study, we ...sought to project the potential distribution of the WCSB based on dual CLIMEX modeling and random forest (RF) analysis to obtain basic data for WCSB monitoring strategies. The CLIMEX model, a semimechanistic niche model that responds to climate‐based environmental parameters, is a species distribution model that focuses on regional climatic suitability. Given that this model can be used to select areas that are likely to reflect the climatically favorable spread of species, which we initially used CLIMEX to evaluate the potential distribution of the WCSB. The RF algorithm was used to predict the potential occurrence of WCSB and to evaluate the relative importance of environmental variables for WCSB occurrence. Using the RF model, land cover was found to be the most important variable for classifying the presence/pseudo‐absence of the WCSB, with an accuracy of 77.1%. Climatic suitability for the WCSB was predicted to be 2.4‐fold higher in Southern Europe than in Western Europe, and the WCSB was predicted to occur primarily near coniferous forests. Given that CLIMEX and RF analyses yielded different prediction results, using the findings of both models may compensate for the shortcomings of these models when used independently. Consequently, to ensure greater prediction reliability, we believe that it would be beneficial to base predictions on the combined potential distribution data obtained using both modeling approaches.
This study developed an ensemble model with a dual modeling of a mechanistic model (CLIMEX) and a machine learning model (random forest). The developed models showed a reliable prediction of the potential distribution of Leptoglossus occidentalis in Europe in response to climate change.
Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, ...Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.
The cell fate determinant Numb is aberrantly expressed in cancer. Numb is alternatively spliced, with one isoform containing a long proline‐rich region (PRRL) compared to the other with a short PRR ...(PRRS). Recently, PRRL was reported to enhance proliferation of breast and lung cancer cells. However, the importance of Numb alternative splicing in hepatocellular carcinoma (HCC) remains unexplored. We report here that Numb PRRL expression is increased in HCC and associated with early recurrence and reduced overall survival after surgery. In a panel of HCC cell lines, PRRL generally promotes and PRRS suppresses proliferation, migration, invasion, and colony formation. Knockdown of PRRS leads to increased Akt phosphorylation and c‐Myc expression, and Akt inhibition or c‐Myc silencing dampens the proliferative impact of Numb PRRS knockdown. In the cell models explored in this study, alternative splicing of Numb PRR isoforms is coordinately regulated by the splicing factor RNA‐binding Fox domain containing 2 (RbFox2) and the kinase serine/arginine protein–specific kinase 2 (SRPK2). Knockdown of the former causes accumulation of PRRL, while SRPK2 knockdown causes accumulation of PRRS. The subcellular location of SRPK2 is regulated by the molecular chaperone heat shock protein 90, and heat shock protein 90 inhibition or knockdown phenocopies SRPK2 knockdown in promoting accumulation of Numb PRRS. Finally, HCC cell lines that predominantly express PRRL are differentially sensitive to heat shock protein 90 inhibition. Conclusion: Alternative splicing of Numb may provide a useful prognostic biomarker in HCC and is pharmacologically tractable. (Hepatology 2015;62:1122‐1131)
A glucose/oxygen biofuel cell (BFC) that can operate continuously under oxygen-free conditions is described. The oxygen-deficit limitations of metabolite/oxygen enzymatic BFCs have been addressed by ...using an oxygen-rich cathode binder material, polychlorotrifluoroethylene (PCTFE), which provides an internal oxygen supply for the BFC reduction reaction. This oxygen-rich cathode component mitigates the potential power loss in oxygen-free medium or during external oxygen fluctuations through internal supply of oxygen, while the bioanode employs glucose oxidase-mediated reactions. The internal oxygen supply leads to a prolonged energy-harvesting in oxygen-free solutions, e.g., maintaining over 90% and 70% of its initial power during 10- and 24-h operations, respectively, in the absence of oxygen. The new strategy holds considerable promise for energy-harvesting and self-powered biosensing applications in oxygen-deficient conditions.
•A glucose/O2 biofuel cell operating continuously under oxygen-free conditions.•An O2-rich cathode binder material, providing internal oxygen supply for the BFC reduction reaction.•Energy-harvesting and self-powered applications in O2-fluctuating conditions.
Drones in many applications need the ability to fly fully or partially autonomously to accomplish their mission. To allow these fully/partially autonomous flights, first, the drone needs to be able ...to locate itself constantly. Then the navigation command signal would be generated and passed on to the controller unit of the drone. In this paper, we propose a localization scheme for drones called iDROP (Robust Localization for Indoor Navigation of Drones with Optimized Beacon Placement) that is specifically devised for GPS-denied environments (e.g., indoor spaces). Instead of GPS signals, iDROP relies on speaker-generated ultrasonic acoustic signals to enable a drone to estimate its location. In general, localization error is caused by two factors: the ranging error and the error induced by relative geometry between the transmitters and the receiver. iDROP mitigates these two types of errors and provides a high-precision three-dimensional localization scheme for drones. iDROP employs a waveform that is robust against multipath fading. Moreover, placing beacons in optimal locations reduces the localization error induced by the relative geometry between the transmitters and the receiver.
The development of energy‐efficient artificial synapses capable of manifoldly tuning synaptic activities can provide a significant breakthrough toward novel neuromorphic computing technology. Here, a ...new class of artificial synaptic architecture, a three‐terminal device consisting of a vertically integrated monolithic tungsten oxide memristor, and a variable‐barrier tungsten selenide/graphene Schottky diode, termed as a ‘synaptic barrister,’ are reported. The device can implement essential synaptic characteristics, such as short‐term plasticity, long‐term plasticity, and paired‐pulse facilitation. Owing to the electrostatically controlled barrier height in the ultrathin van der Waals heterostructure, the device exhibits gate‐controlled memristive switching characteristics with tunable programming voltages of 0.2−0.5 V. Notably, by electrostatic tuning with a gate terminal, it can additionally regulate the degree and tuning rate of the synaptic weight independent of the programming impulses from source and drain terminals. Such gate tunability cannot be accomplished by previously reported synaptic devices such as memristors and synaptic transistors only mimicking the two‐neuronal‐based synapse. These capabilities eventually enable the accelerated consolidation and conversion of synaptic plasticity, functionally analogous to the synapse with an additional neuromodulator in biological neural networks.
A synaptic barristor, an artificial synaptic architecture formed by monolithically integrating a memristor and a barristor using phase‐engineered 2D heterostructures, is presented. This three‐terminal artificial synapse could implement fundamental synaptic functions with external gate controllability. Such unique capabilities enable the accelerated consolidation and conversion of synaptic plasticity, functionally analogous to the synapse with an additional neuromodulator in biological neural networks.
Objective
To characterize health care resource utilization (HCRU), health care costs, and adverse events (AEs) among patients with systemic lupus erythematosus (SLE) initiating oral corticosteroids ...(OCS) versus patients without OCS use.
Methods
In this retrospective cohort study (GSK Study 213061), eligible patients (aged ≥5 years at first OCS claim) with SLE from the IQVIA Real‐World Data Adjudicated Claims‐US database (January 2006 to July 2019) had continuous enrollment during the 6‐month preindex (baseline) and 12‐month postindex (observation) periods and one or more inpatient or emergency department SLE diagnosis codes or two or more outpatient SLE diagnosis codes during baseline. The “OCS‐initiator cohort” comprised patients with one or more OCS pharmacy claims during the study period and no evidence of preindex OCS use and was classified into three exposure categories based on the number of 6‐month periods of more than 5 mg/day of OCS use (0, 1, 2). The “no‐OCS‐use cohort” comprised patients without OCS claims, although patients may have received OCS prior to the study period. Clinical and economic outcomes were reported over the observation period.
Results
Adjusted health care costs differed significantly ($6542 95% confidence interval (CI): $5761‐$7368, $19,149 95% CI: $16,954‐$21,471, $28,985 95% CI: $25,546‐$32,885). HCRU incidence rates were significantly greater for all OCS‐initiator exposure categories (n = 16,216) versus the no‐OCS‐use cohort (n = 11,137; adjusted incidence rate ratios 95% CI: 1.22 1.19‐1.24, 1.39 1.34‐1.43, 1.66 1.60‐1.73). OCS‐related AEs were experienced by 67.1% to 74.1% of patients with OCS initiation, most commonly affecting the immune system.
Conclusion
Within 12 months of OCS initiation, patients with SLE experienced substantial clinical and economic burden, which may imply a need to minimize OCS use.
Multiple neurological complications have been associated with the coronavirus disease-19 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2. This is a narrative review to ...gather information on all aspects of COVID-19 in elderly patients with cognitive impairment. First, the following three mechanisms have been proposed to underlie the neurological complications associated with COVID-19: 1) direct invasion, 2) immune and inflammatory reaction, and 3) hypoxic brain damage by COVID-19. Next, because the elderly dementia patient population is particularly vulnerable to COVID-19, we discussed risk factors and difficulties associated with cognitive disorders in this vulnerable population. We also reviewed the effects of the patient living environment in COVID-19 cases that required intensive care unit (ICU) care. Furthermore, we analyzed the impact of stringent social restrictions and COVID-19 pandemic-mediated policies on dementia patients and care providers. Finally, we provided the following strategies for working with elderly dementia patients: general preventive methods; dementia care at home and nursing facilities according to the activities of daily living and dementia characteristics; ICU care after COVID-19 infection; and public health care system and government response. We propose that longitudinal follow-up studies are needed to fully examine COVID-19 associated neurological complications, such as dementia, and the efficacy of telemedicine/telehealth care programs.
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