Search

This study aims to investigate the impact of vagus nerve stimulation (VNS) on the connectivity and small-world metrics of brain functional networks during seizure periods.

ObjectivesThis two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations.MethodsPhase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens.ResultsThe primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events-most commonly diarrhea, nausea, and fatigue-were manageable.ConclusionsTrametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.

This study aimed to determine the safety and effectiveness of DTI-assisted neuroendoscopy for treating intracranial hemorrhage (ICH).

The paper focuses on a variant of hub location routeing problem arising in the design of intra-city express service networks, named as capacitated single allocation hub location routeing problem, in which each non-hub node should be served by exactly one hub, and both hub capacity and vehicle capacity are considered. A new mixed-integer programming formulation for the problem is provided, and a solution algorithm is developed on the basis of the column generation scheme to exactly solve the problem for the first time. The pricing subproblem is solved by a bidirectional labelling algorithm, and the master problem is strengthened by valid inequalities. Numerical experiments are conducted on the instances generated from the Australian Post dataset to test the performance of the model and the developed algorithm. Computational results prove that the algorithm outperforms the CPLEX and is able to provide optimal solutions for instances with up to 35 non-hub nodes and high-quality solutions for instances with 40 non-hub nodes within reasonable computational time, which indicates the feasibility and efficiency of the model and algorithm proposed. [ABSTRACT FROM AUTHOR]

Objective: Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized placebo‐controlled and open‐label extension phases. On intent‐to‐treat (ITT) survival analysis, median overall survival (OS) was 4.8 months longer and risk of death 36% lower in those originally randomized to an initial 6‐month double‐blind period of PB and TURSO versus placebo. To estimate PB and TURSO treatment effect without placebo‐to‐active crossover, we performed a post hoc survival analysis comparing PB and TURSO‐randomized participants from CENTAUR and a propensity score–matched, PB and TURSO‐naïve external control cohort from the Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) database. Methods: Clinical trial control participants from the PRO‐ACT database who met prespecified eligibility criteria were propensity score matched 1:1 with PB and TURSO‐randomized CENTAUR participants using prognostically significant covariates in ALS. Results: Baseline characteristics including propensity score–matched covariates were generally well balanced between CENTAUR PB and TURSO (n = 89) and PRO‐ACT external control (n = 85) groups. Estimated median (IQR) OS was 23.54 (14.56–39.32) months in the CENTAUR PB and TURSO group and 13.15 (9.83–19.20) months in the PRO‐ACT external control group; hazard of death was 52% lower in the former group (hazard ratio, 0.48; 95% CI, 0.31–0.72; p = 0.00048). Interpretation: This analysis suggests potentially greater survival benefit with PB and TURSO in ALS without placebo‐to‐active crossover than seen on ITT analysis in CENTAUR. Analyses using well‐matched external controls may provide additional context for evaluating survival effects in future ALS trials. [ABSTRACT FROM AUTHOR]

Recently, advanced in-vehicle technologies have led to the emergence of connected and automated vehicles (CAVs). CAVs are supposed to improve traffic efficiency and safety by coordinating the vehicles based on the communication among vehicles. This study addresses the trajectory optimization of CAVs in the drop-off area of the departure curbside, which consists of many conflict points. We first propose a centralized control method to optimize the trajectories of CAVs and then propose an implementation procedure to deal with the dynamic features and reduce the problem scales for practical instances. Contrast experiments are conducted to test the performance of the proposed control method. Results under various scenarios (different volumes, safety gaps, and desired speeds) demonstrate that CAVs controlled by the proposed method significantly outperform human-driven vehicles without control concerning mean travel time in the drop-off area. [ABSTRACT FROM AUTHOR]

Image reconstruction of conductivity distribution is a highly nonlinear ill-posed inverse problem in electrical impedance tomography (EIT). To solve the problem, Tikhonov regularization and total variation (TV) regularization methods have been generally adopted. However, reconstructed images suffer from excessive smoothness or staircase effect. In this article, a novel approach is proposed for imaging conductivity distribution. Unlike traditional regularization methods, fidelity term based on $L_{1}$ -norm is introduced to stabilize the ill-posed problem and enforce sparsity in the solution. Moreover, a first-order and high-order TV combined hybrid penalty term is introduced to keep the sharp profile and restrain the staircase effect. During image reconstruction, regularization parameter and weighting factor are determined by the adaptive method. In addition, a soft-thresholding operator is introduced to remove artifact and enhance robustness to noise. Numerical simulations have been performed to validate the performance of the proposed approach against Landweber, Tikhonov, TV, high-order TV, and iterated soft-thresholding methods. The impacts of conductivity distribution, conductivity contrast, contact impedance, and boundary shape on reconstruction are studied. Besides, robustness to noise and computation time are evaluated. The performance of the proposed approach is also verified by phantom experiments. Simulation and experimental results demonstrate that the proposed approach performs well in image reconstruction of conductivity distribution. Clearer background is observed and inclusions with sharp or smooth edges can be better reconstructed. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between aspirin use and the risks of unruptured intracranial aneurysm (UIA) growth and aneurysmal subarachnoid hemorrhage (aSAH). Methods: We searched PubMed and Scopus from inception to 1 September 2020. Studies evaluating the associations between aspirin prescription and the risk of UIA growth or the risk of aSAH were included. The study only included patients with intracranial aneurysms. We assessed the quality of included studies using the Newcastle-Ottawa scale. Random-effects meta-analysis was conducted to pool the estimates of effect size quantitatively. Sensitivity analyses using the leave-one-out strategy were performed to identify any potential source of heterogeneity. Results: After a review of 2,226 citations, five cohort studies, two case-control studies, and one nested case-control study involving 8,898 participants were included. Pooled analyses showed that aspirin use, regardless of frequency and duration, was associated with a statistically significantly lower risk of UIA growth (OR 0.25, 95% CI 0.11–0.54; I 2 = 0.0%, p = 0.604) and aSAH (OR, 0.37, 95% CI, 0.23–0.58; I 2 = 79.3%, p = 0.001) in patients presented with intracranial aneurysms. The results did not significantly change in sensitivity analyses. Conclusions: Summarizing available evidence in the literature, our findings indicate that aspirin use, regardless of frequency and duration, was associated with a statistically significantly lower risk of UIA growth and aSAH in patients with UIA. Well-designed and large-scale clinical trials are needed to help define the role of aspirin as a protective pharmaceutical for UIAs. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is one of the most frequent primary malignant brain tumors with a poor prognosis. Unfortunately, due to the intrinsic or acquired chemoresistance of GBM cells, it easily becomes refractory disease and tumors are easy to recur. Therefore, it is critical to elucidate the molecular mechanisms underlying the chemoresistance of GBM cells to discover more efficient therapeutic treatments. Kinesin family member C1 (KIFC1) is a normal nonessential kinesin motor that affects the progression of multiple types of cancers. However, whether KIFC1 have a function in GBM is still unexplored. Here we found that KIFC1 was upregulated in human temozolomide (TMZ)-resistant GBM tissues. KIFC1 silencing is sufficient to inhibit GBM cell proliferation and amplify TMZ-induced repression of cell proliferation. Mechanistically, KIFC1 silencing contributed to DNA damage, cell cycle arrest, and apoptosis through regulating Rad51, Akt, and DNA-PKcs phosphorylation. We also noticed that KIFC1 silencing also inhibited tumor formation and increased TMZ sensitivity through regulating Ki67, Rad51, γ-H2AX, and phosphorylation of AKT in vivo. Our findings therefore confirm the involvement of KIFC1 in GBM progression and provide a novel understanding of KIFC1-Akt axis in the sensitivity of GBM to chemotherapy. [ABSTRACT FROM AUTHOR]

Electrical impedance tomography (EIT) is a potential imaging technique for reconstructing the interior conductivity distribution within an object. The reconstruction is realized by processing the boundary voltage measured from the EIT. Mathematically, the reconstruction of conductivity distribution is a highly nonlinear ill-posed inverse problem as the solution is not unique and is sensitive to the noise, which largely hinders the practical application of the EIT technique. In this paper, a novel modified non-convex ${L}_{1}$ -norm penalty based total generalized variation (NCP-TGV) model is proposed to solve the inverse problem and reconstruct the conductivity distribution. An iteratively reweighted ${L}_{1}$ algorithm is developed to convert the non-convex model to convex function and the Chambolle-Pock primal-dual algorithm is then applied to solve the minimization problem. To demonstrate the performance of the proposed NCP-TGV model in reconstructing the conductivity distribution, extensive numerical simulation and experimental work have been carried out. Additionally, the proposed approach has been validated by comparing its performance with the convex ${L}_{1}$ -norm penalty based total variation (TV) and TGV inverse models. The results indicate that the images reconstructed by the proposed NCP-TGV model show better quality with the advantages of simultaneous reduction of staircase effect and preservation of edge in comparison to the TV and TGV approaches. [ABSTRACT FROM AUTHOR]

Background Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors. Methods This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker. Results Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60–100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%–42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3–7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months. Conclusions Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC. [ABSTRACT FROM AUTHOR]

Background: RAS/RAF/mitogen-activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias.Methods: This phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1. In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild-type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3).Results: The most commonly reported treatment-related adverse events were diarrhea, rash, nausea, and increased alanine aminotransferase levels. The phase 2 recommended dose for Trametinib was 2 mg orally daily. The overall response rates were 20%, 3%, and 27% for cohorts 1, 2, and 3, respectively, and this indicated preferential activity among RAS-mutated myeloid malignancies. Repeated cycles of trametinib were well tolerated with manageable or reversible toxicities; these results were similar to those of other trametinib studies.Conclusions: The selective, single-agent activity of trametinib against RAS-mutated myeloid malignancies validates its therapeutic potential. Combination strategies based on a better understanding of the hierarchical role of mutations and signaling in myeloid malignancies are likely to improve the response rate and duration. Cancer 2016;122:1871-9. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

In dose-finding clinical studies, it is common that multiple endpoints are of interest. For instance, in phase I/II studies, efficacy and toxicity are often the primary endpoints, which are observed simultaneously and which need to be evaluated together. Motivated by this, we confine ourselves to bivariate responses and focus on the most analytically difficult case: a mixture of continuous and categorical responses. We adopt the bivariate probit dose-response model and quantify our goal by a utility function. We study locally optimal designs, two-stage optimal designs, and fully adaptive designs under different ethical and cost constraints in the experiments. We assess the performance of two-stage designs and fully adaptive designs via simulations. Our simulations suggest that the two-stage designs are as efficient as and may be more efficient than the fully adaptive designs if there is a moderate sample size in the initial stage. In addition, two-stage designs are easier to construct and implement and thus can be a useful approach in practice. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We introduce a two-stage design for dose-finding in the context of Phase I/II studies, where two binary correlated endpoints are available, for instance, one for efficacy and one for toxicity. The bivariate probit model is used as a working model for the dose-response relationship. Given a 'desirable point' for the marginal probabilities of efficacy and toxicity, the goal is to find the target dose that is 'closest' to the desirable point. The criterion of optimality (objective function) is the variance of the estimator for that dose. Optimal experimental design methodology is used to construct efficient dose allocation procedures that treat patients in the study at doses that are both safe and efficacious. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Often in clinical trials the observed responses are continuous but a regulatory agency will approve the drug only if the probability is sufficiently large that the efficacy measure exceeds a predefined threshold and the toxicity does not exceed another given threshold. Thus the measure of interest (utility) is based on dichotomized responses. We consider normally distributed correlated responses and build a utility function using the probit transform. Locally optimal designs are used as benchmarks for more practical designs such as composite and adaptive designs. We focus on D-criterion (i.e., all parameters of the dose-response model are of interest) and consider only two-stage designs. It is shown that the practice of reporting dichotomized responses leads to a substantial loss in the precision of estimated parameters (or in the power loss). [ABSTRACT FROM AUTHOR]

Whenever a response is naturally confined to a finite interval (such as a visual analog scale for pain severity), the beta distribution provides a simple and flexible probability distribution to model such a response. The parameters of the distribution can then be related to covariates, such as dose, in a clinical trial through the generation of a beta regression model. In this article, we explore locally optimal designs for this class of regression models, focusing mainly on minimization of the generalized variance of maximum likelihood estimators (D-optimality). Optimal designs and sensitivity to misspecification of model parameters are examined using a candidate points searching algorithm. Although formally the model assumes that the response is continuous, it provides a parsimonious approximation for ordinal data when there is a relatively large number of categories. The resulting estimators and optimal designs are simpler and may offer more ease in interpretation than those derived from models for ordered categorical outcomes. The proposed methods are applied to data from a clinical trial. [ABSTRACT FROM AUTHOR]

Abstract: A simple and accurate method has been developed to simultaneously separate and determine 10 bioactive compounds in citrus fruits by high-performance liquid chromatography coupled with diode array detection and electrospray ionisation mass spectrometry (HPLC-DAD–ESI/MS). This HPLC assay was performed on a reversed-phase C18 column with acetonitrile and 0.1% (v/v) aqueous formic acid as mobile phase. DAD has been performed at 273, 283 and 324nm for quantification of the alkaloids, flavanones and hydroxycinnamic acids. MS was also employed to identify the each analyte. Ten analytes (naringin, hesperidin, neohesperidin, ferulic acid, p-coumaric acid, chlorogenic acid, caffeic acid, octopamine, synephrine and tyramine) demonstrated good linearity (r ⩾0.9990) in a relatively wide concentration range. The method revealed high average recovery (range, 92.1–97.9%) and good precision with interday and intraday variations with less than 4.71%. The limits of detection (LODs) ranged from 0.02 to 0.11μg/ml, while the limits of quantification (LOQs) were defined in the range of 0.08–0.39μg/ml. The proposed method has been successfully applied to analyse three types of bioactive constituents in eight citrus hybrids pulps and eight citrus hybrids peels, which has been successfully cultivated in China. [Copyright &y& Elsevier]

Objective: The study aimed to find the difference in functional network topology on interictal electroencephalographic (EEG) between patients with drug-resistant epilepsy (DRE) and healthy people., Methods: We retrospectively analyzed the medical records as well as EEG data of ten patients with DRE and recruited five sex-age-matched healthy controls (HC group). Each participant remained awake while undergoing video-electroencephalography (vEEG) monitoring. After excluding data that contained abnormal discharges, we screened EEG segments that were free of artifacts and put them together into 20-min segments. The screened data was bandpass filtered to different frequency bands (delta, theta, alpha, beta, and gamma). The weighted phase lag index (wPLI) and the network properties were calculated to evaluate changes in the topology of the functional network. Finally, the results were statistically analyzed, and the false discovery rate (FDR) was used to correct for differences after multiple comparisons., Results: In the full frequency band (0.5-45 Hz), the functional connectivity in the DRE group during the interictal period was significantly lower than that in the HC group ( p  < 0.05). Compared to the HC group, in the full frequency band, the DRE group exhibited significantly decreased clustering coefficient (CC), node degree (D), and global efficiency (GE), while the characteristic path length (CPL) significantly increased ( p  < 0.05). In the sub-frequency bands, the functional connectivity of the DRE group was significantly lower than that of the HC group in the delta band but higher in the alpha, beta, and gamma bands ( p  < 0.05). The statistical results of network properties revealed that in the delta band, the DRE group had significantly decreased values for D, CC, and GE, but in the alpha, beta, and gamma bands, these values were significantly increased ( p  < 0.05). Additionally, the CPL of the DRE group significantly increased in the delta and theta bands but significantly decreased in the alpha, beta, and gamma bands ( p  < 0.05)., Conclusion: The topology structure of the functional network in DRE patients was significantly changed compared with healthy people, which was reflected in different frequency bands. It provided a theoretical basis for understanding the pathological network alterations of DRE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ding, Guo, Shan, Chen, Wu, Wu, Wang and Li.)

Extreme heat caused by global climate change has become a serious threat to the sustainable development of urban areas. Scientific assessment of the impacts of extreme heat on urban areas and in-depth knowledge of the cross-scale mechanisms of heat vulnerability forming in urban systems are expected to support policymakers and stakeholders in developing effective policies to mitigate the economic, social, and health risks. Based on the perspective of the human-environment system, this study constructed a conceptual framework and index system of "exposure-susceptibility-adaptive capacity" for urban heat vulnerability (UHV) and proposed its assessment methods. Taking Xiamen City, a coastal metropolis, as an example, spatial analysis and Geodetector were used to explore the spatial and temporal changes, spatial characteristics, and patterns of UHV under multiple external disturbances from natural to anthropological factors, and to reveal the main factors influencing UHV forming and spatial differentiation. Results showed that the exposure, susceptibility, adaptive capacity, and UHV in Xiamen City had a spatial structure of "coastal-offshore-inland". On the hot day, both the exposure and UHV showed a temporal pattern of "rising and then falling, peaking at 14:00" and a spatial pattern of "monsoonal-like" movement between coast and inland. Coastal zoning with favorable socioeconomic conditions had less magnitude of changes in UHV, where the stability of the urban system was more likely to be maintained. During the hot months, the high UHV areas were mainly distributed in the inland, while coastal areas showed low UHV levels. Further, coastal UHV was mainly dominated by "heat exposure", offshore by "comprehensive factors", and inland in the northern mountainous areas by "lack of adaptive capacity". Multi-scale urban adaptive capacity was confirmed to alter spatial distribution of exposure and reshape the spatial pattern of UHV. This study promotes the application of multi-scale vulnerability framework to disaster impact assessment, enriches the scientific knowledge of the urban system vulnerability, and provides scientific references for local targeted cooling policy development and extreme heat resilience building programs., Competing Interests: Author DZ is a key member of this study and currently works for Fujian Zhitianqi Information Technology Co., Ltd. This study has no commercial or financial relationship with this company and received no funding from Fujian Zhitianqi Information Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Shui, Huang, Wang, Wu, Wu, Xue, Huang, Zhang and Zheng.)

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is an acute and sometimes fatal cerebrovascular disease. The chronobiological patterns of aSAH are still unclear worldwide. This 15-year time-series study aims to clarify the chronobiological patterns including seasonal, monthly, weekly, and circadian distributions of aSAH., Methods: We retrospectively analyzed the medical records of aSAH patients in central China. To investigate seasonal and weekly distributions, we used the χ2 goodness-of-fit test to analyze the uniformity of the onset time. To explore monthly and circadian distributions, we established Fourier models to show the rhythmicity in chronobiological patterns. Subgroup analyses were conducted to assess the impact of age, gender, hypertension statuses, and aneurysmal characteristics (number, size, and location) on the chronobiological patterns of aSAH., Results: A total of 1469 patients with aSAH were recruited in the study. The seasonal and monthly distribution exhibited significantly higher incidence in winter and January/December and lower incidence in summer and July. The weekly distribution of aSAH onset showed no significant uneven variation. The circadian distribution of aSAH exhibited a significant pattern (p = 0.0145), with a morning peak around 8:00, and a late afternoon peak at 16:00-20.00. The circadian rhythmicity varied in subgroups of different ages, genders, and aneurysmal locations., Conclusion: The occurrence of aSAH exhibits significant circannual and circadian patterns among the Chinese population. Patients with aSAH of different ages, genders, and aneurysmal locations would present different chronobiological patterns., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted., (© 2021 UICC.)

Background: Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors., Methods: This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker., Results: Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60-100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%-42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t 1/2 : 3-7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months., Conclusions: Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC., (© The Author(s) 2019. Published by Oxford University Press.)

Objective: We aimed to compare the therapeutic effects of stereotactic aspiration and best medical management in patients who developed supratentorial hypertensive intracerebral haemorrhage (HICH) with a volume of haemorrhage between 20 and 40 mL., Methods: The clinical data of 220 patients with supratentorial HICH with a volume between 20 and 40 mL were retrospectively analysed. Among them, 142 received stereotactic aspiration surgery (stereotactic aspiration group) and 78 received best medical management (conservative group). All were followed up for 6 months. Multivariate logistic regression and Kaplan-Meier survival curves were used to compare the outcome between the two groups., Results: The rebleeding rate was lower in the group that had stereotactic aspiration when compared with the group with medical treatment (6 [4.2%] vs 9 [11.5%], χ 2 =4.364, p=0.037). After 6 months, although the mortality rate did not differ significantly between the two groups (8 cases [5.6%] vs 10 cases [12.8%], χ 2 =3.461, p=0.063), the rate of a favourable outcome was higher in the group who received stereotactic aspiration (χ 2 =15.870, p=0.000). Logistic regression identified that medical treatment (OR=1.64, p=0.000) was an independent risk factor for an unfavourable outcome. The Kaplan-Meier curves indicated that the median favourable outcome time in the stereotactic aspiration group was 59.5 days compared with that in the medically treated group (87.0 days). The log-rank test indicated that the prognosis at 6 months was better for those treated with stereotactic haematoma aspiration (χ 2 =29.866, p=0.000). However, the 6-month survival rate was similar between the two groups (χ 2 =3.253, p=0.068)., Conclusions: Stereotactic haematoma aspiration significantly improved the quality of life, although did not effectively reduce the rate of mortality. When selected appropriately, patients with HICH may benefit from this type of surgical intervention., Competing Interests: Competing interests: None declared.

Glioma is the most common and aggressive type of primary brain tumor. MicroRNA (miR)-130b functions as a tumor-associated miR. The dysregulation of miR-130b is involved in numerous biological characteristics and properties of certain types of cancer. The present study revealed the function and possible molecular mechanism of miR-130b in glioma cells, reporting that the level of miR-130b was markedly higher, increasing progressively as the histologic grade of the glioma increased, compared with the level in normal tissues. Additionally, the present study demonstrated that patients with high miR-130b expression exhibited a poor 3-year survival rate and miR-130b was an independent factor for predicting the prognosis of patients with glioma. The downregulation of miR-130b reduced invasion and migration in U373 and U87 cells. Furthermore, the downregulation of miR-130b increased peroxisome proliferator-activated receptor-γ (PPARγ) expression and inhibited epithelial-mesenchymal transition (EMT) in glioma cells. The present study identified PPARγ as a direct target of miR-130b in glioma in vitro . Furthermore, PPARγ knockdown was revealed to reduce the effect on EMT caused by the downregulation of miR-130b in U87 cells. The present study demonstrated that miR-130b promotes glioma proliferation, migration and invasion by suppressing PPARγ and subsequently inducing EMT.

Adenosine triphosphatase inhibitory factor 1 (IF1) has previously been considered to be a driving oncogene in human cancers. Several studies have revealed that IF1 overexpression is present in a variety of tumor types and promotes tumor growth and metastasis. The present study aimed to investigate the clinical significance of IF1 in glioma and the role of IF1 in cell migration and invasion. The mRNA and protein expression of IF1 in glioma tissues was found to be significantly increased compared with the expression in normal brain tissues (P<0.05). The presence of IF1 expression was significantly associated with an advanced clinical stage in glioma (P<0.05). Furthermore, the presence of IF1 expression was found to be associated with a reduced overall survival rate of glioma patients (P<0.05). Multivariate Cox regression analysis indicated that IF1 was an independent factor for predicting the overall survival rate of patients with glioma (P<0.05). IF1 knockdown also significantly reduced the number of migratory and invasive U251 and U87 cells (P<0.05). In addition, IF1 knockdown inhibited the expression of nuclear factor-κB (NF-κB) and Snai1, and led to increased E-cadherin expression and reduced vimentin expression. In conclusion, the presence of IF1 expression is associated with poor clinicopathological features in glioma. IF1 expression is an independent prognostic marker for predicting the overall survival rate of patients with glioma. Mechanistically, IF1 may promote glioma cell migration and invasion through the NF-κB/Snai1 axis.