GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics.

Genetic epilepsy with febrile seizures plus (GEFS+) is a genetic epilepsy syndrome characterized by a marked hereditary tendency inherited as an autosomal dominant trait. Patients with GEFS+ may develop typical febrile seizures (FS), while generalized tonic-clonic seizures (GTCSs) with fever commonly occur between 3 months and 6 years of age, which is generally followed by febrile seizure plus (FS+), with or without absence seizures, focal seizures, or GTCSs. GEFS+ exhibits significant genetic heterogeneity, with polymerase chain reaction, exon sequencing, and single nucleotide polymorphism analyses all showing that the occurrence of GEFS+ is mainly related to mutations in the gamma-aminobutyric acid type A receptor gamma 2 subunit (GABRG2) gene. The most common mutations in GABRG2 are separated in large autosomal dominant families, but their pathogenesis remains unclear. The predominant types of GABRG2 mutations include missense (c.983A → T, c.245G → A, p.Met199Val), nonsense (R136*, Q390*, W429*), frameshift (c.1329delC, p.Val462fs*33, p.Pro59fs*12), point (P83S), and splice site (IVS6+2T → G) mutations. All of these mutations types can reduce the function of ion channels on the cell membrane; however, the degree and mechanism underlying these dysfunctions are different and could be linked to the main mechanism of epilepsy. The γ2 subunit plays a special role in receptor trafficking and is closely related to its structural specificity. This review focused on investigating the relationship between GEFS+ and GABRG2 mutation types in recent years, discussing novel aspects deemed to be great significance for clinically accurate diagnosis, anti-epileptic treatment strategies, and new drug development.

Safety, pharmacokinetic, pharmacodynamic and clinical activity of molibresib for the treatment of nuclear protein in testis carcinoma and other cancers: Results of a Phase I/II open-label, dose escalation study.

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.

Non-Coding RNAs as Circulating Biomarkers for the Diagnosis of Intracranial Aneurysm: A Systematic Review and Meta-Analysis.

BACKGROUND: Early diagnosis of intracranial aneurysm (IA) is arduous in the current situation, and no biomarker is available for the screening of IA. We here systematically evaluate the diagnostic value of circulating non-coding RNA (ncRNA) for the diagnosis of IA. METHODS: We searched PubMed, Web of Science, Embase, Scopus and Cochrane Library databases from inception to June 2020. We included studies that investigated the diagnostic performance of circulating ncRNAs for the diagnosis of IA. We performed Random-effect meta-analyses for the diagnostic test accuracy to calculate pooled estimates. Subgroup analyses and sensitivity analyses were conducted to explore the source of heterogeneity. RESULTS: Thirteen studies, including 1,105 patients and 28 ncRNAs, were included. The pooled sensitivity and specificity were 0.80 (95% confidence interval [CI], 0.76-0.83) and 0.80 (95% CI, 0.76-0.84), respectively, and the area under the hierarchical summary receiver operating characteristic curve was 0.87 (95% CI, 0.84-0.89). The pooled positive and negative likelihood ratios were 3.97 (95% CI, 3.17-4.98) and 0.25 (95% CI, 0.21-0.31), corresponding with a diagnostic odds ratio of 15.63 (95% CI, 10.41-23.47). Subgroup analyses revealed that the diagnostic accuracy of miRNA, lncRNA and circRNA were not significantly different (p > 0.05). Circulating ncRNAs showed higher diagnostic accuracy for patients with unruptured IA than those with ruptured IA (p = 0.0122). CONCLUSION: Current evidence suggests that the circulating ncRNA test could be an effective method for universal IA screening. Future clinical studies need to confirm the diagnostic role of specific ncRNAs.

Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies.

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.

Brain functional connectivity and network characteristics changes after vagus nerve stimulation in patients with refractory epilepsy.

Objective: 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. Methods: Ten refractory epilepsy patients underwent video encephalographic monitoring before and after VNS treatment. The 2-min electroencephalogram segment containing the ictal was selected for each participant, resulting in a total of 20 min of seizure data. The weighted phase lag index (wPLI) and small-world metrics were calculated for the whole frequency band and different frequency bands (delta, theta, alpha, beta, and gamma). Finally, the relevant metrics were statistically analyzed, and the false discovery rate was used to correct for differences after multiple comparisons. Results: In the whole band, the wPLI was notably enhanced, and the network metrics, including degree (D), clustering coefficient (CC), and global efficiency (GE), increased, while characteristic path length (CPL) decreased (P < 0.01). In different frequency bands, the wPLI between the parieto-occipital and frontal regions was significantly strengthened in the delta and beta bands, while the wPLI within the frontal region and between the frontal and parieto-occipital regions were significantly reduced in the beta and gamma bands (P < 0.01). In the low-frequency band (<13 Hz), the small-world metrics demonstrated significantly increased CC, D, and GE, with a significantly decreased CPL, indicating a more efficient network organization. In contrast, in the gamma band, the GE decreased, and the CPL increased, suggesting a shift toward less efficient network organization. Conclusion: VNS treatment can significantly change the wPLI and small-world metrics. These findings contribute to a deeper understanding of the impact of VNS therapy on brain networks and provide objective indicators for evaluating the efficacy of VNS.

Analysis of sodium phenylbutyrate and taurursodiol survival effect in ALS using external controls.

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.

Alterations in brain network functional connectivity and topological properties in DRE patients.

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.

Optimal dose-finding designs with correlated continuous and discrete responses.

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.

Chronobiological Patterns of Aneurysmal Subarachnoid Hemorrhage in Central China.

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.

Urban heat vulnerability: A dynamic assessment using multi-source data in coastal metropolis of Southeast China.

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.

Arrangement of boundary electrodes for detection of frontal lobe disease with electrical impedance tomography.

Purpose: Caused by brain trauma or blood vessel abnormality, intracerebral hemorrhage and secondary ischemia have become prevalent and severe neurological diseases. The timely and accurate detection of disease is essential for the recovery of patients. As an emerging visualization technique, electrical impedance tomography (EIT) offers an alternative. It is able to reconstruct the conductivity distribution that reflects the pathological variation of human tissue. Approach: In the EIT-based detection, electrodes are usually in uniform arrangement, which may be not suitable in some conditions. To enhance sensitivity in the region of interest, EIT with a novel offset arrangement of boundary electrodes is proposed to image a simulated frontal lobe hemorrhage and secondary ischemia. To cope with the ill-posed inverse problem, the L1 regularization method is developed during the reconstruction. In addition, the impact of noise with a signal-to-noise ratio of 56 dB is studied. Results: Compared with the traditional uniform electrode arrangement, the results demonstrate that EIT with the proposed offset arrangement of electrodes is more advantageous for imaging frontal lobe disease. Conclusions: The proposed offset arrangement of electrodes is superior to the traditional uniform arrangement in imaging frontal lobe disease, especially under the impact of noise.

The Role of Aspirin in the Management of Intracranial Aneurysms: A Systematic Review and Meta-Analyses.

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.

Sparse image reconstruction of intracerebral hemorrhage with electrical impedance tomography.

Purpose: Intracerebral hemorrhage (ICH) is a common disease that is known for its high morbidity, high mortality, and high disability. The fast and accurate detection of ICH is essential for the acute care of patients. Electrical impedance tomography (EIT) offers an alternative with which pathological tissues can be detected by reconstructing conductivity variation. Nevertheless, the sensitive field of EIT is greatly affected by medium distribution, which is referred to as soft-field effect. In addition, the image reconstruction is a severely ill-posed inverse problem. Furthermore, due to the low conductivity of skull, the sensitivity in the sensing area is extremely low. Therefore, the reconstruction of ICH with EIT is great challenge. Approach: A sparse image reconstruction method is proposed for EIT to visualize the conductivity variation caused by ICH. To reduce the impact of soft-field effect, the normalization of sensitivity distribution is conducted for monolayer and three-layer head model. In addition, a constrained sparse L 1 -norm minimization model is developed for the image reconstruction. Augmented Lagrangian multiplier method and alternating minimization scheme are adopted to solve the proposed model. Results: The results show that the sensitivity in the sensing area is largely enhanced. Numerical simulation based on monolayer head model and three-layer head model is respectively carried out. Both the reconstructed images and the quantitative evaluations show that image reconstructed by the proposed method is much better than that reconstructed by traditional Tikhonov method. The reconstructions evaluated under the impact of noise also show that the proposed method has superior anti-noise performance. Conclusions: With the proposed method, the quality of the reconstructed image would be greatly improved. It is an effective approach for imaging ICH with EIT technique.

A new surgical method of treatment spontaneous intracranial hemorrhage.

OBJECTIVE: This study aimed to determine the safety and effectiveness of DTI-assisted neuroendoscopy for treating intracranial hemorrhage (ICH). METHODS: This retrospective study included clinical data from 260 patients with spontaneous supratentorial ICH who received neuroendoscopic hematoma removal. Patients were separated into groups based on the surgery method they received: DTI-assisted neuroendoscopy (69 cases) and standard neuroendoscopy (191 cases). All patients were followed up for 6 months. Multivariate logistic regression analyzed the risk factors affecting the prognosis of patients. The outcomes of the two groups were compared using Kaplan-Meier survival curves. RESULTS: The prognostic modified Rankin Scale (mRS) score was significantly better (P = 0.027) in the DTI-assisted neuroendoscopy group than in the standard neuroendoscopy group. Logistic regression analysis showed that DTI-assisted neuroendoscopy is an independent protective factor for a favorable outcome (model 1: odds ratio [OR] = 0.42, P = 0.015; model 2: OR = 0.40, P = 0.013). Kaplan-Meier survival curves were used to show that the median time for a favorable outcome was 66 days (95% confidence interval [CI] = 48.50-83.50 days) in the DTI-assisted neuroendoscopy group and 104 days (95% CI = 75.55-132.45 days) in the standard neuroendoscopy group. Log-rank testing showed that the DTI-assisted neuroendoscopy group had a lower pulmonary infection rate (χ 2 = 4.706, P = 0.030) and a better prognosis (χ 2 = 5.223, P = 0.022) than the standard neuroendoscopy group. The survival rate did not differ significantly between the DTI-assisted neuroendoscopy group and the standard neuroendoscopy group (P > 0.05). CONCLUSIONS: The use of DTI in neuroendoscopic hematoma removal can significantly improve neurological function outcomes in patients, but it does not significantly affect the mortality of patients.

Kinesin Family Member C1 Increases Temozolomide Resistance of Glioblastoma Through Promoting DNA Damage Repair.

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.

Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors.

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.

Stereotactic aspiration for hypertensive intracerebral haemorrhage in a Chinese population: a retrospective cohort study.

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%], χ2=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%], χ2=3.461, p=0.063), the rate of a favourable outcome was higher in the group who received stereotactic aspiration (χ2=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 (χ2=29.866, p=0.000). However, the 6-month survival rate was similar between the two groups (χ2=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.

Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC.

INTRODUCTION: This first-time-in-humans study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of GSK2879552 in patients with relapsed or refractory SCLC. METHODS: This phase I, multicenter, open-label study (NCT02034123) enrolled patients (≥18 years old) with relapsed or refractory SCLC (after ≥1 platinum-containing chemotherapy or refusal of standard therapy). Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Dose escalations were based on safety, PK, and PD. The primary end point (Part 1) was to determine the safety, tolerability, and recommended dose and regimen of GSK2879552. Secondary end points were to characterize PK and PD parameters and measure disease control rate at week 16. Part 2 was not conducted. RESULTS: Between February 4, 2014, and April 18, 2017, a total of 29 patients were allocated to one of nine dose cohorts (0.25 mg-3 mg once daily and 3-mg or 4-mg intermittent dosing). In all, 22 patients completed the study; 7 withdrew, primarily owing to adverse events (AEs). Most patients (24 of 29 [83%]) had at least one treatment-related AE, most commonly thrombocytopenia (12 of 29 [41%]). Twelve serious AEs (SAEs) were reported by nine patients; six were considered treatment related, the most common of which was encephalopathy (four SAEs). Three patients died; one death was related to SAEs. PK was characterized by rapid absorption, slow elimination, and a dose-proportional increase in exposure. CONCLUSIONS: GSK2879552 is a potent, selective inhibitor of lysine demethylase 1A and has demonstrated favorable PK properties but provided poor disease control and a high AE rate in patients with SCLC. The study was terminated, as the risk-benefit profile did not favor continuation.

MicroRNA-130b promotes cell migration and invasion by inhibiting peroxisome proliferator-activated receptor-γ in human glioma.

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.