Search

The recently introduced orientation selective deep brain stimulation (OS-DBS) technique freely controls the direction of the electric field's spatial gradient by using multiple contacts with independent current sources within a multielectrode array. The goal of OS-DBS is to align the electrical field along the axonal track of interest passing through the stimulation site. Here we utilized OS-DBS with a planar 3-channel electrode for stimulating the rat entorhinal cortex (EC) and medial septal nucleus (MSN), two promising areas for DBS treatment of Alzheimer's disease. The brain responses to OS-DBS were monitored by whole brain functional magnetic resonance imaging (fMRI) at 9.4 T with Multi-Band Sweep Imaging with Fourier Transformation (MB-SWIFT). Varying the in-plane OS-DBS stimulation angle in the EC resulted in activity modulation of multiple downstream brain areas involved in memory and cognition. Contrary to that, no angle dependence of brain activations was observed when stimulating the MSN, consistent with predictions based on the electrode configuration and on the main axonal directions of the targets derived from diffusion MRI tractography and histology. We conclude that tuning the OS-DBS stimulation angle modulates the activation of brain areas relevant to Alzheimer's disease, thus holding great promise in the DBS treatment of the disease. [ABSTRACT FROM AUTHOR]

This single-arm, multi-center clinical trial aimed to evaluate the safety, tolerability, DLT, recommended dose (RD), preliminary efficacy, and pharmacokinetics (PK) characteristics of lurbinectedin, a selective inhibitor of oncogenic transcription, in Chinese patients with advanced solid tumors, including relapsed SCLC. Patients with advanced solid tumors were recruited in the dose-escalation stage and received lurbinectedin in a 3 + 3 design (two cohorts: 2.5 mg/m2 and 3.2 mg/m2, IV, q3wk). The RD was expanded in the following dose-expansion stage, including relapsed SCLC patients after first-line platinum-based chemotherapy. The primary endpoints included safety profile, tolerability, DLT, RD, and preliminary efficacy profile, while the secondary endpoints included PK characteristics. In the dose-escalation stage, ten patients were included, while one patient had DLT in the 3.2 mg/m2 cohort, which was also the RD for the dose-expansion stage. At cutoff (May 31, 2022), 22 SCLC patients were treated in the ongoing dose-expansion stage, and the median follow-up was 8.1 months (range 3.0–11.7). The most common grade ≥ 3 treatment-related adverse events (TRAEs) included neutropenia (77.3%), leukopenia (63.6%), thrombocytopenia (40.9%), anemia (18.2%), and ALT increased (18.2%). The most common severe adverse events (SAEs) included neutropenia (27.3%), leukopenia (22.7%), thrombocytopenia (18.2%), and vomiting (9.1%). No treatment-related deaths occurred. The Independent Review Committee (IRC)-assessed ORR was 45.5% (95% CI 26.9–65.3). Lurbinectedin at the RD (3.2 mg/m2) showed manageable safety and acceptable tolerability in Chinese patients with advanced solid tumors, and demonstrates promising efficacy in Chinese patients with SCLC as second-line therapy. Trial registration: This study was registered with ClinicalTrials.gov NCT04638491, 20/11/2020. [ABSTRACT FROM AUTHOR]

The application of the composite of Ni3S2 nanoparticles and 3D graphene as a novel cathode material for supercapacitors is systematically investigated in this study. It is found that the electrode capacitance increases by up to 111% after the composite electrode is activated by the consecutive cyclic voltammetry scanning in 1 M KOH. Due to the synergistic effect, the capacitance and the diffusion coefficient of electrolyte ions of the activated composite electrode are ca. 3.7 and 6.5 times higher than those of the Ni3S2 electrode, respectively. Furthermore, the activated composite electrode exhibits an ultrahigh specific capacitance of 3296 F/g and great cycling stability at a current density of 16 A/g. To obtain the reasonable matching of cathode/anode electrodes, the composite of Fe3O4 nanoparticles and chemically reduced graphene oxide (Fe3O4/rGO) is synthesized as the anode material. The Fe3O4/rGO electrode exhibits the specific capacitance of 661 F/g at 1 A/g and excellent rate capability. More importantly, an asymmetric supercapacitor fabricated by two different composite electrodes can be operated reversibly between 0 and 1.6 V and obtain a high specific capacitance of 233 F/g at 5 mV/s, which delivers a maximum energy density of 82.5 Wh/kg at a power density of 930 W/kg. [ABSTRACT FROM AUTHOR]

Approximately 36% of patients with neuromyelitis optica spectrum disorders (NMOSD) suffer from severe visual and motor disability (blindness or light perception or unable to walk) with abnormalities of whole-brain functional networks. However, it remains unclear how whole-brain functional networks and their dynamic properties are related to clinical disability in patients with NMOSD. Our study recruited 30 NMOSD patients (37.70 ± 11.99 years) and 45 healthy controls (HC, 41.84 ± 11.23 years). The independent component analysis, sliding-window approach and graph theory analysis were used to explore the static strength, time-varying and topological properties of large-scale functional networks and their associations with disability in NMOSD. Compared to HC, NMOSD patients showed significant alterations in dynamic networks rather than static networks. Specifically, NMOSD patients showed increased occurrence (fractional occupancy; P < 0.001) and more dwell times of the low-connectivity state (P < 0.001) with fewer transitions (P = 0.028) between states than HC, and higher fractional occupancy, increased dwell times of the low-connectivity state and lower transitions were related to more severe disability. Moreover, NMOSD patients exhibited altered small-worldness, decreased degree centrality and reduced clustering coefficients of hub nodes in dynamic networks, related to clinical disability. NMOSD patients exhibited higher occurrence and more dwell time in low-connectivity states, along with fewer transitions between states and decreased topological organizations, revealing the disrupted communication and coordination among brain networks over time. Our findings could provide new perspective to help us better understand the neuropathological mechanism of the clinical disability in NMOSD. [ABSTRACT FROM AUTHOR]

Epidural spinal cord stimulation (ESCS) is widely used for chronic pain treatment, and is also a promising tool for restoring motor function after spinal cord injury. Despite significant positive impact of ESCS, currently available protocols provide limited specificity and efficiency partially due to the limited number of contacts of the leads and to the limited flexibility to vary the spatial distribution of the stimulation field in respect to the spinal cord. Recently, we introduced Orientation Selective (OS) stimulation strategies for deep brain stimulation, and demonstrated their selectivity in rats using functional MRI (fMRI). The method achieves orientation selectivity by controlling the main direction of the electric field gradients using individually driven channels. Here, we introduced a similar OS approach for ESCS, and demonstrated orientation dependent brain activations as detected by brain fMRI. The fMRI activation patterns during spinal cord stimulation demonstrated the complexity of brain networks stimulated by OS-ESCS paradigms, involving brain areas responsible for the transmission of the motor and sensory information. The OS approach may allow targeting ESCS to spinal fibers of different orientations, ultimately making stimulation less dependent on the precision of the electrode implantation. [ABSTRACT FROM AUTHOR]

Homologous recombination deficiency (HRD) causes faulty double-strand break repair and is a prevalent cause of tumorigenesis. However, the incidence of HRD and its clinical significance in pan-cancer patients remain unknown. Using computational analysis of Single-nucleotide polymorphism array data from 10,619 cancer patients, we demonstrate that HRD frequently occurs across multiple cancer types. Analysis of the pan-cancer cohort revealed that HRD is not only a biomarker for ovarian cancer and triple-negative breast cancer, but also has clinical prognostic value in numerous cancer types, including adrenocortical cancer and thymoma. We discovered that homologous recombination–related genes have a high mutation or deletion frequency. Pathway analysis shows HRD is positively correlated with the DNA damage response and the immune-related signaling pathways. Single cell RNA sequencing of tumor-infiltrating lymphocytes reveals a significantly higher proportion of exhausted T cells in HRD patients, indicating pre-existing immunity. Finally, HRD could be utilized to predict pan-cancer patients' responses to Programmed cell death protein 1 immunotherapy. In summary, our work establishes a comprehensive map of HRD in pan-cancer. The findings have significant implications for expanding the scope of Poly ADP-ribose polymerase inhibitor therapy and, possibly, immunotherapy. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that handgrip strength (HGS) is a conspicuous marker for assessing some diseases affecting middle-aged and elderly individuals. However, research regarding HGS and heart failure (HF) is sparse and controversial. Hence, we aimed to investigate the association between HGS and HF among adults aged 45 years and older in the United States. In this cross-sectional study, we included 4524 adults older than 45 years who were part of the National Health and Nutrition Examination Survey. A generalized additive model was used to estimate the association between HGS and HF. Age, gender, race, income, education, body mass index, smoking status, drinking status, diabetes, hypertension, stroke, vigorous physical activity, total energy intake, total protein intake, total sugars intake, and total fat intake covariates were adjusted using multiple regression models. And further subgroup analysis was conducted. We documented 189 cases of HF, including 106 men and 83 women. HGS was negatively associated with HF after adjusting for all the covariates (odds ratio = 0.97, 95% confidence interval = 0.96–0.99; P < 0.001). Compared with the lowest quintile, the highest quintile was associated with an 82% lower incidence of HF (odds ratio = 0.18, 95% confidence interval = 0.08–0.43; P < 0.001). Subgroup analysis showed that the results remained stable. In US adults older than 45, HGS was negatively associated with HF after adjusting for covariates. This finding had the potential to draw attention to the physiological and pathological effects of decreased muscle function on HF and may influence further prospective studies with intervention trials. [ABSTRACT FROM AUTHOR]

To understand the association between sodium and potassium consumption levels, hypertension and knowledge, attitudes and behaviors (KAB) toward salt and the commitment to effective sodium reduction and potassium supplementation to achieve the purpose of suppressing hypertension. A stratified multistage random sampling method was used to obtain a representative provincial sample of 7512 residents aged 18–69 years through a cross-sectional survey by the Salt Reduction and Hypertension Prevention Project (SRHPP) in Zhejiang Province of China in 2017–2018. A screening including demographic, anthropometric, salt-related KAB and physical measurements was implemented, and 24-h urine of approximately 1/5 of the participants was collected and tested. The mean age was 44.8 years, 50.1% were women, 44.0% lived in urban areas, and hypertension or prehypertension accounted for approximately 35.0%. The mean 24-h urinary sodium and potassium excretion were 3848.5 (1661.1) mg/d and 1491.1 (710.9) mg/d, respectively. KAB in urban areas was generally more favorable than in rural areas, women were better than men, and the optimal blood pressure group was better than the other two groups (P < 0.05). However, the awareness and correct use rate of salt-restricted spoons, low-sodium salt and nutrition labeling were lower. A multivariable linear regression model indicated that KAB had a smaller effect on sodium (two indicators effective for promoting sodium reduction) and a greater effect on potassium (six indicators effective for promoting potassium supplementation) and mainly focused on knowledge and behavior indicators. A multivariable logistic regression model indicated that mastering more knowledge and taking active measures could effectively reduce the transition to hypertension, even if the individual was already in prehypertension. There is much room for improvement of salt-related KAB in the Chinese population. A clear association indicates that KAB can help to reduce sodium and supplement potassium, especially potassium, and help to suppress the development of hypertension. The role of beliefs in KAB should be fully valued and improved, similar to knowledge and behaviors. This study provides important evidence and insight into China's efforts to meet the targets of salt reduction and hypertension prevention. [ABSTRACT FROM AUTHOR]

Models of how high elevations formed across Tibet predict: (a) the continuous thickening of a 'viscous sheet'; (b) time-dependent, oblique stepwise growth; and (c) synchronous deformation across Tibet that accompanied collision. Our new observations may shed light on this issue. Here, we use 40Ar/39Ar and (U-Th)/He thermochronology from massifs in the hanging walls of thrust structures along the Kunlun Belt, the first-order orogenic range at the northern Tibetan margin, to elucidate the exhumation history. The results show that these massifs, and hence the plateau margin, were subject to slow, steady exhumation during the Early Cenozoic, followed by a pulse of accelerated exhumation during 40-35 Ma. The exhumation rate increases westward (from ~0.22 to 0.34 and 0.5 mm/yr). The two-fold increase in exhumation in the western part (0.5 mm/yr) compared to the eastern part suggests westward increases in exhumation and compressional stress along the Kunlun Belt. We relate these observations to the mechanisms responsible for the oblique stepwise rise of Tibet. After collision, oblique subduction beneath Kunlun caused stronger compressional deformation in the western part than in the eastern part, resulting in differential growth and lateral extrusion. [ABSTRACT FROM AUTHOR]

Amyloid precursor protein (APP), commonly associated with Alzheimer's disease, also marks axonal degeneration. In the recent studies, we demonstrated that APP aggregated at nodes of Ranvier (NORs) in myelinated central nervous system (CNS) axons and interacted with Nav1.6. However, the physiological function of APP remains unknown. In this study, we described reduced sodium current densities in APP knockout hippocampal neurons. Coexpression of APP or its intracellular domains containing a VTPEER motif with Nav1.6 sodium channels in Xenopus oocytes resulted in an increase in peak sodium currents, which was enhanced by constitutively active Go mutant and blocked by a dominant negative mutant. JNK and CDK5 inhibitor attenuated increases in Nav1.6 sodium currents induced by overexpression of APP. Nav1.6 sodium currents were increased by APPT668E (mutant Thr to Glu) and decreased by T668A (mutant Thr to ALa) mutant, respectively. The cell surface expression of Nav1.6 sodium channels in the white matter of spinal cord and the spinal conduction velocity is decreased in APP, p35 and JNK3 knockout mice. Therefore, APP modulates Nav1.6 sodium channels through a Go-coupled JNK pathway, which is dependent on phosphorylation of APP at Thr668. [ABSTRACT FROM AUTHOR]

The treatment for ischemic stroke is one of the most challenging problems and the therapeutic effect remains unsatisfied due to the poor permeation of drugs across the blood brain barrier (BBB). In this study, HAIYPRH (T7), a peptide that targeted to transferrin receptor (TfR) can mediate the transport of nanocarriers across the BBB, was conjugated to liposomes for ischemic stroke targeting treatment of a novel neuroprotectant (ZL006). T7-conjugated PEGylated liposomes (T7-P-LPs) loaded with ZL006 (T7-P-LPs/ZL006) were showed satisfactory vesicle size and size distribution. Furthermore, the cellular uptake results showed that T7 modification increased liposomes uptake by the brain capillary endothelial cells (BCECs) and little cytotoxicity of liposomes with or without ZL006 was observed. The in vivo biodistribution and near-infrared fluorescence imaging evidenced that T7 modification rendered liposomes significantly enhanced the transport of liposomes across the BBB. The pharmacodynamic study suggested that, T7-P-LPs/ZL006 exhibited reduced infarct volume and ameliorated neurological deficit compared with unmodified liposomes or free ZL006. T7-P-LPs/ZL006 could be targeted to brain and displayed remarkable neuroprotective effects. They could be used as a potential targeted drug delivery system of ischemic stroke treatment. [ABSTRACT FROM AUTHOR]