The path to sustainable cardiac surgery in Rwanda: analysis of costs for consumables used during cardiac surgery for a non-governmental organization.

BACKGROUND: Until local healthcare infrastructure is strengthened, cardiac surgical care in low- and middle-income countries is often provided by non-governmental organizations by way of visiting healthcare teams. This is generally considered to be a cost-effective alternative to transporting patients to high income countries for surgical care, but the costs of cardiac surgery consumables under this model are poorly understood. Our objective was to identify the per-patient cost of cardiac surgery consumables used in single and double valve replacements performed by a non-governmental organization in Rwanda. METHODS: Financial data from 2020 were collected from Team Heart, a non-governmental organization that supports cardiac surgical care in Rwanda. A comprehensive list of consumables was generated, including surgical, perfusion, anesthesia, and inpatient supplies and medications. Acknowledging the variability in perioperative needs, the quantities of consumables were calculated from an average of six patients who underwent single or double-valve replacement in 2020. Total costs were calculated by multiplying purchasing price by average quantity per patient. Costs absorbed by the local hospital were excluded from the calculations. RESULTS: The total cost per patient was estimated at $9,450. Surgical supplies comprised the majority of costs ($6,140 per patient), with the most substantial cost being that of replacement valves ($3,500 per valve), followed by surgical supplies ($1,590 per patient). CONCLUSIONS: This preliminary analysis identifies a cost of just over $9,000 per patient for consumables used in cardiac valve surgery in Rwanda, which is lower than the estimated costs of transporting patients to centers in high income countries. This work highlights the relative cost effectiveness of cardiac surgical care in low- and middle- income countries under this model and will be instrumental in guiding the allocation of local and international resources in the future.

Development and dissemination of a series of surgical skills and procedures video tutorials using a novel, low-cost, and sustainable simulation kit (GlobalSurgBox).

INTRODUCTION: Surgical simulation and video-based learning are limited in lower-resource settings. We sought to develop and assess a series of surgical tutorials using a low-cost simulator. METHODS: We created 8 surgical skills and procedures videos using low-cost equipment. We assessed video quality using the DISCERN scale and the Global Quality Scale (GQS). RESULTS: Videos ranged from surgical techniques to complex procedures. We uploaded these to Youtube and included them in the curriculum of a medical school in Rwanda. Excluding the cost of the kit (25 USD), production costs ranged from 2 to 5 USD. All videos scored a mean DISCERN of 2.44 â€‹± â€‹1.05 and GQS of 3.06 â€‹± â€‹0.90. Generally, these lacked points on providing additional sources of information and addressing areas of uncertainty. CONCLUSIONS: This study addresses the demand for accessible surgical education resources. Using low-cost, standardized materials ensures consistency, democratization of training, and feasibility.

Is it possible to obtain substitutes for human milk oligosaccharides from bovine milk, goat milk, or other mammal milks?

Considering the current level of chemical and biological synthesis technology, it was a sensible selection to obtain milk oligosaccharides (MOs) from other mammals as the potential substitute for human MOs (HMOs) that possessed various structural features in the infant formula. Through a comprehensive analysis of the content, structure, and function of MOs in six distinct varieties of mammal milk, it has been shown that goat milk was the most suitable material for the preparation as a human milk substitute. Goat MOs (GMOs) had a relatively high content and diverse structural features compared to those found in other mammalian milks. The concentration of GMOs in colostrum ranged from 60 to 350 mg/L, whereas in mature milk, it ranged from 200 to 24,00 mg/L. The acidic oligosaccharides in goat milk have attracted considerable attention due to their closeness in acidic content and structural diversity with HMOs. Simultaneously, it was discovered that some structures, like N-glycolylneuraminic acid, were found to have a certain content in GMOs and served essential functional properties. Moreover, studies focused on the extraction of MOs from goat milk indicated that the production of GMOs on an industrial scale was viable. Furthermore, it is imperative to do further study on GMOs to enhance the preparation process, discover of new MOs structures and bioactivity evaluation, which will contribute to the development of both the commercial production of MOs and the goat milk industry.

Promoter DNA methylation and transcription factor condensation are linked to transcriptional memory in mammalian cells.

The regulation of genes can be mathematically described by input-output functions that are typically assumed to be time invariant. This fundamental assumption underpins the design of synthetic gene circuits and the quantitative understanding of natural gene regulatory networks. Here, we found that this assumption is challenged in mammalian cells. We observed that a synthetic reporter gene can exhibit unexpected transcriptional memory, leading to a shift in the dose-response curve upon a second induction. Mechanistically, we investigated the cis-dependency of transcriptional memory, revealing the necessity of promoter DNA methylation in establishing memory. Furthermore, we showed that the synthetic transcription factor's effective DNA binding affinity underlies trans-dependency, which is associated with its capacity to undergo biomolecular condensation. These principles enabled modulating memory by perturbing either cis- or trans-regulation of genes. Together, our findings suggest the potential pervasiveness of transcriptional memory and implicate the need to model mammalian gene regulation with time-varying input-output functions. A record of this paper's transparent peer review process is included in the supplemental information.

Teaching With the GlobalSurgBox: Trainer Perceptions of a Portable Surgical Simulator.

OBJECTIVES: Evaluate the utility of a low cost, portable surgical simulator (GlobalSurgBox) for surgical teaching and its ability to dismantle barriers faced by trainers when attempting to use surgical simulation. DESIGN: An anonymous survey was administered to surgical trainers who were involved in leading simulation events using the GlobalSurgBox in the past 2 years. The survey was designed to understand current barriers to using simulation as a trainer, and the utility of the GlobalSurgBox in overcoming these barriers. SETTING: Academic medical training centers or conferences in the United States, Rwanda and Kenya. PARTICIPANTS: 10 practicing surgeons, 3 practicing physicians, 11 surgical residents, 15 medical students and 1 anesthesia resident. RESULTS: The top 3 barriers for effective teaching were lack of convenient access to the simulator (50%), lack of trainer time (43%) and cost (28%). After using the GlobalSurgBox, 100% and 98% of respondents felt that it encourages more practice and offers significant advantages over current simulators in their program. About 90%, 88% and 70% of respondents believed that the GlobalSurgBox makes surgical simulation more convenient, affordable, and compatible with trainer time limitations, respectively. 83% of trainers agreed that it is a good replica of the operating room experience, and 85% practicing physicians were more likely to give autonomy to trainees after demonstrating competence on the GlobalSurgBox. CONCLUSION: The GlobalSurgBox mitigates several barriers surgical educators experience when practicing surgical skills with trainees. The convenience of the GlobalSurgBox can help facilitate the development of foundational surgical skills outside of the operating room.

Network model with internal complexity bridges artificial intelligence and neuroscience.

Artificial intelligence (AI) researchers currently believe that the main approach to building more general model problems is the big AI model, where existing neural networks are becoming deeper, larger and wider. We term this the big model with external complexity approach. In this work we argue that there is another approach called small model with internal complexity, which can be used to find a suitable path of incorporating rich properties into neurons to construct larger and more efficient AI models. We uncover that one has to increase the scale of the network externally to stimulate the same dynamical properties. To illustrate this, we build a Hodgkin-Huxley (HH) network with rich internal complexity, where each neuron is an HH model, and prove that the dynamical properties and performance of the HH network can be equivalent to a bigger leaky integrate-and-fire (LIF) network, where each neuron is a LIF neuron with simple internal complexity.

Therapeutic efficacy of platelet-rich plasma in the management of rib fractures.

BACKGROUND: This study aimed to investigate the therapeutic efficacy of platelet-rich plasma (PRP) therapy in patients with rib fractures. METHODS: This study retrospectively collected data from patients with acute rib fractures at Ming-Sheng General Hospital from 2020 to 2022 and excluded those who underwent surgical intervention or with severe extrathoracic injuries. PRP was extracted using the patient's blood and injected via ultrasound guidance near the fracture site. Patients self-assessed pain levels and medication usage at 0, 1, 2, 4, and 8 weeks. Pulmonary function tests were conducted at 4 weeks. RESULTS: This study included 255 patients, with 160 and 95 patients in the conservative (only pain medications administered) and PRP groups (PRP and analgesics administered), respectively. The PRP group reported lower pain levels than the conservative group at 2 and 4 weeks. No substantial differences in medication usage were observed between the groups. The PRP group demonstrated lower pain levels and medication usage than the conservative group in severe rib fractures (≥3 ribs) and better lung function improvement at 4 weeks. After propensity score matching, the PRP group still had a better treatment outcome in pain control and lung function recovery. CONCLUSION: PRP demonstrated considerable therapeutic efficacy in patients with severe rib fractures, resulting in reduced pain, decreased medication usage, and improved lung function but with no substantial benefits in patients with mild rib fractures.

Clinicopathologic Characterization of 2 Individuals With TBK1 Variants-1 Novel Splice Variant, 2 Proteinopathies: A Case Series.

Objectives: Here, we report detailed clinicopathologic evaluation of 2 individuals with pathogenic variants in TBK1, including one novel likely pathogenic splice variant. We describe the striking diversity of clinical phenotypes among family members and also the brain and spinal cord neuropathology associated with these 2 distinct TBK1 variants. Methods: Two individuals with pathogenic variants in TBK1 and their families were clinically characterized, and the probands subsequently underwent extensive postmortem neuropathologic examination of their brains and spinal cords. Results: Multiple affected individuals within a single family were found to carry a previously unreported c.358+3A>G variant, predicted to alter splicing. Detailed histopathologic evaluation of our 2 TBK1 variant carriers demonstrated distinct TDP-43 pathologic subtypes, but shared argyrophilic grain disease (AGD) tau pathology. Discussion: Although all pathogenic TBK1 variants are associated with TDP-43 pathology, the clinical and histologic features can be highly variable. Within one family, we describe distinct neurologic presentations which we propose are all caused by a novel c.358+3A>G variant. AGD is typically associated with older age, but it has been described as a copathologic finding in other TBK1 variant carriers and may be a common feature in FTLD-TDP due to TBK1.

Optimal content for a surgical curriculum for general practice in Rwanda: A Delphi study.

BACKGROUND: In Rwanda, a nationwide shortage of surgeons necessitates general practitioners (GPs) perform many common procedures and minor surgeries. However, GPs only receive a 1-year internship to prepare them to provide this care. We performed a Delphi survey of practicing GPs to assess essential content for a surgical curriculum for Rwandan interns to better prepare them for general practice. METHODS: We invited 56 practicing GPs to participate in a two-round anonymous electronic survey in February 2023. The first round assessed demographics and solicited free-text responses to gather knowledge and procedural content suggestions for the curriculum. The second round refined these responses into key content areas. RESULTS: Thirty-one GPs responded to both rounds of the Delphi survey. They provided insight into the most commonly performed procedures, most important technical skills, and the top areas of surgical knowledge necessary for general practice. They expressed a need for more exposure to a variety of surgical pathologies and interventions across multiple specialties, highlighting the value of foundational skills in trauma, obstetrics and gynecology, and orthopedics, both at the beginning of their internship, as well as at the beginning of their general practice. CONCLUSIONS: GPs emphasized the importance of broad exposure to common acute surgical pathology and interventions across several surgical subspecialties, as well as a need for foundational technical skills and surgical knowledge. The results of our study underscore the necessity of a surgical education providing a solid basis in the foundational knowledge and techniques of surgical care.

Reproductive health among women of child-bearing age after surgery for rheumatic heart disease in Rwanda.

OBJECTIVE: To determine maternal and fetal outcomes in postoperative women with rheumatic heart disease who become pregnant after valve surgery and evaluate current anticoagulation management during pregnancy. METHODS: Data from the Rwandan rheumatic heart disease cardiac surgical registry identified all female patients who underwent valve surgery before or during childbearing age since 2006. In total, 136 participants completed a mixed-methods questionnaire detailing each pregnancy after surgery, including anticoagulation regimen and outcomes. RESULTS: We found that 38.2% (n = 136) of patients reported at least 1 pregnancy after surgery, of which more than one half were unintentional (53.9%, n = 52). Among those patients with mechanical valves, most remained on warfarin alone during pregnancy (58.5%, n = 53) whereas one third were switched to low molecular weight heparin during the first, second, or third trimesters (5 vs 4 vs 7, n = 18). Women with bioprosthetic valve replacement or valve repair were more likely to experience live term births (84.6% vs 45.3%, P < .01) and less likely to report spontaneous abortion (3.9% vs 30.2%, P < .01) compared with women with mechanical valve replacement. Excessive bleeding was the most common complication during pregnancy (9.1%, n = 79), and 2 infants were diagnosed with congenital defects associated with warfarin embryopathy (4.8%, n = 42). CONCLUSIONS: Despite preoperative counseling discouraging conception, many women with prosthetic valves still become pregnant after surgery. The results of this study will inform evidence-based and context-specific practices for anticoagulation during pregnancy in Rwanda and the region.

Identification of a combined hypoxia and lactate metabolism prognostic signature in lung adenocarcinoma : Author.

BACKGROUND: In the tumor microenvironment (TME), a bidirectional relationship exists between hypoxia and lactate metabolism, with each component exerting a reciprocal influence on the other, forming an inextricable link. The aim of the present investigation was to develop a prognostic model by amalgamating genes associated with hypoxia and lactate metabolism. This model is intended to serve as a tool for predicting patient outcomes, including survival rates, the status of the immune microenvironment, and responsiveness to therapy in patients with lung adenocarcinoma (LUAD). METHODS: Transcriptomic sequencing data and patient clinical information specific to LUAD were obtained from comprehensive repositories of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A compendium of genes implicated in hypoxia and lactate metabolism was assembled from an array of accessible datasets. Univariate and multivariate Cox regression analyses were employed. Additional investigative procedures, including tumor mutational load (TMB), microsatellite instability (MSI), functional enrichment assessments and the ESTIMATE, CIBERSORT, and TIDE algorithms, were used to evaluate drug sensitivity and predict the efficacy of immune-based therapies. RESULTS: A novel prognostic signature comprising five lactate and hypoxia-related genes (LHRGs), PKFP, SLC2A1, BCAN, CDKN3, and ANLN, was established. This model demonstrated that LUAD patients with elevated LHRG-related risk scores exhibited significantly reduced survival rates. Both univariate and multivariate Cox analyses confirmed that the risk score was a robust prognostic indicator of overall survival. Immunophenotyping revealed increased infiltration of memory CD4 + T cells, dendritic cells and NK cells in patients classified within the high-risk category compared to their low-risk counterparts. Higher probability of mutations in lung adenocarcinoma driver genes in high-risk groups, and the MSI was associated with the risk-score. Functional enrichment analyses indicated a predominance of cell cycle-related pathways in the high-risk group, whereas metabolic pathways were more prevalent in the low-risk group. Moreover, drug sensitivity analyses revealed increased sensitivity to a variety of drugs in the high-risk group, especially inhibitors of the PI3K-AKT, EGFR, and ELK pathways. CONCLUSIONS: This prognostic model integrates lactate metabolism and hypoxia parameters, offering predictive insights regarding survival, immune cell infiltration and functionality, as well as therapeutic responsiveness in LUAD patients. This model may facilitate personalized treatment strategies, tailoring interventions to the unique molecular profile of each patient's disease.

DCAF16-Based Covalent Handle for the Rational Design of Monovalent Degraders.

Targeted protein degradation with monovalent molecular glue degraders is a powerful therapeutic modality for eliminating disease causing proteins. However, rational design of molecular glue degraders remains challenging. In this study, we sought to identify a transplantable and linker-less covalent handle that could be appended onto the exit vector of various protein-targeting ligands to induce the degradation of their respective targets. Using the BET family inhibitor JQ1 as a testbed, we synthesized and screened a series of covalent JQ1 analogs and identified a vinylsulfonyl piperazine handle that led to the potent and selective degradation of BRD4 in cells. Through chemoproteomic profiling, we identified DCAF16 as the E3 ligase responsible for BRD4 degradation-an E3 ligase substrate receptor that has been previously covalently targeted for molecular glue-based degradation of BRD4. Interestingly, we demonstrated that this covalent handle can be transplanted across a diverse array of protein-targeting ligands spanning many different protein classes to induce the degradation of CDK4, the androgen receptor, BTK, SMARCA2/4, and BCR-ABL/c-ABL. Our study reveals a DCAF16-based covalent degradative and linker-less chemical handle that can be attached to protein-targeting ligands to induce the degradation of several different classes of protein targets.

Uncommon presentations of type A quadricuspid aortic valve in the Septuagenarian.

BACKGROUND: Quadricuspid aortic valve (QAV) is a rare congenital anomaly characterized by the presence of four cusps instead of the usual three. It is estimated to occur in less than 0.05% of the population, with Type A (four equal-sized leaflets) accounting for roughly 30% of QAV subtypes. Based on limited clinical series, the usual presentation is progressive aortic valve regurgitation (AR) with symptoms occurring in the fourth to sixth decade of life. Severe aortic valve stenosis (AS) and acute AR are very uncommon. CASE PRESENTATION: We describe two cases of Type A QAV in patients who remained asymptomatic until their seventies with very uncommon presentations: one with severe AS and one with acute, severe AR and flail leaflet. In Case A, a 72-year-old patient with history of moderate AS presents to clinic with progressive exertional dyspnea. During work-up for transcatheter vs. surgical replacement pre-operative computed tomography angiogram (CTA) reveals a quadricuspid aortic valve with severe AS, and the patient undergoes surgical aortic valve replacement. Pre-discharge transthoracic echocardiography (TTE) shows good prosthetic valve function with no gradient or regurgitation. In Case B, a 76-year-old patient is intubated upon arrival to the hospital for acute desaturation, found to have wide open AR on catheterization, and transferred for emergent intervention. Intraoperative TEE reveals QAV with flail leaflet and severe AR. Repair is considered but deferred ultimately due to emergent nature. Post-operative TTE demonstrates good prosthetic valve function with no regurgitation and normal biventricular function. CONCLUSIONS: QAV can present as progressive severe AS and acute AR, with symptoms first occurring in the seventh decade of life. The optimal treatment for QAV remains uncertain. Although aortic valve repair or transcatheter option may be feasible in some patients, aortic valve replacement remains a tenable option.

Recent advances in c-Met-based dual inhibitors in the treatment of cancers.

The cellular-mesenchymal epithelial transition factor (c-Met) is a receptor tyrosine kinase (RTK) located on the 7q31 locus encoding the Met proto-oncogene and plays a critical role in regulating cell proliferation, metastasis, differentiation, and apoptosis through various signaling pathways. However, its aberrant activation and overexpression have been implicated in many human cancers. Therefore, c-Met is a promising target for cancer treatment. However, the anticancer effect of selective single-targeted drugs is limited due to the complexity of the signaling system and the involvement of different proteins and enzymes. After inhibiting one pathway, signal molecules can be transmitted through other pathways, resulting in poor efficacy of single-targeted drug therapy. Dual inhibitors that simultaneously block c-Met and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, We introduced c-Met kinase and the synergism between c-Met and other anti-tumor targets, then dual-target inhibitors based on c-Met for the treatment of cancers were summarized and their design concepts and structure-activity relationships (SARs) were discussed elaborately, providing a valuable insight for the further development of novel c-Met-based dual inhibitors.

Fibroblast expression of transmembrane protein smoothened governs microenvironment characteristics after acute kidney injury.

The smoothened (Smo) receptor facilitates hedgehog signaling between kidney fibroblasts and tubules during acute kidney injury (AKI). Tubule-derived hedgehog is protective in AKI, but the role of fibroblast-selective Smo is unclear. Here, we report that Smo-specific ablation in fibroblasts reduced tubular cell apoptosis and inflammation, enhanced perivascular mesenchymal cell activities, and preserved kidney function after AKI. Global proteomics of these kidneys identified extracellular matrix proteins, and nidogen-1 glycoprotein in particular, as key response markers to AKI. Intriguingly, Smo was bound to nidogen-1 in cells, suggesting that loss of Smo could affect nidogen-1 accessibility. Phosphoproteomics revealed that the 'AKI protector' Wnt signaling pathway was activated in these kidneys. Mechanistically, nidogen-1 interacted with integrin ß1 to induce Wnt in tubules to mitigate AKI. Altogether, our results support that fibroblast-selective Smo dictates AKI fate through cell-matrix interactions, including nidogen-1, and offers a robust resource and path to further dissect AKI pathogenesis.

A vision chip with complementary pathways for open-world sensing.

Image sensors face substantial challenges when dealing with dynamic, diverse and unpredictable scenes in open-world applications. However, the development of image sensors towards high speed, high resolution, large dynamic range and high precision is limited by power and bandwidth. Here we present a complementary sensing paradigm inspired by the human visual system that involves parsing visual information into primitive-based representations and assembling these primitives to form two complementary vision pathways: a cognition-oriented pathway for accurate cognition and an action-oriented pathway for rapid response. To realize this paradigm, a vision chip called Tianmouc is developed, incorporating a hybrid pixel array and a parallel-and-heterogeneous readout architecture. Leveraging the characteristics of the complementary vision pathway, Tianmouc achieves high-speed sensing of up to 10,000 fps, a dynamic range of 130 dB and an advanced figure of merit in terms of spatial resolution, speed and dynamic range. Furthermore, it adaptively reduces bandwidth by 90%. We demonstrate the integration of a Tianmouc chip into an autonomous driving system, showcasing its abilities to enable accurate, fast and robust perception, even in challenging corner cases on open roads. The primitive-based complementary sensing paradigm helps in overcoming fundamental limitations in developing vision systems for diverse open-world applications.

Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Proteome characterization of liver-kidney comorbidity after microbial sepsis.

Sepsis is a life-threatening condition that occurs when the body responds to an infection but subsequently triggers widespread inflammation and impaired blood flow. These pathologic responses can rapidly cause multiple organ dysfunction or failure either one by one or simultaneously. The fundamental common mechanisms involved in sepsis-induced multiple organ dysfunction remain unclear. Here, employing quantitative global and phosphoproteomics, we examine the liver's temporal proteome and phosphoproteome changes after moderate sepsis induced by cecum ligation and puncture. In total, 4593 global proteins and 1186 phosphoproteins according to 3275 phosphosites were identified. To characterize the liver-kidney comorbidity after sepsis, we developed a mathematical model and performed cross-analyses of liver and kidney proteome data obtained from the same set of mice. Beyond immune response, we showed the commonly disturbed pathways and key regulators of the liver-kidney comorbidity are linked to energy metabolism and consumption. Our data provide open resources to understand the communication between the liver and kidney as they work to fight infection and maintain homeostasis.

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis.

Brain metastasis of HER2+ breast cancer occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with Trastuzumab +/-HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in-vivo models for HER2+ BCBM has compromised the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. We have generated and characterized new HER2+ BCBM cells (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM in mice. The clinically used receptor tyrosine kinase inhibitor (RTKi) Lapatinib blocked phosphorylation of all ErbB1-4 receptors and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin-1 (NRG1), a ligand for ErbB3 and ErbB4 that is abundantly expressed in the brain, was able to rescue Lapatinib-induced apoptosis and clonogenic ability in BCBM94 and in HER2+ BT474. ErbB3 was essential to mediate the NRG1-induced survival pathway that involved PI3K-AKT signalling and the phosphorylation of BAD at serine 136 to prevent apoptosis. High throughput RTKi screening identified the brain penetrable Poziotinib as highly potent compound to reduce cell viability in HER2+ BCBM in the presence of NRG1. Successful in-vivo ablation of BCBM94- and BT474-derived HER2+ brain tumors was achieved upon two weeks of treatment with Poziotinib. MRI revealed BCBM remission upon poziotinib, but not with Lapatinib treatment. In conclusion, we have established a new patient-derived HER2+ BCBM in-vivo model and identified Poziotinib as highly efficacious RTKi with excellent brain penetrability that abrogated HER2+ BCBM brain tumors in our mouse models.

Construction of SnO2 buffer layer and analysis of its interface modification for Li and Li1.5Al0.5Ge1.5(PO4)3 in solid-state batteries.

SnO2 layer between Li1.5Al0.5Ge1.5(PO4)3 (LAGP) and lithium anode was prepared through simple scratch-coating process to improve interface properties. The physical phase, morphology, and electrochemical properties of Li/SnO2/LAGP structure were characterized by X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, and electrochemical analytical methods. It was found that SnO2 layer effectively improved the interface stability of LAGP and lithium anode. The prepared Li/SnO2/LAGP/SnO2/Li symmetric cell exhibited a large critical current density of 1.8 mA cm-2 and demonstrated excellent cycling characteristics. The polarization voltages of symmetric cell were 0.1 V and 0.8 V after 1000 h of cycling at current densities of 0.04 mA cm-2 and 0.5 mA cm-2, respectively. Li/SnO2@LAGP/LiFePO4 solid-state full cells were also assembled, exhibiting a discharge specific capacity of 150 mAh g-1 after 200 cycles at 0.1C with capacity retention rate of 96 %. The good interface properties of Li/SnO2/LAGP structure are attributed to the transformation of SnO2 layer into a buffer layer containing Li2O, Sn0, and LixSny alloy during cycling process, which effectively inhibits the reduction reaction between LAGP and lithium anode.