Asymmetrical Functionalization of Polarizable Interface Restructuring Molecules for Rapid and Longer Operative Lithium Metal Batteries.

Lithium metal batteries (LMBs) have been recognized as high-energy storage alternatives; however, problematic surface reactions due to dendritic Li growth are major obstacles to their widespread utilization. Herein, a 3-mercapto-1-propanesulfonic acid sodium salt (MPS) with asymmetrically functionalized thiol and sulfonate groups as polarizable interface-restructuring molecules is proposed to achieve rapid and longer-operating LMBs. Under a harsh condition of 5 mA cm-2, Li-Li symmetric cells employing MPS can be cycled over 1200 cycles, outperforming those employing other molecules symmetrically functionalized by thiol or sulfonate groups. The improved performance of the Li|V2O5 full cell is demonstrated by introducing MPS additives. MPS additives offer advantages by flattening the surface, reconfiguring Li nucleation and growth along the stable (110) plane, and forming a durable and conductive solid-electrolyte interface layer (SEI). This study suggests an effective way to develop a new class of electrolyte additives for LMBs by controlling engineering factors, such as functional groups and polarizable properties.

Symmetric Catalyst Design Employing Ir Nanoparticles on Black WO3- x Nanofiber Support for Boosting Water Electrolysis.

The efficient evolution of gaseous hydrogen and oxygen from water is required to realize sustainable energy conversion systems. To address the sluggish kinetics of the multielectron transfer reaction, bifunctional catalyst materials for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) should be developed. Herein, a tailored combination of atomically minimized iridium catalysts and highly conductive black WO3- x nanofiber supports are developed for the bifunctional electrolyzer system. Atomic Ir catalysts, particularly those that activate the OER, minimize the utilization of precious metals. The oxygen-deficient black WO3- x NF support, which boosts the HER, offers increased electronic conductivity and favorable nucleation sites for Ir loading. The Ir-black WO3- x NFs exhibit increased double-layer capacitance, a significantly reduced onset potential, lower Tafel slope, and stable cyclability for both the OER and HER, compared to large-sized Ir catalysts loaded on white WO3 nanofibers. This study offers a strategy for developing an optimal catalyst material with suitable supports for high-performance and economical water electrolysis systems for achieving carbon-negative targets.

Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation.

Transcriptional programs governed by YAP play key roles in conferring resistance to various molecular-targeted anticancer agents. Strategies aimed at inhibiting YAP activity have garnered substantial interest as a means to overcome drug resistance. However, despite extensive research into the canonical Hippo-YAP pathway, few clinical agents are currently available to counteract YAP-associated drug resistance. Here, we present a novel mechanism of YAP stability regulation by MAP3K3 that is independent of Hippo kinases. Furthermore, we identified MAP3K3 as a target for overcoming anticancer drug resistance. Depletion of MAP3K3 led to a substantial reduction in the YAP protein level in melanoma and breast cancer cells. Mass spectrometry analysis revealed that MAP3K3 phosphorylates YAP at serine 405. This MAP3K3-mediated phosphorylation event hindered the binding of the E3 ubiquitin ligase FBXW7 to YAP, thereby preventing its p62-mediated lysosomal degradation. Robust YAP activation was observed in CDK4/6 inhibitor-resistant luminal breast cancer cells. Knockdown or pharmacological inhibition of MAP3K3 effectively suppressed YAP activity and restored CDK4/6 inhibitor sensitivity. Similarly, elevated MAP3K3 expression supported the prosurvival activity of YAP in BRAF inhibitor-resistant melanoma cells. Inhibition of MAP3K3 decreased YAP-dependent cell proliferation and successfully restored BRAF inhibitor sensitivity. In conclusion, our study reveals a previously unrecognized mechanism for the regulation of YAP stability, suggesting MAP3K3 inhibition as a promising strategy for overcoming resistance to CDK4/6 and BRAF inhibitors in cancer treatment.

Age-Based Incidence of Dens Fracture Has Unimodal Distribution Rather Than Commonly Claimed Bimodal Distribution.

Background: Type-II dens fractures have long been described in the literature as occurring in a bimodal distribution, peaking in young adulthood as well as in older adulthood; however, the origin of this claim is unclear. The primary goal of this study was to examine the incidence of type-II dens fractures and assess for bimodality. Methods: This is a retrospective cross-sectional review of the National Trauma Data Bank (NTDB) records on traumatic type-II dens fractures between October 2015 and December 2016. Rates were obtained from the NTDB, and the incidence per 100,000 was ascertained by utilizing U.S. Census data from 2016. Subgroupings by gender and Black or White race were also examined. Results: Dens fractures occur unimodally, peaking around 89 years of age overall, skewed left by high rates in older White adults. The Black subgroup demonstrated trimodality, with the fracture incidence peaking at 25, 62, and 82 years of age. Rates among Black and White patients were similar until age 65, after which dens fractures occurred disproportionately in White patients. Fractures prior to age 75 occurred predominantly in men. Conclusions: The evidence derived in this study challenges the common belief that type-II dens fractures occur bimodally across the entire population. However, there remains utility in considering younger and older patients as distinct groups for the purposes of management.

Academic career progression in AANS/CNS Spine Section award recipients.

OBJECTIVE: The American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Joint Spine Section awards highlight outstanding abstracts submitted to the AANS/CNS Section on Disorders of the Spine and Peripheral Nerves by trainees interested in spine surgery, although the academic trajectory of awardees has not been studied. The aim of this study was to assess the academic career progression of prior recipients of the Journalistic and Academic Neurosurgical Excellence (JANE), Mayfield, and Kuntz research awards. METHODS: Prior JANE, Mayfield, and Kuntz award recipients were identified using awardee records accrued between 1984 and February 2022. Awardee sex, country of residence, specialty, subspecialty focus, and current academic appointment status (if applicable) were searched online. Awardee h-indices and number of peer-reviewed publications were assessed via Google Scholar profiles (or Scopus if unavailable) and PubMed, respectively. Receipt of federal research funding as principal investigator (PI) was determined using the websites of the National Institutes of Health, the National Science Foundation, and the Department of Defense Congressionally Directed Medical Research Programs. The abstract-to-publication rate was assessed. RESULTS: A total of 7 JANE awards, 57 Mayfield awards, and 149 Kuntz awards were identified. Of the JANE awardees, all recipients were male. Of the 4 unique JANE awardees who completed training, 2 (50.0%) held academic appointments at the time of the study. All of the JANE abstracts were published in peer-reviewed journals. The mean h-index of all JANE awardees was 28 and the mean number of publications was 126. None of the awardees have received federal research funding. Of the Mayfield awards, 98.2% were awarded to males. Of the 43 unique Mayfield awardees who completed training, 20 (46.5%) held faculty appointments at academic medical centers. All of the Mayfield abstracts since 2011 were published in peer-reviewed journals. The mean h-index of all Mayfield awardees was 26 and the mean number of publications was 82. Five Mayfield awardees received National Institutes of Health funding as PI, and 7 awardees received Department of Defense funding as PI. Of the Kuntz awards, 95.3% were awarded to males. Most awards were given to current residents and fellows (46.3%). Of the 55 unique Kuntz awardees who completed training, 31 (56.4%) held faculty appointments at academic medical centers. The abstract-to-publication rate of the total Kuntz abstracts was 70.5%. The mean h-index of all Kuntz awardees was 15 and the mean number of publications was 58. Five Kuntz awardees (3.4%) received federal research funding as PI. CONCLUSIONS: Many recipients of the JANE, Mayfield, and Kuntz Joint Spine Section awards have successfully translated award abstracts into peer-reviewed publications. Furthermore, approximately one-third of the awardees are active in academic neurosurgery, with some having secured federal research funding.

Risk factors for C5 palsy: a systematic review and multivariate analysis.

OBJECTIVE: Postoperative C5 palsy (C5P) is a known complication in cervical spine surgery. However, its exact pathophysiology is unclear. The authors aimed to provide a review of the current understanding of C5P by performing a comprehensive, systematic review of the existing literature and conducting a critical appraisal of existing evidence to determine the risk factors of C5P. METHODS: A systematic search of PubMed/MEDLINE (January 1, 2019, to July 2, 2021), EMBASE (inception to July 2, 2021), and Cochrane (inception to July 2, 2021) databases was conducted. Preestablished criteria were used to evaluate studies for inclusion. Studies that adjusted for one or more of the following factors were considered: preoperative foraminal diameter (FD) at C4/5, posterior spinal cord shift at C4/5, preoperative anterior-posterior diameter (APD) at C4/5, preoperative spinal cord rotation, and change in C2-7 Cobb angle. Studies were rated as good, fair, or poor based on the Quality in Prognosis Studies (QUIPS) tool. Random effects meta-analyses were done using methods outlined by Cochrane methodologists for pooling of prognostic studies. Overall quality (strength) of evidence was based on Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methods for prognostic studies. The protocol for this review was published on the PROSPERO (CRD264358) website. RESULTS: Of 303 potentially relevant citations of studies, 12 met the inclusion criteria set a priori. These works provide moderate-quality evidence that preoperative FD substantially increases the odds of C5P in patients undergoing posterior cervical surgery. Pooled estimates across 7 studies in which various surgical approaches were used indicate that the odds of C5P approximately triple for each millimeter decrease in preoperative FD (OR 3.05, 95% CI 2.07-4.49). Preoperative APD increases the odds of C5P, but the confidence is low. Across 3 studies, each using different surgical approaches, each millimeter decrease in preoperative APD was associated with a more than 2-fold increased odds of C5P (pooled OR 2.51, 95% CI 1.69-3.73). Confidence that there is an association with postoperative C5P and posterior spinal cord shift, change in sagittal Cobb angle, and preoperative spinal cord rotation is very low. CONCLUSIONS: The exact pathophysiological process resulting in postoperative C5P remains an enigma but there is a clear association with foraminal stenosis, especially when performing posterior procedures. C5P is also related to decreased APD but the association is less clear. The overall quality (strength) of evidence provided by the current literature is low to very low for most factors. Systematic review registration no.: CRD264358 (https://www.crd.york.ac.uk/prospero/).

Characterizing utilization patterns and reoperation risk factors of interspinous process devices: analysis of a national claims database.

INTRODUCTION: Interspinous process devices (IPDs) were developed as minimally invasive alternatives to open decompression surgery for spinal stenosis. However, given high treatment failure and reoperation rates, there has been minimal adoption by spine surgeons. This study leveraged a national claims database to characterize national IPD usage patterns and postoperative outcomes after IPD implantation. METHOD: Using the PearlDiver database, we identified all patients who underwent 1- or 2-level IPD implantation between 2010 and 2018. Univariate and multivariable logistic regression was performed to identify predictors of the number of IPD levels implanted and reoperation up to 3 years after the index surgery. Right-censored Kaplan-Meier curves were plotted for duration of reoperation-free survival and compared with log-rank tests. RESULTS: Patients (n = 4865) received 1-level (n = 3246) or 2-level (n = 1619) IPDs. Patients who were older (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.01-1.03, P < .001), male (aOR 1.31, 95% CI 116-1.50, P < .001), and obese (aOR 1.19, 95% CI 1.05-1.36, P < .01) were significantly more likely to receive a 2-level IPD than to receive a 1-level IPD. The 3-year reoperation rate was 9.3% of patients when mortality was accounted for during the follow-up period. Older age decreased (aOR 0.97, 95% CI 0.97-0.99, P = .0039) likelihood of reoperation, whereas 1-level IPD (aOR 1.37, 95% CI 1.01-1.89, P = .048), Charlson Comorbidity Index (aOR 1.07, 95% CI 1.01-1.14, P = .018), and performing concomitant open decompression increased the likelihood of reoperation (aOR 1.68, 95% CI 1.35-2.09, P = .0014). CONCLUSION: Compared with 1-level IPDs, 2-level IPDs were implanted more frequently in older, male, and obese patients. The 3-year reoperation rate was 9.3%. Concomitant open decompression with IPD placement was identified as a significant risk factor for subsequent reoperation and warrants future investigation.

Impact of State Laws on Dispensing Opioid Prescriptions Following Posterior Lumbar Interbody Fusion Procedures: A Retrospective Large National Database Study.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVES: This study aimed to examine the effect of state legislation on prescribing behavior after a commonly performed spinal procedure, posterior lumbar interbody fusion (PLIF). METHODS: Two cohorts of patients from the Pearl Diver Database were created based on patients who underwent PLIF surgery in 2014-15 and 2018-19. We compared opioid prescription rates and morphine-milli-equivalent (MME) between states with and without prescription legislation. RESULTS: We analyzed 50 958 PLIF patients from 2014-15 and 46 751 patients from 2018-19. Among them, 38 states passed opioid prescription laws in 2016-2017, while 12 states did not. The percentage of patients receiving opioid prescriptions within 365 days post-surgery remained similar in both time periods (49% in 2014-15 and 48% in 2018-2019). This trend was consistent across states with and without prescription legislation (50% vs 48% in 2014-2015, and similar in 2018-19). Opioid prescription quantity significantly decreased in all states between 2014-15 and 2018-19. In states with legislation, average MME dropped from 9198 ± 21 002 to 4932 ± 13 213 (46.4% decrease), and in states without legislation, it decreased from 9175 ± 21 032 to 4994 ± 11 687 (45.6% decrease). However, these differences were not statistically significant (P = .7985). CONCLUSION: From 2014 to 2018, there was a significant decrease in the number of opioids prescribed after PLIF. However, this decrease occurred irrespective of state legislation on prescribing practices being passed. We believe the reduction in opioids prescribed was due to increased awareness surrounding the dangers of opioids among physicians.

Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein.

IGHV3-33-encoded antibodies are prevalent in the human humoral response against the Plasmodium falciparum circumsporozoite protein (PfCSP). Among VH3-33 antibodies, cross-reactivity between PfCSP major repeat (NANP), minor (NVDP), and junctional (NPDP) motifs is associated with high affinity and potent parasite inhibition. However, the molecular basis of antibody cross-reactivity and the relationship with efficacy remain unresolved. Here, we perform an extensive structure-function characterization of 12 VH3-33 anti-PfCSP monoclonal antibodies (mAbs) with varying degrees of cross-reactivity induced by immunization of mice expressing a human immunoglobulin gene repertoire. We identify residues in the antibody paratope that mediate cross-reactive binding and delineate four distinct epitope conformations induced by antibody binding, with one consistently associated with high protective efficacy and another that confers comparably potent inhibition of parasite liver invasion. Our data show a link between molecular features of cross-reactive VH3-33 mAb binding to PfCSP and mAb potency, relevant for the development of antibody-based interventions against malaria.

Posterior Fixation Without Debridement for Vertebral Body Osteomyelitis and Discitis: A 10-Year Retrospective Review.

BACKGROUND: Surgical treatment of vertebral osteomyelitis, discitis, and epidural abscesses is indicated in the setting of failure of antibiotic therapy, neurological deficits, epidural abscess, or spinal instability/deformity. Historically, surgical treatment mandated aggressive debridement and spinal stabilization. However, there is growing evidence that direct debridement may not be necessary and may contribute to morbidity. The purpose of this study was to evaluate the efficacy of posterior instrumentation without debridement in treating spinal infections. METHODS: A retrospective medical record review was performed to identify patients treated with posterior instrumentation for spontaneous spinal infections. Success of treatment was determined based on postoperative ambulatory status, surgical complications, and need for revision surgery. RESULTS: Twenty-seven patients treated with posterior-only long-segmented rigid fixation without formal debridement of infected material were included. The most common indications for surgical intervention included spinal instability (67%), neurologic compromise (67%), and failure of prolonged antibiotic treatment (63%). There were no recurrent deep infections in 21 of 22 patients who had long-term follow-up. Four patients required revision surgery, and 3 additional patients requested elective hardware removal. Postoperatively, 70% were ambulatory with no assistive devices postoperatively. CONCLUSIONS: Vertebral osteomyelitis/discitis are challenging medical problems. Single-stage long-segment fusion without formal debridement combined with antibiotics is effective in the management of spontaneous spinal infections. CLINICAL RELEVANCE: The present study suggests that acute instrumentation without anterior debridement is associated with a resolution of infection and improvements in neurologic deficits in patient with spontaneous spine infections.

Copy number aberrations in circulating tumor DNA enables prognosis prediction and molecular characterization of breast cancer.

BACKGROUND: Low-pass whole-genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis is a versatile tool for somatic copy number aberration (CNA) detection, and this study aims to explore its clinical implication in breast cancer. METHODS: We analyzed LP-WGS ctDNA data from 207 metastatic breast cancer (MBC) patients to explore prognostic value of ctDNA CNA burden and validated it in 465 stage II-III triple-negative breast cancer (TNBC) patients who received neoadjuvant chemotherapy in phase III PEARLY trial (NCT02441933). The clinical implication of locus level LP-WGS ctDNA profiling was further evaluated. RESULTS: We found that a high baseline ctDNA CNA burden predicts poor overall survival and progression-free survival of MBC patients. The post hoc analysis of the PEARLY trial showed that a high baseline ctDNA CNA burden predicted poor disease-free survival independent from pathologic complete response (pCR), validating its robust prognostic significance. The 24-month disease-free survival rate was 96.9% and 55.9% in [pCR(+) and low I-score] and [non-pCR and high I-score] patients, respectively. The locus-level ctDNA CNA profile classified MBC patients into 5 molecular clusters and revealed targetable oncogenic CNAs. LP-WGS ctDNA and in vitro analysis identified the BCL6 amplification as a resistance factor for CDK4/6 inhibitors. We estimated ctDNA-based homologous recombination deficiency status of patients by shallowHRD algorithm, which was highest in the TNBC and correlated with platinum-based chemotherapy response. CONCLUSIONS: These results demonstrate LP-WGS ctDNA CNA analysis as an essential tool for prognosis prediction and molecular profiling. Particularly, ctDNA CNA burden can serve as a useful determinant for escalating or de-escalating (neo)adjuvant strategy in TNBC patients.

Molecular Dipoles as a Surface Flattening and Interface Stabilizing Agent for Lithium-Metal Batteries.

Reaching the border of the capable energy limit in existing battery technology has turned research attention away from the rebirth of unstable Li-metal anode chemistry in order to achieve exceptional performance. Strict regulation of the dendritic Li surface reaction, which results in a short circuit and safety issues, should be achieved to realize Li-metal batteries. Herein, this study reports a surface-flattening and interface product stabilizing agent employing methyl pyrrolidone (MP) molecular dipoles in the electrolyte for cyclable Li-metal batteries. The excellent stability of the Li-metal electrode over 600 cycles at a high current density of 5 mA cm-2 has been demonstrated using an optimal concentration of the MP additive. This study has identified the flattening surface reconstruction and crystal rearrangement behavior along the stable (110) plane assisted by the MP molecular dipoles. The stabilization of the Li-metal anodes using molecular dipole agents has helped develop next-generation energy storage devices using Li-metal anodes, such as Li-air, Li-S, and semi-solid-state batteries.

Nonsteroidal Anti-inflammatory Drugs in the Acute Post-operative Period Are Associated With an Increased Incidence of Pseudarthrosis, Hardware Failure, and Revision Surgery Following Single-level Spinal Fusion.

STUDY DESIGN: Retrospective study. SUMMARY OF BACKGROUND DATA: Research has shown that the use of NSAIDs and COX-2 inhibitors increases the risk of pseudoarthrosis following spinal fusion surgery. Pseudoarthrosis can lead to complications such as chronic pain and the need for additional surgeries. OBJECTIVE: The purpose of this study was to examine the relationship between NSAID and COX-2 inhibitor use and pseudarthrosis, hardware complications, and revision surgeries in patients undergoing posterior spinal instrumentation and fusion. METHODS: We queried the PearlDiver database using CPT and ICD-10 codes to identify patients between the ages of 50 and 85 who underwent posterior spinal instrumentation between 2016 and 2019 and experienced pseudarthrosis, hardware failure, or revision surgery. Information regarding age, Charlson Comorbidity Index, tobacco use, osteoporosis, and obesity were extracted from the database along with COX-2 or NSAID use during the first 6-week post-surgery period. Logistic regression was used to identify associations while adjusting for confounders. RESULTS: There were 178,758 patients included in the cohort; 9,586 experienced pseudarthrosis (5.36%), 2828 (1.58%) experienced hardware failure, and 10,457 (5.85%) patients underwent revision fusion surgery. Of these patients 23,602 (13.2%) filled NSAID and 5278 (2.95%) filled COX-2 prescriptions. A significantly higher proportion of patients using NSAIDs experienced pseudarthrosis, hardware failure, and revision surgery compared to patients not taking NSAIDs. COX-2 inhibitors were also associated with a significantly higher rate of pseudarthrosis, hardware failure, and revision surgery. Postoperative ketorolac use was not associated with these complications. Regression models demonstrated that both NSAIDs and COX-2 inhibitors were associated with statistically higher pseudarthrosis, hardware failure, and revision surgery rates. CONCLUSIONS: Both NSAID and COX-2 inhibitor use in the early post-surgical period may be associated with increased rates of pseudarthrosis, hardware failure, and revision surgery in patients undergoing posterior spinal instrumentation and fusion.

Lipid raft protein flotillin-1 is important for the interaction between SOS1 and H-Ras/K-Ras, leading to Ras activation.

Ras mutations have been frequently observed in human cancer. Although there is a high degree of similarity between Ras isomers, they display preferential coupling in specific cancer types. The binding of Ras to the plasma membrane is essential for its activation and biological functions. The present study elucidated Ras isoform-specific interactions with the membrane and their role in Ras-mediated biological activities. We investigated the role of a lipid raft protein flotillin-1 (Flot-1) in the activations of Ras. We found that Flot-1 was co-localized with H-Ras, but not with N-Ras, in lipid rafts of MDA-MB-231 human breast cells. The amino-terminal hydrophobic domain (1-38) of Flot-1 interacted with the hypervariable region of H-Ras. The epidermal growth factor-stimulated activation of H-Ras required Flot-1 which was not necessary for that of N-Ras in breast cancer cells. Flot-1 interacted with son of sevenless (SOS)-1, which promotes the conversion of Ras-bound GDP to GTP. Notably, Flot-1 was crucial for the interaction between SOS1 and H-Ras/K-Ras in breast and pancreatic cancer cells. Stable knockdown of Flot-1 reduced the in vivo metastasis in a mouse xenograft model with human breast carcinoma cells. A tissue microarray composed of 61 human pancreatic cancer samples showed higher levels of Flot-1 expression in pancreatic tumor tissues compared to normal tissues, and a correlation between K-Ras and Flot-1. Taken together, our findings suggest that Flot-1 may serve as a membrane platform for the interaction of SOS1 with H-Ras/K-Ras in human cancer cells, presenting Flot-1 as a potential target for Ras-driven cancers.

On-treatment derived neutrophil-to-lymphocyte ratio and survival with palbociclib and endocrine treatment: analysis of a multicenter retrospective cohort and the PALOMA-2/3 study with immune correlates.

BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been established as a standard treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC); however, predictive biomarkers with translational relevance have not yet been elucidated. METHODS: Data from postmenopausal women who received the CDK4/6 inhibitor palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (N = 221; exploratory cohort). Pre- and on-treatment neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR; neutrophil/[leukocyte-neutrophil]) were correlated with survival outcomes. Data from the PALOMA-2 (NCT01740427) and PALOMA-3 studies (NCT01942135) involving patients treated with endocrine treatment with or without palbociclib were also analyzed (validation cohort). Prospectively enrolled patients (N = 20) were subjected to immunophenotyping with circulating immune cells to explore the biological implications of immune cell dynamics. RESULTS: In the exploratory cohort, palbociclib administration significantly reduced leukocyte, neutrophil, and lymphocyte counts on day 1 of cycle 2. Although the baseline dNLR was not significantly associated with progression-free survival (PFS), higher on-treatment dNLRs were associated with worse PFS (hazard ratio = 3.337, P < 0.001). In the PALOMA-2 validation cohort, higher on-treatment dNLRs were associated with inferior PFS in patients treated with palbociclib and letrozole (hazard ratio = 1.498, P = 0.009), and reduction in the dNLR after treatment was predictive of a survival benefit (hazard ratio = 1.555, P = 0.026). On-treatment dNLRs were also predictive of PFS following palbociclib and fulvestrant treatment in the PALOMA-3 validation cohort. Using flow cytometry analysis, we found that the CDK4/6 inhibitor prevented T cell exhaustion and diminished myeloid-derived suppressor cell frequency. CONCLUSIONS: On-treatment dNLR significantly predicted PFS in patients with HR-positive, HER2-negative ABC receiving palbociclib and endocrine treatment. Additionally, we observed putative systemic immune responses elicited by palbociclib, suggesting immunologic changes upon CDK4/6 inhibitor treatment.

Cathodes Coating Layer with Li-Ion Diffusion Selectivity Employing Interactive Network of Metal-Organic Polyhedras for Li-Ion Batteries.

Surface modification of cathodes using Ni-rich coating layers prevents bulk and surface degradation for the stable operation of Li-ion batteries at high voltages. However, insulating and dense inorganic coating layers often impede charge transfer and ion diffusion kinetics. In this study, the fabrication of dual functional coating materials using metal-organic polyhedra (MOP) with 3D networks within microporous units of Li-ion batteries for surface stabilization and facile ion diffusion is proposed. Zr-based MOP is modified by introducing acyl groups as a chemical linkage (MOPAC), and MOPAC layers are homogenously coated by simple spray coating on the cathode. The coating allow the smooth transport of electrons and ions. MOPAC effectively suppress side reactions between the cathode and electrolyte and protect active materials against aggressive fluoride ions by forming a Li-ion selective passivation film. The MOPAC-coated Ni-rich layered cathode exhibited better cycle retention and enhanced kinetic properties than pristine and MOP-coated cathodes. Reduction of undesirable gas evolution on the cathode by MOPAC is also verified. Microporous MOPAC coating can simultaneously stabilize both the bulk and surface of the Ni-rich layered cathode and maintain good electrochemical reaction kinetics for high-performance Li-ion batteries.

Structural optimization of novel Ras modulator for treatment of Colorectal cancer by promoting ß-catenin and Ras degradation.

Ras protein has been considered a fascinating target for anticancer therapy because its malfunction is closely related to cancer. However, Ras has been considered undruggable because of the failure to regulate its malfunction by controlling the Ras activation mechanism. Recently, Lumakras targeting the G12C mutation was approved, and therapeutic interest in Ras for anticancer therapy has been rejuvenated. Here, we present a series of compounds that inhibit Ras via a unique mechanism of action that exploits the relationship between the Wnt/ß-catenin pathway and Ras. KYA1797K (1) binds to axin to stabilize the ß-catenin destruction complex that causes the phosphorylation and subsequent degradation of Ras, similar to canonical ß-catenin regulation. Based on the chemical structure of 1, we performed a structural optimization and identified 3-(2-hydroxyethyl)-5-((6-(4-nitrophenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (13d) as the most potent compound. 13d displayed antitumor effects in a colorectal cancer model with enhanced inhibition activity on Ras. The results of this study suggest that the further development of 13d could contribute to the development of Ras inhibitors with novel mechanisms of action.

Utilization of Vertebroplasty/Kyphoplasty in the Management of Compression Fractures: National Trends and Predictors of Vertebroplasty/Kyphoplasty.

OBJECTIVE: The purpose of this study is to examine the utilization of kyphoplasty/vertebroplasty procedures in the management of compression fractures. With the growing elderly population and the associated increase in rates of osteoporosis, vertebral compression fractures have become a daily encounter for spine surgeons. However, there remains a lack of consensus on the optimal management of this patient population. METHODS: A retrospective analysis of 91 million longitudinally followed patients from 2016 to 2019 was performed using the PearlDiver Patient Claims Database. Patients with compression fractures were identified using International Classification of Disease, 10th Revision codes, and a subset of patients who received kyphoplasty/vertebroplasty were identified using Common Procedural Terminology codes. Baseline demographic and clinical data between groups were acquired. Multivariable regression analysis was performed to determine predictors of receiving kyphoplasty/vertebroplasty. RESULTS: A total of 348,457 patients with compression fractures were identified with 9.2% of patients receiving kyphoplasty/vertebroplasty as their initial treatment. Of these patients, 43.5% underwent additional kyphoplasty/vertebroplasty 30 days after initial intervention. Patients receiving kyphoplasty/vertebroplasty were significantly older (72.2 vs. 67.9, p < 0.05), female, obese, had active smoking status and had higher Elixhauser Comorbidity Index scores. Multivariable analysis demonstrated that female sex, smoking status, and obesity were the 3 strongest predictors of receiving kyphoplasty/vertebroplasty (odds ratio, 1.27, 1.24, and 1.14, respectively). The annual rate of kyphoplasty/vertebroplasty did not change significantly (range, 8%-11%). CONCLUSION: The majority of vertebral compression fractures are managed nonoperatively. However, certain patient factors such as smoking status, obesity, female sex, older age, osteoporosis, and greater comorbidities are predictors of undergoing kyphoplasty/vertebroplasty.

Resource Allocation in Downlink VLC-NOMA Systems for Factory Automation Scenario.

Industry 4.0 requires high-speed data exchange that includes fast, reliable, low-latency, and cost-effective data transmissions. As visible light communication (VLC) can provide reliable, low-latency, and secure connections that do not penetrate walls and are immune to electromagnetic interference; it can be considered a solution for Industry 4.0. The non-orthogonal multiple access (NOMA) technique can achieve high spectral efficiency using the same frequency and time resources for multiple users. It means that smaller amounts of resources will be used compared with orthogonal multiple access (OMA). Therefore, handling multiple data transmissions with VLC-NOMA can be easier for factory automation than OMA. However, as the transmit power is split, the reliability is reduced. Therefore, this study proposed a deep neural network (DNN)-based power-allocation algorithm (DBPA) to improve the reliability of the system. Further, to schedule multiple nodes in VLC-NOMA system, a priority-based user-pairing (PBUP) scheme is proposed. The proposed techniques in VLC-NOMA system were evaluated in terms of the factory automation scenario and showed that it improves reliability and reduces missed deadlines.

Pyruvate Kinase M2 Promotes Hair Regeneration by Connecting Metabolic and Wnt/ß-Catenin Signaling.

Hair follicle stem cells (HFSCs) utilize glycolytic metabolism during their activation and anagen induction. However, the role of pyruvate kinase M2 (PKM2), which catalyzes the final step of glycolysis, in hair regeneration has not been elucidated. In this study, we investigated the expression pattern and activity of PKM2 during the depilation-induced anagen progression in mice. We found that TEPP-46, a selective activator of PKM2, enhanced hair re-growth and proliferation of HFSCs. PKM2 expression was increased via up-regulation of Wnt/ß-catenin signaling, which is involved in hair regeneration. Moreover, a combined treatment with KY19382, a small molecule that activates Wnt/ß-catenin signaling, and TEPP-46 significantly enhanced hair re-growth and wound-induced hair follicle neogenesis (WIHN). These results indicate that simultaneous activation of the PKM2 and Wnt/ß-catenin signaling could be a potential strategy for treating alopecia patients.