Ultra-Fast-Charging, Long-Duration, and Wide-Temperature-Range Sodium Storage Enabled by Multiwalled Carbon Nanotube-Hybridized Biphasic Polyanion-Type Phosphate Cathode Materials.

Sodium-ion batteries (SIBs) represent a promising energy storage technology with great safety. Because of their high operating potential, superior structural stability, and prominent thermal stability, polyanion-type phosphates have garnered significant interest in superior prospective cathode materials for SIBs. Nevertheless, the disadvantages of poor intrinsic electronic conductivity, sluggish kinetics, and volume variation during sodiation/desodiation remain great challenges for satisfactory rate performance and cycle stability, which severely hinder their further practical applications. In this work, by adjusting the amounts of pretreated multiwalled carbon nanotubes (CNT) added intentionally at the beginning of the preparation, biphasic polyanion-type phosphate materials (marked as NFC) are synthesized through a one-pot solid state reaction methodology, which are composed of CNT-interwoven Na3V2(PO4)2F3 (NVPF) and a small amount of Na3V2(PO4)3 (NVP). Benefiting from the improved electronic conductivity and unique composition and structure, the optimized sample (labeled as NFC-2) illustrates exceptional cycle stability and remarkable rate performance. The discharge capacities of the NFC-2 electrode are 114.8 and 78.6 mAh g-1 tested at 20 and 5000 mA g-1, respectively. Notably, such an electrode still gives out 75.7% capacity retention upon 10 000 cycles at 5000 mA g-1. In situ X-ray diffraction analysis demonstrates that the NFC-2 cathode has outstanding structural reversibility during charge/discharge cycles. More importantly, such a biphasic material has achieved impressive electrochemical performance within a wide operating temperature range of -20-50 °C. When temperature is decreased to -20 °C, the NFC-2 electrode still delivers an initial discharge capacity of 102.4 mAh g-1 and exhibits a remarkable capacity retention of 97.8% even after 500 cycles at 50 mA g-1. In addition, the sodium-ion full cell assembled by integrating NFC-2 cathode and hard carbon anode shows a satisfying energy density of 431.3 Wh kg-1 at 20 mA g-1 with a better long-term cycle performance. The synergistic effect among high energy NVPF, conductive CNT, and stable NVP may lead to the great improvement in the electrochemical sodium storage performance of the NFC-2 sample. Such biphasic polyanion-type phosphate materials will inject new ideas into the material design for SIBs with excellent electrochemical performance and further promote practical applications of this advanced energy storage technology.

iLipidome: enhancing statistical power and interpretability using hidden biosynthetic interdependencies in the lipidome.

Numerous biological processes and diseases are influenced by lipid composition. Advances in lipidomics are elucidating their roles, but analyzing and interpreting lipidomics data at the systems level remain challenging. To address this, we present iLipidome, a method for analyzing lipidomics data in the context of the lipid biosynthetic network, thus accounting for the interdependence of measured lipids. iLipidome enhances statistical power, enables reliable clustering and lipid enrichment analysis, and links lipidomic changes to their genetic origins. We applied iLipidome to investigate mechanisms driving changes in cellular lipidomes following supplementation of docosahexaenoic acid (DHA) and successfully identified the genetic causes of alterations. We further demonstrated how iLipidome can disclose enzyme-substrate specificity and pinpoint prospective glioblastoma therapeutic targets. Finally, iLipidome enabled us to explore underlying mechanisms of cardiovascular disease and could guide the discovery of early lipid biomarkers. Thus, iLipidome can assist researchers studying the essence of lipidomic data and advance the field of lipid biology.

Pure estrogen receptor antagonists potentiate capecitabine activity in ESR1-mutant breast cancer.

The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.

Immunoregulatory Engineering of Semiconducting Charge-Reversal Nanoantioxidant for Ameliorating Cancer Radioimmunotheranostics.

Radiotherapy (RT) is a crucial clinical modality for cancer. However, nonselectivity, toxicity to normal tissues, and radio-resistance severely limit RT applications. This study develops a versatile X-ray theranostic nano-antioxidant (XTN) to prevent normal tissues from oxidative damage and induce systematic and robust anticancer immunity. XTN owns NIR-II photoacoustic (PA) imaging properties for precise discrimination of the tumor margin through, thereby improving the accuracy of RT. Additionally, XTN is a nano-antioxidant to enhance the cell viability of normal cells after irradiation. Most importantly, XTN scavenges reactive oxygen species (ROS) in the TME to preserve the stimulatory activity of released high mobility group protein B1 to dendritic cells (DCs) and recover T cells' immune function. Meanwhile, XTN achieves charge-reversal specifically releasing an immunomodulator (demethylcantharidin, DMC) in the acidic TME. Moreover, the specifically released DMC inhibits protein phosphatase-2A activity and reduces regulatory T cell (Treg) differentiation. In the bilateral 4T1 tumor model, XTN-mediated radioimmunotherapy remarkably boosts a systemic antitumor immune response and induces durable immunological memory against tumor growth.

The mechanisms of white matter injury and immune system crosstalk in promoting the progression of Parkinson's disease: a narrative review.

Parkinson's disease (PD) is neurodegenerative disease in middle-aged and elderly people with some pathological mechanisms including immune disorder, neuroinflammation, white matter injury and abnormal aggregation of alpha-synuclein, etc. New research suggests that white matter injury may be important in the development of PD, but how inflammation, the immune system, and white matter damage interact to harm dopamine neurons is not yet understood. Therefore, it is particularly important to delve into the crosstalk between immune cells in the central and peripheral nervous system based on the study of white matter damage in PD. This crosstalk could not only exacerbate the pathological process of PD but may also reveal new therapeutic targets. By understanding how immune cells penetrate through the blood-brain barrier and activate inflammatory responses within the central nervous system, we can better grasp the impact of structural destruction of white matter in PD and explore how this process can be modulated to mitigate or combat disease progression. Microglia, astrocytes, oligodendrocytes and peripheral immune cells (especially T cells) play a central role in its pathological process where these immune cells produce and respond to pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1ß(IL-1ß) and interleukin-6(IL-6), and white matter injury causes microglia to become pro-inflammatory and release inflammatory mediators, which attract more immune cells to the damaged area, increasing the inflammatory response. Moreover, white matter damage also causes dysfunction of blood-brain barrier, allows peripheral immune cells and inflammatory factors to invade the brain further, and enhances microglia activation forming a vicious circle that intensifies neuroinflammation. And these factors collectively promote the neuroinflammatory environment and neurodegeneration changes of PD. Overall, these findings not only deepen our understanding of the complexity of PD, but also provide new targets for the development of therapeutic strategies focused on inflammation and immune regulation mechanisms. In summary, this review provided the theoretical basis for clarifying the pathogenesis of PD, summarized the association between white matter damage and the immune cells in the central and peripheral nervous systems, and then emphasized their potential specific mechanisms of achieving crosstalk with further aggravating the pathological process of PD.

A Hydrogel-coated Wood Membrane with Intelligent Oil Pollution Detection for Emulsion Separation.

Considering the potential threats posed by oily wastewater to the ecosystem, it is urgently in demand to develop efficient, eco-friendly, and intelligent oil/water separation materials to enhance the safety of the water environment. Herein, an intelligent hydrogel-coated wood (PPT/PPy@DW) membrane with self-healing, self-cleaning, and oil pollution detection performances is fabricated for the controllable separation of oil-in-water (O/W) emulsions and water-in-oil (W/O) emulsions. The PPT/PPy@DW is prepared by loading polypyrrole (PPy) particles on the delignified wood (DW) membranes, further modifying the hydrogel layer as an oil-repellent barrier. The layered porous structure and selective wettability endow PPT/PPy@DW with great separation performance for various O/W emulsions (≥98.69% for separation efficiency and ≈1000 L m-2 h-1 bar-1 for permeance). Notably, the oil pollution degree of PPT/PPy@DW can be monitored in real-time based on the changed voltage generated during O/W emulsion separation, and the oil-polluted PPT/PPy@DW can be self-cleaned by soaking in water to recover its separation performance. The high affinity of PPT/PPy@DW for water makes it effective in trapping water from the mixed surfactant-stabilized W/O emulsions. The prepared eco-friendly and low-cost multifunctional hydrogel wood membrane shows promising potential in on-demand oil/water separation and provides new ideas for the functional improvement of new biomass oil/water separation membrane materials.

Efficacy of multicomponent interventions on injury risk among ice and snow sports participants-a systematic review and meta-analysis.

BACKGROUND: Ice and snow sports, which are inherently high risk due to their physically demanding nature, pose significant challenges in terms of participant safety. These activities increase the likelihood of injuries, largely due to reduced bodily agility and responsiveness in cold, often unpredictable winter environments. The critical need for effective injury prevention in these sports is emphasized by the considerable impact injuries have on the health of participants, alongside the economic and social costs associated with medical and rehabilitative care. In the context of ice and snow sports environments, applying the E principles of injury prevention to evaluate intervention measures can guide the implementation of future sports safety and other health promotion intervention measures in this field. When well executed, this approach can substantially reduce both the frequency and severity of injuries, thereby significantly enhancing the safety and long-term viability of these challenging sports. OBJECTIVE: The objective of this study was to rigorously assess and statistically substantiate the efficacy of diverse injury prevention strategies in ice and snow sports, aiming to bolster future safety measures with solid empirical evidence. DESIGN: Systematic review and meta-analysis. METHODS: The overarching aim of this research was to meticulously aggregate and scrutinize a broad spectrum of scholarly literature, focusing on the quantifiable efficacy of diverse, multicomponent intervention strategies in mitigating the incidence of injuries within the realm of ice and snow sports. This endeavour entailed an exhaustive extraction of data from esteemed academic databases, encompassing publications up to September 30, 2023. In pursuit of methodological excellence and analytical rigor, the study employed advanced bias assessment methodologies, notably the AMSTAR 2 and GRADE approaches, alongside sophisticated random-effects statistical modelling. This comprehensive approach was designed to ensure the utmost validity, reliability, and scholarly integrity of the study's findings. RESULTS: Fifteen papers, including 9 randomized controlled trials, 3 case‒control studies, and 3 cohort studies with 26,123 participants and 4,382 injuries, were analysed. The findings showed a significant reduction in injury rates through various interventions: overall injury prevention (RR = 0.50, 95% CI 0.42-0.63), educational training (RR = 0.50, 95% CI 0.34-0.73), educational videos (RR = 0.53, 95% CI 0.34-0.81), protective equipment (RR = 0.64, 95% CI 0.46-0.87), and policy changes (RR = 0.28, 95% CI 0.16-0.49). Subgroup analysis revealed potential heterogeneity in compliance (p = 0.347). Compared to controls, multicomponent interventions effectively reduced injury rates. CONCLUSION: This systematic review and meta-analysis demonstrated that multicomponent interventions significantly prevent injuries in ice and snow sports. By applying the E principles of injury prevention and constructing a framework for practical injury prevention research in ice and snow sports, we can gradually shift towards a systemic paradigm for a better understanding of the development and prevention of sports injuries. Moreover, sports injury prevention is a complex and dynamic process. Therefore, high-quality experiments in different scenarios are needed in future research to provide more reliable evidence, offer valuable and relevant prevention information for practitioners and participants, and help formulate more effective preventive measures in practice.

Recycling of Ti and Si from Ti-bearing blast furnace slag and diamond wire saw silicon waste by flux alloying technique.

Two industrial solid wastes, Ti-bearing blast furnace slag (TBFS) and diamond wire saw silicon waste (DWSSW), contain large amounts of Ti and Si, and their accumulation wastes resources and intensifies environmental pollution. In the present study, DWSSW was used as the silicon source to reduce titanium oxide in TBFS by electromagnetic induction smelting, and meanwhile Na3AlF6 was added as a flux to improve the recycling of the wastes. Ti and Si of the two wastes were simultaneously recovered in the form of alloy. The effects of different addition amount of Na3AlF6 flux in the mixture of DWSSW and TBFS on chemical composition, viscosity, basicity and structure of slag were investigated. The dissolution behavior of SiO2 in Na3AlF6 flux was theoretically deduced and experimentally verification. The optimized recovery rate of Ti and Si were obtained, and the research realizes the efficient recycling of DWSSW and TBFS simultaneously.

Supplier selection in green supply chain management using correlation-based TOPSIS in a q-rung orthopair fuzzy soft environment.

Fuzzy hybrid models are efficient mathematical tools for managing unclear and vague data in real-world scenarios. This research explores the q-rung orthopair fuzzy soft set (q-ROFSS), which presents incomplete and ambiguous details in decision-making problems. The main intention of this study is to describe and evaluate the characteristics of the correlation coefficient (CC) and weighted correlation coefficient (WCC) for q-ROFSS. Also, the technique for order preference should be enhanced by similarity to the ideal solution (TOPSIS) with extended measures in q-ROFSS settings. Furthermore, we integrated mathematical formulations of correlation obstructions to confirm the consistency of the planned technique. It helps handle difficulties involving multi-attribute group decision-making (MAGDM). Moreover, a numerical illustration is presented to clarify how the advocated decision-making methodology can be implemented in evaluating suppliers in green supply chain management (GSCM). As a result, each alternative is assessed using multiple criteria, such as quality and reliability, capacity and scalability, compliance and certifications, and sustainability practices. The technique proposed in this study retains the selected research's specific structure more effectively than current techniques. A comparative analysis further substantiates the feasibility and effectiveness of the proposed approach over other decision-making techniques.

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Inhibition of zinc ions in sulfur-driven autotrophic denitrification process: What is the behavior of extracellular polymeric substances?

Sulfur-driven autotrophic denitrification (SAD) process is a cost-effective and sustainable method for nitrogen removal from wastewater. However, a higher concentration of zinc ions (Zn(II)) flowing into wastewater treatment plants poses a potential threat to the SAD process. This study examined that a half maximal inhibitory concentration (IC50) of Zn(II) was 7 mg·L-1 in the SAD process. Additionally, the addition of 20 mg·L-1 Zn(II) resulted in a severe accumulation of nitrite to 150.20 ±â€¯6.00 mg·L-1 when the initial concentration of nitrate was 500 mg·L-1. Moreover, the activities of nitrate reductase, nitrite reductase, dehydrogenase and electron transport system were significantly inhibited under Zn(II) stress. The addition of Zn(II) inhibited EPS secretion and worsened electrochemical properties. The result was attributed to the spontaneous binding between EPS and Zn(II), with a ΔG of -17.50 KJ·mol-1 and a binding constant of 1.77 × 104 M-1, respectively. Meanwhile, the protein, fulvic acid, and humic-like substances occurred static quenching after Zn(II) addition, with -OH and -C=O groups providing binding sites. The binding sequence was fulvic acid→protein→humic acid and -OH → -C=O. Zn(II) also reduced the content of α-helix, which was unfavorable for electron transfer. Additionally, the Zn(II) loosened protein structure, resulting in a 50 % decrease in α-helix/(ß-sheet+random coil). This study reveals the effect of Zn(II) on the SAD process and enhances our understanding of EPS behavior under metal ions stress.

Daphnetin protects neurons in an Alzheimer disease mouse model and normal rat neurons by inhibiting BACE1 activity and activating the Nrf2/HO-1 pathway.

The common neurodegenerative disorder Alzheimer disease (AD) is characterized by memory dysfunction and cognitive decline in the elderly. Neuropathological features include aggregated ß-amyloid (Aß) accumulation, neuroinflammation, and oxidative stress in the brain. Daphnetin (DAPH), a natural coumarin derivative, has the potential for inhibiting inflammatory and oxidative responses. We explored neuroprotective roles of DAPH treatment in the APP/PS1 transgenic mouse AD model. DAPH ameliorated spatial learning disabilities in Morris water maze tests and reduced Aß deposition, assessed by immunohistochemistry. It also reduced the Aß content in supernatants of neurons from fetal APP/PS1 mice, assessed by cell-based soluble ELISA. Molecular docking and fluorescence resonance energy transfer-based assay results suggested that DAPH could directly inhibit BACE1 activity. Furthermore, in vitro experiments utilizing isolated rat neurons assessing RNA expression profiling, immunofluorescence, TUNEL assay, and Western-blot analysis, suggested the potential of DAPH for regulating BDNF and GM-CSF expression and mitigating Aß1-42-induced cortical injury, synaptic loss, and apoptosis. HO-1 and Nrf2 mRNA and protein expression were also increased in a dose-dependent manner. These results underscore the potential of DAPH as a neuroprotective agent in reversing memory deficits associated with AD and bolster its candidacy as a multitarget natural small-molecule drug for AD patients.

Transcriptome sequencing and metabolome analysis reveal the molecular mechanism of Salvia miltiorrhiza in response to drought stress.

Salvia miltiorrhiza is commonly used as a Chinese herbal medicine to treat different cardiovascular and cerebrovascular illnesses due to its active ingredients. Environmental conditions, especially drought stress, can affect the yield and quality of S. miltiorrhiza. However, moderate drought stress could improve the quality of S. miltiorrhiza without significantly reducing the yield, and the mechanism of this initial drought resistance is still unclear. In our study, transcriptome and metabolome analyses of S. miltiorrhiza under different drought treatment groups (CK, A, B, and C groups) were conducted to reveal the basis for its drought tolerance. We discovered that the leaves of S. miltiorrhiza under different drought treatment groups had no obvious shrinkage, and the malondialdehyde (MDA) contents as well as superoxide dismutase (SOD) and peroxidase (POD) activities dramatically increased, indicating that our drought treatment methods were moderate, and the leaves of S. miltiorrhiza began to initiate drought resistance. The morphology of root tissue had no significant change under different drought treatment groups, and the contents of four tanshinones significantly enhanced. In all, 5213, 6611, and 5241 differentially expressed genes (DEGs) were shared in the A, B, and C groups compared with the CK group, respectively. The results of KEGG and co-expression analysis showed that the DEGs involved in plant-pathogen interactions, the MAPK signaling pathway, phenylpropanoid biosynthesis, flavonoid biosynthesis, and plant hormone signal transduction responded to drought stress and were strongly correlated with tanshinone biosynthesis. Furthermore, the results of metabolism analysis indicated that 67, 72, and 92 differentially accumulated metabolites (DAMs), including fumarate, ferulic acid, xanthohumol, and phytocassanes, which were primarily involved in phenylpropanoid biosynthesis, flavonoid biosynthesis, and diterpenoid biosynthesis pathways, were detected in these groups. These discoveries provide valuable information on the molecular mechanisms by which S. miltiorrhiza responds to drought stress and will facilitate the development of drought-resistant and high-quality S. miltiorrhiza production.

Randomized, double-blind, placebo-controlled, multicenter study to evaluate efficacy and safety of the denosumab biosimilar MW031 in Chinese postmenopausal women with osteoporosis.

BACKGROUND: This study aimed to assess the efficacy and safety of MW031 in Chinese postmenopausal women with osteoporosis. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled, multicenter clinical trial, 448 postmenopausal women with osteoporosis were randomized 3:1 to receive MW031 and placebo for 12 months. The primary efficacy endpoint was the percentage change from baseline in BMD at lumbar spine in month 12. The safety and immunogenicity profiles were also included. RESULTS: Of 448 randomized patients, 421 completed the study (MW031, n = 322; placebo, n = 99).After 12 months of MW031 treatment, BMD increased by 5.80% at lumbar spine,3.65% at total hip, and 2.93% at femoral neck. The model-adjusted difference was 3.86% (P<0.0001), 2.34% (P<0.0001), and 1.05% (p = 0.08) compared with placebo group, respectively. For the bone turnover markers, serum CTX level in MW031 group decreased to the maximum difference in month 1 (-71.71%, 95% CI: -77.83%, -65.60%, P<0.0001) compared with the placebo group. The safety analysis showed no significant differences in the proportion of patients reporting any adverse events between the two groups. CONCLUSION: This study demonstrated that MW031 safely and effectively increased BMD and rapidly decreased the level of bone resorption marker in Chinese postmenopausal women with osteoporosis. TRIAL REGISTRATION: NCT05215977 (ClinicalTrials.gov.).

Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma.

PURPOSE: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. RESULTS: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. CONCLUSIONS: KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS: To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS: Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS: This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.

A phase I/II study of nintedanib and capecitabine for refractory metastatic colorectal cancer.

BACKGROUND: Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. METHODS: Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25. RESULTS: Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. CONCLUSIONS: The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT02393755.

Expand available targets for CAR-T therapy to overcome tumor drug resistance based on the "Evolutionary Traps".

Based on the concept of "Evolutionary Traps", targeting survival essential genes obtained during tumor drug resistance can effectively eliminate resistant cells. While, it still faces limitations. In this study, lapatinib-resistant cells were used to test the concept of "Evolutionary Traps" and no suitable target stand out because of the identified genes without accessible drug. However, a membrane protein PDPN, which is low or non-expressed in normal tissues, is identified as highly expressed in lapatinib-resistant tumor cells. PDPN CAR-T cells were developed and showed high cytotoxicity against lapatinib-resistant tumor cells in vitro and in vivo, suggesting that CAR-T may be a feasible route for overcoming drug resistance of tumor based on "Evolutionary Trap". To test whether this concept is cell line or drug dependent, we analyzed 21 drug-resistant tumor cell expression profiles reveal that JAG1, GPC3, and L1CAM, which are suitable targets for CAR-T treatment, are significantly upregulated in various drug-resistant tumor cells. Our findings shed light on the feasibility of utilizing CAR-T therapy to treat drug-resistant tumors and broaden the concept of the "Evolutionary Trap".