ARHGAP15 promotes metastatic colonization in gastric cancer by suppressing RAC1-ROS pathway.

The molecular mechanism of tumor metastasis, especially how metastatic tumor cells colonize in a distant site, remains poorly understood. Here we reported that ARHGAP15, a Rho GTPase activating protein, enhanced gastric cancer (GC) metastatic colonization, which was quite different from its reported role as a tumor suppressor gene in other cancers. It was upregulated in metastatic lymph nodes and significantly associated with a poor prognosis. Ectopic expression of ARHGAP15 promoted metastatic colonization of gastric cancer cells in murine lungs and lymph nodes in vivo or protected cells from oxidative-related death in vitro. However, genetic downregulation of ARHGAP15 had the opposite effect. Mechanistically, ARHGAP15 inactivated RAC1 and then decreased intracellular accumulation of reactive oxygen species (ROS), thus enhancing the antioxidant capacity of colonizing tumor cells under oxidative stress. This phenotype could be phenocopied by inhibition of RAC1 or rescued by the introduction of constitutively active RAC1 into cells. Taken together, these findings suggested a novel role of ARHGAP15 in promoting gastric cancer metastasis by quenching ROS through inhibiting RAC1 and its potential value for prognosis estimation and targeted therapy.

Targeting MFGE8 secreted by cancer-associated fibroblasts blocks angiogenesis and metastasis in esophageal squamous cell carcinoma.

Cancer-associated fibroblasts (CAFs) play vital roles in establishing a suitable tumor microenvironment. In this study, RNA sequencing data revealed that CAFs could promote cell proliferation, angiogenesis, and ECM reconstitution by binding to integrin families and activating PI3K/AKT pathways in esophageal squamous cell carcinoma (ESCC). The secretions of CAFs play an important role in regulating these biological activities. Among these secretions, we found that MFGE8 is specifically secreted by CAFs in ESCC. Additionally, the secreted MFGE8 protein is essential in CAF-regulated vascularization, tumor proliferation, drug resistance, and metastasis. By binding to Integrin αVß3/αVß5 receptors, MFGE8 promotes tumor progression by activating both the PI3K/AKT and ERK/AKT pathways. Interestingly, the biological function of MFGE8 secreted by CAFs fully demonstrated the major role of CAFs in ESCC and its mode of mechanism, showing that MFGE8 could be a driver factor of CAFs in remodeling the tumor environment. In vivo treatment targeting CAFs-secreting MFGE8 or its receptor produced significant inhibitory effects on ESCC growth and metastasis, which provides an approach for the treatment of ESCC.

Enhanced mitophagy driven by ADAR1-GLI1 editing supports the self-renewal of cancer stem cells in HCC.

BACKGROUND AND AIMS: Deregulation of adenosine-to-inosine editing by adenosine deaminase acting on RNA 1 (ADAR1) leads to tumor-specific transcriptome diversity with prognostic values for HCC. However, ADAR1 editase-dependent mechanisms governing liver cancer stem cell (LCSC) generation and maintenance have remained elusive. APPROACH AND RESULTS: RNA-seq profiling identified ADAR1-responsive recoding editing events in HCC and showed editing frequency of GLI1 , rather than transcript abundance was clinically relevant. Functional differences in LCSC self-renewal and tumor aggressiveness between wild-type (GLI1 wt ) and edited GLI1 (GLI1 edit ) were elucidated. We showed that overediting of GLI1 induced an arginine-to-glycine (R701G) substitution, augmenting tumor-initiating potential and exhibiting a more aggressive phenotype. GLI1 R701G harbored weak affinity to SUFU, which in turn, promoted its cytoplasmic-to-nuclear translocation to support LCSC self-renewal by increased pluripotency gene expression. Moreover, editing predisposed to stabilize GLI1 by abrogating ß-TrCP-GLI1 interaction. Integrative analysis of single-cell transcriptome further revealed hyperactivated mitophagy in ADAR1-enriched LCSCs. GLI1 editing promoted a metabolic switch to oxidative phosphorylation to control stress and stem-like state through PINK1-Parkin-mediated mitophagy in HCC, thereby conferring exclusive metastatic and sorafenib-resistant capacities. CONCLUSIONS: Our findings demonstrate a novel role of ADAR1 as an active regulator for LCSCs properties through editing GLI1 in the highly heterogeneous HCC.

CGRP is essential for protection against alveolar epithelial cell necroptosis by activating the AMPK/L-OPA1 signaling pathway during acute lung injury.

Alveolar epithelial cell (AEC) necroptosis is critical to disrupt the alveolar barrier and provoke acute lung injury (ALI). Here, we define calcitonin gene-related peptide (CGRP), the most abundant endogenous neuropeptide in the lung, as a novel modulator of AEC necroptosis in lipopolysaccharide (LPS)-induced ALI. Upon LPS-induced ALI, overexpression of Cgrp significantly mitigates the inflammatory response, alleviates lung tissue damage, and decreases AEC necroptosis. Similarly, CGRP alleviated AEC necroptosis under the LPS challenge in vitro. Previously, we identified that long optic atrophy 1 (L-OPA1) deficiency mediates mitochondrial fragmentation, leading to AEC necroptosis. In this study, we discovered that CGRP positively regulated mitochondrial fusion through stabilizing L-OPA1. Mechanistically, we elucidate that CGRP activates AMP-activated protein kinase (AMPK). Furthermore, the blockade of AMPK compromised the protective effect of CGRP against AEC necroptosis following the LPS challenge. Our study suggests that CRGP-mediated activation of the AMPK/L-OPA1 axis may have potent therapeutic benefits for patients with ALI or other diseases with necroptosis.

Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3SMKO and Best3ECKO, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3SMKO but not Best3ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3SMKO and ApoE-/- mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.

COX-2/sEH-Mediated Macrophage Activation Is a Target for Pulmonary Protection in Mouse Models of Chronic Obstructive Pulmonary Disease.

Effective inhibition of macrophage activation is critical for resolving inflammation and restoring pulmonary function in patients with chronic obstructive pulmonary disease (COPD). In this study, we identified the dual-enhanced cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) as a novel regulator of macrophage activation in COPD. Both COX-2 and sEH were found to be increased in patients and mice with COPD and in macrophages exposed to cigarette smoke extract. Pharmacological reduction of the COX-2 and sEH by 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide (PTUPB) effectively prevented macrophage activation, downregulated inflammation-related genes, and reduced lung injury, thereby improving respiratory function in a mouse model of COPD induced by cigarette smoke and lipopolysaccharide. Mechanistically, enhanced COX-2/sEH triggered the activation of the NACHT, LRR, and PYD domains-containing protein 3 inflammasome, leading to the cleavage of pro-IL-1ß into its active form in macrophages and amplifying inflammatory responses. These findings demonstrate that targeting COX-2/sEH-mediated macrophage activation may be a promising therapeutic strategy for COPD. Importantly, our data support the potential use of the dual COX-2 and sEH inhibitor PTUPB as a therapeutic drug for the treatment of COPD.

Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options.

Drug resistance represents a significant obstacle in cancer treatment, underscoring the need for the discovery of novel therapeutic targets. Ubiquitin-specific proteases (USPs), a subclass of deubiquitinating enzymes, play a pivotal role in protein deubiquitination. As scientific research advances, USPs have been recognized as key regulators of drug resistance across a spectrum of treatment modalities, including chemotherapy, targeted therapy, immunotherapy, and radiotherapy. This comprehensive review examines the complex relationship between USPs and drug resistance mechanisms, focusing on specific treatment strategies and highlighting the influence of USPs on DNA damage repair, apoptosis, characteristics of cancer stem cells, immune evasion, and other crucial biological functions. Additionally, the review highlights the potential clinical significance of USP inhibitors as a means to counter drug resistance in cancer treatment. By inhibiting particular USP, cancer cells can become more susceptible to a variety of anti-cancer drugs. The integration of USP inhibitors with current anti-cancer therapies offers a promising strategy to circumvent drug resistance. Therefore, this review emphasizes the importance of USPs as viable therapeutic targets and offers insight into fruitful directions for future research and drug development. Targeting USPs presents an effective method to combat drug resistance across various cancer types, leading to enhanced treatment strategies and better patient outcomes.

Efficacy and safety of immune checkpoint inhibitors in solid tumor patients combined with chronic coronary syndromes or its risk factor: a nationwide multicenter cohort study.

BACKGROUND: Although, immune checkpoint inhibitors (ICIs) have been widely applied in the therapy of malignant tumors, the efficacy and safety of ICIs in patients with tumors and pre-existing CAD, especially chronic coronary syndromes (CCS) or their risk factors (CRF), is not well identified. METHODS: This was a nationwide multicenter observational study that enrolled participants who diagnosed with solid tumors and received ICIs therapy. The main efficacy indicators were progression-free survival (PFS) and overall survival (OS), followed by objective response rate (ORR) and disease control rate (DCR). Safety was assessed by describing treatment-related adverse events (TRAEs) during ICIs therapy evaluated by the Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0). RESULTS: In the current research, we retrospectively analyzed the data of 551 patients diagnosed with solid tumors and received ICIs therapy, and these patients were divided into CCS/CRF group and non-CCS/CRF group. Patients with CCS/CRF had more favorable PFS and OS than patients without CCS/CRF (P < 0.001) and the pre-existing CCS/CRF was a protective factor for survival. The ORR (51.8% vs. 39.1%) and DCR (95.8% vs. 89.2%) were higher in CCS/CRF group than in non-CCS/CRF group (P = 0.003, P = 0.006). In this study, there was no significant difference in treatment-related adverse events (TRAEs), including immune-related adverse events (irAEs), between the two groups. CONCLUSIONS: We concluded that ICIs appear to have better efficacy in malignant solid tumor patients with pre-existing CCS/CRF and are not accompanied by more serious irAEs.

Dynamic radiological features predict pathological response after neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant immunochemotherapy (NICT) plus esophagectomy has emerged as a promising treatment option for locally advanced esophageal squamous cell carcinoma (LA-ESCC). Pathologic complete response (pCR) is a key indicator associated with great efficacy and overall survival (OS). However, there are insufficient indicators for the reliable assessment of pCR. METHODS: 192 patients with LA-ESCC treated with NICT from December 2019 to October 2023 were recruited. According to pCR status, patients were categorized into pCR group (22.92%) and non-pCR group (77.08%). Radiological features of pretreatment and preoperative CT images were extracted. Logistic and COX regressions were trained to predict pathological response and prognosis, respectively. RESULTS: Four of the selected radiological features were combined to construct an ESCC preoperative imaging score (ECPI-Score). Logistic models revealed independent associations of ECPI-Score and vascular sign with pCR, with AUC of 0.918 in the training set and 0.862 in the validation set, respectively. After grouping by ECPI-Score, a higher proportion of pCR was observed among the high-ECPI group and negative vascular sign. Kaplan Meier analysis demonstrated that recurrence-free survival (RFS) with negative vascular sign was significantly better than those with positive (P = 0.038), but not for OS (P = 0.310). CONCLUSIONS: This study demonstrates dynamic radiological features are independent predictors of pCR for LA-ESCC treated with NICT. It will guide clinicians to make accurate treatment plans.

YaliCMulti and YaliHMulti: Stable, efficient multi-copy integration tools for engineering Yarrowia lipolytica.

Yarrowia lipolytica is widely used in biotechnology to produce recombinant proteins, food ingredients and diverse natural products. However, unstable expression of plasmids, difficult and time-consuming integration of single and low-copy-number plasmids hampers the construction of efficient production pathways and application to industrial production. Here, by exploiting sequence diversity in the long terminal repeats (LTRs) of retrotransposons and ribosomal DNA (rDNA) sequences, a set of vectors and methods that can recycle multiple and high-copy-number plasmids was developed that can achieve stable integration of long-pathway genes in Y. lipolytica. By combining these sequences, amino acids and antibiotic tags with the Cre-LoxP system, a series of multi-copy site integration recyclable vectors were constructed and assessed using the green fluorescent protein (HrGFP) reporter system. Furthermore, by combining the consensus sequence with the vector backbone of a rapidly degrading selective marker and a weak promoter, multiple integrated high-copy-number vectors were obtained and high levels of stable HrGFP expression were achieved. To validate the universality of the tools, simple integration of essential biosynthesis modules was explored, and 7.3 g/L of L-ergothioneine and 8.3 g/L of (2S)-naringenin were achieved in a 5 L fermenter, the highest titres reported to date for Y. lipolytica. These novel multi-copy genome integration strategies provide convenient and effective tools for further metabolic engineering of Y. lipolytica.

Heavy-Quark Pair Production at Lepton Colliders at NNNLO in QCD.

We compute the total cross section and invariant mass distribution for heavy-quark pair production in e^{+}e^{-} annihilation at the next-to-next-to-next-to-leading order in QCD. The obtained results are expressed as piecewise functions defined by several deeply expanded power series, facilitating a rapid numerical evaluation. Utilizing top-pair production at a collision energy of 500 GeV as a benchmark, we observe a correction of approximately 0.1% for the total cross section and around 10% for the majority of the invariant mass distribution range. These results play a crucial role in significantly reducing theoretical uncertainty: the scale dependence has been diminished to 0.06% for the total cross section and to 5% for the invariant mass distribution. This reduction of uncertainty meets the stringent requirements of future lepton colliders.

One-Step Formation of Pickering Double Emulsion Costabilized by Hydrophobic Silica Nanoparticles and Sodium Alginate.

Pickering double emulsions exhibit higher stability and biocompatibility compared with surfactant-stabilized double emulsions. However, tailored synthesis of particle stabilizers with appropriate wettability is time consuming and complicated and usually limits their large-scale adoption. Using binary stabilizers may be a simple and scalable strategy for Pickering double emulsion formation. Herein, commercially available hydrophobic silica nanoparticles (SNPs) and sodium alginate (SA) as binary stabilizers are used to prepare O/W/O Pickering double emulsions in one-step emulsification. The influence of system composition on double emulsion preparation is identified by optical microscopy, confocal laser scanning microscopy, and interfacial tension and water contact angle analyses. The formation of the O/W/O Pickering double emulsion depends critically on the aqueous phase viscosity and occurrence of emulsion inversion. Both hydrophobic SNPs and SA adsorb at the droplet surface to provide a steric barrier, while SA also reduces interfacial tension and increases aqueous phase viscosity, giving double emulsion long-term stability. Their microstructure and stability are controlled by adjusting the SA concentration, water-oil volume ratio, concentration and wettability of the particle stabilizer, and oil type. As a demonstration, the middle layer of the as-prepared O/W/O Pickering double emulsions can be cross-linked in situ with calcium ions to produce calcium alginate porous microspheres. We believe that our strategy for double emulsion formation holds great potential for practical applications in food, cosmetics, or pharmaceuticals.

Shape memory hydrogels with remodelable permanent shapes and programmable cold-induced shape recovery behavior.

Most shape memory polymers apply glass transition or crystallization of domains to fix temporary shapes and shape recovery is induced by heating, which hinders their application under heat-intolerant conditions. Moreover, the permanent shapes of polymers normally cannot be altered arbitrarily after fabrication. Herein, we present a novel shape memory hydrogel with a remodelable permanent shape and programmable cold-induced shape recovery behavior. Poly(acrylic acid) (PAA) hydrogel is prepared in the presence of diethylenetriamine (DETA) and subsequently treated with calcium acetate (Ca(Ac)2). The charge-assisted hydrogen bonding between PAA and DETA imparts the hydrogel with remodelability, while the heat-induced hydrophobic aggregation of polymer chains and acetate groups results in shape fixation by heating and shape recovery by cooling. Afterwards, programmable deformable devices are obtained by assembling hydrogel blocks with different concentrations of Ca(Ac)2. This design strategy promotes the development of shape memory polymers with diverse potential applications.

Helicobacter pylori with trx1 high expression promotes gastric diseases via upregulating the IL23A/NF-κB/IL8 pathway.

BACKGROUND: Helicobacter pylori infection is one of the main causes of gastric cancer. thioredoxin-1 (Trx1) and arginase (RocF) expressed by H. pylori were found to be closely related to its pathogenicity. However, whether Trx1 and RocF can be used in clinical screening of highly pathogenic H. pylori and the pathogenesis of trx1 high expressing H. pylori remain still unknown. MATERIALS AND METHODS: We investigated the expression level of H. pylori trx1 and H. pylori rocF in human gastric antrum tissues using reverse transcription and quantitative real-time PCR (RT-qPCR) and clarified the clinical application value of trx1 and rocF for screening highly pathogenic H. pylori. The pathogenic mechanism of Trx1 were further explored by RNA-seq of GES-1 cells co-cultured with trx1 high or low expressing H. pylori. Differentially expressed genes and signaling pathways were validated by RT-qPCR, Enzyme-linked immunosorbent assay (ELISA), western blot, immunohistochemistry and immunofluorescence. We also assessed the adherence of trx1 high and low expressing H. pylori to GES-1 cells. RESULTS: We found that H. pylori trx1 and H. pylori rocF were more significantly expressed in the gastric cancer and peptic ulcer group than that in the gastritis group and the parallel diagnosis of H. pylori trx1 and H. pylori rocF had high sensitivity. The trx1 high expressing H. pylori had stronger adhesion ability to GES-1 cells and upregulated the interleukin (IL) 23A/nuclear factor κappaB (NF-κB)/IL17A, IL6, IL8 pathway. CONCLUSIONS: H. pylori trx1 and H. pylori rocF can be used in clinical screening of highly pathogenic H. pylori and predicting the outcome of H. pylori infection. The trx1 high expressing H. pylori has stronger adhesion capacity and promotes the development of gastric diseases by upregulating the activation of NF-κB signaling pathway.

LOXL1 promotes tumor cell malignancy and restricts CD8 + T cell infiltration in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer mortality globally. Lymph node metastasis and immunosuppression are main factors of poor prognosis in CRC patients. Lysyl oxidase like 1 (LOXL1), part of the lysyl oxidase (LOX) family, plays a yet unclear role in CRC. This study aimed to identify effective biomarkers predictive of prognosis and efficacy of immunotherapy in CRC patients, and to elucidate the prognostic value, clinical relevance, functional and molecular features, and immunotherapy predictive role of LOXL1 in CRC and pan-cancer. METHODS: Weighted gene co-expression network analysis (WGCNA) was employed to explore gene modules related to tumor metastasis and CD8 + T cell infiltration. LOXL1 emerged as a hub gene through differential gene expression and survival analysis. The molecular signatures, functional roles, and immunological characteristics affected by LOXL1 were analyzed in multiple CRC cohorts, cell lines and clinical specimens. Additionally, LOXL1's potential as an immunotherapy response indicator was assessed, along with its role in pan-cancer. RESULTS: Turquoise module in WGCNA analysis was identified as the hub module associated with lymph node metastasis and CD8 + T cell infiltration. Aberrant elevated LOXL1 expression was observed in CRC and correlated with poorer differentiation status and prognosis. Molecular and immunological characterization found that LOXL1 might mediate epithelial-mesenchymal transition (EMT) process and immunosuppressive phenotypes of CRC. Functional study found that LOXL1 enhanced tumor cell proliferation, migration and invasion. Moreover, high LOXL1 levels corresponded to reduced CD8 + T cell infiltration and predicted poor clinical outcomes of immunotherapy. Similar trends were also observed at the pan-cancer level. CONCLUSIONS: Our findings underscore the critical role of LOXL1 in modulating both malignancy and immunosuppression in CRC. This positions LOXL1 as a promising biomarker for predicting prognosis and the response to immunotherapy in CRC patients.

Catalyst-free MBE growth of PbSnTe nanowires with tunable aspect ratio.

Topological crystalline insulators (TCIs) are interesting for their topological surface states, which hold great promise for scattering-free transport channels and fault-tolerant quantum computing. A promising TCI is SnTe. However, Sn-vacancies form in SnTe, causing a high hole density, hindering topological transport from the surface being measured. This issue could be relieved by using nanowires with a high surface-to-volume ratio. Furthermore, SnTe can be alloyed with Pb reducing the Sn-vacancies while maintaining its topological phase. Here we present the catalyst-free growth of monocrystalline PbSnTe in molecular beam epitaxy. By the addition of a pre-deposition stage before the growth, we have control over the nucleation phase and thereby increase the nanowire yield. This facilitates tuning the nanowire aspect ratio by a factor of four by varying the growth parameters. These results allow us to grow specific morphologies for future transport experiments to probe the topological surface states in a Pb1-xSnxTe-based platform.

Structures, influences, and formation mechanism of planar defects on (100), (001) and (-201) planes in ß-Ga2O3 crystals.

The ß-Ga2O3 crystal is a significant ultrawide bandgap semiconductor with great potential in ultraviolet optoelectronics and high-power devices. Planar defects in ß-Ga2O3 have been observed in experiments, but their structures, influences, formation mechanism, and controlling methods remain to be studied. We conducted a comprehensive study of ß-Ga2O3 planar defects using density functional theory. We determined the atomic structures of planar defects (stacking faults and twins) on (100), (001), and (-201) planes in ß-Ga2O3 crystals and calculated the formation energy and band structure of each defect. Our results indicate that the formation energy of stacking faults on the (100) plane and twins on the (100) and (-201) planes was extremely low, which explained why these planar defects were observed readily. We also studied the influence of common impurities (Si, Sn, Al, H) and vacancies in ß-Ga2O3 crystals on the formation of these planar defects. Our findings revealed that specific impurities and vacancies could facilitate the formation of planar defects or even make them spontaneous. This research provides critical insights into the atomic structures of planar defects in ß-Ga2O3, and explains why they form readily from the perspective of formation energy. These insights are important for future research into ß-Ga2O3 defects.

Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in Alzheimer's disease models.

Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson's disease (PD) by activating autophagy. In this study, we investigated the effect of Cory on AD models in vivo and in vitro. We found that Cory improved learning and memory function, increased neuronal autophagy and lysosomal biogenesis, and reduced pathogenic APP-CTFs levels in 5xFAD mice model. Cory activated TFEB/TFE3 by inhibiting AKT/mTOR signaling and stimulating lysosomal calcium release via transient receptor potential mucolipin 1 (TRPML1). Moreover, we demonstrated that TFEB/TFE3 knockdown abolished Cory-induced APP-CTFs degradation in N2aSwedAPP cells. Our findings suggest that Cory promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in AD models.

The interaction effects of zinc and polygenic risk score with benzo[a]pyrene exposure on lung cancer risk: A prospective case-cohort study among Chinese populations.

The relationship of exposure to benzo[a]pyrene (BaP) with lung cancer risk has been firmly established, but whether this association could be modified by other environmental or genetic factors remains to be explored. To investigate whether and how zinc (Zn) and genetic predisposition modify the association between BaP and lung cancer, we performed a case-cohort study with a 5.4-year median follow-up duration, comprising a representative subcohort of 1399 participants and 359 incident lung cancer cases. The baseline concentrations of benzo[a]pyrene diol epoxide-albumin adduct (BPDE-Alb) and Zn were quantified. We also genotyped the participants and computed the polygenic risk score (PRS) for lung cancer. Our findings indicated that elevated BPDE-Alb and PRS were linked to increased lung cancer risk, with the HR (95%CI) of 1.54 (1.36, 1.74) per SD increment in ln-transformed BPDE-Alb and 1.27 (1.14, 1.41) per SD increment in PRS, but high plasma Zn level was linked to a lower lung cancer risk [HR (95%CI)=0.77 (0.66, 0.91) per SD increment in ln-transformed Zn]. There was evidence of effect modification by Zn on BaP-lung cancer association (P for multiplicative interaction = 0.008). As Zn concentrations increased from the lowest to the highest tertile, the lung cancer risk per SD increment in ln-transformed BPDE-Alb decreased from 2.07 (1.48, 2.89) to 1.33 (0.90, 1.95). Additionally, we observed a significant synergistic interaction of BPDE-Alb and PRS [RERI (95%CI) = 0.85 (0.03, 1.67)], with 42% of the incident lung cancer cases among individuals with high BPDE-Alb and high PRS attributable to their additive effect [AP (95%CI) = 0.42 (0.14, 0.69)]. This study provided the first prospective epidemiological evidence that Zn has protective effect against BaP-induced lung tumorigenesis, whereas high genetic risk can enhance the harmful effect of BaP. These findings may provide novel insight into the environment-environment and environment-gene interaction underlying lung cancer development, which may help to develop prevention and intervention strategies to manage BaP-induced lung cancer.

Cost-effectiveness analysis of mecapegfilgrastim and recombinant human granulocyte stimulating factor for primary prophylaxis of chemotherapy-induced neutropenia in non-small cell lung cancer.

OBJECTIVE: To evaluate the efficacy, safety, and economics of mecapegfilgrastim and recombinant human granulocyte colony-stimulating factor (rhG-CSF) in the primary prevention of chemotherapy-related neutropenia in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Data from 181 patients with NSCLC who received intermediate risk chemotherapy were collected from the information system of a tertiary hospital in China. Patients were categorized into two groups: those treated with mecapegfilgrastim (n = 91) and those treated with rhG-CSF (n = 90). The clinical efficacy rates of neutropenia prevention were used as effect indicators, and a cost-effectiveness analysis was conducted from the perspective of the Chinese healthcare system. Logistic regression, generalized linear regression, and bootstrap methods were used for sensitivity analyses. RESULTS: There was no statistical difference between the mecapegfilgrastim and rhG-CSF groups in clinical efficacy rates (98.9 vs. 97.8%). However, the total cost in the mecapegfilgrastim group was significantly higher than that in the rhG-CSF group (16,341.6 CNY vs. 14,371.1 CNY, p = 0.03). The cost-minimization analysis shows that mecapegfilgrastim is not cost-effective. The sensitivity analyses confirm that these results are robust. CONCLUSION: Compared with rhG-CSF, mecapegfilgrastim is not a cost-effective strategy for NSCLC patients in neutropenia prevention in China.