Exploiting tertiary lymphoid structures gene signature to evaluate tumor microenvironment infiltration and immunotherapy response in colorectal cancer.

Background: Tertiary lymphoid structures (TLS) is a particular component of tumor microenvironment (TME). However, its biological mechanisms in colorectal cancer (CRC) have not yet been understood. We desired to reveal the TLS gene signature in CRC and evaluate its role in prognosis and immunotherapy response. Methods: The data was sourced from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Based on TLS-related genes (TRGs), the TLS related subclusters were identified through unsupervised clustering. The TME between subclusters were evaluated by CIBERSORT and xCell. Subsequently, developing a risk model and conducting external validation. Integrating risk score and clinical characteristics to create a comprehensive nomogram. Further analyses were conducted to screen TLS-related hub genes and explore the relationship between hub genes, TME, and biological processes, using random forest analysis, enrichment and variation analysis, and competing endogenous RNA (ceRNA) network analysis. Multiple immunofluorescence (mIF) and immunohistochemistry (IHC) were employed to characterize the existence of TLS and the expression of hub gene. Results: Two subclusters that enriched or depleted in TLS were identified. The two subclusters had distinct prognoses, clinical characteristics, and tumor immune infiltration. We established a TLS-related prognostic risk model including 14 genes and validated its predictive power in two external datasets. The model's AUC values for 1-, 3-, and 5-year overall survival (OS) were 0.704, 0.737, and 0.746. The low-risk group had a superior survival rate, more abundant infiltration of immune cells, lower tumor immune dysfunction and exclusion (TIDE) score, and exhibited better immunotherapy efficacy. In addition, we selected the top important features within the model: VSIG4, SELL and PRRX1. Enrichment analysis showed that the hub genes significantly affected signaling pathways related to TLS and tumor progression. The ceRNA network: PRRX1-miRNA (hsa-miR-20a-5p, hsa-miR-485-5p) -lncRNA has been discovered. Finally, IHC and mIF results confirmed that the expression level of PRRX1 was markedly elevated in the TLS- CRC group. Conclusion: We conducted a study to thoroughly describe TLS gene signature in CRC. The TLS-related risk model was applicable for prognostic prediction and assessment of immunotherapy efficacy. The TLS-hub gene PRRX1, which had the potential to function as an immunomodulatory factor of TLS, could be a therapeutic target for CRC.

Prognostic value of the Naples prognostic score in patients with intrahepatic cholangiocarcinoma after hepatectomy.

BACKGROUND: The Naples Prognostic Score (NPS), integrating inflammatory and nutritional biomarkers, has been reported to be associated with the prognosis of various malignancies, but there is no report on intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the prognostic value of NPS in patients with ICC. METHODS: Patients with ICC after hepatectomy were collected, and divided into three groups. The prognosis factors were determined by Cox regression analysis. Predictive efficacy was evaluated by the time-dependent receiver operating characteristic (ROC) curves. RESULTS: A total of 174 patients were included (Group 1: 33 (19.0%) patients; Group 2: 83 (47.7%) patients; and Group 3: 58 (33.3%) patients). The baseline characteristics showed the higher the NPS, the higher the proportion of patients with cirrhosis and Child-Pugh B, and more advanced tumors. The Kaplan-Meier curves reflect higher NPS were associated with poor survival. Multivariable analysis showed NPS was an independent risk factor of overall survival (NPS group 2 vs. 1: HR = 1.671, 95% CI: 1.022-3.027, p = 0.009; NPS group 3 vs. 1: HR = 2.208, 95% CI: 1.259-4.780, p = 0.007) and recurrence-free survival (NPS group 2 vs. 1: HR = 1.506, 95% CI: 1.184-3.498, p = 0.010; NPS group 3 vs. 1: HR = 2.141, 95% CI: 2.519-4.087, P = 0.001). The time ROC indicated NPS was superior to other models in predicting prognosis. CONCLUSIONS: NPS is a simple and effective tool for predicting the long-term survival of patients with ICC after hepatectomy. Patients with high NPS require close follow-up, and improving NPS may prolong the survival time.

Glutaryl-CoA dehydrogenase suppresses tumor progression and shapes an anti-tumor microenvironment in hepatocellular carcinoma.

BACKGROUND & AIMS: Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation shows decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression. METHODS: Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and the HCC clinical characteristics as well as anti-PD-1 response. Subcutaneous xenograft, orthotopic xenograft, Trp53Δhep/Δhep; MYC- as well as Ctnnboe; METoe- driven mouse models were adopted to validate GCDH effects on HCC suppression. RESULTS: GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDHhigh cells. These cells induced the infiltration of immune cells by the senescence-associated secretory cell phenotype (SASP) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDHlow population was sensitized to anti-programmed cell death protein 1 (PD-1) therapy. CONCLUSION: GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment by SASP. The GCDHlow population is vulnerable to anti-PD-1 therapy because more PD-1+CD8+ T cells are exhibited in GCDHlow population. IMPACT AND IMPLICATIONS: GCDH is a favorable prognostic indicator in liver, lung, and renal cancers. In addition, most of GCDH depletion-induced toxic metabolites originate from the liver, accumulate locally, and cannot cross the blood-brain barrier. Therefore, studies on the correlation between GCDH and liver cancer would contribute to discovering the initiation and progression of hepatocellular carcinoma, of which over 70% of patients occupied >2-fold GCDH downregulation. Given that the GCDHlow and GCDHhigh HCC population can be distinguished based on serum glucose and ammonia levels, it will be worthwhile to evaluate the curative effects of pro-senescent and immune-therapeutic strategies based on the expression levels of GCDH.

Critical Effects of Insoluble Additives in Liquid Electrolytes for Metal Batteries.

Rechargeable metal batteries have received widespread attention due to their high energy density by using pure metal as the anode. However, there are still many fundamental problems that need to be solved before approaching practical applications. The critical ones are low charge/discharge current due to slow ion transport, short cycle lifetime due to poor anode/cathode stability, and unsatisfied battery safety. To tackle these problems, various strategies have been suggested. Among them, electrolyte additive is one of the most widely used strategies. Most of the additives currently studied are soluble, but their reliability is questionable, and they can easily affect the electrochemical process, causing unwanted battery performance decline. On the contrary, insoluble additives with excellent chemical stability, high mechanical strength, and dimensional tunability have attracted considerable research exploration recently. However, there is no timely review on insoluble additives in metal batteries yet. This review summarizes various functions of insoluble additives: ion transport modulation, metal anode protection, cathode amelioration, as well as battery safety enhancement. Future research directions and challenges for insoluble solid additives are also proposed. It is expected this review will stimulate inspiration and arouse extensive studies on further improvement in the overall performance of metal batteries.

Survival benefit from adjuvant TACE combined with Lenvatinib for patients with hepatocellular carcinoma and microvascular invasion after curative hepatectomy.

BACKGROUND AND AIMS: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy is unsatisfactory, especially for those with microvascular invasion (MVI). This study aimed to determine the impact of adjuvant transcatheter arterial chemoembolization (TACE) and Lenvatinib on the prognosis of patients with HCC and MVI after hepatectomy. METHODS: Patients diagnosed with HCC and MVI were reviewed, and stratified into four groups according to adjuvant TACE and/or Lenvatinib. Multivariate Cox regression analyses are used to determine independent risk factors. RESULTS: 346 patients were included, and divided into four groups (Group I, TACE+ Lenvatinib; Group II, Lenvatinib; Group III, TACE; Group IV, without adjuvant therapy). Multivariable analysis showed that compared to Group IV, Group I had the best effect on improving the overall survival (OS, HR 0.321, 95%CI 0.099-0.406, P = 0.001) and recurrence-free survival (RFS, HR 0.319, 95%CI 0.129-0.372, P = 0.001). Additionally, compared with Group II or Group III, Group I also can significantly improve the OS and RFS. There is no significant difference between Group II and Group III in OS and RFS. CONCLUSION: The combination of TACE and Lenvatinib should be considered for anti-recurrence therapy for patients with HCC and MVI after hepatectomy.

SIRT2 promotes base excision repair by transcriptionally activating OGG1 in an ATM/ATR-dependent manner.

Sirtuin 2 (SIRT2) regulates the maintenance of genome integrity by targeting pathways of DNA damage response and homologous recombination repair. However, whether and how SIRT2 promotes base excision repair (BER) remain to be determined. Here, we found that independent of its catalytic activity SIRT2 interacted with the critical glycosylase OGG1 to promote OGG1 recruitment to its own promoter upon oxidative stress, thereby enhancing OGG1 promoter activity and increasing BER efficiency. Further studies revealed that SIRT2 was phosphorylated on S46 and S53 by ATM/ATR upon oxidative stress, and SIRT2 phosphorylation enhanced the SIRT2-OGG1 interaction and mediated the stimulatory effect of SIRT2 on OGG1 promoter activity. We also characterized 37 cancer-derived SIRT2 mutants and found that 5 exhibited the loss of the stimulatory effects on OGG1 transcription. Together, our data reveal that SIRT2 acts as a tumor suppressor by promoting OGG1 transcription and increasing BER efficiency in an ATM/ATR-dependent manner.

Vitamin D levels and olfactory dysfunction in multiple sclerosis patients.

OBJECTIVE: The objective was to explore the possible relationship between the serum vitamin D level and olfactory impairment in a population of multiple sclerosis (MS) patients in Guizhou, China. METHODS: We included 25 patients with MS and 18 healthy controls (HCs) who were recruited from the Affiliated Hospital of Guizhou Medical University from February 2021 to September 2021. The University of Pennsylvania Smell Identification Test (UPSIT) was used to test the patients' sense of smell, and the level of serum 25-hydroxyethylene polyprotein D was measured. RESULTS: Serum vitamin D levels and UPSIT scores were significantly different between the MS group and the control group (both p < 0.001). Moreover, a significant positive correlation emerged between vitamin D levels and UPSIT scores in MS patients (r = 0.537, p = 0.021). CONCLUSIONS: The serum vitamin D level may be involved in the regulation of olfactory dysfunction in MS patients in Guizhou, China.

Multiple sclerosis is a rare disease in China.Compared with that of healthy controls, the olfactory function of MS patients was severely impaired.Compared with healthy controls, MS patients had low vitamin D levels.A significant positive correlation emerged between vitamin D levels and UPSIT scores in MS patients.The vitamin D levels of MS patients may be associated with olfactory impairment, which may have implications for future mechanistic studies.

Efficient detection of Streptococcus pyogenes based on recombinase polymerase amplification and lateral flow strip.

PURPOSE: This article aims to establish a rapid visual method for the detection of Streptococcus pyogenes (GAS) based on recombinase polymerase amplification (RPA) and lateral flow strip (LFS). METHODS: Utilizing speB of GAS as a template, RPA primers were designed, and basic RPA reactions were performed. To reduce the formation of primer dimers, base mismatch was introduced into primers. The probe was designed according to the forward primer, and the RPA-LFS system was established. According to the color results of the reaction system, the optimum reaction temperature and time were determined. Thirteen common clinical standard strains and 14 clinical samples of GAS were used to detect the selectivity of this method. The detection limit of this method was detected by using tenfold gradient dilution of GAS genome as template. One hundred fifty-six clinical samples were collected and compared with qPCR method and culture method. Kappa index and clinical application evaluation of the RPA-LFS were carried out. RESULTS: The enhanced RPA-LFS method demonstrates the ability to complete the amplification process within 6 min at 33 °C. This method exhibits a high analytic sensitivity, with the lowest detection limit of 0.908 ng, and does not exhibit cross-reaction with other pathogenic bacteria. CONCLUSIONS: The utilization of RPA and LFS allows for efficient and rapid testing of GAS, thereby serving as a valuable method for point-of-care testing.

TKT-PARP1 axis induces radioresistance by promoting DNA double-strand break repair in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) stands as the fifth most prevalent malignant tumor on a global scale and presents as the second leading cause of cancer-related mortality. DNA damage-based radiotherapy (RT) plays a pivotal role in the treatment of HCC. Nevertheless, radioresistance remains a primary factor contributing to the failure of radiation therapy in HCC patients. In this study, we investigated the functional role of transketolase (TKT) in the repair of DNA double-strand breaks (DSBs) in HCC. Our research unveiled that TKT is involved in DSB repair, and its depletion significantly reduces both non-homologous end joining (NHEJ) and homologous recombination (HR)-mediated DSB repair. Mechanistically, TKT interacts with PARP1 in a DNA damage-dependent manner. Furthermore, TKT undergoes PARylation by PARP1, resulting in the inhibition of its enzymatic activity, and TKT can enhance the auto-PARylation of PARP1 in response to DSBs in HCC. The depletion of TKT effectively mitigates the radioresistance of HCC, both in vitro and in mouse xenograft models. Moreover, high TKT expression confers resistance of RT in clinical HCC patients, establishing TKT as a marker for assessing the response of HCC patients who received cancer RT. In summary, our findings reveal a novel mechanism by which TKT contributes to the radioresistance of HCC. Overall, we identify the TKT-PARP1 axis as a promising potential therapeutic target for improving RT outcomes in HCC.

Analysis of the Correlation and Prognostic Significance of Tertiary Lymphoid Structures in Breast Cancer: A Radiomics-Clinical Integration Approach.

BACKGROUND: Tertiary lymphoid structures (TLSs) are potential prognostic indicators. Radiomics may help reduce unnecessary invasive operations. PURPOSE: To analyze the association between TLSs and prognosis, and to establish a nomogram model to evaluate the expression of TLSs in breast cancer (BC) patients. STUDY TYPE: Retrospective. POPULATION: Two hundred forty-two patients with localized primary BC (confirmed by surgery) were divided into BC + TLS group (N = 122) and BC - TLS group (N = 120). FIELD STRENGTH/SEQUENCE: 3.0T; Caipirinha-Dixon-TWIST-volume interpolated breath-hold sequence for dynamic contrast-enhanced (DCE) MRI and inversion-recovery turbo spin echo sequence for T2-weighted imaging (T2WI). ASSESSMENT: Three models for differentiating BC + TLS and BC - TLS were developed: 1) a clinical model, 2) a radiomics signature model, and 3) a combined clinical and radiomics (nomogram) model. The overall survival (OS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were compared to evaluate the prognostic value of TLSs. STATISTICAL TESTS: LASSO algorithm and ANOVA were used to select highly correlated features. Clinical relevant variables were identified by multivariable logistic regression. Model performance was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC), and through decision curve analysis (DCA). The Kaplan-Meier method was used to calculate the survival rate. RESULTS: The radiomics signature model (training: AUC 0.766; test: AUC 0.749) and the nomogram model (training: AUC 0.820; test: AUC 0.749) showed better validation performance than the clinical model. DCA showed that the nomogram model had a higher net benefit than the other models. The median follow-up time was 52 months. While there was no significant difference in 3-year OS (P = 0.22) between BC + TLS and BC - TLS patients, there were significant differences in 3-year DFS and 3-year DMFS between the two groups. DATA CONCLUSION: The nomogram model performs well in distinguishing the presence or absence of TLS. BC + TLS patients had higher long-term disease control rates and better prognoses than those without TLS. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma.

BACKGROUND AND AIMS: Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy. APPROACH AND RESULTS: We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies. CONCLUSIONS: We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.

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Tumor-associated tertiary lymphoid structures (TLSs) are ectopic lymphoid formations within tumor tissue, with mainly B and T cell populations forming the organic aggregates. The presence of TLSs in tumors has been strongly associated with patient responsiveness to immunotherapy regimens and improving tumor prognosis. Researchers have been motivated to actively explore TLSs due to their bright clinical application prospects. Various studies have attempted to decipher TLSs regarding their formation mechanism, structural composition, induction generation, predictive markers, and clinical utilization. Meanwhile, the scientific approaches to qualitative and quantitative descriptions are crucial for TLS studies. In terms of detection, hematoxylin and eosin (H&E), multiplex immunohistochemistry (mIHC), multiplex immunofluorescence (mIF), and 12-chemokine gene signature have been the top approved methods. However, no standard methods exist for the quantitative analysis of TLSs, such as absolute TLS count, analysis of TLS constituent cells, structural features, TLS spatial location, density, and maturity. This study reviews the latest research progress on TLS detection and quantification, proposes new directions for TLS assessment, and addresses issues for the quantitative application of TLSs in the clinic.

Plasma metabolomic signatures of breast cancer.

Background: Breast cancer is a common malignant tumor. A large number of medical evidence shows that breast cancer screening can improve the early diagnosis rate and reduce the mortality rate of breast cancer. In the present study, a wide range of targeted metabolomics profiling was conducted to investigate the plasma signatures of breast cancer. Methods: A total of 86 patients with benign breast abnormalities (L group) and 143 patients with breast cancer (E group) were recruited. We collected their plasma samples and clinical information. Metabolomic analysis, based on the coverage of a wide range of targeted metabolomics was conducted with ultraperformance liquid chromatography- triple quadrupole-linear ion trap mass spectrometer (UPLC-QTRAP-MS). Results: We identified 716 metabolites through widely-targeted metabolomics. Serotonergic synapse was the main different metabolic pathway. The fold change of 14 metabolites was considered significantly different (fold change <0.67 or fold change >2; p < 0.05). By combining all the 14 metabolites, we achieved differentiation of L group vs. E group (AUC = 0.792, 95%Cl: 0.662-0.809). Conclusion: This study provided new insights into plasma biomarkers for differential diagnosis of benign abnormalities and breast cancer.

Durable modulation of Zn(002) plane deposition via reproducible zincophilic carbon quantum dots towards low N/P ratio zinc-ion batteries.

Aqueous zinc-ion batteries (ZIBs) are promising candidates for next-generation energy storage systems due to their intrinsic safety, environmental friendliness, and low cost. However, the uncontrollable Zn dendrite growth during cycling is still a critical challenge for the long-term operation of ZIBs, especially under harsh lean-Zn conditions. Herein, we report nitrogen and sulfur-codoped carbon quantum dots (N,S-CDs) as zincophilic electrolyte additives to regulate the Zn deposition behaviors. The N,S-CDs with abundant electronegative groups can attract Zn2+ ions and co-deposit with Zn2+ ions on the anode surface, inducing a parallel orientation of the (002) crystal plane. The deposition of Zn preferentially along the (002) crystal direction fundamentally avoids the formation of Zn dendrites. Moreover, the co-depositing/stripping feature of N,S-CDs under an electric field force ensures the reproducible and long-lasting modulation of the Zn anode stability. Benefiting from these two unique modulation mechanisms, stable cyclability of the thin Zn anodes (10 and 20 µm) at a high depth of discharge (DOD) of 67% and high Zn||Na2V6O16·3H2O (NVO, 11.52 mg cm-2) full-cell energy density (144.98 W h Kg-1) at a record-low negative/positive (N/P) capacity ratio of 1.05 are achieved using the N,S-CDs as an additive in ZnSO4 electrolyte. Our findings not only offer a feasible solution for developing actual high-energy density ZIBs but also provide in-depth insights into the working mechanism of CDs in regulating Zn deposition behaviors.

[Cervical spondylosis of nerve root type with qi stagnation and blood stasis treated with warming needle with different lengths of moxa stick: a randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy on cervical spondylosis of nerve root type with qi stagnation and blood stasis treated with warming needle with different lengths of moxa stick. METHODS: Six hundred patients with cervical spondylosis of nerve root type with qi stagnation and blood stasis were randomly divided into 4 groups: a 4 cm length group (150 cases, 5 cases dropped off, 2 cases suspended), a 3 cm length group (150 cases, 6 cases dropped off, 2 cases suspended), a 2 cm length group (150 cases, 6 cases dropped off), and a routine acupuncture group (150 cases, 6 cases dropped off). Warming needle with moxa stick in the length of 4 cm, 3 cm and 2 cm was delivered in the 4 cm length group, the 3 cm length group and the 2 cm length group, respectively. In the routine acupuncture group, simple acupuncture was applied. The acupoints selected in the above groups included Dazhui (GV 14) and bilateral Jiaji (EX-B 2) of C5 and C7, Fengchi (GB 20), Jianzhen (SI 9), Quchi (LI 11), Zhongzhu (TE 3), etc. In each group, the intervention was delivered once daily and 5 times a week. One course of intervention was composed of 2 weeks and 2 courses were required. The TCM syndrome score, the score of clinical assessment scale for cervical spondylosis (CASCS), the score of the brachial plexus traction test of the affected upper limb, F wave occurrence rate and conduction velocity of the ulnar nerve, the median nerve and the radial nerve of the affected upper limb were compared before and after treatment in the patients of each group. The levels of serum inflammatory factors, i.e. interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and hypersensitive C-reactive protein (hs-CRP), were measured before and after treatment in the patients of each group. The clinical cfficacy was evaluated in the 4 groups. RESULTS: After treatment, the results of TCM syndrome evaluation, i.e. the scores of neck pain, activity limitation and upper limb numbness and pain, as well as the total scores; and the scores of brachial plexus traction test were reduced when compared with those before treatment in each group (P<0.01, P<0.05). The scores of subjective symptoms and adaptability, and the total scores of CASCS were elevated in comparison with those before treatment in each group (P<0.01, P<0.05). In the 4 cm length group, compared with the other 3 groups, the scores of neck pain and activity limitation for TCM syndrome evaluation, and its total score were lower (P<0.05, P<0.01); and the scores of subjective symptoms and adaptability, and the total score of CASCS were higher (P<0.05, P<0.01). The score of the brachial plexus traction test in the 4 cm length group was lower than that of the routine acupuncture group (P<0.05). After treatment, F wave occurrence rates and conduction velocity of median nerve and radial nerve were increased when compared with those before treatment in each group (P<0.05, P<0.01). F wave occurrence rate and conduction velocity of the radial nerve in the 4 cm length group were higher than those of the other 3 groups (P<0.05), and those of the median nerve were higher when compared with the routine acupuncture group (P<0.05). After treatment, the levels of serum IL-1ß, IL-6 and TNF-α were all reduced when compared with those before treatment in each group (P<0.01, P<0.05); the level of serum IL-6 in the 4 cm length group was lower than those of the other 3 groups and serum level of TNF-α was lower compared with that in the routine acupuncture group (P<0.05). The total effective rate of the 4 cm length group was 78.3% (112/143), which was higher when compared with the 3 cm length group (67.6%, 96/142), the 2 cm length group (65.3%, 94/144) and the routine acupuncture group (53.5%, 77/144), respectively (P<0.05). CONCLUSION: Warming needle with moxa stick of 4 cm in length effectively relieves the clinical symptoms of cervical spondylosis of nerve root type with qi stagnation and blood stasis, improves the nerve function of the upper limbs, and reduces the inflammatory responses caused by nerve compression. The clinical efficacy of this therapy with moxa stick of 4 cm in length is superior to the warming needle with moxa sticks of 3 cm and 2 cm, as well as the routine acupuncture.

The cancer-testis lncRNA LINC01977 promotes HCC progression by interacting with RBM39 to prevent Notch2 ubiquitination.

Cancer-testis genes are involved in the occurrence and development of cancer, but the role of cancer-testis-associated lncRNAs (CT-lncRNAs) in hepatocellular carcinoma (HCC) remains to be explored. Here, we discovered a novel CT-lncRNA, LINC01977, based on the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. LINC01977 was exclusively expressed in testes and highly expressed in HCC. High LINC01977 levels correlated with poorer overall survival (OS) in individuals with HCC. Functional assays showed that LINC01977 promoted HCC growth and metastasis in vitro and in vivo. Mechanistically, LINC01977 directly bound to RBM39 to promote the further entry of Notch2 into the nucleus, thereby preventing the ubiquitination and degradation of Notch2. Furthermore, the RNA binding protein IGF2BP2, one of the m6A modification readers, enhanced the stability of LINC01977, resulting in its high level in HCC. Therefore, the data suggest that LINC01977 interacts with RBM39 and promotes the progression of HCC by inhibiting Notch2 ubiquitination and degradation, indicating that LINC01977 may be a potential biomarker and therapeutic target for HCC patients.

Spin-Lattice Coupled Metamagnetism in Frustrated van der Waals Magnet CrOCl.

The long-range magnetic ordering in frustrated magnetic systems is stabilized by coupling magnetic moments to various degrees of freedom, for example, by enhancing magnetic anisotropy via lattice distortion. Here, the unconventional spin-lattice coupled metamagnetic properties of atomically-thin CrOCl, a van der Waals antiferromagnet with inherent magnetic frustration rooted in the staggered square lattice, are reported. Using temperature- and angle-dependent tunneling magnetoconductance (TMC), in complementary with magnetic torque and first-principles calculations, the antiferromagnetic (AFM)-to-ferrimagnetic (FiM) metamagnetic transitions (MTs) of few-layer CrOCl are revealed to be triggered by collective magnetic moment flipping rather than the established spin-flop mechanism, when external magnetic field (H) enforces a lattice reconstruction interlocked with the five-fold periodicity of the FiM phase. The spin-lattice coupled MTs are manifested by drastic jumps in TMC, which show anomalous upshifts at the transition thresholds and persist much higher above the AFM Néel temperature. While the MTs exhibit distinctive triaxial anisotropy, reflecting divergent magnetocrystalline anisotropy of the c-axis AFM ground state, the resulting FiM phase has an a-c easy plane in which the magnetization axis is freely rotated by H. At the 2D limit, such a field-tunable FiM phase may provide unique opportunities to explore exotic emergent phenomena and novel spintronics devices.

Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity.

Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8+ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

Downregulation of miR-221-3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1.

BACKGROUND: Gastric cancer (GC) is an aggressive gastrointestinal tumor. MiRNAs participate in the tumorigenesis of GC. Nevertheless, the function of miR-221-3p in GC remains largely unknown. METHODS: RNA levels were assessed by RT-qPCR. Western blot was performed to test the protein levels. The relation between miR-221-3p and ATF3 was investigated by dual-luciferase reporter assay. ChIP and dual-luciferase reporter assay were applied to assess the interaction between ATF3 and HRD1 or GPX4. Meanwhile, cell proliferation was investigated by CCK8 and colony formation assay. The content of erastin-induced Fe2+ was investigated by iron assay kit. Erastin-induced lipid ROS level was assessed by C11-BODIPY 581/591. Co-immunoprecipitation was used to detect the interaction between HRD1 and ACSL4. In addition, xenograft mice model was established to detect the effect of miR-221-3p in GC. RESULTS: Depletion of miR-221-3p greatly attenuated GC cell proliferation through promoting ferroptosis. Meanwhile, ATF3 was downregulated in GC, and it was identified to be the downstream mRNA of miR-221-3p. MiR-221-3p downregulation could promoted the ferroptosis in GC cells through upregulation of ATF3. HRD1 mediates ubiquitination and degradation of ACSL4 to inhibit ferroptosis. ATF3 upregulation could reduce GC cell proliferation via downregulating the transcription of GPX4 and HRD1. Furthermore, downregulation of miR-221-3p markedly attenuated the growth of GC in mice. CONCLUSION: HRD1 mediates ubiquitination and degradation of ACSL4 to inhibit ferroptosis. MiR-221-3p depletion upregulates the ferroptosis in GC cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1. Our study might provide a novel target for GC treatment.