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In this paper, we study the weak gravitational deflection of relativistic massive particles for a receiver and source at finite distance from the lens in stationary, axisymmetric and asymptotically flat spacetimes. For this purpose, we extend the generalized optical metric method to the generalized Jacobi metric method by using the Jacobi–Maupertuis Randers–Finsler metric. More specifically, we apply the Gauss–Bonnet theorem to the generalized Jacobi metric space and then obtain an expression for calculating the deflection angle, which is related to Gaussian curvature of generalized optical metric and geodesic curvature of particles orbit. In particular, the finite-distance correction to the deflection angle of signal with general velocity in the the Kerr black hole and Teo wormhole spacetimes are considered. Our results cover the previous work of the deflection angle of light, as well as the deflection angle of massive particles in the limit for the receiver and source at infinite distance from the lens object. In Kerr black hole spacetime, we compared the effects due to the black hole spin, the finite-distance of source or receiver, and the relativistic velocity in microlensings and lensing by galaxies. It is found in these cases, the effect of black hole spin is usually a few orders larger than that of the finite-distance and relativistic velocity, while the relative size of the latter two could vary according to the particle velocity, source or observer distance and other lensing parameters.

This paper investigates charged particle deflection in a Kerr spacetime background with a dipole magnetic field, focusing on the equatorial plane and employing the weak field approximation. We employ the Jacobi–Randers metric to unify the treatment of the gravitational and electromagnetic effects on charged particles. Furthermore, we utilize the Gauss–Bonnet theorem to calculate the deflection angle through curvature integrals. The difference between the prograde and retrograde deflection angles is linked to the non-reversibility of metrics and geodesics in Finsler geometry, revealing that this difference can be considered a Finslerian effect. We analyze the impact of both gravitomagnetic field and dipole magnetic field on particle motion and deflection using the Jacobi–Randers magnetic field. The model considered in this paper exhibits interesting features in the second-order approximation of ( M / b ), i.e., the ratio between the spacetime mass and impact parameters. When q μ = 2 M a E , where q , E are the charge and asymptotic energy of the charged particle and μ , a are the dipole magnetic moment and spacetime spin, the Jacobi–Randers metric possesses reversible geodesics, leading to equal prograde and retrograde deflection angles. In this case, the gravitomagnetic field and dipole magnetic field cancel each other out, distinguishing it from scenarios involving only the gravitomagnetic field or the dipole magnetic field. We also explore the magnetic field’s impact on gravitational lensing of charged particles.

Purpose The claudin 18.2 (CLDN18.2) antigen is frequently expressed in malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). Although CLDN18.2-targeted CAR-T cells demonstrated some therapeutic efficacy in PDAC patients, further improvement is needed. One of the major obstacles might be the abundant cancer-associated fibroblasts (CAFs) in the PDAC tumor microenvironment (TME). Targeting fibroblast activation protein (FAP), a vital characteristic of CAFs provides a potential way to overcome this obstacle. In this study, we explored the combined antitumor activity of FAP-targeted and CLDN18.2-targeted CAR-T cells against PDAC. Methods Novel FAP-targeted CAR-T cells were developed. Sequential treatment of FAP-targeted and CLDN18.2-targeted CAR-T cells as well as the corresponding mechanism were explored in immunocompetent mouse models of PDAC. Results The results indicated that the priorly FAP-targeted CAR-T cells infusion could significantly eliminate CAFs and enhance the anti-PDAC efficacy of subsequently CLDN18.2-targeted CAR-T cells in vivo. Interestingly, we observed that FAP-targeted CAR-T cells could suppress the recruitment of myeloid-derived suppressor cells (MDSCs) and promote the survival of CD8 + T cells and CAR-T cells in tumor tissue. Conclusion In summary, our finding demonstrated that FAP-targeted CAR-T cells could increase the antitumor activities of sequential CAR-T therapy via remodeling TME, at least partially through inhibiting MDSCs recruitment. Sequential infusion of FAP-targeted and CLDN18.2-targeted CAR-T cells might be a feasible approach to enhance the clinical outcome of PDAC.

Incorporation of inverted cytokine receptor (ICR) such as interleukin (IL)-4 vs. IL-7 (4/7) ICR is one strategy to improve the antitumor activities of chimeric antigen receptor (CAR) modified T (CAR-T) cells facing immunosuppressive cytokines. Here we report a novel interleukin (IL)-4 vs. IL-21 ICR (4/21 ICR) that enhanced CAR-T cell potency in IL-4 tumor milieu via a different working-mechanism from 4/7 ICR. Upon IL-4 stimulation, 4/21 ICR activated the STAT3 pathway and promoted Th17-like polarization and tumor-targeted cytotoxicity in CAR-T cells . Furthermore, 4/21 ICR-CAR T cells persisted and eradicated established IL-4 tumors . Thus, 4/21 ICR is a promising clinical CAR-T cell therapeutics for solid tumors rich in IL-4.

Cancer immunotherapy has made unprecedented breakthrough in the fields of chimeric antigen receptor-redirected T (CAR T) cell therapy and immune modulation. Combination of CAR modification and the disruption of endogenous inhibitory immune checkpoints on T cells represent a promising immunotherapeutic modality for cancer treatment. However, the potential for the treatment of hepatocellular carcinoma (HCC) has not been explored. In this study, the gene expressing the programmed death 1 receptor (PD-1) on the Glypican-3 (GPC3)-targeted second-generation CAR T cells employing CD28 as the co-stimulatory domain was disrupted using the CRISPR/Cas9 gene-editing system. It was found that, , the CAR T cells with the deficient PD-1 showed the stronger CAR-dependent anti-tumor activity against native programmed death 1 ligand 1-expressing HCC cell PLC/PRF/5 compared with the wild-type CAR T cells, and meanwhile, the CD4 and CD8 subsets, and activation status of CAR T cells were stable with the disruption of endogenous PD-1. Additionally, the disruption of PD-1 could protect the GPC3-CAR T cells from exhaustion when combating with native PD-L1-expressing HCC, as the levels of Akt phosphorylation and anti-apoptotic protein Bcl-xL expression in PD-1 deficient GPC3-CAR T cells were significantly higher than those in wild-type GPC3-CAR T cells after coculturing with PLC/PRF/5. Furthermore, the anti-tumor activity of the CAR T cells with the deficient PD-1 was investigated using the subcutaneous xenograft tumor model established by the injection of PLC/PRF/5 into NOD-scid-IL-2Rγ-/- (NSG) mice. The results indicated that the disruption of PD-1 enhanced the anti-tumor activity of CAR T cells against HCC, improved the persistence and infiltration of CAR T cells in the NSG mice bearing the tumor, and strengthened the inhibition of tumor-related genes expression in the xenograft tumors caused by the GPC3-CAR T cells. This study indicates the enhanced anti-tumor efficacy of PD-1-deficient CAR T cells against HCC and suggests the potential of precision gene editing on the immune checkpoints to enhance the CAR T cell therapies against HCC.

Background Epidermal growth factor receptor (EGFR), a well-known oncogenic driver, contributes to the initiation and progression of a wide range of cancer types. Aberrant lipid metabolism including highly produced monounsaturated fatty acids (MUFA) is recognized as a hallmark of cancer. However, how EGFR regulates MUFA synthesis in cancer remains elusive. This is the focus of our study. Methods The interaction between EGFR and stearoyl-CoA desaturase-1 (SCD1) was detected byco-immunoprecipitation. SCD1 protein expression, stability and phosphorylation were tested by western blot. The synthesis of MUFA was determined by liquid chromatography-mass spectrometry. The growth of lung cancer was detected by CCK-8 assay, Annexin V/PI staining, colony formation assay and subcutaneous xenograft assay. The expression of activated EGFR, phosphorylated and total SCD1 was tested by immunohistochemistry in 90 non-small cell lung cancersamples. The clinical correlations were analyzed by Chi-square test, Kaplan-Meier survival curve analysis and Cox regression. Results EGFR binds to and phosphorylates SCD1 at Y55. Phosphorylation of Y55 is required for maintaining SCD1 protein stability and thus increases MUFA level to facilitate lung cancer growth. Moreover, EGFR-stimulated cancer growth depends on SCD1 activity. Evaluation of non-small cell lung cancersamples reveals a positive correlation among EGFR activation, SCD1 Y55 phosphorylation and SCD1 protein expression. Furthermore, phospho-SCD1 Y55 can serve as an independent prognostic factor for poor patient survival. Conclusions Ourstudy demonstrates that EGFR stabilizes SCD1 through Y55 phosphorylation, thereby up-regulating MUFA synthesis to promote lung cancer growth. Thus, we provide the first evidence that SCD1 can be subtly controlled by tyrosine phosphorylation and uncover a previously unknown direct linkage between oncogenic receptor tyrosine kinase and lipid metabolism in lung cancer. We also propose SCD1 Y55 phosphorylation as a potential diagnostic marker for lung cancer.

Hepatocellular carcinoma (HCC) is currently the fifth most common malignancy and the third leading cause of cancer-related mortalities worldwide. In the last few years, treatments for HCC have significantly improved from a mere surgical resection to a series of minimally invasive therapies and targeted drugs. However, recurrence frequently occurs even upon curative therapeutics, and drug therapies generally produce disappointing results, with the overall prognosis dismal. This challenging clinical scenario warrants new effective and life-prolonging strategies for patients with HCC. Compelling evidence suggests that NK cells play a critical role in the immune function of the liver and in the immune defenses against HCC, indicating that HCC might be an ideal target for NK cell-based immunotherapies. To obtain comprehensive insights into the putative influence of NK cells on HCC, this paper summarizes current knowledge on NK cells in HCC and discusses the usefulness and prospects of NK cell-based immunotherapies. Critical issues that require consideration for the successful clinical translation of NK cell-based therapies are also addressed. If appropriately used and further optimized, NK cell-based therapies could dominate important roles in the future immunotherapeutic market of HCC.

The clinical efficacy of current therapies for Hepatocellular carcinoma (HCC) are unsatisfactory. In recent years, chimeric antigen receptor (CAR) T-cell therapies have been developed for solid tumors including advanced HCC (aHCC), but limited progress has been made. Glypican-3 is a promising immunotherapeutic target for HCC since it is specifically highly expressed in HCC. A previous study indicated that GPC3-targeted CAR T-(CAR-GPC3) cells were well-tolerated and had prolonged survival for HCC patients and that Sorafenib could increase the antitumor activities of CAR-GPC3 T-cells against HCC in mouse models. Here, we report a patient with aHCC who achieved a complete response (CR) and a long survival period after the combination therapy of CAR-GPC3 T-cell plus sorafenib. A 60-year-old Asian male diagnosed with hepatitis B virus (HBV) related HCC developed liver recurrence and lung metastasis after liver tumor resection and trans-arterial chemoembolization therapy. The patient also previously received microwave ablation therapy for lung metastasis. After the enrollment, the patient underwent leukapheresis for CAR-GPC3 T-cells manufacturing. Seven days after leukapheresis, the patient started to receive 400 mg of Sorafenib twice daily. The patient received 4 cycles of CAR-GPC3 T cells (CT011) treatment and each cycle was divided into two infusions. Prior to each cycle of CT011 treatment, lymphodepletion was performed. The lymphodepletion regimen was cyclophosphamide 500 mg/m 2 /day for 2 to 3 days, and fludarabine 20-25 mg/m 2 /day for 3 to 4 days. A total of 4×10 9 CAR-GPC3 T cells were infused. The CT011 plus Sorafenib combination therapy was well tolerated. All the ≥ grade 3 AEs were hematological toxicities which were deemed an expected event caused by the preconditioning regimen. This patient obtained partial responses from the 3 rd month and achieved CR in the 12 th month after the first cycle of CT011 infusion according to the RECIST1.1 assessment. The tumor had no progression for more than 36 months and maintained the CR status for more than 24 months after the first infusion.

Abbreviations HCC hepatocellular carcinoma IVCTT inferior vena cava tumor thrombus CAR Chimeric antigen receptor GPC3 glypican-3 CNLC china liver cancer staging TACE transcatheter arterial chemoembolization MWA microwave ablation GKRS gamma knife radiosurgery AFP alpha-fetoprotein COVID coronavirus disease MRI magnetic resonance imaging LM lymphatic metastasis RECIST response evaluation criteria in solid tumors CTCs circulating tumor cells Dear Editor, Available evidence regarding the most suitable treatment strategies for hepatocellular carcinoma (HCC) with inferior vena cava tumor thrombus (IVCTT) is extremely limited, and the median overall survival time for these patients after liver resection is only 17.76 months [ 1]. Other local or systemic treatments for HCC with IVCTT result in a median overall survival time ranging from 5.88 to 15.36 months [ 1–3]. [...]new therapeutic strategies are urgently needed to improve the survival of HCC patients with IVCTT. [...]despite extensive research, their success in treating solid tumors remains limited, probably due to the immune-suppressive tumor microenvironment and low infiltration of T cells in solid tumors [ 6]. [...]many effects have been made to focus on developing strategies to mitigate tumor antigen heterogeneity and escape immune suppression [ 7–9]. Among them, two patients with IVCTT underwent local therapy to reduce the tumor load prior to CAR T-cell infusion. [...]we report the 5-year follow-up data of the two specific patients in our current manuscript.

Close excavation section spacing, the mutual influence and interpenetration of various processes, and the multiple disturbances of the middle rock pillar in a small clear-distance tunnel pose great difficulty to construction. This study adopted the small clear-distance tunnel of Xiamen Haicang Evacuate Channel as the research object. The tunnel belonged to a small clear-distance tunnel in an urban super large and complex underground interchange hub where complex adjacent small clear-distance tunnels were adopted. ABAQUS was used to analyze the influence of different excavation schemes, lithological grades, and footage lengths for tunnel stability. The deformation and stress characteristics of the tunnel’s surrounding rock and lining structure in different excavation schemes (full section method, bench method, center diaphragm (CD) method, and double wall heading method), lithological grades (III, IV and V), and footage lengths (3 m, 4 m and 5 m) were introduced. The results showed that the double wall heading method could effectively control the horizontal displacement of the hance, and the overall stress state of the lining in the CD and double wall heading methods were reasonable. The vertical displacement of the surface and vault was positively correlated with the elastic modulus of the rock mass. When no temporary support was present in the grade V rock mass, the area from the hance to the arch foot was prone to large deformation. Reducing the footage was beneficial to controlling the deformation of the vault and hance. This study can provide a reference for the on-site construction of small clear-distance tunnels.