Observation of Topological Transition in Floquet Non-Hermitian Skin Effects in Silicon Photonics.

Non-Hermitian physics has greatly enriched our understanding of nonequilibrium phenomena and uncovered novel effects such as the non-Hermitian skin effect (NHSE) that has profoundly revolutionized the field. NHSE has been predicted in systems with nonreciprocal couplings which, however, are challenging to realize in experiments. Without nonreciprocal couplings, the NHSE can also emerge in systems with coexisting gauge fields and loss or gain (e.g., in Floquet non-Hermitian systems). However, such Floquet NHSE remains largely unexplored in experiments. Here, we realize the Floquet NHSEs in periodically modulated optical waveguides integrated on a silicon photonic platform. By engineering the artificial gauge fields induced by the periodical modulation, we observe various Floquet NHSE phases and unveil their rich topological transitions. Remarkably, we discover the transitions between the unipolar NHSE phases and an unconventional bipolar NHSE phase, which is accompanied by the directional reversal of the NHSEs. The underlying physics is revealed by the band winding in complex quasienergy space which undergoes a topology change from isolated loops with the same winding to linked loops with opposite windings. Our work unfolds a new route toward Floquet NHSEs originating from the interplay between gauge fields and dissipation effects, and thus offers fundamentally new ways for steering light and other waves.

Bound-Extended Mode Transition in Type-II Synthetic Photonic Weyl Heterostructures.

Photonic structures with Weyl points (WPs), including type I and type II, promise nontrivial surface modes and intriguing light manipulations for their three-dimensional topological bands. While previous studies mainly focus on exploring WPs in a uniform Weyl structure, here we establish Weyl heterostructures (i.e., a nonuniform Weyl lattice) with different rotational orientations in the synthetic dimension by nanostructured photonic waveguides. In this work, we unveil a transition between bound and extended modes on the interface of type-II Weyl heterostructures by tuning their rotational phases, despite the reversed topological order across the interface. This mode transition is also manifested from the total transmission to total reflection at the interface. All of these unconventional effects are attributed to the tilted dispersion of type-II Weyl band structure that can lead to mismatched bands and gaps across the interface. As a comparison, the type-I Weyl heterostructures lack the phase transition due to the untilted band structure. This work establishes a flexible scheme of artificial Weyl heterostructures that opens a new avenue toward high-dimensional topological effects and significantly enhances our capabilities in on-chip light manipulations.

Perfect Excitation of Topological States by Supersymmetric Waveguides.

Topological photonic states provide intriguing strategies for robust light manipulations, however, it remains challenging to perfectly excite these topological eigenstates due to their complicated mode profiles. In this work, we propose to realize the exact eigenmode of the topological edge states by supersymmetric (SUSY) structures. By adiabatically transforming the SUSY partner to its main topological structure, the edge modes can be perfectly excited with simple single-site input. We experimentally verify our strategy in integrated silicon waveguides in telecommunication wavelength, showing a broad working bandwidth. Moreover, a shortcut-to-adiabaticity strategy is further applied to speed up the adiabatic pump process by inverse-design approaches, thus enabling fast mode evolutions and leading to reduced device size. Our method is universal and beneficial to the topology-based or complex eigenmodes systems, ranging from photonics and microwaves to cold atoms and acoustics.

Molecular Self-Assembled Ether-Based Polyrotaxane Solid Electrolyte for Lithium Metal Batteries.

Poly(ethylene oxide) has been widely investigated as a potential separator for solid-state lithium metal batteries. However, its applications were significantly restricted by low ionic conductivity and a narrow electrochemical stability window (<4.0 V vs Li/Li+) at room temperature. Herein, a novel molecular self-assembled ether-based polyrotaxane electrolyte was designed using different functional units and prepared by threading cyclic 18-crown ether-6 (18C6) to linear poly(ethylene glycol) (PEG) via intermolecular hydrogen bond and terminating with hexamethylene diisocyanate trimer (HDIt), which was strongly confirmed by local structure-sensitive solid/liquid-state nuclear magnetic resonance (NMR) techniques. The designed electrolyte has shown an obviously increased room-temperature ionic conductivity of 3.48 × 10-4 S cm-1 compared to 1.12 × 10-5 S cm-1 without assembling polyrotaxane functional units, contributing to the enhanced cycling stability of batteries with both LiFePO4 and LiNi0.8Co0.15Al0.05O2 cathode materials. This advanced molecular self-assembled strategy provides a new paradigm in designing solid polymer electrolytes with demanded performance for lithium metal batteries.

GPC3-IL7-CCL19-CAR-T primes immune microenvironment reconstitution for hepatocellular carcinoma therapy.

BACKGROUND: Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary treatment that has become a mainstay of advanced cancer treatment. Conventional glypican-3 (GPC3)-CAR-T cells have not produced ideal clinical outcomes in advanced hepatocellular carcinoma (HCC), and the mechanism is unclear. This study aims to investigate the clinical utility of novel GPC3-7-19-CAR-T cells constructed by our team and to explore the mechanisms underlying their antitumor effects. METHODS: We engineered a novel GPC3-targeting CAR including an anti-GPC3 scFv, CD3ζ, CD28 and 4-1BB that induces co-expression of IL-7 at a moderate level (500 pg/mL) and CCL19 at a high level (15000 pg /mL) and transduced it into human T cells. In vitro, cell killing efficacy was validated by the xCELLigence RTCA system, LDH nonradioactive cytotoxicity assay and was confirmed in primary HCC organoid models employing a 3D microfluid chip. In vivo, the antitumor capacity was assessed in a humanized NSG mouse xenograft model. Finally, we initiated a phase I clinical trial to evaluate the safety and effect of GPC3-7-19-CAR-T cells in the clinic. RESULTS: GPC3-7-19-CAR-T cells had 1.5-2 times higher killing efficiency than GPC3-CAR-T cells. The tumor formation rates in GPC3-7-19-CAR-T cells treated model were reduced (3/5vs.5/5), and the average tumor volumes were 0.74 cm3 ± 1.17 vs. 0.34 cm3 ± 0.25. Of note, increased proportion of CD4+ TEM and CD8+ TCM cells was infiltrated in GPC3-7-19-CAR-T cells group. GPC3-7-19-CAR-T cells obviously reversed the immunosuppressive tumor microenvironment (TME) by reducing polymorphonuclear (PMN)-myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells infiltration and recruiting more dendritic cells (DCs) to HCC xenograft tumor tissues. In one patient with advanced HCC, GPC3-7-19-CAR-T-cell treatment resulted in tumor reduction 56 days after intravenous infusion. CONCLUSIONS: In conclusion, GPC3-7-19-CAR-T cells achieved antitumor effects superior to those of conventional GPC3-CAR-T cells by reconstructing the TME induced by the dominant CD4+ TEM and CD8+ TCM cell subsets. Most importantly, GPC3-7-19-CAR-T cells exhibited good safety and antitumor efficacy in HCC patients in the clinic. ► Novel GPC3-7-19-CAR-T cells designed with mediate level of IL-7 secretion and high level of CCL19 secretion, which could recruit more mature DCs to assist killing on GPC3+HCCs. ►DC cells recruited by CCL19 could interact with CD4+ T cells and promote the differentiation of CD4+TEFF cells into CD4+TEM and CD8+TCM subsets, leading a better anti-tumor effect on GPC3+HCCs. ►Compared with conventional GPC3-CAR-T, GPC3-7-CCL19-CAR-T cells could reverse tumor immunosuppressive microenvironment by reducing PMN-MDSC and Treg cell infiltration.

Anomalous π modes by Floquet engineering in optical lattices with long-range coupling.

Photonic Floquet topological insulators provide a powerful tool to manipulate the optical fields, which have been extensively studied with only nearest-neighbor coupling. Here, we demonstrate that nontrivial Floquet topological phase and photonic π modes are brought from long-range coupling in a one-dimensional periodically driven optical lattice. Interestingly, the long-range coupling is found to give rise to new Floquet π modes that do not exist in the traditional Floquet lattices. We interpret the underlying physics by analyzing the replica bands, which shows quasienergies band crossing and reopening of new nontrivial π gaps due to the long-range coupling. Our results provide a new route in manipulating optical topological modes by Floquet engineering with long-range coupling.

Simulation Method for Blockchain Systems with a Public Chain.

The potential security problems of blockchain technology are constantly restricting the development process of related industrial applications. The cost of deploying a blockchain system in a real environment to conduct research on security issues is relatively high, and the related security analysis and verification are also destructive and irreproducible. Therefore, based on the idea of layered design, this paper proposes a blockchain system simulation platform. The blockchain system is divided into four layers in the simulation platform: the consensus layer, network layer, contract layer, and storage layer. In the consensus layer, the problem of computing resource waste is solved. In the network layer, a peer-to-peer network topology simulation is implemented. In the storage layer, the problem of redundant storage is solved. In the contract layer, the contract replay speed is accelerated. Finally, a prototype of an efficient blockchain simulation system is implemented based on the above methods.

A Generic View Planning System Based on Formal Expression of Perception Tasks.

View planning (VP) is a technique that guides the adjustment of the sensor's postures in multi-view perception tasks. It converts the perception process into active perception, which improves the intelligence and reduces the resource consumption of the robot. We propose a generic VP system for multiple kinds of visual perception. The VP system is built on the basis of the formal description of the visual task, and the next best view is calculated by the system. When dealing with a given visual task, we can simply update its description as the input of the VP system, and obtain the defined best view in real time. Formal description of the perception task includes the task's status, the objects' prior information library, the visual representation status and the optimization goal. The task's status and the visual representation status are updated when data are received at a new view. If the task's status has not reached its goal, candidate views are sorted based on the updated visual representation status, and the next best view that can minimize the entropy of the model space is chosen as the output of the VP system. Experiments of view planning for 3D recognition and reconstruction tasks are conducted, and the result shows that our algorithm has good performance on different tasks.

Poor clinical outcomes and immunoevasive contexture in interleukin-9 abundant muscle-invasive bladder cancer.

Chemotherapy and immunotherapy yield survival benefits for muscle-invasive bladder cancer (MIBC) patients, in which tumor microenvironment has been found to exert crucial roles through tipping the balance between antitumor immunity and immune evasion. Our study aims to explore the clinical significance and therapeutic role of intratumoral interleukin-9-producing cells (IL-9+ cells) in MIBC. Two hundred fifty-nine MIBC patients from two independent clinic centers were utilized for retrospective analysis in the study. Sixty-five fresh MIBC tumor tissues were used to evaluate the infiltration and function of immune cells via flow cytometry and ex vivo intervention experiments. Three hundred ninety-one MIBC patients of The Cancer Genome Atlas were applied for bioinformatics analysis. It was found that patients with high IL-9+ cells infiltration had worse overall survival and relapse-free survival. pT2 patients with low IL-9+ cells infiltration could benefit more from adjuvant chemotherapy (ACT). IL-9+ cells infiltration was correlated with decreased expression of granzyme B from CD8+ T cells and natural killer (NK) cells and perforin from CD8+ T cells, while blockade of IL-9 reactivated the antitumor capacity of both cells leading to tumor regression. Furthermore, IL-9+ cells infiltration could be a biomarker for predicting anti-PD-1 efficacy. In conclusion, IL-9+ cells infiltration could be applied as an independent prognosticator for clinical outcome and ACT/anti-PD-1 effectiveness. IL-9+ cells infiltration diminished the cytotoxicity of CD8+ T cells and NK cells resulting in tumor immune evasion, and thus targeting IL-9 could be a potential therapeutic strategy for MIBC.

Tumor-infiltrating CD39+CD8+ T cells determine poor prognosis and immune evasion in clear cell renal cell carcinoma patients.

PURPOSE: Tumor microenvironment is important in the progression of clear cell renal cell carcinoma (ccRCC), and its prognostic value is still unclear. Recent reports demonstrated tumor-infiltrating CD39+CD8+ T cells are abundant, but their function remains obscure. We aim to assess clinical value of CD39+CD8+ T cells and seek a potential therapeutic target in ccRCC. EXPERIMENTAL DESIGN: We immunohistochemically evaluated clinical value of CD39+CD8+ T cells in a retrospective Zhongshan Hospital cohort of 243 ccRCC patients. Fresh tumor samples (n = 48), non-tumor tissues and peripheral blood for flow cytometry analyses were collected to analyze immune cell functions from Zhongshan Hospital. The survival benefit of tyrosine kinase inhibitors (TKIs) in this subpopulation was evaluated. Kaplan-Meier analysis and COX regression model were applied for survival analyses. Bioinformatics analysis performed in TCGA KIRC cohort and the scRNA-seq cohort. RESULTS: We found that accumulation of CD39+CD8+ T cells indicated poor prognosis (p < 0.0001) and indicated therapeutic benefit of TKIs therapy (p = 0.015). CD39+CD8+ T cells showed decreased TNF-α and IFN-γ with elevated PD-1 and TIM-3 expression. Further analysis of tumor-infiltrating immune cell landscape in the ccRCC revealed the positive correlation between CD39+CD8+ T cells and Tregs (p = 0.037) and M2-polarized macrophages (p < 0.0001). Finally, inhibition of CD39 partially restores the anti-tumor function of CD8+ T cells. CONCLUSIONS: High CD39+CD8+ T cells indicated poor prognosis in ccRCC, due to impaired anti-tumor function of CD39+CD8+ T cells and indicated therapeutic benefit of TKIs therapy.

Analysis of HBsAg mutations in the 25 years after the implementation of the hepatitis B vaccination plan in China.

Since 1992, China has promoted hepatitis B vaccination. Concurrently, during this period, increasing use of immunoglobulins and nucleoside analogues might have exerted selective pressure on the hepatitis B virus (HBV) S gene, driving mutations in the HBsAg and changed the subtype. Using the National Center for Biotechnology Information database, we obtained gene sequence information for HBV strains from China and analysed changes in HBsAg subtypes and substitution mutations in HBsAg in 5-year intervals over 25 years to identify potential challenges to the prevention and treatment of hepatitis B. Most HBV sequences from China were genotype C (1996/2833, 70.46%) or B (706/2833, 24.92%). During the implementation of hepatitis B vaccination (recombinant hepatitis B vaccine was subgenotype A2 and HBsAg subtype adw2), the proportion of subtypes ayw1 and adw3 in genotype B and ayw2 in genotype C increased over the programme period. The overall mutation rate in HBsAg tended to decrease for genotype B, whereas, for genotype C, the rate increased gradually and then decreased slightly. Moreover, the mutation rate at some HBsAg amino acid sites (such as sG145 of genotype B and sG130 and sK141 of genotype C) is gradually increasing. HBV strains with internal stop codons of HBsAg (e.g., sC69*) and additional N-glycosylation (e.g., sG130N) mutations should be studied extensively to prevent them from becoming dominant circulating strains. The development of HBV vaccines and antiviral immunoglobulins and use of antiviral drugs may require making corresponding changes.

Tumor infiltrating mast cells determine oncogenic HIF-2α-conferred immune evasion in clear cell renal cell carcinoma.

PURPOSE: Hypoxia-inducible factor 2α (HIF-2α) overexpression leads to activation of angiogenic pathways. However, little is known about the association between HIF-2α expression and anti-tumor immunity in clear cell renal cell carcinoma (ccRCC). We aimed to explore how HIF-2α influenced the microenvironment and the underlying mechanisms. EXPERIMENTAL DESIGN: We immunohistochemically evaluated immune cells infiltrations and prognostic value of HIF-2α expression in a retrospective Zhongshan Hospital cohort of 280 ccRCC patients. Fresh tumor samples, non-tumor tissues and autologous peripheral blood for RT-PCR, ELISA and flow cytometry analyses were collected from patients who underwent nephrectomy in Zhongshan Hospital from September 2017 to April 2018. The TCGA KIRC cohort and SATO cohort were assessed to support our findings. RESULTS: We demonstrated that ccRCC patients with HIF-2αhigh tumors exhibited reduced overall survival (p = 0.025) and recurrence-free survival (p < 0.001). Functions of CD8+ T cells were impaired in HIF-2αhigh patients. In ccRCC patients, HIF-2α induced the expression of stem cell factor (SCF), which served as chemoattractant for mast cells. Tumor infiltrating mast cells impaired anti-tumor immunity partly by secreting IL-10 and TGF-ß. HIF-2α mRNA level adversely associated with immunostimulatory genes expression in KIRC and SATO cohorts. CONCLUSIONS: HIF-2α contributed to evasion of anti-tumor immunity via SCF secretion and subsequent recruitment of mast cells in ccRCC patients.

Plasma MicroRNA-34a as a Potential Biomarker for Early Diagnosis of Esophageal Cancer.

BACKGROUND: Esophageal cancer (EC) is one of the cancers with high morbidity and mortality in the world. The dysregulation of microRNAs (miRNAs) would affect the development of cancers, which can be used as potential and non-invasive diagnostic marker. miRNA-34a is a tumor suppressor which inhibits EC cell migration and invasion. However, the clinical significance of circulating miRNA-34a remains undiscovered. In this study, we did a preliminary study of plasma miRNA-34a as a potential biomarker for esophageal cancer diagnosis. METHODS: The relationship was analyzed between the expression of microRNA-34a with RT-qPCR in three different cohorts which were collected from patients with 101 esophageal cancers, 31 benign disease and 97 healthy controls. RESULTS: The expression level of plasma miR-34a was upregulated in esophageal cancer. The panel of miR-34a and Cyfra 21-1 had great diagnostic efficiency for the EC patients, the logistic regression model was Y = 0.97*miR-34a + 1.02* Cyfra21-1 - 2.85. The AUC was 0.7981 if the cutoff was 0. 5782. The sensitivity and the specificity were 60.40% and 89.69%, respectively. The sensitivity of miR-34a for the EC patients with stage Tis + I + II was 66.47% and specificity was 60.42%. CONCLUSIONS: Plasma miR-34a may serve as a potential biomarker in detecting early stages of the EC.

Dual-NMS: A Method for Autonomously Removing False Detection Boxes from Aerial Image Object Detection Results.

In the field of aerial image object detection based on deep learning, it's difficult to extract features because the images are obtained from a top-down perspective. Therefore, there are numerous false detection boxes. The existing post-processing methods mainly remove overlapped detection boxes, but it's hard to eliminate false detection boxes. The proposed dual non-maximum suppression (dual-NMS) combines the density of detection boxes that are generated for each detected object with the corresponding classification confidence to autonomously remove the false detection boxes. With the dual-NMS as a post-processing method, the precision is greatly improved under the premise of keeping recall unchanged. In vehicle detection in aerial imagery (VEDAI) and dataset for object detection in aerial images (DOTA) datasets, the removal rate of false detection boxes is over 50%. Additionally, according to the characteristics of aerial images, the correlation calculation layer for feature channel separation and the dilated convolution guidance structure are proposed to enhance the feature extraction ability of the network, and these structures constitute the correlation network (CorrNet). Compared with you only look once (YOLOv3), the mean average precision (mAP) of the CorrNet for DOTA increased by 9.78%. Commingled with dual-NMS, the detection effect in aerial images is significantly improved.

Evaluation of Tumor Pseudocapsule Status and its Prognostic Significance in Renal Cell Carcinoma.

PURPOSE: We determined whether tumor pseudocapsule status, including the extent of invasion by cancer and lack of a pseudocapsule, has prognostic value in renal cell carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the records of 1,577 patients with different stages of renal cell carcinoma who underwent nephrectomy at our institution, of whom 1,307 (82.9%) were eligible for analysis. Presented pseudocapsules were classified as grade 0-completely intact, grade 1-merely involved and grade 2-penetrated. We studied overall and progression-free survival using the Kaplan-Meier method and a Cox regression model. RESULTS: Of the 1,307 patients 1,244 (95.2%) presented with a pseudocapsule, including 350 (28.1%), 643 (51.7%) and 251 (20.2%) with a grade 0, 1 and 2 pseudocapsule invasion extent, respectively. Kaplan-Meier curves revealed great losses in overall and progression-free survival for an increased extent of invasion and pseudocapsule absence. On multivariate analyses we identified significant overall and progression-free survival harms for grade 2 pseudocapsules (HR 2.12 and 2.66, each p <0.0001) and lack of a pseudocapsule (HR 1.95, p = 0.0248 and HR 2.54, p = 0.0007, respectively) compared to grade 0 pseudocapsules. A change in statistical risk from grade 1 to 0 was only detected for progression-free survival. The prognostic value of pseudocapsule status was shown by a higher HR on multivariable analyses in individuals with localized renal cell carcinoma. CONCLUSIONS: Our findings suggest that pseudocapsule status has good prognostic implications in renal cell carcinoma. Lack of a pseudocapsule certainly had a remarkably adverse impact on the patient outcome. Accessibility in use and cost makes pseudocapsule status a potential cost-effective parameter in clinical practice.

Performance evaluation of a chemiluminescence microparticle immunoassay for CK-MB.

BACKGROUND: To verify and evaluate the performance characteristics of a creatine kinase phosphokinase isoenzymes MB (CK-MB) assay kit, which produced by Xiamen Innodx Biotech Co. Ltd. METHODS: Evaluation was carried out according to "Guidelines for principle of analysis performance evaluation of in vitro diagnostic reagent." The performance parameters included detection limit, linearity range, reportable range, recovery test, precision verification, interference test, cross-reactivity, matrix effect, and method comparison. RESULTS: The detection limit was 0.1 ng/mL. The assay had clinical linearity over range of 0.1 ng/mL-500 ng/mL. Reportable range was from 0.1 ng/mL to 1000 ng/mL. The average percent of recovery was 99.66%. The coefficient of variation (CV) for within-run and between-run of low CK-MB sample was 5.55% and 6.16%, respectively. As for high-level sample, it was 7.88% and 7.80%. In medical decision level, the relative deviation (Bias) of all interference tests was lower than 15%. When the sample had mild-hemolysis; hemoglobin ≤15 g/L; triglyceride ≤17 mmol/L; bilirubin ≤427.5 µmol/L; rheumatoid factor ≤206U/mL, there was no significant interference to be found. Moreover, assay kit had no cross-reaction with CK-MM and CK-BB. At last, total diagnostic accuracy of kit was 93.24%, when compared with refer kit. CONCLUSION: Overall the results of the verification study indicated the performance of kit is met the requirements of the clinical test.

Optimization on theBuried Depth of Subsurface Drainage under Greenhouse Condition Based on Entropy Evaluation Method.

Numerous indicators under the plant-soil system should be taken into consideration when developing an appropriate agricultural water conservancy project. Entropy evaluation method offers excellent prospects in optimizing agricultural management schemes. To investigate the impact of different buried depths (30, 45, 60, 75, 90, and 105 cm) of subsurface drainage pipes on greenhouse plant-soil systems, the tomato was employed as plant material, and the marketable yield, fruit sugar to acid ratio, soil electrical conductivity, nitrogen loss rate, as well as crop water and fertilizer use efficiency were observed. Based on these indicators, the entropy evaluation method was used to select the optimal buried depth of subsurface drainage pipes. Both the calculation results of objective and subjective weights indicated that tomato yield and soil electrical conductivity were relatively more crucial than other indexes, and their comprehensive weights were 0.43 and 0.34, respectively. The 45 cm buried depth possessed the optimal comprehensive benefits, with entropy evaluation value of 0.94. Under 45 cm buried depth, the loss rate of soil available nitrogen was 13.9%, the decrease rate of soil salinity was 49.2%, and the tomato yield, sugar to acid ratio, nitrogen use efficiency, and water use efficiency were 112 kg·ha-1, 8.3, 39.7%, and 42.0%, respectively.

NIR-triggered NO production combined with photodynamic therapy for tumor treatment.

Photodynamic therapy (PDT), as one of the most promising cancer therapy methods, is still limited by several drawbacks, such as tissue hypoxia and shallow light penetration of blue-violet light (200-450 nm), and red light (750 nm) is more penetrating to tissues than blue-violet light, but still lower than near-red light (750-1350 nm). Therefore, we proposed a synergistic therapy system by combining the near-infrared light-triggered PDT with nitric oxide (NO)-based gas therapy to enhance the anti-tumor effects. Upconversion nanoparticles (UCNPs) were loaded with the photosensitizers of ZnPc and the NO donors of l-arginine (L-Arg) to obtain the nanocomposites of UCN@mSiO2@ZnPc@L-Arg. Under 980 nm laser irradiation, reactive oxygen species (ROS) could be produced for PDT and react with l-Arg to produce NO, which is previously reported to have a greater killing effect on tumor cells than ROS and also plays an important role in promoting PDT in our study. Both the in vitro and in vivo tests demonstrated that the combined therapy of PDT with NO therapy could enhance the tumor killing effect significantly compared with the unique application of PDT. The UCNPs-based nanocomposites are expected to be widely used in biomedicine for tumor inhibition.

Tumor infiltrating B lymphocytes (TIBs) associate with poor clinical outcomes, unfavorable therapeutic benefit and immunosuppressive context in metastatic clear cell renal cell carcinoma (mccRCC) patients treated with anti-PD-1 antibody plus Axitinib.

PURPOSE: Immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) has become first-line therapy for metastatic renal cell carcinoma patients. This study aims to investigate the effect of tumor infiltrating B lymphocytes (TIBs) on the combination therapy. METHODS: The retrospective analysis was conducted on the clinical records of 115 metastatic clear cell renal cell carcinoma (mccRCC) patients treated with anti-PD-1 antibody plus Axitinib between March 2020 and June 2023. Observation target: objective response rate (ORR), and overall survival (OS), progression-free survival (PFS) and immune profile. RESULTS: Patients with high TIBs portended lower ORR of the combination therapy (p = 0.033). TIBs was an independent predictor for poorer OS (p = 0.013) and PFS (p = 0.021) in mccRCC patients with combination treatment. TIBs infiltration was associated with more CD4+T (p < 0.001), CD8+T (p < 0.001), M2 macrophages (p = 0.020) and regulatory T cells (Tregs) (p = 0.004). In TIBs high patients, the percentages of PD-1, CTLA-4 and TIM-3 positive rate were significantly increased in CD4+T (p = 0.038, 0.029 and 0.002 respectively) and CD8+T cells (p = 0.006, 0.026 and < 0.001 respectively). CONCLUSIONS: Our study revealed TIBs infiltration predicted adverse outcomes in mccRCC patients treated with anti-PD-1 antibody plus Axitinib. As a corollary, TIBs positively associated with M2 macrophages and Tregs, leading to subsequent multiple immune checkpoints related exhaustion of T cells. Thus, only PD-1 blockade are inadequate to reverse T cells exhaustion effectively in high TIBs mccRCC patients.

Programmable activation of berbamine and photosensitizers for enhanced photodynamic therapy using emission-switchable upconversion nanoparticles.

Photodynamic therapy (PDT) shows great potential in precision tumor treatment. However, its efficacy is inhibited by the antioxidant defense capacities of tumor cells. To address this challenge, a near-infrared light-controlled nanosystem (UCNPs@mSiO2@Azo@ZnPc&BBM, PB@UA) was developed using emission-switchable upconversion nanoparticles (UCNPs) to independently and precisely control the release of berbamine (BBM) and activation of photosensitizer for enhanced PDT in deep tissues. Firstly, BBM release was triggered by exciting PB@UA at 980 nm. The BBM could inhibit the activities of antioxidant enzymes and disrupt calcium ion regulation, making the tumor cells more susceptible to ROS-induced cell death in the following PDT treatment. The PDT was initiated by irradiating the photosensitizers of ZnPc on PB@UA at 808 nm and achieved a tumor inhibition rate of 80.91 % in vivo, which is significantly higher than that of unique PDT (31.78 %) or BBM (11.29 %) treatment and demonstrates the potential of our strategy for improved cancer treatment.