The unsatisfactory response rate of immune checkpoint blockade (ICB) immunotherapy severely limits its clinical application as a tumor therapy. Here, we generate a vaccine-based nanosystem by ...integrating siRNA for Cd274 into the commercial human papillomavirus (HPV) L1 (HPV16 L1) protein. This nanosystem has good biosafety and enhances the therapeutic response rate of anti-tumor immunotherapy. The HPV16 L1 protein activates innate immunity through the type I interferon pathway and exhibits an efficient anti-cancer effect when cooperating with ICB therapy. For both resectable and unresectable breast tumors, the nanosystem decreases 71% tumor recurrence and extends progression-free survival by 67%. Most importantly, the nanosystem successfully induces high response rates in various genetically modified breast cancer models with different antigen loads. The strong immune stimulation elicited by this vaccine-based nanosystem might constitute an approach to significantly improve current ICB immunotherapy.
Background
The left-sided and right-sided colon cancer (LCCs and RCCs, respectively) have unique molecular features and clinical heterogeneity. This study aimed to identify the characteristics of ...immune cell infiltration (ICI) subtypes for evaluating prognosis and therapeutic benefits.
Methods
The independent gene datasets, corresponding somatic mutation and clinical information were collected from The Cancer Genome Atlas and Gene Expression Omnibus. The ICI contents were evaluated by “ESTIMATE” and “CIBERSORT.” We performed two computational algorithms to identify the ICI landscape related to prognosis and found the unique infiltration characteristics. Next, principal component analysis was conducted to construct ICI score based on three ICI patterns. We analyzed the correlation between ICI score and tumor mutation burden (TMB), and stratified patients into prognostic-related high- and low- ICI score groups (HSG and LSG, respectively). The role of ICI scores in the prediction of therapeutic benefits was investigated by "pRRophetic" and verified by Immunophenoscores (IPS) (TCIA database) and an independent immunotherapy cohort (IMvigor210). The key genes were preliminary screened by weighted gene co-expression network analysis based on ICI scores. And they were further identified at various levels, including single cell, protein and immunotherapy response. The predictive ability of ICI score for prognosis was also verified in IMvigor210 cohort.
Results
The ICI features with a better prognosis were marked by high plasma cells, dendritic cells and mast cells, low memory CD4
+
T cells, M0 macrophages, M1 macrophages, as well as M2 macrophages. A high ICI score was characterized by an increased TMB and genomic instability related signaling pathways. The prognosis, sensitivities of targeted inhibitors and immunotherapy, IPS and expression of immune checkpoints were significantly different in HSG and LSG. The genes identified by ICI scores and various levels included CA2 and TSPAN1.
Conclusion
The identification of ICI subtypes and ICI scores will help gain insights into the heterogeneity in LCC and RCC, and identify patients probably benefiting from treatments. ICI scores and the key genes could serve as an effective biomarker to predict prognosis and the sensitivity of immunotherapy.
Multi‐modal combination therapy for tumor is expected to have superior therapeutic effect compared with monotherapy. In this study, a super‐small bismuth/copper‐gallic acid coordination polymer ...nanoparticle (BCN) protected by polyvinylpyrrolidone is designed, which is co‐encapsulated with glucose oxidase (GOX) by phospholipid to obtain nanoprobe BCGN@L. It shows that BCN has an average size of 1.8 ± 0.7 nm, and photothermal conversion of BCGN@L is 31.35% for photothermal imaging and photothermal therapy (PTT). During the treatment process of 4T1 tumor‐bearing nude mice, GOX catalyzes glucose in the tumor to generate gluconic acid and hydrogen peroxide (H2O2), which reacts with copper ions (Cu2+) to produce toxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT) and new fresh oxygen (O2) to supply to GOX for further catalysis, preventing tumor hypoxia. These reactions increase glucose depletion for starvation therapy , decrease heat shock protein expression, and enhance tumor sensitivity to low‐temperature PTT. The in vitro and in vivo results demonstrate that the combination of CDT with other treatments produces excellent tumor growth inhibition. Blood biochemistry and histology analysis suggests that the nanoprobe has negligible toxicity. All the positive results reveal that the nanoprobe can be a promising approach for incorporation into multi‐modal anticancer therapy.
A super‐small bismuth/copper‐gallic acid coordination polymer nanoparticle presents good abilities of photothermal‐treatment combined with glucose oxidase for chemodynamic‐starvation therapy in vivo. The ≈2nm Bi and Cu in the depolymerized nanoparticle can be released and flowed through the kidney with the blood. The probe can be used in real‐time monitoring or precision treatment of tumor in vivo through EPR effect.
The role of Fat Mass and Obesity-associated protein （FTO） and its substrate N6-methyladenosine （m6A） in mRNA processing and adipogenesis remains largely unknown. We show that FTO expression and m6A ...levels are inversely correlated during adipogenesis. FTO depletion blocks differentiation and only catalytically active FTO restores adi- pogenesis. Transcriptome analyses in combination with m6A-seq revealed that gene expression and mRNA splicing of grouped genes are regulated by FTO. M6A is enriched in exonic regions flanking 5＇- and 3＇-splice sites, spatially over- lapping with mRNA splicing regulatory serine/arginine-rich （SR） protein exonic splicing enhancer binding regions. Enhanced levels of m6A in response to FTO depletion promotes the RNA binding ability of SRSF2 protein, leading to increased inclusion of target exons. FTO controls exonic splicing of adipogenie regulatory factor RUNX1T1 by regulating m6A levels around splice sites and thereby modulates differentiation. These findings provide compelling evidence that FTO-dependent m6A demethylation functions as a novel regulatory mechanism of RNA processing and plays a critical role in the regulation of adipogenesis.
We propose a one-step scheme for implementing multi-qubit phase gates on microwave photons in multiple resonators mediated by a superconducting bus in circuit quantum electrodynamics (QED) system. In ...the scheme, multiple single-mode resonators carry quantum information with their vacuum and single-photon Fock states, and a multi-level artificial atom acts as a quantum bus which induces the indirect interaction among resonators. The method of pulse engineering is used to shape the coupling strength between resonators and the bus so as to improve the fidelity and robustness of the scheme. We also discuss the influence of finite coherence time for the bus and resonators on gate fidelity respectively. Finally, we consider the suppression of unwanted transitions and propose the method of optimized detuning compensation for offsetting unwanted transitions, showing the feasibility of the scheme within the current experiment technology.
Accurate analysis of microRNAs (miRNAs) at the single-cell level is extremely important for deeply understanding their multiple and intricate biological functions. Despite some advancements in ...analyzing single-cell miRNAs, challenges such as intracellular interferences and insufficient detection limits still remain. In this work, an ultrasensitive nanopore sensor for quantitative single-cell miRNA-155 detection is constructed based on ionic current rectification (ICR) coupled with enzyme-free catalytic hairpin assembly (CHA). Benefiting from the enzyme-free CHA amplification strategy, the detection limit of the nanopore sensor for miRNA-155 reaches 10 fM and the nanopore sensor is more adaptable to complex intracellular environments. With the nanopore sensor, the concentration of miRNA-155 in living single cells is quantified to realize the early diagnosis of triple-negative breast cancer (TNBC). Furthermore, the nanopore sensor can be applied in screening anticancer drugs by tracking the expression level of miRNA-155. This work provides an adaptive and universal method for quantitatively analyzing intracellular miRNAs, which will greatly improve our understanding of cell heterogeneity and provide a more reliable scientific basis for exploring major diseases at the single-cell level.
Cavity optomechanical systems converting quantum state between photons facilitate the development of scalable quantum information processors. The control of state transfer in such systems require ...producing fast and robust transfer to the target state with high fidelity. Shortcuts to adiabaticity (STA) has recently been proved a powerful method for performing fast quantum state conversion in optomechanical systems, which is, however, not robust enough against deviations in control parameters. Here a scheme to realize robust photon state transfer in a universal cavity optomechanical system by combining STA with optimal control technique (OCT) is proposed. Minimizing systematic error sensitivities with adjustable optimization parameters allows to control simultaneously the transfer speed, fidelity, and robustness against errors. Numerical results show that the optimized scheme is insensitive to deviations in optomechanical coupling and frequency detuning over a broad range. The effects of dissipation on the transfer fidelity are also examined for practical implementation of the scheme in realistic scenarios.
A scheme to realize robust photon state transfer in a universal cavity optomechanical system by combining shortcuts to adiabaticity with optimal control technique is proposed. The optimized scheme is insensitive to deviations in optomechanical coupling and frequency detuning over a broad range. The effects of dissipation‐induced decoherence on the transfer fidelity are discussed in detail.
Photothermal therapy directly acting on the nucleus is a potential anti-tumor treatment with higher killing efficiency. However, in practical applications, it is often difficult to achieve precise ...nuclear photothermal therapy because agents are difficult to accurately anchor to the nucleus. Therefore, it is urgent to develop a nanoheater that can accurately locate the nucleus. Here, we designed an amphiphilic arginine-rich dendritic peptide (RDP) with the sequence CRRK(RRCG(Fmoc))
, and prepared a nucleus-targeting nanoplatform RDP/I by encapsulating the photothermal agent IR780 in RDP for precise photothermal therapy of the tumor nucleus. The hydrophobic group Fmoc of the dendritic peptide provides strong hydrophobic force to firmly encapsulate IR780, which improves the solubility and stability of IR780. Moreover, the arginine-rich structure facilitates cellular uptake of RDP/I and endows it with the ability to quickly anchor to the nucleus. The nucleus-targeting nanoplatform RDP/I showed efficient nuclear enrichment ability and a significant tumor inhibition effect.
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