A convenient protonated strategy for constructing nanodrugs from hydrophobic drug-inhibitor conjugates to reverse tumor multidrug resistance.

Combination therapy has proven effective in counteracting tumor multidrug resistance (MDR). However, the pharmacokinetic differences among various drugs and inherent water insolubility for most small molecule agents greatly hinder their synergistic effects, which makes the delivery of drugs for combination therapy in vivo a key problem. Herein, we propose a protonated strategy to transform a water-insoluble small molecule drug-inhibitor conjugate into an amphiphilic one, which then self-assembles into nanoparticles for co-delivery in vivo to overcome tumor MDR. Specifically, paclitaxel (PTX) is first coupled with a third-generation P-glycoprotein (P-gp) inhibitor zosuquidar (Zos) through a glutathione (GSH)-responsive disulfide bond to produce a hydrophobic drug-inhibitor conjugate (PTX-ss-Zos). Subsequently treated with hydrochloric acid ethanol solution (HCl/EtOH), PTX-ss-Zos is transformed into the amphiphilic protonated precursor and then forms nanoparticles (PTX-ss-Zos@HCl NPs) in water by molecular self-assembly. PTX-ss-Zos@HCl NPs can be administered intravenously and accumulated specifically at tumor sites. Once internalized by cancer cells, PTX-ss-Zos@HCl NPs can be degraded under the overexpressed GSH to release PTX and Zos simultaneously, which synergistically reverse tumor MDR and inhibit tumor growth. This offers a promising strategy to develop small molecule self-assembled nanoagents to reverse tumor MDR in combination therapy.

Unveiling intratumoral microbiota: an emerging force for colorectal cancer diagnosis and therapy.

Microbes, including bacteria, viruses, fungi, and other eukaryotic organisms, are commonly present in multiple organs of the human body and contribute significantly to both physiological and pathological processes. Nowadays, the development of sequencing technology has revealed the presence and composition of the intratumoral microbiota, which includes Fusobacterium, Bifidobacteria, and Bacteroides, and has shed light on the significant involvement in the progression of colorectal cancer (CRC). Here, we summarized the current understanding of the intratumoral microbiota in CRC and outline the potential translational and clinical applications in the diagnosis, prevention, and treatment of CRC. We focused on reviewing the development of microbial therapies targeting the intratumoral microbiota to improve the efficacy and safety of chemotherapy and immunotherapy for CRC and to identify biomarkers for the diagnosis and prognosis of CRC. Finally, we emphasized the obstacles and potential solutions to translating the knowledge of the intratumoral microbiota into clinical practice.

Recent advances of ultrasound-responsive nanosystems in tumor immunotherapy.

Immunotherapy has revolutionized cancer treatment by boosting the immune system and preventing disease escape mechanisms. Despite its potential, challenges like limited response rates and adverse immune effects impede its widespread clinical adoption. Ultrasound (US), known for its safety and effectiveness in tumor diagnosis and therapy, has been shown to significantly enhance immunotherapy when used with nanosystems. High-intensity focused ultrasound (HIFU) can obliterate tumor cells and elicit immune reactions through the creation of immunogenic debris. Low-intensity focused ultrasound (LIFU) bolsters tumor immunosuppression and mitigates metastasis risk by concentrating dendritic cells. Ultrasonic cavitation (UC) produces microbubbles that can transport immune enhancers directly, thus strengthening the immune response and therapeutic impact. Sonodynamic therapy (SDT) merges nanotechnology with immunotherapy, using specialized sonosensitizers to kill cancer cells and stimulate immune responses, increasing treatment success. This review discusses the integration of ultrasound-responsive nanosystems in tumor immunotherapy, exploring future opportunities and current hurdles.

Rapamycin inhibits B16 melanoma cell viability invitro and invivo by inducing autophagy and inhibiting the mTOR/p70­S6k pathway.

Rapamycin is an immunosuppressant that has been shown to prevent tumor growth following organ transplantation. However, its exact mode of antitumor action remains unknown. The present study used the B16-F10 (B16) murine melanoma model to explore the antitumor mechanism of rapamycin, and it was revealed that rapamycin reduced B16 cell viability in vitro and in vivo. In addition, in vitro and in vivo, the results of western blotting showed that rapamycin reduced Bcl2 expression, and enhanced the protein expression levels of cleaved caspase 3 and Bax, indicating that it can induce the apoptosis of B16 melanoma cells. Furthermore, the results of cell cycle analysis and western blotting showed that rapamycin induced B16 cell cycle arrest in the G1 phase, based on the reduction in the protein expression levels of CDK1, cyclin D1 and CDK4, as well as the increase in the percentage of cells in G1 phase. Rapamycin also significantly increased the number of autophagosomes in B16 melanoma cells, as determined by transmission electron microscopy. Furthermore, the results of RT-qPCR and western blotting showed that rapamycin upregulated the protein expression levels of microtubule-associated protein light chain 3 (LC3) and Beclin-1, while downregulating the expression of p62 in vitro and in vivo, thus indicating that rapamycin could trigger cellular autophagy. The present study revealed that rapamycin in combination with chloroquine (CQ) further increased LC3 expression compared with that in the CQ group, suggesting that rapamycin induced an increase in autophagy in B16 cells. Furthermore, the results of western blotting showed that rapamycin blocked the phosphorylation of p70 ribosomal S6 kinase (p70-S6k) and mammalian target of rapamycin (mTOR) proteins in vitro and in vivo, thus suggesting that rapamycin may exert its antitumor effect by inhibiting the phosphorylation of the mTOR/p70-S6k pathway. In conclusion, rapamycin may inhibit tumor growth by inducing cellular G1 phase arrest and apoptosis. In addition, rapamycin may exert its antitumor effects by inducing the autophagy of B16 melanoma cells in vitro and in vivo, and the mTOR/p70-S6k signaling pathway may be involved in this process.

Analysis of East Asia subgroup in Study 309/KEYNOTE-775: lenvatinib plus pembrolizumab versus treatment of physician's choice chemotherapy in patients with previously treated advanced or recurrent endometrial cancer.

OBJECTIVE: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician's choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. METHODS: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. RESULTS: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1-43.0) months. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49-1.10) and 0.64 (0.44-0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45-1.02) and 0.61 (0.41-0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3-5, 74% and 72%), respectively. CONCLUSION: Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03517449.

Application of a long short-term memory neural network algorithm fused with Kalman filter in UWB indoor positioning.

Ultra-wideband technology has good anti-interference capabilities and development prospects in indoor positioning. Since ultra-wideband will be affected by random errors in indoor positioning, to exploit the advantages of the Kalman filter (KF) and the long short-term memory (LSTM) network, this paper proposes a long short-term memory neural network algorithm fused with the Kalman filter (KF-LSTM) to improve UWB positioning. First, the ultra-wideband data is processed through KF to weaken the noise in the data, and then the data is fed into the LSTM network for training, and the capability of the LSTM network to process time series features is employed to obtain more accurate label positions. Finally, simulation and measurement results show that the KF-LSTM algorithm achieves 71.31%, 37.28%, and 49.31% higher average positioning accuracy than the back propagation (BP) network, (back propagation network fused with the Kalman filter (KF-BP), and LSTM network algorithms, respectively, and the KF-LSTM algorithm performs more stably. Meanwhile, the more noise the data contains, the more obvious the stability contrast between the four algorithms.

Front-line chemoimmunotherapy for treating epithelial ovarian cancer: Part II promising results of phase 2 study of paclitaxel-carboplatin-oregovomab regimen.

In the Part I, we have discussed the background of CA125 and the development of anti-CA125 monoclonal antibody (MAb) to highlight the potential role of CA125 and anti-CA125 MAb in the management of women with advanced stage epithelial ovarian cancer (EOC). Glycosylation change either by N-link or by O-link of CA125 is supposed to play a role in the modification of immunity. Anti-CA125 MAb, which can be classified as OC 125-like Abs, M11-like Abs, and OV197-like Abs, is often used for diagnosing, screening, monitoring and detecting the mesothelin-related diseases of the abdominal cavity, particular for those women with EOC. Additionally, anti-CA125 MAb also plays a therapeutic role, named as OvaRex MAb-B43.13 (oregovomab), which has also been extensively reviewed in the Part I review article. The main mechanisms include (a) forming CA125 immune complexes to activate the antigen-presenting cells; (b) triggering induction of CA125-specific immune responses, including anti-CA125 Abs against various epitopes and CA125-specific B and T cell responses; and (c) triggering CD4 and CD8 T-cell responses specific for B43.13 to produce specific and non-specific immune response. With success in vitro, in vivo and in primitive studies, phase II study was conducted to test the effectiveness of chemoimmunotherapy (CIT) for the management of EOC patients. In the 97 EOC patients after optimal debulking surgery (residual tumor <1 cm or no gross residual tumor), patients treated with CIT had a dramatical and statistically significant improvement of both progression-free survival (PFS) and overall survival (OS) compared to those treated with chemotherapy alone with a median PFS of 41.8 months versus 12.2 months (hazard ratio [HR] 0.46, 95 % confidence interval [CI] 0.28-0.7) and OS not yet been reached (NE) versus 42.3 months (HR 0.35, 95 % CI 0.16-0.74), respectively. The current review as Part II will explore the possibility of using CIT as front-line therapy in the management of advanced-stage EOC patients after maximal cytoreductive surgery based on the evidence by many phase 2 studies.