Bioorthogonal/Ultrasound Activated Oncolytic Pyroptosis Amplifies In Situ Tumor Vaccination for Boosting Antitumor Immunity.

Personalized in situ tumor vaccination is a promising immunotherapeutic modality. Currently, seeking immunogenic cell death (ICD) to generate in situ tumor vaccines is still mired by insufficient immunogenicity and an entrenched immunosuppressive tumor microenvironment (TME). Herein, a series of tetrazine-functionalized ruthenium(II) sonosensitizers have been designed and screened for establishing a bioorthogonal-activated in situ tumor vaccine via oncolytic pyroptosis induction. Based on nanodelivery-augmented bioorthogonal metabolic glycoengineering, the original tumor is selectively remolded to introduce artificial target bicycle [6.1.0] nonyne (BCN) into cell membrane. Through specific bioorthogonal ligation with intratumoral BCN receptors, sonosensitizers can realize precise membrane-anchoring and synchronous click-activation in desired tumor sites. Upon ultrasound (US) irradiation, the activated sonosensitizers can intensively disrupt the cell membrane with dual type I/II reactive oxygen species (ROS) generation for a high-efficiency sonodynamic therapy (SDT). More importantly, the severe membrane damage can eminently evoke oncolytic pyroptosis to maximize tumor immunogenicity and reverse immunosuppressive TME, ultimately eliciting powerful and durable systemic antitumor immunity. The US-triggered pyroptosis is certified to effectively inhibit the growths of primary and distant tumors, and suppress tumor metastasis and recurrence in "cold" tumor models. This bioorthogonal-driven tumor-specific pyroptosis induction strategy has great potential for the development of robust in situ tumor vaccines.

The mechanisms of multidrug resistance of breast cancer and research progress on related reversal agents.

Chemotherapy is the mainstay in the treatment of breast cancer. However, many drugs that are commonly used in clinical practice have a high incidence of side effects and multidrug resistance (MDR), which is mainly caused by overexpression of drug transporters and related enzymes in breast cancer cells. In recent years, researchers have been working hard to find newer and safer drugs to overcome MDR in breast cancer. In this review, we provide the molecule mechanism of MDR in breast cancer, categorize potential lead compounds that inhibit single or multiple drug transporter proteins, as well as related enzymes. Additionally, we have summarized the structure-activity relationship (SAR) based on potential breast cancer MDR modulators with lower side effects. The development of novel approaches to suppress MDR is also addressed. These lead compounds hold great promise for exploring effective chemotherapy agents to overcome MDR, providing opportunities for curing breast cancer in the future.

Development of PI3K inhibitors: Advances in clinical trials and new strategies (Review).

Phosphatidylinositol 3-kinases (PI3Ks) are the family of vital lipid kinases widely distributed in mammalian cells. The overexpression of PI3Ks leads to hyperactivation of the PI3K/AKT/mTOR pathway, which is considered a pivotal pathway in the occurrence and development of tumors. Hence, PI3Ks are viewed as promising therapeutic targets for anti-cancer therapy. To date, some PI3K inhibitors have achieved desired therapeutic effect via inhibiting the activity of PI3Ks or reducing the level of PI3Ks in clinical trials, among which, Idelalisib, Alpelisib and Duvelisib have been approved by the FDA for treatment of ER+/HER2- advanced metastatic breast cancer and refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphomas (SLL). This review focuses on the latest advances of PI3K inhibitors with efficacious anticancer activity, which are classified into Pan-PI3K inhibitors, isoform-specific PI3K inhibitors and dual PI3K/mTOR inhibitors based on the isoform affinity. Their corresponding structure characteristics and structures-activity relationship (SAR), together with the progress in the clinical application are mainly discussed. Additionally, the new PI3K inhibitory strategy, such as PI3K degradation agent, for the design of potential PI3K candidates to overcome drug resistance is referred as well.

Protective effects of a polysaccharide from Boletus aereus on S180 tumor-bearing mice and its structural characteristics.

A polysaccharide from the aqueous extract of Boletus aereus fruit (BAP) was isolated. The antitumor activities of BAP and/or cyclophosphamide (CTX) were investigated using the model of S180 tumor-bearing mice. Results indicated that BAP could effectively inhibit the growth of S180 solid tumors and protect the immune organs. Hematoxylin and eosin staining, Annexin V-FITC/PI staining, and mitochondrial membrane potential analysis demonstrated that BAP could induce the apoptosis of S180 tumor cells. In combination with CTX, BAP exhibited a significant synergistic antitumor effect on S180 cells. Furthermore, a novel polysaccharide, namely, BAPF, was purified from BAP by using DEAE Cellulose-52 column and Sephadex G-100 gel column. Structural characterization revealed that BAPF was primarily composed of mannose, glucuronic acid, glucose, galactose, arabinose, and fucose at a proportion of 12.98:1:16.8:16.48:1.08:9.1. Its average molecular weight was 1.79 × 106 Da. FTIR and NMR analyses demonstrated that BAPF was a pyranose with α-type and ß-type glycosidic residues.

Graphene-based materials: A new tool to fight against breast cancer.

Breast cancer is one of the most common malignant tumors among women population on a global scale, with a huge number of new cases and deaths each year. In recent years, there has been an increasing number of literatures on the discovery and development of novel anti-breast cancer drugs and materials, aiming to increase the survival rate of breast cancer patients. One of the newest tools used for the therapy of breast cancer is graphene-based materials, which have ultra-high surface area as well as unique physical, chemical and mechanical properties. It is reported that graphene-based materials could induce apoptosis in cancer cells while showing low toxicity due to their carbon structure. Therefore, they can be used as nano-drugs or biological carriers to introduce small molecules such as nucleic acids, drugs, or photosensitizers into the human body to achieve treatment goals. This article introduces the synthetic methods for graphene-based materials, as well as the current status and the future prospects of graphene-based materials' application in the treatment of breast cancer.

A clinical study on acupuncture in combination with routine rehabilitation therapy for early pain recovery of post-stroke shoulder-hand syndrome.

The clinical effect of acupuncture in combination with rehabilitation therapy for post-stroke shoulder-hand syndrome (SHS) was explored. Patients (178) with post-stroke SHS who received treatment in the Dalian Second Hospital from March 2012 to March 2016 were included in this study. The patients were divided into experimental group (89 cases) and control group (89 cases). Patients in the control group received rehabilitation therapy, while those in the treatment group received acupuncture treatment in addition to rehabilitation therapy. Visual analogue scale (VAS) was applied to assess the pain degree of patients. Fugl-Meyer assessment (FMA), functional comprehensive assessment (FCA) and assessment of quality of life (QoL) were used to evaluate rehabilitation condition of the patients. Early pain relief, rehabilitation of upper extremity motor function and improvement of QoL after treatment were compared between the two groups. The scores of VAS, FMA, FCA and QoL showed obvious differences between the two groups after treatment (P<0.05). The scores of the experimental group were significantly better than those of the control group, and the improvement in upper extremity motor function of the patients in the experimental group was better than that of the patients in the control group. The total effective rate of the patients in the experimental group was higher than that of control group (P<0.05). The effect in improving the upper extremity motor function of the patients in the experimental group was better than that of control group. The scores of QoL of the patients in the experimental group were better than that of the patients in the control group (P<0.05). In conclusion, acupuncture in combination with rehabilitation therapy can improve early pain and rehabilitation significantly and enhance QoL for patients with post-stroke SHS, which is worthy of being widely used in clinical practice.