Intraperitoneal administration of carcinoembryonic antigen-directed chimeric antigen receptor T cells is a robust delivery route for effective treatment of peritoneal carcinomatosis from colorectal cancer in pre-clinical study.

BACKGROUND AIMS: Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a highly challenging disease to treat. Systemic chimeric antigen receptor (CAR) T cells have shown impressive efficacy in hematologic malignancies but have been less effective in solid tumors. We explored whether intraperitoneal (i.p.) administration of CAR T cells could provide an effective and robust route of treatment for PC from CRC. METHODS: We generated second-generation carcinoembryonic antigen (CEA)-specific CAR T cells. Various animal models of PC with i.p. and extraperitoneal metastasis were treated by i.p. or intravenous (i.v.) administration of CEA CAR T cells. RESULTS: Intraperitoneally administered CAR T cells exhibited superior anti-tumor activity compared with systemic i.v. cell infusion in an animal model of PC. In addition, i.p. administration conferred a durable effect and protection against tumor recurrence and exerted strong anti-tumor activity in an animal model of PC with metastasis in i.p. or extraperitoneal organs. Moreover, compared with systemic delivery, i.p. transfer of CAR T cells provided increased anti-tumor activity in extraperitoneal tumors without PC. This phenomenon was further confirmed in an animal model of pancreatic carcinoma after i.p. administration of our newly constructed prostate stem cell antigen-directed CAR T cells. CONCLUSIONS: Taken together, our data suggest that i.p. administration of CAR T cells may be a robust delivery route for effective treatment of cancer.

Drug Discovery for Coronary Artery Disease.

Cardiovascular disease is the number one cause of human morbidity and mortality worldwide. Although cholesterol-lowering drugs, including statins and recently approved PCSK9 inhibitors, together with antithrombotic drugs have been historically successful in reducing the occurrence of coronary artery disease (CAD), the high incidence of CAD remains imposing the largest disease burden on our healthcare systems. We reviewed cardiovascular drugs recently approved or under clinical development, with a particular focus on their pharmacology and limitations. New agents targeting cholesterol/triglyceride lowering bear promise of further cardiovascular risk reduction. Some new antidiabetic agents show cardiovascular benefit in patients with diabetes. Improved antithrombotic agents with diminished bleeding risk are in clinical development. The recent clinical success of the IL-1ß antibody in reducing atherothrombosis opens a new era of therapeutic discovery that targets inflammation. Chinese traditional medicine and cardiac regeneration are also discussed. Human genetics studies of CAD and further delineation of key determinants/pathways underlying the residual risk of CAD under current standard therapy will continue to fuel the pipeline of cardiovascular drug discovery.

An Antibiotic Nanobomb Constructed from pH-Responsive Chemical Bonds in Metal-Phenolic Network Nanoparticles for Biofilm Eradication and Corneal Ulcer Healing.

In the treatment of refractory corneal ulcers caused by Pseudomonas aeruginosa, antibacterial drugs delivery faces the drawbacks of low permeability and short ocular surface retention time. Hence, novel positively-charged modular nanoparticles (NPs) are developed to load tobramycin (TOB) through a one-step self-assembly method based on metal-phenolic network and Schiff base reaction using 3,4,5-trihydroxybenzaldehyde (THBA), ε-poly-ʟ-lysine (EPL), and Cu2+ as matrix components. In vitro antibacterial test demonstrates that THBA-Cu-TOB NPs exhibit efficient instantaneous sterilization owing to the rapid pH responsiveness to bacterial infections. Notably, only 2.6 µg mL-1 TOP is needed to eradicate P. aeruginosa biofilm in the nano-formed THBA-Cu-TOB owing to the greatly enhanced penetration, which is only 1.6% the concentration of free TOB (160 µg mL-1). In animal experiments, THBA-Cu-TOB NPs show significant advantages in ocular surface retention, corneal permeability, rapid sterilization, and inflammation elimination. Based on molecular biology analysis, the toll-like receptor 4 and nuclear factor kappa B signaling pathways are greatly downregulated as well as the reduction of inflammatory cytokines secretions. Such a simple and modular strategy in constructing nano-drug delivery platform offers a new idea for toxicity reduction, physiological barrier penetration, and intelligent drug delivery.

Regulation of hematopoietic stem cells differentiation, self-renewal, and quiescence through the mTOR signaling pathway.

Hematopoietic stem cells (HSCs) are important for the hematopoietic system because they can self-renew to increase their number and differentiate into all the blood cells. At a steady state, most of the HSCs remain in quiescence to preserve their capacities and protect themselves from damage and exhaustive stress. However, when there are some emergencies, HSCs are activated to start their self-renewal and differentiation. The mTOR signaling pathway has been shown as an important signaling pathway that can regulate the differentiation, self-renewal, and quiescence of HSCs, and many types of molecules can regulate HSCs' these three potentials by influencing the mTOR signaling pathway. Here we review how mTOR signaling pathway regulates HSCs three potentials, and introduce some molecules that can work as the regulator of HSCs' these potentials through the mTOR signaling. Finally, we outline the clinical significance of studying the regulation of HSCs three potentials through the mTOR signaling pathway and make some predictions.

Under the Hood: Understanding the Features of Mucin in Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is a rare malignant growth characterized by the production of mucin and the potential for peritoneal relapse. This study aimed to investigate the immunohistochemical and biological characteristics of mucin in patients with cellular and acellular PMP. We prospectively analyzed mucin specimens obtained from our patient cohort and described the composition and type of mucin present in each sample. A metagenomic analysis of the samples was performed to investigate the bacterial composition of the PMP microbiome. Secreted mucins 2 and 5AC and membrane-associated mucin-1 were the primary components of mucin in both cellular and acellular tumor specimens. The metagenomic study revealed a predominance of the phylum Proteobacteria and the genus Pseudomonas. Notably, Pseudomonas plecoglossicida, a species not previously reported in the human microbiome, was found to be the most abundant organism in the mucin of pseudomyxoma peritonei. Our findings suggest that the presence of MUC-2 and mucin colonization by Pseudomonas are characteristic features of both cellular and acellular disease. These results may have significant implications for the diagnosis and treatment of this rare entity.

Understanding CAR T cell therapy and its role in ovarian cancer and peritoneal carcinomatosis from ovarian cancer.

Ovarian cancer is the seventh most common cancer worldwide in women and the most lethal gynecologic malignancy due to the lack of accurate screening tools for early detection and late symptom onset. The absence of early-onset symptoms often delays diagnosis until the disease has progressed to advanced stages, frequently when there is peritoneal involvement. Although ovarian cancer is a heterogeneous malignancy with different histopathologic types, treatment for advanced tumors is usually based on chemotherapy and cytoreduction surgery. CAR T cells have shown promise for the treatment of hematological malignancies, though their role in treating solid tumors remains unclear. Outcomes are less favorable owing to the low capacity of CAR T cells to migrate to the tumor site, the influence of the protective tumor microenvironment, and the heterogeneity of surface antigens on tumor cells. Despite these results, CAR T cells have been proposed as a treatment approach for peritoneal carcinomatosis from colorectal and gastric origin. Local intraperitoneal administration of CAR T cells has been found to be superior to systemic administration, as this route is associated with increased tumor reduction, a more durable effect, protection against local relapse and distant metastases, and fewer systemic adverse effects. In this article we review the application of CAR T cells for the treatment of ovarian cancer and peritoneal carcinomatosis from ovarian cancer.

Update for Advance CAR-T Therapy in Solid Tumors, Clinical Application in Peritoneal Carcinomatosis From Colorectal Cancer and Future Prospects.

Latest advances in the field of cancer immunotherapy have developed the (Chimeric Antigen Receptor) CAR-T cell therapy. This therapy was first used in hematological malignancies which obtained promising results; therefore, the use of CAR-T cells has become a popular approach for treating non-solid tumors. CAR-T cells consist of T-lymphocytes that are engineered to express an artificial receptor against any surface antigen of our choice giving us the capacity of offering precise and personalized treatment. This leaded to the development of CAR-T cells for treating solid tumors with the hope of obtaining the same result; however, their use in solid tumor and their efficacy have not achieved the expected results. The reason of these results is because solid tumors have some peculiarities that are not present in hematological malignancies. In this review we explain how CAR-T cells are made, their mechanism of action, adverse effect and how solid tumors can evade their action, and also we summarize their use in colorectal cancer and peritoneal carcinomatosis.

pH-Activatable Organic Nanoparticles for Efficient Low-Temperature Photothermal Therapy of Ocular Bacterial Infection.

Low-temperature photothermal therapy (PTT) systems constructed by integrating organic photothermal agents with other bactericidal components that initiate bacterial apoptosis at low hyperthermia possess a promising prospect. However, these multicomponent low-temperature PTT nanoplatforms have drawbacks in terms of the tedious construction process, suboptimal synergy effect of diverse antibacterial therapies, and high laser dose needed, compromising their biosafety in ocular bacterial infection treatment. Herein, a mild PTT nanotherapeutic platform is formulated via the self-assembly of a pH-responsive phenothiazinium dye. These organic nanoparticles with photothermal conversion efficiency up to 84.5% necessitate only an ultralow light dose of 36 J/cm2 to achieve efficient low-temperature photothermal bacterial inhibition at pH 5.5 under 650 nm laser irradiation. In addition, this intelligent mild photothermal nanoplatform undergoes negative to positive charge reversion in acid biofilms, exhibiting good penetration and highly efficient elimination of drug-resistant E. coli biofilms under photoirradiation. Further in vivo animal tests demonstrated efficient bacterial elimination and inflammatory mitigation as well as superior biocompatibility and biosafety of the photothermal nanoparticles in ocular bacterial infection treatment. Overall, this efficient single-component mild PTT system featuring simple construction processes holds great potential for wide application and clinical transformation.

The Role of CAR-T Cells in Peritoneal Carcinomatosis from Gastric Cancer: Rationale, Experimental Work, and Clinical Applications.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have shown poor effectiveness in treating peritoneal carcinomatosis (PC) of gastric origin with a high tumor burden (high peritoneal cancer index), though there are scarce therapy alternatives that are able to improve survival. In experimental studies, chimeric antigen receptor-T (CAR-T) cell therapy has shown encouraging results in gastric cancer and is currently being evaluated in several clinical trials. Regarding PC, CAR-T cell therapy has also proven useful in experimental studies, especially when administered intraperitoneally, as this route improves cell distribution and lifespan. Although these results need to be supported by ongoing clinical trials, CAR-T cells are a promising new therapeutic approach to peritoneal metastases from gastric cancer. In this review, we summarize the current evidence of the use of CAR-T cells in gastric cancer and PC of gastric origin.

Reversible antibiotic loading and pH-responsive release from polymer brushes on contact lenses for therapy and prevention of corneal infections.

Corneal infection is an important cause of corneal damage and vision loss. In this work, polyhydroxy antibiotics were grafted onto polymer brush-modified contact lenses through dynamic chemical bonds between polyphenolic hydroxyls and phenylboronic acid. Both in vitro and in vivo antibacterial tests demonstrated great promise in the prevention of bacterial keratitis, which could be attributed to the enhanced retention time and drug bioavailability.