In-situ formed thermosensitive hydrogel amplifies statin-mediated immune checkpoint blockade for coordinated tumor chemo-immunotherapy.

Small molecule drugs are the next-generation of immune checkpoint inhibitors (ICIs), but their in vivo therapeutic outcomes remain unsatisfactory for a long time. Herein, we proposed a combinatory regimen that delivered a small molecule ICI and an immunogenic cell death inducer in an in-situ formed hydrogel scaffold based on thermosensitive materials (Pluronic F127). This platform increased the tumor retention of administrated small molecules, creating more opportunities for the interaction between drugs and tumor cells. We found that atorvastatin (ATO) effectively downregulated the expression of programmed death ligand 1 (PD-L1) and reversed compensative PD-L1 upregulation after cyclophosphamide (CTX) chemotherapy on CT26 colon tumors. CTX not only killed tumor cells to reduce the tumor burden, but also release damage-associated molecular patterns (DAMPs) to stimulate T cell immunity, therefore amplifying statin-mediated immunotherapy. The platform reported in this study might be promising to overcome the limitation of small molecule ICIs with short retention time and potentiate tumor chemo-immunotherapy.

Advancing immune checkpoint blockade in colorectal cancer therapy with nanotechnology.

Immune checkpoint blockade (ICB) has gained unparalleled success in the treatment of colorectal cancer (CRC). However, undesired side effects, unsatisfactory response rates, tumor metastasis, and drug resistance still hinder the further application of ICB therapy against CRC. Advancing ICB with nanotechnology can be game-changing. With the development of immuno-oncology and nanomaterials, various nanoplatforms have been fabricated to enhance the efficacy of ICB in CRC treatment. Herein, this review systematically summarizes these recent nano-strategies according to their mechanisms. Despite their diverse and complex designs, these nanoplatforms have four main mechanisms in enhancing ICB: 1) targeting immune checkpoint inhibitors (ICIs) to tumor foci, 2) increasing tumor immunogenicity, 3) remodeling tumor microenvironment, and 4) pre-sensitizing immune systems. Importantly, advantages of nanotechnology in CRC, such as innovating the mode-of-actions of ICB, modulating intestinal microbiome, and integrating the whole process of antigen presentation, are highlighted in this review. In general, this review describes the latest applications of nanotechnology for CRC immunotherapy, and may shed light on the future design of ICB platforms.

Small-Molecule PROTACs for Cancer Immunotherapy.

Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

Single-cell-level microfluidics assisted with resuscitation-promoting factor technology (SMART) to isolate novel biphenyl-degrading bacteria from typical soils in eastern China.

Soil microorganisms represent one of the largest biodiversity reservoirs. However, most low-abundance, slow-growing or dormant microorganisms in soils are difficult to capture with traditional enrichment culture methods. These types of microorganisms represent a valuable "microbial seed bank". To better exploit and utilize this "microbial dark matter", we developed a novel strategy that integrates single-cell-level isolation with microfluidics technology and culture with resuscitation-promoting factor (Rpf) to isolate biphenyl-degrading bacteria from four typical soils (paddy soil, red soil, alluvial soil and black soil) in eastern China. Multitudinous bacteria were successfully isolated and cultured; some of the identified clades have not been previously linked to biphenyl biodegradation, such as Actinotalea, Curtobacterium and Rothia. Soil microcosmic experiments validated that some bacteria are responsible for biphenyl degradation in soil. In addition, genomic sequencing and Illumina MiSeq sequencing of 16S rRNA genes indicated that exogenous Rpf mainly promotes the recovery and growth of bacteria containing endogenous Rpf-encoding genes. In summary, this study provides a novel strategy for capturing target functional microorganisms in soils, indicates potential bioresources for the bioremediation of contaminated soils, and enhances our current understanding of the mechanisms involved in the response to exogenous Rpf.

Enhancement of perchloroethene dechlorination by a mixed dechlorinating culture via magnetic nanoparticle-mediated isolation method.

Highly enriched active dechlorinating cultures are important in advancing microbial remediation technology. This study attempted to enrich a rapid perchloroethene (PCE) dechlorinating culture via magnetic nanoparticle-mediated isolation (MMI). MMI is a novel method that can separate the fast-growing and slow-growing population in a microbial community without labelling. In the MMI process, PCE dechlorination was enhanced but the subsequent trichloroethene (TCE) dechlorination was inhibited, with TCE cumulative rate reached up to 80.6% within 70 days. Meanwhile, the microbial community was also changed, with fast-growing genera like Dehalobacterium and Petrimonas enriched, and slow-growing Methanosarcina almost ruled out. Relative abundances of several major genera including Petrimonas and Methanosarcina were positively related to TCE dechlorination rate and the relative abundance of Dehalococcoides. On the other hand, Dehalobacterium was negatively related to TCE dechlorination rate and Dehalococcoides abundance, suggesting potential competition between Dehalobacterium and Dehalococcoides. The regrowth of Methanosarcina coupled well with the recovery of TCE dechlorination capacity, which implied the important role of methanogens in TCE dechlorination. Via MMI method, a simpler but more active microbial consortium could be established to enhance PCE remediation efficiency. Methanogens may act as the indicators or biomarkers for TCE dechlorination, suggesting that methanogenic activity should also be monitored when enriching dechlorination cultures and remediating PCE contaminated sites. CAPSULE: A rapid perchloroethene dechlorinator was gotten via magnetic nanoparticles and dechlorination of trichloroethene coupled well with growth of Methanosarcina.

Survival Prediction in Gallbladder Cancer Using CT Based Machine Learning.

OBJECTIVE: To establish a classifier for accurately predicting the overall survival of gallbladder cancer (GBC) patients by analyzing pre-treatment CT images using machine learning technology. METHODS: This retrospective study included 141 patients with pathologically confirmed GBC. After obtaining the pre-treatment CT images, manual segmentation of the tumor lesion was performed and LIFEx package was used to extract the tumor signature. Next, LASSO and Random Forest methods were used to optimize and model. Finally, the clinical information was combined to accurately predict the survival outcomes of GBC patients. RESULTS: Fifteen CT features were selected through LASSO and random forest. On the basis of relative importance GLZLM-HGZE, GLCM-homogeneity and NGLDM-coarseness were included in the final model. The hazard ratio of the CT-based model was 1.462(95% CI: 1.014-2.107). According to the median of risk score, all patients were divided into high and low risk groups, and survival analysis showed that high-risk groups had a poor survival outcome (P = 0.012). After inclusion of clinical factors, we used multivariate COX to classify patients with GBC. The AUC values in the test set and validation set for 3 years reached 0.79 and 0.73, respectively. CONCLUSION: GBC survival outcomes could be predicted by radiomics based on LASSO and Random Forest.

Amelanotic Meningeal Melanoma with Leptomeningeal Dissemination: A Case Report and Systematic Literature Review.

BACKGROUND: Meningeal melanoma is a rare tumor of the central nervous system, whose amelanotic variant is called "amelanotic meningeal melanoma" (AMM). AMM does not produce melanin and therefore does not exhibit typical short T1 and short T2 signal on magnetic resonance imaging and thus can be easily misdiagnosed and be inappropriately managed. To date, only 4 AMM cases have been reported in the English literature. Here, we report the fifth case. CASE DESCRIPTION: A 26-year-old female patient presented with a 4-month history of progressive headache and nausea, the conventional magnetic resonance imaging demonstrated a posterior fossa mass accompanied by diffuse leptomeningeal dissemination. Repeated cerebrospinal fluid cytology screening showed negative results. The functional magnetic resonance examinations, including diffusion-weighted imaging, proton magnetic resonance spectroscopy, and dynamic susceptibility contrast perfusion-weighted imaging, provided complementary information. The final diagnosis of AMM was made by immunohistochemistry. Despite gross total excision of the tumor, the disease progressed, and the patient died 10 months after diagnosis. CONCLUSIONS: Our experience with this case demonstrated that meningeal melanoma should be included in the differential diagnosis when an intracranial mass is accompanied by leptomeningeal dissemination, and especially when proton magnetic resonance spectroscopy and dynamic susceptibility contrast perfusion-weighted imaging indicate a malignant tumor whereas diffusion-weighted imaging does not. And the loss of a typical melanin signal should not server as an excluding criterion for meningeal melanoma.