RORc expressing immune cells negatively regulate tertiary lymphoid structure formation and support their pro-tumorigenic functions.

Background And Aims: RORc-expressing immune cells play important roles in inflammation, autoimmune disease and cancer. They are required for lymphoid organogenesis and have been implicated in tertiary lymphoid structure (TLS) formation. TLSs are formed in many cancer types and have been correlated with better prognosis and response to immunotherapy.

The Cross-talk Between Intestinal Microbiota and MDSCs Fuels Colitis-associated Cancer Development.

Unlabelled: Intestinal chronic inflammation is associated with microbial dysbiosis and accumulation of various immune cells including myeloid-derived suppressor cells (MDSC), which profoundly impact the immune microenvironment, perturb homeostasis and increase the risk to develop colitis-associated colorectal cancer (CAC). However, the specific MDSCs-dysbiotic microbiota interactions and their collective impact on CAC development remain poorly understood. In this study, using a murine model of CAC, we demonstrate that CAC-bearing mice exhibit significantly elevated levels of highly immunosuppressive MDSCs, accompanied by microbiota alterations.

Extensive elimination of acinar cells during normal postnatal pancreas growth.

While programmed cell death plays important roles during morphogenetic stages of development, post-differentiation organ growth is considered an efficient process whereby cell proliferation increases cell number. Here we demonstrate that early postnatal growth of the pancreas unexpectedly involves massive acinar cell elimination. Measurements of cell proliferation and death in the human pancreas in comparison to the actual increase in cell number predict daily elimination of 0.

Clinical Characteristics, Response to Platinum-Based Chemotherapy and Poly (Adenosine Phosphate-Ribose) Polymerase Inhibitors in Advanced Lung Cancer Patients Harboring BRCA Mutations.

The oncogenic role and clinical relevance of mutations in NSCLC remain unclear. We aim to evaluate the characteristics and clinical outcomes of patients with NSCLC harboring mutations treated at Hadassah Medical Center (HMC). We retrospectively assessed all patients with advanced NSCLC who underwent next-generation sequencing (NGS) and were found to have pathogenic somatic mutations (p-BRCA).

TET2 and TET3 loss disrupts small intestine differentiation and homeostasis.

TET2/3 play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly understood. Here we show that ablation of TET2/3 in intestinal epithelial cells results in a murine phenotype characterized by a severe homeostasis imbalance in the small intestine.

The NF-ĸB p50 subunit generated by KPC1-mediated ubiquitination and limited proteasomal processing, suppresses tumor growth.

Nuclear factor-ĸB (NF-ĸB) is an important transcriptional regulator of key cellular processes, including cell cycle, immune response, and malignant transformation. We found that the ubiquitin ligase Kip1 ubiquitination-promoting complex subunit 1 (KPC1; also known as Ring finger protein 123 - RNF123) stimulates ubiquitination and limited proteasomal processing of the p105 NF-ĸB precursor to generate p50, the active subunit of the heterodimeric transcription factor. KPC1 binds to the ankyrin repeats' (AR) domain of NF-ĸB p105 via a short binding site of 7 amino acids-968-WILVRLW-974.

DNA-Tetrahedra Corona-Modified Hydrogel Microcapsules: "Smart" ATP- or microRNA-Responsive Drug Carriers.

The assembly of adenosine triphosphate (ATP)-responsive and miRNA-responsive DNA tetrahedra-functionalized carboxymethyl cellulose hydrogel microcapsules is presented. The microcapsules are loaded with the doxorubicin-dextran drug or with CdSe/ZnS quantum dots as a drug model. Selective unlocking of the respective microcapsules and the release of the loads in the presence of ATP or miRNA-141 are demonstrated.

Aptamer-Modified Au Nanoparticles: Functional Nanozyme Bioreactors for Cascaded Catalysis and Catalysts for Chemodynamic Treatment of Cancer Cells.

Polyadenine-stabilized Au nanoparticles (pA-AuNPs) reveal dual nanozyme catalytic activities toward the HO-mediated oxidation of dopamine to aminochrome and toward the aerobic oxidation of glucose to gluconic acid and HO. The conjugation of a dopamine-binding aptamer (DBA) to the pA-AuNPs yields aptananozyme structures catalyzing simultaneously the HO-mediated oxidation of dopamine to aminochrome through the aerobic oxidation of glucose. A set of aptananozymes consisting of DBA conjugated through the 5'- or 3'-end directly or spacer bridges to pA-AuNPs were synthesized.

Vav1 accelerates Ras-driven lung cancer and modulates its tumor microenvironment.

The potential impact of Vav1 on human cancer was only recently acknowledged, as it is detected as a mutant or an overexpressed gene in various cancers, including lung cancer. Vav1, which is normally and exclusively expressed in the hematopoietic system functions as a specific GDP/GTP nucleotide exchange factor (GEF), strictly regulated by tyrosine phosphorylation. To investigate whether Vav1 plays a causative or facilitating role in-vivo in lung cancer development and to examine whether it co-operates with other oncogenes, such as mutant K-Ras, we generated novel mouse strains that express: Vav1 or K-Ras in type II pneumocytes, as well as a transgenic mouse line that expresses both Vav1 and K-Ras in these cells.

Single-Stranded DNA-Encoded Gold Nanoparticle Clusters as Programmable Enzyme Equivalents.

Nanozymes have emerged as a class of novel catalytic nanomaterials that show great potential to substitute natural enzymes in various applications. Nevertheless, spatial organization of multiple subunits in a nanozyme to rationally engineer its catalytic properties remains to be a grand challenge. Here, we report a DNA-based approach to encode the organization of gold nanoparticle clusters (GNCs) for the construction of programmable enzyme equivalents (PEEs).

Vav1 Promotes B-Cell Lymphoma Development.

Vav1 is normally and exclusively expressed in the hematopoietic system where it functions as a specific GDP/GTP nucleotide exchange factor (GEF), firmly regulated by tyrosine phosphorylation. Mutations and overexpression of Vav1 in hematopoietic malignancies, and in human cancers of various histologic origins, are well documented. To reveal whether overexpression of Vav1 in different tissues suffices for promoting the development of malignant lesions, we expressed Vav1 in transgenic mice by using the ubiquitous ROSA26 promoter (Rosa Vav1).

miRNA-Guided Imaging and Photodynamic Therapy Treatment of Cancer Cells Using Zn(II)-Protoporphyrin IX-Loaded Metal-Organic Framework Nanoparticles.

An analytical platform for the selective miRNA-21-guided imaging of breast cancer cells and miRNA-221-guided imaging of ovarian cancer cells and the selective photodynamic therapy (PDT) of these cancer cells is introduced. The method is based on Zn(II)-protoporphyrin IX, Zn(II)-PPIX-loaded UiO-66 metal-organic framework nanoparticles, NMOFs, gated by two hairpins H/H through ligation of their phosphate residues to the vacant Zr-ions associated with the NMOFs. The hairpins are engineered to include the miRNA recognition sequence in the stem domain of H, and in the H and H, partial locked stem regions of G-quadruplex subunits.

Aptamer-modified DNA tetrahedra-gated metal-organic framework nanoparticle carriers for enhanced chemotherapy or photodynamic therapy.

UiO-66 metal-organic framework nanoparticles (NMOFs) gated by aptamer-functionalized DNA tetrahedra provide superior biomarker-responsive hybrid nano-carriers for biomedical applications. Hybrid nano-carriers consisting of ATP-aptamer or VEGF-aptamer functionalized tetrahedra-gated NMOFs are loaded with the chemotherapeutic drug, doxorubicin (DOX). In the presence of ATP or VEGF, both abundant in cancer cells, the tetrahedra-gated NMOFs are unlocked to release the drug.

Immunotherapies for hepatocellular carcinoma.

Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC.

Putative homeostatic role of cancer driver mutations.

Somatic mutations have traditionally been associated with cancer, yet more recently, it was realized that they also appear in nontransformed cells beginning in early life. Remarkably, some of these mutations, commonly viewed as cancer driver mutations, are widely spread among cells of noncancerous tissues, sometimes affecting the majority of the tissue cells. This spreading process intensifies upon aging or exposure to extrinsic insults, such as UV irradiation, inhaling smoke, and inflammatory cues.

pH- and miRNA-Responsive DNA-Tetrahedra/Metal-Organic Framework Conjugates: Functional Sense-and-Treat Carriers.

The synthesis of stimuli-responsive hybrid structures composed of drug-loaded UiO-66 metal-organic framework nanoparticles, NMOFs, locked by DNA tetrahedra gates is presented. The hybrid systems combine the high loading capacity of drugs in the porous NMOFs and the effective cell permeation properties of the DNA tetrahedra. The nucleic acid-functionalized UiO-66 NMOFs are loaded with drugs (doxorubicin, DOX, or camptothecin, CPT) or with dyes as drug models (Rhodamine 6G or fluorescein) and used to prepare stimuli-responsive carriers.

Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions.

Objective: Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised.

Hepatocellular carcinoma.

Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West.

A single cell atlas of the human liver tumor microenvironment.

Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pathologies. Here, we apply single cell RNA-sequencing and spatial analysis of malignant and adjacent non-malignant liver tissues from five patients with cholangiocarcinoma or liver metastases.