Anti-cancer mechanisms of action of therapeutic alternating electric fields(tumor treating fields[TTFields])

Despite improved survival outcomes across many cancer types,the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer.Invariably in these cancers,the control achieved by time-limited interventions such as traditional surgical resection,radiation therapy,and chemotherapy is short-lived.A new form of anti-cancer therapy called therapeutic alternating electric fields(AEFs)or tumor treating fields(TTFields)has been shown,either by itself or in combination with chemotherapy,to have anti-cancer effects that translate to improved survival outcomes in patients.Although the pre-clinical and clinical data are promising,the mechanisms of TTFields are not fully elucidated.Many investigations are underway to better understand how and why TTFields is able to selectively kill cancer cells and impede their proliferation.The purpose of this review is to summarize and discuss the reported mechanisms of action of TTFields from pre-clinical studies(both in vitro and in vivo).An improved understanding of how TTFields works will guide strategies focused on the timing and combination of TTFields with other therapies,to further improve survival outcomes in patients with solid organ cancers.

Formation and repair of DNA-protein crosslink damage

DNA is constantly exposed to a wide array of genotoxic agents, generating a variety of forms of DNA damage. DNA-protein crosslinks(DPCs)—the covalent linkage of proteins with a DNA strand—are one of the most deleterious and understudied forms of DNA damage, posing as steric blockades to transcription and replication. If not properly repaired, these lesions can lead to mutations, genomic instability, and cell death. DPCs can be induced endogenously or through environmental carcinogens and chemotherapeutic agents. Endogenously, DPCs are commonly derived through reactions with aldehydes, as well as through trapping of various enzymatic intermediates onto the DNA. Proteolytic cleavage of the protein moiety of a DPC is a general strategy for removing the lesion. This can be accomplished through a DPC-specific protease and and/or proteasome-mediated degradation.Nucleotide excision repair and homologous recombination are each involved in repairing DPCs, with their respective roles likely dependent on the nature and size of the adduct. The Fanconi anemia pathway may also have a role in processing DPC repair intermediates. In this review, we discuss how these lesions are formed, strategies and mechanisms for their removal, and diseases associated with defective DPC repair.

NetBCE: An Interpretable Deep Neural Network for Accurate Prediction of Linear B-cell Epitopes

Identification of B-cell epitopes(BCEs)plays an essential role in the development of peptide vaccines and immuno-diagnostic reagents,as well as antibody design and production.In this work,we generated a large benchmark dataset comprising 124,879 experimentally supported linear epitope-containing regions in 3567 protein clusters from over 1.3 million B cell assays.Analysis of this curated dataset showed large pathogen diversity covering 176 different families.The accuracy in linear BCE prediction was found to strongly vary with different features,while all sequencederived and structural features were informative.To search more efficient and interpretive feature representations,a ten-layer deep learning framework for linear BCE prediction,namely Net BCE,was developed.Net BCE achieved high accuracy and robust performance with the average area under the curve(AUC)value of 0.8455 in five-fold cross-validation through automatically learning the informative classification features.Net BCE substantially outperformed the conventional machine learning algorithms and other tools,with more than 22.06%improvement of AUC value compared to other tools using an independent dataset.Through investigating the output of important network modules in Net BCE,epitopes and non-epitopes tended to be presented in distinct regions with efficient feature representation along the network layer hierarchy.The Net BCE is freely available at https://github.com/bsml320/Net BCE.

Enhanced CD19 activity in B cells contributes to immunodeficiency in mice deficient in the ICF syndrome gene Zbtb24

Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency.It is caused by mutations in DNMT3B,ZBTB24,CDCA7,or HELLS.While progress has been made in elucidating the roles of these genes in regulating DNA methylation,little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype.Here,we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome.Specifically,Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels of IgM,IgG1,and IgA.Zbtb24-deficient mice are hyper and hypo-responsive to T-dependent and T-independent type 2 antigens,respectively,and marginal zone B-cell activation is impaired.Mechanistically,Zbtb24-deficient B cells show severe loss of DNA methylation in the promoter region of Il5ra(interleukin-5 receptor subunit alpha),and Il5ra derepression leads to elevated CD19 phosphorylation.Heterozygous disruption of Cd19 can revert the hypogammaglobulinemia phenotype of Zbtb24-deficient mice.Our results suggest the potential role of enhanced CD19 activity in immunodeficiency in ICF syndrome.

ZRANB1 is an NBS1 deubiquitinase and a potential target to overcome radioresistance and PARP inhibitor resistance in triple-negative breast cancer

Poly(ADP-ribose)polymerase inhibitors(PARPi)are used to treat ovarian cancer and triple-negative breast cancer(TNBC)with defective homologous recombination repair pathways.However,de novo and acquired PARPi resistance limits clinical benefits.1 The MRE11-RAD50-NBS1(MRN)complex mediates the sensing,processing,and signaling of DNA double-strand breaks(DSBs)and plays important roles in the efficacy of PARPi and radiation treatment,2 and yet the mechanisms for the regulation and degradation of the MRN complex are not well understood.ZRANB1,also known as Trabid,is a breast cancer-promoting deubiquitinase that preferentially cleaves K29-,K33-,and K63-linked ubiquitin chains,3 but its role in therapy resistance remains unknown.

The ZBTB24-CDCA7 axis regulates HELLS enrichment at centromeric satellite repeats to facilitate DNA methylation

Dear Editor,Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by antibody deficiency,facial dysmorphism,failure to thrive,and mental retardation.Patients with ICF syndrome suffer from recurrent and often fatal infections in early childhood.A hallmark of ICF syndrome is loss of DNA methylation in special genomic regions,most notably satellite repeats at centromeric regions,which leads to heterochromatin decondensation and chromosomal abnormalities in lymphocytes(Ehrlich et al.,2008).

Delineating COVID-19 immunological features using single-cell RNA sequencing

Understanding the molecular mechanisms of coronavirus disease 2019(COVID-19)pathogenesis and immune response is vital for developing therapies.Single-cell RNA sequencing has been applied to delineate the cellular heterogeneity of the host response toward COVID-19 in multiple tissues and organs.Here,we review the applications and findings from over 80 original COVID-19 single-cell RNA sequencing studies as well as many secondary analysis studies.We describe that single-cell RNA sequencing reveals multiple features of COVID-19 patients with different severity,including cell populations with proportional alteration,COVID-19-induced genes and pathways,severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)infection in single cells,and adaptation of immune repertoire.We also collect published single-cell RNA sequencing datasets from original studies.Finally,we discuss the limitations in current studies and perspectives for future advance.