MRgFUS is a safe, noninvasive method to deliver spatially targeted monoclonal antibody across the BBB in patients with brain tumors.

Immune checkpoint inhibitors (ICIs) have transformed the treatment of patients with advanced cancers. However, the majority of patients do not respond or develop early progressive disease. A substantial number also develop immune-mediated toxicities that may lead to early treatment discontinuation. Gastrointestinal toxicities in the form of diarrhea and colitis are common and may resemble that observed in patients with inflammatory bowel disease (IBD). Alterations in the gut microbiota are thought to play an important role in mediating the intestinal inflammation that is associated with immune-mediated colitis. In this review, the authors’ objective is to provide an overview of the gastrointestinal and hepatic toxicities that can be seen with ICIs and discuss the interactions between gut microbiota and the immune response. The authors also highlight the potential role for fecal microbial transfer (FMT) as an approach to improve therapeutic efficacy and decrease toxicity.

A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2). However, FAM72A downregulates UNG2 permitting dUs to persist and trigger SHM and CSR. How FAM72A promotes UNG2 degradation is unknown. Here, we show that FAM72A recruits a C-terminal to LisH (CTLH) E3 ligase complex to target UNG2 for proteasomal degradation. Deficiency in CTLH complex components result in elevated UNG2 and reduced SHM and CSR. Cryo-EM structural analysis reveals FAM72A directly binds to MKLN1 within the CTLH complex to recruit and ubiquitinate UNG2. Our study further suggests that FAM72A hijacks the CTLH complex to promote mutagenesis in cancer. These findings show that FAM72A is an E3 ligase substrate adaptor critical for humoral immunity and cancer development.

Triple-negative breast cancers (TNBCs) are a heterogeneous group of aggressive tumors with high relapse rates and propensity to develop visceral or brain metastasis, representing 15% of the breast carcinomas. Their overall survival (OS) has remained static over the past 20 years. Cytotoxic chemotherapy (CT) was the only treatment option for all stages of TNBC until the first targeted therapy Olaparib was approved in patients with germline BRCA-mutation. This unsystematic narrative review is aimed at presenting an overview of the use of CT in advanced/metastatic triple-negative breast cancer (mTNBC) in these times when the personalized medicine era is slowly reaching TNBC with new therapeutic options. The information used to write it was collected from the published literature, treatment guidelines and hand searches of retrieved literature references. Standard anthracycline-based CT is the treatment of choice as first-line for metastatic breast cancer patients not previously treated with anthracyclines. First-line single-agent taxane is offered to patients who have received prior adjuvant anthracyclines or presented anthracycline failure, or as the second line in patients who have received prior anthracyclines in the metastatic setting. TNBC tumors that carry the germline BRCA1/2 mutations can benefit from the targeted use of platinum. Other drugs as eribulin, capecitabine, platinum, and gemcitabine, that have proven efficacy as single-agents or in combination as further lines, but the sequencing is not established. Combination chemotherapy can be considered when the patient presents a severe organ dysfunction aiming to achieve disease stabilization. CT remains the cornerstone treatment for mTNBC which not express targetable receptors or defective molecular pathways, and as a counterpart for targeted or immune therapies; given the limited access to these last in most countries, CT will continue in the landscape for much longer.