PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma.

Anti-epidermal growth factor receptor (EGFR) therapy (cetuximab) shows a limited clinical benefit for patients with locally advanced or recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), due to the frequent occurrence of secondary resistance mechanisms. Here we report that cetuximab-resistant HNSCC cells display a peroxisome proliferator-activated receptor alpha (PPARα)-mediated lipid metabolism reprogramming, with increased fatty acid uptake and oxidation capacities, while glycolysis is not modified. This metabolic shift makes cetuximab-resistant HNSCC cells particularly sensitive to a pharmacological inhibition of either carnitine palmitoyltransferase 1A (CPT1A) or PPARα in 3D spheroids and tumor xenografts in mice.

Protocol for genomic editing in human resting primary NK cells and NK-92 cells via CRISPR-Cas9 ribonucleoproteins.

Here, we present a protocol to perform CRISPR-Cas9 genome editing in human resting primary natural killer (NK) and NK-92 cells. We describe steps for guide RNA selection, ribonucleoprotein (RNP) complex formation, delivery via Nucleofection, and analysis of CRISPR edits to assess editing efficiencies. This protocol offers a tool for functional studies in NK cells, paving the way for potential applications in immunotherapy and beyond.

Managing Pediatric Asthma Exacerbations: The Role of Timely Systemic Corticosteroid Administration in Emergency Care Settings-A Multicentric Retrospective Study.

Background: Asthma is the most prevalent chronic respiratory condition in children. An asthma exacerbation (AE) is a frequent reason for emergency department (ED) visits. An important step in the management of a moderate to severe AE is the administration of systemic corticosteroids (SCS) within 1 h after ED presentation.

Establishment of head and neck squamous cell carcinoma mouse models for cetuximab resistance and sensitivity.

Acquired resistance to the targeted agent cetuximab poses a significant challenge in finding effective anti-cancer treatments for head and neck squamous cell carcinoma (HNSCC). To accurately study novel combination treatments, suitable preclinical mouse models for cetuximab resistance are key yet currently limited. This study aimed to optimize an acquired cetuximab-resistant mouse model, with preservation of the innate immunity, ensuring intact antibody-dependent cellular cytotoxicity (ADCC) functionality.

Correction: Krayem et al. The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma. 2019, , 1093.

In the original article [...

Cellular senescence in cancer: clinical detection and prognostic implications.

Cellular senescence is a state of stable cell-cycle arrest with secretory features in response to cellular stress. Historically, it has been considered as an endogenous evolutionary homeostatic mechanism to eliminate damaged cells, including damaged cells which are at risk of malignant transformation, thereby protecting against cancer. However, accumulation of senescent cells can cause long-term detrimental effects, mainly through the senescence-associated secretory phenotype, and paradoxically contribute to age-related diseases including cancer.

Co-Targeting the EGFR and PI3K/Akt Pathway to Overcome Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma: What about Autophagy?

Resistance to EGFR-targeted therapy is a major obstacle on the road to effective treatment options for head and neck cancers. During the search for underlying mechanisms and regulators of this resistance, there were several indications that EGFR-targeted therapy resistance is (partially) mediated by aberrant signaling of the PI3K/Akt pathway. Genomic alterations in and/or overexpression of major components of the PI3K/Akt pathway are common in HNSCC tumors.

The prognostic impact of the immune signature in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that retain their poor prognosis despite recent advances in their standard of care. As the involvement of the immune system against HNSCC development is well-recognized, characterization of the immune signature and the complex interplay between HNSCC and the immune system could lead to the identification of novel therapeutic targets that are required now more than ever. In this study, we investigated RNA sequencing data of 530 HNSCC patients from The Cancer Genome Atlas (TCGA) for which the immune composition (CIBERSORT) was defined by the relative fractions of 10 immune-cell types and expression data of 45 immune checkpoint ligands were quantified.

Prognostic implications of cellular senescence in resected non-small cell lung cancer.

Background: Cure and long-term survival for non-small cell lung cancer (NSCLC) remains hard to achieve. Cellular senescence, an emerging hallmark of cancer, is considered as an endogenous tumor suppressor mechanism. However, senescent cancer cells can paradoxically affect the surrounding tumor microenvironment (TME), ultimately leading to cancer relapse and metastasis.

Luminescent Human iPSC-Derived Neurospheroids Enable Modeling of Neurotoxicity After Oxygen-glucose Deprivation.

Despite the considerable impact of stroke on both the individual and on society, a neuroprotective therapy for stroke patients is missing. This is partially due to the current lack of a physiologically relevant human in vitro stroke model. To address this problem, we have developed a luminescent human iPSC-derived neurospheroid model that enables real-time read-out of neural viability after ischemia-like conditions.

Microenvironment-driven intratumoral heterogeneity in head and neck cancers: clinical challenges and opportunities for precision medicine.

Squamous cell carcinoma of the head and neck (SCCHN) is among the most prevalent cancer types worldwide. Despite multimodal therapeutic approaches that include surgical resection, radiation therapy or concurrent chemoradiation, targeted therapy and immunotherapy, SCCHN is still associated with a poor prognosis for patients with locally advanced or recurrent/metastatic (R/M) diseases. Although next-generation sequencing data from thousands of SCCHN patients have provided a comprehensive landscape of the somatic genomic alterations in this disease, genomic-based precision medicine is not implemented yet in routine clinical use since no satisfactory genetic biomarker has been identified for diagnosis, patient outcome prediction and selection of tailored therapeutic options.

The Role of Akt in Acquired Cetuximab Resistant Head and Neck Squamous Cell Carcinoma: An Study on a Novel Combination Strategy.

The epidermal growth factor receptor (EGFR) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). Resistance to EGFR-targeted therapies, such as cetuximab, poses a challenging problem. This study aims to characterize acquired cetuximab resistance mechanisms in HNSCC cell lines by protein phosphorylation profiling.

The Right Partner in Crime: Unlocking the Potential of the Anti-EGFR Antibody Cetuximab Combination With Natural Killer Cell Chartering Immunotherapeutic Strategies.

Cetuximab has an established role in the treatment of patients with recurrent/metastatic colorectal cancer and head and neck squamous cell cancer (HNSCC). However, the long-term effectiveness of cetuximab has been limited by the development of acquired resistance, leading to tumor relapse. By contrast, immunotherapies can elicit long-term tumor regression, but the overall response rates are much more limited.

A systematic review on poly(I:C) and poly-ICLC in glioblastoma: adjuvants coordinating the unlocking of immunotherapy.

Immunotherapy is currently under intensive investigation as a potential breakthrough treatment option for glioblastoma. Given the anatomical and immunological complexities surrounding glioblastoma, lymphocytes that infiltrate the brain to develop durable immunity with memory will be key. Polyinosinic:polycytidylic acid, or poly(I:C), and its derivative poly-ICLC could serve as a priming or boosting therapy to unleash lymphocytes and other factors in the (immuno)therapeutic armory against glioblastoma.

Recent insights in the PI3K/Akt pathway as a promising therapeutic target in combination with EGFR-targeting agents to treat head and neck squamous cell carcinoma.

Resistance to therapies targeting the epidermal growth factor receptor (EGFR), such as cetuximab, remains a major roadblock in the search for effective therapeutic strategies in head and neck squamous cell carcinoma (HNSCC). Due to its close interaction with the EGFR pathway, redundant or compensatory activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been proposed as a major driver of resistance to EGFR inhibitors. Understanding the role of each of the main proteins involved in this pathway is utterly important to develop rational combination strategies able to circumvent resistance.

Characterization of acquired nutlin-3 resistant non-small cell lung cancer cells.

: The purpose of this manuscript is to study the potential characteristics of acquired nutlin-3 resistant non-small cell lung cancer cells (NSCLC). Nutlin-3 is an inhibitor of the murine-double minute 2 protein, the main negative regulator of wild type p53, of which several derivatives are currently in clinical development. : A549 NSCLC cells were exposed to increasing concentrations of nutlin-3 for a period of 18 weeks.

Cancer-Associated Fibroblasts as a Common Orchestrator of Therapy Resistance in Lung and Pancreatic Cancer.

Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types of solid tumors. Extensive research over the past decade revealed their ability to modulate cancer metastasis, angiogenesis, tumor mechanics, immunosuppression, and drug access through synthesis and remodeling of the extracellular matrix and production of growth factors.

The art of obtaining a high yield of cell-free DNA from urine.

Although liquid biopsies offer many advantages over tissue biopsies, they are not yet standard practice. An important reason for the lack of implementation is the unavailability of well standardized techniques and guidelines, especially for pre-analytical conditions which are an important factor causing the current sensitivity issues. To overcome these limitations, we investigated the effect of several pre-analytical conditions on the concentration of cell-free DNA (cfDNA) and cellular genomic DNA (gDNA) contamination.

Radiosensitization of Non-Small Cell Lung Cancer Cells by the Plk1 Inhibitor Volasertib Is Dependent on the p53 Status.

Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division, is highly expressed in non-small cell lung cancer (NSCLC) making it an interesting drug target. We examined the in vitro therapeutic effects of volasertib, a Plk1 inhibitor, in combination with irradiation in a panel of NSCLC cell lines with different p53 backgrounds. Pretreatment with volasertib efficiently sensitized p53 wild type cells to irradiation.

The potential and controversy of targeting STAT family members in cancer.

The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors that play a complex and essential role in the regulation of physiologic cell processes, such as proliferation, differentiation, apoptosis and angiogenesis, and serves to organize the epigenetic landscape of immune cells. To date, seven STAT genes have been identified in the human genome; STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. They all account for diverse effects in response to extracellular signaling proteins, mainly by altering gene transcription in the effector cells.

The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma.

Radiotherapy (RT) in patients with melanoma historically showed suboptimal results, because the disease is often radioresistant due to various mechanisms such as scavenging free radicals by thiols, pigmentary machinery, or enhanced DNA repair. However, radiotherapy has been utilized as adjuvant therapy after the complete excision of primary melanoma and lymph nodes to reduce the rate of nodal recurrences in high-risk patients. The resistance of melanoma cells to radiotherapy may also be in relation with the constitutive activation of the MAPK pathway and/or with the inactivation of p53 observed in about 90% of melanomas.

RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review.

RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG), but also has additional more complex levels of regulation.