At the right time: Moving precision therapy to newly diagnosed cancer.

Precision oncology aims to match the right drug(s) to the right patient. Equally important is ensuring that precision therapies are offered at the right time. Transformative, rather than incremental, outcome improvement may require treatment at diagnosis rather than in the advanced/metastatic setting after genomic evolution.

PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization.

Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, preventing unrestrained (phospho)lipid peroxidation by reducing phospholipid hydroperoxides (PLOOH). However, the contribution of other phospholipid peroxidases in ferroptosis protection remains unclear. We show that cells lacking GPX4 still exhibit substantial PLOOH-reducing capacity, suggesting a contribution of alternative PLOOH peroxidases.

The Molecular Tumor Board Turns 10: The Age of Complexity.

Gene sequencing has brought a titanic of complex data into clinical precision oncology. Deciphering this complexity for practice requires new constructs. In 2014, the Molecular Tumor Board (MTB) was introduced into the literature by a publication in The Oncologist.

ADAMTS12 promotes fibrosis by restructuring extracellular matrix to enable activation of injury-responsive fibroblasts.

Fibrosis represents the uncontrolled replacement of parenchymal tissue with extracellular matrix (ECM) produced by myofibroblasts. While genetic fate-tracing and single-cell RNA-Seq technologies have helped elucidate fibroblast heterogeneity and ontogeny beyond fibroblast to myofibroblast differentiation, newly identified fibroblast populations remain ill defined, with respect to both the molecular cues driving their differentiation and their subsequent role in fibrosis. Using an unbiased approach, we identified the metalloprotease ADAMTS12 as a fibroblast-specific gene that is strongly upregulated during active fibrogenesis in humans and mice.

Liquid biopsies and those three little words: finding the perfect match for the MTB.

Monitoring ctDNA by liquid biopsies seems to represent the perfect match for precision oncology and its cornerstone clinical framework: the molecular tumour board (MTB). Detecting and scrutinising the success of targeted therapies or tracking and, for that matter, addressing the therapy with the evolutive nature of a tumour are some of the main advancements one considers to be important for the MTB. One challenge is correlating the estimated allele frequency of each identified genetic alteration determined by analysing the ctDNA sequencing results and matching these with the range of suitable drugs, which may limit the simultaneous treatment of all tumour variations.

A tangible method to assess native ferroptosis suppressor activity.

Ferroptosis, a regulated cell death hallmarked by unrestrained lipid peroxidation, plays a pivotal role in the pathophysiology of various diseases, making it a promising therapeutic target. Glutathione peroxidase 4 (GPX4) prevents ferroptosis by reducing (phospho)lipid hydroperoxides, yet evaluation of its actual activity has remained arduous. Here, we present a tangible method using affinity-purified GPX4 to capture a snapshot of its native activity.

Liquid Biopsy Response Evaluation Criteria in Solid Tumors (LB-RECIST).

Current evaluation of treatment response in solid tumors depends on dynamic changes in tumor diameters as measured by imaging. However, these changes can only be detected when there are enough macroscopic changes in tumor volume, which limits the usability of radiological response criteria in evaluating earlier stages of disease response and necessitates much time to lapse for gross changes to be notable. One promising approach is to incorporate dynamic changes in circulating tumor DNA (ctDNA), which occur early in the course of therapy and can predict tumor responses weeks before gross size changes manifest.

High RIPK3 expression is associated with a higher risk of early kidney transplant failure.

Renal ischemia-reperfusion injury (IRI) is associated with reduced allograft survival, and each additional hour of cold ischemia time increases the risk of graft failure and mortality following renal transplantation. Receptor-interacting protein kinase 3 (RIPK3) is a key effector of necroptosis, a regulated form of cell death. Here, we evaluate the first-in-human RIPK3 expression dataset following IRI in kidney transplantation.

Sodium fluoride (NaF) PET Response Criteria in Solid Tumors (NAFCIST): a framework for response assessment in bone tumors.

The current Response Evaluation Criteria in Solid Tumors for measuring tumor response in osteosarcoma may be sub-optimal, as even responsive bone tumors may show limited change in tumor diameters. This limits the use of traditional imaging assessment tools. Therefore, discerning osteosarcoma response to therapy on magnetic resonance imaging before surgery is often difficult, and it is typically evaluated after surgery by assessing the amount of necrosis in resected surgical specimens.

Diverse biological functions of vitamin K: from coagulation to ferroptosis.

Vitamin K is essential for several physiological processes, such as blood coagulation, in which it serves as a cofactor for the conversion of peptide-bound glutamate to γ-carboxyglutamate in vitamin K-dependent proteins. This process is driven by the vitamin K cycle facilitated by γ-carboxyglutamyl carboxylase, vitamin K epoxide reductase and ferroptosis suppressor protein-1, the latter of which was recently identified as the long-sought-after warfarin-resistant vitamin K reductase. In addition, vitamin K has carboxylation-independent functions.

N-of-1 Trials in Cancer Drug Development.

The current approaches for cancer drug development lag behind an accelerated need in the field for a fast and efficient method for evaluating drugs in the personalized medicine era. In that regard, N-of-1 studies emerge as a potential addition to the drug development arsenal, although there are several considerations before its broad application becomes feasible. In essence, N-of-1 trials are a departure from the traditional "drug-centric" model to a "patient-centric" model.

Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical Implications.

Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored, which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies.

Ferroptosis: Under pressure!

Ferroptosis is a disease-relevant and pervasive form of cell death triggered by iron-dependent lipid peroxidation and resulting in membrane rupture. A new study addresses how tension-sensing channels can balance and modulate membrane tension in the context of ferroptotic cell death.

The effectiveness of intradialytic exercise in ameliorating fatigue symptoms in patients with chronic kidney failure undergoing hemodialysis: A systematic literature review and meta-analysis.

Objective: Hemodialysis in patients with chronic kidney failure is an intervention serving as an alternative to kidney transplantation. In 2019, chronic kidney failure became the world's 6th leading cause of death. In Indonesia, kidney failure has an increasing number of cases every year and is the 10th highest cause of death.

Platelet-instructed SPP1 macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner.

Fibrosis represents the common end stage of chronic organ injury independent of the initial insult, destroying tissue architecture and driving organ failure. Here we discover a population of profibrotic macrophages marked by expression of Spp1, Fn1, and Arg1 (termed Spp1 macrophages), which expands after organ injury. Using an unbiased approach, we identify the chemokine (C-X-C motif) ligand 4 (CXCL4) to be among the top upregulated genes during profibrotic Spp1 macrophage differentiation.

The coming decade in precision oncology: six riddles.

High-throughput methods to investigate tumour omic landscapes have quickly catapulted cancer specialists into the precision oncology era. The singular lesson of precision oncology might be that, for it to be precise, treatment must be personalized, as each cancer's complex molecular and immune landscape differs from patient to patient. Transformative therapies include those that are targeted at the sequelae of molecular abnormalities or at immune mechanisms, and, increasingly, pathways previously thought to be undruggable have become druggable.

Molecular landscape of immune pressure and escape in aplastic anemia.

Idiopathic aplastic anemia (IAA) pathophysiology is dominated by autoreactivity of human leukocyte antigen (HLA)-restricted T-cells against antigens presented by hematopoietic stem and progenitor cells (HSPCs). Expansion of PIGA and HLA class I mutant HSPCs have been linked to immune evasion from T-cell mediated pressures. We hypothesized that in analogy with antitumor immunity, the pathophysiological cascade of immune escape in IAA is initiated by immunoediting pressures and culminates with mechanisms of clonal evolution characterized by hits in immune recognition and response genes.

A study of Telomerase Reverse Transcriptase rare variants in myeloid neoplasia.

Telomere dysfunctions are associated with several hematopoietic stem cell (HSC) malignancies. Recent findings have indicated that the occurrence of rare variants of unknown significance (VUS) in the Telomerase Reverse Transcriptase (TERT) gene influences the outcomes of patients with myelodysplastic syndromes undergoing allogeneic HSC transplantation. However, the role of TERT variants has been historically controversial as initially considered pathogenic variants (H412Y, A202T) presenting functional consequences, were found very frequent in general population questioning their pathogenicity and risk allele significance.

Executioner caspases 3 and 7 are dispensable for intestinal epithelium turnover and homeostasis at steady state.

Apoptosis is widely believed to be crucial for epithelial cell death and shedding in the intestine, thereby shaping the overall architecture of the gastrointestinal tract, but also regulating tolerance induction, pinpointing a role of apoptosis intestinal epithelial cell (IEC) turnover and maintenance of barrier function, and in maintaining immune homeostasis. To experimentally address this concept, we generated IEC-specific knockout mice that lack both executioner caspase-3 and caspase-7 (), which are the converging point of the extrinsic and intrinsic apoptotic pathway. Surprisingly, the overall architecture, cellular landscape, and proliferation rate remained unchanged in these mice.