Tumor-Targeted Cell-Penetrating Peptides Reveal That Monomethyl Auristatin E Temporally Modulates the Tumor Immune Microenvironment.

Chemotherapies remain standard therapy for cancers but have limited efficacy and cause significant side effects, highlighting the need for targeted approaches. In the progression of cancer, tumors increase matrix metalloproteinase (MMP) activity. Leveraging and therapeutically redirecting tumor MMPs through activatable cell-penetrating peptide (ACPP) technology offers new approaches for tumor-selective drug delivery and for studying how drug payloads engage the tumor immune microenvironment.

NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology.

C-terminal mutation of Nucleophosmin 1 (NPM1) was thought to be a primary driving event in acute myeloid leukemia (AML) that reprograms leukemic-associated transcription programs to transform hematopoietic stem and progenitor cells (HSPCs). However, molecular mechanisms underlying NPM1-driven leukemogenesis remain elusive. Here, we report that NPM1 activates signature HOX genes and reprograms cell cycle regulators by altering CTCF-driven topologically associated domains (TADs).

Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy.

Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy.

Kick-off meeting of the TOWWERS showcase project: 1 collaborative value-based healthcare anchored on real-world data involving the 5P.

The COVID-19 pandemic has highlighted the need to modernize healthcare systems to the reality of the 21st century. The first world-wide Strategic Committee to launch Collaborative Value-Based Healthcare (C-VBHC) anchored on populational Real World Data and structured collaboration, took place in Montreal, via TOWWERS showcase project. The meeting covered a broad range of topics from the perspective of each of the various Real-World healthcare actors, the 5P+: Patient, Prescriber, Producer, Policymaker, Payer, including Data and Research stakeholders.

HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia.

HOTTIP lncRNA is highly expressed in acute myeloid leukemia (AML) driven by MLL rearrangements or NPM1 mutations to mediate HOXA topologically associated domain (TAD) formation and drive aberrant transcription. However, the mechanism through which HOTTIP accesses CCCTC-binding factor (CTCF) chromatin boundaries and regulates CTCF-mediated genome topology remains unknown. Here, we show that HOTTIP directly interacts with and regulates a fraction of CTCF-binding sites (CBSs) in the AML genome by recruiting CTCF/cohesin complex and R-loop-associated regulators to form R-loops.