A blood-based DNA damage signature in patients with Parkinson's disease is associated with disease progression.

Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson's Progression Markers Initiative cohort to investigate DNA damage in PD. Patients with PD exhibited disrupted DNA repair pathways and biased suppression of longer transcripts, indicating age-related, transcription-stalling DNA damage.

Detecting Cancer Early with Ultrasensitive Multimodal Liquid Biopsy.

Wang and colleagues showed that ctDNA can be detected in plasma up to 3 years prior to clinical diagnosis. The study highlights the need for ultrasensitive and multimodal approaches that integrate the detection of mutations and copy-number changes with advanced computational platforms to deliver effective early-detection strategies. See related article by Wang et al.

Cargoes move from cis to trans-Golgi compartments and concentrate in the TGN before exiting.

The classical models of intra-Golgi transport envision a movement of cargoes from cis- to trans-Golgi, followed by their sorting at the trans-Golgi network (TGN). During this vectorial transport, the cargoes are processed by sequentially acting glycosylation enzymes. A number of studies challenged the vectorial transport model and proposed alternative transport routes bypassing either directional transport or the TGN.

Structural obstruction to full DNA replication in terminally differentiated skeletal muscle cells.

Terminal cell differentiation is often associated with permanent withdrawal from proliferation, termed the postmitotic state. Though widespread among vertebrates and determinant for their biology, the molecular underpinnings of this state are poorly understood. Postmitotic skeletal muscle myotubes can be induced to reenter the cell cycle; however, they generally die as a result of their inability to complete DNA replication.

Combining BET inhibition with SMAC mimetics restricts tumor growth and triggers immune surveillance in preclinical cancer models.

Second mitochondrial activator of caspase (SMAC) mimetics (SMACm) and bromodomain and extra-terminal domain (BET) inhibitors (BETi) are two distinct classes of novel anticancer therapeutics. So far, broad clinical benefit for either monotherapy has not been achieved, calling for effective combination strategies. We show that the combination of BI 891065, a monovalent oral SMACm antagonist of inhibitor of apoptosis protein 1 (cellular inhibitor of apoptosis protein 1 [cIAP1]), and BI 894999, a potent and selective oral BETi, significantly impaired cancer cell proliferation irrespective of tissue context.

Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells.

Non-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) almost invariably relapse in the long term, due to the emergence of subpopulations of resistant cells. Through a DNA barcoding approach, we show that the clinically approved drug sorafenib specifically abolishes the selective advantage of EGFR-TKI-resistant cells, while preserving the response of EGFR-TKI-sensitive cells. Sorafenib is active against multiple mechanisms of resistance/tolerance to EGFR-TKIs and its effects depend on early inhibition of MAPK-interacting kinase (MKNK) activity and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and later down-regulation of MCL1 and EGFR.

Quantifying Nuclear Shape Fluctuations During Early Mitosis.

This chapter presents a detailed methodology for monitoring nuclear shape fluctuations and their correlation with chromatin condensation, developed for our analyses of early prophase, but applicable to other contexts. Nuclear shape dynamics play a key role in mitotic progression, and understanding the mechanical and biophysical properties associated with the fast-paced fluctuations may offer insights into key cellular processes like chromatin condensation and nuclear envelope breakdown. By employing live-cell imaging and computational analysis such as segmentation and flickering spectroscopy techniques, this approach leverages high-resolution temporal tracking of nuclear shape changes during cell cycle progression to derive insights into the mechanical forces driving chromatin condensation and nuclear envelope instabilities leading to the nuclear envelope breakdown.

Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00.

Phosphorylation of the JNK (pJNK) protein promotes an immunosuppressive tumor microenvironment (TME), enhancing aggressiveness in inflammatory triple-negative breast cancer (TNBC). This study evaluated the role of JNK signaling using a gene signature. RNA sequencing was performed on 347 TNBC tumors from the phase 3 International Breast Cancer Study Group (IBCSG) 22-00 trial, which evaluated adjuvant low-dose cyclophosphamide and methotrexate (CM).

Genotype-phenotype correlations in biallelic carriers of FANCM protein truncating variants: A systematic literature review.

The FANCM gene is involved in the Fanconi Anemia (FA) DNA repair pathway. Although germline biallelic pathogenic variants in genes of this pathway cause the recessive FA syndrome, the role of FANCM in FA or FA-like has been questioned. Biallelic FANCM protein truncating variants (PTVs) have been primarily linked to infertility and cancer, suggesting the gene causes a clinically distinct phenotype.

Structure of the Secretory Compartments in Goblet Cells in the Colon and Small Intestine.

The Golgi of goblet cells represents a specialized machine for mucin glycosylation. This process occurs in a specialized form of the secretory pathway, which remains poorly examined. Here, using high-resolution three-dimensional electron microscopy (EM), EM tomography, serial block face scanning EM (SBF-SEM) and immune EM we analyzed the secretory pathway in goblet cells and revealed that COPII-coated buds on the endoplasmic reticulum (ER) are extremely rare.

Patient-Derived Explants of Osteoarthritic Synovium as Ex Vivo Model for Preclinical Research.

Osteoarthritis (OA) is the most common chronic arthropathy worldwide. OA synovitis is a common feature that predicts the development and progression of symptoms and joint damage. Although the OA synovium is a target for novel therapies, the development of ex vivo models remains an area requiring further research.

RAB5A Promotes Active Fluid Wetting by Reprogramming Breast Cancer Spheroid Mechanics.

Unjamming transitions from a solid-like to a fluid-like state are a gateway to breast epithelial cancer invasion. However, the mechanical interplay between phase transitions and dimension transitions, in particular wetting, remains elusive, despite being critical for understanding the onset of metastatic dissemination. This study shows that unjamming, mediated by the RAB5A GTPase, alters carcinoma spheroid fluidity, rigidity, and rewires adhesion mechanics to drive supracellular active wetting as a new mode of tumor expansion.

Gene expression profiling in a retrospective real-world cohort of breast cancer brain metastases and paired primary tumors identifies biological changes with potential therapeutic implications.

Background: Despite the clinical impact of breast cancer (BC) brain metastases (BMs), their biological complexity remains poorly understood. We evaluated the genomic profile of BCBMs and compared it with paired primary BC samples to characterize biological changes during brain metastasization and their clinical impact in a retrospective real-world cohort.

Materials And Methods: Expression of 758 genes (BC360 Panel, nCounter), hormone receptor (HR) status, and human epidermal growth factor receptor type 2 (HER2) status were evaluated in BCBMs and matched primary BCs.

The 50-nm Free Vesicles Visible in Are Not COPII-Dependent.

According to the current dogma, ER-Golgi transport is mediated by COPII-coated vesicles. However, numerous contradictions have emerged in this field. In this study, we demonstrate that contains three distinct types of membrane spheres, with diameters of approximately 35-45 nm, 47-52 nm, and over 65 nm, respectively.

Aggressive B-cell lymphomas retain ATR-dependent determinants of T-cell exclusion from the Germinal Center Dark Zone.

The germinal center (GC) dark zone (DZ) and light zone (LZ) represent distinct anatomical regions in lymphoid tissue where B-cell proliferation, immunoglobulin diversification, and selection are coordinated. Diffuse Large B-cell Lymphomas (DLBCL) with DZ-like gene expression profiles exhibit poor outcomes, though reasons are unclear and are not directly related to proliferation. Physiological DZs exhibit an exclusion of T-cells, prompting exploration for whether T-cell paucity contributes to DZ-like DLBCL.

Sirtuins and their role in ovarian aging-related fibrosis predisposing to ovarian cancer.

The pursuit of understanding early genetic or protein markers for ovarian aging has garnered considerable attention in the realm of reproductive medicine. Sirtuins (SIRTs) are a group of proteins that are NAD-dependent, and thanks to their properties, they are able to change the acetylation profile of proteins and post-translationally modify their functions, too. Previous research provided evidence that SIRTs influence fibrosis levels in several organs.

TRF1 relies on fork reversal to prevent fragility at human telomeres.

Telomeres pose challenges during replication, with converging forks unlikely to resolve issues. Depleting TRF1 results in fragile telomeres, yet its exact role in telomere replication remains unclear. In our cellular model, insufficient TRF1 density at long telomeres leads to telomere fragility that is alleviated by restoring telomeric TRF1 levels.

Biomarkers of psychological stress are associated with increased susceptibility to the development of breast and prostate cancer in BRCA1/2 mutation carriers.

Background: Epidemiological studies have linked psychological stress with an increased risk of breast cancer, however few studies have linked stress hormone signalling to cancer initiation mechanistically. This may be particularly pertinent in populations already at risk due to mutations in the cancer predisposition genes BRCA1/2.

Methods: Here we employ BRCA1/2 knockdown in breast and prostate epithelial cells to examine the effects of the stress hormone cortisol on DNA damage and repair.

Preoperative ctDNA retains prognostic relevance beyond postoperative assessment in stage II-III colon cancer.

In cancer patients, only a small fraction of circulating cell-free DNA (cfDNA) consists of circulating tumor DNA (ctDNA), which contains tumor-specific features. Detecting ctDNA in peripheral blood through liquid biopsy offers a safe, noninvasive alternative to traditional tissue biopsy, with the added benefit of enabling repeated testing over time. This study investigates the potential of liquid biopsy as an innovative and noninvasive prognostic tool for patients with stage II-III colon cancer.

Immunocytokines in cancer treatment: A systematic review.

Introduction: Immunocytokines are an emerging class of antibody-cytokine fusion proteins combining the specificity of monoclonal antibodies with the potent immunostimulatory effects of cytokines, potentially enhancing the anti-tumor immune response while reducing systemic toxicity.

Methods: We conducted a systematic review following the PRISMA guidelines. We performed a comprehensive literature search using PubMed and ClinicalTrials.

USP37 prevents premature disassembly of stressed replisomes by TRAIP.

The eukaryotic replisome, which consists of the CDC45-MCM2-7-GINS (CMG) helicase, replicative polymerases, and several accessory factors, sometimes encounters proteinaceous obstacles that threaten genome integrity. These obstacles are targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP, which associates with the replisome. However, TRAIP must be carefully regulated to avoid inappropriate ubiquitylation and disassembly of the replisome.

Nuclear deformability increases PARPi sensitivity in BRCA1-deficient cells by increasing microtubule-dependent DNA break mobility.

Microtubules and nuclear transmembrane SUN1/2 proteins promote the mobility of DNA Double Strand Breaks (DSBs) induced by ionizing radiation and the misrepair of one-ended DSBs induced in BRCA1-deficient cells by Poly(ADP-ribose) polymerase inhibitors (PARPi). However, whether microtubules promote aberrant DSBs repair by altering the nuclear structure and whether the nuclear structure itself plays a role in these processes is still unclear. Here we show that microtubule-dependent DSBs mobility in BRCA1-deficient cells after PARPi treatment is associated with nuclear envelope (NE) invaginations.

Case Report WIN-MTB-2023001 WIN International Molecular Tumor Board A 62-year-old male with metastatic colorectal cancer with 5 prior lines of treatment.

Heavily pretreated metastatic colorectal cancer (mCRC) poses significant therapeutic challenges. Advances in molecular profiling enables personalized strategies. We present a 62-year-old male with mCRC harboring , , , and alterations, following FOLFOX and FOLFIRI, dabrafenib plus panitumumab, and a BRAF inhibitor clinical trial, each leading to initial responses followed by disease progression.

Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models.

Hypermutation induced by mismatch repair (MMR) inactivation leads to immune surveillance in colorectal cancer (CRC) and in several other malignancies. We investigated the impact of a rationally designed chemotherapy combination on the generation of hypermutation and immunogenicity in otherwise immune-refractory CRC and breast cancer mouse models. Combinatorial treatment with cisplatin (CDDP) and temozolomide (TMZ) induces an adaptive downregulation of MMR, resulting in chemotherapy-dependent hypermutability and increase in predicted neoantigens.