Enhancing Gene Delivery in NB-4 Cells: Overcoming Transduction and Selection Challenges.

Efficient gene transduction and cell viability are critical factors in genetic manipulation for research and therapeutic purposes. In this study, we explored the challenges associated with transducing the NB-4 cell line, a well-established model for acute promyelocytic leukemia (APL), using lentiviral vectors. While the initial transduction efficiency in NB-4 cells reached approximately 30%, we observed a significant decrease in cell viability, a phenomenon not observed in other acute leukemia cell lines such as THP-1 cells.

XENTURION is a population-level multidimensional resource of xenografts and tumoroids from metastatic colorectal cancer patients.

The breadth and depth at which cancer models are interrogated contribute to the successful clinical translation of drug discovery efforts. In colorectal cancer (CRC), model availability is limited by a dearth of large-scale collections of patient-derived xenografts (PDXs) and paired tumoroids from metastatic disease, where experimental therapies are typically tested. Here we introduce XENTURION, an open-science resource offering a platform of 128 PDX models from patients with metastatic CRC, along with matched PDX-derived tumoroids.

Preclinical efficacy of a HER2 synNotch/CEA-CAR combinatorial immunotherapy against colorectal cancer with HER2 amplification.

HER2 amplification occurs in approximately 5% of colorectal cancer (CRC) cases and is associated only partially with clinical response to combined human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR)-targeted treatment. An alternative approach based on adoptive cell therapy using T cells engineered with anti-HER2 chimeric antigen receptor (CAR) proved to be toxic due to on-target/off-tumor activity. Here we describe a combinatorial strategy to safely target HER2 amplification and carcinoembryonic antigen (CEA) expression in CRC using a synNotch-CAR-based artificial regulatory network.

The 1926 novel, "One, no one, one hundred thousand", metaphorizes the potential danger when the immune system is exposed to a repetitive antigen stimulation.

In the worldwide scenario of infection prevention and control, the vaccine strategies are destined to increase rapidly. The availability of numerous vaccination options allows you to plan individually on how to boost your immune system. The immune system is a highly plastic cognitive dynamic network and performs its function by recognition of the uniqueness of the organism defined as self.

Nuclear Phosphoinositides as Key Determinants of Nuclear Functions.

Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low concentration, these lipids are critical regulators of various cellular processes, including cell cycle, differentiation, gene transcription, apoptosis and motility. PPIns are generated by the phosphorylation of the inositol head group of phosphatidylinositol (PtdIns).

Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT).

Telomere maintenance is necessary to maintain cancer cell unlimited viability. However, the mechanisms maintaining telomere length in colorectal cancer (CRC) have not been extensively investigated. Telomere maintenance mechanisms (TMM) include the re-expression of telomerase or alternative lengthening of telomeres (ALT).

Synthetic Lethal Interaction with BCL-XL Blockade Deepens Response to Cetuximab in Patient-Derived Models of Metastatic Colorectal Cancer.

Purpose: Approximately 20% of patients with RAS wild-type metastatic colorectal cancer (mCRC) experience objective responses to the anti-EGFR antibody cetuximab, but disease eradication is seldom achieved. The extent of tumor shrinkage correlates with long-term outcome. We aimed to find rational combinations that potentiate cetuximab efficacy by disrupting adaptive dependencies on antiapoptotic molecules (BCL2, BCL-XL, MCL1).

Effective drug combinations in breast, colon and pancreatic cancer cells.

Combinations of anti-cancer drugs can overcome resistance and provide new treatments. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments.

Patient-derived tumor models: a more suitable tool for pre-clinical studies in colorectal cancer.

Colorectal cancer (CRC), despite the advances in screening and surveillance, remains the second most common cause of cancer death worldwide. The biological inadequacy of pre-clinical models to fully recapitulate the multifactorial etiology and the complexity of tumor microenvironment and human CRC's genetic heterogeneity has limited cancer treatment development. This has led to the development of Patient-derived models able to phenocopy as much as possible the original inter- and intra-tumor heterogeneity of CRC, reflecting the tumor microenvironment's cellular interactions.

Sustained Inhibition of HER3 and EGFR Is Necessary to Induce Regression of HER2-Amplified Gastrointestinal Carcinomas.

Purpose: Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that cotargeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular underpinnings of this synergy to identify key vulnerabilities susceptible to alternative therapeutic opportunities.

Experimental Design: The phosphorylation/activation of HER2, HER3, EGFR (HER receptors), and downstream transducers was evaluated in HER2-overexpressing colorectal and gastric cancer cell lines by Western blotting and/or multiplex phosphoproteomics.

HER2 activating mutations are targets for colorectal cancer treatment.

Unlabelled: The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation.

IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies.

Among patients with colorectal cancer who benefit from therapy targeted to the epidermal growth factor receptor (EGFR), stable disease (SD) occurs more frequently than massive regressions. Exploring the mechanisms of this incomplete sensitivity to devise more efficacious treatments will likely improve patients' outcomes. We tested therapies tailored around hypothesis-generating molecular features in patient-derived xenografts ("xenopatients"), which originated from 125 independent samples that did not harbor established resistance-conferring mutations.

Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies.

Only approximately 10% of genetically unselected patients with chemorefractory metastatic colorectal cancer experience tumor regression when treated with the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab ("primary" or "de novo" resistance). Moreover, nearly all patients whose tumors initially respond inevitably become refractory ("secondary" or "acquired" resistance). An ever-increasing number of predictors of both primary and acquired resistance to anti-EGFR antibodies have been described, and it is now evident that most of the underlying mechanisms significantly overlap.

Fertility studies in sickle cell disease: semen analysis in adult male patients.

Semen analysis was done on 50 subjects (25 patients with sickle cell anemia and 25 control subjects with normal hemoglobin genotype). The ejaculate volume, sperm motility, sperm density, and normal sperm morphology were significantly reduced in the patients when compared with the control subjects. A significant increase was also observed in the percentage of spermatids and in abnormal spermatozoa with amorphous and tapered heads in the patients' semen.

Evidence for multiple catalytic sites of human acrosin from kinetic evaluation of fructose-induced acrosin inhibition.

Acrosin (acrosomal proteinase; EC 3.4.21.

Changing parameters of donor semen.

Effective contraception and easily available abortion have contributed to the decline of adoptable children. This decline has resulted in a marked increase in the demand for AID. The provider of donor semen must establish minimal semen criteria to meet this demand effectively.

Dietary protein, life-span, and biochemical variables in female mice.

The 50% mortality of female C57BL/6J mice fed ad libitum a diet which contained 26% or 4% casein, was 23.5 and 28 mo., respectively.

Dietary protein life-span, and physiological variables in female mice.

The 50% mortality of female C57BL/6J mice fed ad libitum a diet which contained 26% or 4% casein, was 23.5 and 28 mo., respectively.