The molecular network of the proteasome machinery inhibition response is orchestrated by HSP70, revealing vulnerabilities in cancer cells.

Proteasome machinery is a major proteostasis control system in human cells, actively compensated upon its inhibition. To understand this compensation, we compared global protein landscapes upon the proteasome inhibition with carfilzomib, in normal fibroblasts, cells of multiple myeloma, and cancers of lung, colon, and pancreas. Molecular chaperones, autophagy, and endocytosis-related proteins are the most prominent vulnerabilities in combination with carfilzomib, while targeting of the HSP70 family chaperones HSPA1A/B most specifically sensitizes cancer cells to the proteasome inhibition.

Electromechanical factors associated with favourable outcome in cardiac resynchronization therapy.

Aims: Electromechanical coupling in patients receiving cardiac resynchronization therapy (CRT) is not fully understood. Our aim was to determine the best combination of electrical and mechanical substrates associated with effective CRT.

Methods And Results: Sixty-two patients were prospectively enrolled from two centres.

Histopathological Examination of an Explanted Heart in a Long-Term Responder to Cardiac Stereotactic Body Radiotherapy (STereotactic Arrhythmia Radioablation).

Cardiac stereotactic body radiotherapy is an emerging treatment method for recurrent ventricular tachycardia refractory to invasive treatment methods. The single-fraction delivery of 25 Gy was assumed to produce fibrosis, similar to a post-radiofrequency ablation scar. However, the dynamics of clinical response and recent preclinical findings suggest a possible different mechanism.

Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies.

The family of PIM serine/threonine kinases includes three highly conserved oncogenes, and , which regulate multiple prosurvival pathways and cooperate with other oncogenes such as . Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined.

Cytotoxic Efficacy and Resistance Mechanism of a TRAIL and VEGFA-Peptide Fusion Protein in Colorectal Cancer Models.

TNF-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein capable of selectively inducing apoptosis in cancer cells by binding to its cognate receptors. Here, we examined the anticancer efficacy of a recently developed chimeric AD-O51.4 protein, a TRAIL fused to the VEGFA-originating peptide.

Local electromechanical alterations determine the left ventricle rotational dynamics in CRT-eligible heart failure patients.

Left ventricle, LV wringing wall motion relies on physiological muscle fiber orientation, fibrotic status, and electromechanics (EM). The loss of proper EM activation can lead to rigid-body-type (RBT) LV rotation, which is associated with advanced heart failure (HF) and challenges in resynchronization. To describe the EM coupling and scar tissue burden with respect to rotational patterns observed on the LV in patients with ischemic heart failure with reduced ejection fraction (HFrEF) left bundle branch block (LBBB).

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism.

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology.

G protein-coupled receptor kinase 2 modifies the ability of Caenorhabditis elegans to survive oxidative stress.

Survival and adaptation to oxidative stress is important for many organisms, and these occur through the activation of many different signaling pathways. In this report, we showed that Caenorhabditis (C.) elegans G protein-coupled receptor kinases modified the ability of the organism to resist oxidative stress.

Challenges in Cancer Biomarker Discovery Exemplified by the Identification of Diagnostic MicroRNAs in Prostate Tissues.

Identification and clinical translation of routinely tested biomarkers require a complex and multistep workflow. Here, we described a confirmatory process estimating the utility of previously identified candidate tissue miRNAs for diagnosis of prostate cancer (PCa). RNA was isolated from formalin-fixed paraffin-embedded (FFPE) prostate tissue surgically resected from 44 patients with PCa and 24 patients with benign prostate hyperplasia (BPH).

Serine Biosynthesis Pathway Supports MYC-miR-494-EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells.

Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting biosynthesis of certain amino acids, nucleotides, glutathione, and a methyl group donor, S-adenosylmethionine (SAM).

Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer.

Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets.

Challenges in Stratifying the Molecular Variability of Patient-Derived Colon Tumor Xenografts.

Colorectal cancer (CRC) is the second most common cancer in Europe and a leading cause of death worldwide. Patient-derived xenograft (PDX) models maintain complex intratumoral biology and heterogeneity and therefore remain the platform of choice for translational drug discovery. In this study, we implanted 37 primary CRC tumors and five CRC cell lines into NU/J mice to develop xenograft models.

[History of antibiotics and sulphonamides discoveries].

In the 19th century, the effect of mould on bacterial colonies was investigated. In 1921, Alexander Fleming examined systemic fluids and observed some substances called lyzosomes which were capable of dissolving bacteria. In 1928, he discovered that a specific mould species inhibited the development of Staphylococcus bacteria.

The structural and biochemical characterization of human RNase H2 complex reveals the molecular basis for substrate recognition and Aicardi-Goutières syndrome defects.

RNase H2 cleaves RNA sequences that are part of RNA/DNA hybrids or that are incorporated into DNA, thus, preventing genomic instability and the accumulation of aberrant nucleic acid, which in humans induces Aicardi-Goutières syndrome, a severe autoimmune disorder. The 3.1 Å crystal structure of human RNase H2 presented here allowed us to map the positions of all 29 mutations found in Aicardi-Goutières syndrome patients, several of which were not visible in the previously reported mouse RNase H2.

[Etiology of colorectal cancer and antioxidant barrier of the organism].

Colorectal cancer is a serious medical and economic problem in Poland, as the detection and results of its treatment are very low. Due to this fact, medical research is still conducted in order to find out the symptoms of this tumor and proper preventive measures. According to one hypothesis of carcinogenesis, the process of creating the tumor begins and develops when the balance between the production of reactive oxygen species (ROS) and their deactivation by the "antioxidant protective barrier of the organism" is disturbed.