Genome-scale clustered regularly interspaced short palindromic repeats screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common malignancy that develops in patients with ataxia-telangiectasia, a cancer-predisposing inherited syndrome characterized by inactivating germline ATM mutations. ATM is also frequently mutated in sporadic DLBCL. To investigate lymphomagenic mechanisms and lymphoma-specific dependencies underlying defective ATM, we applied RNA sequencing and genome-scale loss-of-function clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens to systematically interrogate B-cell lymphomas arising in a novel murine model (Atm-/-nu-/-) with constitutional Atm loss, thymic aplasia but residual T-cell populations.

DNA damage response defects in hematologic malignancies: mechanistic insights and therapeutic strategies.

The DNA damage response (DDR) encompasses the detection and repair of DNA lesions and is fundamental to the maintenance of genome integrity. Germ line DDR alterations underlie hereditary chromosome instability syndromes by promoting the acquisition of pathogenic structural variants in hematopoietic cells, resulting in increased predisposition to hematologic malignancies. Also frequent in hematologic malignancies are somatic mutations of DDR genes, typically arising from replication stress triggered by oncogene activation or deregulated tumor proliferation that provides a selective pressure for DDR loss.

The Application of a Multi-Material Flexible Chain Mail for the Design of an Artificial Spinal Disc to Reproduce Natural Nonlinear and Anisotropic Rotational Behavior.

Inspired by the potential of architected materials for achieving biomimicking functionalities and the advancement of multi-material additive manufacturing to fabricate parts with complex structures and heterogeneous material distributions, this study investigates the feasibility of using a multi-material, flexible chain mail sheet for the design of an additively manufactured artificial spinal disc for reproducing patient-specific anisotropic and nonlinear rotational behaviors. The application of a chain mail-based structure is motivated by its similarities in behaviors compared with a natural disc's fiber network that likewise has negligible bending stiffness and shape-changing ability. The proposed approach for the chain mail sheet design includes an initial characterization of the uniaxial tensile responses of the chain mail unit cell defined as the basic building block of the chain mail sheet, modeling and response calculation, and material optimization.

Synthesis of 4-Deoxy-4-Fluoro-d-Sedoheptulose: A Promising New Sugar to Apply the Principle of Metabolic Trapping.

Fluorinated carbohydrates are important tools for understanding the deregulation of metabolic fluxes and pathways. Fluorinating specific positions within the sugar scaffold can lead to enhanced metabolic stability and subsequent metabolic trapping in cells. This principle has, however, never been applied to study the metabolism of the rare sugars of the pentose phosphate pathway (PPP).

SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1 cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction.

Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids.

α-Aminophosphonic acids have a remarkably broad bioactivity spectrum. They can function as highly efficient transition state mimics for a variety of hydrolytic and angiotensin-converting enzymes, which makes them interesting target structures for synthetic chemists. In particular, the phosphonic acid analogs to α-aminocarboxylic acids (P AAs) are potent enzyme inhibitors, but many of them are only available by chiral or enzymatic resolution; sometimes only one enantiomer is accessible, and several have never been prepared in enantiopure form at all.

Decreased TSPAN14 Expression Contributes to NSCLC Progression.

Tspan14 is a transmembrane protein of the tetraspanin (Tspan) protein family. Different members of the Tspan family can promote or suppress tumor progression. The exact role of Tspan14 in tumor cells is unknown.

Auxetic structures used in kinesiology tapes can improve form-fitting and personalization.

Each year 65% of young athletes and 25% of physically active adults suffer from at least one musculoskeletal injury that prevents them from continuing with physical activity, negatively influencing their physical and mental well-being. The treatment of musculoskeletal injuries with the adhesive elastic kinesiology tape (KT) decreases the recovery time. Patients can thus recommence physical exercise earlier.

Novel tech throws knock-out punch to ECG improving GP referral decisions to cardiology.

Purpose: In a comparator study, designed with assistance from the Food and Drug Administration, a State-of-the-Art (SOTA) ECG device augmented with automated analysis, the comparator, was compared with a breakthrough technology, Cardio-HART (CHART).

Methods: The referral decision defined by physician reading biosignal-based ECG or CHART report were compared for 550 patients, where its performance is calculated against the ground truth referral decision. The ground truth was established by cardiologist consensus based on all the available measurements and findings including echocardiography (ECHO).

Signatures of TOP1 transcription-associated mutagenesis in cancer and germline.

The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair. In microorganisms, transcription has been demonstrated to be mutagenic; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes.

Adjacent Joint Restriction Differentially Influences Intra- and Inter-rater Reliability and Agreement of Goniometric Measurements.

Background: Reliability and agreement of goniometric measurements can be altered by variations in measurement technique such as restricting adjacent joints to influence bi-articular muscles. It is unknown if the influence of adjacent joint restriction is consistent across different range of motion (ROM) tests, as this has yet to be assessed within a single study. Additionally, between-study comparisons are challenged by differences between methodology, participants and raters, obscuring the development of a conceptual understanding of the extent to which adjacent joint restriction can influence goniometric ROM measurements.

Correction: Kwok et al. Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives. 2021, , 4681.

The authors wish to make the following corrections to their paper [1] [...

Functional Movement Screen Task Scores and Joint Range-of-motion: A Construct Validity Study.

Little is known about the construct validity of the Functional Movement Screen (FMS). We aimed to assess associations between FMS task scores and measures of maximum joint range-of-motion (ROM) among university varsity student-athletes from 4 sports (volleyball, basketball, ice hockey, and soccer). Athletes performed FMS tasks and had their maximum ankle, hip and shoulder ROM measured.

Dataset of angular and compressive responses of biomimetic artificial spinal discs fabricated using multi-material additive manufacturing.

To explore the influence of different biomimetic designs and multi-material additive manufacturing on the performance of a multi-material artificial spinal disc (ASD) in terms of restoring natural mechanics, four biomimetic ASD designs together with a control design are first fabricated using a Stratasys Connex3 Objet500 inkjet-based, multi-material 3D printer and their mechanical responses are measured using in-vitro mechanical testing. The mechanical tests include an angular test and a compression test to measure the ASD's behavior in the seven most frequent loading scenarios of a spine: flexion, extension, left/right lateral bending, left/right axial rotation, and compression. The angular test is performed using a custom six degrees of freedom, computer-controlled spine testing system together with an optoelectronic motion analysis system, while the compression test is performed using an Instron testing machine.

New Therapeutic Strategy for Overcoming Multidrug Resistance in Cancer Cells with Pyrazolo[3,4-]pyrimidine Tyrosine Kinase Inhibitors.

Tyrosine kinase inhibitors (TKIs) often interact with the multidrug resistant (MDR) phenotype of cancer cells. In some cases, TKIs increase the susceptibility of MDR cancer cells to chemotherapy. As the overexpression of membrane transporter P-glycoprotein (P-gp) is the most common alteration in MDR cancer cells, we investigated the effects of TKI pyrazolo[3,4-]pyrimidines on P-gp inhibition in two cellular models comprising sensitive and corresponding MDR cancer cells (human non-small cell lung carcinoma and colorectal adenocarcinoma).

Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives.

The p53 pathway is a desirable therapeutic target, owing to its critical role in the maintenance of genome integrity. This is exemplified in chronic lymphocytic leukemia (CLL), one of the most common adult hematologic malignancies, in which functional loss of p53 arising from genomic aberrations are frequently associated with clonal evolution, disease progression, and therapeutic resistance, even in the contemporary era of CLL targeted therapy and immunotherapy. Targeting the 'undruggable' p53 pathway therefore arguably represents the holy grail of cancer research.