PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis.

Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins.

Activation of the PP2A-B56α heterocomplex synergizes with venetoclax therapies in AML through BCL2 and MCL1 modulation.

Venetoclax combination therapies are becoming the standard of care in acute myeloid leukemia (AML). However, the therapeutic benefit of these drugs in older/unfit patients is limited to only a few months, highlighting the need for more effective therapies. Protein phosphatase 2A (PP2A) is a tumor suppressor phosphatase with pleiotropic functions that becomes inactivated in ∼70% of AML cases.

Estimation of vaccine effectiveness using the screening method.

The screening method provides a simple and rapid way of estimating vaccine effectiveness. This paper discusses the validity of the screening method with particular reference to bias and precision. Methods for correcting confounding, adjusting for covariates and over-dispersion, and deriving confidence limits are discussed in a modelling framework.

Arteriovenous Fistula Nonmaturation: What's the Immune System Got to Do with It?

Background: Arteriovenous fistula (AVF) nonmaturation is a persistent problem, particularly among female and Black patients. Increasingly, the immune system has been recognized as an important contributor to vascular disease, but few studies have examined immune factors relative to AVF maturation outcomes. This study evaluated the association of serum panel reactive antibodies (PRA), a measure of immune system reactivity assessed in patients undergoing kidney transplant evaluation, with AVF nonmaturation.

PICC line management among patients with chronic kidney disease.

More than 1 million peripherally inserted central catheters (PICC) are placed annually in the US and are used to provide convenient vascular access for a variety of reasons including long term antibiotic treatment, chemotherapy, parenteral nutrition, and blood draws. Although they are relatively easy to place and inexpensive, PICC line use is associated with many complications such as phlebitis/thrombophlebitis, venous thrombosis, catheter-related infection, wound infection, and central vein stenosis. These complications are far more deleterious for patients with chronic kidney disease (CKD) whose lives depend on a functioning hemodialysis access once they reach end stage kidney disease (ESKD).

Targeting protein phosphatase PP2A for cancer therapy: development of allosteric pharmaceutical agents.

Tumor initiation is driven by oncogenes that activate signaling networks for cell proliferation and survival involving protein phosphorylation. Protein kinases in these pathways have proven to be effective targets for pharmaceutical inhibitors that have progressed to the clinic to treat various cancers. Here, we offer a narrative about the development of small molecule modulators of the protein Ser/Thr phosphatase 2A (PP2A) to reduce the activation of cell proliferation and survival pathways.

CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis.

Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells.

Considering Performance in the Automated and Manual Coding of Sociolinguistic Variables: Lessons From Variable (ING).

Impressionistic coding of sociolinguistic variables like English (ING), the alternation between pronunciations like and , has been a central part of the analytic workflow in studies of language variation and change for over a half-century. Techniques for automating the measurement and coding for a wide range of sociolinguistic data have been on the rise over recent decades but procedures for coding some features, especially those without clearly defined acoustic correlates like (ING), have lagged behind others, such as vowels and sibilants. This paper explores computational methods for automatically coding variable (ING) in speech recordings, examining the use of automatic speech recognition procedures related to forced alignment (using the Montreal Forced Aligner) as well as supervised machine learning algorithms (linear and radial support vector machines, and random forests).

Sources of variation in the speech of African Americans: Perspectives from sociophonetics.

African American Language (AAL) is one of the most researched varieties of American English, yet key aspects of its development and spread remain under-theorized. For example, regional and social variation in the speech of African Americans was initially understudied in AAL as scholars sought to demonstrate the overall systematicity of the variety, often at the expense of examining variation across and within communities. More recently, scholars have begun to address this gap by examining different sources of variation in AAL phonology.

Kidney Imaging and Biopsy in Pregnancy.

Physiologic glomerular, tubular, and structural changes related to pregnancy may complicate the detection of underlying kidney disease in pregnant patients. Imaging studies may provide important clinical information to assist in the diagnosis and treatment of kidney disease during pregnancy. Furthermore, in select patients who develop new or worsening kidney disease in pregnancy, kidney biopsy may be essential to ensure the accuracy of diagnosis and guide treatment choices.

Early Predictors of Arteriovenous Fistula Maturation: A Novel Perspective on an Enduring Problem.

Background: Preoperative ultrasound mapping is routinely used to select vessels meeting minimal threshold diameters for surgical arteriovenous fistula (AVF) creation but fails to improve AVF maturation rates. This suggests a need to reassess the preoperative ultrasound criteria used to optimize AVF maturation.

Methods: We retrospectively identified 300 catheter-dependent patients on hemodialysis with a new AVF created between 2010 and 2016.

A qualitative study of clinician attitudes towards closed-loop systems in mainstream diabetes care in England.

Aim: Clinicians mediate access to new technologies. Consequently, their views on specific devices may influence user access to diabetes technology in mainstream care. As yet, little is known about clinicians' views about closed-loop systems.

Who Should Access Closed-Loop Technology? A Qualitative Study of Clinician Attitudes in England.

Clinicians mediate access to closed-loop technology for people with diabetes. Consequently, their attitudes regarding appropriate levels of closed-loop usage will play a key role in future adoption processes. This study aimed to explore clinician attitudes toward future mainstream closed-loop usage in England.

Integration of the Duke Activity Status Index into preoperative risk evaluation: a multicentre prospective cohort study.

Background: The Duke Activity Status Index (DASI) questionnaire might help incorporate self-reported functional capacity into preoperative risk assessment. Nonetheless, prognostically important thresholds in DASI scores remain unclear. We conducted a nested cohort analysis of the Measurement of Exercise Tolerance before Surgery (METS) study to characterise the association of preoperative DASI scores with postoperative death or complications.

Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers.

The tumor suppressor protein phosphatase 2A (PP2A) is a serine/threonine phosphatase whose activity is inhibited in most human cancers. One of the best-characterized PP2A substrates is MYC proto-oncogene basic helix-loop-helix transcription factor (MYC), whose overexpression is commonly associated with aggressive forms of this disease. PP2A directly dephosphorylates MYC, resulting in its degradation.

Deregulating MYC in a model of HER2+ breast cancer mimics human intertumoral heterogeneity.

The c-MYC (MYC) oncoprotein is often overexpressed in human breast cancer; however, its role in driving disease phenotypes is poorly understood. Here, we investigate the role of MYC in HER2+ disease, examining the relationship between HER2 expression and MYC phosphorylation in HER2+ patient tumors and characterizing the functional effects of deregulating MYC expression in the murine NeuNT model of amplified-HER2 breast cancer. Deregulated MYC alone was not tumorigenic, but coexpression with NeuNT resulted in increased MYC Ser62 phosphorylation and accelerated tumorigenesis.

Complications of Hemodialysis Catheter Bloodstream Infections: Impact of Infecting Organism.

Background: Catheter-related bloodstream infections -(CRBSI) are associated with a high burden of morbidity and mortality, but the impact of infecting organism on clinical outcomes has been poorly studied.

Methods: This retrospective analysis of a prospective vascular access database from a large academic dialysis center investigated whether the organism type affected the clinical presentation or complications of CRBSI.

Results: Among 339 patients with suspected CRBSI, an alternate source of infection was identified in 50 (15%).

Ambassadors of hope, research pioneers and agents of change-individuals' expectations and experiences of taking part in a randomised trial of an innovative health technology: longitudinal qualitative study.

Background: While a growing body of research has explored why people take part in clinical trials, this research has not considered how people's understandings, motivations and agendas might influence their conduct during a trial. This is an important area of enquiry because it is now widely recognised that an intervention might lead to different clinical outcomes when delivered as part of a trial than when implemented in routine clinical practice; however, the reasons for this are not fully understood.

Methods/design: We interviewed 24 individuals who took part in a trial of an innovative health technology under development for people with type 1 diabetes which automatically regulates blood glucose: the closed-loop system.

Lulling the Cancer Cell into an Eternal Sleep.

A hallmark of metastasis is the ability of cancer cells to undergo the epithelial-to-mesenchymal transition to invade and disseminate to distal sites. More recently, the case has been made that the critical last step in metastasis is dependent on the ability to undergo reversion to an epithelial phenotype in a process known as the mesenchymal-to-epithelial transition (MET). It is this transition in the metastatic cascade that researchers are focusing on clinically to treat disseminated disease.

Broadening the Debate About Post-trial Access to Medical Interventions: A Qualitative Study of Participant Experiences at the End of a Trial Investigating a Medical Device to Support Type 1 Diabetes Self-Management.

Increasing ethical attention and debate is focusing on whether individuals who take part in clinical trials should be given access to post-trial care. However, the main focus of this debate has been upon drug trials undertaken in low-income settings. To broaden this debate, we report findings from interviews with individuals (n = 24) who participated in a clinical trial of a closed-loop system, which is a medical device under development for people with type 1 diabetes that automatically adjusts blood glucose to help keep it within clinically recommended ranges.

Seroconversion of 1-year-old Mice to Murine Norovirus.

Rodent sentinel screening for adventitious pathogens is an integral part of many biomedical research institutes and universities that use rodents in research. Typical screening programs involving live sentinel animals typically purchase young SPF sentinel animals that are sampled and replaced quarterly. Previous reports suggest that mice as old as 6 mo are effective sentinels for various agents.

Using the 6-minute walk test to predict disability-free survival after major surgery.

Background: The 6-min walk test (6MWT) is a common means of functional assessment. Its relationship to disability-free survival (DFS) is uncertain.

Methods: This sub-study of the Measurement of Exercise Tolerance for Surgery study had co-primary outcome measures: correlation of the preoperative 6MWT distance with 30 day quality of recovery (15-item quality of recovery) and 12 month WHO Disability Assessment Schedule scores.