Differential impact of lymphatic outflow pathways on cerebrospinal fluid homeostasis.

Dysfunctional lymphatic drainage from the central nervous system (CNS) has been linked to neuroinflammatory and neurodegenerative disorders, but our understanding of the lymphatic contribution to CNS fluid autoregulation remains limited. Here, we studied forces that drive the outflow of the cerebrospinal fluid (CSF) into the deep and superficial cervical lymph nodes (dcLN and scLN) and tested how the blockade of lymphatic networks affects CNS fluid homeostasis. Outflow to the dcLN occurred spontaneously in the absence of lymphatic pumping and was coupled to intracranial pressure (ICP), whereas scLN drainage was driven by pumping.

Abemaciclib Plus Fulvestrant in Advanced Breast Cancer Following Progression on CDK4/6 Inhibition: Results from the Phase III postMONARCH Trial.

Purpose: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i.

Methods: This double-blind, randomized Phase III study enrolled patients with disease progression on prior CDK4/6i plus aromatase inhibitor as initial therapy for advanced disease or recurrence on/after adjuvant CDK4/6i+ET.

Insights into substrate recognition and export tunnel preferences in the efflux transporter AcrB.

In Escherichia coli AcrB is a major multidrug exporter, which confers the bacterium resistance to many antibiotics with diverse structural and chemical proprieties. Studies have identified three possible tunnels (or channels) within AcrB that different substrates use before reaching the distal pocket, from which they are subsequently extruded. Recently, we reported that mutations in the AcrB gate loop may affect the conformational change kinetics involved in substrate export rather than directly affecting molecular interactions with this loop, and we highlighted the distinct export tunnel preferences between erythromycin and doxorubicin.

Imlunestrant with or without Abemaciclib in Advanced Breast Cancer.

Background: Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα ().

Methods: In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib.

Blood methylation biomarkers are associated with diabetic kidney disease progression in type 1 diabetes.

Background: DNA methylation differences are associated with kidney function and diabetic kidney disease (DKD), but prospective studies are scarce. Therefore, we aimed to study DNA methylation in a prospective setting in the Finnish Diabetic Nephropathy Study type 1 diabetes (T1D) cohort.

Methods: We analysed baseline blood sample-derived DNA methylation (Illumina's EPIC array) of 403 individuals with normal albumin excretion rate (early progression group) and 373 individuals with severe albuminuria (late progression group) and followed-up their DKD progression defined as decrease in eGFR to <60 mL/min/1.