LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclax-resistant chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax.

CSF1 receptor inhibition of tenosynovial giant cell tumor using novel disease-specific MRI measures of tumor burden.

Monitoring treatment of tenosynovial giant cell tumor (TGCT) is complicated by the irregular shape and asymmetrical growth of the tumor. We compared responses to pexidartinib by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with those by tumor volume score (TVS) and modified RECIST (m-RECIST).

Results from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT.

Purpose: To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity.

Patients And Methods: From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO).

Multi-omic molecular profiling guide's efficacious treatment selection in refractory metastatic breast cancer: a prospective phase II clinical trial.

This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi-omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.

Spatial organization of FcγR and TLR2/1 on phagosome membranes differentially regulates their synergistic and inhibitory receptor crosstalk.

Many innate immune receptors function collaboratively to detect and elicit immune responses to pathogens, but the physical mechanisms that govern the interaction and signaling crosstalk between the receptors are unclear. In this study, we report that the signaling crosstalk between Fc gamma receptor (FcγR) and Toll-like receptor (TLR)2/1 can be overall synergistic or inhibitory depending on the spatial proximity between the receptor pair on phagosome membranes. Using a geometric manipulation strategy, we physically altered the spatial distribution of FcγR and TLR2 on single phagosomes.

Identification of Metal Stresses in Using Hyperspectral Reflectance Imaging.

Industrial accidents, such as the Fukushima and Chernobyl disasters, release harmful chemicals into the environment, covering large geographical areas. Natural flora may serve as biological sensors for detecting metal contamination, such as cesium. Spectral detection of plant stresses typically employs a few select wavelengths and often cannot distinguish between different stress phenotypes.

Unique Orientation of the Solid-Solid Interface at the Janus Particle Boundary Induced by Ionic Liquids.

This study reveals the unique role on Janus particles of the solid-solid interface at the boundary in determining particle interactions and assembly. In an aqueous ionic liquid (IL) solution, Janus spheres adopt intriguing orientations with their boundaries pinned on the glass substrate. It was further discovered that the orientation was affected by the particle amphiphilicity as well as the chemical structure and concentration of the IL.

Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia.

Purpose: Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7+3 induction therapy.

Patients And Methods: A multiinstitutional phase I dose-escalation study of alvocidib on days 1-3 followed by 7+3 (cytarabine 100 mg/m/day i.

Imaging effectiveness calculator for non-design microscope samples.

When attempting to integrate single-molecule fluorescence microscopy with microfabricated devices such as microfluidic channels, fabrication constraints may prevent using traditional coverslips. Instead, the fabricated devices may require imaging through material with a different thickness or index of refraction. Altering either can easily reduce the quality of the image formation (measured by the Strehl ratio) by a factor of 2 or more, reducing the signal-to-noise ratio accordingly.

Surfactant-Mediated Assembly of Amphiphilic Janus Spheres.

We investigate how amphiphilic Janus particle assembly structures, including clusters and striped two-dimensional (2D) crystals, are influenced by the addition of surfactant molecules. Janus particles are fabricated using silica particles coated with Au on one side, which is further modified with a hydrophobic self-assembled monolayer. Analysis on the cluster assembly structures suggests that in addition to hydrophobic attraction, van der Waals (VDW) attraction plays a significant role in the assembly process, which is modulated by the Au coating thickness.

Cellular localization of tolyporphins, unusual tetrapyrroles, in a microbial photosynthetic community determined using hyperspectral confocal fluorescence microscopy.

The cyanobacterial culture HT-58-2, composed of a filamentous cyanobacterium and accompanying community bacteria, produces chlorophyll a as well as the tetrapyrrole macrocycles known as tolyporphins. Almost all known tolyporphins (A-M except K) contain a dioxobacteriochlorin chromophore and exhibit an absorption spectrum somewhat similar to that of chlorophyll a. Here, hyperspectral confocal fluorescence microscopy was employed to noninvasively probe the locale of tolyporphins within live cells under various growth conditions (media, illumination, culture age).

Drying mediated orientation and assembly structure of amphiphilic Janus particles.

Amphiphilic Janus particles demonstrate unique assembly structures when dried on a hydrophilic substrate. Particle orientations are influenced by amphiphilicity and Janus balance. A three-stage model is developed to describe the process.

Cargos Rotate at Microtubule Intersections during Intracellular Trafficking.

Intracellular cargos are transported by molecular motors along actin and microtubules, but how their dynamics depends on the complex structure of the cytoskeletal network remains unclear. In this study, we investigated this longstanding question by measuring simultaneously the rotational and translational dynamics of cargos at microtubule intersections in living cells. We engineered two-faced particles that are fluorescent on one hemisphere and opaque on the other and used their optical anisotropy to report the rotation of cargos.

Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study.

Background: Carfilzomib is approved in the United States and Europe for treatment of relapsed or refractory multiple myeloma (MM). This study evaluated pharmacokinetics (PK) and safety of carfilzomib in patients with relapsed or progressive advanced malignancies and varying degrees of impaired hepatic function.

Methods: Patients with normal hepatic function (normal) or hepatic impairment (mild, moderate, or severe) received carfilzomib infusion in 28-day cycles.

Single-Janus Rod Tracking Reveals the "Rock-and-Roll" of Endosomes in Living Cells.

Endosomes in cells are known to move directionally along microtubules, but their rotational dynamics have rarely been investigated. Even less is known, specifically, about the rotation of nonspherical endosomes. Here we report a single-Janus rod rotational tracking study to reveal the rich rotational dynamics of rod-shaped endosomes in living cells.

Safety and Pharmacokinetics of Bendamustine Rapid-Infusion Formulation.

Bendamustine hydrochloride (BDM) is approved in the United States to treat chronic lymphocytic leukemia and relapsed indolent B-cell non-Hodgkin lymphoma. The first formulation marketed in the United States (original BDM) was a lyophilized product requiring reconstitution prior to dilution to the final admixture. A liquid formulation of BDM was subsequently introduced that did not require reconstitution before dilution.

Enrichment of PI3K-AKT-mTOR Pathway Activation in Hepatic Metastases from Breast Cancer.

Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis. Next-generation sequencing-based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases.

Removing Cosmic Spikes Using a Hyperspectral Upper-Bound Spectrum Method.

Cosmic ray spikes are especially problematic for hyperspectral imaging because of the large number of spikes often present and their negative effects upon subsequent chemometric analysis. Fortunately, while the large number of spectra acquired in a hyperspectral imaging data set increases the probability and number of cosmic spikes observed, the multitude of spectra can also aid in the effective recognition and removal of the cosmic spikes. Zhang and Ben-Amotz were perhaps the first to leverage the additional spatial dimension of hyperspectral data matrices (DM).

Lipid membrane-assisted condensation and assembly of amphiphilic Janus particles.

Amphiphilic Janus particles self-assemble into complex metastructures, but little is known about how their assembly might be modified by weak interactions with a nearby biological membrane surface. Here, we report an integrated experimental and molecular dynamics simulation study to investigate the self-assembly of amphiphilic Janus particles on a lipid membrane. We created an experimental system in which Janus particles are allowed to self-assemble in the same medium where zwitterionic lipids form giant unilamellar vesicles (GUVs).

Patient-reported Symptoms of Tenosynovial Giant Cell Tumors.

Purpose: Tenosynovial giant cell tumor (TGCT), a rare locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, inflammation, pain, and swelling, in part due to colony-stimulating factor 1 receptor-bearing macrophages recruited to the tumor by genetic elevation of colony-stimulating factor 1 activity. The most common treatment is surgery, although promising pharmacologic treatments are in development. Patient-reported outcome (PRO) instruments are critical end points in demonstrating the clinical relevance of standard oncologic outcome measures and the overall impact of novel pharmacologic therapies in nonmalignant neoplastic conditions such as TGCT.

Dynamics and Interactions of Individual Proteins in the Membrane of Single, Living Cells.

Total internal reflection fluorescence (TIRF) microscopy is a powerful technique for interrogating protein dynamics in the membranes of living single cells. Receptor-ligand interactions are of particular interest for improving our understanding of cell signaling networks in a variety of applications. Here, we describe methods for fluorescently labeling individual receptors and their ligands, conducting single-molecule TIRF microscopy of receptors and ligands in single, living cells, and importantly, performing image analysis on the resulting time sequence of images to extract quantitative dynamics.

Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.

Background: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R).

Methods: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation.

Tracking single-particle rotation during macrophage uptake.

We investigated the rotational dynamics of single microparticles during their internalization by macrophage cells. The microparticles used were triblock patchy particles that display two fluorescent patches on their two poles. The optical anisotropy made it possible to directly visualize and quantify the orientation and rotation of the particles.