Unzipping hBN with ultrashort mid-infrared pulses.

Manipulating the nanostructure of materials is critical for numerous applications in electronics, magnetics, and photonics. However, conventional methods such as lithography and laser writing require cleanroom facilities or leave residue. We describe an approach to creating atomically sharp line defects in hexagonal boron nitride (hBN) at room temperature by direct optical phonon excitation with a mid-infrared pulsed laser from free space.

Phonon-enhanced nonlinearities in hexagonal boron nitride.

Polar crystals can be driven into collective oscillations by optical fields tuned to precise resonance frequencies. As the amplitude of the excited phonon modes increases, novel processes scaling non-linearly with the applied fields begin to contribute to the dynamics of the atomic system. Here we show two such optical nonlinearities that are induced and enhanced by the strong phonon resonance in the van der Waals crystal hexagonal boron nitride (hBN).

Treatment scheduling effects on the evolution of drug resistance in heterogeneous cancer cell populations.

The effect of scheduling of targeted therapy combinations on drug resistance is underexplored in triple-negative breast cancer (TNBC). TNBC constitutes heterogeneous cancer cell populations the composition of which can change dynamically during treatment resulting in the selection of resistant clones with a fitness advantage. We evaluated crizotinib (ALK/MET inhibitor) and navitoclax (ABT-263; Bcl-2/Bcl-xL inhibitor) combinations in a large design consisting of 696 two-cycle sequential and concomitant treatment regimens with varying treatment dose, duration, and drug holiday length over a 26-day period in MDA-MB-231 TNBC cells and found that patterns of resistance depend on the schedule and sequence in which the drugs are given.

Nonlinear refractive index of solids in mid-infrared.

We measure the third-order nonlinear optical response of various dielectrics and semiconductors using the spectrally resolved two-beam coupling method at 2.3 µm, 3.5 µm, 4.

Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells.

Cancer cells employ various defense mechanisms against drug-induced cell death. Investigating multi-omics landscapes of cancer cells before and after treatment can reveal resistance mechanisms and inform new therapeutic strategies. We assessed the effects of navitoclax, a BCL2 family inhibitor, on the transcriptome, methylome, chromatin structure, and copy number variations of MDA-MB-231 triple-negative breast cancer (TNBC) cells.

Ionization-assisted refocusing of femtosecond Gaussian beams.

Ionization occurs ubiquitously in intense laser-matter interaction and often leads to rapid decrease in laser intensity via plasma defocusing, shortening the effective interaction length of desired high-field processes. Refocusing of pulses may compensate for this adverse effect. However, it typically relies on Kerr-induced self-focusing and requires sufficiently high power.

Identification and Validation of a Novel Biologics Target in Triple Negative Breast Cancer.

The goal of this study was to identify a novel target for antibody-drug conjugate (ADC) development in triple negative breast cancer (TNBC), which has limited treatment options, using gene expression datasets and in vitro siRNA/CRISPR and in vivo functional assays. We analyzed 4467 breast cancers and identified GABRP as top expressed gene in TNBC with low expression in most normal tissues. GABRP protein was localized to cell membrane with broad range of receptors/cell (815-53,714) and expressed by nearly half of breast cancers tissues.

Increased epigenetic age in normal breast tissue from luminal breast cancer patients.

Background: Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes.

Ionization-assisted spatiotemporal localization in gas-filled capillaries.

We demonstrate numerically and experimentally that intense pulses propagating in gas-filled capillaries can undergo localization in space and time due to strong plasma defocusing. This phenomenon can occur below or above the self-focusing threshold P as a result of ionization-induced refraction that excites higher-order modes. The constructive interference of higher-order modes leads to spatiotemporal localization and resurgence of the intensity.

Ceramide channels: destabilization by Bcl-xL and role in apoptosis.

Ceramide is a bioactive sphingolipid involved in mitochondrial-mediated apoptosis. Our data suggest that ceramides directly regulate a key initiation step in apoptosis: mitochondrial outer membrane permeabilization (MOMP). MOMP allows release of intermembrane space proteins to the cytosol, inducing the execution of the cell.

Sphingolipids and mitochondrial apoptosis.

The sphingolipid family of lipids modulate several cellular processes, including proliferation, cell cycle regulation, inflammatory signaling pathways, and cell death. Several members of the sphingolipid pathway have opposing functions and thus imbalances in sphingolipid metabolism result in deregulated cellular processes, which cause or contribute to diseases and disorders in humans. A key cellular process regulated by sphingolipids is apoptosis, or programmed cell death.

Ceramide modulates pre-mRNA splicing to restore the expression of wild-type tumor suppressor p53 in deletion-mutant cancer cells.

Mutants of tumor suppressor p53 not only lose the activity in genome stabilizing and in tumor suppression, but also exhibit oncogenic function in cancer cells. Most efforts in restoring p53 biological activity focus on either altering mutant-protein conformation or introducing an exogenous p53 gene into cells to eliminate p53-mutant cancer cells. Being different from these, we report that ceramide can restore the expression of wild-type p53 and induce p53-dependent apoptosis in deletion-mutant cancer cells.

Glucosylceramide synthase, a factor in modulating drug resistance, is overexpressed in metastatic breast carcinoma.

Drug resistance causes treatment failure in approximately 50% of breast cancer patients with chemotherapy. Overexpression of glucosylceramide synthase (GCS) confers drug resistance in cancer cells, and suppression of GCS sensitizes cancers to chemotherapy in preclinical studies. Thus, GCS becomes a potential target to reverse drug resistance; however, little is known about GCS expression levels in normal tissues and whether GCS overexpression is associated with metastatic cancers.

Suppression of glucosylceramide synthase restores p53-dependent apoptosis in mutant p53 cancer cells.

Tumor suppressor p53 plays an essential role in protecting cells from malignant transformation by inducing cell-cycle arrest and apoptosis. Mutant p53 that is detected in more than 50% of cases of cancers loses its role in suppression of tumors but gains in oncogenic function. Strategies to convert mutant p53 into wild-type p53 have been suggested for cancer prevention and treatment, but they face a variety of challenges.

Sphingolipids and expression regulation of genes in cancer.

Sphingolipids including glycosphingolipids have myriad effects on cell functions and affect cancer in aspects of tumorigenesis, metastasis and tumor response to treatments. Bioactive ones like ceramide, sphingosine 1-phosphate and globotriaosylceramide initiate and process cellular signaling to alter cell behaviors immediately responding to oncogenic stress or treatment challenges. Recent studies pinpoint that sphingolipid-mediated gene expression has long and profound impacts on cancer cells, and these play crucial roles in tumor progression and in treatment outcome.

Mixed backbone antisense glucosylceramide synthase oligonucleotide (MBO-asGCS) loaded solid lipid nanoparticles: in vitro characterization and reversal of multidrug resistance in NCI/ADR-RES cells.

In this study, solid lipid nanoparticles (SLN) loaded with MBO-asGCS oligonucleotide were prepared, characterized and evaluated for cytotoxicity against NCI/ADR-RES human ovary cancer cells. Two types of cetyltrimethyl ammonium bromide (CTAB) stabilized SLN, with or without ceramide VI, were prepared by mixed homogenization/ultrasonication technique. Complexes were characterized for size, zeta-potential, and stability in biorelevant media and against DNaseI activity.

Glucosylceramide synthase upregulates MDR1 expression in the regulation of cancer drug resistance through cSrc and beta-catenin signaling.

Background: Drug resistance is the outcome of multiple-gene interactions in cancer cells under stress of anticancer agents. MDR1 overexpression is most commonly detected in drug-resistant cancers and accompanied with other gene alterations including enhanced glucosylceramide synthase (GCS). MDR1 encodes for P-glycoprotein that extrudes anticancer drugs.

Direct assessment of P-glycoprotein efflux to determine tumor response to chemotherapy.

Multidrug resistance is a major impediment to the success of cancer chemotherapy. The overproduced P-glycoprotein that extrudes anticancer drugs from cells, is the most common mechanism detected in multidrug-resistant cancers. Direct measurement of cellular efflux of tumors in vivo, rather than estimation of MDR1 mRNA and P-glycoprotein levels in samples stored or embedded, can functionally characterize the mechanism of drug resistance and determine the choice of anticancer drugs for cancer patients.

Direct quantitative determination of ceramide glycosylation in vivo: a new approach to evaluate cellular enzyme activity of glucosylceramide synthase.

Glucosylceramide synthase (GCS or GlcT-1), converting ceramide to glucosylceramide, is a key enzyme for the synthesis of glycosphingolipids. Due to its diverse roles in physiology and diseases, GCS may be a disease marker and drug target. Current assays for enzymes including GCS are based on reactions conducted in a test tube using enzyme preparations.

A new mixed-backbone oligonucleotide against glucosylceramide synthase sensitizes multidrug-resistant tumors to apoptosis.

Enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) limits therapeutic efficiencies of antineoplastic agents including doxorubicin in drug-resistant cancer cells. Aimed to determine the role of GCS in tumor response to chemotherapy, a new mixed-backbone oligonucleotide (MBO-asGCS) with higher stability and efficiency has been generated to silence human GCS gene. MBO-asGCS was taken up efficiently in both drug-sensitive and drug-resistant cells, but it selectively suppressed GCS overexpression, and sensitized drug-resistant cells.

A role for ceramide in driving cancer cell resistance to doxorubicin.

Advanced cancers acquire resistance to chemotherapy, and this results in treatment failure. The cellular mechanisms of chemotherapy resistance are not well understood. Here, for the first time, we show that ceramide contributes to cellular resistance to doxorubicin through up-regulating the gene expression of glucosylceramide synthase (GCS).