Emerging treatment options for the management of brain metastases in patients with HER2-positive metastatic breast cancer.

The widespread use of trastuzumab in the past decade has led to a significant and measureable improvement in the survival of patients with human epidermal growth factor receptor-2 (HER2) overexpressing breast cancer, and in many ways has redefined the natural history of this aggressive breast cancer subtype. Historically, survival in patients with HER2-positive disease was dictated by the systemic disease course, and what appears to be the central nervous system (CNS) tropism associated with HER2-amplified tumors was not clinically evident. With improved systemic control and prolonged survival, the incidence of brain metastases has increased, and CNS disease, often in the setting of well-controlled extracranial disease, is proving to be an increasingly important and clinically challenging cause of morbidity and mortality in patients with HER2-positive advanced breast cancer. This review summarizes the known clinical data for the systemic treatment of HER2-positive CNS metastases and includes information about ongoing clinical trials of novel therapies as well as emerging strategies for early detection and prevention

APOL1 CKD Risk Alleles in New Mexico African American and American Indian Populations: Racial Disparity

Purpose/Background: Two haplotypes of human apolipoprotein L1 gene (gene: APOL1; protein: ApoL1) harboring three coding sequence mutations have been demonstrated as risk variants associated with non-diabetic chronic kidney diseases (CKD) in African Americans. The first one, termed G1, is a two non-synonymous SNP haplotype (rs73885319 (A\u3eG; p.S342G) and rs60910145 (G\u3eT; p.I384M). The second one, termed G2, is a two codon deletion haplotype rs71785313 (6-bp in frame deletion) These two coding-sequence variants have been discovered in CKD patients of African ancestry and linked to the pathogenesis of primary focal and segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, and HIV-associated nephropathy (HIVAN), under a recessive inheritance pattern. Marked disparities exist in races, rates, and etiological classifications of CDK between African Americans (AAs) and European Americans. Sequencing and genotyping analysis of known APOL1 SNPs showed that only APOL1 G1 and G2 confer kidney risk, and other common and rare APOL1 missense variants, including the G3 haplotype, do not contribute to FSGS and HIVAN in the US population. According to the report of US census bureau, African American and American Indian (AI) citizens in New Mexico make up nearly 2.5% and 10.9% of the state\u27s entire population in 2018 (2). However, whether APOL1 G1 and G2 kidney-risk alleles are linked with hypertension-attributed CKD in AAs and AIs in New Mexico has not been investigated. Materials & Methods: We analyzed the published results of a retrospective analysis of inpatient and discharge data from hospitals across the state of New Mexico, known as Hospital Inpatient and Discharge Dataset (HIDD; 3). Results: A pattern persisted for all three years (2012-2014) that AAs had the highest rate of CKD followed by AIs per 10,000 population in New Mexico. AAs had the highest age adjusted rate of CKD with hypertension at 102.6 per 10,000 population (29.7% (102.6/345.7) of all CKD with hypertension patients) followed by American Indians at 91.9 (26.6% (91.9/345.7) of all CKD with hypertension patients). Interestingly, in terms of CKD with diabetes, AIs had the highest age adjusted rate at 79.9 per 10,000 followed by AAs at 66.5. Discussion/Conclusion: The prevalence of CKD with hypertension in AA and AI populations is significantly high in New Mexico, To understand the etiology of CKD in AAs and AIs in New Mexico, genotyping the APOL1 G1 and G2 risk alleles in these two populations is warranted. Detection of APOL1 associations with CKD and delineation of injury pathways (autophagy, necroptosis and ferroptosis) would bring hope for effective treatment for these kidney diseases. In addition, modifier loci can influence APOL1 risk for the development of CKD. ‘Second hits’, for example viral and environmental, may alter the outcome of APOL1 risk variants

Driving denaturation: Nanoscale thermal transport as a probe of DNA melting

DNA denaturation has long been a subject of intense study due to its relationship to DNA transcription and its fundamental importance as a nonlinear, structural transition. Many aspects of this phenomenon, however, remain poorly understood. Existing models fit quite well with experimental results on the fraction of unbound base pairs versus temperature. Yet, these same models give incorrect results for other essential quantities. For example, the predicted base pair fluctuation timescales - relevant to transcription - are orders of magnitude different from those observed experimentally. Here, we demonstrate that nanoscale thermal transport can serve as a sensitive probe of the underlying microscopic mechanisms responsible for the dynamics of DNA denaturation. Specifically, we show that the heat transport properties of DNA are altered significantly and abruptly as it denaturates, and this alteration encodes detailed information on the dynamics of thermal fluctuations and their interaction along the chain. This finding allows for the unambiguous discrimination between models of DNA denaturation. Measuring the thermal conductance will thus shed new light on the nature of this important molecule.Comment: 7 pages, 2 figures (revised version) Accepted for publication in Physical Review E, Rapid Communication

Sharp-edged geometric obstacles in microfluidics promote deformability-based sorting of cells

Sorting cells based on their intrinsic properties is a highly desirable objective, since changes in cell deformability are often associated with various stress conditions and diseases. Deterministic lateral displacement (DLD) devices offer high precision for rigid spherical particles, while their success in sorting deformable particles remains limited due to the complexity of cell traversal in DLDs. We employ mesoscopic hydrodynamics simulations and demonstrate prominent advantages of sharp-edged DLD obstacles for probing deformability properties of red blood cells (RBCs). By consecutive sharpening of the pillar shape from circular to diamond to triangular geometry, a pronounced cell bending around an edge is achieved, serving as a deformability sensor. Bending around the edge is the primary mechanism, which governs the traversal of RBCs through such DLD device. This strategy requires an appropriate degree of cell bending by fluid stresses, which can be controlled by the flow rate, and exhibits good sensitivity to moderate changes in cell deformability. We expect that similar mechanisms should be applicable for the development of novel DLD devices that target intrinsic properties of many other cells.Comment: 16 pages, 9 figure