IL-17-CXCR2 Axis Promotes Breast Cancer Metastasis and Therapy Resistance

Cancer-related fatalities rank as the second leading cause of death in all ages and both genders in the United States. Moreover, breast cancer-related mortality rank as the second leading cause of death in females in the United States in 2019. The main concerns regarding breast cancer management include chemotherapy resistance and metastasis. Thus, the advanced understanding of cancer progression is required to develop improved therapeutic methods for breast cancer patients. Recent studies demonstrate that neutrophils, as the most abundant leukocytes, play an essential role in breast progression. However, the mechanisms regarding neutrophils recruitment to the tumor sites, and the precise role of neutrophils in the tumor microenvironment, together with the specific mechanisms of neutrophil stimulated cancer progression remains unclear. Therefore, this dissertation mainly investigated the role of IL17-CXCR2 axis, which positively promotes the recruitment of tumor-associated neutrophils to the tumor sites, and how tumor-associated neutrophils facilitated cancer progression. Our results indicated that there were higher levels of CXCR2, CXCR2 ligands, and IL17R present on the resistant and metastatic tumors. In addition, resistant tumors recruited higher levels of neutrophils and Th17 cells. Moreover, our experimental results revealed that IL17 facilitated cancer cell proliferation and secretion of CXCR2 ligands, which resulted in increased neutrophil chemotaxis; additionally, the neutrophil chemotaxis was dependent on CXCR2 signaling. We also observed that the neutrophils facilitated cancer progression through multiple mechanisms, including upregulation of IL1b and CCLs, and the formation of neutrophil extracellular traps (NETs). When cultured in chemotherapy-resistant tumor cells’ supernatant, the neutrophils especially possessed elongated survival time and secretion of MMP2 and MMP9. Moreover, our studies indicated the differences between the chemotherapy-resistant tumor microenvironment and the non-resistant tumor microenvironment, which indicates why patients with established chemo-resistance result in lower survival rates. Our experimental results showed the therapeutic biomarkers for these patients and facilitated the improved clinical benefits for cancer patients in the future. In addition, our studies demonstrated that neutrophils could be considered as therapeutic targets and biomarkers for breast cancer patients, shedding light on an improved therapeutic strategy for breast cancer treatment

A Simple Graphene NH₃ Gas Sensor via Laser Direct Writing.

Ammonia gas sensors are very essential in many industries and everyday life. However, their complicated fabrication process, severe environmental fabrication requirements and desorption of residual ammonia molecules result in high cost and hinder their market acceptance. Here, laser direct writing is used to fabricate three parallel porous 3D graphene lines on a polyimide (PI) tape to simply construct an ammonia gas sensor. The middle one works as an ammonia sensing element and the other two on both sides work as heaters to improve the desorption performance of the sensing element to ammonia gas molecules. The graphene lines were characterized by scanning electron microscopy and Raman spectroscopy. The response and recovery time of the sensor without heating are 214 s and 222 s with a sensitivity of 0.087% ppm-1 for sensing 75 ppm ammonia gas, respectively. The experimental results prove that under the optimized heating temperature of about 70 °C the heaters successfully help implement complete desorption of residual NH₃ showing a good sensitivity and cyclic stability

Co-skeletons:Consistent curve skeletons for shape families

We present co-skeletons, a new method that computes consistent curve skeletons for 3D shapes from a given family. We compute co-skeletons in terms of sampling density and semantic relevance, while preserving the desired characteristics of traditional, per-shape curve skeletonization approaches. We take the curve skeletons extracted by traditional approaches for all shapes from a family as input, and compute semantic correlation information of individual skeleton branches to guide an edge-pruning process via skeleton-based descriptors, clustering, and a voting algorithm. Our approach achieves more concise and family-consistent skeletons when compared to traditional per-shape methods. We show the utility of our method by using co-skeletons for shape segmentation and shape blending on real-world data

WuYun: Exploring hierarchical skeleton-guided melody generation using knowledge-enhanced deep learning

Although deep learning has revolutionized music generation, existing methods for structured melody generation follow an end-to-end left-to-right note-by-note generative paradigm and treat each note equally. Here, we present WuYun, a knowledge-enhanced deep learning architecture for improving the structure of generated melodies, which first generates the most structurally important notes to construct a melodic skeleton and subsequently infills it with dynamically decorative notes into a full-fledged melody. Specifically, we use music domain knowledge to extract melodic skeletons and employ sequence learning to reconstruct them, which serve as additional knowledge to provide auxiliary guidance for the melody generation process. We demonstrate that WuYun can generate melodies with better long-term structure and musicality and outperforms other state-of-the-art methods by 0.51 on average on all subjective evaluation metrics. Our study provides a multidisciplinary lens to design melodic hierarchical structures and bridge the gap between data-driven and knowledge-based approaches for numerous music generation tasks

The Effect of Hydroxylamine on K ATP Channels in Vascular Smooth Muscle and Underlying Mechanisms

ABSTRACT Hydroxylamine (HA) is a putative intermediate in the conversion of L-arginine to nitric oxide (NO). HA was reported to cause the relaxation of precontracted aorta strips; however, the ionic mechanisms of HA-induced vasorelaxation were not yet known. In the present study, the whole-cell patch-clamp technique was used to examine the effects of HA on ATP-sensitive K ϩ (K ATP ) currents and membrane potentials in vascular smooth muscle cells from rat mesenteric arteries and underlying mechanisms. It was found that bath-applied HA reversibly enhanced K ATP currents in a concentration-dependent fashion with an EC 50 of 54 Ϯ 3.4 M and hyperpolarized the cell membrane from Ϫ48 Ϯ 5.2 to Ϫ65 Ϯ 7.5 mV (n ϭ 6, p Ͻ 0.01). The increase in K ATP currents induced by HA was suppressed by superoxide dismutase (Ϫ380 Ϯ 45 to Ϫ160 Ϯ 20 pA, n ϭ 4, p Ͻ 0.01) and N-acetyl-L-cysteine (Ϫ385 Ϯ 55 to Ϫ150 Ϯ 16 pA, n ϭ 5, p Ͻ 0.01), indicating the involvement of different free radicals, including superoxide anion. Hypoxanthine/xanthine oxidase increased not only basal K ATP currents, but also HAenhanced K ATP currents (from Ϫ355 Ϯ 40 to Ϫ480 Ϯ 62 pA, n ϭ 6, p Ͻ 0.05). Sodium nitroprusside, a spontaneous NO donor, and a membrane-permeable cGMP analog (8-bromocGMP) were without effects on HA-enhanced K ATP currents or basal K ATP currents. Our results indicate that HA augmented K ATP channel activity and hyperpolarized cell membrane, possibly via increased free radical generation