Recent Advance in Tumor Microenvironment-Based Stimuli-Responsive Nanoscale Drug Delivery and Imaging Platform

The tumor microenvironment (TME) plays an important role in the development, progression, and metastasis of cancer, and the extremely crucial feature is hypoxic and acidic. Cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), mesenchymal cells, blood vessels, and interstitial fluid are widely recognized as fundamentally crucial hallmarks for TME. As nanotechnology briskly boomed, the nanoscale drug delivery and imaging platform (NDDIP) emerged and has attracted intensive attention. Based on main characteristics of TME, NDDIP can be classified into pH-sensitive delivery and imaging platforms, enzyme-sensitive delivery and imaging platforms, thermo-sensitive delivery and imaging platforms, redox-sensitive delivery and imaging platforms, and light-sensitive delivery and imaging platforms. Furthermore, imageology is one of the significant procedures for disease detection, image-guided drug delivery, and efficacy assessment, including magnetic resonance imaging (MRI), computed tomography (CT), ultrasound (US), and fluorescence imaging. Therefore, the stimuli-responsive NDDIP will be a versatile and practicable tumor disease diagnostic procedure and efficacy evaluation tool. In this review article, we mainly introduce the characteristics of TME and summarize the progress of multitudinous NDDIP as well as their applications

Discovery of Potential piRNAs from Next Generation Sequences of the Sexually Mature Porcine Testes

Piwi- interacting RNAs (piRNAs), a new class of small RNAs discovered from mammalian testes, are involved in transcriptional silencing of retrotransposons and other genetic elements in germ line cells. In order to identify a full transcriptome set of piRNAs expressed in the sexually mature porcine testes, small RNA fractions were extracted and were subjected to a Solexa deep sequencing. We cloned 6,913,561 clean reads of Sus Scrofa small RNAs (18–30 nt) and performed functional characterization. Sus Scrofa small RNAs showed a bimodal length distribution with two peaks at 21 nt and 29 nt. Then from 938,328 deep-sequenced small RNAs (26–30 nt), 375,195 piRNAs were identified by a k-mer scheme and 326 piRNAs were identified by homology searches. All piRNAs predicted by the k-mer scheme were then mapped to swine genome by Short Oligonucleotide Analysis Package (SOAP), and 81.61% of all uniquely mapping piRNAs (197,673) were located to 1124 defined genomic regions (5.85 Mb). Within these regions, 536 and 501 piRNA clusters generally distributed across only minus or plus genomic strand, 48 piRNA clusters distributed on two strands but in a divergent manner, and 39 piRNA clusters distributed on two strands in an overlapping manner. Furthermore, expression pattern of 7 piRNAs identified by homology searches showed 5 piRNAs displayed a ubiquitous expression pattern, although 2 piRNAs were specifically expressed in the testes. Overall, our results provide new information of porcine piRNAs and their specific expression pattern in porcine testes suggests that piRNAs have a role in regulating spermatogenesis

Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

BACKGROUND: Approximately 75% of objective responses to anti–programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. METHODS: We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti–PD-1 therapy (pembrolizumab) followed by disease progression months to years later. RESULTS: Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor–associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I. CONCLUSIONS: In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.

Tuning the Chemical Hardness of Boron Nitride Nanosheets by Doping Carbon for Enhanced Adsorption Capacity

The chemical hardness of adsorbents is an important physicochemical property in the process of adsorption based on the hard and soft acids and bases (HSAB) theory. Tuning chemical hardness of adsorbents modulated by their concomitants is a promising approach to enhance the adsorptive capacity in principle. In the present work, we report an efficient strategy that the adsorption capacity for aromatic sulfocompounds can be enhanced by tuning the chemical hardness. This strategy is first theoretically explored by introducing C element into the network of hexagonal boron nitride (h-BN) based on a series of model materials (model_<i>x</i>C, <i>x</i> = 1–5). Computational results show that the chemical hardness is reduced after gradually C-doping, which may lead to an enhancement of adsorption capacity according to the HSAB theory. Then, a series of C-doped h-BN materials (BCN-<i>x</i>, <i>x</i> = 10–50) were controlled synthesized. All of the as-prepared materials show better adsorption capacities (e.g., 27.43 mg g^–1 for BCN-50) than pure h-BN. Experiment results show that the adsorption capacity correlates well with the C content in the BCN-<i>x</i>, which is consistent with the results predicted by theoretical calculation. This strategy may be helpful to rationally design highly efficient adsorbents in separation engineering and may be expanded to similar two-dimensional materials, where the π–π interaction is the dominant driven force

Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma

PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types