The DNA methylome of pediatric brain tumors appears shaped by structural variation and predicts survival.

Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children's Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN.

Design, synthesis, pharmacological evaluation, and computational study of benzo[d] isothiazol-based small molecule inhibitors targeting PD-1/PD-l1 interaction.

Blockade of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy, but the clinical application of small molecule PD-1/PD-L1 inhibitors remains unclear. In this work, based on BMS-202 and our previous work YLW-106, a series of compounds with benzo[d]isothiazol structure as scaffold were designed and synthesized. Their inhibitory activity against PD-1/PD-L1 interaction was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay.

Dietary Folate and Cofactors Accelerate Age-dependent p16 Epimutation to Promote Intestinal Tumorigenesis.

Unlabelled: The extent to which non-genetic environmental factors, such as diet, contribute to carcinogenesis has been long debated. One potential mechanism for the effects of environmental factors is through epigenetic modifications that affect gene expression without changing the underlying DNA sequence. However, the functional cooperation between dietary factors and cancer-causing epigenetic regulation is largely unknown.

Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer.

Background: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

Methods: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation.

Discovery of benzo[d]isothiazole derivatives as novel scaffold inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction through "ring fusion" strategy.

The inhibition of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction by monoclonal antibodies (mAbs) has achieved promising outcomes in cancer immunotherapy. Due to the inherent deficiencies of mAbs drugs, such as high cost of treatment, immunogenicity, poor pharmacokinetics and penetration of solid tumors, researchers are encouraged to develop small molecule inhibitors, to overcome mAbs drugs' deficiencies and change the situation where small molecule drugs are not available on the market. Herein, we reported a series of benzo[d]isothiazole derivatives targeting the PD-1/PD-L1 interaction through "ring fusion" strategy using BMS-202 as a starting point.

The concurrence of DNA methylation and demethylation is associated with transcription regulation.

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing.

Drug discovery targeting p21-activated kinase 4 (PAK4): a patent review.

: The Ser/Thr protein kinase PAK4 is a downstream regulator of Cdc42, mediating cytoskeleton remodeling, and cell motility, and inhibiting apoptosis and transcriptional regulation. Nowadays, efforts in PAK4 inhibitor development are focusing on improving inhibitory selectivity, cellular potency, and pharmacokinetic properties, and identifying the feasibility of immunotherapy combination in oncology therapy.: This review summarized the development of PAK4 inhibitors that reported on patents in the past two decades.

Epigenome - A mediator for host-microbiome crosstalk.

The interaction between the gut and its eventual trillions of microbe inhabitants during microbial colonization, represents a critical time period for establishing the overall health and wellbeing of an individual. The gut microbiome represents a diverse community of microbes that are critical for many physiological roles of the host including host metabolism. These processes are controlled by a fine-tuned chemical cross talk between the host and microbiota.

Classify multicategory outcome in patients with lung adenocarcinoma using clinical, transcriptomic and clinico-transcriptomic data: machine learning versus multinomial models.

Classification of multicategory survival-outcome is important for precision oncology. Machine learning (ML) algorithms have been used to accurately classify multi-category survival-outcome of some cancer-types, but not yet that of lung adenocarcinoma. Therefore, we compared the performances of 3 ML models (random forests, support vector machine [SVM], multilayer perceptron) and multinomial logistic regression (Mlogit) models for classifying 4-category survival-outcome of lung adenocarcinoma using the TCGA.

Predict multicategory causes of death in lung cancer patients using clinicopathologic factors.

Background: Random forests (RF) is a widely used machine-learning algorithm, and outperforms many other machine learning algorithms in prediction-accuracy. But it is rarely used for predicting causes of death (COD) in cancer patients. On the other hand, multicategory COD are difficult to classify in lung cancer patients, largely because they have multiple labels (versus binary labels).

A freestanding electrochromic copolymer for multicolor smart window.

Electrochromic devices with low-cost, energy-saving advantages, and controllable color switching have gained widely attention. Yet, electrochromic materials are limited for smart window due to challenges such as difficulty freestanding, monotonous color change, slow switching capability, and low optical contrast. In this work, a freestanding copolymers based on Poly(N-vinylcarbazole) (PVK) and 3, 4-ethoxylenedioxythiophene (EDOT) are designed.

Study of Environmental Enteropathy and Malnutrition (SEEM) in Pakistan: protocols for biopsy based biomarker discovery and validation.

Background: Environmental Enteropathy (EE), characterized by alterations in intestinal structure, function, and immune activation, is believed to be an important contributor to childhood undernutrition and its associated morbidities, including stunting. Half of all global deaths in children < 5 years are attributable to under-nutrition, making the study of EE an area of critical priority.

Methods: Community based intervention study, divided into two sub-studies, 1) Longitudinal analyses and 2) Biopsy studies for identification of EE features via omics analyses.

Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia.

Background: There is evidence that maternal genotypes in folate-related genes are associated with pediatric acute lymphoblastic leukemia (ALL) independent of offspring genotype. We evaluated the relationship between maternal genotypes in methionine synthase (MTR) and DNA methylation status in ALL to better characterize the molecular mechanism underlying this association.

Procedure: We obtained bone marrow samples from 51 patients with ALL at diagnosis and from 6 healthy donors.

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene-induced lung tumors in aged mice.

Aging is often accompanied by a dramatic increase in cancer susceptibility. To gain insights into how aging affects tumor susceptibility, we generated a conditional mouse model in which oncogenic Kras was activated specifically in lungs of young (3-5 months) and old (19-24 months) mice. Activation of Kras in old mice resulted in shorter survival and development of higher-grade lung tumors.

[The Detection of Atmospheric HONO and NO2 with Fiber Coupling Long-Path Differential Optical Absorption Spectroscopy System].

A new type of fiber coupling Long-Path Differential Optical Absorption Spectroscopy System(LP-DOAS) based on schmidt - cassegrain telescope was introduced in detail in this paper and it was applied to the accurate measurement of the actual atmospheric HONO and NO2. This measuring system simplified the structure of traditional LP-DOAS system, combining with the design of optical fiber coupling.It made full use of the telescope primary mirror’s effective area.

[Cruise Observation of SO2, NO2 and Benzene with Mobile Portable DOAS in the Industrial Park].

The self-developed portable DOAS instrument based on differential optical absorption spectroscopy(DOAS) and composed of optical fiber spectrograph and multiple-pass cell was introduced. The standard gases of SO2 and NO2 were employed to test the accuracy and stability of the system, and then cruise observation of SO2, NO2 and benzene was carried out using the system in Tongling industrial park. During the entire period, the polluted gases showed high concentrations near the contaminated areas and the maximum concentrations of SO2, NO2 and benzene were 5 023.

[An Incoherent Broadband Optical Cavity Spectroscopy for Measuring Weak Absorption Cross Section of Sulfur Dioxide].

As a highly sensitive detection technology, incoherent broadband cavity enhanced absorption spectroscopy (IBBCEAS) have successfully measured a variety of trace gases. According to the principle of cavity enhanced absorption spectroscopy, if the accurate concentration of the target gas, the curve of the mirror reflectance, effective absorption path length, the light intensity of the absorbing gas and non-absorbing gas are known, the absorption cross section of the absorption gas can be measured. The accurate measurements of absorption cross section are necessary for satellite retrievals of atmospheric trace gases and the atmospheric research.

Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome.

Background: DNA methylation is an epigenetic mechanism central to development and maintenance of complex mammalian tissues, but our understanding of its role in intestinal development is limited.

Results: We use whole genome bisulfite sequencing, and find that differentiation of mouse colonic intestinal stem cells to intestinal epithelium is not associated with major changes in DNA methylation. However, we detect extensive dynamic epigenetic changes in intestinal stem cells and their progeny during the suckling period, suggesting postnatal epigenetic development in this stem cell population.

Regulation of AURKC expression by CpG island methylation in human cancer cells.

AURKC, a member of the Aurora kinase gene family, is highly expressed in testis but is either moderately expressed or repressed in most somatic cells. Varying expression of AURKC has been observed in human cancers, but the underlying mechanisms of differential expression have been investigated only to a limited extent. We investigated the role of promoter CpG methylation in the regulation of AURKC gene expression in human cancer cells, in relation to a recently reported AURKC transcription repressor PLZF/ZBTB16, implicated in transformation and tumorigenesis.

Phase-change properties of GeSbTe thin films deposited by plasma-enchanced atomic layer depositon.

Phase-change access memory (PCM) appears to be the strongest candidate for next-generation high-density nonvolatile memory. The fabrication of ultrahigh-density PCM depends heavily on the thin-film growth technique for the phase-changing chalcogenide material. In this study, Ge2Sb2Te5 (GST) and GeSb8Te thin films were deposited by plasma-enhanced atomic layer deposition (ALD) method using Ge [(CH3)2 N]4, Sb [(CH3)2 N]3, Te(C4H9)2 as precursors and plasma-activated H2 gas as reducing agent of the metallorganic precursors.

Cell-autonomous activation of Hedgehog signaling inhibits brown adipose tissue development.

Although recent studies have shown that brown adipose tissue (BAT) arises from progenitor cells that also give rise to skeletal muscle, the developmental signals that control the formation of BAT remain largely unknown. Here, we show that brown preadipocytes possess primary cilia and can respond to Hedgehog (Hh) signaling. Furthermore, cell-autonomous activation of Hh signaling blocks early brown-preadipocyte differentiation, inhibits BAT formation in vivo, and results in replacement of neck BAT with poorly differentiated skeletal muscle.

CDC42 inhibition suppresses progression of incipient intestinal tumors.

Mutations in the APC or β-catenin genes are well-established initiators of colorectal cancer, yet modifiers that facilitate the survival and progression of nascent tumor cells are not well defined. Using genetic and pharmacologic approaches in mouse colorectal cancer and human colorectal cancer xenograft models, we show that incipient intestinal tumor cells activate CDC42, an APC-interacting small GTPase, as a crucial step in malignant progression. In the mouse, Cdc42 ablation attenuated the tumorigenicity of mutant intestinal cells carrying single APC or β-catenin mutations.

Targeted p16(Ink4a) epimutation causes tumorigenesis and reduces survival in mice.

Cancer has long been viewed as a genetic disease; however, epigenetic silencing as the result of aberrant promoter DNA methylation is frequently associated with cancer development, suggesting an epigenetic component to the disease. Nonetheless, it has remained unclear whether an epimutation (an aberrant change in epigenetic regulation) can induce tumorigenesis. Here, we exploited a functionally validated cis-acting regulatory element and devised a strategy to induce developmentally regulated genomic targeting of DNA methylation.