Discovery of Oncogenic Mediator Genes in Rectal Cancer Chemotherapy Response using Gene Expression Data from Matched Tumor and Patient-Derived Organoid.

Rectal cancer (RC) presents significant treatment challenges, particularly in the context of chemotherapy resistance. Addressing this, our study pioneers the use of matched RC tumor tissue and patient-derived organoid (PDO) models coupled with the innovative computational tool, Moonlight, to explore the gene expression landscape of RC tumors and their response to chemotherapy. We analyzed 18 tissue samples and 32 matched PDOs, ensuring a high-fidelity representation of the tumor bioloy. Our comprehensive integration strategy involved differential expression analyses (DEAs) and gene regulatory network (GRN) analyses, facilitating the identification of 5,199 genes governing at least one regulon. By using the biological processes (BPs) collected from Moonlight closely related to cancer, we pinpointed 2,118 regulator-regulon groups with potential roles in oncogenic processes. Further, through integration of Moonlight and DEA results identified 334 regulator-regulon groups significantly enriched in both tissue and PDO samples, classifying them as oncogenic mediators (OMs). Among these, four genes (NCKAP1L, LAX1, RAD51AP1, and NAT2) demonstrated an association with drug responsiveness and recurrence-free survival (RFS), offering new insights into the molecular mechanisms of chemotherapy response in RC. Our integrated approach not only underscores the translational fidelity of PDOs, but also harnesses the analytical prowess of Moonlight, setting a new benchmark for targeted therapy research in rectal cancer.

Enhancing Chemotherapy Response Prediction via Matched Colorectal Tumor-Organoid Gene Expression Analysis and Network-Based Biomarker Selection.

Colorectal cancer (CRC) poses significant challenges in chemotherapy response prediction due to its molecular heterogeneity. This study introduces an innovative methodology that leverages gene expression data generated from matched colorectal tumor and organoid samples to enhance prediction accuracy. By applying Consensus Weighted Gene Co-expression Network Analysis (WGCNA) across multiple datasets, we identify critical gene modules and hub genes that correlate with patient responses, particularly to 5-fluorouracil (5-FU). This integrative approach advances precision medicine by refining chemotherapy regimen selection based on individual tumor profiles. Our predictive model demonstrates superior accuracy over traditional methods on independent datasets, illustrating significant potential in addressing the complexities of high-dimensional genomic data for cancer biomarker research.

MIAMI-AD (Methylation in Aging and Methylation in AD): an integrative knowledgebase that facilitates explorations of DNA methylation across sex, aging, and Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder with a significant impact on aging populations. DNA methylation (DNAm) alterations have been implicated in both the aging processes and the development of AD. Given that AD affects more women than men, it is also important to explore DNAm changes that occur specifically in each sex. We created MIAMI-AD, a comprehensive knowledge base containing manually curated summary statistics from 97 published tables in 37 studies, all of which included at least 100 participants. MIAMI-AD enables easy browsing, querying, and downloading DNAm associations at multiple levels - at individual CpG, gene, genomic regions, or genome-wide, in one or multiple studies. Moreover, it also offers tools to perform integrative analyses, such as comparing DNAm associations across different phenotypes or tissues, as well as interactive visualizations. Using several use case examples, we demonstrated that MIAMI-AD facilitates our understanding of age-associated CpGs in AD and the sex-specific roles of DNAm in AD. This open-access resource is freely available to the research community, and all the underlying data can be downloaded. MIAMI-AD (https://miami-ad.org/) facilitates integrative explorations to better understand the interplay between DNAm across aging, sex, and AD.

Design of high SERS sensitive substrates based on branched Ti nanorods.

This paper reports a rational design of branched titanium (Ti) nanorods formed by glancing angle physical vapor deposition and their applications as substrates for surface-enhanced Raman scattering (SERS). Ti nanorods with branches have larger surface areas than non-branched nanorods. However, Ti surface oxidizes easily resulting in very little SERS effect. The SERS sensitivity of the branched titanium nanorod is improved by annealing Ti nanorods in nitrogen in an effort to reduce oxidation. Additionally, the plasmonic resonance of the branched titanium nanorod is further improved by coating the top of the nanorods and branches with silver (Ag). The sensitivity of the SERS substrates is about 3700% that of as-deposited branched Ti nanorods with a native oxide layer. Our investigation provides a mechanism to fabricate sensitive SERS sensors of Ti nanorods that are known to be thermally and chemically stable and compatible with silicon-based electronics.

Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes.

Triple-negative breast cancer (TNBC) is a collection of biologically diverse cancers characterized by distinct transcriptional patterns, biology, and immune composition. TNBCs subtypes include two basal-like (BL1, BL2), a mesenchymal (M) and a luminal androgen receptor (LAR) subtype. Through a comprehensive analysis of mutation, copy number, transcriptomic, epigenetic, proteomic, and phospho-proteomic patterns we describe the genomic landscape of TNBC subtypes. Mesenchymal subtype tumors display high mutation loads, genomic instability, absence of immune cells, low PD-L1 expression, decreased global DNA methylation, and transcriptional repression of antigen presentation genes. We demonstrate that major histocompatibility complex I (MHC-I) is transcriptionally suppressed by H3K27me3 modifications by the polycomb repressor complex 2 (PRC2). Pharmacological inhibition of PRC2 subunits EZH2 or EED restores MHC-I expression and enhances chemotherapy efficacy in murine tumor models, providing a rationale for using PRC2 inhibitors in PD-L1 negative mesenchymal tumors. Subtype-specific differences in immune cell composition and differential genetic/pharmacological vulnerabilities suggest additional treatment strategies for TNBC.

Branching of Titanium Nanorods.

One dimensional titanium nanorod structures formed by glancing angle physical vapor deposition have branches while other hexagonal closed packed metals do not. Based on physical vapor deposition and characterizations using electron microscopy and X-ray diffraction, this paper reports that Ti nanorod branching occurs at a low homologous temperature of 0.28. The side surface of the nanorods consists of {101¯1} facets arranged in a zigzag shape. Further, branches form on the {101¯1} side facets that are parallel to the deposition flux. The length of the branches increases as they are farther away from the nanorod top and tend to reach a constant. The top surface facet of Ti nanorods is {0001} and that of the branches is {101¯1}. The insight into conditions for branching, together with the determination of the morphology and crystal orientation of the branches, lay the foundation for further studies of branching mechanisms and driving force.

Phosphoglucose isomerase gene expression as a prognostic biomarker of gastric cancer.

OBJECTIVE: Tumor heterogeneity renders identification of suitable biomarkers of gastric cancer (GC) challenging. Here, we aimed to identify prognostic genes of GC using computational analysis. METHODS: We first used microarray technology to profile gene expression of GC and paired nontumor tissues from 198 patients. Based on these profiles and patients' clinical information, we next identified prognostic genes using novel computational approaches. Phosphoglucose isomerase, also known as glucose-6-phosphate isomerase (GPI), which ranked first among 27 candidate genes, was further investigated by a new analytical tool namely enviro-geno-pheno-state (E-GPS) analysis. Suitability of GPI as a prognostic marker, and its relationship with physiological processes such as metabolism, epithelial-mesenchymal transition (EMT), as well as drug sensitivity were evaluated using both our own and independent public datasets. RESULTS: We found that higher expression of GPI in GC correlated with prolonged survival of patients. Particularly, a combination of CDH2 and GPI expression effectively stratified the outcomes of patients with TNM stage II/III. Down-regulation of GPI in tumor tissues correlated well with depressed glucose metabolism and fatty acid synthesis, as well as enhanced fatty acid oxidation and creatine metabolism, indicating that GPI represents a suitable marker for increased probability of EMT in GC cells. CONCLUSIONS: Our findings strongly suggest that GPI acts as a novel biomarker candidate for GC prognosis, allowing greatly enhanced clinical management of GC patients. The potential metabolic rewiring correlated with GPI also provides new insights into studying the relationship between cancer metabolism and patient survival.

The novel lncRNA p4516 acts as a prognostic biomarker promoting gastric cancer cell proliferation and metastasis.

Purpose: Emerging evidence has shown that long noncoding RNAs (lncRNAs) participate in oncogenesis and tumor progression. We previously found a novel lncRNA p4516 which was closely associated with prognosis by preliminary study of lncRNA expression profile from paired tumors and nontumor tissues in 198 gastric cancer (GC) patients. However, the exact biological functions and the underlying molecular mechanisms of p4516 in gastric tumorigenesis still remain unclear. Materials and methods: The RNA fluorescence in situ hybridization (RNA-FISH) analysis, cytoplasmic and nuclear RNA isolation and qRT-PCR were applied to determine the subcellular localization of p4516. Expression levels of p4516 were assessed using qRT-PCR in both GC cell lines and in 142 primary GC tissues. Correlations between p4516 expression and GC patients' clinicopathological parameters were analyzed. Gain- and loss-of-function experiments were employed to investigate the role of p4516 in proliferation, migration and invasion both in vitro and in vivo. In addition, Western blotting and immunohistochemical staining were used to examine the protein expression levels. Results: LncRNA p4516 was mainly localized in the nucleus of GC cells and p4516 tended to have higher expression levels in GC cells compared to the normal gastric mucosa-derived cells GES-1. Furthermore, higher expression levels of p4516 correlated with worse clinical outcomes in GC patients and acted as an independent prognostic biomarker. Functional analysis revealed that p4516 participated in the regulation of GC cell proliferation, invasion and migration both in vivo and in vitro. Moreover, p4516 was involved in epithelial-mesenchymal transition (EMT) in GC cells. Conclusion: Our study demonstrated the oncogenic role of novel lncRNA p4516 in the gastric carcinogenesis for the first time. High expression of p4516 may act as prognostic marker in patient with gastric cancer.

Simultaneous Thermal Stability and Ultrahigh Sensitivity of Heterojunction SERS Substrates.

This paper reports the design of Ag-Al2O3-Ag heterojunctions based on Ag nanorods (AgNRs) and their applications as thermally stable and ultrasensitive substrates of surface-enhanced Raman scattering (SERS). Specifically, an ultrathin Al2O3 capping layer of 10 nm on top of AgNRs serves to slow down the surface diffusion of Ag at high temperatures. Then, an additional Ag layer on top of the capping layer creates AgNRs-Al2O3-Ag heterojunctions, which lead to giant enhancement of electromagnetic fields within the Al2O3 gap regions that could boost the SERS enhancement. As a result of this design, the SERS substrates are thermally stable up to 200 °C, which has been increased by more than 100 °C compared with bare AgNRs, and their sensitivity is about 400% that of pure AgNRs. This easy yet effective capping approach offers a pathway to fabricate ultrasensitive, thermally stable and easily prepared SERS sensors, and to extend SERS applications for high-temperature detections, such as monitoring in situ the molecule reorientation process upon annealing. Such simultaneous achievement of thermal stability and SERS sensitivity represents a great advance in the design of SERS sensors and will inspire the fabrication of novel hetero-nanostructures.

Degradation Mechanism of Ag Nanorods for Surface Enhanced Raman Spectroscopy.

This paper reports a degradation mechanism of silver (Ag) nanorods that are used as substrates for surface enhanced Raman spectroscopy (SERS). The attachment of sulfur and hydrocarbons to the surfaces of Ag nanorods is observed when they are stored in ambient over four months. This attachment is observed to correlate with ~20% decrease in SERS signal. The attachment, and thereby the signal degradation, takes three weeks to complete, and remains stable after the initial decay over the rest of the four month test period. While this degradation mechanism is a limitation to the gross enhancement, the ensuing stability beyond three weeks is encouraging.

Design of Ag nanorods for sensitivity and thermal stability of surface-enhanced Raman scattering.

The technology of surface-enhanced Raman scattering (SERS) has found many applications and may find more if it can possess both sensitivity and thermal stability. This paper reports a rational design of Ag nanorods to simultaneously achieve two competing goals: the sensitivity and the thermal stability of SERS substrates. The Ag nanorods are designed and synthesized using physical vapor deposition under the condition of glancing angle incidence. The working pressure of the vacuum chamber is controlled so the mean free path of depositing atoms is comparable to the dimension of the chamber, so as to grow Ag nanorods with small diameter, and small but clear separation for optimal SERS sensitivity. Such Ag nanorods are further capped with Al2O3 on their top surfaces to reduce the diffusion-induced coarsening at high temperatures, and thereby to improve the thermal stability for SERS detections. Meanwhile, since the side surfaces of Ag nanorods are not coated with oxides in this approach, the SERS sensitivity is largely preserved while good thermal stability is achieved.

Clustering on Magnesium Surfaces - Formation and Diffusion Energies.

The formation and diffusion energies of atomic clusters on Mg surfaces determine the surface roughness and formation of faulted structure, which in turn affect the mechanical deformation of Mg. This paper reports first principles density function theory (DFT) based quantum mechanics calculation results of atomic clustering on the low energy surfaces {0001} and [Formula: see text]. In parallel, molecular statics calculations serve to test the validity of two interatomic potentials and to extend the scope of the DFT studies. On a {0001} surface, a compact cluster consisting of few than three atoms energetically prefers a face-centered-cubic stacking, to serve as a nucleus of stacking fault. On a [Formula: see text], clusters of any size always prefer hexagonal-close-packed stacking. Adatom diffusion on surface [Formula: see text] is high anisotropic while isotropic on surface (0001). Three-dimensional Ehrlich-Schwoebel barriers converge as the step height is three atomic layers or thicker. Adatom diffusion along steps is via hopping mechanism, and that down steps is via exchange mechanism.

Applying spatial analysis techniques to assess the suitability of multipurpose uses of spring water in the Jiaosi Hot Spring Region, Taiwan.

The Jiaosi Hot Spring Region is one of the most famous tourism destinations in Taiwan. The spring water is processed for various uses, including irrigation, aquaculture, swimming, bathing, foot spas, and recreational tourism. Moreover, the multipurpose uses of spring water can be dictated by the temperature of the water. To evaluate the suitability of spring water for these various uses, this study spatially characterized the spring water temperatures of the Jiaosi Hot Spring Region by integrating ordinary kriging (OK), sequential Gaussian simulation (SGS), and Geographic information system (GIS). First, variogram analyses were used to determine the spatial variability of spring water temperatures. Next, OK and SGS were adopted to model the spatial uncertainty and distributions of the spring water temperatures. Finally, the land use (i.e., agriculture, dwelling, public land, and recreation) was determined using GIS and combined with the estimated distributions of the spring water temperatures. A suitable development strategy for the multipurpose uses of spring water is proposed according to the integration of the land use and spring water temperatures. The study results indicate that the integration of OK, SGS, and GIS is capable of characterizing spring water temperatures and the suitability of multipurpose uses of spring water. SGS realizations are more robust than OK estimates for characterizing spring water temperatures compared to observed data. Furthermore, current land use is almost ideal in the Jiaosi Hot Spring Region according to the estimated spatial pattern of spring water temperatures.

Control of Separation and Diameter of Ag Nanorods through Self-organized Seeds.

This paper proposes a mechanism of controlling the diameter and separation of metallic nanorods from physical vapor deposition through self-organized seeds and experimentally demonstrates the feasibility using Ag as the prototype metal, In as the seed, and Si the substrate. Being non-wetting on Si substrates, deposited In atoms self-organize into islands. Subsequently deposited Ag atoms attach to In islands, rather than to Si substrates, due to preferential bonding and geometrical shadowing. The experimental results show that self-organized In seeds of 5 nm nominal thickness give rise to the best separation and the smallest diameter of Ag nanorods.

Wedding Cake Growth Mechanism in One-Dimensional and Two-Dimensional Nanostructure Evolution.

The kinetic processes and atomistic mechanisms in nanostructure growth are of fundamental interest to nanomaterial syntheses with precisely controlled morphology and functionality. By programming deposition conditions at time domain, we observed the wedding cake growth mechanism in the formation of 1D and 2D ZnO nanostructures. Within a narrow growth window, the surfaces of the 1D and 2D structures were covered with a unique concentric terrace feature. This mechanism was further validated by comparing the characteristic growth rates to the screw dislocation-driven model. An interesting 1D to 2D morphology transition was also found during the wedding cake growth, when the adatoms overcome the Ehrlich-Schwoebel (ES) barrier along the edge of the top crystal facet triggered by lowering the supersaturation. The wedding cake model might be a general growth mechanism for flat-tipped nanowires that do not possess any dislocations. This study enriches our understanding on the fundamental kinetics of nanostructured crystal growth and provides a transformative strategy to achieve rational design and control of nanoscale geometry.

Shape and surface chemistry effects on the cytotoxicity and cellular uptake of metallic nanorods and nanospheres.

Metallic nanoparticles (such as gold and silver) have been intensely studied for wound healing applications due to their ability to be easily functionalized, possess antibacterial properties, and their strong potential for targeted drug release. In this study, rod-shaped silver nanorods (AgNRs) and gold nanorods (AuNRs) were fabricated by electron beam physical vapor deposition (EBPVD), and their cytotoxicity toward human skin fibroblasts were assessed and compared to sphere-shaped silver nanospheres (AgNSs) and gold nanospheres (AuNSs). Results showed that the 39.94 nm AgNSs showed the greatest toxicity with fibroblast cells followed by the 61.06 nm AuNSs, ∼556 nm × 47 nm (11.8:1 aspect ratio) AgNRs, and the ∼534 nm × 65 nm (8.2:1 aspect ratio) AuNRs demonstrated the least amount of toxicity. The calculated IC50 (50% inhibitory concentration) value for the AgNRs exposed to fibroblasts was greater after 4 days of exposure (387.3 µg mL(-1)) compared to the AgNSs and AuNSs (4.3 and 23.4 µg mL(-1), respectively), indicating that these spherical metallic nanoparticles displayed a greater toxicity to fibroblast cells. The IC50 value could not be measured for the AuNRs due to an incomplete dose response curve. The reduced cell toxicity with the presently developed rod-shaped nanoparticles suggests that they may be promising materials for use in numerous biomedical applications.

Combined hydrophobicity and mechanical durability through surface nanoengineering.

This paper reports combined hydrophobicity and mechanical durability through the nanoscale engineering of surfaces in the form of nanorod-polymer composites. Specifically, the hydrophobicity derives from nanoscale features of mechanically hard ZnO nanorods and the mechanical durability derives from the composite structure of a hard ZnO nanorod core and soft polymer shell. Experimental characterization correlates the morphology of the nanoengineered surfaces with the combined hydrophobicity and mechanical durability, and reveals the responsible mechanisms. Such surfaces may find use in applications, such as boat hulls, that benefit from hydrophobicity and require mechanical durability.

Controllable growth of aluminum nanorods using physical vapor deposition.

This letter proposes and experimentally demonstrates that oxygen, through action as a surfactant, enables the growth of aluminum nanorods using physical vapor deposition. Based on the mechanism through which oxygen acts, the authors show that the diameter of aluminum nanorods can be controlled from 50 to 500 nm by varying the amount of oxygen present, through modulating the vacuum level, and by varying the substrate temperature. When grown under medium vacuum, the nanorods are in the form of an aluminum metal - aluminum oxide core-shell. The thickness of the oxide shell is ~2 nm as grown and is stable when maintained in ambient for 30 days or annealed in air at 475 K for 1 day. As annealing temperature is increased, the nanorod morphology remains stable while the ratio of oxide shell to metallic core increases, resulting in a fully aluminum oxide nanorod at 1,475 K.

Pressure effect on stabilities of self-interstitials in HCP-zirconium.

The self-interstitial atoms (SIAs) mediate the evolution of micro-structures which is crucial in understanding the instabilities of hexagonal close packed (HCP) structures. Taking zirconium as a prototype, we investigate the pressure effect on the stabilities of SIAs using first-principles calculations based on density-functional theory. We found that the pressure greatly affects the stability of the SIAs. The SIAs in basal planes are more stable under pressure. The SIA configuration of the lowest formation energy changes from basal octahedral (BO) to octahedral (O) at a pressure of 21 GPa. The lowest formation enthalpy configuration switches from BO to S (split-dumbbell) at the pressure of 30 GPa. The formation volumes of SIAs decrease monotonically in response to an increase in pressure. Our results reveal that it is important to take pressure effects into account when predicting the micro-structural evolution of HCP structures.

Mechanical properties of silicon carbide nanowires: effect of size-dependent defect density.

This paper reports quantitative mechanical characterization of silicon carbide (SiC) nanowires (NWs) via in situ tensile tests inside scanning electron microscopy using a microelectromechanical system. The NWs are synthesized using the vapor-liquid-solid process with growth direction of ⟨111⟩. They consist of three types of structures, pure face-centered cubic (3C) structure, 3C structure with an inclined stacking fault (SF), and highly defective structure, in a periodic fashion along the NW length. The SiC NWs are found to deform linear elastically until brittle fracture. Their fracture origin is identified in the 3C structures with inclined SFs, rather than the highly defective structures. The fracture strength increases as the NW diameter decreases from 45 to 17 nm, approaching the theoretical strength of 3C SiC. The size effect on fracture strength of SiC NWs is attributed to the size-dependent defect density rather than the surface effect that is dominant for single crystalline NWs.