Chiral Transfer of Linear Polysiloxane with Preferred-Handed Helical Conformation.

We report the preparation of chiral silica using a linear polysiloxane main chain with a preferred-handed helical structure as the template. Poly(methylvinyl siloxane) (PMVS) with a cysteine derivative side chain designated as PMVS-Cys was prepared using anionic polymerization and an ene-thiol reaction. PMVS-Cys forms a helical conformation in both solution and film via hydrogen bonding between amide groups at side chains. The helical structure remains during the calcination process, resulting in silica with helical structure. The silica with a helical structure shows optical activity.

Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer.

In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.

Tumor-Infiltrating Myeloid Cells Confer De Novo Resistance to PD-L1 Blockade through EMT-Stromal and Tgfß-Dependent Mechanisms.

SIGNIFICANCE: Most patients with bladder cancer do not respond to ICB targeting of the PD-L1 signaling axis. Our modeling applied a de novo resistance signature to show that tumor-infiltrating myeloid cells promote poor treatment response in a TGFß-dependent mechanism.

Global DNA methylation of WTC prostate cancer tissues show signature differences compared to non-exposed cases.

There is increased incidence of prostate cancer (PC) among World Trade Center (WTC)-exposed responders and community members, with preliminary evidence suggestive of more aggressive disease. While previous research is supportive of differences in DNA methylation and gene expression as a consequence of WTC exposure, as measured in blood of healthy individuals, the epigenetics of WTC PC tissues has yet to be explored. Patients were recruited from the World Trade Center Health Program. Non-WTC PC samples were frequency matched on age, race/ethnicity and Gleason score. Bisulfite-treated DNA was extracted from tumor tissue blocks and used to assess global DNA methylation with the MethylationEPIC BeadChip. Differential and pathway enrichment analyses were conducted. RNA from the same tumor blocks was used for gene expression analysis to further support DNA methylation findings. Methylation data were generated for 28 samples (13 WTC and 15 non-WTC). Statistically significant differences in methylation were observed for 3,586 genes; on average WTC samples were statistically significantly more hypermethylated (P = 0.04131). Pathway enrichment analysis revealed hypermethylation in epithelial mesenchymal transition (EMT), hypoxia, mitotic spindle, TNFA signaling via NFKB, WNT signaling, and TGF beta signaling pathways in WTC compared to non-WTC samples. The androgen response, G2M and MYC target pathways were hypomethylated. These results correlated well with RNA gene expression. In conclusion, long-term epigenic changes associated with WTC dust exposure were observed in PC tissues. These occurred in genes of critical pathways, likely increasing prostate tumorigenesis potential. This warrants analysis of larger WTC groups and other cancer types.

An RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness.

Notch signaling represents a key mechanism mediating cancer metastasis and stemness. To understand how Notch signaling is overactivated to couple tumor metastasis and self-renewal in NSCLC cells, we performed the current study and showed that RFC4, a DNA replication factor amplified in more than 40% of NSCLC tissues, directly binds to the Notch1 intracellular domain (NICD1) to competitively abrogate CDK8/FBXW7-mediated degradation of NICD1. Moreover, RFC4 is a functional transcriptional target gene of Notch1 signaling, forming a positive feedback loop between high RFC4 and NICD1 levels and sustained overactivation of Notch signaling, which not only leads to NSCLC tumorigenicity and metastasis but also confers NSCLC cell resistance to treatment with the clinically tested drug DAPT against NICD1 synthesis. Furthermore, together with our study, analysis of two public datasets involving more than 1500 NSCLC patients showed that RFC4 gene amplification, and high RFC4 and NICD1 levels were tightly correlated with NSCLC metastasis, progression and poor patient prognosis. Therefore, our study characterizes the pivotal roles of the positive feedback loop between RFC4 and NICD1 in coupling NSCLC metastasis and stemness properties and suggests its therapeutic and diagnostic/prognostic potential for NSCLC therapy.

A Network Analysis of Multiple Myeloma Related Gene Signatures.

Multiple myeloma (MM) is the second most prevalent hematological cancer. MM is a complex and heterogeneous disease, and thus, it is essential to leverage omics data from large MM cohorts to understand the molecular mechanisms underlying MM tumorigenesis, progression, and drug responses, which may aid in the development of better treatments. In this study, we analyzed gene expression, copy number variation, and clinical data from the Multiple Myeloma Research Consortium (MMRC) dataset and constructed a multiple myeloma molecular causal network (M3CN). The M3CN was used to unify eight prognostic gene signatures in the literature that shared very few genes between them, resulting in a prognostic subnetwork of the M3CN, consisting of 178 genes that were enriched for genes involved in cell cycle (fold enrichment = 8.4, p value = 6.1 × 10-26). The M3CN was further used to characterize immunomodulators and proteasome inhibitors for MM, demonstrating the pleiotropic effects of these drugs, with drug-response signature genes enriched across multiple M3CN subnetworks. Network analyses indicated potential links between these drug-response subnetworks and the prognostic subnetwork. To elucidate the structure of these important MM subnetworks, we identified putative key regulators predicted to modulate the state of these subnetworks. Finally, to assess the predictive power of our network-based models, we stratified MM patients in an independent cohort, the MMRF-CoMMpass study, based on the prognostic subnetwork, and compared the performance of this subnetwork against other signatures in the literature. We show that the M3CN-derived prognostic subnetwork achieved the best separation between different risk groups in terms of log-rank test p-values and hazard ratios. In summary, this work demonstrates the power of a probabilistic causal network approach to understanding molecular mechanisms underlying the different MM signatures.

Prostate Cancer in World Trade Center Responders Demonstrates Evidence of an Inflammatory Cascade.

An excess incidence of prostate cancer has been identified among World Trade Center (WTC) responders. In this study, we hypothesized that WTC dust, which contained carcinogens and tumor-promoting agents, could facilitate prostate cancer development by inducing DNA damage, promoting cell proliferation, and causing chronic inflammation. We compared expression of immunologic and inflammatory genes using a NanoString assay on archived prostate tumors from WTC Health Program (WTCHP) patients and non-WTC patients with prostate cancer. Furthermore, to assess immediate and delayed responses of prostate tissue to acute WTC dust exposure via intratracheal inhalation, we performed RNA-seq on the prostate of normal rats that were exposed to moderate to high doses of WTC dust. WTC prostate cancer cases showed significant upregulation of genes involved in DNA damage and G2-M arrest. Cell-type enrichment analysis showed that Th17 cells, a subset of proinflammatory Th cells, were specifically upregulated in WTC patients. In rats exposed to WTC dust, we observed upregulation of gene transcripts of cell types involved in both adaptive immune response (dendritic cells and B cells) and inflammatory response (Th17 cells) in the prostate. Unexpectedly, genes in the cholesterol biosynthesis pathway were also significantly upregulated 30 days after acute dust exposure. Our results suggest that respiratory exposure to WTC dust can induce inflammatory and immune responses in prostate tissue. IMPLICATIONS: WTC-related prostate cancer displayed a distinct gene expression pattern that could be the result of exposure to specific carcinogens. Our data warrant further epidemiologic and cellular mechanistic studies to better understand the consequences of WTC dust exposure.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/8/1605/F1.large.jpg.

Forecasting of oil-spill trajectories by using SCHISM and X-band radar.

In this study, we propose a two-step strategy for tracking oil-spill trajectories. First, an X-band radar is established to monitor oil spills. Accordingly, we propose a radar image-processing technique for identifying the oil slicks from the nautical radar images. Second, we apply the SCHISM to determine the water surface elevations and currents at the event site and obtain the trajectories of the oil slicks using a Lagrangian particle-tracking method incorporated in the SCHISM. An oil-spill event caused by the container ship T. S. Taipei is used as a case study for testing the capability of the proposed oil-tracking strategy. The SCHISM simulation results for the fouled coastline obtained using the wind data from a nearby data buoy agree quite well with those obtained from field observations. However, the predicted fouled coastline based on the forecasted wind data is unsatisfactory. The reasons for the unsatisfactory prediction are discussed and revealed.

Steroid hormones (17beta-estradiol and hydrocortisone) upregulate hepatocyte nuclear factor (HNF)-3beta and insulin-like growth factors I and II expression in the gonads of tilapia (Oreochromis mossambicus) in vitro.

Hepatocyte nuclear factors (HNF-1alpha, -1beta and -3beta) and insulin-like growth factors (IGF-I and -II), which are involved in liver-specific gene expression, metabolism, development and cell growth, have been found in the gonads of tilapia (Oreochromis mossambicus). However, the functions of these factors and how they interact within the gonads of bony fish are not understood. In the present study, we provided experimental evidence that the expression of HNF-3beta in the gonads of tilapia, but not HNF-1alpha and -1beta, was affected in vitro by 17beta-estradiol and hydrocortisone. Immunohistochemical staining confirmed that tilapia HNF-3beta was mainly found in the nuclei of hepatocytes, the follicular granulosa cells of the ovaries, and the interstitial cells of the testes of adult tilapia. Further data were gathered at various steroid concentrations (0.1, 1, 10, 100, and 1000 nM) over various culture intervals (6, 12, 18, 24, 30, and 36 h) and subjected to semi-quantitative RT-PCR analysis. The expression of downstream genes (IGF-I and -II) followed the same temporal patterns as HNF-3beta, albeit at decreased levels for 30 and 36 h culture intervals. Both hormones upregulated HNF-3beta mRNA expression at concentrations of 0.1-10 nM, and reached optimal physiological concentrations for induction of IGFs at 1-10 nM. The identity of the PCR fragments was concurrently verified by sequencing and PCR-Southern hybridization. We inferred that HNF-3beta and IGFs may play a regulatory role in tilapia gonads during oocyte maturation and spermatogenesis.