Upregulation of CXCL1 and LY9 contributes to BRCAness in ovarian cancer and mediates response to PARPi and immune checkpoint blockade.

BACKGROUND: Mutations in BRCA1 or BRCA2 (BRCA1/2) cause homologous recombination deficiency (HRD). Ovarian cancer (OvCa) patients harbouring HRD beyond BRCA1/2 mutation result in a state referred to as "BRCAness". OvCa with BRCAness could benefit from PARP inhibitors. This study aims to identify a signature to detect the BRCAness population at the transcriptome level. METHODS: We used a rank-based algorithm to develop a qualitative BRCAness signature for OvCa. Upregulation of CXCL1 with downregulation of SV2A and upregulation of LY9 with downregulation of CHRNB3 were constructed as the BRCAness signature (2 gene pairs, 2-GPS) for OvCa. RESULTS: OvCa samples that were classified as BRCAness by 2-GPS showed improved overall survival, progression-free survival and exhibited increased multi-omics alterations in homologous recombination genes and enhanced sensitivity to immune checkpoint blockade. BRCAness cells were sensitive to PARP inhibitors. By biological experiments, we validated SKOV3 cells and patients with HRD exhibited higher expression of CXCL1 than SV2A and higher expression of LY9 than CHRNB3 at mRNA level. Both SKOV3 and A2780 with HRD were sensitive to mitomycin C, cisplatin and olaparib. CONCLUSIONS: In conclusion, 2-GPS could robustly predict BRCAness OvCa at the individual level and extend the population who may benefit from PARP inhibitors.

A genetic map of the chromatin regulators to drug response in cancer cells.

BACKGROUND: Diverse drug vulnerabilities owing to the Chromatin regulators (CRs) genetic interaction across various cancers, but the identification of CRs genetic interaction remains challenging. METHODS: In order to provide a global view of the CRs genetic interaction in cancer cells, we developed a method to identify potential drug response-related CRs genetic interactions for specific cancer types by integrating the screen of CRISPR-Cas9 and pharmacogenomic response datasets. RESULTS: Totally, 625 drug response-related CRs synthetic lethality (CSL) interactions and 288 CRs synthetic viability (CSV) interactions were detected. Systematically network analysis presented CRs genetic interactions have biological function relationship. Furthermore, we validated CRs genetic interactions induce multiple omics deregulation in The Cancer Genome Atlas. We revealed the colon adenocarcinoma patients (COAD) with mutations of a CRs set (EP300, MSH6, NSD2 and TRRAP) mediate a better survival with low expression of MAP2 and could benefit from taxnes. While the COAD patients carrying at least one of the CSV interactions in Vorinostat CSV module confer a poor prognosis and may be resistant to Vorinostat treatment. CONCLUSIONS: The CRs genetic interaction map provides a rich resource to investigate cancer-associated CRs genetic interaction and proposes a powerful strategy of biomarker discovery to guide the rational use of agents in cancer therapy.

Design and Stereochemical Research (DFT, ECD and Crystal Structure) of Novel Bedaquiline Analogs as Potent Antituberculosis Agents.

A series of bedaquiline analogs containing H-bond donors were designed as anti-Mycobacterium tuberculosis drugs. A pair of diastereoisomers (R/S- and S/S-isomers) was selected from these designed compounds for synthetic and stereochemical research. The title compounds were synthesized from chiral precursors for the first time and the absolute configurations (ACs) were determined by electronic circular dichroism (ECD) with quantum chemical calculations. Moreover, a single crystal of the S/S compound was obtained for X-ray diffraction analysis, and the crystal structure showed high consistency with the geometry, confirming the reliability of ACs obtained by ECD analyses and theoretical simulation. Furthermore, the effect of stereochemistry on the anti-tuberculosis activity was investigated. The MICs of the R/S- and S/S-isomers against Mycobacterium phlei 1180 are 9.6 and 32.1 µg·mL(-1), respectively. Finally, molecular docking was carried out to evaluate the inhibitory nature and binding mode differences between diastereoisomers.

The adverse effects of developmental exposure to polystyrene nanoparticles on cognitive function in weaning rats and the protective role of trihydroxy phenolacetone.

Polystyrene nanoplastic(PS-NP) can originate from sources such as plastic waste and industrial wastewater and have been shown to have deleterious effects on abnormal neurobehaviors. However, evidence regarding the health impacts, biological mechanisms, and treatment strategies underlying developmental exposure to low dose PS-NP is still lacking. This study aimed to fill this knowledge gap by administering low doses of PS-NP(50 and 100 µg/L) to weaning rats for 4 consecutive weeks. Behavioral and morphological experiments were performed to evaluate hippocampal damage, and transcriptomics and Assay for Transposase Accessible Chromatin with hight-throughput sequencing(ATAC) analyses were conducted to identify potential key targets. Additionally, Connectivity Map(CMap) database, Limited proteolysis-mass spectrometry(LiP-SMap), and molecular-protein docking were used to examine potential phytochemicals with therapeutic effects on key targets. The results indicated that developmental exposure to PS-NP can induce hippocampal impairment and aberrant neurobehaviors in adulthood. Multi-omics analyses consistently showed that apoptosis-related signaling pathways were sensitive to PS-NP exposure, and mitogen-activated protein kinase 3(Mapk3) was identified as the core gene by the gene network, which was further validated in vitro experiments. The CMap database provided a series of phytochemicals that might regulate Mapk3 expression, and trihydroxy-phenolacetone(THP) was found to have directly binding sites with Mapk3 through LiP-SMap and molecular docking analysis. Furthermore, THP administration could significantly alleviate apoptosis induced by PS-NP exposure in primary hippocampal cells through down-regulation of Mapk3. These findings suggested that developmental exposure to PS-NP has adverse effects on cognitive function and that THP can alleviate these effects by directly binding to Mapk3.

LiqBioer: a manually curated database of cancer biomarkers in body fluid.

Cancer biomarkers are measurable indicators that play vital roles in clinical applications. Biomarkers in body fluids have gained considerable attention since the development of liquid biopsy, and their data volume is rapidly increasing. Nevertheless, current research lacks the compilation of published cancer body fluid biomarkers into a centralized and sustainable repository for researchers and clinicians, despite a handful of small-scale and specific data resources. To fulfill this purpose, we developed liquid biomarker (LiqBioer) containing 6231 manually curated records from 3447 studies, covering 3056 biomarkers and 74 types of cancer in 22 tissues. LiqBioer allows users to browse and download comprehensive information on body liquid biomarkers, including cancer types, source studies and clinical usage. As a comprehensive resource for body fluid biomarkers of cancer, LiqBioer is a powerful tool for researchers and clinicians to query and retrieve biomarkers in liquid biopsy. DATABASE URL: http://www.medsysbio.org:8080/LiqBioer.

Systematic exploration of the underlying mechanism of gemcitabine resistance in pancreatic adenocarcinoma.

Resistance to gemcitabine is the main challenge of chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Hence, the development of a response signature to gemcitabine is essential for precision therapy of PDAC. However, existing quantitative signatures of gemcitabine are susceptible to batch effects and variations in sequencing platforms. Therefore, based on within-sample relative expression ordering of pairwise genes, we developed a transcriptome-based gemcitabine signature consisting of 28 gene pairs (28-GPS) that could predict response to gemcitabine for PDAC at the individual level. The 28-GPS was superior to previous quantitative signatures in terms of classification accuracy and prognostic performance. Resistant samples classified by 28-GPS showed poorer overall survival, higher genomic instability, lower immune infiltration, higher metabolic level and higher-fidelity DNA damage repair compared with sensitive samples. In addition, we found that gemcitabine combined with phosphoinositide 3-kinase (PI3K) inhibitor may be an alternative treatment strategy for PDAC. Single-cell analysis revealed that cancer cells in the same PDAC sample showed both the characteristics of sensitivity and resistance to gemcitabine, and the activation of the TGFß signalling pathway could promote progression of PDAC. In brief, 28-GPS could robustly determine whether PDAC is resistant or sensitive to gemcitabine, and may be an auxiliary tool for clinical treatment.

A transcriptional signature detects homologous recombination deficiency in pancreatic cancer at the individual level.

Pancreatic cancer (PC) with homologous recombination deficiency (HRD) has been reported to benefit from poly ADP-ribose polymerase (PARP) inhibitors. However, accurate identification of HRD status for PC patients from the transcriptional level is still a great challenge. Here, based on a relative expression ordering (REO)-based algorithm, we developed an HRD signature including 24 gene pairs (24-GPS) using PC transcriptional profiles from The Cancer Genome Atlas (TCGA). HRD samples classified by 24-GPS showed worse overall survival (p = 4.4E-3 for TCGA; p = 1.2E-3 for International Cancer Genome Consortium-Australia cohort; p = 6.4E-2 for GSE17891; p = 7.5E-2 for GSE57495) and higher HRD scores than non-HRD samples (p = 1.4E-4). HRD samples showed highly unstable genomic characteristics and also displayed HRD-related alterations at the epigenomic and proteomic levels. Moreover, HRD cell lines identified by 24-GPS tended to be sensitive to PARP inhibitors (p = 6.6E-2 for olaparib; p = 2.6E-3 for niraparib). Compared with the non-HRD group, the HRD group presented lower immune scores and CD4/CD8 T cell infiltration proportion. Interestingly, PC tumor cells with co-inhibition of PARP-related genes and ATR showed reduced survival ability. In conclusion, 24-GPS can robustly identify PC patients with HRD status at the individualized level.

Study on molecular structure, spectroscopic investigation (IR, Raman and NMR), vibrational assignments and HOMO-LUMO analysis of L-sodium folinate using DFT: a combined experimental and quantum chemical approach.

In the present work, an exhaustive conformational search of N-[4-[[(2-amino-5-formyl-(6S)-3,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid disodium salt (L-SF) has been preformed. The optimized structure of the molecule, vibrational frequencies and NMR spectra studies have been calculated by density functional theory (DFT) using B3LYP method with the 6-311++G (d, p) basis set. IR and FT-Raman spectra for L-SF have been recorded in the region of 400-4000 cm(-1) and 100-3500 cm(-1), respectively. 13C and 1H NMR spectra were recorded and 13C and 1H nuclear magnetic resonance chemical shifts of the molecule were calculated based on the gauge-independent atomic orbital (GIAO) method. Finally all of the calculation results were applied to simulate IR, Raman, 1H NMR and 13C NMR spectrum of the title compound which showed excellent agreement with observed spectrum. Furthermore, reliable vibrational assignments which have been made on the basis of potential energy distribution (PED) and characteristic vibratinonal absorption bands of the title compound in IR and Raman have been figured out. HOMO-LUMO energy and Mulliken atomic charges have been evaluated, either.