Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells.

RNA splicing is involved in cancer initiation and progression, but how it influences host antitumor immunity in the metabolically abnormal tumor microenvironment (TME) remains unclear. Here, we demonstrate that lactate modulates Foxp3-dependent RNA splicing to maintain the phenotypic and functional status of tumor-infiltrating regulatory T (Treg) cells via CTLA-4. RNA splicing in Treg cells was correlated with the Treg cell signatures in the TME. Ubiquitin-specific peptidase 39 (USP39), a component of the RNA splicing machinery, maintained RNA-splicing-mediated CTLA-4 expression to control Treg cell function. Mechanistically, lactate promoted USP39-mediated RNA splicing to facilitate CTLA-4 expression in a Foxp3-dependent manner. Moreover, the efficiency of CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patients with colorectal cancer. These findings highlight the immunological relevance of RNA splicing in Treg cells and provide important insights into the environmental mechanism governing CTLA-4 expression in Treg cells.

Population-based heteropolymer design to mimic protein mixtures.

Biological fluids, the most complex blends, have compositions that constantly vary and cannot be molecularly defined1. Despite these uncertainties, proteins fluctuate, fold, function and evolve as programmed2-4. We propose that in addition to the known monomeric sequence requirements, protein sequences encode multi-pair interactions at the segmental level to navigate random encounters5,6; synthetic heteropolymers capable of emulating such interactions can replicate how proteins behave in biological fluids individually and collectively. Here, we extracted the chemical characteristics and sequential arrangement along a protein chain at the segmental level from natural protein libraries and used the information to design heteropolymer ensembles as mixtures of disordered, partially folded and folded proteins. For each heteropolymer ensemble, the level of segmental similarity to that of natural proteins determines its ability to replicate many functions of biological fluids including assisting protein folding during translation, preserving the viability of fetal bovine serum without refrigeration, enhancing the thermal stability of proteins and behaving like synthetic cytosol under biologically relevant conditions. Molecular studies further translated protein sequence information at the segmental level into intermolecular interactions with a defined range, degree of diversity and temporal and spatial availability. This framework provides valuable guiding principles to synthetically realize protein properties, engineer bio/abiotic hybrid materials and, ultimately, realize matter-to-life transformations.

Single-chain heteropolymers transport protons selectively and rapidly.

Precise protein sequencing and folding are believed to generate the structure and chemical diversity of natural channels1,2, both of which are essential to synthetically achieve proton transport performance comparable to that seen in natural systems. Geometrically defined channels have been fabricated using peptides, DNAs, carbon nanotubes, sequence-defined polymers and organic frameworks3-13. However, none of these channels rivals the performance observed in their natural counterparts. Here we show that without forming an atomically structured channel, four-monomer-based random heteropolymers (RHPs)14 can mimic membrane proteins and exhibit selective proton transport across lipid bilayers at a rate similar to those of natural proton channels. Statistical control over the monomer distribution in an RHP leads to segmental heterogeneity in hydrophobicity, which facilitates the insertion of single RHPs into the lipid bilayers. It also results in bilayer-spanning segments containing polar monomers that promote the formation of hydrogen-bonded chains15,16 for proton transport. Our study demonstrates the importance of the adaptability that is enabled by statistical similarity among RHP chains and of the modularity provided by the chemical diversity of monomers, to achieve uniform behaviour in heterogeneous systems. Our results also validate statistical randomness as an unexplored approach to realize protein-like behaviour at the single-polymer-chain level in a predictable manner.

Identification of G-quadruplex-interacting proteins in living cells using an artificial G4-targeting biotin ligase.

G-quadruplexes (G4s) are noncanonical nucleic acid structures pivotal to cellular processes and disease pathways. Deciphering G4-interacting proteins is imperative for unraveling G4's biological significance. In this study, we developed a G4-targeting biotin ligase named G4PID, meticulously assessing its binding affinity and specificity both in vitro and in vivo. Capitalizing on G4PID, we devised a tailored approach termed G-quadruplex-interacting proteins specific biotin-ligation procedure (PLGPB) to precisely profile G4-interacting proteins. Implementing this innovative strategy in live cells, we unveiled a cohort of 149 potential G4-interacting proteins, which exhibiting multifaceted functionalities. We then substantiate the directly binding affinity of 7 candidate G4-interacting-proteins (SF3B4, FBL, PP1G, BCL7C, NDUV1, ILF3, GAR1) in vitro. Remarkably, we verified that splicing factor 3B subunit 4 (SF3B4) binds preferentially to the G4-rich 3' splice site and the corresponding splicing sites are modulated by the G4 stabilizer PDS, indicating the regulating role of G4s in mRNA splicing procedure. The PLGPB strategy could biotinylate multiple proteins simultaneously, which providing an opportunity to map G4-interacting proteins network in living cells.

G-quadruplex in hepatitis B virus pregenomic RNA promotes its translation.

Hepatitis B virus (HBV) is a hepatotropic DNA virus that has a very compact genome. Due to this genomic density, several distinct mechanisms are used to facilitate the viral life cycle. Recently, accumulating evidence show that G-quadruplex (G4) in different viruses play essential regulatory roles in key steps of the viral life cycle. Although G4 structures in the HBV genome have been reported, their function in HBV replication remains elusive. In this study, we treated an HBV replication-competent cell line and HBV-infected cells with the G4 structure stabilizer pyridostatin (PDS) and evaluated different HBV replication markers to better understand the role played by the G4. In both models, we found PDS had no effect on viral precore RNA (pcRNA) or pre-genomic RNA (pgRNA), but treatment did increase HBeAg/HBc ELISA reads and intracellular levels of viral core/capsid protein (HBc) in a dose-dependent manner, suggesting post-transcriptional regulation. To further dissect the mechanism of G4 involvement, we used in vitro-synthesized HBV pcRNA and pgRNA. Interestingly, we found PDS treatment only enhanced HBc expression from pgRNA but not HBeAg expression from pcRNA. Our bioinformatic analysis and CD spectroscopy revealed that pgRNA harbors a conserved G4 structure. Finally, we introduced point mutations in pgRNA to disrupt its G4 structure and observed the resulting mutant failed to respond to PDS treatment and decreased HBc level in in vitro translation assay. Taken together, our data demonstrate that HBV pgRNA contains a G4 structure that plays a vital role in the regulation of viral mRNA translation.

Integrated Multi-Omics Landscape of Liver Metastases.

BACKGROUND & AIMS: Lack of thorough knowledge about the complicated immune microenvironment (IM) within a variety of liver metastases (LMs) leads to inappropriate treatment and unsatisfactory prognosis. We aimed to characterize IM subtypes and investigate potential mechanisms in LMs. METHODS: Mass cytometry was applied to characterize immune landscape of a primary liver cancers and liver metastases cohort. Transcriptomic and whole-exome sequencing were used to explore potential mechanisms across distinct IM subtypes. Single-cell transcriptomic sequencing, multiplex fluorescent immunohistochemistry, cell culture, mouse model, Western blot, quantitative polymerase chain reaction, and immunohistochemistry were used for validation. RESULTS: Five IM subtypes were revealed in 100 LMs and 50 primary liver cancers. Patients featured terminally exhausted (IM1) or rare T-cell-inflamed (IM2 and IM3) immune characteristics showed worse outcome. Increased intratumor heterogeneity, enriched somatic TP53, KRAS, APC, and PIK3CA mutations and hyperactivated hypoxia signaling accounted for the formation of vicious subtypes. SLC2A1 promoted immune suppression and desert via increasing proportion of Spp1+ macrophages and their inhibitory interactions with T cells in liver metastatic lesions. Furthermore, SLC2A1 promoted immune escape and LM through inducing regulatory T cells, including regulatory T cells and LAG3+CD4+ T cells in primary colorectal cancer. CONCLUSIONS: The study provided integrated multi-omics landscape of LM, uncovering potential mechanisms for vicious IM subtypes and confirming the roles of SLC2A1 in regulating tumor microenvironment remodeling in both primary tumor and LM lesions.

Ultrathin and Biodegradable Bismuth Oxycarbonate Nanosheets with Massive Oxygen Vacancies for Highly Efficient Tumor Therapy.

Nanomaterials doped with high atom number elements can improve the efficacy of cancer radiotherapy, but their clinical application faces obstacles, such as being difficult to degrade in vivo, or still requiring relatively high radiation dose. In this work, a bismuth oxycarbonate-based ultrathin nanosheet with the thickness of 2.8 nm for safe and efficient tumor radiotherapy under low dose of X-ray irradiation is proposed. The high oxygen content (62.5% at%) and selective exposure of the facets of ultrathin 2D nanostrusctures facilitate the escape of large amounts of oxygen atoms on bismuth nanosheets from surface, forming massive oxygen vacancies and generating reactive oxygen species that explode under the action of X-rays. Moreover, the exposure of almost all atoms to environmental factors and the nature of oxycarbonates makes the nanosheets easily degrade into biocompatible species. In vivo studies demonstrate that nanosheets could induce apoptosis in cancer cells after low dose of X-ray irradiation without causing any damage to the liver or kidney. The tumor growth inhibition effect of radiotherapy increases from 49.88% to 90.76% with the help of bismuth oxycarbonate nanosheets. This work offers a promising future for nanosheet-based clinical radiotherapies of malignant cancers.

A late eating midpoint is associated with increased risk of diabetic kidney disease: a cross-sectional study based on NHANES 2013-2020.

BACKGROUND: Modifying diet is crucial for diabetes and complication management. Numerous studies have shown that adjusting eating habits to align with the circadian rhythm may positively affect metabolic health. However, eating midpoint, eating duration, and their associations with diabetic kidney disease (DKD) are poorly understood. METHODS: The National Health and Nutrition Examination Survey (2013-2020) was examined for information on diabetes and dietary habits. From the beginning and ending times of each meal, we calculated the eating midpoint and eating duration. Urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g and/or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 were the specific diagnostic criteria for DKD. RESULTS: In total, details of 2194 subjects with diabetes were collected for analysis. The overall population were divided into four subgroups based on the eating midpoint quartiles. The prevalence of DKD varied noticeably (P = 0.037) across the four categories. When comparing subjects in the second and fourth quartiles of eating midpoint to those in the first one, the odds ratios (ORs) of DKD were 1.31 (95% CI, 1.03 to 1.67) and 1.33 (95% CI, 1.05 to 1.70), respectively. And after controlling for potential confounders, the corresponding ORs of DKD in the second and fourth quartiles were 1.42 (95% CI, 1.07 to 1.90) and 1.39 (95% CI, 1.04 to 1.85), respectively. CONCLUSIONS: A strong correlation was found between an earlier eating midpoint and a reduced incidence of DKD. Eating early in the day may potentially improve renal outcomes in patients with diabetes.

TFAM-Mediated mitochondrial transfer of MSCs improved the permeability barrier in sepsis-associated acute lung injury.

Vascular endothelial cell barrier disruption is a hallmark of sepsis-induced acute lung injury (ALI). Mesenchymal stem cells (MSCs)-based therapy has been regarded as a promising treatment for repairing injured lungs, and mitochondrial transfer was shown to be important for the therapeutic effects of MSCs. Here we investigated the ability of MSCs to modulate endothelial barrier integrity through mitochondrial transfer in sepsis-induced ALI. We found that mitochondrial transfer from MSCs to LPS-induced PMVECs through forming tunneling nanotubes (TNTs). Due to the inhibition of TNTs (using LAT-A), MSCs-mediated reparation on PMVECs functions, including cell apoptosis, MMP, ATP generation, TEER level and monolayer permeability of FITC-dextran were greatly inhibited. In addition, silencing of mitochondrial transcription factor A (TFAM) in MSCs could also partly inhibit the TNTs formation and aggravate the LPS-induced mitochondrial dysfunction and permeability barrier in PMVECs. Furthermore, the LPS-induced pulmonary edema and higher pulmonary vascular permeability were alleviated by MSCs while that of lung tissue bounced back after MSCs were pre-incubated by LAT-A and or down-regulation of TFAM. Therefore, we firstly revealed that regulation of TFAM expression in MSCs played a critical role to improve the permeability barrier of PMVECs by TNTs mediating mitochondrial transfer in sepsis-associated ALI. This study provided a new therapeutic strategy for the treatment of sepsis-induced ALI.

The Value of the Cardiac Magnetic Resonance Intravoxel Incoherent Motion Technique in Evaluating Microcirculatory Dysfunction in Hypertrophic Cardiomyopathy.

Objective: To evaluate the value of the cardiac magnetic resonance intravoxel incoherent motion (IVIM) technique in microcirculatory dysfunction in patients with hypertrophic cardiomyopathy (HCM). Methods: The medical records of 19 patients with HCM in our hospital from January 2020 to May 2021 were collected retrospectively, and 23 healthy people with a similar age and gender distribution to the patients with HCM were included as controls. All the included subjects underwent clinical assessment and cardiac magnetic resonance imaging. The original IVIM images were analysed, and the imaging parameters of each segment were measured. The HCM group was divided into non-hypertrophic myocardium and hypertrophic myocardium groups. The differences in imaging parameters between the normal and HCM groups were compared. A Spearman correlation analysis was used to explore the correlation between end-diastolic thickness (EDTH) and each IVIM parameter. Results: The D∗ and f values in the HCM group were lower than those in the normal group (p < 0.0001 and p = 0.004, respectively). The f, D, D∗, and EDTH values of the hypertrophic segment, non-hypertrophic segment, and normal groups were statistically significant (p < 0.05). The difference in D∗ values among the mild, moderate, severe, and very severe HCM groups was statistically significant (p < 0.05). There was a statistically significant difference in EDTH among the mild, moderate, severe, and very severe groups (p < 0.001). There were significant differences in the values of D, D∗, and f between the non-delayed enhancement group and the delayed enhancement group (p < 0.05). The EDTH values of 304 segments in the HCM group were negatively correlated with f (r = -0.219, p = 0.028) and D∗ values (r = -0.310, p < 0.001). Conclusion: The use of IVIM technology can achieve a non-invasive early quantitative assessment of microvascular disease in HCM without the injection of a contrast agent and provide a reference for the early diagnosis of and intervention in myocardial ischemia in patients with HCM.

Association between the platelet/high-density lipoprotein cholesterol ratio and nonalcoholic fatty liver disease: results from NHANES 2017-2020.

The platelet/high-density lipoprotein cholesterol ratio (PHR) is a novel inflammatory and hypercoagulability marker that represents the severity of metabolic syndrome. Liver metabolic syndrome is manifested by nonalcoholic fatty liver disease (NAFLD), which is associated with inflammation and hypercoagulability. This cross-sectional investigation aimed to identify the relationship between PHR and NAFLD. Participants in the National Health and Nutrition Examination Survey (NHANES) 2017-2020 were evaluated for hepatic steatosis and fibrosis using vibration-controlled transient elastography. The PHR was calculated as the ratio of platelets to high-density lipoprotein cholesterol. Increased PHR was associated with an increased incidence of NAFLD and hepatic fibrosis. Compared with patients in the first PHR quartile, after adjustment for clinical variables, the corresponding odds ratio (OR) for NAFLD in the fourth quartile was 2.36 (95% CI, 1.76 to 3.18) (p < 0.05); however, the OR for hepatic fibrosis was not statistically significant (p > 0.05). Furthermore, restricted cubic spline analyses showed an S-shaped association between PHR and NAFLD and an L-shaped relationship between PHR and hepatic fibrosis. The results support the effectiveness of PHR as a marker for NAFLD and hepatic fibrosis. Therefore, interventions to improve the PHR may be of benefit in reducing the incidence of both hepatic steatosis and fibrosis.

Long term exposure of saxitoxin induced cognitive deficits and YAP1 cytoplasmic retention.

While most studies assessed the acute toxicity of saxitoxin (STX), fewer studies focus on the long-term degenerative effects of STX on the central nervous system. We investigated the cognitive impairment and hippocampal damages of 6 months' exposure of low-dose STX to C57BL/6NJ mice with behavioral tests, H&E staining, and Western blots, and the possible mechanism (Ppp1C, YAP1, tau-phosphorylation) underlies the pathological changes. Furthermore, we discussed the specific localization of YAP1 in N2a cells induced by STX and the effect of inactivated Ppp1C on its downstream protein YAP1 in the Hippo signal pathway. We found STX intoxicated mice showed declined cognitive performance in both NOR test and MWM test, degenerations in the CA1 area of hippocampi. STX induced up-regulation expression of Ppp1C and YAP1 in hippocampus and N2a cells. Meanwhile, STX treatment induced cell apoptosis and Tau protein hyperphosphorylation. In addition, STX treatment promoted YAP1 cytoplasmic retention that indicates the activation of Hippo pathway, while depletion of Ppp1C inactivate YAP1 during the treatment of STX. Our results highlight the role of Ppp1C and YAP1 cytoplasmic retention in chronic low-dose STX intoxication.

A Molecularly Imprinted Electrochemical Sensor Based on TiO2@Ti3C2Tx for Highly Sensitive and Selective Detection of Chlortetracycline.

In view of the serious side effects of chlortetracycline (CTC) on the human body, it is particularly important to develop rapid, sensitive, and selective technologies for the detection of CTC in food. In this work, a molecularly imprinted electrochemical sensor with [Fe(CN)6]3-/4- as signal probe was proposed for the highly sensitive and selective detection of CTC. For this purpose, TiO2, which acts as an interlayer scaffold, was uniformly grown on the surface of Ti3C2Tx sheets through a simple two-step calcination process using Ti3C2Tx as the precursor to effectively avoid the stacking of Ti3C2Tx layers due to hydrogen bonding and van der Waals forces. This endowed TiO2@Ti3C2Tx with large specific surface, abundant functional sites, and rapid mass transfer. Then, polypyrrole molecularly imprinted polymers (MIPs) with outstanding electrical conductivity were modified on the surface of TiO2@Ti3C2Tx via simple electro-polymerization, where the pyrrole was employed as a polymeric monomer and the CTC provided a source of template molecules. This will not only provide specific recognition sites for CTC, but also facilitate electron transport on the electrode surface. The synergistic effects between TiO2@Ti3C2Tx and polypyrrole MIPs afforded the TiO2@Ti3C2Tx/MIP-based electrochemical sensor excellent detection properties toward CTC, including ultra-low limits of detection (LOD) (0.027 nM), a wide linear range (0.06-1000 nM), and outstanding stability, reproducibility, selectivity, and feasibility in real samples. The results indicate that this strategy is feasible and will broaden the horizon for highly sensitive and selective detection of CTC.

An Electrochemical Sensor Based on a Porous Biochar/Cuprous Oxide (BC/Cu2O) Composite for the Determination of Hg(II).

Mercuric ion (Hg2+) in aqueous media is extremely toxic to the environment and organisms. Therefore, the ultra-trace electrochemical determination of Hg2+ in the environment is of critical importance. In this work, a new electrochemical Hg2+ sensing platform based on porous activated carbon (BC/Cu2O) modified with cuprous oxide was developed using a simple impregnation pyrolysis method. Differential pulse anodic stripping voltammetry (DPASV) was used to investigate the sensing capability of the BC/Cu2O electrode towards Hg2+. Due to the excellent conductivity and large specific surface area of BC, and the excellent catalytic activity of Cu2O nanoparticles, the prepared BC/Cu2O electrode exhibited excellent electrochemical activity. The high sensitivity of the proposed system resulted in a low detection limit of 0.3 ng·L-1 and a wide linear response in the ranges from 1.0 ng·L-1 to 1.0 mg·L-1. In addition, this sensor was found to have good accuracy, acceptable precision, and reproducibility. All of these results show that the BC/Cu2O composite is a promising material for Hg2+ electrochemical detection.

The wound adjuncts effect of closed incision negative pressure wound therapy on stopping groin surgical site wound infection in arterial surgery: A meta-analysis.

A meta-analysis study was conducted to assess the influence of the wound adjuncts therapy of closed incision negative pressure wound therapy (ciNPWT) on stopping groin site wound infection (SWSI) in arterial surgery. A comprehensive literature examination till January 2023 was implemented and 2186 linked studies were appraised. The picked studies contained 2133 subjects with groin surgical wounds of arterial surgery in the picked studies' baseline, 1043 of them were using ciNPWT, and 1090 were using standard care. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to calculate the consequence of the wound adjuncts therapy of ciNPWT on stopping groin SWSI in arterial surgery by the dichotomous and continuous styles and a fixed or random model. The ciNPWT had a significantly lower SWSI (OR, 0.42; 95% CI, 0.33-0.55, P < .001), superficial SWSI (OR, 0.46; 95% CI, 0.33-0.66, P < .001), and deep SWSI (OR, 0.39; 95% CI, 0.25-0.63, P < .001) compared with the standard care in groin surgical wound of arterial surgery. The ciNPWT had a significantly, lower SWSI, superficial SWSI, and deep SWSI compared with the standard care in groin surgical wounds of arterial surgery. Although precautions should be taken when commerce with the consequences because some of the picked studies for this meta-analysis was with low sample sizes.

Stepwise evolutionary genomics of early-stage lung adenocarcinoma manifesting as pure, heterogeneous and part-solid ground-glass nodules.

BACKGROUND: This study was designed to unravel the genomic landscape and evolution of early-stage subsolid lung adenocarcinomas (SSN-LUADs) manifesting as pure ground-glass nodules (pGGNs), heterogeneous ground-glass nodules (HGGNs) and part-solid nodules (PSNs). METHODS: Samples subjected to either broad-panel next-generation sequencing (NGS) or whole-exome sequencing (WES) were included. Clinicopathologic and genomic features were compared among pGGN, HGGN and PSN, while tumour evolutionary trajectories and mutational signatures were evaluated in the entire cohort. RESULTS: In total, 247 SSN-LUAD samples subjected to broad-panel NGS and 125 to WES were identified. Compared with PSNs, HGGNs had significantly lower tumour mutation count (P < 0.001), genomic alteration count (P < 0.001), and intra-tumour heterogeneity (P = 0.005). Statistically significant upward trends were observed in alterations involving driver mutations and oncogenic pathways from pGGNs to HGGNs to PSNs. EGFR mutation was proved to be a key early event in the progression of SSN-LUADs, with subsequently two evolutionary trajectories involving either RBM10 or TP53 mutation in the cancer-evolution models. CONCLUSIONS: This study provided evidence for unravelling the previously unknown genomic underpinnings associated with SSN-LUAD evolution from pGGN to HGGN to PSN, proving that HGGN was an intermediate SSN form between pGGN and PSN genetically.

Berberine inhibits glioma cell migration and invasion by suppressing TGF-ß1/COL11A1 pathway.

Glioma is a clinically heterogeneous disease with a poor prognosis. Berberine (BBR), as a multi-target anti-tumor alkaloid, has the ability to penetrate the blood-brain barrier and shows cytotoxicity to glioma cells. In previous studies, we demonstrated that berberine inhibits glioma cell proliferation by inhibiting mutant p53 protein and promoting mitochondrial damage. In addition, berberine has been shown to reduce collagen accumulation in pulmonary fibrosis, diabetic nephropathy and arthritis. However, its effect on collagen in cancer needs to be further elucidated. In this study, we proved that the collagen XI alpha 1 chain (COL11A1) is highly expressed in glioma cell lines and associated with migration and invasion of glioma cells. Knocking down COL11A1 caused decreased expression of MMPs. Berberine could inhibit the migration and invasion of glioma cells by suppressing the TGF-ß1/COL11A1 pathway and changes actin cytoskeleton arrangement. Nude mouse subcutaneous xenografts model also showed that berberine inhibited the expression of COL11A1 in vivo. Collectively, berberine that targets COL11A1 to inhibit glioma migration and invasion, may serve as a promising candidate for the development of anti-glioma drugs in the future.

Bipartite graph-based approach for clustering of cell lines by gene expression-drug response associations.

MOTIVATION: In pharmacogenomic studies, the biological context of cell lines influences the predictive ability of drug-response models and the discovery of biomarkers. Thus, similar cell lines are often studied together based on prior knowledge of biological annotations. However, this selection approach is not scalable with the number of annotations, and the relationship between gene-drug association patterns and biological context may not be obvious. RESULTS: We present a procedure to compare cell lines based on their gene-drug association patterns. Starting with a grouping of cell lines from biological annotation, we model gene-drug association patterns for each group as a bipartite graph between genes and drugs. This is accomplished by applying sparse canonical correlation analysis (SCCA) to extract the gene-drug associations, and using the canonical vectors to construct the edge weights. Then, we introduce a nuclear norm-based dissimilarity measure to compare the bipartite graphs. Accompanying our procedure is a permutation test to evaluate the significance of similarity of cell line groups in terms of gene-drug associations. In the pharmacogenomic datasets CTRP2, GDSC2 and CCLE, hierarchical clustering of carcinoma groups based on this dissimilarity measure uniquely reveals clustering patterns driven by carcinoma subtype rather than primary site. Next, we show that the top associated drugs or genes from SCCA can be used to characterize the clustering patterns of haematopoietic and lymphoid malignancies. Finally, we confirm by simulation that when drug responses are linearly dependent on expression, our approach is the only one that can effectively infer the true hierarchy compared to existing approaches. AVAILABILITY AND IMPLEMENTATION: Bipartite graph-based hierarchical clustering is implemented in R and can be obtained from CRAN: https://CRAN.R-project.org/package=hierBipartite. The source code is available at https://github.com/CalvinTChi/hierBipartite. The datasets were derived from sources in the public domain, which are the Cancer Cell Line Encyclopedia (https://portals.broadinstitute.org/ccle), the Cancer Therapeutics Response Portal (https://portals.broadinstitute.org/ctrp.v2.1/?page=#ctd2BodyHome), and the Genomics of Drug Sensitivity in Cancer (https://www.cancerrxgene.org/). These datasets can be downloaded using the PharmacoGx R package (https://bioconductor.org/packages/release/bioc/html/PharmacoGx.html). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Collagen XI alpha 1 chain, a potential therapeutic target for cancer.

Extracellular matrix (ECM) plays an important role in the progression of cancer. Collagen is the most abundant component in ECM, and it is involved in the biological formation of cancer. Although type XI collagen is a minor fibrillar collagen, collagen XI alpha 1 chain (COL11A1) has been found to be upregulated in a variety of cancers including ovarian cancer, breast cancer, thyroid cancer, pancreatic cancer, non-small-cell lung cancer, and transitional cell carcinoma of the bladder. High levels of COL11A1 usually predict poor prognosis, while COL11A1 is related to angiogenesis, invasion, and drug resistance of cancer. However, little is known about the specific mechanism by which COL11A1 regulates tumor progression. Here, we have organized and summarized the recent developments regarding elucidation of the relationship between COL11A1 and various cancers, as well as the interaction between COL11A1 and intracellular signaling pathways. In addition, we have selected therapeutic agents targeting COL11A1. All these indicate the possibility of using COL11A1 as a target for cancer treatment.