Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer.

Importance: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater). Objective: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers. Design, Setting, and Participants: RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023. Exposure: Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy. Main Outcomes and Measures: Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily. Results: Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater. Conclusions and Relevance: In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies.

The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

ε-Poly-l-lysine-hydroxyphenyl propionic acid/IL-4 composite hydrogels with inflammation regulation and antibacterial activity for improving integration stability of soft tissues and orthopedic implants.

The failure of orthopedic implants is usually caused by inflammation, poor tissue integration, and infection, which can lead to pain, limited mobility, dysfunction of patients. This may require additional surgical interventions, such as removal, replacement, or repair of implants, as well as related treatment measures such as antibiotic therapy, physical therapy. Here, an injectable hydrogel carrier was developed for the steady release of inflammatory regulators to reduce the surface tissue inflammatory response of orthopedic implants and induce soft tissue regeneration, ultimately achieving the promotion of implants stability. The hydrogels carrier was prepared by hydroxyphenyl propionic acid-modified ε-Poly-l-lysine (EPA), hydrogen peroxide and horseradish peroxidase, which showed antibacterial bioactive and stable factor release ability. Due to the introduction of IL-4, EPA@IL-4 hydrogels showed good inflammatory regulation. EPA@IL-4 hydrogels regulated the differentiation of macrophages into M2 in inflammatory environment in vitro, and promoted endothelial cells to show a more obvious trend of tube formation. The composite hydrogels reduced the inflammation on the surface of the implants in vivo, induced local endothelial cell angiogenesis, and had more collagen deposition and new granulation tissue. Therefore, EPA hydrogels based on IL-4 release are promising candidates for promoting of implants surface anti-inflammatory, soft tissue regeneration, and anti-infection.

C-C Motif Chemokine Ligand 5 (CCL5): A Potential Biomarker and Immunotherapy Target for Osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant tumor of bone tissue, which has an insidious onset and is difficult to detect early, and few early diagnostic markers with high specificity and sensitivity. Therefore, this study aims to identify potential biomarkers that can help diagnose OS in its early stages and improve the prognosis of patients. METHODS: The data sets of GSE12789, GSE28424, GSE33382 and GSE36001 were combined and normalized to identify Differentially Expressed Genes (DEGs). The data were analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG) and Disease Ontology (DO). The hub gene was selected based on the common DEG that was obtained by applying two regression methods: the Least Absolute Shrinkage and Selection Operator (LASSO) and Support vVector Machine (SVM). Then the diagnostic value of the hub gene was evaluated in the GSE42572 data set. Finally, the correlation between immunocyte infiltration and key genes was analyzed by CIBERSORT. RESULTS: The regression analysis results of LASSO and SVM are the following three DEGs: FK501 binding protein 51 (FKBP5), C-C motif chemokine ligand 5 (CCL5), complement component 1 Q subcomponent B chain (C1QB). We evaluated the diagnostic performance of three biomarkers (FKBP5, CCL5 and C1QB) for osteosarcoma using receiver operating characteristic (ROC) analysis. In the training group, the area under the curve (AUC) of FKBP5, CCL5 and C1QB was 0.907, 0.874 and 0.676, respectively. In the validation group, the AUC of FKBP5, CCL5 and C1QB was 0.618, 0.932 and 0.895, respectively. It is noteworthy that these genes were more expressed in tumor tissues than in normal tissues by various immune cell types, such as plasma cells, CD8+ T cells, T regulatory cells (Tregs), activated NK cells, activated dendritic cells and activated mast cells. These immune cell types are also associated with the expression levels of the three diagnostic genes that we identified. CONCLUSION: We found that CCL5 can be considered an early diagnostic gene of osteosarcoma, and CCL5 interacts with immune cells to influence tumor occurrence and development. These findings have important implications for the early detection of osteosarcoma and the identification of novel therapeutic targets.

Association between polycystic ovary syndrome and risk of non-alcoholic fatty liver disease: a meta-analysis.

INTRODUCTION: There have been many studies assessing whether abnormal metabolic and hormone levels among women with polycystic ovary syndrome (PCOS) are associated with a greater risk of non-alcoholic fatty liver disease (NAFLD). However, previous studies repported no consistent outcomes. To provide a comprehensive evaluation regarding the role of PCOS in the risk of NAFLD, we updated the published literature and conducted this systemic review and meta-analysis. MATERIAL AND METHODS: Electronic databases (Web of Science and PubMed) were searched for literature up to October 2022. We used STATA 12.0 software to compute odds ratios (ORs) and 95% confidence intervals (CIs), to evaluate the association between PCOS and risk of NAFLD. RESULTS: The study indicated that PCOS was significantly related to an elevated risk of NAFLD (OR = 2.93, 95% CI 2.38 to 3.62, I2 = 83.7%, p < 0.001). Meta-regression analysis showed that age and body mass index (BMI) were not responsible for heterogeneity across the studies (age: p = 0.096; BMI: p = 0.418). Sensitivity analysis indicated no alteration in the direction of effect when any study was eliminated. Begg's test, Egger's test, Begg's test, and funnel plot indicated a significant risk of publication bias (Egger's test: p = 0.028; Begg's test: p < 0.001). CONCLUSION: This meta-analysis reported that PCOS was associated with an elevated risk of NAFLD. Early proper detection of NAFLD for PCOS women is essential. All patients with PCOS should undergo appropriate diagnostics for early detection of fatty liver and fibrosis.

Therapeutic Drug Monitoring of Imatinib and N-Desmethyl Imatinib in Chronic Myeloid Leukemia Patients Using LC-MS/MS in a Cohort Study.

Imatinib is an oral tyrosine kinase inhibitor (TKI) and first-line therapy for patients with chronic myeloid leukemia (CML). There is a positive correlation between serum imatinib concentrations and treatment response. However, the specific relationship between the blood concentration of imatinib and its influencing factors remains unclear. This study collected basic information from 102 patients using imatinib as first-line treatment for CML. Further, we analyzed the individual differences in imatinib concentration and explored its influencing factors. Through intra-day and inter-day precision studies, we found that the precision for the imatinib assay methodology was within ±13% and that the recovery rate was above 85%. There is notable individual variation in the blood concentration of imatinib; the recommended treatment concentration is 860-1500 ng/mL, with only 41.40% of patients achieving this concentration. Also, there was a negative correlation between age and imatinib trough concentration (Ctrough ), as is observed between age and N-desmethyl imatinib. Moreover, compared with the adolescent group, the serum imatinib Ctrough for groups aged 17-47 and 48-68 years was significantly reduced. Further analysis shows that imatinib Ctrough values reaching therapeutic concentrations (59%) increased dramatically for patients with CML aged 17-47 years. Moreover, groups dosed with 400 mg/day resulted in therapeutic imatinib concentrations for 68% of patients with CML, which was the best performance. The established method was validated, with acceptable accuracy, precision, linearity, and stability, as required, and then successfully applied to the therapeutic drug monitoring of imatinib. Age, dose, and metabolites can influence the imatinib concentration and its therapeutic effect in patients with CML.

Benzeneboronic-alginate/quaternized chitosan-catechol powder with rapid self-gelation, wet adhesion, biodegradation and antibacterial activity for non-compressible hemorrhage control.

Although hemostatic powders have excellent adaptability for irregular and inaccessible wounds, their hemostasis for continuous bleeding or bleeding wounds of non-compressible organs remains a critical challenge. Herein, a series of benzeneboronic acid-modified sodium alginate/catechol-modified quaternized chitosan (SA-BA/QCS-C, SBQCC) powders is developed by borate ester crosslinking for non-compressible hemorrhage control. SBQCC powders possess remarkable tissue adhesion, rapid self-gelation, good cytocompatibility and antibacterial activity against S. aureus and E. coil. The blood coagulation assays show that SBQCC powders display excellent blood clotting ability due to the synergistic effect of SA-BA and QCS-C. The SBQCC2 powder with the SA-BA to QCS-C mass ratio of 5 to 3 has the greatest effect on the blood-clotting rate. Upon depositing SBQCC2 powder to bleeding wounds of rabbit liver, the powder can absorb a large amount of blood and form a stable hydrogel physical barrier at the bleeding wounds in situ to achieve non-pressing rapid hemostasis. The SBQCC2 powder also has good biocompatibility and can be degraded in vivo. Altogether, the SBQCC powders can be a promising candidate for rapid hemostasis, and these findings may provide a new perspective for improving the hemostatic efficiency of the hemostatic powder in biomedical fields.

DRAVP: A Comprehensive Database of Antiviral Peptides and Proteins.

Viruses with rapid replication and easy mutation can become resistant to antiviral drug treatment. With novel viral infections emerging, such as the recent COVID-19 pandemic, novel antiviral therapies are urgently needed. Antiviral proteins, such as interferon, have been used for treating chronic hepatitis C infections for decades. Natural-origin antimicrobial peptides, such as defensins, have also been identified as possessing antiviral activities, including direct antiviral effects and the ability to induce indirect immune responses to viruses. To promote the development of antiviral drugs, we constructed a data repository of antiviral peptides and proteins (DRAVP). The database provides general information, antiviral activity, structure information, physicochemical information, and literature information for peptides and proteins. Because most of the proteins and peptides lack experimentally determined structures, AlphaFold was used to predict each antiviral peptide's structure. A free website for users (http://dravp.cpu-bioinfor.org/, accessed on 30 August 2022) was constructed to facilitate data retrieval and sequence analysis. Additionally, all the data can be accessed from the web interface. The DRAVP database aims to be a useful resource for developing antiviral drugs.

Effects of chemotherapy and immunotherapy on microbial diversity in TME and engineered bacterial-mediated tumor therapy.

Tumor microbiota is a group of microorganisms located in tumor tissues with rich diversity that can promote tumorigenesis and development, and different types of tumors have different tumor microbiotas, which has important implications for tumor research, detection, and clinical treatment. In this review, we examine the diversity of the tumor microbiota, discuss the impact of chemotherapy and immunotherapy on tumor microbiota diversity, and summarize recent advances in the use of genetically engineered bacteria for the treatment of tumors. In addition, we propose key questions that need to be further addressed by the tumor microbiota.

Claudin18.2 expression and clinicopathological features in cytology effusion specimens from gastric adenocarcinoma: A comparative study with tissue specimens.

BACKGROUND: Zolbetuximab (IMAB362) is under investigation for treating advanced gastrointestinal tumors because it targets Claudin18.2 (CLDN18.2). CLDN18.2 is a promising molecule along with the presence of human epidermal growth factor receptor 2 in gastric cancer. This study evaluated cell block (CB) preparations of serous cavity effusions for the feasibility for CLDN18.2 protein expression and compared the results with those of biopsy or resection specimens. The association of CLDN18.2 expression in effusion samples and the clinicopathological features were also investigated. METHODS: Cytological effusion specimens and matched surgical pathology biopsy or resection specimens of 43 gastric and gastroesophageal junctional cancer cases were stained for CLDN18.2 expression and quantified using immunohistochemistry based on the manufacturer's instructions. RESULTS: Positive staining was detected in 34 (79.1%) tissue and 27 (62.8%) effusion CB samples in this study. When "positivity" was defined as moderate-to-strong staining in ≥40% viable tumor cells, CLDN18.2 expression was observed in 24 (55.8%) tissue and 22 (51.2%) effusion CB samples. A cutoff of 40% for CLDN18.2 positivity was used to demonstrate high concordance (83.7%) between cytology CB and tissue specimens. The results showed that CLDN18.2 expression in effusion specimens correlated with tumor size (p = .021) but not with sex, age at diagnosis, primary tumor location, staging, Lauren phenotype, cytomorphologic features, or Epstein-Barr virus infection. Cytological effusions with or without CLDN18.2 expression did not significantly affect overall survival. CONCLUSIONS: This study's results show that serous body cavity effusions may be suitable for CLDN18.2 biomarker testing; however, discordant cases should be interpreted cautiously.

Association Between Metformin Use and the Risk, Prognosis of Gynecologic Cancer.

Background: For gynecological cancer patients, the beneficial effect of metformin use remains controversial due to inconsistent results of published articles. By conducting a meta-analysis, we aimed to evaluate the effect of metformin in reducing the risk and improving the survival of gynecological cancer among women with diabetes mellitus (DM). Methods: Articles exploring association between metformin use and the risk, as well as prognosis of gynecologic cancer in DM, were searched in the databases: PubMed, Web of Science, SCOPUS, EMBASE, EBSCO, and PROQUEST. Articles were published before May 2022. All the studies were conducted using STATA 12.0 software. Results: The meta-analysis showed no significant association between metformin use and risk of gynecologic cancer in DM with a random effects model [odds ratio (ORs)/relative risk (RR) = 0.91, 95% confidence intervals (CI) 0.77 to 1.08, I2 = 84.2%, p < 0.001]. Metformin use was associated with reduced overall survival (OS) and progression-free survival (PFS) of gynecologic cancer in DM with random effects models [OS: hazard ratio (HR) = 0.60, 95% CI 0.49-0.74, I2 = 55.2%, p = 0.002; PFS: HR = 0.55, 95% CI 0.33-0.91, I2 = 69.1%, p = 0.006], whereas no significant association was showed between metformin use and recurrence-free survival (RFS), as well as cancer-specific survival (CSS) of gynecologic cancer in DM with random effects models (RFS: HR = 0.60, 95% CI 0.30-1.18, I2 = 73.7%, p = 0.010; CSS: HR = 0.78, 95% CI 0.43-1.41, I2 = 72.4%, p = 0.013). Conclusions: In conclusion, this meta-analysis indicated that metformin may be a useful adjuvant agent for gynecological cancer with DM, especially for patients with ovarian cancer and endometrial cancer.

HORDB a comprehensive database of peptide hormones.

Peptide hormones (also known as hormone peptides and polypeptide hormones) are hormones composed of peptides and are signal transduction molecules produced by a class of multicellular organisms. It plays an important role in the physiological and behavioral regulation of animals and humans as well as in the growth of plants. In order to promote the research on peptide hormones, we constructed HORDB database. The database currently has a total of 6024 entries, including 5729 peptide hormones, 40 peptide drugs and 255 marketed pharmaceutical preparations information. Each entry provided comprehensive information related to the peptide, including general information, sequence, activity, structure, physical information and literature information. We also added information on IC50, EC50, ED50, target, and whether or not the blood-brain barrier was crossed to the activity information note. In addition, HORDB integrates search and sequence analysis to facilitate user browsing and data analysis. We believe that the peptide hormones information collected by HORDB will promote the design and discovery of peptide hormones, All data are hosted and available in figshare https://doi.org/10.6084/m9.figshare.c.5522241 .

Metallurgical Coke Production with Biomass Additives: Study of Biocoke Properties for Blast Furnace and Submerged Arc Furnace Purposes.

Biocoke has the potential to reduce the fossil-based materials in metallurgical processes, along with mitigating anthropogenic CO2- and greenhouse gas (GHG) emissions. Reducing those emissions is possible by using bio-based carbon, which is CO2-neutral, as a partial replacement of fossil carbon. In this paper, the effect of adding 5, 10, 15, 30, and 45 wt.% biomass pellets on the reactivity, the physicomechanical, and electrical properties of biocoke was established to assess the possibility of using it as a fuel and reducing agent for a blast furnace (BF) or as a carbon source in a submerged arc furnace (SAF). Biocoke was obtained under laboratory conditions at final coking temperatures of 950 or 1100 °C. Research results indicate that for BF purposes, 5 wt.% biomass additives are the maximum as the reactivity increases and the strength after reaction with CO2 decreases. On the other hand, biocoke's physicomechanical and electrical properties, obtained at a carbonization temperature of 950 °C, can be considered a promising option for the SAF.

Brain metastasis in de novo breast cancer: An updated population-level study from SEER database.

PURPOSE: Although there are current studies on breast cancer brain metastasis, population-level analysis is still lacking. As treatment for metastatic breast cancer has improved, an updated population-level analysis is necessary. Our aim was to use the SEER database to characterize the incidence and survival of patients with brain metastases at the initial diagnosis of breast cancer. PATIENTS AND METHODS: Patients with breast cancer from 2010 to 2018 were identified using the SEER database. The stratified incidence and median survival of patients with BM at diagnosis were described. Multivariate logistic and Cox regression were performed to determine the covariates associated with brain metastasis and survival outcomes, respectively. Multiple comparisons based on Cox proportional hazards model were performed for the analysis of interactive effects on overall survival. RESULTS: A total of 2,248 patients with brain metastases at the initial diagnosis of breast cancer were identified, accounting for 0.40% of all patients with breast cancer, and 7.26% of patients with metastatic disease. Incidence proportions were highest, and survival outcomes were worst among patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes. For patients with brain metastases, the prognostic differences among different molecular subtypes have been gradually narrowing, and the survival benefits from various treatment methods have been all increased over time. CONCLUSION: Our study provides an updated population-level estimate of the incidence and survival for patients with brain metastases at the diagnosis of breast cancer, thus may help early identification, prognostic stratification and treatment planning for such patients.

Development of a Whole-urine, Multiplexed, Next-generation RNA-sequencing Assay for Early Detection of Aggressive Prostate Cancer.

BACKGROUND: Despite biomarker development advances, early detection of aggressive prostate cancer (PCa) remains challenging. We previously developed a clinical-grade urine test (Michigan Prostate Score [MiPS]) for individualized aggressive PCa risk prediction. MiPS combines serum prostate-specific antigen (PSA), the TMPRSS2:ERG (T2:ERG) gene fusion, and PCA3 lncRNA in whole urine after digital rectal examination (DRE). OBJECTIVE: To improve on MiPS with a novel next-generation sequencing (NGS) multibiomarker urine assay for early detection of aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: Preclinical development and validation of a post-DRE urine RNA NGS assay (Urine Prostate Seq [UPSeq]) assessing 84 PCa transcriptomic biomarkers, including T2:ERG, PCA3, additional PCa fusions/isoforms, mRNAs, lncRNAs, and expressed mutations. Our UPSeq model was trained on 73 patients and validated on a held-out set of 36 patients representing the spectrum of disease (benign to grade group [GG] 5 PCa). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The area under the receiver operating characteristic curve (AUC) of UPSeq was compared with PSA, MiPS, and other existing models/biomarkers for predicting GG ≥3 PCa. RESULTS AND LIMITATIONS: UPSeq demonstrated high analytical accuracy and concordance with MiPS, and was able to detect expressed germline HOXB13 and somatic SPOP mutations. In an extreme design cohort (n = 109; benign/GG 1 vs GG ≥3 PCa, stratified to exclude GG 2 cancer in order to capture signal difference between extreme ends of disease), UPSeq showed differential expression for T2:ERG.T1E4 (1.2 vs 78.8 median normalized reads, p < 0.00001) and PCA3 (1024 vs 2521, p = 0.02), additional T2:ERG splice isoforms, and other candidate biomarkers. Using machine learning, we developed a 15-transcript model on the training set (n = 73) that outperformed serum PSA and sequencing-derived MiPS in predicting GG ≥3 PCa in the held-out validation set (n = 36; AUC 0.82 vs 0.69 and 0.69, respectively). CONCLUSIONS: These results support the potential utility of our novel urine-based RNA NGS assay to supplement PSA for improved early detection of aggressive PCa. PATIENT SUMMARY: We have developed a new urine-based test for the detection of aggressive prostate cancer, which promises improvement upon current biomarker tests.

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer.

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

Survival Benefit of Surgical Treatment Added Into Systemic Treatment for Isolated Breast Cancer Liver Metastases: A Systematic Review and Meta-Analysis.

Background: Compared with systemic treatment alone, whether surgical treatment combined with systemic treatment can improve survival outcomes of patients with isolated breast cancer liver metastases (BCLM) is still controversial. This meta-analysis was designed to evaluate the efficacy of surgical treatment for patients with isolated BCLM. Methods: A systematic search of PubMed, Embase, and Cochrane Library up to May 13, 2021 was conducted for relevant studies. The primary outcome was overall survival. The meta-analysis was performed using R software. The quality of the pooled study was assessed using the Newcastle-Ottawa scale. The publication bias was evaluated by funnel plots and Begg's and Egger's tests. Fixed- and random-effects models were applied according to heterogeneity. Results: 9 retrospective studies involving 13 cohorts (7 unmatched cohorts and 6 matched cohorts) were included in this study. The surgical cohorts had better overall survival than the systemic cohorts in the pooled analysis of all the included studies, in the subgroup analysis of liver resection, and in the subset of the matched cohorts. Conclusions: Compared with systemic treatment alone, surgical treatment combined with systemic treatment was proven to be associated with superior survival outcomes, which should be considered in selected patients with isolated BCLM.

Simultaneous determination of dacomitinib and its major metabolite, O-desmethyl dacomitinib in human plasma by LC-MS/MS and its application to clinical testing in patients with non-small cell lung cancer.

Dacomitinib, an irreversible pan-ErbB tyrosine kinase inhibitor targeting the human epidermal growth factor receptor, is used for the treatment of metastatic non-small cell lung cancer. To facilitate the investigations on its metabolism and other relevant studies, based on high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), a rapid and sensitive bioanalytical technique was established and fully validated for simultaneous quantification of dacomitinib and its main metabolite in human plasma. The plasma samples were treated with acetonitrile containing 0.1% formic acid and the liquid supernatant was collected, dried and dissolved in methanol-water-formic acid (200:800:1, v/v) before injection. The chromatographic separation was performed on an ACE Excel C18 column (2.1 mm × 50.0 mm, i.d., 5 µm) by gradient elution with a mixture of buffer (5 mM ammonium acetate in 0.1% formic acid) and acetonitrile, serving as the mobile phase, with an overall run time of 4 min. Dacomitinib, O-desmethyl dacomitinib and IS were subsequently detected on an AB QTRAP 5500 mass spectrometer in positive ion and multiple reaction monitoring modes at the precursor-to-product transitions of m/z 470.4 â†’ 385.0, m/z 456.0 â†’ 370.9 and m/z 480.2 â†’ 385.1, respectively. The accuracy and precision of determinations were guaranteed within the concentration ranges of 0.25-100 ng/mL for dacomitinib and 0.20-80 ng/mL for O-desmethyl dacomitinib. The intra- and inter-assay accuracy ranged from 92.00% to 104.50% and the intra- and inter-assay precision was less than 8.20% for each analyte. The method was validated and the relevant parameters, including selectivity, interference among analytes and internal standard, carry-over effect, dilution integrity, extraction recovery, matrix effect, and stability, all satisfied the requirements formulated by the US Food and Drug Administration and the European Medicines Agency. The clinical applicability of the fully-validated method was evaluated in medicated samples from patients on dacomitinib.

Microwave-assisted solid-phase synthesis of nitrogen-doping carbon dot with good solvent compatibility and its sensing of sunitinib.

Microwave-assisted solid-phase synthesis method was simple, convenient, and fast, and herein adopted to produce nitrogen-doping carbon dots (N-CDs) in only 3 min. The N-CDs possessed high fluorescence quantum yield up to 15.9% with satisfactory stability to the environmental pH, ionic strength, and ultraviolet radiation. Particularly, the N-CDs had excellent dispersibility in both water and water-compatible organic solvents with similar fluorescence properties. Sunitinib, a small-molecule tyrosine inhibitor effective for some solid tumors, was found to quench the fluorescence of N-CDs in these media via the inner-filter effect. Hence, it was convenient to combine the proper sample pretreatment with the N-CD probe for sensing sunitinib avoiding the medium incompatibility problem. For rat plasma sample, salting-out liquid-liquid extraction was employed to minimize the sample matrix and concentrate the target sunitinib from aqueous to acetonitrile. The fluorescence detection of sunitinib was then achieved in acetonitrile by the addition of the proper amount of N-CDs. The method provided a good linearity of 0.1 µg/mL to 7 µg/mL with a limit of detection of 30 ng/mL, which met the requirement of the therapeutic drug monitoring of sunitinib. The developed method was potential for on-site detection of sunitinib.