Genetic profile of Chinese patients with small bowel cancer categorized by anatomic location.

BACKGROUND: Small bowel cancer (SBC) is a very rare solid malignancy. Consequently, compared with other malignant gastrointestinal tumors, our knowledge regarding SBC, specifically its molecular attributes, remains limited. Herein, we aim to provide an overview of the gene characteristics of Chinese patients with SBC, We particularly focus on elucidating the genetic intricacies that differentiate SBC patients whose primary tumors originate in distinct anatomical regions within the small bowel. METHODS: During the period ranging from February 2018 to December 2022, a total of 298 tumor samples were consecutively collected from Chinese patients diagnosed with small bowel cancer.. Next-generation sequencing (NGS) was performed to detect gene mutation, assess microsatellite instability (MSI), and evaluate tumor mutational burden (TMB). Additionally,, IHC was used to analyze the level of PD-L1 expression within the samples. RESULTS: The outcomes of the next-generation sequencing (NGS) unveiled the predominant gene mutations observed in Chinese patients with small bowel cancer (SBC). The top ten gene mutations identified were as follows: TP53 (53%), KRAS (51%), APC (31%), SMAD4 (19%), VEGFA (15%), CDKN2A (15%), RAC1 (15%), LRP1B (14%), MGMT (14%, CD74 (13%). Subsequent analysis revealed disparities in the gene landscape between the cohort in this study and that of the Memorial Sloan Kettering Cancer Center (MSKCC), Notably, distinguishable mutational frequencies were identified in several genes, including ERBB2, FBXW7, PIK3CA, etc. which exhibited contrasting presence in both this cohort and the MSKCC cohort.. Furthermore, we noticed variations in the frequency of gene mutations among SBC patients depending on the specific anatomical site where the tumors originated within the small bowel. In addition, the distribution of patients with high microsatellite instability (MSI-H) and tumor mutational burden (TMB) levels varied among SBC patients with tumors originating from the duodenum, jejunum, and ileum. CONCLUSION: Chinese patients with small bowel cancer exhibited a distinct genetic profile in comparison to other populations, highlighting a unique genetic landscape. Furthermore, noticeable disparities in the genetic landscape were observed between patients with cancer situated in the duodenum and those with cancer affecting other regions of the small bowel, this suggests that these patients should be treated differently.

Design, synthesis and biological evaluation of novel selective PI3Kδ inhibitors containing pyridopyrimidine scaffold.

Aim: In our study compounds with pyrido[3,2-d]pyrimidine and pyrido[3,4-d]pyrimidine were designed, synthesized and evaluated for their biological activity against hematologic tumors. Methods: The biological activity of compounds was evaluated by ADP-Glo Luminescence assay, MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide] assay, western blotting and flow cytometry, respectively. Results: Compounds A1, A5 and A7 containing pyrido[3,2-d]pyrimidine inhibited phosphoinositide 3-kinase-δ (PI3Kδ) at subnanomolar levels and had good δ-isoform selectivity. A1, A5 and A7 showed significant inhibitory effects against SU-DHL-6 cells and effectively inhibited Akt phosphorylation in a good concentration-dependent manner. A7 induced apoptosis and caused cell cycle arrest in SU-DHL-6 cells. Docking studies showed that A1, A5 and A7 bound tightly to PI3Kδ through key hydrogen bonding interactions. Conclusion: This study suggests that employing pyrido[3,2-d]pyrimidine can facilitate the design of novel potent and selective PI3Kδ inhibitors.

Discovery of potent and selective PI3Kδ inhibitors bearing amino acid fragments.

The selective inhibition of PI3Kδ is a potential therapeutic strategy for the treatment of hematologic malignancies. Herein, we report a series of compounds bearing amino acid fragments as potent and selective PI3Kδ inhibitors. Among them, compound A10 exhibited sub-nanomolar PI3Kδ potency. In cellular assays, A10 achieved strong antiproliferation against SU-DHL-6 cells, and caused cell cycle arrest, and induced apoptosis in SU-DHL-6 cells. The docking study showed that A10 tightly bound to PI3Kδ protein with a planar-shaped conformation. Collectively, compound A10 represented a promising potent and selective PI3Kδ inhibitor bearing amino acid fragement albeit with moderate selectivity over PI3Kγ but superior selectivity against PI3Kα and ß. This study suggested that using the amino acid fragments instead of the pyrrolidine ring is new strategy for design of potent PI3Kδ inhibitors.

M1 macrophage predicted efficacy of neoadjuvant camrelizumab combined with chemotherapy vs chemotherapy alone for locally advanced ESCC: A pilot study.

Introduction: The efficacy and safety of immunotherapy have been widely recognized in gastrointestinal-related cancers. However, the efficacy of neoadjuvant camrelizumab for locally advanced esophageal squamous cell carcinoma (ESCC) has not been firmly established. This study compared the efficacy of camrelizumab in combination with neoadjuvant DCF (docetaxel, cisplatin and fluorouracil), with DCF alone for ESCC, and exploring biomarkers related to immune infiltration of the ESCC immunotherapy response. Methods: We enrolled and randomly assigned patients with stage II-IVa ESCC to two study treatments: camrelizumab combined with docetaxel, cisplatin and fluorouracil (DCF) regimen and DCF regimen alone. The tissue for multiplex immunofluorescence (mIF) was obtained before and after neoadjuvant therapy. The Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1) and Tumor Regression Grade (TRG) was used to evaluate efficacy. Results: A total of 30 patients were enrolled in the study. Following neoadjuvant camrelizumab, the objective response rate (ORR) and the disease control rate (DCR) were 46.7% (7/15) and 95.7% (14/15), respectively. No patients reported complete remission, while ORR and DCR in the chemotherapy group were 26.7% (4/15) and 86.7% (13/15), respectively. R0 resection after neoadjuvant treatment was achieved in 3 out of 15 patients in the combined group and in all patients (15/15) in the chemotherapy group. In the combined group, M1-type tumor-associated macrophages and CD56dim NK cells were more abundant in responders than in non-responders (p < 0.05). A higher M1/M2 ratio was observed in responders (p < 0.05). With respect to the NGS, among the copy number amplified genes, the 11q13 amplicon (CCND1/FGF19/FGF4/FGF3) showed the highest frequency (47%, 7/15). Conclusions: Neoadjuvant camrelizumab combined with chemotherapy improved ORR in locally advanced ESCC. M1-type tumor-associated macrophages and CD56dim NK cells might be utilized to predict camrelizumab efficacy.

Landscape of RB1 alterations in 22,432 Chinese solid tumor patients.

Background: The human retinoblastoma susceptibility gene (RB1) is a tumor-suppressor gene mutated at different frequencies in many different cancers. The aim of the present study was to investigate the distribution of overall RB1 mutation and different mutation types in a range of Chinese patients with solid tumors. Methods: We investigated RB1 mutations in formalin-fixed, paraffin-embedded (FFPE) tissues of cancer patients who underwent next-generation sequencing (NGS) at 3DMed Clinical Laboratory Inc from January 1, 2017 to April 15, 2020. Results: Genomic alterations in RB1 were identified in 1,712 (7.6%) of 22,432 patients with more than 20 different cancer entities (58% males and 42% females, median age: 60 years). RB1 mutations occurred most frequently in small-cell lung cancer (SCLC; 138/165, 83.6%), followed by neuroendocrine neoplasms (40/170, 23.5%), bladder cancer (40/209, 19.1%), hepatocellular carcinoma (233/1,649, 14.1%), sarcomas (71/554, 12.8%), and esophageal cancer (32/293, 10.9%). Of these 1,712 patients, 185 (10.8%) had germline RB1 mutations. When stratified by mutational type, 1,258 (5.6%) had single-nucleotide variants (SNVs), 59 (0.3%) had fusions, and 210 (0.9%) had RB1 loss. Conclusions: Our findings indicate that RB1 alterations are widely distributed in solid cancers of many different histotypes in China, with specific mutations differing largely among different tumor types. The present study provides a comprehensive landscape of RB1 mutations in Chinese solid tumor patient and suggests a novel therapeutic target for cancer treatment.

Variation of the ileocolic artery and superior mesenteric artery in a patient with right-sided colon cancer with Lynch syndrome: a case report.

Background: Complete mesangectomy and central vascular detachment are the core elements of laparoscopic right hemicolectomy. Failure to identify vascular variations in patients undergoing laparoscopic right hemicolectomy can result in unwanted bleeding, a prolonged surgical time, transfer to open surgery, and an elevated risk of postoperative complications. In this case report, we describe a new vascular variation that has not yet been reported in the literature. Parallelly vascular variation and the management of vessels in key areas are essential for successful surgery. Case Description: The patient was a 32-year-old female who was referred to the department of gastrointestinal surgery of our hospital due to intermittent abdominal pain accompanied by changes in stool habits for 3 months. She had not experienced other symptoms. Physical examination revealed mild tenderness in the right lower abdomen. Subsequently, she underwent laparoscopic radical right hemicolectomy for ascending colon cancer under general anesthesia in our hospital. Preoperative abdominal contrast-enhanced computed tomography (CT) and intraoperative photos confirmed that there were two ileocolic arteries derived from the superior mesenteric artery (SMA). On the other side, the SMA and superior mesenteric vein (SMV) were found to be accompanied like "X"-shaped variant. The final surgical pathological diagnosis was pT3N1aM0 adenocarcinoma of the ascending colon. Given the patient's family history of colon and uterine cancer combined with the results of immunohistochemical staining and next-generation sequencing, we concluded that she had Lynch syndrome (LS). Conclusions: This report describes the first case of simultaneous variation of the ileocolic artery (ICA) and SMA in a female patient with colon cancer. This type of vascular variation should be fully recognized by surgeons in order to avoid unnecessary intraoperative bleeding.

Histone Deacetylase Inhibition Restores Behavioral and Synaptic Function in a Mouse Model of 16p11.2 Deletion.

BACKGROUND: Microdeletion of the human 16p11.2 gene locus confers risk for autism spectrum disorders and intellectual disability. How 16p11.2 deletion is linked to these neurodevelopmental disorders and whether there are treatment avenues for the manifested phenotypes remain to be elucidated. Emerging evidence suggests that epigenetic aberrations are strongly implicated in autism. METHODS: We performed behavioral and electrophysiological experiments to examine the therapeutic effects of epigenetic drugs in transgenic mice carrying 16p11.2 deletion (16p11del/+). RESULTS: We found that 16p11del/+ mice exhibited a significantly reduced level of histone acetylation in the prefrontal cortex (PFC). A short (3-day) treatment with class I histone deacetylase (HDAC) inhibitor MS-275 or Romidepsin led to the prolonged (3-4 weeks) rescue of social and cognitive deficits in 16p11del/+ mice. Concomitantly, MS-275 treatment reversed the hypoactivity of PFC pyramidal neurons and the hyperactivity of PFC fast-spiking interneurons. Moreover, the diminished N-methyl-D-aspartate (NMDA) receptor-mediated synaptic currents and the elevated GABAA receptor-mediated synaptic currents in PFC pyramidal neurons of 16p11del/+ mice were restored to control levels by MS-275 treatment. CONCLUSIONS: Our results suggest that HDAC inhibition provides a highly effective therapeutic strategy for behavioral deficits and excitation/inhibition imbalance in 16p11del/+ mice, likely via normalization of synaptic function in the PFC.

M2-phenotype tumour-associated macrophages upregulate the expression of prognostic predictors MMP14 and INHBA in pancreatic cancer.

Pancreatic cancer is one of the most lethal gastrointestinal tumours, the most common pathological type is pancreatic adenocarcinoma (PAAD). In recent year, immune imbalanced in tumour microenvironment has been shown to play an important role in the evolution of tumours progression, and the efficacy of immunotherapy has been gradually demonstrated in clinical practice. In this study, we propose to construct an immune-related prognostic risk model based on immune-related genes MMP14 and INHBA expression that can assess the prognosis of pancreatic cancer patients and identify potential therapeutic targets for pancreatic cancer, to provide new ideas for the treatment of pancreatic cancer. We also investigate the correlation between macrophage infiltration and MMP14 and INHBA expression. First, the gene expression data of pancreatic cancer and normal pancreatic tissue were obtained from The Cancer Genome Atlas Program (TCGA) and The Genotype-Tissue Expression public database (GTEx). The differentially expressed immune-related genes between pancreatic cancer samples and normal sample were screened by R software. Secondly, univariate Cox regression analysis were used to evaluate the relationship between immune-related genes and the prognosis of pancreatic cancer patients. A polygenic risk score model was constructed by Cox regression analysis. The prognostic nomogram was constructed, and its performance was evaluated comprehensively by internal calibration curve and C-index. Using the risk model, each patient gets a risk score, and was divided into high- or low- risk groups. The proportion of 22 types of immune cells infiltration in pancreatic cancer samples was inferred by CIBERSOFT algorithm, correlation analysis (Pearson method) was used to analyse the correlation between the immune-related genes and immunes cells. Then, we applied macrophage conditioned medium to culture pancreatic cancer cell line PANC1, detected the expression of MMP14 and INHBA by qRT-PCR and Western blot methods. Knock-down MMP14 and INHBA in PANC1 cells by transfected with shRNA lentiviruses. Detection of migration ability of pancreatic cells was done by trans-well cell migration assay. A subcutaneous xenograft tumour model of human pancreatic cancer in nude mice was constructed. In conclusion, an immune-related gene prognostic model was constructed, patients with high-risk scores have poorer survival status, M2-phenotype tumour-associated macrophages (TAMs) up-regulate two immune-related genes, MMP14 and INHBA, which were used to establish the prognostic model. Knock-down of MMP14 and INHBA inhibited invasion of pancreatic cancer.

Establishment and validation of a novel predictive model to quantify the risk of bone metastasis in patients with prostate cancer.

BACKGROUND: Patients with prostate cancer (PCa) commonly suffer from bone metastasis during disease progression. This study aims to construct and validate a nomogram to quantify bone metastasis risk in patients with PCa. METHODS: Clinicopathological data of patients diagnosed with PCa between 2010 and 2015 were retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Predictors for bone metastasis were identified by logistic regression analyses to establish a nomogram. The concordance index (c-index) and calibration plots were generated to assess the nomogram's discrimination, and the area under the receiver operating characteristic curve (AUC) was used to compare the precision of the nomogram with routine staging systems. The nomogram's clinical performance was evaluated by decision curve analysis (DCA) and clinical impact curves (CIC). Independent prognostic factors were identified by Cox regression analysis. RESULTS: A total of 168,414 eligible cases were randomly assigned to the training cohort or validation cohort at a ratio of 1:1. The nomogram, which was established based on independent factors, showed good accuracy, with c-indexes of 0.911 in the training set and 0.910 in the validation set. Calibration plots also approached 45 degrees. After other distant metastatic sites were included in the predictive model, the new nomogram displayed superior prediction performance. The AUCs and net benefit of the nomograms were both higher than those of other routine staging systems. Furthermore, bone metastasis prediction points were shown to be a new risk factor for overall survival. CONCLUSIONS: Novel validated nomograms can effectively predict the risk of bone metastasis in patients with PCa and help clinicians improve cancer management.

Tumor-associated macrophages promote the metastasis and growth of non-small-cell lung cancer cells through NF-κB/PP2Ac-positive feedback loop.

Non-small-cell lung cancer (NSCLC), with its aggressive biological behavior, is one of the most diagnosed cancers. Tumor-associated inflammatory cells play important roles in the interaction between chronic inflammation and lung cancer, however the mechanisms involved are far from defined. In the present study, by developing an orthotopic NSCLC mouse model based on chronic inflammation, we proved that an inflammatory microenvironment accelerated the growth of orthotopic xenografts in vivo. Tumor-associated macrophages, the most abundant population of inflammatory cells, were identified. Treatment with macrophage-conditioned medium (MCM) promoted the growth and migration of NSCLC cells. Using bioinformatics analysis, we identified downregulated PP2Ac expression in NSCLC cells upon treatment with MCM. We further confirmed that this downregulation was executed in an NF-κB pathway-dependent manner. As IκB kinase (IKK) has been proved to be a substrate of PP2Ac, inhibition on PP2Ac could result in amplification of NF-κB pathway signaling. Overexpression of PP2Ac, or the dominant-negative forms of IKK or IκB, attenuated the acceleration of growth and metastasis by MCM. Using bioinformatics analysis, we further identified that CXCL1 and COL6A1 could be downstream of NF-κB/PP2Ac pathway. Luciferase assay and ChIP assay further confirmed the location of response elements on the promoter regions of CXCL1 and COL6A1. Elevated CXCL1 facilitated angiogenesis, whereas upregulated COL6A1 promoted proliferation and migration.

The prospect of immunotherapy combined with chemotherapy in patients with advanced non-small cell lung cancer: a narrative review.

OBJECTIVE: Based on a thorough analysis of monotherapy (pembrolizumab) and chemoimmunotherapy, the immunomodulatory effects of chemotherapy agents are emphasized. BACKGROUND: The combination of chemotherapy and immune checkpoint inhibitors should and is already being regarded as a new standard strategy for the first-line treatment of advanced NSCLC. As some scientists hold, chemoimmunotherapy is the beginning of a new era of lung cancer therapy. Scientists of this field are trying to make the perfect blend, that is, to explore the perfect condition for combination therapy. However, first, we should fully understand the specific role of chemotherapy agents in combination therapy and its specific mechanism. However, our current consideration of this aspect is not comprehensive enough. Based on a full understanding of the mechanisms and roles of these partner treatments, can the perfect blend or a more appropriate combination strategy of cancer immunotherapy be established? METHODS: Search and discuss the literature of pembrolizumab in the treatment of non-small cell lung cancer, as well as previous studies on the immune regulatory function of chemotherapeutic agents, to analyze the mechanism of chemotherapeutic agents in combination immunotherapy. CONCLUSION: Here, we carefully analyzed the details of clinical trials of pembrolizumab in the treatment of NSCLC, and reviewed literature in this field. Therefore, we aim to put forward that chemoimmunotherapy is not a simple model of one plus another. Accordingly, we believe that the more likely role of chemotherapeutics in combination therapy with pembrolizumab is an immunomodulator. Based on this perspective, we propose that more attention and efforts should be devoted to understanding and exploring the immunomodulatory function of chemotherapy agents.

A bioinformatics analysis to evaluate the prognostic value of stemness-related genes in gastric cancer.

BACKGROUND: This study aimed to identify potential stemness-related targets in gastric cancer (GC) in order to support the development of new treatment strategies and improve patient survival. METHODS: Using the edgeR package, we identified stemness-related differentially expressed genes (DEGs) using GSE112631 and the stemness-related signaling pathways in the Gene Set Enrichment Analysis (GSEA) database. Lasso-penalized Cox regression analysis and multivariate Cox regression analysis tested by Akaike Information Criterion (AIC) were used to screen out survival genes in order to construct a prognostic model. We verified the accuracy of our prognostic model using a nomogram and receiver operating characteristic (ROC) curve analysis. Patients were divided into two groups based on the median risk score, and functional enrichment analysis was used to explore the differences between the two groups. RESULTS: Eight genes were selected to establish a prognostic model of The Cancer Genome Atlas (TCGA) and a validation model of the GSE84437 dataset from the Genome Expression Omnibus (GEO). In both models, we found that the low risk score group had better overall survival (OS) than the high-risk score group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between the two risk groups were totally different. CONCLUSIONS: We used eight stemness-related genes to build a prognostic model. The high-risk score group had a worse prognosis compared to the low-risk score group.

Identification of key genes and pathways at the downstream of S100PBP in pancreatic cancer cells by integrated bioinformatical analysis.

BACKGROUND: The aim of the present study was to identify key genes and pathways downstream of S100PPBP in pancreatic cancer cells. METHODS: The microarray datasets GSE35196 (S100PBP knockdown) and GSE35198 (S100PBP overexpression) were downloaded from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were obtained separately from GEO2R, and heatmaps showing clustering analysis of DEGs were generated using R software. Gene Ontology and pathway enrichment analyses were performed for identified DEGs using the Database for Annotation, Visualization, and Integrated Discovery and Kyoto Encyclopedia of Genes and Genomes, respectively. A protein-protein interaction (PPI) network was created using the Search Tool for the Retrieval of Interacting Genes and Cytoscape software. Relevant expression datasets of key identified genes were downloaded from The Cancer Genome Atlas, and overall survival (OS) analysis was performed with R software. Finally, Gene Expression Profiling Interactive Analysis was used to evaluate the expression of key DEGs in pancreatic cancer tissues. RESULTS: A total of 34 DEGs (11 upregulated and 23 downregulated) were screened out from the two datasets. Gene Ontology enrichment analysis revealed that the identified DEGs were mainly functionally enriched in ATPase activity, production of siRNA involved in RNA interference, and production of miRNAs involved in gene silencing by miRNA. The pathway enrichment analysis of the identified DEGs showed enrichment mainly in apoptosis, non-homologous end-joining, and miRNA pathways in cancer. The protein-protein interaction network was composed of 21 nodes and 30 edges. After survival analysis and gene expression analysis, 4 genes associated with poor prognosis were selected, including LMNB1, PRKRA, SEPT2, and XRCC5. CONCLUSIONS: LMNB1, PRKRA, SEPT2, and XRCC5 could be key downstream genes of the S100PBP gene in the inhibition of pancreatic cancer cell adhesion.

A novel nomogram based on SEER database for the prediction of liver metastasis in patients with small-cell lung cancer.

BACKGROUND: To establish and validate a nomogram to predict liver metastasis in patients with small-cell lung cancer (SCLC). METHODS: Information on patients diagnosed with SCLC between 2010 and 2015 was retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Risk factors for liver metastasis were identified by logistic regression analyses to construct a nomogram. The predictive accuracy was evaluated by concordance indexes (c-index) and calibration plots, and the comparison of discrimination between the nomogram and other routine staging systems was achieved with the area under receiver operating characteristic curve (AUC) analysis. Decision curve analysis (DCA) was performed to measure the clinical performance of the nomogram. RESULTS: A total of 12,957 patients met our inclusion criteria and were randomly assigned to training (n=6,479) and validation (n=6,478) sets. The nomogram which was established based on independent clinicopathological factors had poor accuracy, and after other distant metastatic sites were added into the predictive model, the new nomogram displayed better discrimination power, with c-indexes of 0.703 in the training set and 0.712 in the validation set. Both internal and external calibration plots approached 45 degrees. The AUCs and net benefit of the predictive model were both higher than those of routine staging systems. CONCLUSIONS: The validated nomogram might be a practical tool for clinicians to quantify the risk of liver metastasis in patients with SCLC and improve cancer management.

The prognostic roles of red blood cell-associated indicators in patients with resectable gastric cancers.

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. This study was designed to investigate the prognostic values of red blood cell (RBC)-associated indicators, including RBC, hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and RBC distribution width (RDW) in resectable GC patients. METHODS: In this retrospective study, a total of 104 pathologically confirmed GC patients were recruited. These cases were divided into two groups according to the median values of pretreatment RBC, HGB, HCT, MCV, MCH, MCHC, or RDW. To evaluate the changes in RBC-associated indicators values after treatment, we introduced the concept of post-/pre-treatment ratios (≤1 suggested RBC, HGB, HCT, MCV, MCH, MCHC, or RDW values were not increased after therapy, while >1 represented those in increased levels). RESULTS: The lower pretreatment MCHC levels were correlated with worse overall survival (OS), while pretreatment levels of RBC, HGB, HCT, MCV, MCH, or RDW were not. The whole course of treatment (surgery plus adjuvant chemotherapy) significantly decreased the values of MCHC, and increased the values of MCV and RDW, whereas it had no obvious effects on the values of RBC, HGB, HCT, or MCH. Patients with post-/pre-treatment MCV ratio >1 had an increased survival ratio. Meanwhile, post-/pre-treatment RBC, HGB, HCT, MCH, MCHC, or RDW ratios were not correlated with outcomes. Multivariate Cox regression analysis revealed that the American Joint Committee on Cancer (AJCC) stage (III), and lower pretreatment MCHC levels were independent risk factors affecting OS. The receiver operating characteristic (ROC) curve analysis showed that an MCHC value of 341.98 g/L was the optimal cutoff value for prognosis, with a sensitivity of 58.3% and a specificity of 75.0%. CONCLUSIONS: Pretreatment MCHC levels could become a potential prognostic factor for resectable GC.

Synthesis and biological evaluation of 4-(piperid-3-yl)amino substituted 6-pyridylquinazolines as potent PI3Kδ inhibitors.

PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds A5 and A8 were identified as potent PI3Kδ inhibitors, with IC50 values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC50 = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound A5 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kß and PI3Kγ. A8 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kß. Moreover, compounds A5 and A8 selectively exhibited anti-proliferation against SU-DHL-6 in vitro with IC50 values of 0.16 and 0.12 µM. Western blot analysis indicated that A8 could attenuate the AKTS473 phosphorylation. Molecular docking study suggested that A8 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.

Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors.

Phosphoinositide 3-kinases (PI3Ks) are regarded as promising targets for treatment of various cancers due to their roles in regulating cell proliferation, differentiation, migration, and survival. Here we report our efforts to develop potent and orally bioavailable PI3K inhibitors for the treatment of cancers. The alkylsulfonamide-containing quinazoline derivatives A1-A18 significantly inhibited PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC50 = 4.5 nM), PI3Kß (IC50 = 4.5 nM), PI3Kγ (IC50 = 4.5 nM), PI3Kδ (IC50 = 4.5 nM) and significantly inhibited the growth of HCT-116, MCF-7 and SU-DHL-6 cell lines with IC50 values of 0.82 µM, 0.99 µM and 0.19 µM, respectively. Western blot analysis demonstrated A1 significantly suppressed the phosphorylation of AKTS473 in a dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing significant weight loss or toxicity.

Bruton's tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018).

INTRODUCTION: Bruton's tyrosine kinase (BTK) plays a critical role in the regulation of survival, proliferation, activation and differentiation of B-lineage cells. It participates by regulating multiple cellular signaling pathways, including B cell receptor and FcR signaling cascades. BTK is abundantly expressed and constitutively active in the pathogenesis of B cell hematological malignancies, as well as several autoimmune diseases. Therefore, BTK is considered as an attractive target for treatment of B-lineage lymphomas, leukemias, and some autoimmune diseases. Many industry and academia efforts have been made to explore small molecular BTK inhibitors. AREAS COVERED: This review aims to provide an overview of the patented BTK inhibitors for the treatment of cancer from 2010 to 2018. EXPERT OPINION: BTK inhibitors attract much interest for their therapeutic potential in the treatment of cancers and autoimmune diseases, especially for B cell hematological malignancies. In 2013, ibrutinib was approved by the FDA as the first-in-class BTK inhibitors for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), and now it is also undergoing clinical evaluation for other indications in either single or combined therapy. It is clear that BTK inhibitors can provide a promising clinical benefit in treating B-lineage lymphomas and leukemias.

Prognostic evaluation of patients with resectable lung cancer using systemic inflammatory response parameters.

Lung cancer is one of the leading causes of cancer-associated mortality. C-reactive protein (CRP), albumin (ALB), globulin (GLB), lactate dehydrogenase (LDH), neutrophil-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been identified as general parameters for systemic inflammatory response (SIR). Furthermore, these parameters are also associated with tumor development and metastasis. The present study aimed to investigate the predictive values of these SIR parameters in patients with resectable lung cancer. In total, 101 patients with resectable lung cancer were recruited in the present study. The patients were divided into two groups according to the median value of pre-treatment CRP, ALB, GLB, LDH, NLR or PLR values. The post-/pre-treatment ratios were defined as the ratio of pre-treatment blood parameter values and the corresponding values obtained following therapy. A ratio of ≤1.1 indicated that the values were not increased, while a ratio of >1.1 suggested that the values were increased following treatment. Patients with lower pre-treatment ALB levels had poorer overall survival (OS) rates, whereas GLB, LDH, CRP, NLR or PLR levels were not associated with outcomes. Whole course treatment (surgery combined with adjuvant chemotherapy) significantly increased the value of ALB, but decreased the value of NLR, whereas it had no effect on the values of LDH, CRP or PLR. Post-/pre-treatment LDH and PLR were associated with outcomes. Post-/pre-treatment ALB, GLB, CRP and NLR were not associated with outcomes. Multivariate analysis revealed that a low pre-treatment ALB level and increased post-/pre-treatment PLR were independent risk factors affecting OS. The receiver operating characteristic curve analysis demonstrated that an ALB value of 47.850 g/l was considered to be the optimal cut-off value for prognosis; the sensitivity was 28.8% and specificity was 95.9%. It was suggested that the pre-treatment ALB and post-/pre-treatment PLR may be potential prognostic factors in resectable lung cancer.