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Translational Cancer Research Dec 2023Gastric cancer (GC) is one of the most prevalent cancer types that reduce human life expectancy. The current tumor-node-metastasis (TNM) staging system is inadequate in...
BACKGROUND
Gastric cancer (GC) is one of the most prevalent cancer types that reduce human life expectancy. The current tumor-node-metastasis (TNM) staging system is inadequate in identifying higher or lower risk of GC patients because of tumor heterogeneity. Research shows that complement plays a dual role in the tumor development and progression of GC.
METHODS
We downloaded GC data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A complement-related risk signature was constructed through bioinformatics analysis. Subsequently, the predictive ability of this signature was validated with GSE84437 dataset, and a nomogram integrating risk score and common clinical factors was established. Besides, we evaluated the association of risk score with the immune and stromal cell infiltration in TCGA. Furthermore, immunotherapy response prediction and drug susceptibility analysis were conducted to access the ability of the risk signature in predicting the therapeutic effect.
RESULTS
A complement-related gene (CRG) signature, based on six genes (, , , , , and ), was established. In both the training and validation sets, the overall survival of GC patients in the high-risk group was lower than that of the low-risk group, and the nomogram to predict the 1-, 2-, and 3-year survival rates of GC patients was developed. In addition, CIBERSORT algorithm showed the high-risk patients had higher levels of immune cell infiltration than low-risk patients, and the ESTIMATE results implied that the high-risk group had more stromal component in tumor microenvironment. Besides, compared to the low-risk group, there were higher expressions of most immune checkpoint genes and HLA genes in the high-risk group, and the high-risk patients showed higher sensitivity to the chemotherapy and targeted drugs (axitinib, dasatinib, pazopanib, saracatinib, sunitinib and temsirolimus).
CONCLUSIONS
The novel CRG signature may act as a reliable, efficient tool for prognostic prediction and treatment guidance in future clinical practice.
PubMed: 38192986
DOI: 10.21037/tcr-23-628 -
Neuropsychopharmacology : Official... Mar 2022Altered striatal regulation of the GluN2B subunit of N-methyl-D-aspartate (NMDA) glutamate receptors by the Fyn/Src family of protein tyrosine kinases has been... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of the Fyn kinase inhibitor saracatinib on ventral striatal activity during performance of an fMRI monetary incentive delay task in individuals family history positive or negative for alcohol use disorder. A pilot randomised trial.
Altered striatal regulation of the GluN2B subunit of N-methyl-D-aspartate (NMDA) glutamate receptors by the Fyn/Src family of protein tyrosine kinases has been implicated in animal alcohol consumption. Previously, we have described differences between individuals positive (FHP) and negative (FHN) for familial alcohol use disorder (AUD) in the ventral striatal (VS) activation associated with monetary incentive delay task (MIDT) performance during functional magnetic resonance imaging (fMRI). Here, we used AZD0530 (saracatinib), a centrally active Fyn/Src inhibitor to probe the role of Fyn/Src regulation of NMDA receptors (NMDAR) in VS activation differences between FHP and FHN individuals during fMRI MIDT performance. We studied 21 FHN and 22 FHP individuals, all without AUD. In two sessions, spaced 1 week apart, we administered 125 mg of saracatinib or placebo in a double-blind manner, prior to measuring VS signal during fMRI MIDT performance. MIDT comprises reward prospect, anticipation, and outcome phases. During the initial (prospect of reward) task phase, there was a significant group-by-condition interaction such that, relative to placebo, saracatinib reduced VS BOLD signal in FHP and increased it in FHN individuals. This study provides the first human evidence that elevated signaling in striatal protein kinase A-dependent pathways may contribute to familial AUD risk via amplifying the neural response to the prospect of reward. As Fyn kinase is responsible for NMDAR upregulation, these data are consistent with previous evidence for upregulated NMDAR function within reward circuitry in AUD risk. These findings also suggest a possible therapeutic role for Src/Fyn kinase inhibitors in AUD risk.
Topics: Alcohol Drinking; Alcoholism; Benzodioxoles; Humans; Magnetic Resonance Imaging; Motivation; Pilot Projects; Quinazolines; Reward
PubMed: 34475522
DOI: 10.1038/s41386-021-01157-5 -
JAMA Psychiatry Nov 2021The COVID-19 pandemic has raised considerable concerns about increased risk for suicidal behavior among US military veterans, who already had elevated rates of suicide...
IMPORTANCE
The COVID-19 pandemic has raised considerable concerns about increased risk for suicidal behavior among US military veterans, who already had elevated rates of suicide before the pandemic.
OBJECTIVE
To examine longitudinal changes in suicidal behavior from before the COVID-19 pandemic to nearly 10 months into the pandemic and identify risk factors and COVID-related variables associated with new-onset suicide ideation (SI).
DESIGN, SETTING, AND PARTICIPANTS
This population-based prospective cohort study used data from the first and second wave of the National Health and Resilience in Veterans Study, conducted from November 18, 2019, to December 19, 2020. Median dates of data collection for the prepandemic and peripandemic assessments were November 21, 2019, and November 14, 2020, nearly 10 months after the start of the COVID-19 public health emergency in the US. A total of 3078 US military veterans aged 22 to 99 years were included in the study.
MAIN OUTCOMES AND MEASURES
Past-year SI and suicide attempts.
RESULTS
In this cohort study of 3078 US veterans (mean [SD] age, 63.2 [14.7] years; 91.6% men; 79.3% non-Hispanic White veterans, 10.3% non-Hispanic Black veterans, and 6.0% Hispanic veterans), 233 (7.8%) reported past-year SI, and 8 (0.3%) reported suicide attempts at the peripandemic assessment. Past-year SI decreased from 10.6% prepandemic (95% CI, 9.6%-11.8%) to 7.8% peripandemic (95% CI, 6.9%-8.8%). A total of 82 veterans (2.6%) developed new-onset SI over the follow-up period. After adjusting for sociodemographic and military characteristics, the strongest risk factors and COVID-19-related variables for new-onset SI were low social support (odds ratio [OR], 2.77; 95% CI, 1.46-5.28), suicide attempt history (OR, 6.31; 95% CI, 2.71-14.67), lifetime posttraumatic stress disorder and/or depression (OR, 2.25; 95% CI, 1.16-4.35), past-year alcohol use disorder severity (OR, 1.06; 95% CI, 1.01-1.12), COVID-19 infection (OR, 2.41; 95% CI, 1.41-5.01), and worsening of social relationships during the pandemic (OR, 1.47; 95% CI, 1.16-1.88).
CONCLUSIONS AND RELEVANCE
The results of this cohort study suggest that despite grim forecasts that the COVID-19 pandemic would exacerbate suicidality among US military veterans, the rate of SI decreased at the population level nearly 10 months into the pandemic. Veterans who were infected with COVID-19 were more than twice as likely to report SI, which suggests the need for future research to examine the potential link between COVID-19 infection and suicidal behavior.
Topics: Adult; Aged; COVID-19; Female; Humans; Longitudinal Studies; Male; Middle Aged; Prevalence; Risk Factors; Suicidal Ideation; United States; Veterans
PubMed: 34431973
DOI: 10.1001/jamapsychiatry.2021.2332 -
The American Journal of Pathology Sep 2023Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive mitogen-activated protein kinase...
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. To identify potential therapeutic targets, previous studies used genome-scale shRNA screens that implicated the neuregulin-1 receptor erb-B2 receptor tyrosine kinase 3 (erbB3) in MPNST proliferation and/or survival. The current study shows that erbB3 is commonly expressed in MPNSTs and MPNST cell lines and that erbB3 knockdown inhibits MPNST proliferation and survival. Kinomic and microarray analyses of Schwann and MPNST cells implicate Src- and erbB3-mediated calmodulin-regulated signaling as key pathways. Consistent with this, inhibition of upstream (canertinib, sapitinib, saracatinib, and calmodulin) and parallel (AZD1208) signaling pathways involving mitogen-activated protein kinase and mammalian target of rapamycin reduced MPNST proliferation and survival. ErbB inhibitors (canertinib and sapitinib) or erbB3 knockdown in combination with Src (saracatinib), calmodulin [trifluoperazine (TFP)], or proviral integration site of Moloney murine leukemia kinase (AZD1208) inhibition even more effectively reduces proliferation and survival. Drug inhibition enhances an unstudied calmodulin-dependent protein kinase IIα phosphorylation site in an Src-dependent manner. The Src family kinase inhibitor saracatinib reduces both basal and TFP-induced erbB3 and calmodulin-dependent protein kinase IIα phosphorylation. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events; and when combined with TFP, it even more effectively reduces proliferation and survival compared with monotherapy. These findings implicate erbB3, calmodulin, proviral integration site of Moloney murine leukemia kinases, and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective.
Topics: Humans; Mice; Animals; Neurofibrosarcoma; Receptor, ErbB-2; Nerve Sheath Neoplasms; Calmodulin; Sirolimus; Cell Proliferation; TOR Serine-Threonine Kinases; Mitogen-Activated Protein Kinases; Leukemia; Cell Line, Tumor; Mammals
PubMed: 37328102
DOI: 10.1016/j.ajpath.2023.05.016 -
Cell Communication and Signaling : CCS Jan 2024Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by...
BACKGROUND
Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by which CAFs promote tumorigenesis has been well investigated, the underlying mechanism of CAFs activation by neighboring cancer cells remains elusive. In this study, we aim to investigate the signaling pathways involved in CAFs activation by gastric cancer cells (GC) and to provide insights into the therapeutic targeting of CAFs for overcoming GC.
METHODS
Alteration of receptor tyrosine kinase (RTK) activity in CAFs was analyzed using phospho-RTK array. The expression of CAFs effector genes was determined by RT-qPCR or ELISA. The migration and invasion of GC cells co-cultured with CAFs were examined by transwell migration/invasion assay.
RESULTS
We found that conditioned media (CM) from GC cells could activate multiple receptor tyrosine kinase signaling pathways, including ERK, AKT, and STAT3. Phospho-RTK array analysis showed that CM from GC cells activated PDGFR tyrosine phosphorylation, but only AKT activation was PDGFR-dependent. Furthermore, we found that connective tissue growth factor (CTGF), a member of the CCN family, was the most pronouncedly induced CAFs effector gene by GC cells. Knockdown of CTGF impaired the ability of CAFs to promote GC cell migration and invasion. Although the PDGFR-AKT pathway was pronouncedly activated in CAFs stimulated by GC cells, its pharmacological inhibition affected neither CTGF induction nor CAFs-induced GC cell migration. Unexpectedly, the knockdown of SRC and SRC-family kinase inhibitors, dasatinib and saracatinib, significantly impaired CTGF induction in activated CAFs and the migration of GC cells co-cultured with CAFs. SRC inhibitors restored the reduced expression of epithelial markers, E-cadherin and Zonula Occludens-1 (ZO-1), in GC cells co-cultured with CAFs, as well as CAFs-induced aggregate formation in a 3D tumor spheroid model.
CONCLUSIONS
This study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC. Video Abstract.
Topics: Humans; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Movement; Cell Proliferation; Connective Tissue Growth Factor; Fibroblasts; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Stomach Neoplasms; Tumor Microenvironment
PubMed: 38167009
DOI: 10.1186/s12964-023-01396-7 -
An organ-on-a-chip model for pre-clinical drug evaluation in progressive non-genetic cardiomyopathy.Journal of Molecular and Cellular... Nov 2021Angiotensin II (Ang II) presents a critical mediator in various pathological conditions such as non-genetic cardiomyopathy. Osmotic pump infusion in rodents is a...
Angiotensin II (Ang II) presents a critical mediator in various pathological conditions such as non-genetic cardiomyopathy. Osmotic pump infusion in rodents is a commonly used approach to model cardiomyopathy associated with Ang II. However, profound differences in electrophysiology and pharmacokinetics between rodent and human cardiomyocytes may limit predictability of animal-based experiments. This study investigates the application of an Organ-on-a-chip (OOC) system in modeling Ang II-induced progressive cardiomyopathy. The disease model is constructed to recapitulate myocardial response to Ang II in a temporal manner. The long-term tissue cultivation and non-invasive functional readouts enable monitoring of both acute and chronic cardiac responses to Ang II stimulation. Along with mapping of cytokine secretion and proteomic profiles, this model presents an opportunity to quantitatively measure the dynamic pathological changes that could not be otherwise identified in animals. Further, we present this model as a testbed to evaluate compounds that target Ang II-induced cardiac remodeling. Through assessing the effects of losartan, relaxin, and saracatinib, the drug screening data implicated multifaceted cardioprotective effects of relaxin in restoring contractile function and reducing fibrotic remodeling. Overall, this study provides a controllable platform where cardiac activities can be explicitly observed and tested over the pathological process. The facile and high-content screening can facilitate the evaluation of potential drug candidates in the pre-clinical stage.
Topics: Angiotensin II; Animals; Cardiomyopathies; Cardiotonic Agents; Cell Line; Cell Survival; Coculture Techniques; Drug Evaluation, Preclinical; Fibroblasts; Fibrosis; Humans; Induced Pluripotent Stem Cells; Lab-On-A-Chip Devices; Losartan; Mice; Myocytes, Cardiac; Pilot Projects; Proteome; Proteomics; Recombinant Proteins; Relaxin; Ventricular Remodeling
PubMed: 34216608
DOI: 10.1016/j.yjmcc.2021.06.012 -
IScience Sep 2021Resistance to current therapies is common for pancreatic cancer and hence novel treatment options are urgently needed. In this work, we developed and validated a...
Resistance to current therapies is common for pancreatic cancer and hence novel treatment options are urgently needed. In this work, we developed and validated a computational method to select synergistic compound combinations based on transcriptomic profiles from both the disease and compound side, combined with a pathway scoring system, which was then validated prospectively by testing 30 compounds (and their combinations) on PANC-1 cells. Some compounds selected as single agents showed lower GI50 values than the standard of care, gemcitabine. Compounds suggested as combination agents with standard therapy gemcitabine based on the best performing scoring system showed on average 2.82-5.18 times higher synergies compared to compounds that were predicted to be active as single agents. Examples of highly synergistic in vitro validated compound pairs include gemcitabine combined with Entinostat, thioridazine, loperamide, scriptaid and Saracatinib. Hence, the computational approach presented here was able to identify synergistic compound combinations against pancreatic cancer cells.
PubMed: 34585118
DOI: 10.1016/j.isci.2021.103080 -
Sarcoma 2020Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in...
PURPOSE
Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. . Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles.
RESULTS
Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (=0.47). Median OS was not reached in either arm.
CONCLUSIONS
Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.
PubMed: 32398945
DOI: 10.1155/2020/7935475 -
Journal of Ethnopharmacology Apr 2023Jiawei Taohe Chengqi Decoction (JTCD) is a Traditional Chinese Medicine (TCM) formula modified from Taohe Chengqi Decoction in the classic ancient literature of TCM...
ETHNOPHARMACOLOGICAL RELEVANCE
Jiawei Taohe Chengqi Decoction (JTCD) is a Traditional Chinese Medicine (TCM) formula modified from Taohe Chengqi Decoction in the classic ancient literature of TCM "Treatise on Febrile Diseases". Clinical and pharmacological studies have shown that JTCD has a therapeutic effect on hepatic encephalopathy, non-alcoholic fatty liver, cirrhotic ascites, and can alleviate acute liver injury in rats. Our previous studies confirmed that JTCD could alleviate hepatic fibrosis and activation of hepatic stellate cells (HSCs). However, its mechanism remains unclear.
AIM OF THE STUDY
This study aimed to elucidate the mechanism of Src Signal on hepatic fibrosis and HSCs activation, and whether JTCD inhibited hepatic fibrosis and HSCs activation through affecting Src Signal.
MATERIALS AND METHODS
In vivo, sixty specific pathogen free male C57/BL6 mice were divided into following six groups: Control group, Model group, SARA group, JTCD low dose group, JTCD medium dose group and JTCD high dose group. Then we established a carbon tetrachloride (CCL)-induced hepatic fibrosis mice model, each JTCD group was given the corresponding dose of JTCD by gavage, the SARA group was given Saracatinib and the control group was given saline, once a day for 4 consecutive weeks. UPLC-Q-TOF-MS analyzed chemical components of JTCD. Pathological examination including Hematoxylin and Eosin (H&E), Masson and Sirius red staining was used to observe the characteristic of hepatic fibrosis. Automatic biochemical analyzer detected the levels of alanine aminotransfease (ALT), and aspartate transaminase (AST) in serum. Western-blot and immunohistochemical staining (IHC) detected protein expression. In vitro, we used shRNA to knock down the expression of Src in immortalized human hepatic stellate cell line (LX-2), then intervened with ERK1/2 agonists/inhibitors and JTCD-containing serum after transforming growth factor β1 (TGF-β1) treatment. Immunofluorescence and western-blot detected protein expression. The migratory characteristic of HSCs was assessed by wound-healing assay.
RESULTS
We identified 135 chemical components in the water extract of JTCD, and the water extract of JTCD contains a variety of anti-hepatic fibrosis components. Compared to the model group, hepatic fibrosis performance was significantly improved, the serum levels of ALT and AST were significantly decreased in JTCD groups and SARA group, IHC staining and western blot results indicated that JTCD decreased the expressions of α-smooth muscle actin (α-SMA), phospho-Src (Tyr416), phospho-ERK1/2 and phospho-Smad3. In vitro, JTCD-containing serum could significantly decrease the protein expressions of α-SMA, phospho-Src (Tyr416), phospho-ERK1/2 and phospho-Smad3 according to the results of western-blot and immunofluorescence, in addition, JTCD-containing serum inhibited the mobility and activation of LX-2. What's more, after intervening with Src-shRNA, ERK1/2 agonists/inhibitors and JTCD-containing serum, the western-blot results showed that Src/ERK/Smad3 signal has an important role in hepatic fibrosis and HSCs, and JTCD attenuates hepatic fibrosis by preventing activation of HSCs through regulating Src/ERK/Smad3 signal pathway.
CONCLUSIONS
The results showed that Src kinase promoted hepatic fibrosis and HSCs activation through the ERK/Smad3 signal pathway. More importantly, the mechanism by which JTCD attenuated hepatic fibrosis and HSCs activation was by inhibiting the Src/ERK/Smad3 signal pathway.
Topics: Animals; Humans; Male; Mice; Carbon Tetrachloride; Hepatic Stellate Cells; Liver; Liver Cirrhosis; MAP Kinase Signaling System; RNA, Small Interfering; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta1
PubMed: 36549368
DOI: 10.1016/j.jep.2022.116059 -
Pharmaceuticals (Basel, Switzerland) Sep 2021Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant...
Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed and optimized a phenotypic screen for drugs that may target OS disseminated tumor cells (DTCs) and inhibit their metastatic outbreak rather than merely screening for cytotoxic activity against proliferating cells, as is commonly conducted in conventional drug discovery approaches. We report on the validation of a previously described 3D reconstituted basement membrane extract (3D BME) model system for tumor dormancy and metastatic outgrowth adapted to clonal pairs of high and low metastatic OS cells. A post-hoc validation of the assay was possible by comparing the activity of a drug in our assay with early evidence of activity in human OS clinical trials (regorafenib and saracatinib). In this validation, we found concordance between our assay and human clinical trial experience We then explored an approved veterinary small molecule inhibitor of Janus kinase-1 (oclacitinib) as a potential drug candidate to take advantage of the high prevalence of OS in pet dogs and its translational value to humans. Despite the biological rationale, we found no evidence to support the use of oclacitinib as an antimetastatic agent in OS. The findings support our 3D BME assay as a highly efficient method to examine drugs for activity in targeting OS DTCs.
PubMed: 34681195
DOI: 10.3390/ph14100971