Resveratrol promotes the differentiation of human umbilical cord mesenchymal stem cells into esophageal fibroblasts via AKT signaling pathway.

Objectives: Resveratrol has been implicated in the differentiation and development of human umbilical cord mesenchymal stem cells. The differentiation of into esophageal fibroblasts is a promising strategy for esophageal tissue engineering. However, the pharmacological effect and underlying mechanism of resveratrol on human umbilical cord mesenchymal stem cells differentiation are unknown. Here, we investigated the effects and mechanism of resveratrol on the differentiation of human umbilical cord mesenchymal stem cells. Methods: Using a transwell-membrane coculture system to culture human umbilical cord mesenchymal stem cells and esophageal fibroblasts, we examined how resveratrol act on the differentiation of human umbilical cord mesenchymal stem cells. Immunocytochemistry, Sirius red staining, quantitative real-time PCR, and Western blotting were performed to examine collagen synthesis and possible signaling pathways in human umbilical cord mesenchymal stem cells. Results: We found that resveratrol promoted collagen synthesis and AKT phosphorylation. However, co-treatment of cells with resveratrol and the PI3K inhibitor LY294002 inhibited collagen synthesis and AKT phosphorylation. We demonstrated that resveratrol down-regulated the expression of IL-6, TGF-ß, caspase-9, and Bax by activating the AKT pathway in human umbilical cord mesenchymal stem cell. Furthermore, resveratrol inhibited phosphorylated NF-ĸB in human umbilical cord mesenchymal stem cells. Conclusion: Our data suggest that resveratrol promotes the differentiation of human umbilical cord mesenchymal stem cells into fibroblasts. The underlying mechanism is associated with the downregulation of IL-6 and TGF-ß via the AKT pathway and by inhibiting the NF-ĸB pathway. Resveratrol may be useful for esophageal tissue engineering.

Cuproptosis and Immune-Related Gene Signature Predicts Immunotherapy Response and Prognosis in Lung Adenocarcinoma.

Cuproptosis and associated immune-related genes (IRG) have been implicated in tumorigenesis and tumor progression. However, their effects on lung adenocarcinoma (LUAD) have not been elucidated. Therefore, we investigated the impact of cuproptosis-associated IRGs on the immunotherapy response and prognosis of LUAD using a bioinformatical approach and in vitro experiments analyzing clinical samples. Using the cuproptosis-associated IRG signature, we classified LUAD into two subtypes, cluster 1 and cluster 2, and identified three key cuproptosis-associated IRGs, NRAS, TRAV38-2DV8, and SORT1. These three genes were employed to establish a risk model and nomogram, and to classify the LUAD cohort into low- and high-risk subgroups. Biofunctional annotation revealed that cluster 2, remarkably downregulating epigenetic, stemness, and proliferation pathways activity, had a higher overall survival (OS) and immunoinfiltration abundance compared to cluster 1. Real-time quantitative PCR (RT-qPCR) validated the differential expression of these three genes in both subgroups. scRNA-seq demonstrated elevated expression of NRAS and SORT1 in macrophages. Immunity and oncogenic and stromal activation pathways were dramatically enriched in the low-risk subgroup, and patients in this subgroup responded better to immunotherapy. Our data suggest that the cuproptosis-associated IRG signature can be used to effectively predict the immunotherapy response and prognosis in LUAD. Our work provides enlightenment for immunotherapy response assessment, prognosis prediction, and the development of potential prognostic biomarkers for LUAD patients.

Metastatic Colorectal Cancer Patient with Microsatellite Stability and Germline BRAC2 Mutation Shows a Complete Response to Olaparib in Combination with a PD-1 Inhibitor and Bevacizumab: A Case Report and Review of the Literature.

Metastatic colorectal cancer (mCRC) has a poor prognosis. Combining chemotherapy with targeted therapy constitutes a basic form of mCRC treatment. Immune checkpoint inhibitors have been recommended for microsatellite instability mCRC, while most patients harboring microsatellite stability (MSS) or proficient mismatch repair (pMMR) are less responsive to immunotherapy. Combinational targeted therapy, including poly-ADP ribose polymerase (PARP) inhibitors, has been considered a promising way to reverse immunotherapy resistance; however, there is no clear and consistent conclusions can be drawn from the current research. Here, we report the case of a 59-year-old woman diagnosed with stage IVB MSS mCRC who received three courses of capecitabine/oxaliplatin chemotherapy combined with bevacizumab as a first-line treatment, resulting in an overall evaluation of stable disease (-25.7%). However, the occurrence of adverse events of intolerable grade 3 diarrhea and vomiting forced the cessation of this therapy. A germline BRCA2 mutation was found by next-generation sequencing, and the patient further received a combination of olaparib, tislelizumab, and bevacizumab. This treatment regime resulted in a complete metabolic response and a partial response (-50.9%) after 3 months of treatment. Mild asymptomatic interstitial pneumonia and manageable hematologic toxicity were two adverse events associated with this combination therapy. This study provides new insights into the combination of PARP inhibitors and immunotherapy for MSS mCRC patients carrying germline BRCA2 mutations.

Investigating the Impact of Displacement Cascades on Tritium Diffusion in MgT2: A Molecular Dynamics Study.

Molecular dynamics methods were utilized to investigate displacement cascades and tritium diffusion in α-MgT2. It was observed from collision cascades results that the stable number of defects weakly depended on temperature, while the peak and stable number of defects linearly increased with increasing the primary knock-on atom energy. The results of the mean square displacement study revealed that defects had a significant impact on tritium diffusion. The clustering of magnesium self-interstitial atoms and diffusing tritium atoms results in an increased diffusion barrier, whereas the formation of clusters between tritium interstitial atoms is relatively difficult and has no significant impact on the diffusion barrier. The presence of magnesium and tritium vacancies has a minimal effect on the diffusion barrier due to the large number of diffusing tritium atoms that offset the adsorption of vacancies on diffusing atoms. Both magnesium and tritium interstitial atoms increase the collision probability of diffusing atoms, leading to an increased diffusion prefactor. Magnesium vacancies cause significant lattice distortion, increasing the diffusion barrier, while the impact of tritium vacancies on the diffusion barrier is small due to their minimal lattice distortion effect. The research uncovered significant disparities in the diffusion properties of hydrogen and tritium, indicating that the results of the study of hydrogen storage could not be applied to tritium.

Immunopotentiating Activity of Fucoidans and Relevance to Cancer Immunotherapy.

Fucoidans, discovered in 1913, are fucose-rich sulfated polysaccharides extracted mainly from brown seaweed. These versatile and nontoxic marine-origin heteropolysaccharides have a wide range of favorable biological activities, including antitumor, immunomodulatory, antiviral, antithrombotic, anticoagulant, antithrombotic, antioxidant, and lipid-lowering activities. In the early 1980s, fucoidans were first recognized for their role in supporting the immune response and later, in the 1990s, their effects on immune potentiation began to emerge. In recent years, the understanding of the immunomodulatory effects of fucoidan has expanded significantly. The ability of fucoidan(s) to activate CTL-mediated cytotoxicity against cancer cells, strong antitumor property, and robust safety profile make fucoidans desirable for effective cancer immunotherapy. This review focusses on current progress and understanding of the immunopotentiation activity of various fucoidans, emphasizing their relevance to cancer immunotherapy. Here, we will discuss the action of fucoidans in different immune cells and review how fucoidans can be used as adjuvants in conjunction with immunotherapeutic products to improve cancer treatment and clinical outcome. Some key rationales for the possible combination of fucoidans with immunotherapy will be discussed. An update is provided on human clinical studies and available registered cancer clinical trials using fucoidans while highlighting future prospects and challenges.

Expression Profile of Sphingosine Kinase 1 Isoforms in Human Cancer Tissues and Cells: Importance and Clinical Relevance of the Neglected 1b-Isoform.

Background: Overexpression of sphingosine kinase 1 (SphK1) is casually associated with many types of cancer, and inhibitors of SphK1 sensitize tumors to chemotherapy. SphK1 is expressed as two major isoforms, SphK1a and SphK1b. To date, no information has been reported on the SphK1 isoform expression profile and its clinical relevance. Objective: The objective is to examine the expression profile of the SphK1a and SPhK1b isoforms in human cancer and noncancer tissues and cell lines and explore their clinical relevance. Methods: We used PCR to qualitatively examine the expression profile of these two isoforms in breast, liver, and prostate cancer tissues plus paired adjacent tissues and in 11 cancer and normal cell lines (breast, cervical, bone, prostate, colon, brain, mesothelioma tumor and benign, and human kidney cells). Results: We found that SphK1a was ubiquitously expressed in all cancer cells and tissues tested; in contrast, SphK1b was only expressed in selective cell types in breast, prostate, and lung cancer. Conclusions: Our data suggest that SphK1a is important for generic SphK1/S1P functions, and SphK1b mediates specialized and/or unique pathways in a specific type of tissue and could be a biomarker for cancer. This discovery is important for future SphK1-related cancer research and may have clinical implications in drug development associated with SphK1-directed cancer treatment.

Development of a diagnostic assay by three-tube multiplex real-time PCR for simultaneous detection of nine microorganisms causing acute respiratory infections.

Acute respiratory infections are widespread in vulnerable populations of all ages and are characterized by a variety of symptoms. The underlying infection can be caused by a multitude of microorganisms, including viruses and bacteria. Early detection of respiratory infections through rapid pathogen screening is vital in averting infectious respiratory disease epidemics. This study utilized a multiplex real-time PCR system to develop a three-tube reverse transcription-PCR (RT-PCR) assay, enabling simultaneously detect nine respiratory pathogens, including: influenza A and B, adenovirus, respiratory syncytial virus (RSV), Streptococcus pneumoniae, Legionella pneumophila, Haemophilus influenzae, Chlamydia pneumoniae, and Mycoplasma pneumoniae. This technique utilizes a one-step assay, with specifically designed TaqMan primer-probe sets combined in the same tube. This assay provided rapid and simplified detection of the nine prevalent pathogens, as well as increased sensitivity and reduced cross-contamination. This assay was evaluated using 25 related viral/bacterial strains as positive references, the other 25 irrelevant strains as negative controls, and clinical specimens from 179 patients. All positive strains were detected with no amplification of the non-target microorganism mixtures and the assay's detection limits ranged between 250-500 copies/ml (1.25-2.5 copies/reaction). A total of 167 (93.3%) samples tested positive for at least one of the pathogens identified; 109 of these samples were from patients confirmed to have RSV infections. The diagnostic accuracy of our assay was further confirmed by matching results from classical direct immunofluorescence assay and nucleotide sequencing. These data demonstrate the innovative multiplex real-time PCR assay as a promising alternative to the current approaches used for early screening of acute respiratory infections.

circHIPK3 regulates cell proliferation and migration by sponging microRNA-124 and regulating serine/threonine kinase 3 expression in esophageal squamous cell carcinoma.

Circular RNAs (circRNAs) are a type of important non-coding RNAs that widely involve in the physiological and pathophysiological process. Recent research has established a link between circHIPK3 and the malignant activity of cancer cells. However, circHIPK3' role in esophageal squamous cell carcinoma (ESCC) still needs more focus. To determine the prognostic value of circHIPK3 in patients with ESCC, the expression of circHIPK3 was quantified in 32 pairs of ESCC using real-time polymerase chain reaction (RT-qPCR). Then, the correlation between circHIPK3 expression and clinical characteristics of patients was also analyzed. The function of circHIPK3 in the development of ESCC was investigated using cell biology studies and bioinformatics. The results showed that the expression of circHIPK3 was considerably higher in tumor tissues from ESCC patients than that of adjacent tissues, which was associated with a poor prognosis. Additionally, silencing of circHIPK3 expression retarded esophageal cancer cell proliferation, migration and epithelial-mesenchymal transition (EMT) in vitro, as well as the growth in vivo. Mechanistically, we discovered that circHIPK3 behaved like a sponge, absorbing microRNA-124 (miR-124) and promoting serine/threonine kinase 3 (AKT3) expression. Our findings indicate that circHIPK3 acts as an oncogene in ESCC and that the circHIPK3-AKT3 axis may be a therapeutic target for patients with ESCC.

Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway.

Incidence of gastrointestinal (GI) cancers is increasing, and late-stage diagnosis makes these cancers difficult to treat. Chronic and low-grade inflammation are recognized risks for most GI cancers. The GI mucosal immune system maintains healthy homeostasis and signalling molecules made from saturated fats, bioactive sphingolipids, play essential roles in healthy GI immunity. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, is a key mediator in a balanced GI immune response. Disruption in the S1P pathway underlies systemic chronic metabolic inflammatory disorders, including diabetes and GI cancers, providing a strong rationale for using modulators of the S1P pathway to treat pathological inflammation. Here, we discuss the effects of bioactive sphingolipids in immune homeostasis with a focus on S1P in chronic low-grade inflammation associated with increased risk of GI carcinogenesis. Contemporary information on S1P signalling involvement in cancers of the digestive system, from top to bottom, is reviewed. Further, we discuss the use of novel S1P receptor modulators currently in clinical trials and their potential as first-line drugs in the clinic for chronic inflammatory diseases. Recently, ozanimod (ZeposiaTM) and etrasimod have been approved for clinical use to treat ulcerative colitis and eosinophilic oesophagitis, respectively, which may have longer term benefits in reducing risk of GI cancers.

PseUdeep: RNA Pseudouridine Site Identification with Deep Learning Algorithm.

Background: Pseudouridine (Ψ) is a common ribonucleotide modification that plays a significant role in many biological processes. The identification of Ψ modification sites is of great significance for disease mechanism and biological processes research in which machine learning algorithms are desirable as the lab exploratory techniques are expensive and time-consuming. Results: In this work, we propose a deep learning framework, called PseUdeep, to identify Ψ sites of three species: H. sapiens, S. cerevisiae, and M. musculus. In this method, three encoding methods are used to extract the features of RNA sequences, that is, one-hot encoding, K-tuple nucleotide frequency pattern, and position-specific nucleotide composition. The three feature matrices are convoluted twice and fed into the capsule neural network and bidirectional gated recurrent unit network with a self-attention mechanism for classification. Conclusion: Compared with other state-of-the-art methods, our model gets the highest accuracy of the prediction on the independent testing data set S-200; the accuracy improves 12.38%, and on the independent testing data set H-200, the accuracy improves 0.68%. Moreover, the dimensions of the features we derive from the RNA sequences are only 109,109, and 119 in H. sapiens, M. musculus, and S. cerevisiae, which is much smaller than those used in the traditional algorithms. On evaluation via tenfold cross-validation and two independent testing data sets, PseUdeep outperforms the best traditional machine learning model available. PseUdeep source code and data sets are available at https://github.com/dan111262/PseUdeep.

Cancer-associated fibroblasts-derived exosomal miR-3656 promotes the development and progression of esophageal squamous cell carcinoma via the ACAP2/PI3K-AKT signaling pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most common gastrointestinal tumors, accounting for almost half a million deaths per year. Cancer-associated fibroblasts (CAFs) are the major constituent of the tumor microenvironment (TME) and dramatically impact ESCC progression. Recent evidence suggests that exosomes derived from CAFs are able to transmit regulating signals and promote ESCC development. In this study, we compared different the component ratios of miRNAs in exosomes secreted by CAFs in tumors and with those from normal fibroblasts (NFs) in precancerous tissues. The mRNA level of hsa-miR-3656 was significantly upregulated in the former exosomes. Subsequently, by comparing tumor cell development in vitro and in vivo, we found that the proliferation, migration and invasion capabilities of ESCC cells were significantly improved when miR-3656 was present. Further target gene analysis confirmed ACAP2 was a target gene regulated by miR-3656 and exhibited a negative regulatory effect on tumor proliferation. Additionally, the downregulation of ACAP2 triggered by exosomal-derived miR-3656 further promotes the activation of the PI3K/AKT and ß-catenin signaling pathways and ultimately improves the growth of ESCC cells both in vitro and in xenograft models. These results may represent a potential therapeutic target for ESCC and provide a new basis for clinical treatment plans.

METTL3 Promotes Esophageal Squamous Cell Carcinoma Metastasis Through Enhancing GLS2 Expression.

Recent studies have identified pleiotropic roles of methyltransferase-like 3 (METTL3) in tumor progression. However, the roles of METTL3 in esophageal squamous cell carcinoma (ESCC) are still unclear. Here, we investigated the function and mechanism of METTL3 in ESCC tumorigenesis. We reported that higher METTL3 expression was found in ESCC tissues and was markedly associated with depth of invasion and poor prognosis. Loss- and gain-of function studies showed that METTL3 promoted the migration and invasion of ESCC cells in vitro. Integrated methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq) analysis first demonstrated that glutaminase 2 (GLS2) was regulated by METTL3 via m6A modification. Our findings identified METTL3/GLS2 signaling as a potential therapeutic target in antimetastatic strategies against ESCC.

A Computational Framework to Identify Biomarkers for Glioma Recurrence and Potential Drugs Targeting Them.

Background: Recurrence is still a major obstacle to the successful treatment of gliomas. Understanding the underlying mechanisms of recurrence may help for developing new drugs to combat gliomas recurrence. This study provides a strategy to discover new drugs for recurrent gliomas based on drug perturbation induced gene expression changes. Methods: The RNA-seq data of 511 low grade gliomas primary tumor samples (LGG-P), 18 low grade gliomas recurrent tumor samples (LGG-R), 155 glioblastoma multiforme primary tumor samples (GBM-P), and 13 glioblastoma multiforme recurrent tumor samples (GBM-R) were downloaded from TCGA database. DESeq2, key driver analysis and weighted gene correlation network analysis (WGCNA) were conducted to identify differentially expressed genes (DEGs), key driver genes and coexpression networks between LGG-P vs LGG-R, GBM-P vs GBM-R pairs. Then, the CREEDS database was used to find potential drugs that could reverse the DEGs and key drivers. Results: We identified 75 upregulated and 130 downregulated genes between LGG-P and LGG-R samples, which were mainly enriched in human papillomavirus (HPV) infection, PI3K-Akt signaling pathway, Wnt signaling pathway, and ECM-receptor interaction. A total of 262 key driver genes were obtained with frizzled class receptor 8 (FZD8), guanine nucleotide-binding protein subunit gamma-12 (GNG12), and G protein subunit ß2 (GNB2) as the top hub genes. By screening the CREEDS database, we got 4 drugs (Paclitaxel, 6-benzyladenine, Erlotinib, Cidofovir) that could downregulate the expression of up-regulated genes and 5 drugs (Fenofibrate, Oxaliplatin, Bilirubin, Nutlins, Valproic acid) that could upregulate the expression of down-regulated genes. These drugs may have a potential in combating recurrence of gliomas. Conclusion: We proposed a time-saving strategy based on drug perturbation induced gene expression changes to find new drugs that may have a potential to treat recurrent gliomas.

Effective management of advanced colon cancer genotyping microsatellite stable/microsatellite instable-low with Kirsten rat sarcoma viral oncogene mutation using nivolumab plus ipilimumab combined with regorafenib and irinotecan: A case report.

Microsatellite stable /microsatellite instable-low is the most common colorectal cancer genotype, counting for approximately 85% of common colorectal cancer patients. Treatment of advanced microsatellite stable/microsatellite instable-low colorectal cancer is difficult and successful pharmacological treatment options are currently lacking. Here, we report a case of a 37-year-old man with advanced colorectal cancer genotyping microsatellite stable/microsatellite instable-low with a Kirsten rat sarcoma viral oncogene (G12V) mutation. Following palliative surgery, the patient did not response to the common recommended chemotherapy FOLFIRI regimen and other chemotherapy options. Finally, the patient was successfully treated using a unique combinational immunotherapy, using nivolumab plus ipilimumab combined with regorafenib and irinotecan. Significant improvement in the Karnofsky Performance Status scores, liver function and well-being, reduction in serum tumor biomarkers, and reduction in the size of multiple liver metastatic tumors was evident. This report provides a rare case in which a unique and effective combinational immunotherapy for refractory advanced colon cancer patients is discussed. It encourages further research into combined immunotherapy for immuno-insensitive colon cancer patients.

Revealing the Interactions Between Diabetes, Diabetes-Related Diseases, and Cancers Based on the Network Connectivity of Their Related Genes.

Diabetes-related diseases (DRDs), especially cancers pose a big threat to public health. Although people have explored pathological pathways of a few common DRDs, there is a lack of systematic studies on important biological processes (BPs) connecting diabetes and its related diseases/cancers. We have proposed and compared 10 protein-protein interaction (PPI)-based computational methods to study the connections between diabetes and 254 diseases, among which a method called DIconnectivity_eDMN performs the best in the sense that it infers a disease rank (according to its relation with diabetes) most consistent with that by literature mining. DIconnectivity_eDMN takes diabetes-related genes, other disease-related genes, a PPI network, and genes in BPs as input. It first maps genes in a BP into the PPI network to construct a BP-related subnetwork, which is expanded (in the whole PPI network) by a random walk with restart (RWR) process to generate a so-called expanded modularized network (eMN). Since the numbers of known disease genes are not high, an RWR process is also performed to generate an expanded disease-related gene list. For each eMN and disease, the expanded diabetes-related genes and disease-related genes are mapped onto the eMN. The association between diabetes and the disease is measured by the reachability of their genes on all eMNs, in which the reachability is estimated by a method similar to the Kolmogorov-Smirnov (KS) test. DIconnectivity_eDMN achieves an area under receiver operating characteristic curve (AUC) of 0.71 for predicting both Type 1 DRDs and Type 2 DRDs. In addition, DIconnectivity_eDMN reveals important BPs connecting diabetes and DRDs. For example, "respiratory system development" and "regulation of mRNA metabolic process" are critical in associating Type 1 diabetes (T1D) and many Type 1 DRDs. It is also found that the average proportion of diabetes-related genes interacting with DRDs is higher than that of non-DRDs.

[Comparison of B-NDG? and BALB/c mouse models bearing patient-derived xenografts of esophageal squamous cell carcinoma].

OBJECTIVE: To investigate the difference of tumor formation in different mouse strains bearing patient-derived xenograft of esophageal squamous cell carcinoma(ESCC) and establish a better animal model for preclinical study of individualized treatment of ESCC. METHODS: The tumor tissues collected from 22 ESCC patients were used to establish tumor-bearing mouse models in B-NDG? (NSG) mice and BALB/c nude mice. The tumor formation rate and tumor formation time were compared between the two mouse models, and HE staining, immunohistochemistry and genome sequencing were carried out to assess the consistency between transplanted tumor tissues in the models and patient-derived tumor tissues. RESULTS: The tumor-bearing models were established successfully in both NSG mice (50%, 11/22) and BALB/c nude mice (18.18%, 4/22). The average tumor formation time was significantly shorter in NSG mice than in BALB/c nude mice (75.95 vs 91.67 days, P < 0.001). In both of the mouse models, the transplanted tumors maintained morphological characteristics identical to those of patient-derived ESCC tumors. Genetic analysis showed that the xenografts in NSG mice had a greater genetic similarity to the patients' tumors than those in BALB/c nude mice (P < 0.0001). CONCLUSIONS: Mouse models bearing xenografts of patient-derived ESCC can be successfully established in both NSG mice and BALB/c nude mice, but the models in the former mouse strain can be more reliable.

Development and validation of a droplet digital PCR assay for the evaluation of PML-RARα fusion transcripts in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is an aggressive disease that requires prompt treatment. Promyelocytic leukemia protein-retinoic acid receptor α (PML-RARα) fusion genes resulting from reciprocal translocation are considered a molecular basis for diagnosing APL. Moreover, PML-RARα fusion gene testing is an essential tool for monitoring the response to therapy via minimal residual disease and providing a diagnosis before rapid disease progression in APL. The present study developed a novel droplet digital PCR (ddPCR) assay to rapidly detect two PML-RARα variants (bcr1 and bcr3) and compared its limit of detection (LOD) with quantitative PCR (qPCR). It was demonstrated that the LOD of ddPCR for PML-RARα reached 0.001%, and the evaluation of high copy number samples of PML-RARα by ddPCR correlated well with qPCR. Furthermore, clinical sample testing with ddPCR found that 34 and 24% samples were bcr-1-positive and bcr3-positive, respectively. However, according to qPCR, 30% of the samples were bcr1-positive and 20% were bcr3-positive. In addition, the concordance rate between ddPCR and qPCR reaction was 86%. While monitoring minimal residual disease, the PML-RARα mutation rate of three patients who recovered well decreased to 0.34%. However, one patient who was bcr3-positive and relapsed had a mutation rate of 13% while in remission, indicating that the bcr3 isoform may be an adverse prognostic factor affecting recovery. Therefore, the present results suggested that this novel ddPCR assay may be useful for monitoring and evaluating the treatment effects and prognosis of APL.

HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma.

PURPOSE: Currently, the paucity of classical effective pharmacological drugs to treat esophageal squamous cell carcinoma (ESCC) is a major problem. The c-Myc (MYC) protein is a promising target as it is overexpressed in ESCC. MYC is a sensitive client protein of the heat shock protein 90 (HSP90) and, therefore, targeting the HSP90-MYC axis by inhibition of HSP90 is a potential therapeutic strategy for ESCC. Here, we evaluated the clinical application value of the HSP90 inhibitor (Ganetespib, STA-9090) as an anti-cancer agent for MYC-positive ESCC. MATERIALS AND METHODS: We first analyzed ESCC tissue microarrays and clinical tissue samples to determine MYC expression. The relationship between MYC and HSP90 was analyzed by co-immunoprecipitation assays and immunofluorescence. In in vitro cell models, cell growth was analyzed using the CCK-8 kit, and MYC protein expression was analyzed by Western blot. The in vivo antitumor activity of STA-9090 was assessed in two xenograft animal models. RESULTS: We demonstrated that MYC-overexpressing ESCC cells were highly sensitive to STA-9090 treatment through suppressing ESCC cell proliferation, cell cycle progression and survival. Moreover, STA-9090 treatment decreased MYC expression, reducing the half-life of the MYC protein. We further established two xenograft mouse models using ESCC cells and clinical ESCC samples to validate the effectiveness of STA-9090 in vivo. In both xenograft models, STA-9090 substantially inhibited the growth of MYC-positive ESCC tumors in vivo. In contrast, STA-9090 treatment demonstrated no beneficial effects in mice with low-MYC expressing ESCC tumors. CONCLUSION: In conclusion, our data support that the HSP90 inhibitor, STA-9090, suppresses the expression of the MYC protein and interferes with HSP90-MYC protein-protein interaction. This, in turn, leads to inhibition of ESCC cell proliferation and promotion of apoptosis in ESCC cells in vitro and reduction of ESCC tumors in vivo. We propose, based on our findings, that STA-9090 is a potential novel therapeutic target for MYC-positive ESCC.

PD-1 disrupted CAR-T cells in the treatment of solid tumors: Promises and challenges.

Unprecedented efficacy of chimeric antigen receptor (CAR) T cell therapy in the treatment of hematologic malignancies brings new hope for patients with many cancer types including solid tumors. However, the challenges for CAR-T cell therapy in eradicating solid tumors are immense. To overcome these seemingly intractable hurdles, more "powerful" CAR-T cells with enhanced antitumor efficacy are required. Emerging data support that the anti-tumor activity of CAR-T cells can be enhanced significantly without evident toxicity through simultaneous PD-1 disruption by genome editing. This review focuses on the current progress of PD-1 gene disrupted CAR-T cells in cancer therapy. Here we discuss key rationales for this new combination strategy and summarize the available pre-clinical studies. An update is provided on human clinical studies and available registered cancer clinical trials using CAR-T cells with PD-1 disruption. Future prospects and challenges are also discussed.