Rapid response to fifth-line brigatinib plus entrectinib in an ALK-rearranged lung adenocarcinoma with an acquired ETV6-NTRK3 fusion: a case report.

The management of non-small cell lung cancer (NSCLC), specifically targeting the anaplastic lymphoma kinase (ALK) with tyrosine kinase inhibitors (TKIs), is challenged by the emergence of therapeutic resistance. Resistance mechanisms to ALK TKIs can be broadly classified into ALK-dependent and ALK-independent pathways. Here, we present a case with lung adenocarcinoma (LUAD) harboring an ALK rearrangement. The patient had developed resistance to sequential ALK TKI therapies, with an acquired ETV6-NTRK3 (E4:N14) fusion as a potential mechanism of ALK-independent resistance to lorlatinib. Subsequently, the patient was treated with the combination of brigatinib plus entrectinib and demonstrated a positive response, achieving an 8-month progression-free survival. Our case provides a potential treatment option for LUAD patients with ALK rearrangements and highlights the utility of next-generation sequencing (NGS) in uncovering genetic alterations that can guide the selection of effective treatment strategies.

Human bone marrow-derived mesenchymal stem overexpressing microRNA-124-3p inhibit DLBCL progression by downregulating the NFATc1/cMYC pathway.

BACKGROUND: Exosomes play important roles in intercellular communication by delivering microRNAs (miRNAs) that mediate tumor initiation and development, including those in diffuse large B cell lymphoma (DLBCL). To date, however, limited studies on the inhibitory effect of exosomes derived from human bone marrow mesenchymal stem cells (hBMSCs) on DLBCL progression have been reported. Therefore, this study aimed to investigate the role of hBMSC exosomes carrying microRNA-124-3p in the development of DLBCL. METHODS: Microarray-based expression analysis was adopted to identify differentially expressed genes and regulatory miRNAs, which revealed the candidate NFATc1. Next, the binding affinity between miR-124-3p and NFATc1 was detected by luciferase activity assays. The mechanism underlying NFATc1 regulation was investigated using lentiviral transfections. Subsequently, DLBCL cells were cocultured with exosomes derived from hBMSCs transfected with a miR-124-3p mimic or control. Proliferation and apoptosis were measured in vitro. Finally, the effects of hBMSC-miR-124-3p on tumor growth were investigated in vivo. RESULTS: MiR-124-3p was expressed at low levels, while NFATc1 was highly expressed in DLBCL cells. MiR-124-3p specifically targeted and negatively regulated the expression of NFATc1 in DLBCL cells, upregulated miR-124-3p-inhibited DLBCL cell proliferation and promoted apoptosis. The miR-124-3p derived from hBMSCs inhibits tumor growth both in vivo and in vitro via downregulation of the NFATc1/cMYC pathway. CONCLUSION: Human bone marrow-derived mesenchymal stem cell overexpressing microRNA-124-3p represses the development of DLBCL through the downregulation of NFATc1.

Secondary hemophagocytic lymphohistiocytosis triggered by peripheral T-cell lymphoma: An unusual case report.

Hemophagocytic lymphohistiocytosis (HLH) is a severe syndrome of pathological immune activation caused by activated macrophages and cytotoxic T cells. We report a 65-year-old male Chinese patient with typical HLH features caused by peripheral T-cell lymphoma and then received chemotherapy. However, though the patient's symptoms and signs improved much, his liver function, especially bilirubin, worsened which could be caused by overwhelming cytokines production. Therefore, plasmapheresis was conducted two times and then his liver function significantly recovered. The patient got temporary remission and good quality of life for nearly 2 months but died because of disease progression. In conclusion, as HLH is associated with multiorgan failure, high rates of morbidity and mortality, there are three points to be mentioned. First, it is critical that HLH should be screened as early as possible and initiate effective therapies. Second, plasmapheresis could be a useful method to eliminate excess cytokines production and improve liver function. Third, organs support and nutrient supply are also necessary and important.

The effectiveness of percutaneous endoscopic lumbar discectomy combined with external lumbar drainage in the treatment of intervertebral infections.

Objective: To analyze the effect of percutaneous endoscopic lumbar discectomy in treating lumbar intervertebral infections. Methods: A total of 13 patients with lumbar intervertebral infections who underwent percutaneous endoscopic lumbar discectomy combined with external drainage between November 2016 and December 2019 were enrolled in the present study. After the operation, sensitive antibiotics were used based on the results of the bacterial culture. If no pathogens were detected in the biopsy culture of the infected tissues, empirical antibiotics were administrated to these patients. The clinical efficacy was evaluated by using a visual analog scale (VAS), Japanese Orthopaedic Association (JOA), Oswestry Disability Index (ODI), and standard Macnab's evaluation. Postoperative computed tomography (CT) and MRI were also used to evaluate clinical efficacy. Results: The follow-up time was 10-18 months, and the average time was (13.69 ± 2.63) months. Causative bacteria were isolated in 7 of 13 infected tissue biopsy cultures. Systemic antibiotics and anti-tuberculous chemotherapy were administered according to sensitivity studies for identified. There were no pathogens isolated from the other six patients. Empiric antibiotics were administrated in these patients. One week after the operation, WBC, a fractional fraction of medium granulocytes, ESR and CRP were significantly lower compared to before the operation (all P < 0.05). At the last follow-up visit, the above-mentioned markers were all within normal range, which differed compared to the pre-operative data (P < 0.05). The VAS and ODI of the patients at 1 week and 3 months after operation were significantly lower compared to preoperative data (all P < 0.05). During the last follow-up visit, seven patients were excellent, five were good, and one was poor according to standard Macnab's evaluation. No serious complications were recorded. Conclusions: Percutaneous lumbar discectomy combined with external drainage resulted as an effective method for treating lumbar intervertebral infections and was associated with fewer injuries, less pain, low cost, and low recurrence rate.

Bufalin inhibits peritoneal dissemination of gastric cancer through endothelial nitric oxide synthase-mitogen-activated protein kinases signaling pathway.

Peritoneal dissemination threatens the survival of patients with gastric cancer (GC). Bufalin is an extract of traditional Chinese medicine, which has been proved to have anticancer effect. The target of bufalin in suppressing gastric cancer peritoneal dissemination (GCPD) and the underlying mechanism are still unclear. In this research, GC cell line MGC-803 and high-potential peritoneal dissemination cell line MKN-45P were treated with bufalin or L-NAME. Malignant biological behavior and protein level of GC cell lines were detected with MTT, wound healing, transwell, adhesion, and western blotting. Bioinformatics analysis and patient tissues were used to verify the role of endothelial nitric oxide synthase (NOS3) in GC. Mice model was used to assess the effect of bufalin and role of NOS3 in vivo. We found that bufalin inhibited the proliferation, invasion, and migration in GC cell lines. NOS3, which was an independent prognostic factor of GC patients, was predicted to be a potential target of bufalin. Further experiments proved that bufalin reduced the phosphorylation of NOS3, thereby inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway, and ultimately suppressed GCPD by inhibiting EMT process. In conclusion, NOS3 was a potential therapeutic target and prognostic biomarker of GC. Bufalin could suppress GCPD through NOS3-MAPK signaling pathway, which provided more evidence support for intraperitoneal perfusion of bufalin to treat GCPD.

Pan-Cancer Analysis of NOS3 Identifies Its Expression and Clinical Relevance in Gastric Cancer.

Background: NOS3 (endothelial NOS, eNOS) is a member of the nitric oxide synthase (NOS) enzyme family, mainly participating in nitric oxide (NO) generation. NOS3 has been reported to inhibit apoptosis and promote angiogenesis, proliferation, and invasiveness. However, the expression pattern of NOS3 and its diagnostic and prognostic potential has not been investigated in a pan-cancer perspective. Methods: Data from the Genotype-Tissue Expression (GTEx), the Cancer Genome Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE), and the Cancer Therapeutics Response Portal (CTRP) were employed and NOS3 expression was comprehensively analyzed in normal tissues, cancer tissues, and cell lines. Immunohistochemical staining of tissue sections were used to validate the prognostic role of NOS3 in gastric cancer patients. GSVA and GSEA analyses were performed to investigate signaling pathways related to NOS3 expression. Results: In normal tissues, NOS3 was expressed highest in the spleen and lowest in the blood. NOS3 expression was increased in stomach adenocarcinoma (STAD) and significantly associated with poor prognosis of patients. Immunohistochemical staining validated that NOS3 was an independent prognostic factor of gastric cancer. Several canonical cancer-related pathways were found to be correlated with NOS3 expression in STAD. The expression of NOS3 was related to the response to QS-11 and brivinib in STAD. Conclusions: NOS3 was an independent prognostic factor for patients with STAD. Increased expression of NOS3 influenced occurrence and development of STAD through several canonical cancer-related pathways. Drug response analysis reported drugs to suppress NOS3. NOS3 might be a novel target for gastric cancer treatment.

Bufalin inhibits human diffuse large B-cell lymphoma tumorigenesis by inducing cell death through the Ca2+/NFATC1/cMYC pathway.

The 5-year survival rate of diffuse large B-cell lymphoma (DLBCL) can reach 60%. However, nearly half of patients undergo relapse/refractory issues with a survival period of less than 2 years. New therapeutic approaches are therefore needed to improve chemotherapy efficacy and patient survival. Bufalin (BF), isolated from the traditional Chinese medicine Chansu, has been reported to play an anticancer role in multiple cancer cell types. However, there are few reports of the effects of BF on the growth of DLBCL. In the present study, we demonstrated that BF exerts antitumor activity in DLBCL cells, both in vitro and in vivo. Treatment of DLBCL cells with BF resulted in increased proliferation and apoptosis in a dose- and time-dependent manner. Daily intraperitoneal injection of 1.5 mg/kg BF significantly delayed DLBCL xenograft growth in NOD/SCID mice without affecting body weight. Bioinformatics analysis showed that BF may regulate NFATC1 protein and affect expression of its downstream gene, cMYC. Our results suggest that BF can attenuate NFATC1 translocation by reducing the intracellular calcium concentration; BF may also have a low synergistic effect with cyclosporin A. In conclusion, we demonstrated that BF exerts antitumor activity that is mediated at least in part by the Ca2+/NFATC1/cMYC pathway. Our findings suggest that BF can be effectively applied as a novel potential therapeutic agent for DLBCL.

Melatonin increases the chemosensitivity of diffuse large B-cell lymphoma cells to epirubicin by inhibiting P-glycoprotein expression via the NF-κB pathway.

BACKGROUND: Epirubicin is a first-line chemotherapeutic drug for the clinical treatment of diffuse large B cell lymphoma (DLBCL), but the overexpression of multidrug resistance (MDR) transporter proteins, especially P-glycoprotein (P-gp), renders epirubicin ineffective. Some studies reveal the potential role of melatonin in chemotherapeutic synergy and MDR. METHODS: The cell viability and apoptosis were determined by CCK-8 assay and acridine orange/ethidium bromide (AO/EB) fluorescence staining assay. Immunofluorescence and immunohistochemical staining were used to detect the expression of P-gp in DLBCL cells and tissues. Rhodamine-123 accumulation assay was used to evaluate the pump function of P-gp. The possible mechanisms of melatonin sensitize DLBCL cells to epirubicin were explored by western blotting, cytochrome C release, and pulldown assay. RESULTS: Melatonin significantly enhanced the epirubicin-induced cell proliferation suppression, epirubicin-induced apoptosis, and reduced the IC50 value of epirubicin. Further, melatonin synergized with epirubicin to promote the activation of the mitochondria-mediated apoptosis pathway and increased the accumulation of epirubicin in DLBCL cells by inhibiting the expression and function of P-gp. Immunohistochemical staining studies revealed that P-gp expression was positively correlated with P65 expression. Epirubicin was subsequently discovered to upregulate the expression of P-gp by activating the NF-κB pathway in the DLBCL cells. Melatonin reduced the amount of P65 protein in the nucleus and abrogated the ability of P65 to bind to the ABCB1 promoter, decisively suppressing P-gp expression. CONCLUSIONS: Our results demonstrated that melatonin inactivates the NF-κB pathway and downregulates the expression of P-gp, ultimately sensitizing DLBCL cells to the epirubicin that suppresses their growth.

Bufalin: A Systematic Review of Research Hotspots and Antitumor Mechanisms by Text Mining and Bioinformatics.

Bufalin is an anticancer drug extract from traditional Chinese medicine. Several articles about bufalin have been published. However, the literature on bufalin has not yet been systematically studied. This study aimed to identify the study status and knowledge structures of bufalin and to summarize the antitumor mechanism. Data were retrieved and downloaded from the PubMed database. The softwares of BICOMB, gCLUTO, Ucinet 6.0, and NetDraw2.084 were used to analyze these publications. The bufalin related genes were recognized and tagged by ABNER software. Then these BF-related genes were performed by Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, and protein-protein interaction (PPI) network analysis. A total of 474 papers met the search criteria from 2000 to 2019. By biclustering clustering analysis, the 50 high-frequency main MeSH terms/subheadings were classified into 5 clusters. The clusters of drug therapy and the mechanism of bufalin were hotspot topics. A total of 50 genes were identified as BF-related genes. PPI network analysis showed that inducing apoptosis was the main effect of bufalin, and apoptosis-related gene Caspase 3 was the most reported by people. Bufalin could inhibit the proliferation, invasion, and metastasis of cancer cells through multiple signaling pathways, such as PI3K/AKT, Hedgehog, MAPK/JNK, Wnt/[Formula: see text]-catenin, TGF-[Formula: see text]/Smad, Integrin signaling pathway, and NF-KB signaling pathway via KEGG analysis. Through the quantitative analysis of bufalin literature, we revealed the research status and hot spots in this field and provided some guidance for further research.

High SYT7 expression is associated with poor prognosis in human non-small cell lung carcinoma.

Synaptotagmin 7 (SYT7) can encode a single-pass 46-kDa transmembrane protein which located on human chromosome 11q12.2. It has been reported to be dysregulated in several cancers; however, there are few reports on the role of SYT7 in non-small cell lung carcinoma (NSCLC). The purpose of our study was to investigate the expression of SYT7 in NSCLC and its relationship with the prognosis of NSCLC. Differences in SYT7 expression were explored by using a public database and tissue samples. The prognostic value of SYT7 and its expression correlation with clinical parameters were evaluated by statistical analysis. Our current study found that elevated mRNA and protein levels of SYT7 in NSCLC tissues compared to adjacent normal tissues. The high expression of SYT7 in NSCLC patients was positively correlated with tumour differentiation (P = 0.031) and pT (P = 0.041). The higher SYT7 expression had a shorter survival time than those with lower SYT7 expression in NSCLC patients. Furthermore, multivariate analysis demonstrated that the expression of SYT7 was an unfavourable independent prognostic factor for NSCLC (P = 0.044). In conclusion, SYT7 was upregulated in NSCLC tissues and maybe a prognostic and diagnostic factor of NSCLC.

TFPI2 suppresses breast cancer progression through inhibiting TWIST-integrin α5 pathway.

BACKGROUND: Tissue factor pathway inhibitor 2 (TFPI2) participates in carcinogenesis of various tumors, and is associated with poor survival of breast cancer patients. However, the effect and underlying mechanism of TFPI2 on breast cancer progression remains to be investigated. METHODS: The expression level of TFPI2 in breast cancer tissues and cell lines was examined via qRT-PCR (quantitative real-time polymerase chain reaction) and immunohistochemistry. CCK8 (Cell Counting Kit-8), colony formation, wound healing or transwell assays were used to detect cell viability, proliferation, migration or invasion, respectively. In vivo subcutaneous xenotransplanted tumor model was established to detect tumorigenic function of TFPI2, and the underlying mechanism was evaluated by immunohistochemistry and western blot. RESULTS: TFPI2 was down-regulated in breast cancer tissues and cell lines, and was associated with poor prognosis of patients diagnosed with breast cancer. Over-expression of TFPI2 inhibited cell viability, proliferation, migration and invasion of breast cancer cells. Mechanistically, Twist-related protein 1 (TWIST1) was negatively associated with TFPI2 in breast cancer patients, whose expression was decreased by TFPI2 over-expression or increased by TFPI2 knockdown. Moreover, TWIST1 could up-regulate integrin α5 expression. Functional assays indicated that the inhibition abilities of TFPI2 over-expression on breast cancer progression were reversed by TWIST1 over-expression. In vivo subcutaneous xenotransplanted tumor model also revealed that over-expression of TFPI2 could suppress breast tumor growth via down-regulation of TWIST1-mediated integrin α5 expression. CONCLUSIONS: TFPI2 suppressed breast cancer progression through inhibiting TWIST-integrin α5 pathway, providing a new potential therapeutic target for breast cancer treatment.

Effective remission of chidamide on treatment of advanced mycosis fungoides: An unusual case report.

Mycosis fungoides (MF) and Sézary syndrome are the most common types of primary cutaneous T cell lymphoma, which primarily involves skin without curative treatment. We report a case of a 29-year-old female Chinese patient, who developed multiple cutaneous lesions gradually for 5 years. However, the patient could not tolerate pruritus and ulceration of cutaneous lesions, so she was admitted to hospital and diagnosed with advanced MF based on clinical manifestation, laboratory, and image results. Then she received four cycles of COPE regimen (cyclophosphamide, vincristine, prednisolone, and etoposide). Although the skin lesions shrinked and sense of pruritus alleviated quickly after the chemotherapy, the effective remission duration was not satisfactory. Therefore, the patient received gemcitabine and thalidomide for three cycles subsequently. Still the remission duration was not long lasting. After that, she took chidamide orally two times a week. By the time of 7 weeks, the patches almost diminished and the patient did not feel itching for almost 6 months. And, she did not have any adverse effect and had a better quality of life than the period of chemotherapy.

Brain metastasis in a patient with melanoma receiving Pembrolizumab therapy: A case report and review of the literature.

RATIONALE: Melanoma with brain metastasis is associated with a poor prognosis and high mortality rate. As patients with this condition have been excluded from most clinical trials, data on the use of anti-programmed death 1 therapy for these patients are limited. PATIENT CONCERNS: The patient was a 62-year-old man with a 10-year history of melanotic nevus in his right forearm. He was admitted to another hospital in August 2015 due to the growth of the melanotic nevus over 1 year and complaint of a mass in the right mid-axillary area. The patient had no relevant medical, surgical, or family history. DIAGNOSES: The biopsy of his right axillary lymph node showed malignant melanoma. INTERVENTIONS: He was subsequently treated with adjuvant high-dose interferon after dacarbazine. Numerous metastatic lesions were found in his lung, abdomen, pelvic cavity, and brain after five months later, and then Pembrolizumab was used for six cycles (2 mg/kg every 3 weeks). He experienced immunorelated adverse events and we gave him cortisol to treat immunorelated disease until pneumonia was found. OUTCOMES: We observed a delayed effect after three cycles of Pembrolizumab, the intracranial lesion presented clear margins and localization, while the other lesions became much smaller. A mixed response was observed after four cycles, with still stable extracranial metastases but growing a new lesion in brain. After two additional cycles of Pembrolizumab, the treatment was stopped due to the patient's inability to pay for it and a decline in his performance status. He then received palliative treatment at a local hospital and died for severe pulmonary infection, with an overall survival time of 7 months from metastasis. LESSONS: In the case reported here, a delayed and mixed response was observed after Pembrolizumab was used. Because of causing severe pulmonary infection, the use of steroids should be considered carefully when treating immunorelated adverse events. It seemed that the Pembrolizumab has a positive effect on melanoma brain metastases especially combined with other treatments. However, there are still some challenges including patient selection, predictors of response, drug tolerance, optimizing combination strategies and control of adverse effects. More carefully designed clinical trials are urgently needed.

Beta-elemene blocks epithelial-mesenchymal transition in human breast cancer cell line MCF-7 through Smad3-mediated down-regulation of nuclear transcription factors.

Epithelial-mesenchymal transition (EMT) is the first step required for breast cancer to initiate metastasis. However, the potential of drugs to block and reverse the EMT process are not well explored. In the present study, we investigated the inhibitory effect of beta-elemene (ELE), an active component of a natural plant-derived anti-neoplastic agent in an established EMT model mediated by transforming growth factor-beta1 (TGF-ß1). We found that ELE (40 µg/ml ) blocked the TGF-ß1-induced phenotypic transition in the human breast cancer cell line MCF-7. ELE was able to inhibit TGF-ß1-mediated upregulation of mRNA and protein expression of nuclear transcription factors (SNAI1, SNAI2, TWIST and SIP1), potentially through decreasing the expression and phosphorylation of Smad3, a central protein mediating the TGF-ß1 signalling pathway. These findings suggest a potential therapeutic benefit of ELE in treating basal-like breast cancer.