Identification and evaluation of a six-lncRNA prognostic signature for multiple myeloma.

PURPOSE: Multiple myeloma (MM) is the second most common hematologic malignancy, and there is no cure for this disease. This study aimed to explore the prognostic value of long noncoding RNAs (lncRNAs) in MM and to reveal related immune and chemotherapy resistance mechanisms. METHODS: In this study, lncRNA profiles from the Multiple Myeloma Research Foundation (MMRF) and Gene Expression Omnibus (GEO) databases were analyzed to identify lncRNAs linked to MM patient survival. A risk assessment model stratified patients into high- and low-risk groups, and survival was evaluated. Additionally, a triple-ceRNA (lncRNA-miRNA-mRNA) network was constructed, and functional analysis was performed. The research also involved immune function analysis and chemotherapy drug sensitivity assessment using oncoPredict and the GDSC dataset. RESULTS: We identified 422 lncRNAs significantly associated with overall survival in MM patients and ultimately focused on the 6 with the highest prognostic value. These lncRNAs were used to develop a risk score formula that stratified patients into high- and low-risk groups. Kaplan-Meier analysis revealed shorter survival in high-risk patients. We integrated this lncRNA signature with clinical parameters to construct a nomogram for predicting MM prognosis. Additionally, a triple-ceRNA network was constructed to reveal potential miRNA targets, coding genes related to these lncRNAs and significantly enriched pathways. Immune checkpoint gene expression and immune cell composition were also analyzed in relation to the lncRNA risk score. Finally, using the oncoPredict tool, we observed that high-risk patients exhibited decreased sensitivity to key MM chemotherapeutics, suggesting that lncRNA profiles are linked to chemotherapy resistance.

MYC overexpression in natural killer cell lymphoma: prognostic and therapeutic implications.

The current clinical management of Extranodal NK/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the PINK-E prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown (KD) in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA-sequencing (RNA-seq) used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-seq data upon MYC KD with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.

Treatment of multiple myeloma with selinexor: a review.

Over the last 20 years, breakthroughs in accessible therapies for the treatment of multiple myeloma (MM) have been made. Nevertheless, patients with MM resistant to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have a very poor outcome. Therefore, it is necessary to explore new drugs for the treatment of MM. This review summarizes the mechanism of action of selinexor, relevant primary clinical trials, and recent developments in both patients with relapsed/refractory myeloma and patients with newly diagnosed myeloma. Selinexor may be useful for the treatment of refractory MM.

The Potential and Challenges of Selinexor in the Treatment of Multiple Myeloma Multiple myeloma (MM) is a plasma-cell neoplasm that presents with a variety of clinical manifestations, including bone destruction, anemia, renal dysfunction, and hypercalcemia, which pose a serious threat to people's health. Over the past 20 years, the survival of MM patients has significantly improved thanks to the development of several new treatments. However, the disease remains incurable, and almost all patients eventually develop a disease that is ineffective against available treatments. Therefore, an important area of research is the discovery of drugs with novel mechanisms of action to overcome the resistance mechanisms of current drugs. Selinexor is an oral XPO1 inhibitor that exerts anti-tumor activity through a novel mechanism. Here, we review the current clinical trials evaluating its role in the treatment of multiple myeloma and have a discussion of its mechanism, adverse events, challenges, and limitations. Selinexor is a promising drug. It may be a good addition to the treatment of relapsed and refractory multiple myeloma, but more research is needed to unlock its further potential.

Niclosamide improves cancer immunotherapy by modulating RNA-binding protein HuR-mediated PD-L1 signaling.

BACKGROUND: Immune checkpoint blockade (ICB) represents a revolutionary advance in cancer treatment but remains limited success in triple-negative breast cancer (TNBC). Here we aim to explore the mechanism of RNA-binding protein (RBP) HuR in cancer immune evasion by post-transcriptionally regulating PD-L1 and evaluate the potential of HuR inhibition to improve immune response. METHODS: The binding between HuR and PD-L1 mRNA was determined by ribonucleoprotein immunoprecipitation and RNA pull-down assays. The HuR knockout clones were established by CRISPR/Cas9 technology. The protein levels were assessed by Western blot, immunohistochemistry, and immunocytochemistry. The function and molecular mechanism of HuR-PD-L1 were determined by in vitro T cell activation and killing assay and in vivo efficacy assay. RESULTS: We found that HuR directly bound to and stabilized PD-L1 mRNA. Knocking out HuR reduced PD-L1 levels and promoted T cell activation. We discovered that niclosamide reduced PD-L1 by inhibiting HuR cytoplasmic translocation, and diminished glycosylation of PD-L1. Niclosamide enhanced T cell-mediated killing of cancer cells and significantly improved the efficacy of anti-PD-1 immunotherapy in two syngeneic animal tumor models. CONCLUSION: We identified HuR as a novel posttranscriptional regulator of PD-L1, which plays an important role in tumor immune evasion. Niclosamide might be a promising repurposed drug to improve the patient response to immunotherapy by targeting HuR-PD-L1 axis. Our study demonstrates a novel strategy for targeting HuR/PD-L1 and provides the first proof-of-principle for repurposing niclosamide as a HuR inhibitor to overcome cancer immune evasion and improve response to ICB immunotherapy.

Repurposing Niclosamide as a Novel Anti-SARS-CoV-2 Drug by Restricting Entry Protein CD147.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic, and the search for effective treatments has been limited. Furthermore, the rapid mutations of SARS-CoV-2 have posed challenges to existing vaccines and neutralizing antibodies, as they struggle to keep up with the increased viral transmissibility and immune evasion. However, there is hope in targeting the CD147-spike protein, which serves as an alternative point for the entry of SARS-CoV-2 into host cells. This protein has emerged as a promising therapeutic target for the development of drugs against COVID-19. Here, we demonstrate that the RNA-binding protein Human-antigen R (HuR) plays a crucial role in the post-transcriptional regulation of CD147 by directly binding to its 3'-untranslated region (UTR). We observed a decrease in CD147 levels across multiple cell lines upon HuR depletion. Furthermore, we identified that niclosamide can reduce CD147 by lowering the cytoplasmic translocation of HuR and reducing CD147 glycosylation. Moreover, our investigation revealed that SARS-CoV-2 infection induces an upregulation of CD147 in ACE2-expressing A549 cells, which can be effectively neutralized by niclosamide in a dose-dependent manner. Overall, our study unveils a novel regulatory mechanism of regulating CD147 through HuR and suggests niclosamide as a promising therapeutic option against COVID-19.

Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147.

Background The burst of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the global COVID-19 pandemic. But until today only limited numbers of drugs are discovered to treat COVID-19 patients. Even worse, the rapid mutations of SARS-CoV-2 compromise the effectiveness of existing vaccines and neutralizing antibodies due to the increased viral transmissibility and immune escape. CD147-spike protein, one of the entries of SRAR-CoV-2 into host cells, has been reported as a promising therapeutic target for developing drugs against COVID-19. Methods CRISPR-Cas9 induced gene knockout, western blotting, tet-off protein overexpression, ribonucleoprotein IP and RNA-IP were used to confirm the regulation of HuR on mRNA of CD147. Regulation of niclosamide on HuR nucleo-translocation was assessed by immunofluorescence staining of cell lines, IHC staining of tissue of mouse model and western blotting. Finally, the suppression of niclosamide on SARS-CoV-2 infection induced CD147 was evaluated by ACE2-expressing A549 cells and western blotting. Results We first discovered a novel regulation mechanism of CD147 via the RNA-binding protein HuR. We found that HuR regulates CD147 post-transcription by directly bound to its 3'-UTR. The loss of HuR reduced CD147 in multiple cell lines. Niclosamide inhibited CD147 function by blocking HuR cytoplasmic translocation and diminishing CD147 glycosylation. SARS-CoV-2 infection induced CD147 in ACE2-expressing A549 cells, which could be neutralized by niclosamide in a dose-dependent manner. Conclusion Together, our study reveals a novel regulation mechanism of CD147 and niclosamide can be repurposed as an effective COVID-19 drug by targeting the virus entry, CD147-spike protein.

Randomized Trial of First-Line Tyrosine Kinase Inhibitor With or Without Radiotherapy for Synchronous Oligometastatic EGFR-Mutated Non-Small Cell Lung Cancer.

BACKGROUND: Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether these findings translate to epidermal growth factor receptor (EGFR)-mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual. METHODS: Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided. RESULTS: A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was 17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in the TKI with RT arm. Based on the efficacy results of this prespecified interim analysis, the ethics committee recommended premature cessation of this trial. CONCLUSIONS: As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.

Purification and Analysis of the CREPT Antibody from Mouse Ascites.

Methods: Cells were cultivated properly to obtain 3E10 CREPT monoclonal antibody cells in the logarithmic growth stage. Monoclonal antibody cells were injected into the abdominal cavity of sensitized mice. The flowing ascites were observed for 7-15 days. The antibody protein was obtained by collection, filtration, dilution, loading, and chromatography. Furthermore, its binding force was detected by SDS-PAGE and Western blot techniques. Results: The antibody protein was successfully obtained with a purity of 1895 µg/mL with high liveness. Conclusion: This study establishes a one-step purification method for obtaining monoclonal antibody with high liveness and purity for CREPT ascites antibody. This method is simple to perform and lays a foundation for the preparation and purification of humanized monoclonal antibodies in the future. In addition, it provides a basis for further research to investigate how CREPT affects the occurrence and development of different tumors.

Evaluation of the clinical application effect of eSource record tools for clinical research.

BACKGROUND: Electronic sources (eSources) can improve data quality and reduce clinical trial costs. Our team has developed an innovative eSource record (ESR) system in China. This study aims to evaluate the efficiency, quality, and system performance of the ESR system in data collection and data transcription. METHODS: The study used time efficiency and data transcription accuracy indicators to compare the eSource and non-eSource data collection workflows in a real-world study (RWS). The two processes are traditional data collection and manual transcription (the non-eSource method) and the ESR-based source data collection and electronic transmission (the eSource method). Through the system usability scale (SUS) and other characteristic evaluation scales (system security, system compatibility, record quality), the participants' experience of using ESR was evaluated. RESULTS: In terms of the source data collection (the total time required for writing electronic medical records (EMRs)), the ESR system can reduce the time required by 39% on average compared to the EMR system. In terms of data transcription (electronic case report form (eCRF) filling and verification), the ESR can reduce the time required by 80% compared to the non-eSource method (difference: 223 ± 21 s). The ESR accuracy in filling the eCRF field is 96.92%. The SUS score of ESR is 66.9 ± 16.7, which is at the D level and thus very close to the acceptable margin, indicating that optimization work is needed. CONCLUSIONS: This preliminary evaluation shows that in the clinical medical environment, the ESR-based eSource method can improve the efficiency of source data collection and reduce the workload required to complete data transcription.

LncRNA PVT1 facilitates DLBCL development via miR-34b-5p/Foxp1 pathway.

Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma and is a very aggressive malignancy with tumor growing rapidly in organs like lymph nodes. The pathogenesis of DLBCL is not clear and the prognosis of DLBCL requires improvement. Here, we investigated the mechanisms of DLBCL, with the focus on lncRNA PVT1/miR-34b-5p/Foxp1 axis. Human DLBCL tissues from diagnosed DLBCL patients and four human DLBCL cell lines, one normal human B lymphoblastoid cell line were used. qRT-PCR and western blotting were employed to measure expression levels of lncRNA PVT1, Foxp1, miR-34b-5p, ß-catenin, and proliferation-related proteins. MTT assay and colony formation assay were performed to determine cell proliferation. Flow cytometry was used to examine cell apoptosis. ChIP and Dual-luciferase assay were utilized to validate interactions of Foxp1/promoters, PVT1/miR-34b-5p and miR-34b-5p/Foxp1. Mouse tumor xenograft model was used to determine the effect of sh-PVT1 on tumor growth in vivo. In this study, we found PVT1 and Foxp1 were elevated in DLBCL tissues and cells while miR-34b-5p was decreased. Knockdown of PVT1, overexpression of miR-34b-5p, or Foxp1 knockdown repressed DLBCL cell proliferation but enhanced cell apoptosis. PVT1 directly bound miR-34b-5p to disinhibit Foxp1/ß-catenin signaling. Foxp1 regulated CDK4, CyclinD1, and p53 expression via binding with their promoters. Knockdown of Foxp1 partially reversed the effects of miR-34b-5p inhibitor on DLBCL cell proliferation and apoptosis. Inhibition of PVT1 through shRNA suppressed DLBCL tumor growth in vivo. All in all, lncRNA PVT1 promotes DLBCL progression via acting as a miR-34b-5p sponge to disinhibit Foxp1/ß-catenin signaling.

MicroRNA­145 promotes the apoptosis of leukemic stem cells and enhances drug­resistant K562/ADM cell sensitivity to adriamycin via the regulation of ABCE1.

Leukemia is a type of cancer which originates in blood­forming tissues. MicroRNAs (miRNAs or miRs) have been shown to be involved leukemogenesis. In the present study, following the gain­ and loss­function of miR­145 and ATP­binding cassette sub­family E member 1 (ABCE1) in K562 cells and K562 adriamycin­resistant cells (K562/ADM cells), the levels of multidrug resistance protein 1 (MRP1) and P­glycoprotein (P­gp) were measured. The viability of the K562 cells and K562/ADM cells treated with various concentrations of ADM, and cell sensitivity to ADM were measured. The apoptosis of stem cells was detected. K562/ADM cells were transfected with miR­145 mimic or with miR­145 mimic together with ABCE1 overexpression plasmid to examine the effects of ABCE1 on the sensitivity of K562/ADM cells to ADM. The association between miR­145 and ABCE1/MRP1 was then verified. The dose­ and time­dependent effects of ADM on the K562 cells and K562/ADM cells were examined. The K562/ADM cells exhibited a greater resistance to ADM, higher levels of MRP1 and P­gp, and a lower miR­145 expression. The K562/ADM cells and stem cells in which miR­145 was overexpressed exhibited a suppressed cell proliferation, decreased MRP1 and P­gp levels, and an increased apoptotic rate. However, K562 cells with a low expression of miR­145 exhibited an increased cell proliferation, increased levels of MRP1 and P­gp, and a suppressed apoptotic rate. Compared with the overexpression of miR­145, the combination of miR­145 and ABCE1 decreased the sensitivity of drug­resistant K562/ADM cells to ADM. The above­mentioned effects of miR­145 were achieved by targeting ABCE1. Taken together, the findings of the present study demonstrate that the overexpression of miR­145 promotes leukemic stem cell apoptosis and enhances the sensitivity of K562/ADM cells to ADM by inhibiting ABCE1.

Management of medically inoperable and tyrosine kinase inhibitor-naïve early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: a retrospective multi-institutional analysis.

BACKGROUND: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for medically inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations has not yet been determined. In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI treatment alone and combined radiation and TKI treatment on the survival outcomes in this patient subgroup. METHODS: A total of 132 cases of medically inoperable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from 5 centers. Among these patients, 65 received combined radiation and EGFR-TKI therapy (R + TKI) (49.2%), while 67 received EGFR-TKI (50.8%) treatment alone. All patients were followed until death. RESULTS: For the R + TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < 0.001). In terms of progression-free survival (PFS), the median PFS in these two treatment groups was 24 months and 14.7 months respectively (log-rank p < 0.001). Multivariate analysis showed that R + TKI was independently associated with improved OS (adjusted HR 0.420; 95% CI 0.287 to 0.614; p < 0.001) and PFS (adjusted HR 0.420; 95% CI 0.291 to 0.605; p < 0.001) compared to TKI alone. Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients. CONCLUSIONS: Upfront radiation to primary sites with subsequent TKI treatment is a feasible option for patients with medically inoperable EGFR-mutant non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with those yielded by TKI treatment alone.

Trends of female and male breast cancer incidence at the global, regional, and national levels, 1990-2017.

PURPOSE: Breast cancer is a major public health concern worldwide and shows significant heterogeneity between male and female. Knowing the global incidence landscape in both sexes is critical for the breast cancer prevention and the reduction in disease burden. METHODS: We retrieved the incidence data of breast cancer in both sexes from the Global Burden of Disease 2017 database. Average annual percentage change was used to quantify the temporal trends of breast cancer incidence. RESULTS: Between 1990 and 2017, the number of newly diagnosed female breast cancer (FBC) cases increased from 870.2 thousand to 1937.6 thousand, with the age-standardized incidence rate (ASR) significantly increased from 39.2/100,000 to 45.9/100,000. A total of 166 countries experienced a significant increase in FBC-ASR. The most pronounced increase was mainly found in developing countries. The decrease was mostly detected in several developed countries, such as the USA and the UK. Male breast cancer (MBC) is a rare carcinoma and has no evident cluster across the world. Worldwide, the number of newly diagnosed MBC cases increased from 8.5 thousand in 1990 to 23.1 thousand in 2017, with the ASR significantly increased from 0.46/100,000 to 0.61/100,000. A total of 123 countries showed a significant increasing trend in MBC-ASR. CONCLUSIONS: Breast cancer incidence rates are increasing in most countries in both sexes, although the epidemiological features were not completely shared between FBC and MBC. More emphases should be placed on breast cancer primary prevention and the prevention strategies might need to be tailored for both FBC and MBC.

Association between variant alleles of major histocompatibility complex class II regulatory genes and nasopharyngeal carcinoma susceptibility.

Major histocompatibility complex (MHC) class II regulatory genes play a paramount role in immune response that can exert a predominant influence on clinical outcome of Epstein-Barr virus infection consistently assumed as the main pathogenetic factor for nasopharyngeal carcinoma. To elucidate the relationship between allelic variants of MHC class II regulatory genes and susceptibility to nasopharyngeal carcinoma, a total of 28 polymorphic loci at MHC class II regulatory genes, involving CIITA, CREB1, RFX family genes (RFX5, RFXAP, and RFXANK), and NFY family genes (NFYA, NFYB, and NFYC), were genotyped by multiplex SNaPshot minisequencing in 137 patients with nasopharyngeal carcinoma and 107 healthy controls from the southern Chinese population. Allelic analysis disclosed that rs7404873, rs6498121, rs6498126, and rs56074043 shared correlations with nasopharyngeal carcinoma (Ptrend < 0.05). Further, rs6498126 on CIITA was independently associated with the risk of developing nasopharyngeal carcinoma (CC vs. GG, odds ratio: 7.386, 95% confidence interval: 1.934-28.207, Ptrend < 0.01). Conversely, rs7404873 on CIITA and rs56074043 on NFYB manifested epistatic interaction to decreased susceptibility of nasopharyngeal carcinoma (rs7404873, TT vs. GG, odds ratio: 0.256, 95% confidence interval: 0.088-0.740, Ptrend < 0.05; rs56074043, AA vs. AG, odds ratio: 0.341, 95% confidence interval: 0.129-0.900, Ptrend < 0.05). Additionally, bioinformatics analysis revealed that the three variants were transcriptional regulatory in function and might impact the expression of nearby genes. The findings suggested genetic variants on MHC class II regulatory genes contributed to nasopharyngeal carcinoma susceptibility and might provide new insights for screening high-risk population.

A retrospective study comparing D1 limited lymph node dissection and D2 extended lymph node dissection for N3 gastric cancer.

BACKGROUND: In countries in East Asia, the typical treatment for curable gastric cancer is gastrectomy with D2 lymphadenectomy. However, whether D2 lymphadenectomy is beneficial for high-risk N3 node disease remains controversial. We conducted a multi-institution retrospective study on patients with high-risk, locally advanced gastric cancer. To compare the rates of disease-free survival (DFS) and overall survival (OS) between radical D2-type gastric resection and lymphadenectomy and the more limited D1 type resection and lymphadenectomy. METHODS: From July 2010 to June 2015, 74 patients out of 949 who underwent curative-intent R0 surgery were selected in pairs to compare the survival outcomes between those who underwent radical D2 type (n=37) vs. the more limited D1 type (n=37) gastric resection and lymphadenectomy. RESULTS: The median DFS was 9.72 and 7.81 months for the D2 and D1 types, respectively (P=0.746), and the OS was 16.39 and 15.85 months for the D2 and D1 types, respectively (P=0.937). CONCLUSIONS: No statistically significant differences in DFS and OS were noted between D1 and D2 procedures for those with N3 disease. Our results support the hypothesis that a novel multidisciplinary approach rather than a surgical approach alone is needed to improve the survival outcomes of high-risk patients with N3 gastric cancer.

Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas.

MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy, and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B-cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (-)-SDS-1-021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.

LncRNA FUNDC2P4 down-regulation promotes epithelial-mesenchymal transition by reducing E-cadherin expression in residual hepatocellular carcinoma after insufficient radiofrequency ablation.

PURPOSE: Hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA) could induce epithelial-mesenchymal transition (EMT) in residual tumours, resulting in rapid and aggressive recurrence. However, the role of EMT-related Long noncoding RNAs (lncRNAs) in residual tumour progression remains unclear. METHODS: Insufficient RFA was simulated in vitro by heating Huh7 cells in water bath at 47 °C, named as Huh7-H. Cell invasion, migration assays and wound healing assay were conducted for functional analysis. Cell proliferation was determined by CCK8 assay. Differential expression profile of EMT-related lncRNAs between Huh7-H and Huh7 was analysed by LncPath human EMT array, and validated by qRT-PCR. Gain/loss-of-function assays of selected lncRNA were conducted by over-expressing or silencing its expression. RESULTS: Huh7-H presented characteristic EMT morphological changes. WB analysis showed significantly decreased E-cadherin in Huh7-H cells. Transwell assays indicated the abilities of Huh7-H cells in migration and invasion were evidently strengthened. A new lncRNA, FUNDC2P4, was identified by LncPath human EMT array to be significantly down-regulated in Huh7-H cells. In vitro studies showed overexpression of FUNDC2P4 inhibited proliferation, invasion and migration potential and up-regulated E-cadherin expression in SMMC-7721 cells, whereas silencing FUNDC2P4 promoted these potentials and down-regulated E-cadherin expression in Huh7 cells. CONCLUSIONS: We explored that lncRNA FUNDC2P4 down-regulation promoted EMT leading to tumour proliferation, invasion and migration by reducing E-cadherin expression in residual HCC after insufficient RFA in vitro. These results suggest that FUNDC2P4 may have potentially therapeutic value for prevention and treatment of HCC recurrence after RFA in the future.

Apatinib alone or combined with radiotherapy in metastatic prostate cancer: Results from a pilot, multicenter study.

BACKGROUND: To study safety and efficacy of apatinib in combination of radiotherapy in patients with symptomatic bony disease prostate cancer(SBPC), based on the potential synergistic antitumor activity between apatinib and Radiation Therapy (RT). PATIENTS AND METHODS: In phase I dose escalation part, 18 patients received apatinib dose at 250 mg every other day, 250 mg daily and 500 mg daily. In phase II part, the 250 mg daily cohorts were expanded to 20 patients in combination of RT (6 Gy/fraction, 5 fraction in total), one patient lost followed up and excluded the study, comparing with RT alone cohort with 10 patients, ratio of RT to RT + apatinib was 1 to 2. Evaluations included adverse events (AEs), prostate specific antigen (PSA) changes, radiographic evaluation and pain relief. RESULTS: In phase I study, common apatinib-related AEs (arAEs) were fatigue, anorexia, hand foot syndrome, proteinuria, and hypertension (HTN). Grade 3arAEs included HTN, proteinuria, liver dysfunction. In phase II study, combination apatinib with RT cohorts, AEs events increased comparing with either apatinib alone or RT alone; at the same time, combination cohorts showed PSA declines of ≥50% in 12 patients, and stable disease in 6 patients. Combination cohorts had pain control significantly improved in both level and duration comparing with RT alone. CONCLUSIONS: In SBPC patients, apatinib at less than 500 mg daily dose as mono-therapy had tolerable toxicity. Apatinib at dose of 250 mg daily in combining with RT synergized pain control, the overall AEs were manageable. Further studies are needed in large sample size future trials.

The metronomic therapy with prednisone, etoposide, and cyclophosphamide reduces the serum levels of VEGF and circulating endothelial cells and improves response rates and progression-free survival in patients with relapsed or refractory non-Hodgkin's lymphoma.

PURPOSE: There is an urgent need for a better strategy in the management of relapsed or refractory non-Hodgkin's lymphoma (NHL). The present study was designed to evaluate the efficacy and safety of the regimen using metronomic prednisone, etoposide, and cyclophosphamide in the treatment of patients with relapsed or refractory NHL, in comparison with conventional salvage chemotherapy. METHODS: Eligible patients were randomized to the test group (n = 23) receiving metronomic prednisone, etoposide, and cyclophosphamide or the control group (n = 21) receiving conventional salvage chemotherapy. The serum levels of circulating endothelial cells (CECs) and vascular endothelial growth factor (VEGF) were measured before and after two cycles of treatment; overall response rate (ORR) and disease control rate (DCR) were evaluated at cycles 2, 4, 6, and 12 months after treatment. RESULTS: After two cycles of treatment, the ORRs of the test and control groups were statistically similar, while the DCR of the test group (87.0 %) was significantly higher than that of the control group (57.1 %). At 12 months after treatment, the ORR and DCR of the test group (47.8 and 69.6 %, respectively) were significantly higher than that of the control group (19.0 and 33.3 %, respectively). The serum CECs and VEGF levels in the test group after treatment were significantly lower than that before treatment or that of the control group. In the patients with ORR and DCR in the test group, the serum CECs and VEGF levels remained relatively low at cycles 2, 4, and 6 and at 12 months after treatment. There was a progression-free survival (PFS) benefit of 6.5 months in the test group, compared with the control group. CONCLUSION: Metronomic chemotherapy with prednisone, etoposide, and cyclophosphamide resulted in higher ORR and DCR, fewer adverse effects, and longer PFS in patients with relapsed or refractory NHL, with significant reduction in serum CECs and VEGF levels.

Clinical efficacy of metronomic chemotherapy after cool-tip radiofrequency ablation in the treatment of hepatocellular carcinoma.

PURPOSE: Anti-angiogenic agents have shown promise for treating advanced hepatocellular carcinoma (HCC), and the primary mechanism of low-dose metronomic chemotherapy using traditional cytotoxic drugs is anti-angiogenic. This study evaluated the efficacy of metronomic capecitabine and thalidomide after cool-tip radiofrequency ablation (RFA), relative to RFA alone, for treating patients with HCC. METHODS AND MATERIALS: Patients with HCC were randomly apportioned to a test group (n = 22) receiving metronomic chemotherapy with capecitabine and thalidomide after RFA, or a control group (n = 28) receiving RFA only. Serum circulating endothelial cells (CECs) and vascular endothelial growth factor (VEGF) were measured in all patients before and 1 month after RFA treatment. Enhanced computed tomography or ultrasound imaging was performed to evaluate efficacy during 12 months of follow-up. The treatment groups were further stratified as HCC within or outside the Milan criteria for transplantation. RESULTS: One month post-treatment, the tumour response rate (TRR), including complete response and partial response rate, of the test and control groups was statistically similar. At 12 months, the TRR of the test group (68.2%) was significantly higher than that of the control group (35.7%). In the test group, the TRR of patients whose tumour burdens were outside the Milan criteria was significantly higher than that of the control group. One month post-treatment, CECs and VEGF levels of the test group were significantly lower than baseline, while those of the control group were significantly higher. At the end of the 12-month follow-up, there was a progression-free survival (PFS) benefit of 2 months in the test group. CONCLUSION: Metronomic capecitabine and thalidomide after RFA significantly reduced recurrence of HCC and extended PFS, especially for HCC outside the Milan criteria, perhaps via reduction of serum CECs and VEGF levels and inhibition of tumour angiogenesis.