Efficacy and safety of CD19 CAR-T cell therapy for acute lymphoblastic leukemia patients relapsed after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for B-cell acute lymphoblastic leukemia (B-ALL). Although allo-HSCT can be curative for some B-ALL patients, relapse still occurs in some patients following allo-HSCT. Conventional chemotherapies show poor efficacy in B-ALL patients who have relapsed following allo-HSCT. In the past decade, chimeric antigen receptor T-cell (CAR-T) therapy has shown to be efficacious for B-ALL patients. In particular, autologous CD19 CAR-T therapy results in a high remission rate. However, there are challenges in the use of CD19 CAR-T therapy for B-ALL patients who have relapsed following allo-HSCT, including the selection of CAR-T cell source for manufacturing, post-CAR-T graft-versus-host disease (GVHD) risk, maintenance of long-term efficacy after remission through CAR-T therapy, and whether a consolidative second transplant is needed. In this review, we describe the current status of CAR-T therapy for B-ALL patients who have relapsed following allo-HSCT, the advantages and disadvantages of various CAR-T cell sources, the characteristics and management of GVHD following CAR-T therapy, and the risk factors that may affect long-term efficacy.

AKR1C1 promotes non-small cell lung cancer proliferation via crosstalk between HIF-1α and metabolic reprogramming.

Non-small cell lung cancer (NSCLC) ranks first among cancer death worldwide. Despite efficacy and safety priority, targeted therapy only benefits ∼30% patients, leading to the unchanged survival rates for whole NSCLC patients. Metabolic reprogramming occurs to offer energy and intermediates for fuelling cancer cells proliferation. Thus, mechanistic insights into metabolic reprogramming may shed light upon NSCLC proliferation and find new proper targets for NSCLC treatment. Herein, we used loss- and gain-of-function experiments to uncover that highly expressed aldo-keto reductase family1 member C1 (AKR1C1) accelerated NSCLC cells proliferation via metabolic reprogramming. Further molecular profiling analyses demonstrated that AKR1C1 augmented the expression of hypoxia-inducible factor 1-alpha (HIF-1α), which could drive tumour metabolic reprogramming. What's more, AKR1C1 significantly correlated with HIF-1α signaling, which predicted poor prognosis for NSCLC patients. Collectively, our data display that AKR1C1 reprograms tumour metabolism to promote NSCLC cells proliferation by activating HIF-1α. These newly acquired data not only establish the specific role for AKR1C1 in metabolic reprogramming, but also hint to the possibility that AKR1C1 may be a new therapeutic target for NSCLC treatment.

AKR1C1 connects autophagy and oxidative stress by interacting with SQSTM1 in a catalytic-independent manner.

Targeting autophagy might be a promising anticancer strategy; however, the dual roles of autophagy in cancer development and malignancy remain unclear. NSCLC (non-small cell lung cancer) cells harbour high levels of SQSTM1 (sequestosome 1), the autophagy receptor that is critical for the dual roles of autophagy. Therefore, mechanistic insights into SQSTM1 modulation may point towards better approaches to treat NSCLC. Herein, we used multiple autophagy flux models and autophagy readouts to show that aldo-keto reductase family 1 member C1 (AKR1C1), which is highly expressed in NSCLC, promotes autophagy by directly binding to SQSTM1 in a catalytic-independent manner. This interaction may be strengthened by reactive oxygen species (ROS), important autophagy inducers. Further mechanistic research demonstrated that AKR1C1 interacts with SQSTM1 to augment SQSTM1 oligomerization, contributing to the SQSTM1 affinity for binding cargo. Collectively, our data reveal a catalytic-independent role of AKR1C1 for interacting with SQSTM1 and promoting autophagy. All these findings not only reveal a novel functional role of AKR1C1 in the autophagy process but also indicate that modulation of the AKR1C1-SQSTM1 interaction may be a new strategy for targeting autophagy.

Hematopoietic stem cell transplantation activity in China 2019: a report from the Chinese Blood and Marrow Transplantation Registry Group.

Between 2008 and 2019, 58,914 hematopoietic stem cell transplantations (HSCTs) were reported to the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) throughout China. In this report, we focus on 2019 data and describe current trends in HSCT in China. There was continued growth in transplant activity in China, with a rapid increase in haploidentical HSCT. In 2019, a total of 12,323 cases of HSCT were reported from 149 transplant teams, 78% (9597 cases) were allogeneic HSCTs. Haploidentical donor (HID) HSCT accounted for 60% (5771 cases) of allogeneic HSCT. The most common indications for allogeneic HSCT for malignant disease were acute myeloid leukemia (AML) (37%) and acute lymphoblastic leukemia (ALL) (24%), and the largest proportion of non-malignant diseases comprised aplastic anemia (AA) (13%). Multiple stem cell source composed 70% of HID and 28% of MSD, which was typical in China. The BuCy based regimen (59%) was the most popular conditioning regimen for allogeneic HSCT, followed by the BuFlu based regimen (23%) and TBI-based regimen (12%). This survey clearly shows comprehensive information about the current state and recent trends for HSCT in China. Further efforts should be made to obtain detailed information.

Dissecting the Conformational Dynamics of the Bile Acid Transporter Homologue ASBTNM.

Apical sodium-dependent bile acid transporter (ASBT) catalyses uphill transport of bile acids using the electrochemical gradient of Na+ as the driving force. The crystal structures of two bacterial homologues ASBTNM and ASBTYf have previously been determined, with the former showing an inward-facing conformation, and the latter adopting an outward-facing conformation accomplished by the substitution of the critical Na+-binding residue glutamate-254 with an alanine residue. While the two crystal structures suggested an elevator-like movement to afford alternating access to the substrate binding site, the mechanistic role of Na+ and substrate in the conformational isomerization remains unclear. In this study, we utilized site-directed alkylation monitored by in-gel fluorescence (SDAF) to probe the solvent accessibility of the residues lining the substrate permeation pathway of ASBTNM under different Na+ and substrate conditions, and interpreted the conformational states inferred from the crystal structures. Unexpectedly, the crosslinking experiments demonstrated that ASBTNM is a monomer protein, unlike the other elevator-type transporters, usually forming a homodimer or a homotrimer. The conformational dynamics observed by the biochemical experiments were further validated using DEER measuring the distance between the spin-labelled pairs. Our results revealed that Na+ ions shift the conformational equilibrium of ASBTNM toward the inward-facing state thereby facilitating cytoplasmic uptake of substrate. The current findings provide a novel perspective on the conformational equilibrium of secondary active transporters.

BRDT promotes ovarian cancer cell growth.

Bromodomain testis-specific factor (BRDT) is a member of the bromodomain and extra-terminal (BET) family proteins. Its expression and potential functions in ovarian cancer were examined. We show that BRDT is overexpressed in human ovarian cancer tissues and in established (CaOV3)/primary ovarian cancer cells. However, its expression is low in ovarian epithelial tissues and cells. Significantly, shRNA-induced silencing or CRISPR/Cas9-mediated knockout of BRDT inhibited ovarian cancer cell growth, viability, proliferation and migration, and induced significant apoptosis activation. Conversely, exogenous overexpression of BRDT, by a lentiviral construct, augmented CaOV3 cell proliferation and migration. In CaOV3 cells expression of two key BRDT target genes, polo-like kinase 1 (PLK1) and aurora kinase C (AURKC), was downregulated by BRDT shRNA or knockout, but upregulated with BRDT overexpression. In vivo, xenograft tumors-derived from BRDT-knockout CaOV3 cells grew significantly slower than control tumors in severe combined immunodeficient (SCID) mice. Furthermore, intratumoral injection of BRDT shRNA lentivirus potently inhibited the growth of primary ovarian cancer xenografts in SCID mice. Downregulation of PLK1 and AURKC was detected in BRDT-knockout and BRDT-silenced tumor tissues. Collectively, BRDT overexpression promotes ovarian cancer cell progression. Targeting BRDT could be a novel strategy to treat ovarian cancer.

Real-World Issues and Potential Solutions in Hematopoietic Cell Transplantation during the COVID-19 Pandemic: Perspectives from the Worldwide Network for Blood and Marrow Transplantation and Center for International Blood and Marrow Transplant Research Health Services and International Studies Committee.

The current COVID-19 pandemic, caused by SARS-CoV-2, has impacted many facets of hematopoietic cell transplantation (HCT) in both developed and developing countries. Realizing the challenges as a result of this pandemic affecting the daily practice of the HCT centers and the recognition of the variability in practice worldwide, the Worldwide Network for Blood and Marrow Transplantation (WBMT) and the Center for International Blood and Marrow Transplant Research's (CIBMTR) Health Services and International Studies Committee have jointly produced an expert opinion statement as a general guide to deal with certain aspects of HCT, including diagnostics for SARS-CoV-2 in HCT recipient, pre- and post-HCT management, donor issues, medical tourism, and facilities management. During these crucial times, which may last for months or years, the HCT community must reorganize to proceed with transplantation activity in those patients who urgently require it, albeit with extreme caution. This shared knowledge may be of value to the HCT community in the absence of high-quality evidence-based medicine. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Advances in the development of chimeric antigen receptor-T-cell therapy in B-cell acute lymphoblastic leukemia.

CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy is effective in refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL). This review focuses on achievements, current obstacles, and future directions in CAR-T research. A high complete remission rate of 68% to 93% could be achieved after anti-CD19 CAR-T treatment for B-ALL. Cytokine release syndrome and CAR-T-related neurotoxicity could be managed. In view of difficulties collecting autologous lymphocytes, universal CAR-T is a direction to explore. Regarding the high relapse rate after anti-CD19 CAR-T therapy, the main solutions have been developing new targets including CD22 CAR-T, or CD19/CD22 dual CAR-T. Additionally, some studies showed that bridging into transplant post-CAR-T could improve leukemia-free survival. Some patients who did not respond to CAR-T therapy were found to have an abnormal conformation of the CD19 exon or trogocytosis. Anti-CD19 CAR-T therapy for R/R B-ALL is effective. From individual to universal CAR-T, from one target to multi-targets, CAR-T-cell has a chance to be off the shelf in the future.

The Importance of a Conjoint Analysis of Tumor-Associated Macrophages and Immune Checkpoints in Pancreatic Cancer.

OBJECTIVES: Tumor-associated macrophages are dominant players in establishing the inmmunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC). Immune checkpoint inhibitor monotherapy has achieved limited clinical effectiveness. To date, the interaction of macrophages and checkpoint regulators and their correlation with clinicopathologic characteristics in PDAC have been largely unavailable. METHODS: Macrophages and immune checkpoint expression were assessed by immunohistochemistry from 80 PDAC samples. Clinicopathologic features and the prognostic value of each marker were evaluated. In vitro changes in the expression of immune markers in cocultured macrophages and PDAC cells were detected by Western blot and immunosorbance assays. RESULTS: The macrophages marker CD163 and the checkpoint marker programmed death-ligand 1 (PD-L1) remained as the independent prognostic factors for overall survival (hazard ratio, 2.543; P = 0.017 and hazard ratio, 2.389; P = 0.021). Furthermore, integrated analysis of CD163 and PD-L1 served as more optimal indicators of survival (P = 0.000). In vitro coculture of macrophages and PDAC cells significantly increased the expression of CD163 and PD-L1, compared with monocultured counterpart (P < 0.05). CONCLUSIONS: Combined analysis of CD163 and PD-L1 was enhanced indicators of survival in PDAC patients. The interaction of macrophages and immune checkpoints implied the value of the combination therapy.

Triptonide inhibits human nasopharyngeal carcinoma cell growth via disrupting Lnc-RNA THOR-IGF2BP1 signaling.

Advanced stage nasopharyngeal carcinoma (NPC) has a poor prognosis. Triptonide ("TN") is a small molecule monomer extract from the ancient Chinese herb Tripterygium wilfordii Hook. We show that TN, at nanomolar concentrations, potently inhibited survival and proliferation of multiple established and primary human NPC cells. TN induced NPC cell cycle arrest and apoptosis activation. NPC cell migration and invasion were also inhibited by TN. Importantly, TN was non-cytotoxic to nasopharyngeal epithelial cells. TN treatment in NPC cells disrupted LncRNA THOR ("Lnc-THOR")-IGF2BP1 association, causing depletion of Lnc-THOR and downregulation of IGF2BP1 mRNA targets (Myc, IGF2 and Gli1). Lnc-THOR or IGF2BP1 knockout by CRISPR/Cas9 gene-editing methods mimicked and abolished TN's actions in NPC cells. Conversely, ectopic Lnc-THOR overexpression inhibited TN-induced cytotoxicity in NPC cells. Significantly, Lnc-THOR, IGF2BP1 and its mRNA targets are elevated in human NPC tissues and cells, but almost undetectable in nasopharyngeal epithelial tissues and cells. In vivo, intraperitoneal TN administration significantly inhibited subcutaneous NPC xenograft growth in mice. Similarly, Lnc-THOR-knockout HONE-1 xenografts grew significantly slower than control tumors. Thus, TN inhibits human NPC cell growth in vitro and in vivo via disrupting Lnc-THOR-IGF2BP1 signaling.

Challenges in managing graft-versus-host disease in developing countries: a perspective.

Hematopoietic cell transplant (HCT) activity is increasing worldwide due to safer techniques, widening indications, and more availability of donors. New HCT centers have recently been established in many developing countries including Asian and African countries. Due to limited resources, logistic, political, and social issues in developing countries, the treatment of orphan diseases like graft-versus-host disease (GVHD) can be challenging. We intended to delineate the current issues that institutions and clinicians face in managing GVHD. We conducted a comprehensive systematic electronic review of peer-reviewed published articles on GVHD management in developing countries. We used PubMed, Cochrane, and Embase databases as our primary source of data. Studies that were included described the treatments for both acute and chronic GVHD. Consensus on the use of high-dose methyl-prednisone and prednisolone as the initial therapy was widely accepted and used in practice. Socio-economic factors were found to be the major factor involved in GVHD management in lower income patients. Delayed diagnosis and treatment, lack of availability of healthcare professionals, lack of knowledge among cancer patients, and poverty are major concerns in the developing world. For optimal management, HCT programs should develop systems in place for long-term follow-up of HCT survivors and have a low threshold to initiate treatments for GVHD early. Awareness and health policy programs must be initiated at the grass-root level for long-term management of these survivors in developing countries.

Molecular mechanism of panaxydol on promoting axonal growth in PC12 cells.

Nerve growth factor (NGF) promotes axonal growth in PC12 cells primarily by regulating the RTK-RAS-MEK-ERK pathway. Panaxydol, a polyacetylene isolated from Panax notoginseng, can mimic the effects of NGF. Panaxydol promotes neurite outgrowth in PC12 cells, but its molecular mechanism remains unclear. Indeed, although alkynol compounds such as panaxydol can increase intracellular cyclic adenosine 3',5'-monophosphate (cAMP) levels and the ERK inhibitor U0126 inhibits alkynol-induced axonal growth, how pathways downstream of cAMP activate ERK have not been investigated. This study observed the molecular mechanism of panaxydol-, NGF- and forskolin-induced PC12 cell axon growth using specific signaling pathway inhibitors. The results demonstrated that although the RTK inhibitor SU5416 obviously inhibited the growth-promoting effect of NGF, it could not inhibit the promoting effect of panaxydol on axonal growth of PC12 cells. The adenylate cyclase inhibitor SQ22536 and cAMP-dependent protein kinase inhibitor RpcAMPS could suppress the promoting effect of forskolin and panaxydol on axonal growth. The ERK inhibitor U0126 inhibited axonal growth induced by all three factors. However, the PKA inhibitor H89 inhibited the promoting effect of forskolin on axonal growth but could not suppress the promoting effect of panaxydol. A western blot assay was used to determine the effects of stimulating factors and inhibitors on ERK phosphorylation levels. The results revealed that NGF activates the ERK pathway through tyrosine receptors to induce axonal growth of PC12 cells. In contrast, panaxydol and forskolin increased cellular cAMP levels and were inhibited by adenylyl cyclase inhibitors. The protein kinase A inhibitor H89 completely inhibited forskolin-induced axonal outgrowth and ERK phosphorylation, but could not inhibit panaxydol-induced axonal growth and ERK phosphorylation. These results indicated that panaxydol promoted axonal growth of PC12 cells through different pathways downstream of cAMP. Considering that exchange protein directly activated by cAMP 1 (Epac1) plays an important role in mediating cAMP signaling pathways, RNA interference experiments targeting the Epac1 gene were employed. The results verified that Epac1 could mediate the axonal growth signaling pathway induced by panaxydol. These findings suggest that compared with NGF and forskolin, panaxydol elicits axonal growth through the cAMP-Epac1-Rap1-MEK-ERK-CREB pathway, which is independent of PKA.

Itraconazole-Induced Inhibition on Human Esophageal Cancer Cell Growth Requires AMPK Activation.

We here evaluated the antiesophageal cancer cell activity by the antifungal drug itraconazole. Our results show that µg/mL concentrations of itraconazole potently inhibited survival and proliferation of established (TE-1 and Eca-109) and primary human esophageal cancer cells. Itraconazole activated AMPK signaling, which was required for subsequent esophageal cancer cell death. Pharmacologic AMPK inhibition, AMPKα1 shRNA, or dominant negative mutation (T172A) almost completely abolished itraconazole-induced cytotoxicity against esophageal cancer cells. Significantly, itraconazole induced AMPK-dependent autophagic cell death (but not apoptosis) in esophageal cancer cells. Furthermore, AMPK activation by itraconazole induced multiple receptor tyrosine kinases (RTKs: EGFR, PDGFRα, and PDGFRß), lysosomal translocation, and degradation to inhibit downstream Akt activation. In vivo, itraconazole oral gavage potently inhibited Eca-109 tumor growth in SCID mice. It was yet ineffective against AMPKα1 shRNA-expressing Eca-109 tumors. The in vivo growth of the primary human esophageal cancer cells was also significantly inhibited by itraconazole administration. AMPK activation, RTK degradation, and Akt inhibition were observed in itraconazole-treated tumors. Together, itraconazole inhibits esophageal cancer cell growth via activating AMPK signaling. Mol Cancer Ther; 17(6); 1229-39. ©2018 AACR.

Prognostic value of CD146 in solid tumor: A Systematic Review and Meta-analysis.

CD146, also known as melanoma cell adhesion molecule, was initially identified as a marker of melanoma progression and metastasis. Recently many clinical studies investigated overexpression of CD146 predict poor prognosis of solid tumor, however, the results was inconclusive, partly due to small numbers of patients included. This present meta-analysis was therefore performed utilizing the results of all clinical studies concerned to determine the prognostic value of CD146 expression in solid tumors. Relevant articles were identified through searching the PubMed, Web of Science and Embase database. In this meta-analysis, 12 studies involving 2,694 participants were included, and we drew the conclusion that strong significant associations between CD146 expression and all endpoints: overall survival (OS) [hazard ratio (HR) = 2.496, 95% confidence interval (95% CI) 2.115-2.946], time to progression (TTP) (HR = 2.445, 95% CI 1.975-3.027). Furthermore, the subgroup analysis revealed that the associations between CD146 overexpression and the outcome endpoints (OS or TTP) were significant in Mongoloid patients and Caucasian patients, as well in patients with lung cancer and digestive system cancer. In conclusion, these results showed that high CD146 was associated with poor survival in human solid tumors. CD146 may be a valuable prognosis predictive biomarker; nevertheless, whether CD146 could be a potential therapeutic target in human solid tumors needs to be further studied.

Identification of DNA-PKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells.

The current study tested the anti-hepatocellular carcinoma (HCC) cell activity of TIC10, a first-in-class small-molecule tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) inducer. TIC10 exerted potent anti-proliferative and pro-apoptotic actions in primary and established human HCC cells. TIC10 blocked Akt-Erk activation, leading to Foxo3a nuclear translocation, as well as TRAIL and death receptor-5 (DR5) transcription in HCC cells. We propose that DNA-PKcs is a major resistance factor of TIC10 possibly via inhibiting Foxo3a nuclear translocation. DNA-PKcs inhibition, knockdown or mutation facilitated TIC10-induced Foxo3a nuclear translocation, TRAIL/DR5 expression and cell apoptosis. Reversely, exogenous DNA-PKcs over-expression inhibited above actions by TIC10. In vivo, oral administration of TIC10 significantly inhibited HepG2 tumor growth in nude mice, which was further potentiated with Nu7026 co-administration. Thus, TIC10 shows promising anti-HCC activity, alone or together with DNA-PKcs inhibitors.

AMPKα phosphatase Ppm1E upregulation in human gastric cancer is required for cell proliferation.

Activation of AMP-activated protein kinase (AMPK) is a valuable anti-cancer strategy. In the current study, we tested expression and potential function of Ca2+/calmodulin-dependent protein kinase phosphatase (Ppm1E), an AMPKα phosphatase, in human gastric cancers. Ppm1E expression was elevated in human gastric cancer tissues (vs. normal tissues), which was correlated with AMPK (p-AMPKα, Thr-172) dephosphorylation and mTOR complex 1 (mTORC1) activation. Ppm1E upregulation, AMPK inhibition and mTORC1 activation were also observed in human gastric cancer cell lines (AGS, HGC-27, and SNU601). Intriguingly, Ppm1E knockdown by shRNA induced AMPK activation, mTORC1 inactivation, and proliferation inhibition in AGS cells. On the other hand, forced over-expression of Ppm1E induced further AMPK inhibition and mTORC1 activation to enhance AGS cell proliferation. Remarkably, microRNA-135b-5p ("miR-135b-5p"), an anti-Ppm1E microRNA, was downregulated in both human gastric cancer tissues and cells. Reversely, miR-135b-5p exogenous expression caused Ppm1E depletion, AMPK activation, and AGC cell proliferation inhibition. Together, Ppm1E upregulation in human gastric cancer is important for cell proliferation, possible via regulating AMPK-mTOR signaling.

Identification of sphingosine kinase 1 (SphK1) as a primary target of icaritin in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is a highly aggressive neoplasm. We aim to explore the anti-HCC activity by a natural prenylflavonoid icaritin. Icaritin was cytotoxic and pro-apoptotic when added to established (HepG2, KYN-2 and Huh-7 lines) and primary human HCC cells. At the signaling level, icaritin inhibited sphingosine kinase 1 (SphK1) activity in HCC cells, which led to pro-apoptotic ceramide production and JNK1 activation. SphK1 inhibition or silence (by shRNA/microRNA) mimicked icaritin-mediated cytotoxicity, and almost nullified icaritin's activity in HepG2 cells. Reversely, exogenous over-expression of SphK1 sensitized icaritin-induced HepG2 cell apoptosis. In vivo, oral administration of icaritin dramatically inhibited HepG2 xenograft growth in SCID mice. Further, SphK1 activity in icaritin-treated tumors was largely inhibited. In summary, icaritin exerts potent anti-HCC activity in vitro and in vivo. SphK1 inhibition could be the primary mechanism of its actions in HCC cells.

Tetraspanin CD151 as an emerging potential poor prognostic factor across solid tumors: a systematic review and meta-analysis.

Tetraspanin CD151, also known as PETA-3 or SFA-1, has been reported to predict prognosis in various solid tumors. Yet, the results of these studies remained inconclusive. Here, we performed this meta-analysis of relevant studies published on the topic to quantitatively evaluate the clinicopathological significance of CD151 in solid tumors. The relevant articles were identified via searching the PubMed, Web of Science and Embase database. The pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CI) of overall survival (OS) and disease-free survival (DFS) were calculated to evaluate the prognostic value of CD151 expression in patients with solid tumors. A total of 19 studies involving 4, 270 participants were included in the study, we drew the conclusion that CD151 overexpression was associated with statistically significant poor OS (pooled HR = 1.498, 95% CI = 1.346-1.667, P<0.001) and poor DFS (pooled HR = 1.488, 95% CI = 1.314-1.685, P<0.001). Furthermore, the subgroup analysis revealed that the associations between CD151 overexpression and the outcome endpoints (OS or TTP) were significant within the Asian region and European, as well in patients with breast cancer or gastric cancer. Taken together, the incorporative HR showed CD151 overexpression was associated with poor survival in human solid tumors. CD151 could be a valuable prognosis biomarker or a potential therapeutic target of solid tumors.

Impact of TROP2 expression on prognosis in solid tumors: A Systematic Review and Meta-analysis.

Over-expression of TROP2 (the trophoblast cell surface antigen 2) was reported to predict poor prognosis in various solid tumors in number of studies. However, the results remained not comprehensive. Therefore, we here carried out this meta-analysis of relevant studies published on this topic to quantitatively evaluate the clinicopathological significance of TROP2 in solid tumors. Relevant articles were identified through searching the PubMed, Web of Science and Embase database. The primary outcomes were overall survival (OS) and disease-free survival (DFS). In this meta-analysis, 16 studies involving 2,569 participants were included, and we drew the conclusion that TROP2 overexpression was significantly associated with poor OS (pooled HR = 1.896, 95% CI = 1.599-2.247, P < 0.001) and short DFS (pooled HR = 2.336, 95% CI = 1.596-3.419, P < 0.001). Furthermore, the subgroup analysis revealed that the associations between TROP2 overexpression and the outcome endpoints (OS or DFS) were significant in in patients with female genital system neoplasms, as well in gastrointestine neoplasms. In addition, subgroup analysis found no difference HR across populations of different descent.Taken together, TROP2 overexpression was associated with poor survival in human solid tumors. TROP2 may be a valuable prognosis predictive biomarker and a potential therapeutic target in human solid tumors.

Aqueous Oldenlandia diffusa extracts inhibits colorectal cancer cells via activating AMP-activated protein kinase signalings.

Here we evaluated the anti-cancer activity of aqueous Oldenlandia diffusa (OD) extracts (ODE) in colorectal cancer (CRC) cells. We showed that ODE exerted potent anti-proliferative, cytotoxic and pro-apoptotic activities against a panel of established CRC lines (HCT-116, DLD-1, HT-29 and Lovo) and primary (patient-derived) human CRC cells. ODE activated AMP-activated protein kinase (AMPK) signaling, which led to subsequent mTORC1 inhibition and Bcl-2/HIF-1α downregulation in CRC cells. In ODE-treated CRC cells, AMPKα1 formed a complex with p53. This might be important for p53 activation and subsequent cancer cell apoptosis. Inhibition of AMPK signaling, though dominant negative (dn) mutation or shRNA/siRNA knockdown of AMPKα1 attenuated ODE-exerted CRC cytotoxicity. In vivo, i.p. administration of ODE inhibited HCT-116 xenograft tumor growth in SCID mice. In addition, AMPK activation, mTORC1 inhibition and p53 activation were observed in ODE-treated HCT-116 xenograft tumors. These results suggest that ODE inhibits CRC cells in vitro and in vivo, possibly via activation of AMPK-dependent signalings.