m6A modification: recent advances, anticancer targeted drug discovery and beyond.

Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future.

Preparation and Characterization of Protein Molecularly Imprinted Poly (Ionic Liquid)/Calcium Alginate Composite Cryogel Membrane with High Mechanical Strength for the Separation of Bovine Serum Albumin.

In order to improve the mechanical strength and imprinting efficiency, a novel bovine serum albumin (BSA) molecularly imprinted poly(ionic liquid)/calcium alginate composite cryogel membrane (MICM) was prepared. The results of the tensile test indicated that the MICM had excellent mechanical strength which could reach up to 90.00 KPa, 30.30 times higher than the poly (ionic liquid) membrane without calcium alginate; the elongation of it could reach up to 93.70%, 8.28 times higher than the poly (ionic liquid) membrane without calcium alginate. The MICM had a very high welling ratio of 1026.56% and macropore porosity of 62.29%, which can provide effective mass transport of proteins. More remarkably, it had a very high adsorption capacity of 485.87 mg g-1 at 20 °C and 0.66 mg mL-1 of the initial concentration of BSA. Moreover, MICM also had good selective and competitive recognition toward BSA, exhibiting potential utility in protein separation. This work can provide a potential method to prepare the protein-imprinted cryogel membrane with both high mechanical strength and imprinting efficiency.

CDC20 and its downstream genes: potential prognosis factors of osteosarcoma.

BACKGROUND: We investigated the microarray data GSE42352 to identify genes that can be used as prognosis factors in osteosarcoma. METHODS: Gene Ontology (GO) biological process analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of Cytoscape ClueGo were used in verifying the function of different genes. Realtime-PCR were used to confirm the microarray results. 83 patient samples were collected and underwent Kaplan-Meier survival analysis and multivariate analysis to predict the prospect of genes using as prognosis factors. RESULTS: After analyzing the microarray data GSE42352, mitosis metaphase to anaphase-related genes CDC20, securin, cyclin A2 and cyclin B2 were found to be overexpressed in osteosarcoma cell lines. Kaplan-Meier survival analysis showed that overexpression of these genes can predict poor prognosis outcomes in osteosarcoma patients. Furthermore, any combination of the four genes seems to be more effective in predicting osteosarcoma outcomes than any of these genes alone. CONCLUSIONS: CDC20 and its downstream substracts securin, cyclin A2 and cyclin B2 are good factors that can predict prognosis outcomes in osteosarcoma. Any two combination of these four genes are more effective to be used as osteosarcoma prognosis factors.

Arenobufagin induces MCF-7 cell apoptosis by promoting JNK-mediated multisite phosphorylation of Yes-associated protein.

BACKGROUND: It has been demonstrated that bufadienolides exert potent anti-cancer activity in various tumor types. However, the mechanisms that underlie their anti-cancer properties remain unclear. Yes-associated protein, a key effector of Hippo signaling, functions as a transcription coactivator, plays oncogenic and tumor suppressor roles under different conditions. Here, we report that arenobufagin (ABF), a representative bufadienolide, induced breast cancer MCF-7 cells to undergo apoptosis, which occurred through the JNK-mediated multisite phosphorylation of YAP. METHODS: Cytotoxicity was examined using an MTT assay. ABF-induced apoptosis was measured with a TUNEL assay and Annexin V-FITC/PI double staining assay. Western blotting, immunofluorescence, qRT-PCR and coimmunoprecipitation were employed to assess the expression levels of the indicated molecules. Lose-of-function experiments were carried out with siRNA transfection and pharmacological inhibitors. ABF-induced phosphopeptides were enriched with Ti4+-IMAC chromatography and further subjected to reverse-phase nano-LC-MS/MS analysis. RESULTS: ABF significantly reduced the viability of MCF-7 cells and increased the percentage of early and late apoptotic cells in a concentration- and time-dependent manner. Following ABF treatment, YAP accumulated in the nucleus and bound to p73, which enhanced the transcription of the pro-apoptotic genes Bax and p53AIP1. YAP knock-down significantly attenuated ABF-induced apoptotic cell death. Importantly, we found that the mobility shift of YAP was derived from its phosphorylation at multiple sites, including Tyr357. Moreover, mass spectrometry analysis identified 19 potential phosphorylation sites in YAP, with a distribution of 14 phosphoserine and 5 phosphothreonine residues. Furthermore, we found that the JNK inhibitor SP600125 completely diminished the mobility shift of YAP and its phosphorylation at Tyr357, the binding of YAP and p73, the transcription of Bax and p53AIP1 as well as the apoptosis induced by ABF. These data indicate that ABF induced YAP multisite phosphorylation, which was associated with p73 binding, and that apoptosis was mediated by the JNK signaling pathway. CONCLUSIONS: Our data demonstrate that ABF suppresses MCF-7 breast cancer proliferation by triggering the pro-apoptotic activity of YAP, which is mediated by JNK signaling-induced YAP multisite phosphorylation as well as its association with p73. The present work not only provides additional information on the use of ABF as an anti-breast cancer drug, but also offers evidence that the induction of the tumor suppressor role of YAP may be a therapeutic strategy.

Incidence, clinical characteristics, and outcome of interstitial pneumonia in patients with lymphoma.

Interstitial pneumonia (IP) is a lethal complication in lymphoma patients undergoing chemotherapy. A total of 2212 consecutive patients diagnosed with lymphoma between 2009 and 2014 were enrolled in the present study. IP was defined as diffuse pulmonary interstitial infiltrate found on computed tomography scans. IP was observed in 106 patients. Of these, 23 patients were excluded from the study. Finally, 83 patients with IP were included in this study. The incidence of IP was 3.9% (7/287) in Hodgkin lymphoma and 2.4% (76/1925) in non-Hodgkin lymphoma (P = 0.210). The median number of chemotherapy cycles before IP was 3. The median time from the cessation of chemotherapy to IP was 17 days. Eighty-two (98.8%) patients recovered after the treatment with glucocorticoids. Sixty-six (79.5%) patients had a delay in chemotherapy, and 14 (16.9%) patients had premature termination of chemotherapy. Sixty-nine patients were re-treated with chemotherapy after remission from IP, of which 22 (31.9%) experienced IP recurrence. The incidence of IP recurrence was significantly higher in patients re-treated with a similar regimen than in those re-treated with an alternative regimen (65.4 vs. 11.6%, P < 0.001). In a multivariate Cox regression analysis, B symptoms and a history of drug allergies were identified as risk factors for IP. In conclusion, IP is a life-threatening complication in lymphoma patients. Glucocorticoid therapy with continuous monitoring of chest radiographic changes may be a favourable strategy for treating IP. However, IP may recur, especially in patients re-treated with a similar chemotherapy regimen.

Oxabicycloheptene Sulfonate Protects Against ß-Amyloid-induced Toxicity by Activation of PI3K/Akt and ERK Signaling Pathways Via GPER1 in C6 Cells.

Oxabicycloheptene sulfonate (OBHS) is a novel bicyclic core selective estrogen receptor modulator (SERM) with estrogen receptor (ER) antagonistic-activity and anti-inflammatory activity. However, little is known about protective action of OBHS on neurodegenerative disorders. In the present study, OBHS demonstrated a remarkably protective effect against amyloid beta (Aß) induced cytotoxicity via G-protein-coupled estrogen receptor 1 (GPER1) in rat astroglial cell line (C6). The C6 cell death induced by Aß was decreased by OBHS (1 µM) treatment for 45 min. This rapid protective action was blocked by GPER1 specific antagonist or siRNA knockdown. Inhibitors of phosphatidylinositol 3-kinase (PI3k)/Akt and extracellular signal-regulated kinase (ERK) activation also exhibited similar effects as GPER1 antagonist in blocking the protective effects of OBHS. Moreover, the expression of anti-apoptotic protein Bcl-2 was also increased by OBHS as a consequence of the activation of GPER1-PI3K/Akt and ERK pathways. Additionally, the phenyl sulfonate moiety of OBHS played a vital role in producing GPER1's agonist property according to the molecular docking analysis. These findings suggest that OBHS provide protection directed at enhancing glial cell survival through the activation of GPER1, which, in turn, offers a novel insight into the molecular mechanisms behind the potential application of OBHS in treating Alzheimer's disease (AD).

Molecular characterization of the planktonic microorganisms in water of two mountain brackish lakes.

The prokaryotic diversity in two brackish lakes (Sayram Lake and Chaiwopu Lake) was investigated by constructing bacterial and archaeal clone libraries of 16S rRNA genes. Bacterial clones from Sayram Lake were classified into six phyla (Proteobacteria, Verrucomicrobia, Bacteroidetes, Planctomycetes, Acidobacteria, Actinobacteria). Of these, Proteobacteria and Verrucomicrobia were the most dominant, representing 50.4 and 16.8% of the clone library, respectively. Sequences related to Proteobacteria (58.1%), Cyanobacteria (17.2%), Bacteroidetes (15%), Verrucomicrobia (4.3%), Actinobacteria (3.2%) constituted over 97% of the bacterial clone library from Chaiwopu Lake. In addition, 58.8% (Sayram Lake) and 48% (Chaiwopu Lake) of bacterial clones showed high sequence identity to pure cultures. The composition of Archaea was obviously different between the two lakes. Only the Crenarchaeota phylum was found in the Sayram Lake, whereas Archaeal sequences from Chaiwopu Lake were classified into three phyla: Crenarchaeota (5.8%), Thaumarchaeota (81.2%), and Euryarchaeota (13%). Among the archaeal sequences, 94.2% were highly related to cultivable species of the genus Nitrosopumilus, Methanoculleus, and Methanobacterium. These results showed a high diversity of potential cultivable heterotrophic bacteria in Sayram Lake and Chaiwopu Lake. Chaiwopu Lake was a source of potentially novel, cultivable archaea.

A novel DDIT3 activator dehydroevodiamine effectively inhibits tumor growth and tumor cell stemness in pancreatic cancer.

BACKGROUND: The existence of pancreatic cancer stem cells (PCSCs) results in limited survival benefits from current treatment options. There is a scarcity of effective agents for treating pancreatic cancer patients. Dehydroevodiamine (DeHE), a quinazoline alkaloid isolated from the traditional Chinese herb Evodiae fructus, exhibited potent inhibition of pancreatic ductal adenocarcinoma (PDAC) cell proliferation and tumor growth both in vitro and in vivo. METHODS: The cytotoxic effect of DeHE on PDAC cells was assessed using CCK-8 and colony formation assays. The antitumor efficacy of DeHE were appraised in human PANC-1 xenograft mouse model. Sphere formation assay and flow cytometry were employed to quantify the tumor stemness. RNA-Seq analysis, drug affinity responsive target stability assay (DARTS), and RNA interference transfection were conducted to elucidate potential signaling pathways. Western blotting and immunohistochemistry were utilized to assess protein expression levels. RESULTS: DeHE effectively inhibited PDAC cell proliferation and tumor growth in vitro and in vivo, and exhibited a better safety profile compared to the clinical drug gemcitabine (GEM). DeHE inhibited PCSCs, as evidenced by its suppression of self-renewal capabilities of PCSCs, reduced the proportion of ALDH+ cells and downregulated stemness-associated proteins (Nanog, Sox-2, and Oct-4) both in vitro and in vivo. Furthermore, there is potential involvement of DDIT3 and its downstream DDIT3/TRIB3/AKT/mTOR pathway in the suppression of stemness characteristics within DeHE-treated PDAC cells. Additionally, results from the DARTS assay indicated that DeHE interacts with DDIT3, safeguarding it against degradation mediated by pronase. Notably, the inhibitory capabilities of DeHE on PDAC cell proliferation and tumor stemness were partially restored by siDDIT3 or the AKT activator SC-79. CONCLUSION: In summary, our study has identified DeHE, a novel antitumor natural product, as an activator of DDIT3 with the ability to suppress the AKT/mTOR pathway. This pathway is intricately linked to tumor cell proliferation and stemness characteristics in PDAC. These findings suggest that DeHE holds potential as a promising candidate for the development of innovative anticancer therapeutics.

Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway.

Hepatocellular carcinoma (HCC) is a deadly form of cancer without effective chemotherapy so far. Currently, only sorafenib, a multitargeted tyrosine kinase inhibitor, slightly improves survival in HCC patients. In searching for natural anti-HCC components from toad venom, which is frequently used in the treatment of liver cancer in traditional Chinese medicine, we discovered that arenobufagin, a bufadienolide from toad venom, had potent antineoplastic activity against HCC HepG2 cells as well as corresponding multidrug-resistant HepG2/ADM cells. We found that arenobufagin induced mitochondria-mediated apoptosis in HCC cells, with decreasing mitochondrial potential, as well as increasing Bax/Bcl-2 expression ratio, Bax translocation from cytosol to mitochondria. Arenobufagin also induced autophagy in HepG2/ADM cells. Autophagy-specific inhibitors (3-methyladenine, chloroquine and bafilomycin A1) or Beclin1 and Atg 5 small interfering RNAs (siRNAs) enhanced arenobufagin-induced apoptosis, indicating that arenobufagin-mediated autophagy may protect HepG2/ADM cells from undergoing apoptotic cell death. In addition, we observed the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway by arenobufagin. Interestingly, inhibition of mTOR by rapamycin or siRNA duplexes augmented arenobufagin-induced apoptosis and autophagy. Finally, arenobufagin inhibited the growth of HepG2/ADM xenograft tumors, which were associated with poly (ADP-ribose) polymerase cleavage, light chain 3-II activation and mTOR inhibition. In summary, we first demonstrated the antineoplastic effect of arenobufagin on HCC cells both in vitro and in vivo. We elucidated the underlying antineoplastic mechanisms of arenobufagin that involve cross talk between apoptosis and autophagy via inhibition of the PI3K/Akt/mTOR pathway. This study may provide a rationale for future clinical application using arenobufagin as a chemotherapeutic agent for HCC.

[Angioimmunoblastic T cell lymphoma: clinical analysis of 42 cases].

OBJECTIVE: To explore the clinical characteristics and prognosis of patients with angioimmunoblastic T cell lymphoma (AITL). METHODS: The clinical features and prognostic factors of 42 cases newly diagnosed as AITL at Peking University Cancer Hospital from January 2007 to August 2012 were retrospectively analyzed. RESULTS: Their median age was 59(34-76) years. Among them, 97.6% cases (41/42) belonged to Ann Arbor stage III/IV, 73.8% (31/42) cases presented with B symptoms, 85.7% (36/42)cases had painless lymphadenopathy, 52.4% (22/42)cases extranodal involvement, 64.3% (27/42) cases elevated lactate dehydrogenase and 45.2% (19/42) cases elevated ß2-microglobulin at diagnosis. And 40.5% (17/42) cases had 3 points of international prognostic index (IPI) score with the highest proportion.First-line chemotherapy was predominantly CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) or CHOP-like-based and complete response was achieved in 44.7% (17/38) of them. The median follow-up time was 40 (2-106) months The 1, 2, 5-year survival rates were 78%, 57% and 39% respectively.Statistical analysis showed that IPI was an independent prognostic factor (P = 0.009).Other factors included gender (P = 0.311), age (P = 0.263), with or without B symptoms (P = 0.102), Ki-67 index (P = 0.146) as well as the choice of first-line chemotherapy (P = 0.292) each had a tendency of affecting; the survival rate, but failed to reach statistical significance. CONCLUSIONS: Angioimmunoblastic T-cell lymphoma is a major type of peripheral T-cell lymphoma. Most AITL patients are elders with a late stage. The disease generally displays an aggressive clinical course and poor prognosis.

[Primary testicular non-Hodgkin's lymphoma: clinical analysis of 21 cases].

OBJECTIVE: To explore the clinical characteristics and prognosis of patients with primary testicular non-Hodgkin's lymphoma. METHODS: The clinical profiles and prognostic factors of 21 cases newly diagnosed as primary testicular non-Hodgkin's lymphoma at Peking University Cancer Hospital from January 2005 to December 2012 were retrospectively analyzed. RESULTS: Their median age was 59 (34-86) years. And they were classified as Ann Arbor stage I (n = 8), stage II (n = 2) and stage IV (n = 11). There were B symptoms (n = 4), extranodal involvement outside testis (n = 12) and elevated lactate dehydrogenase (LDH) at diagnosis (n = 6). The scores of international prognostic index (IPI) were 0-1 point (n = 10), 3 points (n = 10) and 4 points (n = 1). The regimens included orchidectomy as the initial treatment (n = 15), chemotherapy followed by radiotherapy (n = 7) and CNS prophylaxis during treatment (n = 15). All patients were pathologically diagnosed as diffuse large B-cell lymphoma. And 11 cases belonged to the non-germinal center B cell-like subgroup.First-line chemotherapy was either R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) or CHOP-like-based regimen. Complete response was achieved in 85.7% of patients. The median follow-up period was 18 (6-58) months. The 1, 2 and 3-year survival rates were 100%, 80% and 60% respectively. Statistical analysis showed that the first-line chemotherapy with rituximab was a prognostic factor (P = 0.038).Other factors included stage (P = 0.275), LDH level (P = 0.179) , ß2-microglobulin level (P = 0.229) and IPI (P = 0.275) . CONCLUSIONS: The prognosis of primary testicular non-Hodgkin's lymphoma is usually poor. The first-line chemotherapy with rituximab is a prognostic factor.

Model for Predicting Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Discussion of Prophylaxis Measures.

OBJECTIVE: Relapse of the central nervous system (CNS) is a rare but fatal complication in diffuse large B-cell lymphoma (DLBCL). The purpose of this study is to learn how to identify high-risk patients and take effective preventive measures. METHODS: We retrospectively analyzed 1,290 adult patients with DLBCL at Peking University Cancer Hospital and Shanxi Bethune Hospital between 2010 and 2020. RESULTS: There were 55 patients with CNS relapse who had a median follow-up of 5 years. The risk of CNS relapse was 1.58% in the low-risk group, 5.66% in the moderate-risk group, and 11.67% in the high-risk group based on CNS International Prognostic Index (CNS-IPI). We found that CNS-IPI and testicular involvement were risk factors for CNS relapse, with OR 1.913 (95% CI: 1.036∼3.531; P = 0.038) versus. OR 3.526 (95% CI: 1.335∼9.313; P = 0.011), respectively. Intrathecal MTX and/or cytarabine prophylaxis was used in 166 patients (13.94%), intravenous (IV) high-dose methotrexate (HD-MTX) prophylaxis in 8 patients (0.67%), and intrathecal plus intravenous prophylaxis in 15 patients (1.26%). There was no significant difference in CNS relapse risk between IT, HD-MTX, and no prophylaxis recipients (12.7% vs. 0% vs. 23.6%, respectively, P = 0.170). The risk of CNS relapse was similar whether or not patients accepted prophylaxis (5-year risk 4.1% vs. 2.2%, P = 0.140). CONCLUSIONS: Central nervous system (CNS) relapse is associated with high risk CNS-IPI and testicular involvement. Therefore, it is necessary to pursue novel prophylactic strategies for CNS relapse.

Erianin inhibits the growth and metastasis through autophagy-dependent ferroptosis in KRASG13D colorectal cancer.

Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide. Approximately 40% of CRC patients are KRAS sequence variation, including KRAS G13D mutation (KRASG13D) CRC patients, accounting for approximately 8% of all KRAS mutations in CRC patients and showing little benefit from anti-EGFR therapy. Therefore, there is an urgent need for new and effective anticancer agents in patients with KRASG13D CRC. Here, we identified a natural product, erianin, that directly interacted with purified recombinant human KRASG13D with a Kd of 1.1163 µM, which also significantly improve the thermal stability of KRASG13D. The cell viability assay showed that KRASG13D cells were more sensitive to erianin than KRASWT or KRASG12V cells. In vitro, results showed that erianin suppressed the migration, invasion and epithelial-mesenchymal transition (EMT) of KRASG13D CRC cells. Furthermore, erianin induced ferroptosis, as evidenced by the accumulation of Fe2+ and reactive oxygen species (ROS), lipid peroxidation, and changes in the mitochondrial morphology of KRASG13D CRC cells. Interestingly, we also found that erianin-induced ferroptosis was accompanied by autophagy. Moreover, the occurrence of erianin-induced ferroptosis is reversed by autophagy inhibitors (NH4Cl and Bafilomycin A1) and ATG5 knockdown, suggesting that erianin-induced ferroptosis is autophagy-dependent. In addition, we evaluated the inhibition of tumor growth and metastasis by erianin in vivo using a subcutaneous tumor model and a spleen-liver metastasis model, respectively. Collectively, these data provide novel insights into the anticancer activity of erianin, which is valuable for the further discussion and investigation of the use of erianin in clinical anticancer chemotherapy for KRASG13D CRC.

Periplocin inhibits hepatocellular carcinoma progression and reduces the recruitment of MDSCs through AKT/NF-κB pathway.

AIMS: We aimed to evaluate the effect of periplocin on inhibiting hepatocellular carcinoma (HCC) and further determine its mechanisms. MAIN METHODS: Cytotoxic activity of periplocin against HCC cells was tested by CCK-8 and colony formation assays. The antitumor effects of periplocin were evaluated in human HCC SK-HEP-1 xenograft and murine HCC Hepa 1-6 allograft mouse models. Flow cytometry was used to measure cell cycle distribution, apopotosis, and the number of myeloid-derived suppressor cells (MDSCs). Hoechst 33258 dye was applied to observe the nuclear morphology. Network pharmacology was performed to predict possible signaling pathways. Drug affinity responsive target stability assay (DARTS) was used to evaluate AKT binding of periplocin. Western blotting, immunohistochemistry, and immunofluorescence were used to examine the protein expression levels. KEY FINDING: Periplocin inhibited cell viability with IC50 values from 50 nM to 300 nM in human HCC cells. Periplocin disrupted cell cycle distribution and promoted cell apoptosis. Moreover, AKT was predicted as the target of periplocin by network pharmacology, which was confirmed by that AKT/NF-κB signaling was inhibited in periplocin-treated HCC cells. Periplocin also inhibited the expression of CXCL1 and CXCL3, leading to decreased accumulation of MDSCs in HCC tumors. SIGNIFICANCE: These findings reveal the function of periplocin in inhibiting HCC progression by G2/M arrest, apoptosis and suppression of MDSCs accumulation through blockade of the AKT/NF-κB pathway. Our study further suggests that periplocin has the potential to be developed as an effective therapeutic agent for HCC.

Orelabrutinib for the treatment of relapsed or refractory MCL: a phase 1/2, open-label, multicenter, single-arm study.

Relapsed or refractory (r/r) mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a poor prognosis. Bruton tyrosine kinase (BTK) is a mediator of B-cell receptor signaling and is associated with the development of B-cell lymphomas. Patients with r/r MCL were enrolled in this phase 1/2 study and treated with orelabrutinib, a novel, highly selective BTK inhibitor. The median number of prior regimens was 2 (range, 1-4). The median age was 62 years (range, 37-73 years). Eligible patients received oral orelabrutinib 150 mg once daily (n = 86) or 100 mg twice daily (n = 20) until disease progression or unacceptable toxicity. A dose of 150 mg once daily was chosen as the preferred recommended phase 2 dose. After a median follow-up duration of 23.8 months, the overall response rate was 81.1%, with 27.4% achieving a complete response and 53.8% achieving a partial response. The median duration of response and progression-free survival were 22.9 and 22.0 months, respectively. The median overall survival (OS) was not reached, and the rate of OS at 24 months was 74.3%. Adverse events (AEs) occurring in >20% of patients were thrombocytopenia (34.0%), upper respiratory tract infection (27.4%), and neutropenia (24.5%). Grade ≥3 AEs were infrequent and most commonly included thrombocytopenia (13.2%), neutropenia (8.5%), and anemia (7.5%). Three patients discontinued treatment because of treatment-related adverse events (TRAEs), but no fatal TRAEs were reported. Orelabrutinib showed substantial efficacy and was well tolerated in patients with r/r MCL. This trial was registered at www.clinicaltrials.gov as #NCT03494179.

The clinical features, therapeutic responses, and prognosis of the patients with mantle cell lymphoma.

Mantle cell lymphoma(MCL), a special type of non-Hodgkin's lymphoma, is incurable through conventional treatment. This study aimed to analyze the clinical features, therapeutic responses, and prognosis of patients with MCL. Clinical data of 30 patients with MCL treated in our hospital between April 2006 and July 2011 were analyzed. Eighteen patients were treated with CHOP plus rituximab (R-CHOP) regimen, 12 underwent conventional chemotherapy. The median age of the 30 patients was 58 years, 23 were men, all patients had Cyclin D1 overexpression, 29 (96.7%) had advanced disease, 11 (36.7%) had bone marrow involvement, 9 (30.0%) had gastrointestinal involvement, and 15 (50.0%) had splenomegaly. The complete response(CR) rate and overall response rate(ORR) were significantly higher in patients undergoing R-CHOP immunochemotherapy than in those undergoing conventional chemotherapy (38.9% vs. 16.7%, P = 0.187; 72.2% vs. 41.4%, P = 0.098). The difference of 2-year overall survival rate between the two groups was not significant (P = 0.807) due to the short follow-up time. The 2-year progression-free survival (PFS) rate was higher in R-CHOP group than in conventional chemotherapy group (53% vs. 25%, P = 0.083), and was higher in patients with a lower mantle cell lymphoma international prognostic index (MIPI) (51% for MIPI 0-3, 33% for MIPI 4-5, and 0% for MIPI 6-11, P = 0.059). Most patients with MCL were elderly; in an advanced stage; showed a male predominance; and usually had bone marrow involvement, gastrointestinal involvement, or splenomegaly. R-CHOP regimen could improve the CR rate and ORR of MCL patients. MIPI can be a new prognostic index for predicting the prognosis of advanced MCL.

[Safety and adverse event profiling of pegylated L-asparaginase combined chemotherapy in the treatment of lymphoma].

OBJECTIVE: To analyze the safety and adverse event profiling of pegylated L-asparaginase (PEG-asp) combined chemotherapy in the treatment of lymphoma patients. METHODS: The clinical data of 32 lymphoma patients on PEG-asp-based chemotherapy from January 2008 to March 2012 were retrospectively collected and analyzed. RESULTS: There were 22 males and 10 females with a median age of 40 years. They were diagnosed as NK/T cell lymphoma (n = 22) and lymphoblastic lymphoma (n = 10). The overall response rate was 71.9% (23/32). And complete remission was 40.6% (13/32) and partial remission 31.3% (10/32). Myelosuppression was the most common adverse event at an incidence of 81.2% (26/32). Other adverse events included a low level of fibrinogen (n = 13, 40.6%), hypoalbuminemia (n = 8, 25%) and hyperlipidemia (n = 9, 28.1%). No instance of anaphylaxis, acute pancreatitis and thrombosis occurred. CONCLUSION: PEG-asp is both effective and safe in the treatment of lymphoma and it is well-tolerated.

[Prognostic value of maximum standard uptake on pretreatment 18F-FDG PET/CT scan in newly diagnosed diffuse large B cell lymphoma].

OBJECTIVE: To evaluate the prognostic value of maximum standard uptake (SUVmax) on pretreatment (18)F-fluoro-2-deoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) scan in patients with newly diagnosed diffuse large B cell lymphoma (DLBCL). METHODS: The clinical data of 39 DLBCL patients undergoing a PET/CT scan at pre-treatment from December 2009 to October 2011 were analyzed retrospectively. SUVmax on PET/CT was evaluated by SPSS 13.0 for the associations with patient characteristics, prognostic factors, treatment efficacy and survival time. RESULTS: The median SUVmax was higher in non-germinal center B cell-like (non-GCB) patients than that in GCB ones (18.0(2.2 - 40.5) vs 11.6 (5.3 - 18.7), P = 0.039). No difference of SUVmax was observed between the patients with and without bulky disease (P = 0.539). SUVmax was not associated with such patient characteristics as international protein index, age, stage, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, number of extranodal involvement and Ki-67 (all P > 0.05). No significant difference in median SUVmax existed between complete remission (CR) and non-CR patients (P = 0.312). The difference of SUVmax was insignificant for the patients with efficacy and no efficacy (P = 0.243). With the cut-off values of 10, 15, 20, the CR rate, response rate, 2-year progression-free survival (PFS) rate and 2-year overall survival (OS) rate were not different between the patients with SUVmax below and above cut-off value (all P > 0.05). CONCLUSIONS: The prognostic value of SUVmax on PET/CT is indeterminate. And it can not be used to predict the patient prognosis.

Huangbai liniment and berberine promoted wound healing in high-fat diet/Streptozotocin-induced diabetic rats.

Diabetic ulcer is a challenging complication of diabetes mellitus but current treatments cannot achieve satisfactory results. In this study, the effect of Huangbai liniment (HB) and berberine on the wound healing in high fat diet/streptozotocin injection induced diabetic rats was investigated by RNA-seq technology. HB topical treatment promoted wound healing in the diabetic patients and diabetic rats, and it affected multiple processes, of which IL-17 signalling pathway was of importance. Inhibiting IL-17a by its inhibitor or antibody remarkably facilitated wound healing and HB significantly repressed the high IL-17 expression and its downstream targets, including Cxcl1, Ccl2, Mmp3, Mmp9, G-CSF, IL1B and IL6, in diabetic wounds, promoted T-AOC, SOD activity and GSH levels; decreased the levels of nitrotyrosine and 8-OHdG; enhanced angiogenesis-related CD31, PDGF-BB and ANG1 expression; inhibited cleaved caspase-3 levels and promoted TIMP1 and TGFB1. Moreover, berberine (a major component in HB) repressed the IL-17 signalling pathway, and promoted wound healing in diabetes mellitus. This study highlights the strategy of targeting IL-17a in diabetic wounds, deepens the understanding of wound healing in diabetes mellitus in a dynamic way and reveals the characteristics of HB and berberine in promoting wound healing of type 2 diabetes mellitus.

Emerging roles of long non-coding RNA in depression.

Depression is the second most common psychiatric disorder, affecting more than 340 million people of all ages worldwide. However, the mechanisms underlying the development of depression remain unclear, and existing antidepressants may cause clinical dependence and toxic side effects. Recently, emerging evidence from the fields of neuroscience, genetics, and genomics supports the modulatory role of long non-coding RNA (lncRNA) in depression. LncRNAs may mediate the pathogenesis of depression through multiple pathways, including regulating neurotransmitters and neurotrophic factors, affecting synaptic conduction, and regulating the ventriculo-olfactory neurogenic system. In addition, relying on genome-wide association study and molecular biological experiment, the possibility of lncRNA as a potential biomarker for the differential diagnosis of depression and other mental illnesses, including schizophrenia and anxiety disorders, is gradually being revealed. Thus, it is important to explore whether lncRNAs are potential therapeutic targets and diagnostic biomarkers for depression. Here, we summarize the genesis and function of lncRNAs and discuss the aberrant expression and functional roles of lncRNAs in the development, diagnosis, and therapy of depression, as well as the deficiencies and limitations of these studies. Moreover, we established a lncRNA-miRNA-mRNA-pathway-drug network of depression through bioinformatics analysis methods to deepen our understanding of the relationship between lncRNA and depression, promoting the clinical application of epigenetic research.