Crucial roles of Rab22a in endosomal cargo recycling.

Endosomal cargo recycling lies at the heart of subcellular trafficking processes under the management of several Ras-related GTP-binding proteins (Rabs) which are coordinated by their upstream regulators and require their downstream effectors to display their functions. In this regard, several Rabs have been well-reviewed except Rab22a. Rab22a is a crucial regulator of vesicle trafficking, early endosome and recycling endosome formation. Notably, recent studies demonstrated the immunological roles of Rab22a, which are closely associated with cancers, infection and autoimmune disorders. This review provides an overview of the regulators and effectors of Rab22a. Also, we highlight the current knowledge of the role of Rab22a in endosomal cargo recycling, including the biogenesis of recycling tubules with the help of a complex with Rab22a at its core, and how different internalized cargo chooses different recycling routes thanks to the cooperation of Rab22a, its effectors and its regulators. Of note, contradictions and speculation related to endosomal cargo recycling that Rab22a brings impacts on are also discussed. Finally, this review endeavors to briefly introduce the various events impacted by Rab22a, particularly focusing on the commandeered Rab22a-associated endosomal maturation and endosomal cargo recycling, in addition to the extensively investigated oncogenic role of Rab22a.

1q21+ is associated with poor prognosis in newly diagnosed multiple myeloma patients with extramedullary disease: a retrospective study.

1q21+ is a common cytogenetic abnormality in multiple myeloma (MM) and is considered an independent predictor of poor prognosis; however, its impact on extramedullary disease (EMD) remains unknown. Our study reviewed the clinical relevance and prognostic value of 1q21+ status in 92 patients with NDMM and EMD. 1q21+ was detected in 23.9% (22/92) of patients. Patients with 1q21+ presented with advanced International Staging System stages (P = 0.006), lower level of hemoglobin (P = 0.004), higher percentage of plasma cells in the bone marrow (P < 0.001), higher level of serum ß2-microglobulin (7.24 g/L vs. 3.85 g/L, P = 0.003), and higher levels of lactic dehydrogenase (LDH) (206.5 U/L vs. 177 U/L, P = 0.019). The prevalence of soft tissue-related EMD (EMD-S) (54.5% vs. 18.6%, P < 0.001), renal dysfunction (50.5% vs. 17.7%, P = 0.002), and hypercalcemia (27.3% vs. 7.1%, P = 0.011) was also higher. 1q21+ was strongly associated with other high-risk cytogenetic abnormalities, including IgH/FGFR3 (22.7% vs. 4.3%, P = 0.007) and IgH/MAF translocations (22.7% vs. 1.4%, P < 0.001). 1q21+ patients had significantly shorter overall survival (OS) and progression-free survival (PFS) (OS: 24 months vs. 47 months, P = 0.002; PFS: 14 months vs. 38 months, P < 0.001); the poor survival outcomes could not be reversed by autologous hematopoietic stem cell transplantation. Multivariate analysis suggested that 1q21+ , EMD-S, elevated lactate dehydrogenase (LDH) levels, and P53 deletion were independent risk factors for poor prognosis in patients with EMD. In patients with 1q21+ EMD, hypercalcemia, elevated LDH levels, and P53 deletion were independent adverse risk prognostic factors.

Genetic and prognostic analysis of blastoid and pleomorphic mantle cell lymphoma: a multicenter analysis in China.

Blastoid or pleomorphic mantle cell lymphoma (B/P-MCL) is characterized by high invasiveness and unfavorable outcomes, which is still a challenge for treating MCL. This retrospective study was performed to comprehensively analyze the clinical, genomic characteristics and treatment options of patients with B/PMCL from multicenter in China. Data were obtained from 693 patients with B/PMCL from three centers in China between April 1999 and December 2019. Seventy-four patients with BMCL (n = 43) or PMCL (n = 31) were included in the analysis. The median age of the cohort was 60.0 years with a male-to-female ratio of 2.89:1. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 44.1% and 46.0%, respectively. Mutations of TP53, ATM, NOTCH1, NOTCH2, NSD2, SMARCA4, CREBBP, KMT2D, FAT1, and TRAF2 genes were the most common genetic changes in B/P-MCL. Progression of disease within 12 months (POD12) could independently predict the poor prognosis of patients with blastoid and pleomorphic variants. Patients with POD12 carried a distinct mutation profile (TP53, SMARCA4, NSD2, NOTCH2, KMT2D, PTPRD, CREBBP, and CDKN2A mutations) compared to patients with non-POD12. First-line high-dose cytosine arabinoside exposure obtained survival benefits in these populations, and BTKi combination therapy as the front-line treatment had somewhat improvement in survival with no significant difference in the statistic. In conclusion, B/P-MCL had inferior outcomes and a distinct genomic profile. Patients with POD12 displayed a distinct mutation profile and a poor prognosis. New therapeutic drugs and clinical trials for B/P-MCL need to be further explored.

The retrospective comparison between submucosal tunneling endoscopic resection and endoscopic submucosal excavation for managing esophageal submucosal tumors originating from the muscularis propria layer.

BACKGROUND: Submucosal tunneling endoscopic resection (STER) and endoscopic submucosal excavation (ESE) were recently introduced to cure submucosal tumors (SMTs) originating from the muscularis propria (MP) layer. This study aimed to compare clinical performance and safety of STER and ESE in treating esophageal SMTs originating from the MP layer. METHODS: From January 2011 to December 2017, retrospective data collection and follow-up were applied for all STER or ESE cases with esophageal SMTs originating from the MP layer in our endoscopy center, including clinical characteristics, procedure success, efficacy, and adverse events. Subgroup analysis was further done based on tumor size and origin. RESULTS: 90 STER and 77 ESE were enrolled in this study. There were no significant difference for patient characteristics, procedure performance, and complications for ESE and STER intervention (P > 0.05). STER was faster than ESE (3.90 mm2/min vs 2.82 mm2/min, P < 0.05). For large tumors (≥ 20 mm), both techniques had the similar performance (P > 0.05), while STER led to the shorter hospitalization (4.0d vs 7.0d, P < 0.05) and lower postoperative complication (16.3% vs 45.5%, P < 0.05). For small tumors (< 20 mm), STER achieved faster operation (STER vs ESE, 2.57 mm2/min vs 1.83 mm2/min, P < 0.05). Regardless of tumor origin, there were no significant difference for both techniques, but STER resulted in short hospitalization for SMTs from the deep MP layer (STER vs ESE, 5.0d vs 7.0d, P < 0.05). During the follow-up, 2 residual and 4 recurrence occurred in the STER group, as well as 1 residual and 2 recurrence in the ESE group. CONCLUSIONS: Both STER and ESE were effective for treating esophageal SMTs originating from the MP layer. STER might be better due to its faster operation, less complications, and shorter hospitalization.

WITHDRAWN: Endoscopic intervention for acute appendicitis: retrospective study of 101 cases.

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Label-free multiphoton microscopic imaging as a novel real-time approach for discriminating colorectal lesions: A preliminary study.

BACKGROUND AND AIM: Although various endoscopic technologies have been developed to increase the visual diagnostic accuracy of colorectal precancerosis and early carcinoma, the biopsy-dependent pathology still remains the golden standard. During routine endoscopy, real-time optical histological diagnosis is desired. Without fluorescent label, multiphoton microscopy (MPM) imaging directly reveals live cellular morphology and tissue microenvironment based on intrinsic two-photon excited fluorescence and second harmonic generation signals. Its high-imaging resolution and performance are comparable with the histopathology. We thus aimed to initially investigate the original features of colorectal diseases under MPM and evaluate its potential for real-time diagnosis. METHODS: Experimental and diagnostic cohorts were designed. Multiphoton images of 40 ex vivo fresh tissues confirmed pathologically of colorectal normal tissues, hyperplastic polyps, adenomas, and adenocarcinomas were collected. Features were recorded to establish diagnostic standards with MPM. For the second cohort with 92 fresh tissues, we distinguished the various colorectal diseases with conclusive MPM features. RESULTS: Through the investigation, the colorectal diseases were presented differences in the crypt opening, gland structure, epithelial cells, and collagen fibers. With the typical features, we preliminarily tested the diagnostic efficiency and found that its sensitivity for distinguishing normal, hyperplastic polyps, adenoma and adenocarcinoma was 88.89%, 76.47%, 83.33%, and 97.92%, while the specificity was 99.32%, 94.00%, 94.92%, and 94.12%, respectively. CONCLUSION: The real-time multiphoton microscopic imaging can be effective to identify the colorectal lesions with high resolution. Via integrating with the endoscopes in the future, it could promote precise optical diagnosis in clinics.

Thermoresponsive aerification and tissue vacuolization for facilitating endoscopic submucosal resection.

BACKGROUND AND AIMS: Mucosal lifting and its persistence are critical for maintaining the operational space and preventing perforation in endoscopic operation. Although numerous agents have been investigated, optimization is still required for improving their clinical performance. In the present study, we proposed a novel concept of thermoresponsive aerification and tissue vacuolization for submucosal injection. METHODS: Lifting performance and operational condition were first evaluated in porcine stomachs in vitro and rabbits in vivo. Dodecafluoropentane (DDFP) injection dosage, lifting persistency and operational assistance were quantitatively recorded. Gross and histological pathology were also analyzed to identify DDFP acute toxicity and long-term safety. The endoscopic submucosal dissection (ESD) procedure with DDFP was carried out on pigs in vivo to confirm its operational feasibility, efficacy, and safety. RESULTS: Dodecafluoropentane aerification could achieve better mucosal lift with lower dosage (1% of normal saline dosage). Thermoresponsive DDFP aerification could provide continuous replenishment and longer persistence. Meanwhile, its tissue vacuolization effect significantly facilitated submucosal tissue dissection in in vitro study. Similar performance was verified in vivo. The particular vacuole-like submucosal structure was seen after DDFP onset, which also promoted reepithelization and wound healing. No tissue damage, gas embolism, biotoxicity, and physicochemical risk were observed. CONCLUSION: Bioinert DDFP was feasible, efficient, and safe as the novel submucosal lifting candidate.

The effectiveness of E-health interventions promoting physical activity in cancer survivors: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: This systematic review and meta-analysis aimed to identify whether E-health interventions effectively improve physical activity (PA) in cancer survivors. METHODS: PubMed, Web of Science, and Cochrane Library databases were searched from inception to October 21, 2023. Randomized controlled trials reporting the effect of E-health interventions on PA among cancer survivors were included. Random-effect models were used to calculate standardized mean differences (SMD) and the 95% confidence interval (CI). RESULTS: In total, 15 trials with 2,291 cancer survivors were included in this meta-analysis. The results showed that E-health interventions improved moderate to vigorous physical activity (MVPA) among cancer survivors (SMD = 0.26, 95% CI 0.08, 0.43, N = 8, p < 0.001, I2 = 37%), as well as moderate physical activity (MPA) (SMD = 0.22, 95% CI 0.05, 0.38, N = 9, p < 0.001, I2 = 28%) and vigorous physical activity (VPA) (SMD = 0.34, 95% CI 0.15, 0.54, N = 6, p < 0.001, I2 = 11%). CONCLUSION: E-health interventions are effective at promoting PA among cancer survivors. As current research primarily focuses on immediate post-intervention measurements with limited follow-up data, further investigation is required to explore the long-term effects of E-health interventions on PA.

Effect of Metaldehyde on Survival, Enzyme Activities, and Histopathology of the Apple Snail Pomacea canaliculata (Lamarck 1822).

Pomacea canaliculata, as an invasive exotic species in Asia, can adversely affect crop yields, eco-environment, and human health. Application of molluscicides containing metaldehyde is one effective method for controlling P. canaliculata. In order to investigate the effects of metaldehyde on adult snails, we conducted acute toxicological experiments to investigate the changes in enzyme activities and histopathology after 24 h and 48 h of metaldehyde action. The results showed that the median lethal concentrations (LC) of metaldehyde on P. canaliculata were 3.792, 2.195, 1.833, and 1.706 mg/L at exposure times of 24, 48, 72, and 96 h, respectively. Treatment and time significantly affected acetylcholinesterase (AChE), glutathione S-transferase (GST), and total antioxidant capacity (TAC) activity, with sex significantly affecting AChE, GST, and TAC activity and time significantly affecting carboxylesterase (CarE). In addition, the interaction of treatment and time significantly affected the activity of GST, CarE and TAC. In addition, histopathological changes occurred in the digestive glands, gills and gastropods of apple snail exposed to metaldehyde. Histological examination of the digestive glands included atrophy of the digestive cells, widening of the hemolymph gap, and an increase in basophils. In treated snails, the hemolymph gap in the gills was widely dilated, the columnar cells were disorganized or even necrotic, and the columnar muscle cells in the ventral foot were loosely arranged and the muscle fibers reduced. The findings of this study can provide some references for controlling the toxicity mechanism of invasive species.

Moxifloxacin promotes two-photon microscopic imaging for discriminating different stages of DSS-induced colitis on mice.

BACKGROUND: Accurate diagnosis of patients with ulcerative colitis (UC) can reduce their risk of developing colorectal cancer. This study intended to explore whether moxifloxacin, an agent with fluorescence potential, could promote two-photon microscopy (TPM) diagnosis for mice with dextran sodium sulfate (DSS)-induced colitis, which could imitate human UC. METHODS: 32 Balb/c mice were randomly divided into 4 groups: control, acute colitis, remission colitis and chronic colitis. Fluorescence parameters, imaging performance, and tissue features of different mouse models were compared under moxifloxacin-assisted TPM and label-free TPM. RESULTS: Excitation wavelength of 720 nm and moxifloxacin labeling time of 2 min was optimal for moxifloxacin-assisted TPM. With moxifloxacin labeling for colonic tissues, excitation power was decreased to 1/10 of that without labeling while fluorescence intensity was increased to 10-fold of that without labeling. Photobleaching was negligible after moxifloxacin labeling and moxifloxacin fluorescence kept stable within 2 h. Compared with the control group, moxifloxacin fluorescence was reduced in the three colitis groups (P < 0.05). Meanwhile, the proportion of enhanced moxifloxacin fluorescence regions was (22.4 ± 1.6)%, (7.7 ± 1.0)%, (13.5 ± 1.7)% and (5.0 ± 1.3)% in the control, acute, remission and chronic groups respectively, with significant reduction in the three colitis groups (P < 0.05). Besides, variant tissue features of experimental colitis models were presented under moxifloxacin-assisted TPM, such as crypt opening, glandular structure, adjacent glandular space and moxifloxacin distribution. CONCLUSIONS: With unique biological interaction between moxifloxacin and colonic mucosa, moxifloxacin-assisted TPM imaging is feasible and effective for accurate diagnosis of different stages of experimental colitis.

MePP2C24, a cassava (Manihot esculenta) gene encoding protein phosphatase 2C, negatively regulates drought stress and abscisic acid responses in transgenic Arabidopsis thaliana.

Abscisic acid (ABA) signaling plays a crucial role in plant development and response to abiotic/biotic stress. However, the function and regulation of protein phosphatase 2C (PP2C), a key component of abscisic acid signaling, under abiotic stress are still unknown in cassava, a drought-tolerant crop. In this study, a cassava PP2C gene (MePP2C24) was cloned and characterized. The MePP2C24 transcripts increased in response to mannitol, NaCl, and ABA. Overexpression of MePP2C24 in Arabidopsis resulted in increased sensitivity to drought stress and decreased sensitivity to exogenous ABA. This was demonstrated by transgenic lines having higher levels of malondialdehyde (MDA), ion leakage (IL), and reactive oxygen species (ROS), lower activities of catalase (CAT) and peroxidase (POD), and lower proline content than wild type (WT) under drought stress. Moreover, MePP2C24 overexpression caused decrease in expression of drought-responsive genes related to ABA signaling pathway. In addition, MePP2C24 was localized in the cell nucleus and showed self-activation. Furthermore, many MePYLs (MePYL1, MePYL4, MePYL7-9, and MePYL11-13) could interact with MePP2C24 in the presence of ABA, and MePYL1 interacted with MePP2C24 in both the presence and absence of ABA. Additionally, MebZIP11 interacted with the promoter of MePP2C24 and exerted a suppressive effect. Taken together, our results suggest that MePP2C24 acts as a negative regulator of drought tolerance and ABA response.

Sex-Biased Survival, Behavior Response, and Recovery Performance of Pomacea canaliculata Snails to Drought Stress and Rewatering Condition.

As the frequency of droughts increases with climate change, the tolerance of aquatic organisms to abiotic stressors will become critical determinants of survival. Pomacea canaliculata has become a widely distributed agricultural and environmental pest in southern China. To evaluate their tolerance and adaptation under the drought condition, the survival, feeding, behavior, and antioxidant system changes in female and male P. canaliculata were investigated during drought stress and rewatering process through an indoor simulation experiment. The results showed that female snails laid eggs before burrowing into the soil to ensure offspring reproduction. Female P. canaliculata had higher survival rates than males under drought stress, and their recovery ability of activity after rewatering was also superior to those of males. The antioxidant system of P. canaliculata showed obvious activation with gender differences after rewatering. Overall, the survival rate of female P. canaliculata was higher after drought stress, and the resilience ability of female snails after rewatering was stronger, including in their behavior, feeding, and antioxidant system recovery. The P. canaliculata tolerance to drought and the ability to recover quickly after drought may contribute to their long-term survival and facilitate continuous invasion.

Ca2+ addition facilitates the shell repair with eggs production of Pomacea canaliculata through biomineralization and food intaking regulation.

Pomacea canaliculata was by far one of the most harmful invasive organisms in the world, causing serious harm to aquatic crops and ecosystem. Calcium carbonate is a common component of aquatic environment, which is important for the growth of Pomacea canaliculata. Therefore, the objective of this study was to investigate the response characteristics of P. canaliculata suffered shell breakage to the addition of calcium carbonate in water environment. In this experiment, we explored the effects of calcium carbonate addition on the P. canaliculata shell repair rate, food intake, egg production, shell strength, and calcium content through breaking the snails shell and the addition of calcium carbonate treatment. The results showed that snail broken-shell repaired mostly within 21 days. The snails experienced a significant increase in shell repair rates during earlier days of the treatment, especially for female snails. Food intake of snails exhibited different patterns when their shells were broken and calcium carbonate was added. Shell breakage treatment combined with calcium carbonate addition significantly increased the diameter of snail eggs compared with the control and the calcium carbonate addition treatment without shell-broken snail group. There was no significant difference in shell strength or calcium content of male snails between the treatments. The study suggests that P. canaliculata exhibits a sex-dependent response pattern when subjected to shell damage and calcium carbonate addition. The findings can provide some references to better understand the invasion mechanism and survival strategy of the P. canaliculata.

Molluscicidal activity of Nicotiana tabacum extracts on the invasive snail Pomacea canaliculata.

Botanical molluscicides for controlling the invasive snail Pomacea canaliculata have attracted worldwide attention because of their cost and environmental friendliness. Aqueous extracts from discarded tobacco leaf (Nicotiana tobacum) were evaluated for molluscicidal activity against different-sized P. canaliculata under laboratory conditions. The results showed that over 90% of the snails died in 1 g/L tobacco extract within 4 days, and the survival of P. canaliculata was inversely proportional to the snail size, tobacco extract concentration and length of exposure time. Adult males were more susceptible to tobacco extract than females. The snails had few chances to feed or mate in 0.5 g/L tobacco extract, and reproduction was greatly limited in 0.2 g/L. The growth of juvenile snails was inhibited in 0.2 g/L tobacco extract, but adults were unaffected. The antioxidant capacity of P. canaliculata in response to tobacco extract can be size- and sex-dependent, and the activities of superoxide dismutase, catalase, and acetylcholinesterase and the contents of glutathione and malondialdehyde were increased in adult males. These results suggest that discarded tobacco leaves can be useful as a molluscicide for controlling the invasive snail P. canaliculata based on its effects on survival, behaviour, food intake, growth performance and antioxidant capacity.

Effects of exogenous organic matter addition on agricultural soil microbial communities and relevant enzyme activities in southern China.

Soil microbial community composition plays a key role in the decomposition of organic matter, while the quality of exogenous organic matter (EOM: rice straw, roots and pig manure) can influence soil chemical and biological properties. However, the evidences of the effect of combination of crop residues and pig manure on the changes in soil microbial community and enzymes activities are scarce. A greenhouse pot experiment was conducted to investigate the potential effect of EOM by analyzing soil properties, enzyme activities and microbial communities. The experiment consisted of eight treatments: CK (control), S (1% (w/w) rice straw), R (1% (w/w) rice root), SR (1% (w/w) rice straw + 1% (w/w) rice root), and added 1% (w/w) pig manure to CK, S, R and SR, respectively. Results showed that the straw treatment significantly increased the microbial biomass (carbon and nitrogen) and total carbon and nitrogen contents, cellulase and ß-1,4-glucosidase activities, bacteria (i.e., gram-positive bacteria and gram-negative bacteria) PLFAs contents relative to CK regardless of whether pig manure was added. Moreover, the interaction between crop residues (e.g., straw and roots) and pig manure significantly influenced the contents of microbial biomass nitrogen and microbial biomass phosphorus, and the ratio of gram-positive bacteria to gram-negative bacteria. Redundance analysis confirmed that pH, nitrate nitrogen, ammonium nitrogen and dissolve organic carbon contents were significantly associated with soil microbial community under crop residues without pig manure addition. Furthermore, the experiment results showed that pig manure application not only provided more abundant nutrients (C, N and P) but also induced higher microbial and enzymatic activity compared with no pig manure addition. Our findings suggest that the combination of above-ground straw and pig manure is a better option for improving the functions of soil ecosystem.

Moxifloxacin as a contrast agent of two-photon microscopic imaging for detecting colorectal diseases.

Since two-photon microscopy (TPM) can obtain high-resolution images at cellular and subcellular level and moxifloxacin has multiphoton fluorescence characteristic, our study aimed to explore the feasibility and diagnostic value of moxifloxacin-assisted TPM in different human colorectal diseases, including low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN) and cancer tissues. Excitation power for TPM imaging with and without moxifloxacin was (2.74 ± 0.16) mW and (0.28 ± 0.02) mW, respectively (p < 0.05). Whether labeled with moxifloxacin or not, images of normal, LGIN, HGIN and cancer tissues all reached the strongest signal at 30 µm from the mucosa. Normalized fluorescence intensity of TPM images with moxifloxacin was approximately 10 times stronger than that without moxifloxacin. Fluorescence signal was differed significantly in normal, LGIN, HGIN and cancer tissues with or without moxifloxacin (p < 0.05). Besides, moxifloxacin-assisted TPM could present variant tissue features with different colorectal diseases, such as the crypt opening, glandular structure, adjacent glandular space and fluorescence distribution.

p53 directly downregulates the expression of CDC20 to exert anti-tumor activity in mantle cell lymphoma.

BACKGROUND: Cell cycle dysregulation characterized by cyclin D1 overexpression is common in mantle cell lymphoma (MCL), while mitotic disorder was less studied. Cell division cycle 20 homologue (CDC20), an essential mitotic regulator, was highly expressed in various tumors. Another common abnormality in MCL is p53 inactivation. Little was known about the role of CDC20 in MCL tumorigenesis and the regulatory relationship between p53 and CDC20 in MCL. METHODS: CDC20 expression was detected in MCL patients and MCL cell lines harboring mutant p53 (Jeko and Mino cells) and wild-type p53 (Z138 and JVM2 cells). Z138 and JVM2 cells were treated with CDC20 inhibitor apcin, p53 agonist nutlin-3a, or in combination, and then cell proliferation, cell apoptosis, cell cycle, cell migration and invasion were determined by CCK-8, flow cytometry and Transwell assays. The regulatory mechanism between p53 and CDC20 was revealed by dual-luciferase reporter gene assay and CUT&Tag technology. The anti-tumor effect, safety and tolerability of nutlin-3a and apcin were investigated in vivo in the Z138-driven xenograft tumor model. RESULTS: CDC20 was overexpressed in MCL patients and cell lines compared with their respective controls. The typical immunohistochemical marker of MCL patients, cyclin D1, was positively correlated with CDC20 expression. CDC20 high expression indicated unfavorable clinicopathological features and poor prognosis in MCL patients. In Z138 and JVM2 cells, either apcin or nutlin-3a treatment could inhibit cell proliferation, migration and invasion, and induce cell apoptosis and cell cycle arrest. GEO analysis, RT-qPCR and WB results showed that p53 expression was negatively correlated with CDC20 expression in MCL patients, Z138 and JVM2 cells, while this relationship was not observed in p53-mutant cells. Dual-luciferase reporter gene assay and CUT&Tag assay revealed mechanistically that CDC20 was transcriptionally repressed by p53 through directly binding p53 to CDC20 promoter from - 492 to + 101 bp. Moreover, combined treatment of nutlin-3a and apcin showed better anti-tumor effect than single treatment in Z138 and JVM2 cells. Administration of nutlin-3a/apcin alone or in combination confirmed their efficacy and safety in tumor-bearing mice. CONCLUSIONS: Our study validates the essential role of p53 and CDC20 in MCL tumorigenesis, and provides a new insight for MCL therapeutics through dual-targeting p53 and CDC20.