Practical Value of Environment-friendly Sample Release Agent Combined with Ultrasound in the Preparation of Pathological Tissue Sections / 中山大学学报(医学科学版)

ObjectiveTo explore the practical value of environment-friendly sample release agent combined with ultrasound in the preparation of pathological tissue sections. MethodsFrom February 2013 to December 2022， 2 518 pathological specimens submitted by Foshan Municipal Hospital of Traditional Chinese Medicine were selected as the study objects. Two samples of the same specimen were randomly divided into two groups： the environment-friendly fast group， in which the pathological tissue sections were made by using the environment-friendly sample release agent combined with ultrasound； and the traditional group， in which formaldehyde， ethanol and xylene were used to make slices in the conventional way. The differences of hematoxylin （HE） staining effect， immunohistochemistry （IHC） staining effect and MDM2 gene detection result of atypical lipomatous tumor/highly differentiated liposarcoma （ALT/WDL） tissue sections between the two groups were compared. Results① The wax of the two groups' pathological tissues was dehydrated well and the tissue hardness was moderate. After HE staining， the sections of the two groups were intact， without cracks and tremor marks， and the contrast between nucleus and cytoplasm was appropriate， with good transparency， uniform staining， and no tissue loss. The excellent rate and score of HE staining in the environmental fast group were higher than those in the traditional group， but the difference was not statistically significant （χ2 = 3.125，P1 = 0.070；t = 0.965，P2 = 0.334）. ②After IHC staining of the two groups of sections， the positive location of the cells was accurate， the staining was specific and uniform， the staining intensity was moderate， the staining sensitivity was good， and there was no tissue loss. The excellent rate of IHC staining and the positive rate of IHC staining in the environmental fast group were lower than those in the traditional group， but the difference was not statistically significant （χ12 = 2.769，P1 = 0.092；χ22 = 0.800，P2 = 0.375）. ③The background and outline of the two groups of WDL tissue sections were clear， the staining was uniform， the cells were clear and visible， the nuclear boundary was clear， the hybridization signal was clear and bright under the background fluorescence， and there was no miscellaneous signal. The two groups of sections were hybridized successfully， and MDM2 showed positive amplification. The number of cells successfully hybridized in the environment-friendly fast group was lower than that in the traditional group， but the difference was not statistically significant （t = 1.414，P = 0.230）. ConclusionsThe tissue treatment method of using environment-friendly sample release agent combined with ultrasound can ensure the detection effect of HE staining， IHC staining and MDM2 gene detection of pathological tissue sections， and is more efficient and environment-friendly， suitable for promotion and use in hospitals at all levels.

Clinical value of fluorescence in situ hybridization with MDM2 and DDIT3 probe in diagnosis of liposarcoma / 北京大学学报(医学版)

OBJECTIVE@#To investigate the value of using MDM2 amplification probe and DDIT3 dual-color, break-apart rearrangement probe fluorescence in situ hybridization (FISH) technique in the diagnosis of liposarcoma.@*METHODS@#In the study, 62 cases of liposarcoma diagnosed in Peking University First Hospital from January 2015 to December 2019 were analysed for clinicopathological information. Of these 62 cases of liposarcoma, all were analysed for MDM2 amplification and 48 cases were analysed for DDIT3 rearrangement using a FISH technique. Our study aimed to evaluate the status of MDM2 and DDIT3 by FISH in liposarcoma and correlate it with diagnosis of different subtypes of liposarcoma. The subtypes of liposarcoma were classified according to the FISH results, combined with the relevant clinicopathological features.@*RESULTS@#The patients aged 31-89 years (mean: 59 years) with a 1.75:1 male to female ratio. Histologically, there were 20 cases of atypical lipomatous tumour/well-differentiated liposarcoma (ALT/WDLPS), 26 cases of dedifferentiated liposarcoma (DDLPS), 13 myxoid liposarcoma (MLPS) and 3 pleomorphic liposarcoma (PLPS). Tumors with DDLPS (23/26) and WDLPS (8/20) were localized retroperitoneally, while both tumours of MLPS and PLPS were localized extra-retroperitoneally, and the difference of sites among the four subtypes of liposarcoma was statistically significant (P < 0.05). Histologically, varied mucoid matrix could be observed in the four subtypes of liposarcoma, and the difference was statistically significant (P < 0.05). MDM2 gene amplification was demonstrated in all cases of ALT/WDLPS and DDLPS (100%, 20/20 and 26/26 respectively); DDIT3 gene rearrangement was noted only in MLPS (100%, 13/13); most cases of DDLPS (96.2%, 25/26) and ALT/WDLPS (83.3%, 5/6, 6 cases selected for detection) demonstrated the picture of amplification of the DDIT3 telomeric tag. According to the instructions of DDIT3 break-apart rearrangement probe, the 5' telomere probe and 3' centromere probe spanned but did not cover the DDIT3 gene itself, on the contrary, the 5' telomere probe covered the CDK4 gene, while the DDIT3 and CDK4 gene were located adjacent to each other on chromosome, therefore, when the amplification signal appeared on the telomeric tag of the DDIT3 rearrangement probe, it indeed indicated the CDK4 gene amplification rather than the DDIT3 gene rearrangement. Then the 10 cases with DDIT3 telomeric tag amplification were selected for CDK4 and DDIT3 gene amplification probe FISH tests, and all the cases showed CDK4 gene amplification (100%, 10/10) and two of the 10 cases demonstrated co-amplification of CDK4 and DDIT3 (20%, 2/10); DDIT3 polysomy detected by DDIT3 gene rearrangement probe was found in 1 case of DDLPS and 2 cases of PLPS (66.7%, 2/3) with morphology of high-grade malignant tumour and poor prognosis.@*CONCLUSION@#Our results indicate that a diagnosis of different subtype liposarcoma could be confirmed based on the application of MDM2 and DDIT3 FISH, combined with clinicopathological findings. It is also noteworthy that atypical signals should be correctly interpreted to guide correct treatment of liposarcomas.

MDM2 Inhibitor RG-7388 Promotes Apoptosis and Cell Cycle Arrest of Diffuse Large B Cell Lymphoma / 肿瘤防治研究

Objective To investigate the effect of MDM2 inhibitor RG-7388 on the proliferation, cell cycle, and apoptosis of diffuse large B-lymphoma (DLBCL) cells. Methods DLBCL cell strains SUDHL2 and HBL1 were treated with 2, 4, and 8 μmol/LRG7388, respectively. Cell proliferation was detected by CCK8 and EdU methods. Apoptosis was measured by Annexin V–FITC/PI double staining and Caspase 3/7-Glo enzyme activity methods. Cell cycle was assessed by flow cytometry. Changes in the expression of cell cycle and apoptosis-related proteins were determined by Western blot. Results The IC50 of RG7388 for inhibiting SUDHL2 and HBL1 cells were 3.36 and 3.76 μmol/L, respectively, and the inhibitory effect of RG7388 was dose dependent. The proportions of G1 phase and apoptotic cells in the SUDHL2 and HBL1 cells treated with different doses of RG7388 were significantly higher than those in the control group (all P<0.05). The activity of Caspase 3/7 increased gradually with RG7388 concentration, compared with that in the control group. The expression levels of p53, p27, p21, and PARP increased, whereas the expression of Mcl-1 and Bcl-xL was down-regulated (all P<0.05). Conclusion MDM2 inhibitor RG-7388 inhibits the proliferation of DLBCL cells, triggers cell cycle arrest in the G1 phase, and induces apoptosis through the p53 pathway.

TRIB3 promotes pulmonary fibrosis through inhibiting SLUG degradation by physically interacting with MDM2

Pulmonary fibrosis (PF) is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration (LAR). Here, we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells (AEC2s). The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells (AEC1s). We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s, which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK, two critical kinases supporting LAR, leading to LAR failure. TRIB3, a stress sensor, interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination. Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF. Our study reveals a mechanism of the TRIB3-MDM2-SLUG-SLC34A2 axis causing the LAR failure in PF, which confers a potential strategy for treating patients with fibroproliferative lung diseases.

Detection of MDM2 gene amplification on tissue microarray-based Fluorescence In-Situ Hybridization (FISH) in well-differentiated and dedifferentiated liposarcomas, displaying a wide morphological spectrum: A validation study at a tertiary cancer referral centre

Background: Liposarcomas including atypical lipomatous tumors (ALT)/well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPSs) display a histomorphological spectrum with their several diagnostic mimics. Murine double minute 2(MDM2) gene amplification characterizes ALT/WDLPS and DDLPS. Presently, there is no documented study from our subcontinent on the validation of MDM2 gene testing in these tumors. Material and Methods: Twenty-eight cases, diagnosed as ALT/WDLPS (n = 5) and DDLPSs (n = 23), along with 10 other tumors were tested for MDM2 gene amplification, using fluorescence in situ hybridization (FISH) on tissue microarrays (TMAs). Fourteen cases, diagnosed as ALT/WDLPS and DDLPS, along with 49 other tumors were tested for MDM2 immunostaining. Twenty tumors were tested for p16INK4a immunostaining. Results: FISH was interpretable in 25 (89.2%) cases. Among the 20 cases diagnosed as DDLPSs, 19 displayed MDM2 gene amplification. Among the 5 cases diagnosed as ALT/WDLPS, four showed MDM2 gene amplification. Finally, 19 cases were confirmed as DDLPS and 4 as ALT/WDLPS. Furthermore, 7/19 cases confirmed as DDLPS and all 4 cases as ALT/WDLPS tested for MDM2 immunostaining, displayed its diffuse immunoexpression, while a single case of DDLPS showed its focal immunostaining. None of the 49 control cases displayed diffuse MDM2 immunoexpression. ALL 16 DDLPSs and 4 cases of ALT/WDLPS displayed p16INK4a immunostaining. The sensitivity for diffuse MDM2 immunostaining was 87.5% in cases of DDLPS, 100% in ALT/WDLPS, and specificity was 100%. The sensitivity for MDM2 gene amplification was 94.7% in cases of DDLPS and 100% in cases of ALT/WDLPS. The sensitivity for p16INK4a was 100%. Conclusion: This constitutes the first sizable study on MDM2 testing in ALT/WDLPS and DDLPS from our subcontinent using TMAs. MDM2 gene amplification testing continues as the diagnostic gold standard for ALTs/WDLPSs and DDLPSs and is useful in cases of diagnostic dilemmas. Diffuse MDM2 (IF2 clone) and p16INK4a immunostaining, together seem useful for triaging cases for FISH.

Design of ultrahigh-affinity and dual-specificity peptide antagonists of MDM2 and MDMX for P53 activation and tumor suppression

Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53

Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

The dose-related adverse effects of MDM2‒P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2‒P53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC

Recent advances of MDM2-p53 inhibitors / 药学学报

Protein-protein interactions (PPI) are involved in a variety of biological processes, including cell-to-cell interactions, metabolism and development control. The misregulation, post-translational modification and interference of PPI are related to a variety of human diseases, making the regulation of these interactions a very attractive field of drug discovery. In recent years, the interaction between MDM2 and p53 has become a research hotspot, which plays an important role in the treatment of tumors. But unfortunately there are no such inhibitors approved all over the world. In this view, recent advances of MDM2-p53 inhibitors were briefly described and its inhibitors with potential therapeutic activities in clinical studies were introduced.

Research progress of p53-MDM2/MDM4 related anti-tumor drugs and their mechanisms / 中国肿瘤生物治疗杂志

@#[摘 要] 由抑癌基因TP53编码的p53是体内最重要的抑癌因子之一。MDM2/MDM4是p53的负向调控因子，通过p53-MDM2/MDM4负反馈环路调控p53功能。几乎所有肿瘤均存在p53异常，主要包括p53突变和MDM2/MDM4扩增引起的p53失活。p53相关药物研发一直是肿瘤研究中的热点，然而，直到最近10年才研发出相对成熟的药物。目前，以逆转p53失活为目标的药物研发存在以下几种设计思路：（1）诱导突变p53恢复野生型功能，如PRIMA-1/PRIMA-1MET、COTI-2；（2）促进突变p53降解，如Ganetespib、伏立诺他；（3）阻断MDM2/MDM4，如RG7388、ALRN-6924等。上述药物均已进入临床试验，其中伏立诺他、PRIMA-1MET和ALRN-6924已分别在卵巢癌及骨髓增生异常综合征、皮肤T细胞淋巴瘤、急性髓系白血病中取得较好的疗效。进一步阐明p53-MDM2/MDM4环路异常在肿瘤中的作用机制，对于未来研发p53相关抗肿瘤药物以及指导临床用药具有重要意义。

Discovery of bepridil as a valuable lead compound with potent p53-MDM2 inhibitory activity / 药学实践杂志

Objective To find novel lead compounds as p53-MDM2 inhibitors by drug repurposing strategy. Methods The p53-MDM2 inhibitory activities of compounds were determined by FP and western blotting. MTT method was used to determine the in-vitro antitumor activities. The metabolites in human liver microsomes were tested. Results Bepridil showed excellent in-vitro anti-tumor activity and strong p53-MDM2 protein binding inhibitory activity, which can significantly reduce the expression of MDM2 protein in a dose-dependent manner. The metabolites in human liver microsomes are mainly benzene ring hydroxyl mono-oxidation metabolites. Conclusion Bepridil can be used as a lead compound for p53-MDM2 protein binding small molecule inhibitors for subsequent structural optimization design studies.

Extract from Zanthoxylum piperitum Induces Apoptosis of AGS Gastric Cancer Cells Through Akt/MDM2/p53 Signaling Pathway / 中国结合医学杂志

OBJECTIVE@#To determine the effect of Zanthoxylum piperitum extracet (ZPE) on apoptosis and analyze anticancer substances in ZPE, changes in proteins related to apoptosis, and pathological changes in tumors in mouse.@*METHODS@#Fifteen 4-week-old female BALB/c nu/nu mice were divided into 3 groups depending on ZPE dose, with 5 in each group. AGS gastric carcinoma cells (1 × 10@*RESULTS@#High performance liquid chromatography (HPLC) analysis showed that ZPE contained organic sulfur compounds such as alliin and S-allylcysteine. MTT assay results revealed that ZPE (10-85 µ g/mL) could effectively inhibit the growth of AGS gastric cancer cells at higher concentrations (P<0.05, P<0.01). The annexin V & dead cell staining assay and cell cycle arrest assay confirmed a dose-dependent increase in the apoptosis rate and G@*CONCLUSION@#ZPE decreases AGS cell proliferation and induces apoptosis by inhibiting Akt and MDM2 expression.

Clinicopathological features of dedifferentiated liposarcomas with meningothelial-like whorls: report of six cases / 中华病理学杂志

To investigate the histopathologic, immunohistochemical, molecular genetic characteristics of dedifferentiated liposarcomas with meningothelial-like whorls(DDLMW). Six cases of DDLMW diagnosed at Jiangsu Province Hospital(the First Affiliated Hospital of Nanjing Medical University) from March 2012 to August 2018 were enrolled. The cases were analyzed by routine HE staining, immunohistochemistry(MDM2, CDK4 and p16) and fluorescent in-situ hybridization(FISH) on MDM2 gene. Related literatures were also reviewed. Three of the 6 patients were male.The patient ages ranged from 40 to 77 years (mean, 58 years). Four tumors occurred in the retroperitoneum and two in the mediastinum. Histologically, the tumors showed, in addition to foci of well-differentied liposarcoma, characteristic, scattered meningothelial-like concentrical whorls. The whorls were composed of tightly, concentrically arranged, spindle to ovoid cells with mild to mederate cytological atypia. Metaplastic bone was present within or in their immediate vicinity in four case. The tumors cell also showed strong and diffuse immunoreactivity to MDM2, CDK4 and p16, but no immunoreactivity to S-100 protein, SMA, SOX10, EMA, CD21, CD23 or CD35. The Ki-67 labeling indexes were low, while FISH showed high levels of MDM2 amplification in all cases. DDLMW is a rare morphologic variant of dedifferentiated liposarcoma. The whorls in DDLMW do not represent perineurial or follicular dendritic differentiation. Recognition and familiarity with its existence, as well as combined application of immunohistochemical staining and MDM FISH, are important to avoid confusion with other lesions.

Clinicopathological features of dedifferentiated liposarcomas with meningothelial-like whorls: report of six cases / 中华病理学杂志

Objective@#To investigate the histopathologic, immunohistochemical, molecular genetic characteristics of dedifferentiated liposarcomas with meningothelial-like whorls(DDLMW).@*Methods@#Six cases of DDLMW diagnosed at Jiangsu Province Hospital(the First Affiliated Hospital of Nanjing Medical University) from March 2012 to August 2018 were enrolled. The cases were analyzed by routine HE staining, immunohistochemistry(MDM2, CDK4 and p16) and fluorescent in-situ hybridization(FISH) on MDM2 gene. Related literatures were also reviewed.@*Results@#Three of the 6 patients were male.The patient ages ranged from 40 to 77 years (mean, 58 years). Four tumors occurred in the retroperitoneum and two in the mediastinum. Histologically, the tumors showed, in addition to foci of well-differentied liposarcoma, characteristic, scattered meningothelial-like concentrical whorls. The whorls were composed of tightly, concentrically arranged, spindle to ovoid cells with mild to mederate cytological atypia. Metaplastic bone was present within or in their immediate vicinity in four case. The tumors cell also showed strong and diffuse immunoreactivity to MDM2, CDK4 and p16, but no immunoreactivity to S-100 protein, SMA, SOX10, EMA, CD21, CD23 or CD35. The Ki-67 labeling indexes were low, while FISH showed high levels of MDM2 amplification in all cases.@*Conclusions@#DDLMW is a rare morphologic variant of dedifferentiated liposarcoma. The whorls in DDLMW do not represent perineurial or follicular dendritic differentiation. Recognition and familiarity with its existence, as well as combined application of immunohistochemical staining and MDM FISH, are important to avoid confusion with other lesions.

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives

Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers. Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure-activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions.

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

Simultaneous inhibition of MDM2 and CDK4 may be an effective treatment against glioblastoma. A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids for this purpose have been developed. Appropriate stereochemistry in THN-fused spirooxindole compounds is key to their inhibitory activity: selectivity differed by over 40-fold between the least and most potent stereoisomers in time-resolved FRET and KINOMEscan® assays. Studies in glioblastoma cell lines showed that the most active compound induced apoptosis and cell cycle arrest by interfering with MDM2 -P53 interaction and CDK4 activation. Cells treated with showed up-regulation of proteins involved in P53 and cell cycle pathways. The compound showed good anti-tumor efficacy against glioblastoma xenografts in mice. These results suggested that rational design, asymmetric synthesis and biological evaluation of novel tetrahydronaphthalene fused spirooxindoles could generate promising MDM2-CDK4 dual inhibitors in glioblastoma therapy.

Molecular mechanism of miR-221 promoting apoptosis of human retinal vascular endothelial cells induced by high glucose by regulating p53/MDM2 signaling pathway / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To study the effect of miR-221 on apoptosis of high glucose-induced human retinal vascular endothelial cells and to explore its mechanism. <p>METHODS: High-glucose-induced HRCECs were established by treatment of HRCECs cells with glucose at 30mmol/L for 48h; HG+miR-NC group(transfected miR-NC), HG+miR-221 group(transfected miR-221 mimics), HG+anti-miR-NC group(transfected anti-miR-NC), HG+anti-miR-221 group(transfected anti-miR-221), HG+miR-221+pcDNA 3.1 group(co-transfected miR-221 mimics and pcDNA 3.1), HG+miR-221+pcDNA 3.1-MDM2 group(co-transfected miR-221 mimics and pcDNA 3.1-MDM2), transfected into HRCECs cells by liposome method, and then treated with high glucose; qRT-PCR method for detection the expression of miR-221, p53 and MDM2; the protein expression of p53 and MDM2 were detected by Western blot. The apoptosis of cells was detected by flow cytometry. <p>RESULTS: Compared with NG group, the expression of miR-221 and p53 was significantly increased, the expression of MDM2 was significantly decreased, and the apoptosis rate was significantly increased in high glucose-induced HRCECs. Overexpression of miR-221 induced apoptosis of high glucose-induced HRCECs cells is more obvious. Inhibition of miR-221 can down-regulate the apoptosis of high glucose-induced HRCECs and down-regulate p53, up-regulate MDM2; overexpression of MDM2 can reverse the inhibition by miR-221 anti-apoptotic effect of cells and regulation of p53 and MDM2 of high-glucose-induced HRCECs. <p>CONCLUSION: miR-221 can promote the apoptosis of high-glucose-induced human retinal vascular endothelial cells, and its mechanism is related to p53/MDM2 signaling pathway.

The role of MDM2/p53 pathway in regulating apoptosis of multiple myeloma RPMI8226 cells / 西安交通大学学报(医学版)

Objective:To study the regulatory effect and mechanism of MDM2/p53 pathway on apoptosis in multiple myeloma (MM). Methods: RPMI8226 cells were cultured in vitro and divided into Nutlin-3a group, control group and blank group. CCK-8 method was used to detect the cell inhibition rate, Western blot was used to detect the expression of apoptosis-related protein, and flow cytometry was used to detect the apoptosis in the two groups. Results: Compared with that in control group, the inhibition rate of cells in the experimental group increased significantly at 24 h, 48 h and 72 h (P<0.05). Compared with those in the control group, the expression levels of MDM2 and Bcl-2 in the experimental group decreased significantly (P<0.05), while the expression level of p53 increased significantly (P<0.05). The apoptosis rate was significantly higher in the experimental group than in the control group at 24 h, 48 h and 72 h (38.42%, 82.26% and 82.74% vs. 4.80%, 8.06% and 14.69%). Conclusion: The degradation trans-activation pathway between MDM2 and p53 affects the expression of Bcl-2, inhibits the proliferation of MM cells, and promotes the apoptosis of MM cells.

Primary colonic liposarcomatosis: report of a case with review of literature

The colon is a rare site of occurrence of liposarcoma, as either the primary site or by secondary involvement from a retroperitoneal liposarcoma. Liposarcomatosis denotes simultaneous occurrence of multiple liposarcomas. There are only 17 cases of primary colonic liposarcoma reported in the English literature­one of which was primary colonic liposarcomatosis. We depict the second case of primary colonic liposarcomatosis in a 57-year-old female who presented with abdominal swelling and pain. On exploratory laparotomy, two large masses were seen arising from the wall of the right colon along with multiple smaller masses attached to the colon. Right hemicolectomy with en bloc excision of the masses was performed along with hysterectomy and pelvic floor repair. Macroscopically, multiple exophytic masses and one endophytic mass were identified. The exophytic masses were of variable size and were found to hang from the colon by a thin pedicle simulating variable-sized appendices epiploicae. Histopathologically, the lesions showed the morphology of well-differentiated liposarcoma. This appears to be a case of primary colonic liposarcomatosis. There is only one other similar case reported in the English literature, to the best of our knowledge.

Dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features: a clinicopathological analysis of five cases / 中华病理学杂志

Objective@#To investigate the clinicopathological features, diagnosis and differential diagnosis of dedifferentiated liposarcoma (DDLPS) with inflammatory myofibroblastic tumor (IMT)-like features.@*Methods@#Five cases of DDLPS with IMT-like features were collected from the First Affiliated Hospital of Nanjing Medical University, the Affiliated Hospital of Nanjing University of Traditional Chinese Medicine and the First People′s Hospital of Qinzhou between 2013 and 2018. EnVision method and fluorescence in situ hybridization (FISH) were used to detect the immunophenotype of the tumor cells and the profile of MDM2 gene amplification respectively.@*Results@#All five cases were male and the median age was 61 (range 53 to 65) years. The clinical symptoms were mainly related to the space-occupying lesions. The tumors were located in duodenal mesentery (two cases), intestinal wall (one case), retroperitoneum (one case), and spermatic cord (one case). Grossly, the tumors were not well encapsulated, ranging from 3 to 13 cm (median 6.7 cm) in diameter, with tan to gray and firm cut surface. Histologically, the dedifferentiated component closely resembled inflammatory myofibroblastic tumor (IMT), with spindle/polygonal/stellate-shaped cells arranged in storiform, sheet-like, or random pattern, with varying degrees of chronic inflammation and fibrosis. All three major patterns seen in IMT (myxoid, cellular and hypocellular fibrous) were observed, the hypocellular fibrous pattern was the most common. Well-differentiated liposarcomatous component was found in the peripheral areas of all the tumors. One case had high grade dedifferentiated component. Four cases were strongly positive for MDM2 and p16. Two cases were positive for SMA, and one case was focally positive for desmin and one for CD34. None of the cases stained for ALK-1. FISH demonstrated MDM2 gene amplification in all five cases. Clinical follow-ups were available in all five cases and the interval ranged from 3 to 66 months (median 23 months). Two patients developed recurrences and one patient had metastasis. The remaining two patients were alive with no evidence of tumor recurrence at 3 and 14 months after surgery respectively.@*Conclusions@#DDLPS with IMT-like features is a more aggressive neoplasm than its histological mimic (IMT), and should not be misdiagnosed as other intermediate or low-grade malignant tumors, such as IMT, sclerosing liposarcoma, inflammatory liposarcoma, aggressive fibromatosis, solitary fibrous tumors, low-grade myofibroblastic sarcoma, and low-grade fibrosarcoma.

Effect of Helicobacter pylori Lipopolysaccharide on Malignant Transformation of Gastric Epithelial Cells by Regulating MDM2 Expression / 胃肠病学

Background: Helicobacter pylori lipopolysaccharide (Hp-LPS) plays an important role in gastric carcinogenesis. Aims: To investigate the regulatory effect of Hp-LPS on MDM2 gene expression and its impact on malignant transformation of gastric epithelial cells. Methods: After stimulated with Hp-LPS 1 μg/mL or Escherichia coli (E. coli)-LPS 1 μg/mL for 24 hours, expression of MDM2 in human gastric epithelial cell line (GES-1) and gastric cancer cell line (HGC-27 and MKN45) was detected by Western blotting. Plasmid containing MDM2 promoter luciferase reporter gene was constructed and transfected into HGC-27 cells, and the relative luciferase activity was measured after treated with Hp-LPS for 24 hours. RNA interference plasmid targeting to MDM2 was constructed and transfected into GES-1, HGC-27, and MKN45 cells, then changes in cell apoptosis and invasiveness were analyzed by flow cytometry and Transwell invasion assay. Growth inhibition of MKN45 and HGC-27 xenograft tumors in nude mice was observed after receiving caudal vein injection of siRNA-hMDMA2-3 for silencing MDM2 expression. Results: Hp-LPS enhanced the transcriptional activity of MDM2 promoter and up-regulated MDM2 protein expression in gastric epithelial and gastric cancer cells. In GES-1, HGC-27, and MKN45 cells transfected with siRNA-hMDMA2-3, the cell apoptosis was increased and the cell invasive capacity was reduced as compared with those transfected with negative control siRNA (P<0.05). Furthermore, the tumor inhibition rate of nude mice treated with siRNA-hMDMA2-3 was increased significantly as compared with those treated with negative control siRNA (P<0.05). Conclusions: Hp-LPS can induce malignant transformation of gastric epithelial cells by up-regulating MDM2 expression. Inhibiting MDM2 expression might suppress the malignant transformation and tumor growth by inducing cell apoptosis and reducing cell invasiveness.