Mediator structure and conformation change.

Mediator is a universal adaptor for transcription control. It serves as an interface between gene-specific activator or repressor proteins and the general RNA polymerase II (pol II) transcription machinery. Previous structural studies revealed a relatively small part of Mediator and none of the gene activator-binding regions. We have determined the cryo-EM structure of the Mediator at near-atomic resolution. The structure reveals almost all amino acid residues in ordered regions, including the major targets of activator proteins, the Tail module, and the Med1 subunit of the Middle module. Comparison of Mediator structures with and without pol II reveals conformational changes that propagate across the entire Mediator, from Head to Tail, coupling activator- and pol II-interacting regions.

A proposal for grading the risk of lymph node metastasis after endoscopic resection of T1 colorectal cancer.

PURPOSE: At present, for patients with early colorectal cancer as long as having any one risk factor of lymph node metastasis (LNM) after endoscopic resection (ER), additional surgery will be considered, regardless of the degree of LNM risk; however, most patients are free of LNM. This study aimed to further grade these patients according to LNM risk. METHODS: We assessed 271 patients with T1 colorectal cancers treated initially with ER to analyze the correlation between LNM-associated risk factors and LNM rate. Differences in this rate between groups were estimated using the χ2 test or Fisher's exact test. RESULTS: Poorly differentiated adenocarcinoma (Por) (3.4% vs. 40%, p < 0.001) and lymphovascular infiltration (LV) (1.6% vs. 29.0%, p < 0.001) were the only parameters correlated with LNM. When we divided the cases into LV-negative (LV(-)) and LV-positive (LV(+)) groups, we found a significantly higher LNM rate in the LV(+) group (29.0% vs. 1.6%, p < 0.001). Additionally, the rate of LNM in those positive for each parameter did not differ from the control rate in the same group, except in the Por subgroup. When the cases were divided into four groups based on the presence of LV infiltration and Por, the LNM rate in each group was 2/233 cases (0.8%) in the LV(-)Por(-) group, 2/7 cases (28.5%) in the LV(-)Por(+) group, 7/28 cases (25.0%) in the LV(+)Por(-) group, and 2/3 cases (66.6%) in the LV(+)Por(+) group. CONCLUSIONS: Based on LV and histological differentiation, patients were classified into three LNM risk grades: low (LNM, 0.8%), moderate (LNM, 25.0-28.5%), and high (LNM, 66.6%).

Hyperglycemia induces PFKFB3 overexpression and promotes malignant phenotype of breast cancer through RAS/MAPK activation.

BACKGROUND: Breast cancer is the most common tumor in women worldwide. Diabetes mellitus is a global chronic metabolic disease with increasing incidence. Diabetes mellitus has been reported to positively regulate the development of many tumors. However, the specific mechanism of hyperglycemic environment regulating breast cancer remains unclear. PFKFB3 (6-phosphofructose-2-kinase/fructose-2, 6-bisphosphatase 3) is a key regulatory factor of the glycolysis process in diabetes mellitus, as well as a promoter of breast cancer. So, we want to explore the potential link between PFKFB3 and the poor prognosis of breast cancer patients with hyperglycemia in this study. METHODS: Cell culture was utilized to construct different-glucose breast cancer cell lines. Immunohistochemistry was adopted to analyze the protein level of PFKFB3 in benign breast tissues, invasive ductal carcinoma with diabetes and invasive ductal carcinoma without diabetes. The Kaplan-Meier plotter database and GEO database (GSE61304) was adopted to analyze the survival of breast cancer patients with different PFKFB3 expression. Western blot was adopted to analyze the protein level of PFKFB3, epithelial-mesenchymal transition (EMT)-related protein and extracellular regulated protein kinases (ERK) in breast cancer cells. Gene Set Cancer Analysis (GSCA) was utilized to investigate the potential downstream signaling pathways of PFKFB3. TargetScan and OncomiR were utilized to explore the potential mechanism of PFKFB3 overexpression by hyperglycemia. Transfections (including siRNAs and miRNA transfection premiers) was utilized to restrain or mimic the expression of the corresponding RNA. Cell functional assays (including cell counting, MTT, colony formation, wound-healing, and cell migration assays) were utilized to explore the proliferation and migration of breast cancer cells. RESULTS: In this study, we demonstrated that the expression of PFKFB3 in breast cancer complicated with hyperglycemia was higher than that in breast cancer with euglycemia through cell experiment in vitro and histological experiment. PFKFB3 overexpression decreased the survival period of breast cancer patients and was correlated with a number of clinicopathological parameters of breast cancer complicated with diabetes. PFKFB3 promoted the proliferation and migration of breast cancer in a hyperglycemic environment and might be regulated by miR-26. In addition, PFKFB3 stimulated epithelial-mesenchymal transition of breast cancer in a hyperglycemic environment. In terms of downstream mechanism exploration, we predicted and verified the cancer-promoting effect of PFKFB3 in breast cancer complicated with hyperglycemia through RAS/MAPK pathway. CONCLUSIONS: In conclusion, PFKFB3 could be overexpressed by hyperglycemia and might be a potential therapeutic target for breast cancer complicated with diabetes.

Expression of SET domain bifurcated histone lysine methyltransferase 1 and its clinical prognostic significance in hepatocellular carcinoma.

BACKGROUND: To detect the expression of histone methyltransferase SETDB1 in hepatocellular carcinoma, and to analyze the relationship between SETDB1 expression and tumor size, microvascular invasion, pTNM stage, gender, age, tumor number, tumor differentiation, and other clinicopathological characteristics. METHODS: Immunohistochemical method was used to detect the expression of SETDB1 proteins in liver cancer tissues and adjacent tissues of 100 cases. The qRT-PCR method was used to detect the expression of SETDB1 mRNA in hepatocellular carcinoma and adjacent tissues of 64 cases. RESULTS: The expression of SETDB1 protein and mRNA in hepatocellular carcinoma was higher than that of adjacent normal liver tissue (p < 0.05). High protein expression of SETDB1 was associated with tumor size, MVI presence, and pTNM stage (p < 0.05). Univariate analysis revealed that the tumor size, tumor differentiation, MVI grade, and pTNM stage were correlated with DFS, while tumor size, MVI grade, pTNM stage, and SETDB1 protein expression were correlated with OS. Multivariate analysis showed that the combination of MVI grade and pTNM stage has statistical significance in predicting prognosis, while SETDB1 protein expression was not significant prognosis factor. CONCLUSIONS: SETDB1 has a certain role in HCC progression and may act as a prognostic predictor concerning the survival of HCC patients.

Circular RNA UBAP2 contributes to tumor growth and metastasis of cervical cancer via modulating miR-361-3p/SOX4 axis.

BACKGROUND: Increasing researches have reported that circular RNA UBAP2 (circUBAP2) may be a potential prognosis biomarker and participate in the development of several cancers; however, the role of circUBAP2 in cervical cancer (CC) remains largely unclear. METHODS: We applied qRT-PCR and Western blot to examine expression levels of circUBAP2, miR-361-3p, SOX4, Bax, Bcl-2, Cleaved caspase 3, N-cadherin, Vimentin and E-cadherin. Cell proliferation, apoptosis, invasion and migration were analyzed by MTT assay, Flow cytometry, and Transwell assay, respectively. The interaction between miR-361-3p and circUBAP2 or SOX4 was confirmed by luciferase reporter assay and pull-down assay. Murine xenograft model was established by injecting SiHa cells which stably transfected sh-circUBAP2. RESULTS: CircUBAP2 was up-regulated in CC tissues and cell lines and high circUBAP2 expression predicated poor outcome. Knockdown of circUBAP2 suppressed cell proliferation, migration, invasion and EMT, while induced apoptosis in CC in vitro, and inhibited tumor growth and metastasis in vivo. MiR-361-3p directly bound to circUBAP2 or SOX4, and circUBAP2 could regulate SOX4 expression by sponging miR-361-3p in CC cells. Furthermore, rescue assay results demonstrated that the inhibitory effects of circUBAP2 knockdown on cell growth and metastasis were partially reversed by miR-361-3p down-regulation or SOX4 up-regulation in CC. CONCLUSION: CircUBAP2 represents a prognostic marker and contributes to tumor growth and metastasis via modulating miR-361-3p/SOX4 axis in CC, which indicates a potential therapeutic target for CC treatment.

Underwater versus conventional endoscopic mucosal resection for small size non-pedunculated colorectal polyps: a randomized controlled trial : (UEMR vs. CEMR for small size non-pedunculated colorectal polyps).

BACKGROUND: Underwater endoscopic mucosal resection (UEMR) is a recently developed technique and can be performed during water-aided or ordinary colonoscopy for the treatment of colorectal polyps. The objective of this clinical trial was to evaluate the efficacy and safety of UEMR in comparison with conventional endoscopic mucosal resection (CEMR) of small non-pedunculated colorectal polyps. METHODS: Patients with small size, non-pedunculated colorectal polyps (4-9 mm in size) who underwent colonoscopic polypectomy were enrolled in this multicenter randomized controlled clinical trial. The patients were randomly allocated to two groups, an UEMR group and a CEMR group. Efficacy and safety were compared between groups. RESULTS: In the intention-to-treat (ITT) analysis, the complete resection rate was 83.1% (59/71) in the UEMR group and 87.3% (62/71) in the CEMR group. The en-bloc resection rate was 94.4% (67/71) in the UEMR group and 91.5% (65/71) in the CEMR group (difference 2.9%; 90% CI - 4.2 to 9.9%), showed noninferiority (noninferiority margin - 5.7% < - 4.2%). No significant difference in procedure time (81 s vs. 72 s, P = 0.183) was observed. Early bleeding was observed in 1.4% of patients in the CEMR group (1/71) and 1.4% of patients in the UEMR group (1/71). None of the patients in the UEMR group complained of postprocedural bloody stool, whereas two patients in the CEMR group (2/64) reported this adverse event. CONCLUSION: Our results indicate that UEMR is safer and just as effective as CEMR in En-bloc resection for the treatment of small colorectal polyps as such, UEMR is recommended as an alternative approach to excising small and non-pedunculated colorectal adenomatous polyps. TRIAL REGISTRATION: Clinical Trials.gov, NCT03833492 . Retrospectively registered on February 7, 2019.

Crystal Structure and Thermostability Characterization of Enterovirus D68 3Dpol.

Enterovirus D68 (EV-D68) is one of the many nonpolio enteroviruses that cause mild to severe respiratory illness. The nonstructural protein 3Dpol is an RNA-dependent RNA polymerase (RdRP) of EV-D68 which plays a critical role in the replication of the viral genome and represents a promising drug target. Here, we report the first three-dimensional crystal structure of the RdRP from EV-D68 in complex with the substrate GTP to 2.3-Å resolution. The RdRP structure is similar to structures of other viral RdRPs, where the three domains, termed the palm, fingers, and thumb, form a structure resembling a cupped right hand. Particularly, an N-terminal fragment (Gly1 to Phe30) bridges the fingers and the thumb domains, which accounts for the enhanced stability of the full-length enzyme over the truncation mutant, as assessed by our thermal shift assays and the dynamic light scattering studies. Additionally, the GTP molecule bound proximal to the active site interacts with both the palm and fingers domains to stabilize the core structure of 3Dpol Interestingly, using limited proteolysis assays, we found that different nucleoside triphosphates (NTPs) stabilize the polymerase structure by various degrees, with GTP and CTP being the most and least stabilizing nucleosides, respectively. Lastly, we derived a model of the core structure of 3Dpol stabilized by GTP, according to our proteolytic studies. The biochemical and biophysical characterizations conducted in this study help us to understand the stability of EV-D68-3Dpol, which may extend to other RdRPs as well.IMPORTANCE Enterovirus D68 (EV-D68) is an emerging viral pathogen, which caused sporadic infections around the world. In recent years, epidemiology studies have reported an increasing number of patients with respiratory diseases globally due to the EV-D68 infection. Moreover, the infection has been associated with acute flaccid paralysis and cranial nerve dysfunction in children. However, there are no vaccines and antiviral treatments specifically targeting the virus to date. In this study, we solved the crystal structure of the RNA-dependent RNA polymerase of EV-D68 and carried out systematic biophysical and biochemical characterizations on the overall and local structural stability of the wild-type (WT) enzyme and several variants, which yields a clear view on the structure-activity relationship of the EV-D68 RNA polymerase.

Aberrant Expression of miR-142-3p and its Target Gene HMGA1 and FZD7 in Breast Cancer and its Clinical Significance.

BACKGROUND: Breast cancer is the second leading cause of cancer-related death among women worldwide. The aim of this study is to investigate the role of miR-142-3p in breast cancer cells and the related mechanism. METHODS: Sixty paired breast cancer tissues were collected and 60 breast tissues from patients with mammary hyperplasia served as the control group. The expression of miR-142-3p was examined using RT-qPCR methods; moreover, we also performed receiver operating characteristic (ROC) curve analysis to determine whether miR142-3p can distinguish breast cancer patients from the controls. Next, HMGA1 and FZD7 have been predicted as target genes of miR-142-3p, and the expressions of HMGA1 and FZD7 in breast cancer tissue and the control group were examined using RT-qPCR and western blot methods. RESULTS: miR-142-3p was significantly down-regulated in breast cancer tissue compared with the controls, and the levels of miR-142-3p was negatively correlated with the tumor size, degree of differentiation, and metastasis (p < 0.01). Moreover, results of ROC curve analysis indicated that the expression of miR-142-3p can distinguish between patients with breast cancer and the control group (AUC = 0.819, 95% CI, 0.756 - 0.881). Furthermore, the expressions of HMGA1 and FZD7 were significantly up-regulated in patients with breast cancer compared with the controls. The level of miR-142-3p was negatively correlated with expressions of HMGA1 (r = -0.3507, p = 0.006) and FZD7 (r = -0.3410, p = 0.0077) in patients with breast cancer. CONCLUSIONS: Our results proved that miR-142-3p may serve as a tumor suppressor in breast cancer by suppressing the expression of oncogene HMGA1 and FZD7, suggesting that miR-142-3p has the potential to become a diagnostic marker and therapeutic target for the early diagnosis and treatment of breast cancer.

Mucoepidermoid carcinoma of the pancreas: A case report and literature review.

INTRODUCTION: Primary mucoepidermoid carcinoma (MEC) is a common malignant neoplasm of the salivary glands, but is very rare in the pancreas. To date, only 10 cases have been reported in the literature. Because MEC of the pancreas is very rare, there is little information about its diagnosis, treatment, and metastasis. Herein, we present the eleventh case and review the relevant literature. PATIENT CONCERNS: A 65-year-old woman presented with a mass in the body of the pancreas and multiple masses in the liver on abdominal magnetic resonance imaging. The patient initially underwent EUS-guided fine-needle aspiration and was diagnosed with adenocarcinoma. After adjuvant chemotherapy, resection of the pancreatic body and tail was performed, and the tissues were pathologically, histologically, and immunochemically examined. Specific strains and gene rearrangements were analyzed. DIAGNOSIS: Mucoepidermoid pancreatic cancer. INTERVENTION: After a 4-month course of adjuvant chemotherapy, laparoscopic surgery was performed. OUTCOMES: The patient is alive until the submission of this paper. CONCLUSION: We presented a case of mucoepidermoid pancreatic cancer in a 65-year-old woman. Pathological examination revealed that the tumor parenchyma consisted of 3 cell types. There are mainly epidermoid cells, intermediate cells between the basal and epidermoid cells, and mucus-producing cells in varying proportions. Immunohistochemical staining showed that there were different types of cells with unique morphological characteristics. In summary, primary MECs of the pancreas are rare and have poor prognosis. Few studies have been conducted on the diagnosis, treatment, and metastasis of MECs; therefore, further studies are needed to detect them.

A neutrophil elastase inhibitor, sivelestat, attenuates sepsis-induced acute kidney injury by inhibiting oxidative stress.

Background: Sivelestat, a selective inhibitor of neutrophil elastase (NE), can mitigate sepsis-related acute lung injury. However, the role of sivelestat in inhibiting oxidative stress and attenuating sepsis-related acute kidney injury (AKI) remains unclear. Here, we reported the effects of sivelestat against oxidative stress-induced AKI by suppressing the production of oxidative stress indicators. Materials and methods: A male Sprague-Dawley rat model of sepsis was established by cecal ligation and puncture (CLP). Sivelestat or normal saline was administered into jugular vein with a sustained-release drug delivery system. Indicators of inflammation and AKI, including white blood cells (WBC), neutrophils, lymphocytes, C-reactive proteins (CRP), procalcitonin (PCT), blood urea nitrogen (BUN), creatinine (Cr) and uric acid (UA), were assessed at 24 h post-sivelestat treatment. Indicators of liver injury, including direct bilirubin (DBIL), indirect bilirubin (IBIL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), were also assessed at 24 h post-sivelestat treatment. Indicators of oxidative stress, including superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), were assessed at 12 h and 24 h post-sivelestat treatment. At 24 h post-sivelestat treatment, H&E staining of kidney and liver tissue was performed to observe pathological alterations. Results: At 24 h post normal saline or sivelestat (0.2 g/kg body weight) treatment, WBC, neutrophil, CRP, PCT, MDA, BUN, Cr, UA, AST, ALT, DBIL and IBIL were increased, while SOD and GSH-Px were decreased, in septic rats treated with normal saline compared with that in non-septic rats treated with normal saline (all p < 0.05). The changes of these indicators were reversed in septic rats treated with sivelestat compared with that in septic rats treated with normal saline (all p < 0.05). Similar results were found regarding the levels of oxidative stress indicators at 12 h post-sivelestat treatment. The degenerative histopathological changes in both kidney and liver tissues were ameliorated upon sivelestat treatment. Conclusions: Sivelestat plays a protective role in sepsis-related AKI by inhibiting oxidative stress. Our study reveals a possible therapeutic potential of sivelestat for oxidative stress-induced AKI.

Undifferentiated carcinoma of the liver with osteoclast-like giant cells: a case report and literature review.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Osteoclast-like giant cells (OGCs) are relatively more common in pancreatic cancer, but extremely rare in HCC. Currently, there have been only a few reported cases of OGCs in HCC, and their presence indicates an aggressive clinical course. Here, we present a case of primary undifferentiated carcinoma of the liver with OGCs in a 49-year-old male patient, and through a literature review, we summarize 20 similar cases to further understand the diagnosis, treatment, and clinical course of this disease entity.

A retrospective cohort study to observe the efficacy and safety of Endoscopic Submucosal Dissection (ESD) with adjuvant radiotherapy for T1a-MM/T1b-SM Esophageal Squamous Cell Carcinoma (ESCC).

BACKGROUND AND AIM: The clinical outcome of endoscopy submucosal dissection with subsequent radiotherapy for esophageal squamous cell carcinoma remain unclear. In this study we aim to investigate the efficacy and safety of endoscopic submucosal dissection with adjuvant radiotherapy in the treatment of superficial esophageal squamous cell carcinoma involving the muscularis mucosae (T1a-MM) or the submucosa < 200 µm (T1b-SM1). METHODS: We analyzed 20 patients with pathologically confirmed T1a-MM or T1b-SM1 esophageal squamous cell carcinoma treated by endoscopic submucosal dissection from 2016 to 2020 in Lihuili Hospital, 9 patients received adjuvant radiotherapy (RT group) and 11 patients received did not (non-RT group). RESULTS: All 20 patients underwent en bloc resection, and both the vertical and horizontal margins were negative. There was no recurrence or lymph node metastasis in the RT group, and no serious complications or death were observed. In the non-RT group, 2 patients had local recurrence and 1 had distant metastasis. None of the 20 patients died of esophageal carcinoma. CONCLUSIONS: Adjuvant radiotherapy following endoscopic submucosal dissection may be a safe and effective method for the treatment of T1a-MM/T1b-SM1 superficial esophageal squamous cell carcinoma.

Case Report: Clinicopathological characteristics of patients with gastric cancer with features of a submucosal tumour.

Purpose: To investigate the clinicopathological characteristics, diagnosis and key points in the differential diagnosis of patients with gastric cancer (GC) with features of a submucosal tumour (GCSMT). Methods: The clinical presentation and imaging findings of four GCSMT cases diagnosed at our centre from 2016 to 2021 were observed and their clinicopathological outcomes were analysed. The related literature was reviewed. Based on our collected data and the related literature, a total of 31 cases of GCSMT can be summarized. Results: 22 out of 31 cases did not present obvious symptoms and were accidentally discovered during gastroscopic examination. Only 10 patients experienced symptoms such as gastric discomfort, upper abdominal swelling and pain, haematemesis, or haematochezia. The male to female ratio was 22:9 and the age of onset ranged from 40 to 81 years (median age: 63 years). Tumours were located in the upper and middle third of the stomach (24/31), and in the lower third(7/31). The tumour diameter ranged from 0.6 to 7.3 cm, with an average value of 2.5 cm. Endoscopically, the disease manifested as SMTs, with the gastric mucosal surface appearing normal. Most patients underwent radical gastrectomy for GC (80.6%, 25/31). The pathological diagnoses of the 31 cases of GCSMT included well- and moderately-differentiated adenocarcinoma (6/31), poorly differentiated adenocarcinoma or signet ring cell carcinoma 6/31), mucinous adenocarcinoma (9/31), lymphoepithelioma-like carcinoma (7/31), gastric adenocarcinoma of the fundic gland type (3/31). Stage T1b and T2 tumours accounted for 56.7% (17/30) and 26.7% (8/30) of all cases. Lymph node metastases were found in six cases (20.0%, 6/30), whereas distant metastasis was not observed in any of the cases. For the 16 patients whose follow-up data were available, the follow-up time was 5-66 months, during which recurrence or metastasis was not observed. Conclusion: GCSMT is a rare disease that is often difficult to accurately diagnose through endoscopic biopsy. The importance of gaining an understanding of this disease lies in differentiating it from other SMTs (mostly mesenchymal tumours) to avoid misdiagnosis and missed diagnosis and enable the early diagnosis and treatment of patients.

Giant desmoplastic small round cell tumor of the abdomen: A case report.

Background: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, mesenchymal malignancy of a separate clinicopathological entity. It has a predilection for young men, with no evidence of any ethnic predilection. The current diagnostic gold standard for DSRCT includes histopathologic, immunohistochemical, and cytogenetic studies in order to confirm the variable phenotypic expression and characteristic chromosomal translocation. Case summary: A 65-year-old man presented with a sensation of an abdominal mass and a presentation of an incomplete bowel obstruction. Initial lab tests were in the normal range except for carbohydrate antigen. Contrast-enhanced CT showed that a large, mass-confounding density was occupied in the omentum majus area of the middle and lower abdominal wall. A 3D reconstruction of the images was performed to clarify the relationship between the tumor and the colon and was confirmed by a colonoscopy. After surgery, immunohistochemistry and fluorescence in situ hybridization (FISH) revealed EWSR1-WT1 gene rearrangement at 22q12, confirming the diagnosis of desmoplastic small round cell tumor. Conclusion: Being different from the predilection of DSRCT for young men, the patient in our case is a 65-year-old man with a huge mass involving the transverse colon and the bladder.

Clinicopathological features of early stage gastric adenocarcinoma of fundic gland type: Case series.

INTRODUCTION: Gastric adenocarcinoma of the fundic gland type (GA-FG) is characterized by a well-differentiated neoplasm. More than 100 cases have been reported, but only a few cases have been described in China. Therefore, its clinicopathological characteristics need to be investigated further. Herein, we report five cases and briefly review the relevant literature. PATIENT CONCERNS: Five patients, including three women and two men, were identified in the Ningbo Clinical Pathological Diagnosis Center between March 2017 and July 2020. Patients (case 1, case 2, and case 5) underwent gastroscopy due to epigastric pain. Apart from the lesion, others were occasionally discovered on physical examination. DIAGNOSIS: Gastric adenocarcinoma of the fundic gland type (GA-FG). INTERVENTION: Five patients were treated with endoscopic submucosal dissection. OUTCOMES: Surgical outcomes were good. Esophagogastroduodenoscopy showed a scar with no recurrence, and no postoperative symptoms were observed from 3 to 43 months during the follow-up. CONCLUSION: We present five cases of well-differentiated tubular adenocarcinoma that mimicked the fundic glands. Cell differentiation by MUC2, MUC5AC, MUC6, pepsinogen-I, and H+/K+-ATPase. Immunohistochemical findings in GA-FG suggested differentiation of the fundic glands. In addition, it has a low proliferation. p53 and Her-2 were negative, and ß-catenin was positive in the cytoplasm, indicating that the pathogenesis of this tumor was different from that of traditional intestinal and diffuse gastric carcinomas. In summary, this neoplasm is rare and unusual. To better understand this issue, similar cases should be monitored in the future.

Extended pancreato-duodenectomy coupled with adjuvant chemotherapy for SMARCB1/INI1 deficient pancreatic carcinoma: A case report and literature review.

INTRODUCTION: SMARCB1/INI1 gene deletion appears to be associated with a rare, malignant and aggressive form of pancreatic carcinoma whose diagnosis is challenging. Our objective is to illustrate that the tumor may masquerade as a duodenal papillary carcinoma, be difficulty to identify on diagnostic imaging and that making an accurate diagnosis may be challenging, however surgical resection may be possible. CASE REPORT: We present a case of a 24-year old male patient presenting with jaundice and itchy skin, elevated TBIL, AST, ALP and CA125. A 2.2 × 1.7 cm pancreatic nodule, later diagnosed as a SMARCB1/INI deficient pancreatic carcinoma was detected on Endoscopic Ultrasound - Fine Needle Aspiration (EUS-FNA). The patient was successfully treated with extended pancreato-duodenectomy coupled with adjuvant chemotherapy, a 7 × 5 × 5 cm tumor resected. DISCUSSION: SMARCB1/INI deficient pancreatic carcinoma has been reported in couple of other articles. However, unlike other cases, in our case identification and accurate assessment of the tumor was particularly difficulty both on imaging and during operation. Our patient has thus far had a positive outcome with no recurrence. CONCLUSION: For rare forms of pancreatic carcinoma, identification and assessment of the tumor size may be challenging on imaging and during operation. However, careful assessment should be performed before ruling out surgical resection. Furthermore, adjuvant chemotherapy may be beneficial to the patient.

A Novel AKR1C3 Specific Prodrug TH3424 With Potent Antitumor Activity in Liver Cancer.

Overexpression of AKR1C3, an aldo-keto reductase, was recently discovered in liver cancers. In this study, an inverse correlation between AKR1C3 expression and survival of patients with liver cancer was observed. AKR1C3 inhibitors, however, failed to suppress liver cancer cell growth. The prodrug TH3424, which releases a DNA alkylating reagent upon reduction by AKR1C3, was developed to target tumors with overexpression of AKR1C3. TH3424 showed specific killing of liver cancer cells with AKR1C3 overexpression both in vitro and in vivo. In patient-derived mouse xenograft models, TH3424 at doses as low as 1.5 mg/kg eliminated liver tumors with no apparent toxicity. Therefore, TH3424 is a promising drug candidate for liver cancer and other types of cancers overexpressing AKR1C3.

An AKR1C3-specific prodrug with potent anti-tumor activities against T-ALL.

AKR1C3 overexpression has been reported in various types of cancers, including T-ALL. AST-006 (TH-3424), an AKR1C3-specific prodrug, was reported recently to have potent cytotoxicity against liver cancer cells overexpressing AKR1C3 and T-ALL. In this study, AST-006 demonstrated potent anti-tumor activity against different T-ALL cell lines in vitro and in vivo, including patient-derived xenograft (PDX) model. AST-006 also exhibited minimal cytotoxicity against primary human T-cells in vitro and lymphocytes in cynomolgus monkeys in vivo, indicating that AST-006 is a promising therapeutic for T-ALL.

[Clinicopathological study of 5 cases of proximal-type epithelioid sarcoma].

OBJECTIVE: To investigate the clinicopathological characteristics, diagnosis and differential diagnoses of proximal-type epithelioid sarcoma (PES). METHODS: Five cases of PES were retrieved from pathology files. Clinical, pathologic and immunohistochemical features of the tumors were reviewed. RESULTS: One patient was female and 4 were male. Ages of the patients ranged from 19 to 46 years. The sites of the tumor involvement were vulvar (2 cases), hypogastric zone (1 case), anterosuperior iliac spine (1 case) and buttock (1 case). Clinically, the tumor masses were painless and progressive solitary nodules. Microscopically, the tumor cell growth was infiltrative in nature, nodular in appearance with degenerative and necrotic cells at the central areas. The tumors consisted of relatively uniform epithelioid cells with round or oval nuclei and eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for vimentin (5/5), CK (4/5), EMA (4/5), beta-catenin (3/5), CD34 (3/5), and S-100 protein (1/5), but were negative for SMA, MyoD1, Desmin, HMB-45, CK7 and CK20. CONCLUSION: Definitive diagnosis of PES relies on its histopathological characteristics in conjunction with appropriate immunohistochemical findings.