Convolutional LSTM model for cine image prediction of abdominal motion.

Objective.In this study, we tackle the challenge of latency in magnetic resonance linear accelerator (MR-Linac) systems, which compromises target coverage accuracy in gated real-time radiotherapy. Our focus is on enhancing motion prediction precision in abdominal organs to address this issue. We developed a convolutional long short-term memory (convLSTM) model, utilizing 2D cine magnetic resonance (cine-MR) imaging for this purpose.Approach.Our model, featuring a sequence-to-one architecture with six input frames and one output frame, employs structural similarity index measure (SSIM) as loss function. Data was gathered from 17 cine-MRI datasets using the Philips Ingenia MR-sim system and an Elekta Unity MR-Linac equivalent sequence, focusing on regions of interest (ROIs) like the stomach, liver, pancreas, and kidney. The datasets varied in duration from 1 to 10 min.Main results.The study comprised three main phases: hyperparameter optimization, individual training, and transfer learning with or without fine-tuning. Hyperparameters were initially optimized to construct the most effective model. Then, the model was individually applied to each dataset to predict images four frames ahead (1.24-3.28 s). We evaluated the model's performance using metrics such as SSIM, normalized mean square error, normalized correlation coefficient, and peak signal-to-noise ratio, specifically for ROIs with target motion. The average SSIM values achieved were 0.54, 0.64, 0.77, and 0.66 for the stomach, liver, kidney, and pancreas, respectively. In the transfer learning phase with fine-tuning, the model showed improved SSIM values of 0.69 for the liver and 0.78 for the kidney, compared to 0.64 and 0.37 without fine-tuning.Significance. The study's significant contribution is demonstrating the convLSTM model's ability to accurately predict motion for multiple abdominal organs using a Unity-equivalent MR sequence. This advancement is key in mitigating latency issues in MR-Linac radiotherapy, potentially improving the precision and effectiveness of real-time treatment for abdominal cancers.

Artificial Intelligence-Assisted Evaluation of the Spatial Relationship between Brain Arteriovenous Malformations and the Corticospinal Tract to Predict Postsurgical Motor Defects.

BACKGROUND AND PURPOSE: Preoperative evaluation of brain AVMs is crucial for the selection of surgical candidates. Our goal was to use artificial intelligence to predict postsurgical motor defects in patients with brain AVMs involving motor-related areas. MATERIALS AND METHODS: Eighty-three patients who underwent microsurgical resection of brain AVMs involving motor-related areas were retrospectively reviewed. Four artificial intelligence-based indicators were calculated with artificial intelligence on TOF-MRA and DTI, including FN5mm/50mm (the proportion of fiber numbers within 5-50mm from the lesion border), FN10mm/50mm (the same but within 10-50mm), FP5mm/50mm (the proportion of fiber voxel points within 5-50mm from the lesion border), and FP10mm/50mm (the same but within 10-50mm). The association between the variables and long-term postsurgical motor defects was analyzed using univariate and multivariate analyses. Least absolute shrinkage and selection operator regression with the Pearson correlation coefficient was used to select the optimal features to develop the machine learning model to predict postsurgical motor defects. The area under the curve was calculated to evaluate the predictive performance. RESULTS: In patients with and without postsurgical motor defects, the mean FN5mm/50mm, FN10mm/50mm, FP5mm/50mm, and FP10mm/50mm were 0.24 (SD, 0.24) and 0.03 (SD, 0.06), 0.37 (SD, 0.27) and 0.06 (SD, 0.08), 0.06 (SD, 0.10) and 0.01 (SD, 0.02), and 0.10 (SD, 0.12) and 0.02 (SD, 0.05), respectively. Univariate and multivariate logistic analyses identified FN10mm/50mm as an independent risk factor for long-term postsurgical motor defects (P = .002). FN10mm/50mm achieved a mean area under the curve of 0.86 (SD, 0.08). The mean area under the curve of the machine learning model consisting of FN10mm/50mm, diffuseness, and the Spetzler-Martin score was 0.88 (SD, 0.07). CONCLUSIONS: The artificial intelligence-based indicator, FN10mm/50mm, can reflect the lesion-fiber spatial relationship and act as a dominant predictor for postsurgical motor defects in patients with brain AVMs involving motor-related areas.

A carcinoid tumor of the middle ear masquerading as a glomus tympanicum presenting with temporal lobe hemorrhage in a 70-year-old woman: Case report and review of the literature.

BACKGROUND: Paragangliomas in the central nervous system account for 0.6% of all head and neck neoplasms, with glomus tympanicum being the most common middle ear tumor. Carcinoid tumors are neuroendocrine tumors, representing less than 1% of neuroendocrine neoplasms in the middle ear. Misdiagnoses have been reported in the literature regarding glomus and carcinoid tumors, however, none have been in the central nervous system or middle ear. CASE DESCRIPTION: A 70-year-old female with a history of left temporal lobe tumor underwent unsuccessful resection due to intraoperative bleeding at an outside institution. However, biopsy prior to aborting the case led to the diagnosis of paraganglioma. Eight years postoperatively, the patient presented at our institution with acute confusion, aphasia, and altered mental status. Imaging revealed a 4cm left temporal intraparenchymal hematoma at the known tumor site with concern for intracranial tumor extension. Surgical resection was performed and previous symptoms resolved. Final pathology revealed a Grade II atypical carcinoid tumor with an unusually high Ki-67 of 50%. CONCLUSIONS: Carcinoid tumors of the middle ear constitute a differential diagnosis for patients presenting with temporal lobe hemorrhage. A combination of immunohistochemical staining with electron microscopy can assist in differentiating the tumor types. This atypical presentation for a carcinoid tumor in the middle ear suggests the need to consider carcinoid as the diagnosis in patients with a middle ear tumor invading into the temporal lobe and causing hemorrhage. These tumors may demonstrate an unusually high Ki-67 rate, in which case they should be treated aggressively.

[Clinical characteristics and outcomes of 111 neonates with upper airway obstruction admitted via transportation].

Objectives: To analyze the clinical characteristics and outcomes of neonates with upper airway obstruction (UAO) who were admitted via transportation, hence to provide more evidence-based information for the clinical management of UAO. Methods: This was a single center retrospective study. Patients were hospitalized in Beijing Children's Hospital from January 1, 2016 to May 31, 2021 with age <28 days or postmenstrual age (PMA) ≤44 weeks, and UAO as the first diagnosis. The general information of patients, obstructed sites in the upper airway, treatment, complications and prognosis were analyzed. The outcomes of surgical UAO vs. non-surgical UAO were analyzed by 2 by 2 χ2 test. Results: A total of 111 cases were analyzed (2.3% of the total NICU hospitalized 4 826 infants in the same period), in which 62 (55.9%) were boys and 101 (91.0%) were term infants, and their gestational age was (38.7±2.0) weeks, birth weight (3 207±585) g, PMA on admission (40.8±2.5) weeks and weight on admission was (3 221±478) g. There were 92 cases (82.9%) with symptoms of UAO presenting on postnatal day 1, and 35 cases (31.5%) had extra-uterine growth retardation on admission. The diagnosis of UAO and the obstructive site was confirmed in 25 cases (22.5%) before transportation. There were 24 cases (21.6%), 71 cases (64.0%), and 16 cases (14.4%) who had UAO due to nasal, throat, and neck problems, respectively. The top 5 diagnosis of UAO were vocal cord paralysis (28 cases), bilateral choanal atresia (20 cases), laryngomalacia (15 cases), pharynx and larynx cysts (7 cases), and subglottic hemangioma (6 cases). The diagnosis and treatment of all the patients followed a multidisciplinary approach consisted of neonatal intensive care unit, ear-nose-throat department and medical image departments. A total of 102 cases (91.9%) underwent both bronchofiberscope and fiber nasopharyngoscope investigation. Seventy cases (63.1%) required ventilation. Among the 58 cases (52.3%) who required surgical intervention, 16 had tracheotomy. For cases with vs. without surgical intervention, the rate of cure and (or) improvement were 94.8% (55/58) vs. 54.7% (29/53), and the rate of being discharged against medical arrangement were 1.7% (1/58) vs. 45.3% (24/53) (χ²=24.21 and 30.11, both P<0.01). Conclusions: Neonatal UAO may locate at various sites of the upper airway. The overall prognosis of neonatal UAO is favorable. A multidisciplinary approach is necessary for efficient evaluation and appropriate surgical intervention.

Tongxin formula protects H9c2 cardiomyocytes from cobalt chloride-induced hypoxic injury via inhibition of apoptosis.

In this study, the effect of the Tongxin formula (TXF) on the apoptosis of H9c2 cardiomyocytes induced by cobalt chloride (CoCl2) was investigated, and the potential mechanism was explored. A hypoxic injury model of H9c2 cardiomyocytes was established using CoCl2. The cell viability was measured using a Cell Counting Kit-8 assay. The lactate dehydrogenase (LDH) release and caspase-3 activity were measured using spectrophotometry. The apoptosis was measured via Annexin V-FITC/PI staining and flow cytometry. The changes in the mitochondrial membrane potential were examined using immunofluorescence microscopy following the loading of JC-1 probes. The expressions of apoptosis-related proteins and key proteins in the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway were examined via immunoblotting. The different TXF concentrations studied significantly improved the percentage of viability of cardiomyocytes with hypoxic injury, and the LDH release, apoptotic rate, caspase-3 activity, and levels of cleaved caspase-3 protein were reduced in the injured cells. Additionally, the TXF group had increased mitochondrial membrane potential, upregulated expression of Bcl-2 and p-Akt proteins, and significantly reduced expression of cleaved caspase-3 protein in the cells with hypoxic injury. Moreover, in the TXF group, the treatment significantly reduced the BAX protein expression, but the difference was not statistically significant compared with the CoCl2 group. In this study, TXF regulated the expression of apoptosis-related proteins, inhibited apoptosis, increased the mitochondrial membrane potential, and alleviated damage to the mitochondrial membrane, thereby protecting the cardiomyocytes from hypoxic injury. The underlying mechanism could be related to activation of the PI3K/Akt signaling pathway and upregulation of the Bcl-2 protein.

[Application of carbon nanoparticles mapping lymph nodes in curative resection for colorectal carcinoma].

Objective: To investigate the clinical application of carbon nanoparticles mapping lymph nodes in curative resection for colorectal carcinoma. Methods: Patients diagnosed with colorectal cancer before operation and undergoing radical surgery with intact postoperative pathological data in the Sixth Affiliated Hospital, Sun Yat-sen University from March 2016 to March 2018 were included in this retrospective case-control study. Those who were diagnosed with ileus, recurrent carcinoma or underwent emergency operation were excluded. A total of 1421 cases were included, with 156 cases in the carbon nanoparticles mapping group and 1265 cases in the control group. Using 1∶3 case control matching based on gender, weight, TNM staging and neoadjuvant chemotherapy, 145 and 435 cases were finally recruited in the carbon nanoparticles mapping group and control group, respectively. Patients in the carbon nanoparticles mapping group underwent preoperative colonoscopy with carbon nanoparticles submucosal injection 2.4 (1.0 - 14.0) days before operation. Carbon nanoparticles of 0.25 ml was injected at 4 points (3, 6, 9 and 12 o'clock each) 0.5-1.0 cm around the tumor. The number of eliminated lymph node, number of positive lymph node and positive rate between the two groups were compared, and the number of eliminated lymph node in different subgroups of T stage, N stage, TNM stage and neoadjuvant chemotherapy was analyzed and compared. Results: After case control matching, total number of eliminated lymph nodes in the carbon nanoparticles mapping group was significantly higher than that in the control group (22.2±11.2 vs. 19.0±9.5, t=3.025, P=0.003). However, no statistically significant differences were found in the number of positive lymph node and lymph node positive rate between two groups (all P>0.05). Subgroup analysis showed that as compared to the control group, total number of eliminated lymph nodes in the carbon nanoparticles mapping group was significantly higher in T3 stage subgroup (median: 22 vs. 18, Z=2.435, P=0.015), N0 stage subgroup (median: 20.5 vs. 17.5, Z=2.772, P=0.006), TNM II stage subgroup (median: 23.5 vs. 19.0, Z=2.654, P=0.008) and neoadjuvant chemotherapy (median: 22.5 vs. 13.0, Z=3.287, P=0.001), while compared to the control group, the number of positive lymph node (median: 4.0 vs. 6.5, Z=-2.530, P=0.011) and the lymph node metastasis degree (median: 16% vs. 31%, Z=-2.862, P=0.004) were lower in the carbon nanoparticles mapping group in N2 subgroup. Conclusion: Carbon nanoparticles mapping lymph nodes can effectively enhance the number of eliminated lymph nodes in curative resection for colorectal cancer.

LINC00702 accelerates the progression of ovarian cancer through interacting with EZH2 to inhibit the transcription of KLF2.

OBJECTIVE: To clarify the role of LINC00702 in the progression of ovarian cancer (OC) and the potential mechanism. PATIENTS AND METHODS: Expression level of LINC00702 in OC tissues and matched normal tissues was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). LINC00702 level in OC cell lines was determined as well. The potential influences of LINC00702 on cellular behaviors of A2780 and HEY cells were evaluated. The subcellular distribution of LINC00702 in A2780 cells was examined. Through RNA immunoprecipitation (RIP) and Chromatin immunoprecipitation (ChIP) assay, the interaction among LINC00702, EZH2, and KLF2 was verified. The rescue experiments were conducted to elucidate the biological function of LINC00702/KLF2 axis in the progression of OC. RESULTS: LINC00702 was upregulated in OC tissues and cell lines. Its level was much higher in OC with worse tumor stage and larger tumor size. The knockdown of LINC00702 attenuated the proliferative ability of A2780 and HEY cells. LINC00702 was mainly distributed in the cell nucleus. The knockdown of LINC00702 or EZH2 downregulated the KLF2 level in the OC cells. The transfection of LINC00702 markedly reduced the occupancy of KLF2 promoter on EZH2 and H3K27me3 relative to IgG. Finally, the knockdown of KLF2 could reverse the regulatory effect of LINC00702 in the proliferative ability of A2780 cells. CONCLUSIONS: LINC00702 is upregulated in OC. It accelerates the progression of OC via interacting with EZH2 to inhibit the transcription of KLF2.

[Changes of WT1 mRNA expression level in patients with myelodysplastic syndromes after hypomethylating agents and its prognostic significance].

Objective: To monitor the WT1 mRNA level and its dynamic changes in patients with myelodysplastic syndromes (MDS) after hypomethylating agents (HMA) , as well as to assess the significance of WT1 mRNA levels and its dynamic changes in evaluating the efficacy of HMA and distinguishing the disease status of heterogeneous patients with stable disease (SD) . Methods: Bone marrow or peripheral blood samples of 56 patients with MDS who underwent hypomethylating agents (≥4 cycles) from November 2009 to March 2018 were tested by real-time quantitative polymerase chain reaction (PCR) to detect the expression of WT1 mRNA, and to observe the correlation between the dynamic changes of WT1 mRNA expression and clinical efficacy and prognosis of patients. Results: WT1 mRNA expression levels of MDS patients decreased significantly after 3 cycles of hypomethylating agent treatment. Besides, the WT1 mRNA expression levels of patients increased significantly after diseases progression. According to the dynamic changes of WT1 mRNA expression levels during SD, 45 cases could be further divided into increased group and non-increased group. In those SD patients with increased WT1 mRNA expression level, the ratio of suffering disease progression or transformation to AML was 95.65% (22/23) , whereas the ratio turned to be 9.09% (2/22) for the non-increased group (χ(2)=33.852, P<0.001) . Compared with those SD patients reporting no increase in WT1 mRNA expression level, the overall survival[17 (95%CI 11-23) months vs not reached, P<0.001] and progression-free survival [13 (95%CI 8-18) months vs not reached, P<0.001] of those SD patients reporting increase in WT1 mRNA expression level were significantly shorter. Conclusion: WT1 mRNA expression level is a useful indicator to assess the efficacy of hypomethylating agents in MDS patients. Especially in patients with SD, detection of the changes in WT1 mRNA expression level is able to predict disease progression and help to make clinical decision.

[Observation on clinical efficacy and prognosis analysis of endoscopic surgery treatment for rT1-rT2 recurrent nasopharyngeal carcinoma].

Objective:To investigate the feasibility of endoscopic surgery for treatment of rT1-rT2 recurrent nasopharyngeal carcinoma.Method: The clinical data and of 57 patients who had recurrence of the primary lesion after treatment of nasopharyngeal carcinoma from February 2011 to December 2015 were retrospectively analyzed. The patients were re-staged according to Union for International Cancer Control(UICC, 2010) staging system for nasopharyngeal carcinoma before surgery. Patients suitable for surgery underwent endoscopic surgery to remove nasopharyngeal lesions; those combined with cervical lymph node metastases underwent cervical lymph node dissection at the same time; patients with positive surgical margins of pharyngeal lesions and cervical lymph node extramembranous filtration were treated with radiotherapy combined with chemotherapy; patients unsuitable for surgery were treated with radiotherapy combined with chemotherapy directly. All patients were followed up regularly to observe clinical efficacy and survival. Result:Fifty-seven patients were re-staged according to UICC(2010) staging system for nasopharyngeal carcinoma: 19 cases in stage Ⅰ,30 cases in stage Ⅱ, 6 cases in stage Ⅲ and 2 cases in stage Ⅳ,including 27 cases in stage rT1, 30 cases in stage rT2, and 43 cases in stage rN0,6 cases in stage rN1,6 cases in stage rN2,2 cases in stage rN3. Forty-four cases of primary lesions were sected for endoscopic surgery. Patients combined with cervical lymph node metastases underwent cervical lymph node dissection at the same time, with 6 cases of positive surgical margins of pharyngeal lesions and 4 cases of cervical lymph node extramembranous infiltration, who were treated with radiotherapy combined with chemotherapy after surgery. Thirteen patients received radiotherapy combined with chemotherapy directly. At a median follow-up of 36 months, the 3-year overall survival rate of 57 patients was 61.4%. The 3-year overall survival rates of patients in stage Ⅰ, Ⅱ, Ⅲ and Ⅳ were 73.7%, 63.3%, 33.3%, 0.0% respectively. Kaplan-Meier survival curve analysis showed a significant difference in the overall survival rate of patients in different stages(P=0.002). The 3-year overall survival rates of rT1 and rT2 patients were 63.0%, 60.0% respectively, and KaplanMeier survival curve analysis showed no significant difference in the overall survival rate between rT1 and rT2 patients(P=0.707). The 3-year overall survival rates of patients in stages rN0, rN1, rN2, rN3 were 69.8%, 50.0%, 33.3%, 0.0% respectively, and Kaplan-Meier Survival curve analysis showed a significant difference in overall survival between patients in different rN stages(P=0.002). The 3-year overall survival rate was 68.2% in 44 surgical patients, and 38.5% in 13 non-surgical patients. Kaplan-Meier survival curve analysis showed significant difference in overall survival rate between surgical and non-surgical patients(P=0.014).Conclusion: Endoscopic surgery for recurrent nasopharyngeal carcinoma is a safe and effective treatment to improve survival.

RETRACTED: Modulation of macrophage phenotype through controlled release of interleukin-4 from gelatine coatings on titanium surfaces.

Pro-inflammatory phenotype (M1) macrophages initiate angiogenesis, while their prolonged activation can induce chronic inflammation. Anti-inflammatory phenotype (M2) macrophages promote vessel maturation and tissue regeneration. Biomaterials which can promote M2 polarisation after appropriate inflammation should enhance angiogenesis and wound healing. Herein, Interleukin-4 (IL-4), an anti-inflammatory cytokine, was adsorbed onto a titanium surface. Then, a genipin cross-linked gelatine hydrogel was coated onto the surface to delay IL-4 release. The cross-linking degree of the hydrogel was modulated by the different amount of genipin to control release of IL-4. When 0.7 wt% (weight %) genipin was used as a cross-linker, the sample (GG07-I) released less IL-4 within the first several days, followed by a sustained release time to 14 d. Meanwhile, the release rate of IL-4 in GG07-I reached a peak between 3 d and 7 d. In culture with macrophages in vitro, GG07-I and GG07 exhibited good cytocompatibility. The phenotypical switch of macrophages stimulated by the samples was determined by FACS, ELISA and PCR. Macrophages cultured with GG07-I, GG07 and PT were firstly activated to the M1 phenotype by interferon-gamma (IFN-γ). Then, due to the release of IL-4 in 5 to 7 d, GG07-I enhanced CD206, increased the secretion and gene expression of M2 marker, such as interleukin-10 (IL-10), arginase-1 (ARG-1) and platelet derived growth factor-BB (PDGF- BB). GG07-I prompted the switch from M1 to M2 phenotype. Those appropriate secretion of cytokines would benefit both vascularisation and osseointegration. Thus, the biomaterial directing inflammatory reaction has good prospects for clinical treatments.

Identification of genes alternatively spliced in developing maize endosperm.

The process of alternative splicing is critical for the regulation of growth and development of plants. Thus far, little is known about the role of alternative splicing in the regulation of maize (Zea mays L.) endosperm development. RNA sequencing (RNA-seq) data of endosperms from two maize inbred lines, Mo17 and Ji419, at 15 and 25 days after pollination (DAP), respectively, were used to identify genes that were alternatively spliced during endosperm development. Intron retention (IR) in GRMZM2G005887 was further validated using PCR and re-sequencing technologies. In total, 49,000 alternatively spliced events and ca. 20,000 alternatively spliced genes were identified in the two maize inbred lines. Of these, 30 genes involved in amino acid biosynthesis and starch biosynthesis were identified, with IR occurring only in a specific sample, and were significantly co-expressed with ten well-known genes related to maize endosperm development. Moreover, IR in GRMZM2G005887, which encodes a cysteine synthase, was confirmed to occur only in the endosperm of Mo17 at 15 DAP, resulting in the retention of a 121-bp fragment in its 5' untranslated region. Two cis-acting regulatory elements, CAAT-box and TATA-box were observed in the retained fragment in Mo17 at 15 DAP; this could regulate the expression of this gene and influence endosperm development. The results suggest that the 30 genes with IR identified herein might be associated with maize endosperm development, and are likely to play important roles in the developing maize endosperm.

Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T Cells.

Chimeric antigen receptor (CAR) T-cell immunotherapies have shown unprecedented success in treating leukemia but limited clinical efficacy in solid tumors. Here, we generated 1928zT2 and m28zT2, targeting CD19 and mesothelin, respectively, by introducing the Toll/interleukin-1 receptor domain of Toll-like receptor 2 (TLR2) to 1928z and m28z. T cells expressing 1928zT2 or m28zT2 showed improved expansion, persistency and effector function against CD19+ leukemia or mesothelin+ solid tumors respectively in vitro and in vivo. In a patient with relapsed B-cell acute lymphoblastic leukemia, a single dose of 5 × 104/kg 1928zT2 T cells resulted in robust expansion and leukemia eradication and led to complete remission. Hence, our results demonstrate that TLR2 signaling can contribute to the efficacy of CAR T cells. Further clinical trials are warranted to establish the safety and efficacy of this approach.

[Diagnostic value of narrow-band imaging in detection of recurrent nasopharyngeal carcinoma].

Objective: To evaluate the diagnostic value and feasibility of narrow-band imaging in detection of recurrent nasopharyngeal carcinoma (NPC). Methods: One thousand three hundred and sixty-four NPC patients who had completed NPC treatment were enrolled. All patients were followed-up with imaging, serological examination of EB virus and nasopharyngeal endoscopy(WL and NBI mode), in which (1) both white light (WL) and NBI modes were done; (2) positive endoscopic patients were given nasopharyngeal biopsy; (3) using histologic finding as criterion standard, the sensitivity, specificity, accuracy and Yonden's index of two modes were compared. Kappa index was used to evaluate the consistency between the two modes and pathological results respectively; (4) the positive rates of WL and NBI in patients with early recurrent (stage Ⅰ+ Ⅱ) were compared. Results: A total of 265 cases were suspected as having recurrent lesions by endoscopy in WL mode and 68 cases of them were pathologically diagnosed as having NPC; and 82 cases were suspected as having recurrent lesions by endoscopy in NBI mode and 74 cases of them were pathologically diagnosed as having NPC. The sensitivity, specificity, accuracy and Yonden's index of WL mode were 91.89%, 0, 25.09% and -0.0811, respectively, with a kappa of -0.045; the sensitivity, specificity, accuracy and Yonden's index of NBI mode were 100.00%, 95.94%, 97.05% and 0.9594, respectively. Conclusion: NBI has higher sensitivity, specificity, early diagnosis rate and Yonden's index than WL.

Mint3-mediated L1CAM expression in fibroblasts promotes cancer cell proliferation via integrin α5ß1 and tumour growth.

Fibroblasts are some of the major cells in tumour tissues that influence tumour progression and drug resistance. However, our understanding on fibroblast-mediated tumour malignancy remains incomplete. Munc18-1-interacting protein 3 (Mint3) is known as an activator of hypoxia-inducible factor-1 (HIF-1) even during normoxia in cancer cells, macrophages and fibroblasts. Although Mint3 promotes ATP production via glycolysis by activating HIF-1 in cancer cells and macrophages, the biological role of Mint3-mediated HIF-1 activation in fibroblasts remains unclear. To address this, we examined whether Mint3 in fibroblasts contributes to tumour growth. Mint3 depletion in mouse embryonic fibroblasts (MEFs) decreased tumour growth of co-injected human breast cancer cells, MDA-MB-231 and epidermoid carcinoma A431 cells in mice. In MEFs, Mint3 also promoted cancer cell proliferation in vitro in a cell-cell contact-dependent manner. Mint3-mediated cancer cell proliferation depended on HIF-1, and further gene expression analysis revealed that the cell adhesion molecule, L1 cell adhesion molecule (L1CAM), was induced by Mint3 and HIF-1 in fibroblasts. Mint3-mediated L1CAM expression in fibroblasts stimulated the ERK signalling pathway via integrin α5ß1 in cancer cells, and promoted cancer cell proliferation in vitro and tumour growth. In cancer-associated fibroblasts (CAFs), knockdown of MT1-MMP, which promotes Mint3-mediated HIF-1 activation, or Mint3 decreased L1CAM expression. As MEFs, CAFs also promoted cancer cell proliferation in vitro, and tumour growth via Mint3 and L1CAM. In human breast cancer specimens, the number of fibroblasts expressing L1CAM, Mint3 and MT1-MMP was higher in cancer regions than in adjacent benign regions. In addition, more phospho-ERK1/2-positive cancer cells existed in the peripheral region surrounded by the stroma than in the central region of solid breast cancer nest. Thus, Mint3 in fibroblasts might be a good target for cancer therapy by regulating cancer cell-stromal cell communication.

[Association between SORCS1 rs1416406 and therapeutic effect of exenatide].

Objective: To study the relationship between SORCS1 gene rs1416406 and efficiency of exenatide. Methods: Between August 2010 and August 2012, a hundred and one newly diagnosed patients with type 2 diabetes mellitus (T2DM) were from CONFIDENCE study covering 25 university-affiliated hospitals in 13 provinces of China. All patients received exenatide treatment for 48 weeks. Hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), body mass index (BMI), oral glucose tolerance test (OGTT) glucose and insulin levels were measured before and after therapy. ß-cell function was assessed by fasting proinsulin/insulin (PI/I), disposition index (DI) and acute insulin response (AIR). SORCS1 gene rs1416406 was genotyped by improved multiple ligase detection reaction. The relationship between rs1416406 and the glucose-lowering effect as well as ß-cell function improvement of exenatide was analyzed by multiple linear regression. Results: There were statistically significant differences of HbA1c, FPG, 2 h plasma glucose (2 h PG), ß-cell function (PI/I, DI and AIR) and changes of PI/I in three genotypes (GG, GA, AA) of rs1416406 between baseline and 48-week therapy of exenatide (all P<0.05). No statistically significant difference was found in changes of HbA1c, FPG, 2 h PG, DI, AIR except for PI/I, after stratifying by genotypes of rs1416406. Multiple linear regression analysis showed rs1416406 was significantly associated with the PI/I change (P<0.05) after adjustment of age, sex, baseline BMI, HbA1c and PI/I. Conclusion: SORCS1 gene rs1416406 was associated with the PI/I improvement induced by exenatide. Patients carrying GG genotype had greater reduction in PI/I after exenatide treatment as compared with those carrying allele A. The results suggests that the newly diagnosed T2DM patients with GG genotype might obtain more benefit from the early treatment of exenatide .