Deciphering resistancemechanisms and novel strategies to overcome drug resistance in ovarian cancer:a comprehensive review

Ovarian cancer is among the most lethal gynecological cancers,primarily due to the lack of specific symptoms leading to an advanced-stage diagnosis and resistance to chemotherapy.Drug resistance(DR)poses the most significant challenge in treating patients with existing drugs.The Food and Drug Administration(FDA)has recently approved three new therapeutic drugs,including two poly(ADP-ribose)polymerase(PARP)inhibitors(olaparib and niraparib)and one vascular endothelial growth factor(VEGF)inhibitor(bevacizumab)for maintenance therapy.However,resistance to these new drugs has emerged.Therefore,understanding the mechanisms of DR and exploring new approaches to overcome them is crucial for effective management.In this review,we summarize the major molecular mechanisms of DR and discuss novel strategies to combat DR.

Detection of tumor stem cell markers in pancreatic carcinoma cell lines

BACKGROUND: Cancer of the pancreas is the fourth leading cause of cancer death in industrialized countries. In malignancy, actively proliferating cells may be effectively targeted and killed by anti-cancer therapies, but stem cells may survive and support re-growth of the tumor. Thus, new strategies for the treatment of cancer clearly will also have to target cancer stem cells. The goal of the present study was to determine whether pancreatic carcinoma cell growth may be driven by a subpopulation of cancer stem cells. Because previous data implicated ABCG2 and CD133 as stem cell markers in hematopoietic and neural stem/progenitor cells, we analyzed the expression of these two proteins in pancreatic carcinoma cell lines. METHODS: Five established pancreatic adenocarcinoma cell lines were analyzed. Total RNA was isolated and real- time RT-PCR was performed to determine the expression of ABCG2 and CD133. Surface expression of ABCG2 and CD133 was analyzed by flow cytometric analysis. RESULTS: All pancreatic carcinoma cell lines tested expressed significantly higher levels of ABCG2 than non-malignant fibroblasts or two other malignant non- pancreatic cell lines, i.e., SaOS2 osteosarcoma and SKOV3 ovarian cancer. Elevated CD133 expression was found in two out of five pancreatic carcinoma cell lines tested. Using flow cytometric analysis we confirmed surface expression of ABCG2 in all five lines. Yet, CD133 surface expression was detectable in the two cell lines, A818-6 and PancTu1, which exhibited higher mRNA levels.CONCLUSIONS: Two stem cell markers, ABCG2 and CD133 are expressed in pancreatic carcinoma cell lines. ABCG2 and/or CD133 positive cells may represent subpopulation of putative cancer stem cells also in this malignancy. Because cancer stem cells are thought to be responsible for tumor initiation and its recurrence after an initial response to chemotherapy, they may be a very promising target for new drug developments.

TRAIL-induced expression of uPA and IL-8 strongly enhanced by overexpression of TRAF2 and Bcl-xL in pancreatic ductal adenocarcinoma cells

BACKGROUND:The death ligand,tumor necrosis factor(TNF)related apoptosis-inducing ligand(TRAIL),induces apoptosis and non-apoptotic signaling in some tumor cells.The purpose of this study was to investigate the roles of the pro-apoptotic TRAIL receptors,TRAIL-R1 and TRAIL-R2,as well as Bcl-xL and TRAF2 in TRAIL-induced expression of the pro-inflammatory cytokine IL-8 and the invasion-promoting protein urokinase(uPA) in pancreatic ductal adenocarcinoma(PDAC) cells.METHODS:Colo357wt,Colo357/TRAF2,Colo357/Bcl-xL,Panc89 and PancTuI cells were stimulated with TRAIL and uPA and IL-8 expression was detected using real-time PCR.Antagonistic,receptor-specific antibodies were used to investigate the effects of TRAIL-R1 or TRAIL-R2 inhibition.RESULTS:Dose-dependent increases in uPA and IL-8 expression were detected following TRAIL stimulation in PDAC cells.These effects were inhibited when TRAIL-R1 but not TRAIL-R2 was blocked.Overexpression of TRAF2 or Bcl-xL strongly increased TRAIL-mediated upregulation of uPA and IL-8.CONCLUSIONS:In PDAC cells,TRAIL strongly induced uPA and IL-8 via TRAIL-R1.This response was further enhanced in cells overexpressing TRAF2 and Bcl-xL.Therefore,inhibition of the non-apoptotic "side-effects" of TRAIL treatments by inactivation of TRAF2 and Bcl-xL might represent additional relevant strategies for the treatment of pancreatic cancer.

Practical guidelines for the treatment of inflammatory bowel disease

In recent years, great progress has been made regarding the treatment of inflammatory bowel disease (IBD), particularly in the field of biological therapies. Nevertheless, the ultimate treatment is not in sight. With the development of new medication, it has become clear that we need a new understanding of IBD. Therapy needs to fit the different subtypes of IBD; e.g. mild disease in comparison to severe chronic active disease or Crohn's disease with or without fistulation or stenosis. The following article gives a practical overview of actual treatments for IBD. The intention of this article is not to provide a complete review of all new scientific developments, but to give a practical guideline for therapy of IBD.

Intraoperative perfusion magnetic resonance imaging: Cutting-edge improvement in neurosurgical procedures

The goal in brain tumor surgery is to remove the maxi-mum achievable amount of the tumor, preventing damage to "eloquent" brain regions as the amount of brain tumor resection is one of the prognostic factors for time to tumor progression and median survival. To achieve this goal, a variety of technical advances have been in-troduced, including an operating microscope in the late 1950 s, computer-assisted devices for surgical navigation and more recently, intraoperative imaging to incorporate and correct for brain shift during the resection of the lesion. However, surgically induced contrast enhancement along the rim of the resection cavity hampers interpretation of these intraoperatively acquired magnetic resonance images. To overcome this uncertainty, perfusion techniques [dynamic contrast enhanced magnetic resonance imaging(DCE-MRI), dynamic susceptibility contrast magnetic resonance imaging(DSC-MRI)] have been introduced that can differentiate residual tumor from surgically induced changes at the rim of the resec-tion cavity and thus overcome this remaining uncer-tainty of intraoperative MRI in high grade brain tumor resection.

Interleukin-6: a villain in the drama of pancreatic cancer development and progression

BACKGROUND： Pancreatic ductal adenocarcinoma（PDAC）is a devastating malignancy with a poor prognosis and little treatment options. The development and progression of the disease is fostered by inflammatory cells and cytokines. One of these cytokines is interleukin-6（IL-6）, which plays an important role in a wide range of biologic activities.DATA SOURCES： A systematic search of PubMed was performed to identify relevant studies using key words such as interleukin-6,inflammatory cytokines, inflammation and pancreatic cancer or PDAC. Articles related to IL-6 and pancreatic cancer were systematically reviewed.RESULTS： IL-6 is elevated in the serum of pancreatic cancer patients and correlates with cachexia, advanced tumor stage and poor survival. Its expression is enhanced by hypoxia and proteins involved in pancreatic cancer development like Kras,mesothelin or ZIP4. IL-6 in turn contributes to the generation of a pro-tumorigenic microenvironment and is probably involved in angiogenesis and metastasis. In experimental mouse models of PDAC, IL-6 was important for the development and progression of precursor lesions.CONCLUSION： IL-6 emerges as a key player in pancreatic cancer development and progression, and hence should be considered as a new therapeutic target.

Significance of an additional unenhanced scan in computed tomography angiography of patients with suspected acute aortic syndrome

AIM To assess potential benefits of an additional unenhanced acquisition in computed tomography angiography(CTA) in patients with suspected acute aortic syndrome(AAS).METHODS A total of 103 aortic CTA(non-electrocardiography-gated, 128 slices) performed due to suspected AAS were retrospectively evaluated for acute aortic dissection(AAD), intramural hematoma(IMH), or penetrating aortic ulcer(PAU). Spiral CTA protocol consisted of an unenhanced acquisition and an arterial phase. If AAS was detected, a venous phase(delay, 90 s) was added. Images were evaluated for the presence and extent of AAD, IMH, PAU, and related complications. The diagnostic benefit of the unenhanced acquisition was evaluated concerning detection of IMH.RESULTS Fifty-six(30% women; mean age, 67 years; median, 68 years) of the screened individuals had AAD or IMH. A triphasic CT scan was conducted in 76.8%(n =43). 56% of the detected AAD were classified as Stanford type A, 44% as Stanford type B. 53.8% of the detected IMH were classified as Stanford type A, 46.2% as Stanford type B. There was no significant difference in the involvement of the ascending aorta between AAD and IMH(P = 1.0) or in the average age between AAD and IMH(P = 0.548), between Stanford type A and Stanford type B in general(P = 0.650) and between Stanford type A and Stanford type B within the entities of AAD and IMH(AAD: P = 0.785; IMH: P = 0.146). Only the unenhanced acquisitions showed a significant density difference between the adjacent lumen and the IMH(P = 0.035). Subadventitial hematoma involving the pulmonary trunk was present in 5 patients(16%) with Stanford A AAD. The difference between the median radiation exposure of a triphasic(2737 mGy*cm) compared to a biphasic CT scan(2135 mGy*cm) was not significant(P = 0.135).CONCLUSION IMH is a common and difficult to detect entity of AAS. An additional unenhanced acquisition within an aortic CTA protocol facilitates the detection of IMH.

Accuracy of myocardial viability imaging by cardiac MRI and PET depending on left ventricular function

AIM To compare myocardial viability assessment accuracy of cardiac magnetic resonance imaging(CMR)compared to[^(18)F]-fluorodeoxyglucose(FDG)-positron emission tomography(PET)depending on left ventricular(LV)function.METHODS One-hundred-five patients with known obstructive coronary artery disease(CAD)and anticipated coronary revascularization were included in the study and examined by CMR on a 1.5T scanner.The CMR protocol consisted of cine-sequences for function analysis and late gadolinium enhancement(LGE)imaging for viability assessment in 8 mm long and contiguous short axis slices.All patients underwent PET using[^(18)F]-FDG.Myocardial scars were rated in both CMR and PET on a segmental basis by a 4-point-scale:Score 1=no LGE,normal FDG-uptake;score 2=LGE enhancement<50% of wall thickness,reduced FDG-uptake(≥50% of maximum);score 3=LGE≥50% ,reduced FDG-uptake(<50% of maximum);score 4=transmural LGE,no FDG-uptake.Segments with score 1 and 2 were categorized"viable",scores 3 and 4 were categorized as"non-viable".Patients were divided into three groups based on LV function as determined by CMR:Ejection fraction(EF),<30% :n=45;EF:30% -50% :n=44;EF>50% :n=16).On a segmental basis,the accuracy of CMR in detecting myocardial scar was compared to PET in the total collective and in the three different patient groups.RESULTS CMR and PET data of all 105 patients were sufficient for evaluation and 5508 segments were compared in total.In all patients,CMR detected significantly more scars(score 2-4)than PET:45% vs 40% of all segments(P<0.0001).In the different LV function groups,CMR found more scar segments than PET in subjects with EF<30% (55% vs 46% ;P<0.0001)and EF 30% -50% (44% vs 40% ;P<0.005).However,CMR revealed less scars than PET in patients with EF>50% (15% vs 23% ;P<0.0001).In terms of functional improvement estimation,i.e.,expected improvement after revascularization,CMR identified"viable"segments(score 1 and 2)in 72% of segments across all groups,PET in 80% (P<0.0001).Also in all LV function subgroups,CMR judged less segments viable than PET:EF<30% ,66% vs 75% ;EF=30% -50% ,72% vs 80% ;EF>50% ,91% vs 94% .CONCLUSION CMR and PET reveal different diagnostic accuracy in myocardial viability assessment depending on LV function state.CMR,in general,is less optimistic in functional recovery prediction.

Lactobacilli,bifi dobacteria and E.coli nissle induce pro-and anti-inflammatory cytokines in peripheral blood mononuclear cells

AIM: To investigate whether the stimulation of peripher- al blood mononuclear cells (PBMNC) with the cell debris and cell extraction of different probiotic strains is similar or species specifi c. METHODS: Three strains of bifi dobacteria, 4 strains of lactobacilli, and E. coli nissle were sonicated and centri- fuged in order to divide them into cell extract and cell debris. PBMNC were separated by density gradient and incubated for 36 h with either the cell debris or the cell extract of single strains of probiotic bacteria in doses from 102 to 108 CFU/mL. Cell supernatants were taken and interleukin (IL)-10, IL-1β, and tumor necosis factor (TNF)-α were determined by ELISA. RESULTS: Depending on the species super-family, the strains had different stimulation patterns. Except for both L. casei strains, the cell extract of bifidobacteriaand lactobacilli had less stimulating capacity than cell debris, whereas the cell extract of E. coli nissle had simi- lar stimulating properties to that of the cell debris of the strain and significantly more stimulating capacity than that of bifi dobacteria and lactobacilli. The cell debris of bifi dobacteria stimulated more cytokine release than the cell debris of lactobacilli. The cell debris of lactobacilli did not have a stimulating capacity when lower concentra- tions were used. Neither cell extraction nor cell debris had an inhibitory effect on the production of the tested cytokines by stimulated PBMNC. CONCLUSION: The incubation of probiotic strains, which have been used in clinical trials for inflammatory diseases, with immunocompetent cells leads to different species specifi c reactions. High IL-10 response to cell de- bris of bifi dobacteria and E. coli nissle can be found. This corresponds to positive effects of bifi dobacteria and E. coli nissle in clinical trials for inflammatory bowel disease compared to negative outcomes obtained with lactoba- cilli.

Reliability of the pronator quadratus fat pad sign to predict the severity of distal radius fractures

AIM To evaluate the reliability of pronator quadratus fat pad sign to detect distal radius fracture and to predict its severity.METHODS Retrospectively we identified 89 consecutive patients(41 female, mean age 49 ± 18 years) who had X-ray(CR) and computed tomography(CT) within 24 h following distal forearm trauma. Thickness of pronator quadratus fat pad complex(PQC) was measured using lateral views(CR) and sagittal reconstructions(CT). Pearson's test was used to determine the correlation of the PQC thickness in CR and CT. A positive pronator quadratus sign(PQS) was defined as a PQC > 8.0 mm(female) or > 9.0 mm(male). Frykman classification was utilized to assess the severity of fractures.RESULTS Forty-four/89 patients(49%) had a distal radius fracture(Frykman Ⅰ n = 3, Ⅱ n = 0, Ⅲ n = 10, Ⅳ n = 5, Ⅴ n = 2, Ⅵ n = 2, Ⅶ n = 9, Ⅷ n = 13). Mean thickness of the PQC thickness can reliably be measured on X-ray views and was 7.5 ± 2.8 mm in lateral views(CR), respectively 9.4 ± 3.0 mm in sagittal reconstructions(CT), resulting in a significant correlation coefficientof 0.795. A positive PQS at CR was present in 21/44 patients(48%) with distal radius fracture and in 2/45 patients(4%) without distal radius fracture, resulting in a specificity of 96% and a sensitivity of 48% for the detection of distal radius fractures. There was no correlation between thickness of the PQC and severity of distal radius fractures.CONCLUSION A positive PQS shows high specificity but low sensitivity for detection of distal radius fractures. The PQC thickness cannot predict the severity of distal radius fractures.

Enhanced microfracture techniques in cartilage knee surgery: Fact or fiction?

The limited intrinsic healing potential of human articular cartilage is a well-known problem in orthopedic surgery. Thus a variety of surgical techniques have been developed to reduce joint pain, improve joint function and delay the onset of osteoarthritis. Microfractures as a bone marrow stimulation technique present the most common applied articular cartilage repair procedure today. Unfortunately the deficiencies of fibrocartilaginous repair tissue inevitably lead to breakdown under normal joint loading and clinical results deteriorate with time. To overcome the shortcomings of microfracture, an enhanced microfracture technique was developed with an additional collagen Ⅰ/Ⅲ membrane(Autologous, Matrix-Induced Chondrogenesis, AMIC). This article reviews the pre-clinical rationale of microfractures and AMIC, presents clinical studies and shows the advantages and disadvantages of these widely usedtechniques. PubM ed and the Cochrane database were searched to identify relevant studies. We used a comprehensive search strategy with no date or language restrictions to locate studies that examined the AMIC technique and microfracture. Search keywords included cartilage, microfracture, AMIC, knee, ChondroGide. Besides this, we included our own experiences and study authors were contacted if more and non published data were needed. Both cartilage repair techniques represent an effective and safe method of treating full-thickness chondral defects of the knee in selected cases. While results after microfracture deteriorate with time, mid-term results after AMIC seem to be enduring. Randomized studies with long-term followup are needed whether the grafted area will maintain functional improvement and structural integrity over time.

Expression of L amino acid transport system 1 and analysis of iodine-123-methyltyrosine tumor uptake in a pancreatic xenotransplantation model using fused high-resolution-micro-SPECT-MRI

BACKGROUND:The specificity in discriminating pancreatitis is limited in the positron emission tomography(PET)using Fluorine-18-fluorodeoxyglucose.Furthermore,PET is not widely available compared to the single photon emission computed tomography(SPECT).Since amino acids play a minor role in metabolism of inflammatory cells,the potential of the SPECT tracer,3-[ 123 I]iodo-L-α-methyltyrosine(123I-IMT),for detecting pancreatic cancer was examined in xenotransplantation models of human pancreatic carcinoma in mice. METHODS: 123 I-IMT was injected to eight mice inoculated with subcutaneous or orthotopic pancreatic tumors.Fused high-resolution-micro-SPECT(Hi-SPECT)and magnetic resonance imaging were performed.The gene expression level of L amino acid transport-system 1(LAT1)was analyzed and correlated with tumor uptake of 123 I-IMT. RESULTS:A high uptake of 123 I-IMT was detected in all tumor-bearing mice.The median tumor-to-background ratio (T/B)was 12.1(2.0-13.2)for orthotopic and 8.4(1.8-11.1)for subcutaneous xenotransplantation,respectively.Accordingly, the LAT1 expression in transplanted Colo357 cells was increased compared to non-malignant controls.CONCLUSIONS:Our mouse model could show a high 123 I-IMT uptake in pancreatic cancer.Fused MRI scans facilitate precise evaluation of uptake in the specific regions of interest.Further studies are required to confirm these findings in tumors derived from other human pancreatic cancer cells.Since amino acids play a minor role in the metabolism of inflammatory cells,the potential for application of 123 I-IMT to distinguish pancreatic tumor from inflammatory pancreatitis warrants further investigation.

Emerging role of caldesmon in cancer:A potential biomarker for colorectal cancer and other cancers

Colorectal cancer(CRC) is a devastating disease, mainly because of metastasis. As a result, there is a need to better understand the molecular basis of invasion and metastasis and to identify new biomarkers and therapeutic targets to aid in managing these tumors. The actin cytoskeleton and actin-binding proteins are known to play an important role in the process of cancer metastasis because they control and execute essential steps in cell motility and contractility as well as cell division. Caldesmon(CaD) is an actin-binding protein encoded by the CALD1 gene as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight CaD, expressed in smooth muscle, and low-molecular weight CaD(l-CaD), expressed in nonsmooth muscle cells. According to our comprehensive review of the literature, CaD, particularly l-CaD, plays a key role in the development, metastasis, and resistance to chemoradiotherapy in colorectal, breast, and urinary bladder cancers and gliomas, among other malignancies. CaD is involved in many aspects of the carcinogenic hallmarks, including epithelial mesenchymal transition via transforming growth factor-beta signaling, angiogenesis, resistance to hormonal therapy, and immune evasion. Recent data show that CaD is expressed in tumor cells as well as in stromal cells, such as cancerassociated fibroblasts, where it modulates the tumor microenvironment to favor the tumor. Interestingly, CaD undergoes selective tumor-specific splicing, and the resulting isoforms are generally not expressed in normal tissues, making these transcripts ideal targets for drug design. In this review, we will analyze these features of CaD with a focus on CRC and show how the currently available data qualify CaD as a potential candidate for targeted therapy in addition to its role in the diagnosis and prognosis of cancer.

Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography evaluation of subcutaneous panniculitis-like T cell lymphoma and treatment response

Subcutaneous panniculitis-like T cell lymphoma(SPTCL) is a very rare variant of non-Hodgkin's lymphoma. Currently, there is no standard imaging method for staging of SPTCL nor for assessment of treatment response. Here, we describe our use of fluorine-18 fluorodeoxyglucose(FDG) positron emission tomography/computed tomography(PET/CT) for staging and monitoring of treatment response in 3 cases of SPTCL. Primary staging by PET/CT showed that all 3 patients had multiple foci in the subcutaneous fat tissue, with SUVmax from 10.5 to 14.6. Involvement of intra-abdominal fat with high SUVmax was identified in 2 of the patients. Use of the triple drug regimen of gemcitabine, cisplatin and methylprednisolone(commonly known as "GEM-P") as first-line therapy or second-line therapy facilitated complete metabolic response for all 3 cases. FDG PET/CT provides valuable information for staging and monitoring of treatment response and can reveal occult involvement of the intraabdominal visceral fat. High FDG uptake on pre-treatment PET can identify patients with aggressive disease and help in selection of first-line therapy.

1.5T和3.0T二维自由稳态进动序列和梯度回波序列呼吸动力学MRI研究:观察者首选研究

比较1．5T和3．0T自由稳态进动序列（SSFP）和梯度回波序列（GRE）肺部动态成像的影像质量。带有模拟肺部病灶的通气猪肺模型和4名健康志愿者在1．5T和3．0T设备上，分别用SSFP（TR／TE=2．9／1．22ms；3ima／s，原文如此）和GRE（TR／1＇E=2．34／0．96ms；8ima／s）序列进行成像作为基准。用改良的SSFP序列以9～10幅／s影像进行成像（并行成像因子PI=2，3）。

Unmodified autologous stem cells at point of care for chronic myocardial infarction

BACKGROUND Numerous studies investigated cell-based therapies for myocardial infarction(MI).The conflicting results of these studies have established the need for developing innovative approaches for applying cell-based therapy for MI.Experimental studies on animal models demonstrated the potential of fresh,uncultured,unmodified,autologous adipose-derived regenerative cells(UAADRCs)for treating acute MI.In contrast,studies on the treatment of chronic MI(CMI;>4 wk post-MI)with UA-ADRCs have not been published so far.Among several methods for delivering cells to the myocardium,retrograde delivery into a temporarily blocked coronary vein has recently been demonstrated as an effective option.AIM To test the hypothesis that in experimentally-induced chronic myocardial infarction(CMI;>4 wk post-MI)in pigs,retrograde delivery of fresh,uncultured,unmodified,autologous adipose-derived regenerative cells(UA-ADRCs)into a temporarily blocked coronary vein improves cardiac function and structure.METHODS The left anterior descending(LAD)coronary artery of pigs was blocked for 180 min at time point T0.Then,either 18×106 UA-ADRCs prepared at“point of care”or saline as control were retrogradely delivered via an over-the-wire balloon catheter placed in the temporarily blocked LAD vein 4 wk after T0(T1).Effects of cells or saline were assessed by cardiac magnetic resonance(CMR)imaging,late gadolinium enhancement CMR imaging,and post mortem histologic analysis 10 wk after T0(T2).RESULTS Unlike the delivery of saline,delivery of UA-ADRCs demonstrated statistically significant improvements in cardiac function and structure at T2 compared to T1(all values given as mean±SE):Increased mean LVEF(UA-ADRCs group:34.3%±2.9%at T1 vs 40.4±2.6%at T2,P=0.037;saline group:37.8%±2.6%at T1 vs 36.2%±2.4%at T2,P>0.999),increased mean cardiac output(UA-ADRCs group:2.7±0.2 L/min at T1 vs 3.8±0.2 L/min at T2,P=0.002;saline group:3.4±0.3 L/min at T1 vs 3.6±0.3 L/min at T2,P=0.798),increased mean mass of the left ventricle(UA-ADRCs group:55.3±5.0 g at T1 vs 71.3±4.5 g at T2,P<0.001;saline group:63.2±3.4 g at T1 vs 68.4±4.0 g at T2,P=0.321)and reduced mean relative amount of scar volume of the left ventricular wall(UA-ADRCs group:20.9%±2.3%at T1 vs 16.6%±1.2%at T2,P=0.042;saline group:17.6%±1.4%at T1 vs 22.7%±1.8%at T2,P=0.022).CONCLUSION Retrograde cell delivery of UA-ADRCs in a porcine model for the study of CMI significantly improved myocardial function,increased myocardial mass and reduced the formation of scar tissue.

Genomic landscape of pancreatic neuroendocrine tumors

AIM:To investigate the prognostic role of genomic stability and copy number alterations(CNAs)pancreatic neuroendocrine tumors(Pan NETs).METHODS:A high-resolution array-based comparative genomic hybridization approach was utilized in order to investigate and quantify chromosomal aberrations in a panel of 37 primary Pan NET and 11 metastatic samples.DNA samples were extracted from formalinfixed and paraffin-embedded tumor specimen.Genomic findings were correlated with histopathological and immunohistochemical data.Moreover,the dataset was subjected to employing an unsupervised hierarchical clustering analysis approach utilizing Euclidean distance and average linkage and associations between genomically defined tumor groups and recurrent CNAs or clinicopathological features of the study group were assessed.RESULTS:Numerous chromosomal aberrations were recurrently detected in both,primary tumor samples and metastases.Copy number gains were most frequently observed at 06p22.2-p22.1(27.1%),17p13.1(20.8%),07p21.3-p21.2(18.8%),09q34.11(18.8%).Genomic losses were significantly less frequent and the only recurrent aberration affected 08q24.3(6.3%).Moreover,we detected a high degree of genomic heterogeneity between primary tumors and metastatic lesions.Unsupervised hierarchical clustering of loci affected by CNAs in more than 3 primary tumor samples revealed two genetically distinct tumor groups as well as two chromosomal clusters of genomic imbalances indicating a small subset of tumors with common molecular features(13.5%).Aberrations affecting6p22.2-22.1,8q24.3,9q34.11 and 17p13.1(P=0.011;0.003;0.003;0.001),were significantly associated with a poorer survival prognosis.CONCLUSION:This study suggests that several frequent CNAs in numerous candidate regions are involved in the pathogenesis and metastatic progression of PanNET.

Pharmacogenomics in oncology

Precision therapy in the field of oncology is rapidly developing. Numerous somatic genetic markers in eg tyrosine kinase receptors or transcription factors have been identified to be indicative for the treatment with anti-cancer drugs. In contrast, only some recommendations have been developed considering hereditary variants in drug metabolizing enzymes such as TPMT, DYPD or UGT1A1. Although a huge knowledge has been gained on the association of drug transporters variants such as ABCB1 or ABCG2 and clinical outcome, the overall data is inconsistent and the predictability of the related phenotype is low. However, there is increasing evidence that individual phenotypic differences may result not only from genetics, but also from epigenetic alterations such as histone-acetylation or DNA-methylation. Moreover,interactions with non-coding RNAs contribute to protein expression and may modulate drug action. Currently intriguing developments of novel therapeutic approaches through epigenetic drugs are emerging. The overall complexity of epigenetics in drug action is so far only little understood. Of significant importance are the consequences of mi RNA interaction for drug resistance in cancer by regulating target genes and efflux transporters. Further intriguing findings address DNAmethylation as modifier of transporter function and its consequences in cancer development and treatment. The progress of science may lead to the discovery of rare, but functionally relevant SNPs and a better understanding of multiple genomic, epigenomic as well as phenotypic factors, contributing to drug response in malignancies.

The Impact of a Bicuspid Aortic Valve on Aortic Geometry and Function in Patients with Aortic Coarctation:A Comprehensive CMR Study

Background:An isolated bicuspid aortic valve(BAV)is associated with structural and functional abnormalities of the aorta and the left ventricle(LV).Although~50%of patients with aortic coarctation(CoA)have a BAV,less is known about its impact on LV function and aortic geometry and function in CoA patients.In this cardiovascular magnetic resonance imaging(CMR)study,we analysed markers of LV and aortic function as well as aortic geometry in a large cohort of CoA patients with a BAVand compared them with CoA patients with a tricuspid aortic valve(TAV).Methods:We included 48 patients with a BAV(18.4±9.3 years)and 45 patients with TAV(20.7±9.9 years).LV volumes,mass and ejection fraction as well as aortic distensibilty,pulse wave velocity(PWV)were measured from standard cine CMR and phase-contrast CMR images.2-dimensional CMR feature tracking(2DCMR-FT)was performed to measure longitudinal,circumferential and radial strain and strain rate of the LV.Aortic arch geometry was classified as romanic,gothic and crenel.Results:LV volumes,mass and ejection fraction as well as aortic distensibility and PWV did not significantly differ between the BAV and the TAV group.There was also no significant difference for LV global longitudinal,radial and circumferential strain and strain rate between both groups.Patients with a BAV had more commonly a gothic aortic arch compared to TAV patients,but this difference was not statistically significant(22 vs.14,p=0.2).Ascending and descending aortic distensibility correlated with LV mass in the entire patient group(p<0.001).Global longitudinal,circumferential and radial strain(GLS,GCS,GRS)and global longitudinal and circumferential strain rate(GLSR,GCSR)correlated with LV ejection fraction(p<0.001).Conclusion:Our data suggest that the presence of a BAV does not adversely impact LV and aortic function in children and young adults with CoA.The correlation of global circumferential,longitudinal and radial strain values with LV ejection fraction demonstrates that 2D-CMR-FT might provide additional information related to ventricular function in CoA patients.

No Correlation between <i>AVPR</i>1A Promoter Polymorphisms and Prepulse Inhibition in Patients with Nocturnal Enuresis

Introduction: A correlation between AVPR1A promoter polymorphisms and prepulse inhibition (PPI) of startle reflexes has been described in healthy adults. Many children with nocturnal enuresis (NE) have a reduced PPI and treatment with desamino arginine vasopressin (dDAVP), a ligand of the arginine vasopressin receptor 1A (AVPR1A), and both improve clanical symptoms and significantly increase PPI. Methods: In 17 children (median 9.1 years, range 6.4-17.3) with NE, promoter repeats within the RS1 and RS3 regions of AVPR1A were quantified and correlated to PPI (native and age-adjusted). Results: No direct correlation was found between the number of promoter repeats at RS1 and PPI (correlation coefficient—0.240, p = 0.346) or RS3 and PPI (correlation coefficient—0.0192, p = 0.936), with no change through age-adjustment of PPI. The different RS3 length subgroups did not show differences in PPI, nor did differentiation of NE according to clinical subtype or treatment response to dDAVP show differences in the number of promoter repeats. Conclusion: The missing reproducibility of the correlation between AVPR1A promoter polymorphisms and PPI in a group with wide range of PPI suggests a more complex interaction. Therefore, further investigations are needed to analyze this very plausible interaction. Conditions with a reduced PPI, such as enuresis, schizophrenia or autism, are particularly interesting for this research.