GlyPerA™ effectively shields airway epithelia from SARS-CoV-2 infection and inflammatory events.

New SARS-CoV-2 variants of concern (VOCs) and waning immunity illustrate that quick and easy-to-use agents are needed to prevent infection. To protect from viral transmission and subsequent inflammatory reactions, we applied GlyperA™, a novel antimicrobial formulation that can be used as mouth gargling solution or as nasal spray, to highly differentiated human airway epithelia prior infection with Omicron VOCs BA.1 and BA.2. This formulation fully protected polarized human epithelium cultured in air-liquid interphase (ALI) from SARS-CoV-2-mediated tissue destruction and infection upon single application up to two days post infection. Moreover, inflammatory reactions induced by the Omicron VOCs were significantly lowered in tissue equivalents either pre-treated with the GlyperA™ solution, or even when added simultaneously. Thus, the GlyperA™ formulation significantly shielded epithelial integrity, successfully blocked infection with Omicron and release of viral particles, and decreased intracellular complement C3 activation within human airway epithelial cell cultures. Crucially, our in vitro data imply that GlyperA™ may be a simple tool to prevent from SARS-CoV-2 infection independent on the circulating variant via both, mouth and nose.

Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics.

Novel drug discoveries have shifted the treatment paradigms of most hematological malignancies, including multiple myeloma (MM). However, this plasma cell malignancy remains incurable, and novel therapies are therefore urgently needed. Whole-genome transcriptome analyses in a large cohort of MM patients demonstrated that alterations in pre-mRNA splicing (AS) are frequent in MM. This manuscript describes approaches to identify disease-specific alterations in MM and proposes RNA-based therapeutic strategies to eradicate such alterations. As a "proof of concept", we examined the causes of aberrant HMMR (Hyaluronan-mediated motility receptor) splicing in MM. We identified clusters of single nucleotide variations (SNVs) in the HMMR transcript where the altered splicing took place. Using bioinformatics tools, we predicted SNVs and splicing factors that potentially contribute to aberrant HMMR splicing. Based on bioinformatic analyses and validation studies, we provided the rationale for RNA-based therapeutic strategies to selectively inhibit altered HMMR splicing in MM. Since splicing is a hallmark of many cancers, strategies described herein for target identification and the design of RNA-based therapeutics that inhibit gene splicing can be applied not only to other genes in MM but also more broadly to other hematological malignancies and solid tumors as well.

Progression of primarily untreated desomorphine drug induced jaw osteonecrosis: A case report.

Desomorphine is a composite of the self-made illicit drug "krokodil", which is popular in Eastern Europe and other parts of the world. It causes toxic damage of different organs including bones. In this paper, a clinical portrait of the patient with drug-induced osteonecrosis of mandible who refused surgical treatment in the early stages of the disease, is presented. At the time of first presentation, the patient displayed swelling of oral soft tissues and purulent discharge in the molar area of the right mandible. Radiographic examination demonstrated several small radiolucent lesions in the body of the mandible. The patient gave consent for surgical treatment and rehabilitation only after 12 months of the diagnosis. During this period of time, the necrosis of the mandibular bone progressed and a pathological fracture of the jaw was developed. Patient underwent surgical treatment - resection of the mandible. Management of drug-induced jaw osteonecrosis is challenging as the necessity of dental and surgical treatment as well as treatment and rehabilitation of substance use disorder arises. Involvement of a multidisciplinary healthcare professionals team is essential in successful treatment of this pathology. The latter includes early surgical intervention/medical treatment and rehabilitation from drug addiction.

The State of Public Health Education and Science During and After the Fall of the Soviet Union: Achievements, Remaining Challenges, and Future Priorities.

Objectives: In the post-COVID-19 world, when the adequacy of public health workforce education is being critically re-evaluated, this study undertakes a historical analysis of how the educational and scientific field of public health developed during and after the fall of the Soviet Union in 1991. The study intends to historically contextualize public health education and science development in former Soviet Republics. It attempts to document achievements after gaining independence and identify remaining challenges that need to be addressed for advancing public health science and education in Former Soviet Union countries to better prepare them for future pandemics and address current health challenges of the nations. Methods: The study used a mixed-methods review approach combining both a literature review, information collection from the school's websites, and secondary analysis of the quantitative data available about scientific outputs-peer-reviewed articles. Results: During communist rule and after the fall of the Soviet Union, the main historical events seem to have shaped the public health field of former Soviet countries, which also determined its eventual evolution. The international efforts post-1991 were instrumental in shifting medically oriented conceptualization of public health toward Western approaches, albeit with variable progress. Also, while scientific output has been growing from 1996 to 2019, sub-regional differences remain prominent. Conclusion: The region seems to have matured enough that it might be time to start and facilitate regional cooperation of public health schools to advance the field of public health and research. Regional and country variabilities feature prominently in the volume and quality of scientific output and call for the immediate attention of national governments and international partners.

Sca-1 is a marker for cell plasticity in murine pancreatic epithelial cells and induced by IFN-ß in vitro.

BACKGROUND & AIMS: Sca-1 is a surface marker for murine hematopoietic stem cells (HSCs) and type-I interferon is a key regulator for Lin-Sca-1+ HSCs expansion through Ifnar/Stat-1/Sca-1-signaling. In this study we aimed to characterize the role and regulation of Sca-1+ cells in pancreatic regeneration. METHODS: To characterize Sca-1 in vivo, immunohistochemistry and immunofluorescence staining of Sca-1 was conducted in normal pancreas, in cerulein-mediated acute pancreatitis, and in Kras-triggered cancerous lesions. Ifnar/Stat-1/Sca-1-signaling was studied in type-I IFN-treated epithelial explants of adult wildtype, Ifnar-/-, and Stat-1-/- mice. Sca-1 induction was analyzed by gene expression and FACS analysis. After isolation of pancreatic epithelial Lin-Sca-1+cells, pancreatosphere-formation and immunofluorescence-assays were carried out to investigate self-renewal and differentiation capabilities. RESULTS: Sca-1+ cells were located in periacinar and periductal spaces and showed an enrichment during cerulein-induced acute pancreatitis (23.2/100 µm2 ± 4.9 SEM) and in early inflammation-mediated carcinogenic lesions of the pancreas of KrasG12D mice (35.8/100 µm2 ± SEM 1.9) compared to controls (3.6/100 µm2 ± 1.3 SEM). Pancreatic Lin-Sca-1+ cells displayed a small population of 1.46% ± 0.12 SEM in FACS. In IFN-ß treated pancreatic epithelial explants, Sca-1 expression was increased, and Lin-Sca-1+ cells were enriched in vitro (from 1.49% ± 0.36 SEM to 3.85% ± 0.78 SEM). Lin-Sca-1+ cells showed a 12 to 51-fold higher capacity for clonal self-renewal compared to Lin-Sca-1- cells and generated cells express markers of the acinar and ductal compartment. CONCLUSIONS: Pancreatic Sca-1+ cells enriched during parenchymal damage showed a significant capacity for cell renewal and in vitro plasticity, suggesting that corresponding to the type I interferon-dependent regulation of Lin-Sca-1+ hematopoietic stem cells, pancreatic Sca-1+ cells also employ type-I-interferon for regulating progenitor-cell-homeostasis.

Combination therapy targeting Erk1/2 and CDK4/6i in relapsed refractory multiple myeloma.

Oncogenic activated RAS mutations have been detected in 50% of de novo and 70% of relapsed multiple myeloma (MM) patients. Translocation t(11;14) involving IgH/CCDN1 and overexpression of cyclin-Ds are early events in MM pathogenesis, enhancing uncontrolled MM cell growth. We hypothesized that targeting both RAS/MAPK pathway molecules including Erk1/2 along with cyclin-Ds enhances MM cytotoxicity and minimizes side effects. Recent studies have demonstrated the high potency of Erk1/2 and CDK4/6 inhibitors in metastatic relapsed cancers, and here we tested anti-MM effects of the Erk1/2 + CDK4/6 inhibitor combination. Our studies showed strong synergistic (IC < 0.5) cytotoxicity of Erk1/2i + CDK4/6i in MM-cells. Erk1/2i + CDK4/6i treatment in a dose-dependent manner arrested MM-cells in the G0/G1 phase and activated mitochondrial apoptotic signaling. Our studies showed that Erk1/2i + CDK4/6i treatment-induced inhibition of key target molecules in Erk1/2 and CDK4/6 signaling, such as c-myc, p-RSK, p-S6, p-RB, and E2F1, suggesting on-target activity of these inhibitors. We identified Erk1/2i + CDK4/6i treatment associated five-gene signature which includes SNRPB and SLC25A5; these genes are involved in RNA processing and mitochondrial metabolism, respectively. Overall, our studies provide the preclinical framework for Erk1/2i + CDK4/6i combination clinical trials to target Ras+CDK pathways to improve patient outcome in MM.

In Vitro Evaluation of the Therapeutic Potential of Phage VA7 against Enterotoxigenic Bacteroides fragilis Infection.

Since the beginning of the 20th century, bacteriophages (phages), i.e., viruses that infect bacteria, have been used as antimicrobial agents for treating various infections. Phage preparations targeting a number of bacterial pathogens are still in use in the post-Soviet states and are experiencing a revival in the Western world. However, phages have never been used to treat diseases caused by Bacteroides fragilis, the leading agent cultured in anaerobic abscesses and postoperative peritonitis. Enterotoxin-producing strains of B. fragilis have been associated with the development of inflammatory diarrhea and colorectal carcinoma. In this study, we evaluated the molecular biosafety and antimicrobial properties of novel phage species vB_BfrS_VA7 (VA7) lysate, as well as its impact on cytokine IL-8 production in an enterotoxigenic B. fragilis (ETBF)-infected colonic epithelial cell (CEC) culture model. Compared to untreated infected cells, the addition of phage VA7 to ETBF-infected CECs led to significantly reduced bacterial counts and IL-8 levels. This in vitro study confirms the potential of phage VA7 as an antibacterial agent for use in prophylaxis or in the treatment of B. fragilis infections and associated colorectal carcinoma.

Protective effects of postconditioning in transvaginally created pneumoperitoneum.

There are reports of ischemic complications in clinical practice after laparoscopy using pneumoperitoneum. Conditioning has a beneficial effect for various ischemic diseases. This experimental study was designed to evaluate the effects of postconditioning in transvaginally created pneumoperitoneum. Sixty adult female rats, weighing 300±50 g were divided into four equal groups. Pneumoperitoneum was created by CO2 insufflation under a pressure of 10 mmHg. Rats in the first group (sham) were subjected to only sham-operation or gas insufflation. The second group (TV/PP) was subjected to pneumoperitoneum for 60 min followed by 30 min of desufflation. The third group (post-5) was subjected to pneumoperitoneum for 60 min followed by 5 min of desufflation, 5 min of insufflation and again followed by 30 min of desufflation. The fourth group (post-2.5) was subjected to pneumoperitoneum for 60 min followed by 2.5 min of desufflation and 2.5 min of insufflation-repeated in two cycles- and then followed by 30 min of desufflation. The rats were sacrificed, and blood was collected after 30 min, 2 and 6 h from the last desufflation. Levels of oxidative stress markers, malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH), sulfhydryl groups (SH) and inflammatory cytokine TNF-α, were analyzed. Levels of MDA in the post-5 group were significantly reduced compared to the TV/PP and post-2.5 groups. The level of GSH in TV/PP animals was markedly reduced compared to the Sham, Post-5 and Post-2.5 groups. In addition, levels of SH were increased in the Post-5 group in comparison to the Sham, TV/PP and Post-2.5 groups. No difference in the activity of SOD between the groups was found, and the concentration of TNF-α in TV/PP animals was significantly higher than that in the Sham and postconditioning groups. Overall, the results of the present study indicate that postconditioning can reduce pneumoperitoneum-induced oxidative injury.

Mesenchymal stem cell transplantation attenuates growth of chemotherapy treated oral squamous cell carcinoma in an animal model.

BACKGROUND: Recent studies have demonstrated mesenchymal stem cell migration toward tumor locations. When applied locally, MSCs interact with the locally residing host cells. The mechanisms behind this are still unclear. We aimed to detect the possible action mechanisms of MSCs on the in vivo growth of primary human oral squamous cell carcinoma. METHODS: In mouse model of OSSC, chemotherapy with Cisplatin was done beginning from 9 day of tumor visualization. 3 weeks after tumor cell injection cultivated MSCs were administrated in tail vein or directly intra-tumorally. Animals underwent surveillance and afterward were sacrificed. Tumor growth was measured. MSCs biodistribution was assessed with bioluminescent analysis. Tumor tissues were tested morphologically and immunohistochemically for angiogenesis, hypoxia status, and cell apoptosis. RESULTS: In the group treated with Cisplatin in combination with mesenchymal stem cell injection, the average size of the tumor was 98.9 ± 7.65 mm3 . In the experimental group, tumor tissues were less outlined and the presence of necrotic areas and connective tissue basal layers was detected. Immunohistochemical surveys with CD31 and anti-carbonic anhydrase 9 demonstrated strongly developed micro-vessel structures and small isles of hypoxia in the tumor tissues. TUNEL assay revealed in the same group that tumor tissues were mostly comprised of apoptotic cells. Viable cell communities presented as small isles. CONCLUSION: The study demonstrates that intra-tumorally injected MSCs, combined with Cisplatin, leads to a minimal hypoxia status and increased apoptotic activity in tumor tissues, compared with the control group. This finding can be explained with better distribution of Cisplatin due to increased angiogenesis.

The effects of MicroRNA deregulation on pre-RNA processing network in multiple myeloma.

Over the last few years, a detailed map of genetic and epigenetic lesions that underlie multiple myeloma (MM) has been created. Regulation of microRNA (miR)-dependent gene expression and mRNA splicing play significant roles in MM pathogenesis; however, to date an interplay between these processes is not yet delineated. Here we investigated miR-mediated regulation of splicing networks at the transcriptome level. Our studies show that a significant number (78%) of miRs which are either up- or down-regulated in patient CD138+ MM cells, but not in healthy donors (HD) CD138+ plasma cells (PC), target genes involved in early stages of pre-mRNA splicing. We also identified deregulated miRs that target core splicing factors (SF) and modifiers (SM, enhancers/silencers) which cause altered splicing in MM. Our studies suggest that Let-7f, in combination other miRs which are frequently and significantly deregulated in patients with overt MM, targets genes that regulate intron excision. Importantly, deregulated expression of certain miRs in MM promote increased intron retention, a novel characteristic of the MM genome, by inducing deregulated expression of the genes that regulate the splicing network. Our studies, therefore, provide the rationale for therapeutically targeting deregulated miRs to reverse aberrant splicing and improve patient outcome in MM.

Gallbladder agenesis: A case report and review of the literature.

INTRODUCTION: Gallbladder agenesis is a rare congenital abnormality with an incidence of 10-65 per 100,000. Approximately half of these patients are surgically operated on because of the symptoms similar to biliary colic, and correct diagnosis is established intra-operatively. We present a clinical case of gallbladder agenesis from our practice. PRESENTATION OF CASE: A 49 (forty-nine) - year- old women was admitted in the Emergency Department of our clinic. Symptoms were similar to the biliary colic. Ultrasonography showed hyperechogenic acoustic shadow on the projection of the gallbladder which was considered as constricted gallbladder and cholecystolithiasis was diagnosed. Laparoscopic cholecystectomy was considered. During laparoscopy gallbladder could not be found. Surgical operation was completed without conversion. Postoperative treatment included analgesics and antispasmodics. Pre-operative symptoms disappeared. One month later magnetic resonance cholangiopancreatography (MRCP) confirmed gallbladder agenesis diagnosis. Health condition of the patient is satisfactory, without any complications after a year of surgery. DISCUSSION: Gallbladder agenesis presented with symptoms similar to biliary colic can be diagnosed without surgical intervention. Conservative treatment consists of antispasmodic drugs. CONCLUSION: If the shrunken gallbladder is detected on the ultrasound, additional radiological examinations are required. MRCP is considered as a test of choice among the radiological investigations. If gallbladder agenesis is identified on laparoscopy, there is no need for further conversion. For postoperative follow up examination MRCP investigation is recommended.

Benign osteoblastoma of the mandible in a 12-year-old female: A case report.

Benign osteoblastoma refers to a benign tumor of the bone. Osteoblastoma most commonly affects the vertebrae and long tubular bones, however, in rare cases is observed in the facial bones. The current study presents the case of a 12-year-old female patient with a tumor in the mandibular body. Radiological imaging revealed a lesion with regular contours. The lesion was radically resected and histological analysis of the specimen demonstrated features that are typical of a benign osteoblastoma. The consequential defects of the jaw were reconstructed using titanium implants and autologous bone transplantation. The patient remains disease free subsequent to a five-month follow-up period. The aim of the present report is to present a rare case of benign osteoblastoma of the mandible. This study demonstrated that correct diagnosis and complete surgical excision are important to reduce the risk of recurrence of a benign osteoblastoma.

The actin binding protein destrin is associated with growth and perineural invasion of pancreatic cancer.

BACKGROUND/OBJECTIVES: The small actin-binding protein destrin is one of the key regulators involved in remodeling of the actin cytoskeleton, a process crucial for cytokinesis, cell migration and polarized cell growth as well as for cancer cell migration and invasion. METHODS: A novel ex vivo nerve invasion model mirroring perineural cancer cell invasion as a key feature of pancreatic ductal adenocarcinoma has been previously established. Using this model, highly nerve-invasive clones of human pancreatic cancer cell lines have been obtained. Genome-wide transcriptional analyses of these cells revealed up-regulation of destrin in highly versus lowly nerve-invasive pancreatic cancer cells. RESULTS: Increased expression of destrin in these nerve-invasive cells was validated using quantitative RT-PCR and immunoblotting; concomitant changes in cell morphology were demonstrated using immunofluorescence analysis. Silencing of destrin by two specific siRNA oligonucleotides in Panc-1 pancreatic cancer cells decreased invasiveness and migration, and reduced proliferation of these cells. CONCLUSIONS: Destrin is upregulated in nerve-invasive pancreatic cancer cells and its expression might be related to perineural invasiveness.

Syndecan-2 promotes perineural invasion and cooperates with K-ras to induce an invasive pancreatic cancer cell phenotype.

BACKGROUND: We have identified syndecan-2 as a protein potentially involved in perineural invasion of pancreatic adenocarcinoma (PDAC) cells. METHODS: Syndecan-2 (SDC-2) expression was analyzed in human normal pancreas, chronic pancreatitis and PDAC tissues. Functional in vitro assays were carried out to determine its role in invasion, migration and signaling. RESULTS: SDC-2 was expressed in the majority of the tested pancreatic cancer cell lines while it was upregulated in nerve-invasive PDAC cell clones. There were 2 distinct expression patterns of SDC-2 in PDAC tissue samples: SDC-2 positivity in the cancer cell cytoplasm and a peritumoral expression. Though SDC-2 silencing (using specific siRNA oligonucleotides) did not affect anchorage-dependent growth, it significantly reduced cell motility and invasiveness in the pancreatic cancer cell lines T3M4 and Su8686. On the transcriptional level, migration-and invasion-associated genes were down-regulated following SDC-2 RNAi. Furthermore, SDC-2 silencing reduced K-ras activity, phosphorylation of Src and--further downstream--phosphorylation of ERK2 while levels of the putative SDC-2 signal transducer p120GAP remained unaltered. CONCLUSION: SDC-2 is a novel (perineural) invasion-associated gene in PDAC which cooperates with K-ras to induce a more invasive phenotype.

Glutamate increases pancreatic cancer cell invasion and migration via AMPA receptor activation and Kras-MAPK signaling.

Glutamate has been implicated in tumorigenesis through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR). However, the function of a glutamate-to-AMPAR signal in pancreatic ductal adenocarcinoma (PDAC) has remained elusive. We now show that glutamate-mediated AMPA receptor activation increases invasion and migration of pancreatic cancer cells via activation of the classical MAPK pathway. Glutamate levels were increased in pancreatic cancer accompanied by downregulation of GluR subunits 1, 2, and 4. In pancreatic cancer precursor lesions, pancreatic intraepithelial neoplasia (PanIN), GluR1 subunit levels were strikingly and step-wise increased but its expression was rare in PDAC. Pharmacological inhibition or RNAi-mediated suppression of GluR1 or GluR2 did not affect cancer cell growth but significantly decreased invasion. In a K-ras wildtype cell line, AMPA receptor activation enhanced K-ras activity and--further downstream--phosphorylation of p38 and of p44/42. Preemptive blockade of AMPA receptors in a mouse model of pancreatic cancer inhibited tumor cell settling. AMPA receptor activation thus not only activates MAPK signalling but also directly increases activity of K-ras. Glutamate might serve as a molecular switch that decreases the threshold of K-ras-induced oncogenic signalling and increases the chance of malignant transformation of pancreatic cancer precursor lesions.

Moesin-dependent cytoskeleton remodelling is associated with an anaplastic phenotype of pancreatic cancer.

Cell motility is controlled by the dynamic cytoskeleton and its related proteins, such as members of the ezrin/radixin/moesin (ERM) family, which act as signalling molecules inducing cytoskeleton remodelling. Although ERM proteins have been identified as important factors in various malignancies, functional redundancy between these proteins has hindered the dissection of their individual contribution. The aim of the present study was to analyse the functional role of moesin in pancreatic malignancies. Cancer cells of different malignant lesions of human and transgenic mice pancreata were evaluated by immunohistochemistry. For functional analysis, cell growth, adhesion and invasion assays were carried out after transient and stable knock-down of moesin expression in pancreatic cancer cells. In vivo tumourigenicity was determined using orthotopic and metastatic mouse tumour models. We now show that moesin knock-down increases migration, invasion and metastasis and influences extracellular matrix organization of pancreatic cancer. Moesin-regulated migratory activities of pancreatic cancer cells were in part promoted through cellular translocation of beta-catenin, and re-distribution and organization of the cytoskeleton. Analysis of human and different transgenic mouse pancreatic cancers demonstrated that moesin is a phenotypic marker for anaplastic carcinoma, suggesting that this ERM protein plays a specific role in pancreatic carcinogenesis.

The microtubule-associated protein MAPRE2 is involved in perineural invasion of pancreatic cancer cells.

Perineural invasion of tumor cells is a characteristic feature of human pancreatic cancer. Unrevealing the molecular mechanisms that enable cancer cells to invade and grow along nerves is important for the development of novel therapeutic strategies in this disease. We have previously identified transcriptional changes in highly nerve invasive pancreatic cancer cells. Here we further analyzed one of the identified deregulated genes, MAPRE2, a microtubule-associated protein. MAPRE2 expression was significantly increased in high versus less nerve invasive pancreatic cancer cells, and changes of MAPRE2 expression resulted in altered actin distribution in these cells. MAPRE2 was predominately expressed in normal pancreatic acinar cells but absent in ductal cells. In pancreatic cancer, there was strong cytoplasmic and occasionally nuclear expression of MAPRE2 in the cancer cells themselves. Increased MAPRE2 mRNA levels in bulk pancreatic cancer tissues tended to be associated with reduced postoperative survival of pancreatic cancer patients. In conclusion, MAPRE2 is highly expressed in pancreatic cancer cells, and seems to be involved in perineural invasion. Therefore, targeting this microtubule-associated protein might be a promising approach in the therapy of pancreatic cancer.

Consensus transcriptome signature of perineural invasion in pancreatic carcinoma.

Perineural invasion, the growth of tumor cells along nerves, is a key feature of pancreatic cancer. The cardinal symptom of pancreatic cancer, abdominal pain often radiating to the back, as well as the high frequency of local tumor recurrence following resection are both attributed to the unique ability of pancreatic tumor cells to invade the neuronal system. The molecular mechanisms underlying the neuroaffinity of pancreatic tumors are not completely understood. In this study, we developed a novel method to monitor ex vivo perineural invasion into surgically resected rat vagal nerves by different human pancreatic tumor cell lines. Genome-wide transcriptional analyses were employed to identify the consensus set of genes differentially regulated in all highly nerve-invasive (nerve invasion passage 3) versus less invasive (nerve invasion passage 0) pancreatic tumor cells. The critical involvement of kinesin family member 14 (KIF14) and Rho-GDP dissociation inhibitor beta (ARHGDIbeta) in perineural invasion was confirmed on RNA and protein levels in human pancreatic tumor specimens. We found significant up-regulation of KIF14 and ARHGDIbeta mRNA levels in patients with pancreatic cancer, and both proteins were differentially expressed in tumor cells invading the perineural niche of pancreatic cancer patients as detected by immunohistochemistry. Moreover, functional knockdown of KIF14 and ARHGDIbeta using small interfering RNA resulted in altered basal and/or perineural invasion of pancreatic tumor cells. Our work provides novel insights into the molecular determinants of perineural invasion in pancreatic cancer. The established nerve invasion model and the consensus signature of perineural invasion could be instrumental in the identification of novel therapeutic targets of pancreatic cancer as exemplified by KIF14 and ARHGDIbeta.

Pancreatic islet and stellate cells are the main sources of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 in pancreatic cancer.

AIMS: Endocrine gland-derived vascular endothelial growth factor (EG-VEGF)/prokineticins have been identified as tissue-specific angiogenic factors. This study investigates the expression and localization of EG-VEGF and its receptors in pancreatic tissues and pancreatic stellate cells (PSCs). METHODS: mRNA levels of EG-VEGF/prokineticin 1 (PK1), prokineticin 2 (PK2) and their receptors 1 (PKR1) and 2 (PKR2) were measured in pancreatic tissues, pancreatic cancer cell lines and PSCs by quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR). Protein expression of PK1, PKR1 and PKR2 was assessed in pancreatic tissues by immunohistochemistry. Growth factor-induced secretion of EG-VEGF was measured by ELISA. RESULTS: QRT-PCR analysis in bulk tissues of normal pancreas, chronic pancreatitis and pancreatic ductal adenocarcinoma showed no significant difference of PK1 mRNA levels, whereas PK2 mRNA was barely detectable. High PK1 mRNA levels were observed only in cultured PSCs and microdissected islet cells, but not in cancer cells, and PK1 protein was localized mainly in islets and cancer-associated stromal cells. PKR1 and PKR2 proteins were present in endothelial cells of small blood vessels. TGF-beta(1) and PDGF-BB specifically stimulated PK1 secretion in PSCs. CONCLUSIONS: Islet and/or PSC-derived PK1 might act through its receptors on endothelial cells to increase angiogenesis in pancreatic diseases.