Publications by authors named "Matthias Kappler"

106 Publications

Identification of lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver for invasion and migration of oral cancer by tumor heterogeneity exploitation.

Mol Cancer 2021 Jun 11;20(1):88. Epub 2021 Jun 11.

Junior Research Group 'RNA biology and pathogenesis', Faculty of Medicine, Martin Luther University Halle-Wittenberg, 06120, Halle, Germany.

Background: Cancer metastases are the main cause of lethality. The five-year survival rate for patients diagnosed with advanced stage oral cancer is 30%. Hence, the identification of novel therapeutic targets is an urgent need. However, tumors are comprised of a heterogeneous collection of cells with distinct genetic and molecular profiles that can differentially promote metastasis making therapy development a challenging task. Here, we leveraged intratumoral heterogeneity in order to identify drivers of cancer cell motility that might be druggable targets for anti-metastasis therapy.

Methods: We used 2D migration and 3D matrigel-based invasion assays to characterize the invasive heterogeneity among and within four human oral cancer cell lines in vitro. Subsequently, we applied mRNA-sequencing to map the transcriptomes of poorly and strongly invasive subclones as well as primary tumors and matched metastasis.

Results: We identified SAS cells as a highly invasive oral cancer cell line. Clonal analysis of SAS yielded a panel of 20 subclones with different invasive capacities. Integrative gene expression analysis identified the Lymphocyte cell-specific protein-tyrosine kinase (LCK) as a druggable target gene associated with cancer cell invasion and metastasis. Inhibition of LCK using A-770041 or dasatinib blocked invasion of highly aggressive SAS cells. Interestingly, reduction of LCK activity increased the formation of adherens junctions and induced cell differentiation.

Conclusion: Analysis of invasive heterogeneity led to the discovery of LCK as an important regulator of motility in oral cancer cells. Hence, small molecule mediated inhibition of LCK could be a promising anti-metastasis therapy option for oral cancer patients.
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http://dx.doi.org/10.1186/s12943-021-01384-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194179PMC
June 2021

GP88/PGRN Serum Levels Are Associated with Prognosis for Oral Squamous Cell Carcinoma Patients.

Biology (Basel) 2021 May 4;10(5). Epub 2021 May 4.

Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.

Progranulin (PGRN)/GP88 is a growth factor that is expressed in a wide range of tumor tissues. The secreted form is involved in various biological processes including proliferation and inflammation. In several tumor types, the serum GP88 level is associated with a patient's prognosis; however, data for oral squamous cell carcinomas (OSCCs) have not yet been reported. We measured the serum GP88 levels in 96 OSCC patients by an enzyme immunosorbent assay (EIA) and correlated these data with clinicopathological parameters and patient outcomes. The GP88 levels in the serum of OSCC patients and healthy volunteers were comparable. In OSCC patients, the levels did not correlate with age, sex, or TNM status. In a Kaplan-Meier survival analysis, a serum GP88 level < 68 ng/mL was significantly associated with worsened survival ( = 0.0005, log-rank-test) as well as in uni- and multivariate Cox regression analyses (RR = 4.6 [1.6-12.9], = 0.004 and RR = 4.2 [1.2-12.0], = 0.008). This effect was predominant in OSCC patients older than 60.5 years ( = 0.027), while in younger patients no significant association between serum GP88 levels and prognosis could be observed. Altogether, lower serum GP88 levels are significantly associated with a worsened outcome for an OSCC and may be an interesting candidate for risk stratification during OSCC therapy.
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http://dx.doi.org/10.3390/biology10050400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147813PMC
May 2021

Modulation of a Stem Cell Gene: LGR4 Knockout in a Human Cell Line by CRISPR/Cas Method.

Methods Mol Biol 2021 ;2269:255-268

Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany.

The modulation of gene expression is essential for the investigation of function or involved pathway of a single gene of interest, in particular in the developmental/stem cell biology. The temporary knock down of gene expression via siRNA is a well-established but with a residual expression connected modulation method. The chapter describes the complete knockout of a defined target and allows a comprehensive study of different gene like the stem cell gene LGR4 (Leucine-rich repeat-containing G-protein-coupled receptor 4) using the new developed CRISPR/Cas method (clustered regularly interspaced short palindromic repeats).
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http://dx.doi.org/10.1007/978-1-0716-1225-5_18DOI Listing
April 2021

Tumor Microenvironment, HLA Class I and APM Expression in HPV-Negative Oral Squamous Cell Carcinoma.

Cancers (Basel) 2021 Feb 4;13(4). Epub 2021 Feb 4.

Institute of Medical Immunology, University Hospital Halle (Saale), 06112 Halle (Saale), Germany.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study, the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN-γ signaling and to the patient's outcome. A heterogeneous but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-I/APM, HLA-I/APM and HLA-I/APM. In the HLA-I/APM group, the highest frequency of intra-tumoral CD8 T cells and lowest number of CD8 T cells close to FoxP3 cells were found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8 T cells, tumoral JAK1 expression as a surrogate marker for IFN-γ signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.
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http://dx.doi.org/10.3390/cancers13040620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914856PMC
February 2021

[Epithelial salivary gland tumors - a monocentric retrospective study of South Saxony-Anhalt].

Laryngorhinootologie 2021 Jan 11. Epub 2021 Jan 11.

Department of Oral and Maxillofacial Plastic Surgery, Paracelsus Medical University Salzburg, Salzburg, Germany.

Objective:  The purpose of this research was to analyze all epithelial salivary gland tumors in this region in a comprehensive monocentric, retrospective study.

Material And Methods:  In the period from 1993 to 2017, all patients with the diagnosis of epithelial salivary gland tumors either treated at the Department of Oral and Maxillofacial Plastic Surgery of the Martin Luther University, Halle-Wittenberg (MLU), University hospital and/or processed at the Institute of Pathology of the MLU, University hospital and/or registered between 2000 and 2017 by the "Statistisches Landesamt" Sachsen-Anhalt were analyzed. The following parameters were summarized and statistically analyzed in a database using SPSS 21.5: demographic data, tumor localization, entity, therapy and disease course.

Results:  382 patients with the diagnosis of epithelial salivary gland neoplasia were identified. With 71 % the most frequent tumor localization was the glandula parotis [n = 271]. 15 % of the tumors originated from minor salivary glands [n = 57]. Most tumors were benign at over 80 % [n = 307]. In Saxony-Anhalt, 5586 patients with epithelial salivary gland tumors were reported in the mentioned period.

Conclusion:  To the best of our knowledge this is the first epidemiologic analysis of frequency, valency and therapy of salivary gland tumors in Saxony-Anhalt. The results confirm the predominance of benign epithelial salivary gland tumors, most of all pleomorphic adenoma in the glandula parotis. Concerning the group of malignant epithelial salivary gland tumors adenoid cystic carcinoma located in the minor salivary glands were most common.
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http://dx.doi.org/10.1055/a-1337-3126DOI Listing
January 2021

SARS-CoV-2 Triggering Severe Acute Respiratory Distress Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in a 3-Year-Old Child With Down Syndrome.

J Pediatric Infect Dis Soc 2021 Apr;10(4):543-546

Dr von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

Down syndrome (DS) predisposes to severe immunologic reaction secondary to infectious triggers. Here, we report a pediatric DS patient with coronavirus disease 2019 (COVID-19) who developed a hyperinflammatory syndrome, severe acute respiratory distress syndrome, and secondary hemophagocytic lymphohistiocytosis requiring pediatric intensive care unit admission and treatment with steroids, intravenous immunoglobulin, and remdesivir. Investigations into genetic susceptibilities for COVID-19 and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-associated complications warrant systematic clinical and scientific studies. We report a pediatric Down syndrome patient with coronavirus disease 2019 (COVID-19) who developed secondary hemophagocytic lymphohistiocytosis requiring treatment with steroids, intravenous immunoglobulin, and remdesivir. Investigations into genetic susceptibilities for COVID-19-associated complications warrant systematic clinical and scientific studies.
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http://dx.doi.org/10.1093/jpids/piaa148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717321PMC
April 2021

Prognostic impact of cytoplasmatic EGFR upregulation in patients with oral squamous cell carcinoma: A pilot study.

Mol Clin Oncol 2020 Dec 21;13(6):88. Epub 2020 Oct 21.

Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, D-06120 Halle (Saale), Germany.

In various tumors, epidermal growth factor-receptor (EGFR) serves a role in tumorigenesis and has an impact on survival. Usually the EGF-receptor is located on the surface of the cell membrane and is involved in various signaling pathways. The dimerization of EGFR with other ErbB family proteins, such as HER2, is important for the tumor progression. Nevertheless, a second EGFR-associated signaling pathway appears to be important for tumor cells, which is cytoplasmic/nuclear EGFR. The present study examined the influence of membranous or cytoplasmic localized EGFR on the prognosis of patients with oral squamous cell carcinoma (OSCC). Slides from 45 OSCC tumor samples were stained against EGFR using immunohistochemistry and analysed by the Remmele score system. The association with histopathological parameters and survival data was analyzed. Cytoplasmatic EGFR localization was identified as an independent predictive biomarker for overall survival in the examined OSCC cohort according to multivariate Cox regression analysis. Positive cytoplasmatic EGFR staining was correlated with a higher risk of early death (RR=3.0; P=0.035), while membranous EGFR localization did not affect patient survival. To the best of our knowledge, the present study is the first study to demonstrate that cytoplasmatic-localized EGFR is an independent prognostic biomarker for the overall survival of patients with OSCC.
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http://dx.doi.org/10.3892/mco.2020.2158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642807PMC
December 2020

Comorbidity and long-term clinical outcome of laryngotracheal clefts types III and IV: Systematic analysis of new cases.

Pediatr Pulmonol 2021 01 5;56(1):138-144. Epub 2020 Nov 5.

Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

Background: Long segment laryngotracheoesophageal clefts (LTECs) are very rare large-airway malformations. Over the last 40 years mortality rates declined substantially due to improved intensive care and surgical procedures. Nevertheless, long-term morbidity, comorbidity, and clinical outcomes have rarely been assessed systematically.

Methods: In this retrospective case series, the clinical presentation, comorbidities, treatment, and clinical outcomes of all children with long-segment LTEC that were seen at our department in the last 15 years were collected and analyzed systematically.

Results: Nine children were diagnosed with long segment LTEC (four children with LTEC type III and five patients with LTEC type IV). All children had additional tracheobronchial, gastrointestinal, or cardiac malformations. Tracheostomy for long-time ventilation and jejunostomy for adequate nutrition was necessary in all cases. During follow-up one child died from multiorgan failure due to sepsis at the age of 43 days. The clinical course of the other eight children (median follow-up time 5.2 years) was stable. Relapses of the cleft, recurrent aspirations, and respiratory tract infections led to repeated hospital admissions.

Conclusions: Long-segment LTECs are consistently associated with additional malformations, which substantially influence long-term morbidity. For optimal management, a multidisciplinary approach is essential.
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http://dx.doi.org/10.1002/ppul.25133DOI Listing
January 2021

Cumulative suppressive index as a predictor of relapse free survival and overall survival in Human Papilloma Virus-negative oral squamous cell carcinomas with negative resection margins.

Head Neck 2021 02 23;43(2):568-576. Epub 2020 Oct 23.

Earle A. Chiles Research Institute at Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, Oregon, USA.

Background: This study aimed to analyze margin status and the impact of the immune elements on recurrence in patients with oral squamous cell carcinoma (OSCC), employing a prognostic biomarker, cumulative suppressive index (CSI), which reflects FoxP3+, PD-L1+, and CD8+ cell spatial relationships in the tumor microenvironment.

Methods: Cox proportional hazards regression was used to evaluate the interactive effect of the margin by CSI discrepancy (high, 3-4 vs low, 0-2) on recurrence free survival (RFS) and overall survival (OS) in 119 patients with stage I to IVA OSCC.

Results: In cases with negative margins, multivariable analysis showed high CSI was significantly associated with worse RFS (HR = 2.59, 95% CI [1.03, 6.49], P = .04) and OS (HR = 5.49, 95% CI [1.48, 20.35], P = .01) compared to low CSI. However, high CSI was not significantly associated with recurrence in cases with positive margins.

Conclusions: Immune architecture analysis can augment our current histopathological risk assessment of margin status.
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http://dx.doi.org/10.1002/hed.26520DOI Listing
February 2021

Immune Escape Mechanisms and Their Clinical Relevance in Head and Neck Squamous Cell Carcinoma.

Int J Mol Sci 2020 Sep 24;21(19). Epub 2020 Sep 24.

Institute of Pathology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany.

Immunotherapy has been recently approved for the treatment of relapsed and metastatic human papilloma virus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC). However, the response of patients is limited and the overall survival remains short with a low rate of long-term survivors. There exists growing evidence that complex and partially redundant immune escape mechanisms play an important role for the low efficacy of immunotherapies in this disease. These are caused by diverse complex processes characterized by (i) changes in the expression of immune modulatory molecules in tumor cells, (ii) alterations in the frequency, composition and clonal expansion of immune cell subpopulations in the tumor microenvironment and peripheral blood leading to reduced innate and adaptive immune responses, (iii) impaired homing of immune cells to the tumor site as well as (iv) the presence of immune suppressive soluble and physical factors in the tumor microenvironment. We here summarize the major immune escape strategies of HNSCC lesions, highlight pathways, and molecular targets that help to attenuate HNSCC-induced immune tolerance, affect the selection and success of immunotherapeutic approaches to overcome resistance to immunotherapy by targeting immune escape mechanisms and thus improve the HNSCC patients' outcome.
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http://dx.doi.org/10.3390/ijms21197032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582858PMC
September 2020

RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma.

Int J Mol Sci 2020 Sep 17;21(18). Epub 2020 Sep 17.

Junior Research Group 'RNA Biology and Pathogenesis', Medical Faculty, Martin-Luther University Halle-Wittenberg, 06120 Halle/Saale, Germany.

Nearly 7.5% of all human protein-coding genes have been assigned to the class of RNA-binding proteins (RBPs), and over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate the post-transcriptional processing of their target RNAs, i.e., alternative splicing, polyadenylation, stability and turnover, localization, or translation as well as editing and chemical modification, thereby tuning gene expression programs of diverse cellular processes such as cell survival and malignant spread. Importantly, metastases are the major cause of cancer-associated deaths in general, and particularly in oral cancers, which account for 2% of the global cancer mortality. However, the roles and architecture of RBPs and RBP-controlled expression networks during the diverse steps of the metastatic cascade are only incompletely understood. In this review, we will offer a brief overview about RBPs and their general contribution to post-transcriptional regulation of gene expression. Subsequently, we will highlight selected examples of RBPs that have been shown to play a role in oral cancer cell migration, invasion, and metastasis. Last but not least, we will present targeting strategies that have been developed to interfere with the function of some of these RBPs.
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http://dx.doi.org/10.3390/ijms21186835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555251PMC
September 2020

Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma.

Int J Mol Sci 2020 Aug 24;21(17). Epub 2020 Aug 24.

Institut für Medizinische Immunologie, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany.

Oral squamous cell carcinoma (OSCC) is the 10th most frequent human malignancy and is thus a global burden. Despite some progress in diagnosis and therapy, patients' overall survival rate, between 40 and 55%, has stagnated over the last four decades. Since the tumor node metastasis (TNM) system is not precise enough to predict the disease outcome, additive factors for diagnosis, prognosis, prediction and therapy resistance are urgently needed for OSCC. One promising candidate is the hypoxia inducible factor-1 (HIF-1), which functions as an early regulator of tumor aggressiveness and is a key promoter of energy adaptation. Other parameters comprise the composition of the tumor microenvironment, which determines the availability of nutrients and oxygen. In our opinion, these general processes are linked in the pathogenesis of OSCC. Based on this assumption, the review will summarize the major features of the HIF system-induced activities, its target proteins and related pathways of nutrient utilization and metabolism that are essential for the initiation, progression and therapeutic stratification of OSCC.
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http://dx.doi.org/10.3390/ijms21176083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504563PMC
August 2020

MiR-155-5p and MiR-203a-3p Are Prognostic Factors in Soft Tissue Sarcoma.

Cancers (Basel) 2020 Aug 12;12(8). Epub 2020 Aug 12.

Clinic of Urology and Pediatric Urology, FA University Hospital Erlangen-Nürnberg, 91054 Erlangen, Germany.

Soft tissue sarcoma (STS) is a heterogeneous group of rare malignancies with a five-year survival rate of approximately 50%. Reliable molecular markers for risk stratification and subsequent therapy management are still needed. Therefore, we analyzed the prognostic potential of miR-155-5p and miR-203a-3p expression in a cohort of 79 STS patients. MiR-155-5p and miR-203a-3p expression was measured from tumor total RNA by qPCR and correlated with the demographic, clinicopathological, and prognostic data of the patients. Elevated miR-155-5p expression was significantly associated with increased tumor stage and hypoxia-associated mRNA/protein expression. High miR-155-5p expression and low miR-203a-3p expression, as well as a combination of high miR-155-5p and low miR-203a-3p expression, were significantly associated with poor disease-specific survival in STS patients in the Kaplan-Meier survival analyses ( = 0.027, = 0.001 and = 0.0003, respectively) and in the univariate Cox regression analyses (RR = 1.96; = 0.031; RR = 2.59; = 0.002 and RR = 4.76; = 0.001, respectively), but not in the multivariate Cox regression analyses. In conclusion, the oncomiR miR-155-5p and the tumor suppressor-miR miR-203a-3p exhibit an association with STS patient prognosis and are suggested as candidates for risk assessment.
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http://dx.doi.org/10.3390/cancers12082254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463991PMC
August 2020

Persistent tachypnea of infancy: Follow up at school age.

Pediatr Pulmonol 2020 11 13;55(11):3119-3125. Epub 2020 Aug 13.

Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, German Center for Lung Research, Munich, Germany.

Background: Persistent tachypnea of infancy (PTI) is a rare pediatric lung disease of unknown origin. The diagnosis can be made by clinical presentation and chest high resolution computed tomography after exclusion of other causes. Clinical courses beyond infancy have rarely been assessed.

Methods: Patients included in the Kids Lung Register diagnosed with PTI as infants and now older than 5 years were identified. Initial presentation, extrapulmonary comorbidities, spirometry and clinical outcome were analyzed.

Results: Thirty-five children older than 5 years with PTI diagnosed as infants were analyzed. At the age of 5 years, 74% of the patients were reported as asymptomatic and did not develope new symptoms during the observational period at school-age (mean, 3.9 years; range, 0.3-6.3). At the age of about 10 years, none of the symptomatic children had abnormal oxygen saturation during sleep or exercise anymore. Lung function tests and breathing frequency were within normal values throughout the entire observational period.

Conclusions: PTI is a pulmonary disease that can lead to respiratory insufficiency in infancy. As at school age most of the previously chronically affected children became asymptomatic and did not develop new symptoms. We conclude that the overall clinical course is favorable.
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http://dx.doi.org/10.1002/ppul.25004DOI Listing
November 2020

DRH1 - a novel blood-based HPV tumour marker.

EBioMedicine 2020 Jun 11;56:102804. Epub 2020 Jun 11.

Department of Otorhinolaryngology-Head&Neck Surgery, General Hospital Ried im Innkreis, Ried, Austria.

Background: To date, no studies have successfully shown that a highly specific, blood-based tumour marker to detect clinically relevant HPV-induced disease could be used for screening, monitoring therapy response or early detection of recurrence. This study aims to assess the clinical performance of a newly developed HPV16-L1 DRH1 epitope-specific serological assay.

Methods: In a multi-centre study sera of 1486 patients (301 Head and Neck Squamous Cell Carcinoma (HNSCC) patients, 12 HIV+ anal cancer patients, 80 HIV-positive patients, 29 Gardasil-9-vaccinees, 1064 healthy controls) were tested for human HPV16-L1 DRH1 antibodies. Analytical specificity was determined using WHO reference-sera for HPV16/18 and 29 pre- and post-immune sera of Gardasil-9-vaccinees. Tumour-tissue was immunochemically stained for HPV-L1-capsidprotein-expression.

Findings: The DRH1-competitive-serological-assay showed a sensitivity of 95% (95% CI, 772-999%) for HPV16-driven HNSCC, and 90% (95% CI, 555-997%) for HPV16-induced anal cancer in HIV-positives. Overall diagnostic specificity was 9946% for men and 9929% for women ≥ 30 years. After vaccination, antibody level increased from average 364 ng/ml to 37,500 ng/ml. During post-therapy-monitoring, HNSCC patients showing an antibody decrease in the range of 30-100% lived disease free over a period of up to 26 months. The increase of antibodies from 2750 to 12,000 ng/ml mirrored recurrent disease. We can also show that the L1-capsidprotein is expressed in HPV16-DNA positive tumour-tissue.

Interpretation: HPV16-L1 DRH1 epitope-specific antibodies are linked to HPV16-induced malignant disease. As post-treatment biomarker, the assay allows independent post-therapy monitoring as well as early diagnosis of tumour recurrence. An AUC of 096 indicates high sensitivity and specificity for early detection of HPV16-induced disease.

Funding: The manufacturer provided assays free of charge.
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http://dx.doi.org/10.1016/j.ebiom.2020.102804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300133PMC
June 2020

Prospective evaluation of hydroxychloroquine in pediatric interstitial lung diseases: Study protocol for an investigator-initiated, randomized controlled, parallel-group clinical trial.

Trials 2020 Apr 3;21(1):307. Epub 2020 Apr 3.

Department of Pediatrics, Dr. von Hauner Children´s Hospital, University Hospital, LMU Munich, German Center for Lung Research (DZL), Lindwurmstraße 4, 80337, Munich, Germany.

Background: Interstitial lung diseases in children (chILD) are rare and consist of many different entities that affect the parenchyma of the lungs, leading to a chronic lung disease. The natural course of many of these diseases is connected with a high morbidity and significant mortality. Symptomatic treatment consists of oxygen supplementation, adequate nutrition adapted to the high energy demand generated by the disease due to the increased breathing effort required, as well as immunization against respiratory pathogens to prevent exacerbations through respiratory infections. No proven pharmacological treatments are available to date. This placebo-controlled study aims to evaluate the efficacy and safety of the mid-term use of hydroxychloroquine in chILD.

Methods And Design: The study is an explorative, prospective, randomized, double-blind, placebo-controlled investigation of hydroxychloroquine (HCQ) in chILD. Patients can be included into the trial when diagnosed with a chronic (≥ 3 weeks' duration) diffuse parenchymal lung disease (chILD) (1) genetically defined, (2) histologically defined or (3) diagnosed with idiopathic pulmonary hemorrhage (hemosiderosis). The study contains of two different study blocks, a START and a STOP block, which can be initiated in any sequence. Each patient can participate in each block only once. In the START block subjects are randomized to parallel groups for 4 weeks treatment, then the placebo group is switched to the active drug. In the STOP block, subjects taking HCQ are randomized into parallel groups treated with placebo or HCQ.

Discussion: This study is the first international, investigator-initiated, prospective and controlled investigation of a pharmacological treatment in chILD. The block design was selected as it has the advantage of accommodating patients who are initiating or withdrawing from HCQ therapy, thus allowing the participation of those who were previously started on off-label HCQ. The cross-over design and selected outcome parameters enables us to include appropriate numbers of patients of all age groups from neonates to adults suffering from these rare diseases.

Trial Registration: This is an exploratory, Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, multinational study investigating the initiation or withdrawal of hydroxychloroquine in subjects with chILD. Study title: Hydroxychloroquine in pediatric ILD: START randomized controlled in parallel groups, then switch placebo to the active drug, and STOP randomized controlled in parallel groups to evaluate the efficacy and safety of hydroxychloroquine (HCQ). Short title: HCQ in pediatric ILD, particularly 4surfdefect. EudraCT, ID: 2013-003714-40. Registered on 2 July 2013. ClinicalTrials.gov, ID: NCT02615938. Registered on 8 November 2015. IZKS trial code: 2013-006; Sponsor: University Hospital, Ludwig-Maximilians University of Munich. Responsible Party: Prof. Dr. med. Matthias Griese, University Hospital, Ludwig-Maximilians University of Munich, Germany.
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http://dx.doi.org/10.1186/s13063-020-4188-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118852PMC
April 2020

Treating Allergic Bronchopulmonary Aspergillosis with Short-Term Prednisone and Itraconazole in Cystic Fibrosis.

J Allergy Clin Immunol Pract 2020 09 6;8(8):2608-2614.e3. Epub 2020 Mar 6.

Dr von Hauner Children's Hospital, Department of Pediatrics, University Hospital LMU München, Munich, Germany; German Center for Lung Research (DZL), Munich, Germany. Electronic address:

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus contributing to cystic fibrosis (CF) lung disease.

Objective: To evaluate the combination of oral prednisone for 18 days together with itraconazole therapy for at least 12 months in CF-related ABPA with regard to long-term pulmonary function and side effects.

Methods: Sixty-five patients with CF treated for ABPA and 127 patients with CF without ABPA serving as matched controls were retrospectively analyzed for a median period of 4.8 years. Serial lung functions were analyzed alongside clinical, microbiological, and laboratory data including itraconazole therapeutic drug monitoring.

Results: The used ABPA treatment regimen restored FEV values to pre-ABPA levels within 3 months (P < .0001). Long-term FEV courses of patients showed no difference when compared with those of ABPA-free controls. Glucocorticoid treatment was not associated with increased CF-related diabetes incidence, growth restriction, or Pseudomonas aeruginosa acquisition. Patients who experienced ABPA relapses displayed lower itraconazole trough levels during the first 3 months of treatment (P < .05). A decreased risk of ABPA recurrence was further associated with P aeruginosa colonization.

Conclusions: The proposed treatment scheme for CF-related ABPA is effective in preserving lung function capacity over years in affected individuals without the known glucocorticoid-associated side effects. Itraconazole therapeutic drug monitoring seems useful to prevent disease flares, for which P aeruginosa-negative patients with CF might be particularly susceptible.
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http://dx.doi.org/10.1016/j.jaip.2020.02.031DOI Listing
September 2020

Evaluation of the Betulinic Acid-Cisplatin conjugate APC and its precursor DE9B for the treatment of human malignant glioma.

Chem Biol Interact 2019 Dec 2;314:108841. Epub 2019 Oct 2.

Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06120, Halle, Germany.

Despite the existence of multimodal therapy concepts, glioblastoma remains a tumor type with one of the worst prognoses. In particular, the poor prognosis is due to the lack of therapeutic efficacy of chemical agents and irradiation in hypoxic tumor areas. New therapeutic strategies could improve the treatment of glioblastoma. In this study, we investigated the therapeutic efficacy of a conjugate of cisplatin (DDP), a widely used chemotherapeutic agent, and betulinic acid (BA), a natural product from plane tree bark, in glioblastoma cells under different oxygen conditions. We investigated the effects of the BA-DDP conjugate κN',N''-{3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide} dichlorido platinum(II) (APC) and its precursor 3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide (DE9B) on cytotoxicity, cell growth, apoptosis, migration and radiosensitivity compared to BA or DDP alone under different oxygen conditions. Based on the EC values, the precursor DE9B exhibited the strongest cytotoxic effects of the analyzed chemotherapeutic agents. The BA-DDP conjugate APC achieved a moderate cytotoxic effect in glioma cells. Both of the newly developed agents induced cell growth delay, apoptosis and inhibition of migration. Furthermore, additive effects could be achieved in combination with irradiation. In contrast to those of BA and DDP, the cell biological effects of APC and DE9B were not influenced by the oxygen concentration. In this study, the linking of BA and DDP did not produce a compound with additive therapeutic effects on glioblastoma cell lines in vitro. Nevertheless, the results of this study suggest that the precursor DE9B is an effective BA derivative for the treatment of glioblastoma in vitro.
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http://dx.doi.org/10.1016/j.cbi.2019.108841DOI Listing
December 2019

Causes and Consequences of A Glutamine Induced Normoxic HIF1 Activity for the Tumor Metabolism.

Int J Mol Sci 2019 Sep 24;20(19). Epub 2019 Sep 24.

Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.

The transcription factor hypoxia-inducible factor 1 (HIF1) is the crucial regulator of genes that are involved in metabolism under hypoxic conditions, but information regarding the transcriptional activity of HIF1 in normoxic metabolism is limited. Different tumor cells were treated under normoxic and hypoxic conditions with various drugs that affect cellular metabolism. HIF1α was silenced by siRNA in normoxic/hypoxic tumor cells, before RNA sequencing and bioinformatics analyses were performed while using the breast cancer cell line MDA-MB-231 as a model. Differentially expressed genes were further analyzed and validated by qPCR, while the activity of the metabolites was determined by enzyme assays. Under normoxic conditions, HIF1 activity was significantly increased by (i) glutamine metabolism, which was associated with the release of ammonium, and it was decreased by (ii) acetylation via acetyl CoA synthetase (ACSS2) or ATP citrate lyase (ACLY), respectively, and (iii) the presence of L-ascorbic acid, citrate, or acetyl-CoA. Interestingly, acetylsalicylic acid, ibuprofen, L-ascorbic acid, and citrate each significantly destabilized HIF1α only under normoxia. The results from the deep sequence analyses indicated that, in HIF1-siRNA silenced MDA-MB-231 cells, 231 genes under normoxia and 1384 genes under hypoxia were transcriptionally significant deregulated in a HIF1-dependent manner. Focusing on glycolysis genes, it was confirmed that HIF1 significantly regulated six normoxic and 16 hypoxic glycolysis-associated gene transcripts. However, the results from the targeted metabolome analyses revealed that HIF1 activity affected neither the consumption of glucose nor the release of ammonium or lactate; however, it significantly inhibited the release of the amino acid alanine. This study comprehensively investigated, for the first time, how normoxic HIF1 is stabilized, and it analyzed the possible function of normoxic HIF1 in the transcriptome and metabolic processes of tumor cells in a breast cancer cell model. Furthermore, these data imply that HIF1 compensates for the metabolic outcomes of glutaminolysis and, subsequently, the Warburg effect might be a direct consequence of the altered amino acid metabolism in tumor cells.
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http://dx.doi.org/10.3390/ijms20194742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802203PMC
September 2019

Current aspects of salivary gland tumors - a systematic review of the literature.

GMS Interdiscip Plast Reconstr Surg DGPW 2019 2;8:Doc12. Epub 2019 Aug 2.

Martin Luther University Halle-Wittenberg, University hospital, Department of Oral and Maxillofacial Plastic Surgery, Halle, Germany.

This study provides an up-to-date overview of the distribution of salivary gland tumors in relation to sex, land of treatment, localization of the tumor in the mouths, and benign/malignant disease of this type of tumor. We hypothesized that the distribution of patients with salivary gland tumors could vary according to country, gender, age and tumor specificity. In addition there is a comparison of the primary classification of salivary gland tumors from 1981 and the recent classification from 2005. Data from the Medline database PubMed.gov and supplementary sources were used to conduct a systematic literature search. For this purpose, data from different studies were independently collected using a previously designed questionnaire. The first section analyzes the general features of the relevant salivary gland tumors from 141 studies involving a total of 25,826 patients across 30 different countries in terms of gender and the occurrence of benign/malignant salivary gland tumors. These data were summarized and presented. This review offers an insight into the dramatic local differences with regard to salivary gland tumor occurrence as a stepping stone to further classify such data in order to derive effective therapy options, prognosis and widen the general understanding of the subject.
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http://dx.doi.org/10.3205/iprs000138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734194PMC
August 2019

Prediction of regulatory targets of alternative isoforms of the epidermal growth factor receptor in a glioblastoma cell line.

BMC Bioinformatics 2019 Aug 22;20(1):434. Epub 2019 Aug 22.

Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle, Germany.

Background: The epidermal growth factor receptor (EGFR) is a major regulator of proliferation in tumor cells. Elevated expression levels of EGFR are associated with prognosis and clinical outcomes of patients in a variety of tumor types. There are at least four splice variants of the mRNA encoding four protein isoforms of EGFR in humans, named I through IV. EGFR isoform I is the full-length protein, whereas isoforms II-IV are shorter protein isoforms. Nevertheless, all EGFR isoforms bind the epidermal growth factor (EGF). Although EGFR is an essential target of long-established and successful tumor therapeutics, the exact function and biomarker potential of alternative EGFR isoforms II-IV are unclear, motivating more in-depth analyses. Hence, we analyzed transcriptome data from glioblastoma cell line SF767 to predict target genes regulated by EGFR isoforms II-IV, but not by EGFR isoform I nor other receptors such as HER2, HER3, or HER4.

Results: We analyzed the differential expression of potential target genes in a glioblastoma cell line in two nested RNAi experimental conditions and one negative control, contrasting expression with EGF stimulation against expression without EGF stimulation. In one RNAi experiment, we selectively knocked down EGFR splice variant I, while in the other we knocked down all four EGFR splice variants, so the associated effects of EGFR II-IV knock-down can only be inferred indirectly. For this type of nested experimental design, we developed a two-step bioinformatics approach based on the Bayesian Information Criterion for predicting putative target genes of EGFR isoforms II-IV. Finally, we experimentally validated a set of six putative target genes, and we found that qPCR validations confirmed the predictions in all cases.

Conclusions: By performing RNAi experiments for three poorly investigated EGFR isoforms, we were able to successfully predict 1140 putative target genes specifically regulated by EGFR isoforms II-IV using the developed Bayesian Gene Selection Criterion (BGSC) approach. This approach is easily utilizable for the analysis of data of other nested experimental designs, and we provide an implementation in R that is easily adaptable to similar data or experimental designs together with all raw datasets used in this study in the BGSC repository, https://github.com/GrosseLab/BGSC .
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http://dx.doi.org/10.1186/s12859-019-2944-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704634PMC
August 2019

Lung disease in STAT3 hyper-IgE syndrome requires intense therapy.

Allergy 2019 09 4;74(9):1691-1702. Epub 2019 Apr 4.

Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.

Background: Pulmonary complications are responsible for high morbidity and mortality rates in patients with the rare immunodeficiency disorder STAT3 hyper-IgE syndrome (STAT3-HIES). The aim of this study was to expand knowledge about lung disease in STAT3-HIES.

Methods: The course of pulmonary disease, radiological and histopathological interrelations, therapeutic management, and the outcome of 14 STAT3-HIES patients were assessed.

Results: The patients' quality of life was compromised most by pulmonary disease. All 14 patients showed first signs of lung disease at a median onset of 1.5 years of age. Lung function revealed a mixed obstructive-restrictive impairment with reduced FEV1 and FVC in 75% of the patients. The severity of lung function impairment was associated with Aspergillus fumigatus infection and prior lung surgery. Severe lung tissue damage, with reduced numbers of ATP-binding cassette sub-family A member 3 (ABCA3) positive type II pneumocytes, was observed in the histological assessment of two deceased patients. Imaging studies of all patients above 6 years of age showed severe airway and parenchyma destruction. Lung surgeries frequently led to complications, including fistula formation. Long-term antifungal and antibacterial treatment proved to be beneficial, as were inhalation therapy, chest physiotherapy, and exercise. Regular immunoglobulin replacement therapy tended to stabilize lung function.

Conclusions: Due to its severity, pulmonary disease in STAT3-HIES patients requires strict monitoring and intensive therapy.
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http://dx.doi.org/10.1111/all.13753DOI Listing
September 2019

Prognostic impact of mRNA levels of LGR5 transcript variants in OSCC patients.

BMC Cancer 2019 Feb 15;19(1):155. Epub 2019 Feb 15.

Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str, 40 06097, Halle/Saale, Germany.

Background: The human leucine-rich, repeat-containing G protein-coupled receptor 5 (LGR5) is a stem cell marker in numerous adult tissues and is overexpressed in a large number of human carcinoma including colon cancer, breast cancer and oral squamous cell carcinomas (OSCC). The role of the full length transcript (LGR5FL) in progression and prognosis of several cancers was reported. However, the biological function of three splice variants of LGR5 (LGR5Δ5, LGR5Δ8 and LGR5Δ5-8) has yet to be thoroughly investigated.

Methods: Seventy-eight frozen tumor samples from adult OSCC patients were studied using quantitative real-time TaqMan™ PCR analysis. The mRNA levels of full length LGR5, the splice variant of LGR5 lacking exon 5 (LGR5Δ5), the splice variant of LGR5 lacking exon 8 (LGR5Δ8) and the mRNA level of all known transcript variants together (LGR5all) were quantified and correlated to overall and disease-specific survival of OSCC patients, clinical parameters and the mRNA level of different tumor-associated markers.

Results: An elevated level of tumoral LGR5Δ5 mRNA, but not LGR5FL, LGR5Δ8 or LGR5all mRNA was significantly associated with a poor prognosis for the overall and disease-specific survival of OSCC patients (hazard ratio (HR) = 2.0; p = 0.02; 95% CI: 1.1-3.7; HR = 3.2; p = 0.01; 95% CI: 1.3-8.0; multivariable Cox regression), respectively. Additionally, a higher tumoral level of LGR5Δ5 mRNA in primary tumors was associated with the occurrence of regional lymph node metastases in OSCC patients (odds ratio (OR) = 3.1; p = 0.022; 95% CI: 1.2-7.9; binary logistic regression). Furthermore, the mRNA levels of all investigated LGR5 transcript variants were significantly correlated with the mRNA expression of Wnt-target genes and markers of epithelial-to-mesenchymal transition (EMT).

Conclusion: The mRNA level of the LGR5 splice variant LGR5Δ5 is an independent negative prognostic marker for overall and disease-specific survival and metastasis in OSCC patients. Additionally, we suggest, all LGR5 transcript variants are involved in the EMT process mainly through activating the Wnt-signalling pathway.
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http://dx.doi.org/10.1186/s12885-019-5327-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377725PMC
February 2019

Investigation of the Prognostic Role of Carbonic Anhydrase 9 (CAIX) of the Cellular mRNA/Protein Level or Soluble CAIX Protein in Patients with Oral Squamous Cell Carcinoma.

Int J Mol Sci 2019 Jan 16;20(2). Epub 2019 Jan 16.

Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.

s Carbonic anhydrase 9 (CAIX) is an important protein that stabilizes the extracellular pH value and is transcriptionally regulated by hypoxia-inducible factor 1 (HIF1), but more stable than HIF1α. Here we show a comparative study that examines the prognostic value of CA9 mRNA, CAIX protein of tumor cells and secreted CAIX protein for oral squamous cell carcinoma (OSCC) patients. Tumor samples from 72 OSCC patients and 24 samples of normal tissue were analyzed for CA9 mRNA levels. A total of 158 OSCC samples were stained for CAIX by immunohistochemistry and 89 blood serum samples were analyzed by ELISA for soluble CAIX protein content. Survival analyses were performed by Kaplan⁻Meier and Cox's regression analysis to estimate the prognostic effect of CA9/CAIX in OSCC patients. The CA9 mRNA and CAIX protein levels of tumor cells correlated with each other, but not with those of the secreted CAIX protein level of the blood of patients. ROC curves showed a significant ( < 0.001) higher mRNA-level of CA9 in OSCC samples than in adjacent normal tissue. Cox's regression analysis revealed an increased risk (i) of death for patients with a high CA9 mRNA level (RR = 2.2; p = 0.02), (ii) of locoregional recurrence (RR = 3.2; p = 0.036) at higher CA9 mRNA levels and (iii) of death at high CAIX protein level in their tumors (RR = 1.7; p = 0.066) and especially for patients with advanced T4-tumors (RR = 2.0; p = 0.04). However, the secreted CAIX protein level was only as a trend associated with prognosis in OSCC (RR = 2.2; p = 0.066). CA9/CAIX is an independent prognostic factor for OSCC patients and therefore a potential therapeutic target.
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http://dx.doi.org/10.3390/ijms20020375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359351PMC
January 2019

Low HIF-1α and low EGFR mRNA Expression Significantly Associate with Poor Survival in Soft Tissue Sarcoma Patients; the Proteins React Differently.

Int J Mol Sci 2018 Dec 3;19(12). Epub 2018 Dec 3.

Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.

In various tumors, the hypoxia inducible factor-1α () and the epidermal growth factor-receptor () have an impact on survival. Nevertheless, the prognostic impact of both markers for soft tissue sarcoma (STS) is not well studied. We examined 114 frozen tumor samples from adult soft tissue sarcoma patients and 19 frozen normal tissue samples. The mRNA levels of HIF-1α, EGFR, and the reference gene hypoxanthine phosphoribosyltransferase (HPRT) were quantified using a multiplex qPCR technique. In addition, levels of EGFR or HIF-1α protein were determined from 74 corresponding protein samples using ELISA techniques. Our analysis showed that a low level of HIF-1α or EGFR mRNA (respectively, relative risk (RR) = 2.8; = 0.001 and RR = 1.9; = 0.04; multivariate Cox´s regression analysis) is significantly associated with a poor prognosis in STS patients. The combination of both mRNAs in a multivariate Cox's regression analysis resulted in an increased risk of early tumor-specific death of patients (RR = 3.1, = 0.003) when both mRNA levels in the tumors were low. The EGFR protein level had no association with the survival of the patient's cohort studied, and a higher level of HIF-1α protein associated only with a trend to significance (multivariate Cox's regression analysis) to a poor prognosis in STS patients (RR = 1.9, = 0.09). However, patients with low levels of HIF-1α protein and a high content of EGFR protein in the tumor had a three-fold better survival compared to patients without such constellation regarding the protein level of HIF-1α and EGFR. In a bivariate two-sided Spearman's rank correlation, a significant correlation between the expression of HIF-1α mRNA and expression of EGFR mRNA ( < 0.001) or EGFR protein ( = 0.001) was found, additionally, EGFR mRNA correlated with EGFR protein level ( < 0.001). Our results show that low levels of HIF-1α mRNA or EGFR mRNA are negative independent prognostic markers for STS patients, especially after combination of both parameters. The protein levels showed a different effect on the prognosis. In addition, our analysis suggests a possible association between HIF-1α and EGFR expression in STS.
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http://dx.doi.org/10.3390/ijms19123842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321736PMC
December 2018

New molecular aspects in the mechanism of oromaxillofacial cleft prevention by B-vitamins.

J Craniomaxillofac Surg 2018 Dec 22;46(12):2058-2062. Epub 2018 Oct 22.

Department of Oral and Maxillofacial and Facial Plastic Surgery, Martin-Luther-University Halle-Wittenberg (Head: apl. Prof. Dr. Dr. A.W. Eckert), Ernst-Grube-Straße 40, 06120, Halle, Germany.

Clinical and experimental studies show a clear positive effect of B-vitamins in the prevention of oromaxillofacial clefts, especially cleft lip and palate (CL/P). Hereby the local effect of thiamin (B1) in the amniotic fluid is very important for the embryonic facial development as seen in palatal organ models stimulated by topical B-vitamin application (Scheller et al., 2013a). Moreover a low B1 concentration in the serum and amniotic fluid was found in pregnant mice with clefts in their offspring (Scheller et al., 2013b). Immunochemical analyses of midface sections (ThTr-1 transporter) and the placenta (ThTr-2 transporter) of cleft fetuses with orofacial clefts showed an atypical cytoplasmatic localization (Scheller et al., 2017). mRNA nalyses of different B-vitamin transporters (B1, B2, B5, B7, B9) were performed and showed ThTr2 transporter in a short splice variant in all cleft fetuses. This splice variant may cause a functional loss of the transport capacity through the placenta barrier and result in a low amniotic fluid concentration of vitamin B1. All other analyzed transport proteins showed no functional change. These findings confirm the hypothesis that cleft prevention by high vitamin B1 substitution fails in genetically determined cleft mice, caused by an insufficient B1 uptake and missing local effect.
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http://dx.doi.org/10.1016/j.jcms.2018.10.008DOI Listing
December 2018

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function.

Am J Hum Genet 2018 07;103(1):100-114

Institute of Human Genetics, Technical University Munich, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.

The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alphabeta phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5'-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.
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http://dx.doi.org/10.1016/j.ajhg.2018.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035289PMC
July 2018

P4HA1: A single-gene surrogate of hypoxia signatures in oral squamous cell carcinoma patients.

Clin Transl Radiat Oncol 2017 Aug 27;5:6-11. Epub 2017 Jun 27.

Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

Background And Purpose: Hypoxia gene expression signatures are of high prognostic value for head and neck cancer patients. Recently, the prognostic information of a multiple-gene hypoxia signature was found to be provided by the mRNA level of alone (Tawk et al., 2016). Therefore, we studied the prognostic value of in an independent cohort of oral squamous cell carcinoma (OSCC) patients.

Material And Methods: Frozen tumor samples of 118 adult OSCC patients were analysed for mRNA level by quantitative real-time TaqMan™ PCR analysis. Kaplan-Meier analysis and Cox's regression analysis were performed to characterize the prognostic impact of mRNA level in OSCC patients.

Results: The analyzed patient cohort was divided into four subgroups according to the quartiles of the mRNA levels. The highest intratumoral mRNA level was significantly correlated with a poor overall survival (RR = 2.2;  = 0.04) and an increased risk of locoregional recurrence (RR = 4.8;  = 0.02). In patients who received radiotherapy ( = 82) highest intratumoral mRNA level was significantly correlated with a poor overall survival (RR = 3.4;  = 0.01) and an increased risk of locoregional recurrence (RR = 10.3;  = 0.005). Moreover, significant correlations between the mRNA level and the mRNA level of several EMT and stem cell markers were found.

Conclusions: A high mRNA level, as a single-gene surrogate of hypoxia, is an independent prognostic marker for the overall survival and locoregional recurrence of OSCC patients.
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http://dx.doi.org/10.1016/j.ctro.2017.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833914PMC
August 2017

Correction to: Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma.

J Transl Med 2018 02 28;16(1):40. Epub 2018 Feb 28.

Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Magdeburger Str. 2, 06110, Halle (Saale), Germany.

The original version of this article [1], published on 5 April 2016, contains a mistake. In the 'Role of pH stabilisation' section, "intracellular pH" has been incorrectly abbreviated as "pHe". The correct abbreviation is "pHi". The affected sentence with the correct abbreviation is given below.
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http://dx.doi.org/10.1186/s12967-018-1407-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830086PMC
February 2018

CMG2 Expression Is an Independent Prognostic Factor for Soft Tissue Sarcoma Patients.

Int J Mol Sci 2017 Dec 7;18(12). Epub 2017 Dec 7.

Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.

The capillary morphogenesis gene 2 (CMG2), also known as the anthrax toxin receptor 2 (ANTXR2), is a transmembrane protein putatively involved in extracellular matrix (ECM) adhesion and tissue remodeling. CMG2 promotes endothelial cell proliferation and exhibits angiogenic properties. Its downregulation is associated with a worsened survival of breast carcinoma patients. Aim of this study was to analyze the CMG2 mRNA and protein expression in soft tissue sarcoma and their association with patient outcome. CMG2 mRNA was measured in 121 tumor samples of soft tissue sarcoma patients using quantitative real-time PCR. CMG2 protein was evaluated in 52 tumor samples by ELISA. CMG2 mRNA was significantly correlated with the corresponding CMG2 protein expression (r = 0.31; = 0.027). CMG2 mRNA expression was associated with the mRNA expressions of several ECM and tissue remodeling enzymes, among them CD26 and components of the uPA system. Low CMG2 mRNA expression was correlated with a worsened patients' disease-specific survival in Kaplan-Meier analyses (mean patient survival was 25 vs. 96 months; = 0.013), especially in high-stage tumors. A decreased CMG2 expression is a negative prognostic factor for soft tissue sarcoma patients. CMG2 may be an interesting candidate gene for the further exploration of soft tissue sarcoma genesis and progression.
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http://dx.doi.org/10.3390/ijms18122648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751250PMC
December 2017