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Diskriminierung von Mitarbeitern Mehrarbeit wird vorausgesetzt kein klares Hierarchie-Gefüge zu wenig und zu kleine Räume ständige Neu-Einstellung wegen neuer Projekte. Wiestler, Präsident der Helmholtz-Gemeinschaft. Bewertungsdurchschnitte 6 Mitarbeiter sagen Sehr gut 3. SkBtV1h3 Als Arbeitgeber kommentieren. Altersvorsorge wird geboten Betriebsarzt wird geboten Mitarbeiterevents wird geboten. Bewertungen - Was Mitarbeiter sagen. September im schönen Verona, Italien, ab. Vorgesetztenverhalten kaum Vergabe von realitätsnahen Prioritäten, wenig Ansprechmöglichkeit seitens der Fachkräfte Kommunikation Meetings bleiben oft ohne Fazit oder klar verteilten ToDos Arbeitsbedingungen kalt temperierte Büroräume, max. Dieser findet um

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Log In Create an Account. Audience Demographics How similar is this site's audience to the general internet population? The devastating prognosis of patients with resectable pancreatic ductal adenocarcinoma PDA presents an urgent need for the development of therapeutic strategies targeting disseminated tumor cells.

Until now, T-cell therapy has been scarcely pursued in PDA, due to the prevailing view that it represents a poorly immunogenic tumor. We systematically analyzed T-cell infiltrates in tumor biopsies from patients with resectable PDA by means of immunohistochemistry, flow cytometry, T-cell receptor TCR deep-sequencing and functional analysis of in vitro expanded T-cell cultures.

Parallel studies were performed on tumor-infiltrating lymphocytes from 44 patients with metastatic melanoma. Prominent T-cell infiltrates, as well as tertiary lymphoid structures harboring proliferating T-cells, were detected in the vast majority of biopsies from PDA patients.

The notion that the tumor is a site of local T-cell expansion was strengthened by TCR deep-sequencing, revealing that the T-cell repertoire in the tumor is dominated by highly frequent CDR3 sequences that can be up to Moreover, in vitro expansion of tumor-infiltrating lymphocytes was equally efficient for PDA and melanoma, resulting in T-cell cultures displaying HLA class I-restricted reactivity against autologous tumor cells.

The tumor-infiltrating T-cell response in PDA shows striking similarity to that in melanoma, where adoptive T-cell therapy has significant therapeutic impact.

Our findings indicate that T-cell based therapies may be used to counter disease recurrence in patients with resectable PDA. First data of an innovative actively personalized peptide vaccination trial in patients with newly diagnosed glioblastoma.

Resected tumor material is analyzed for multiple biomarkers to characterize the tumor in depth and to enable the design of APVACs tailored to each individual patient: Tumor-specific mutations, the HLA peptidome and gene expression profile are assessed by next-generation sequencing, mass spectrometry and RNA microarray analysis, respectively.

Further, the patient-individual immune status is investigated by assessment of leukapheresis samples utilizing an in vitro immunogenicity platform.

APVAC2 is composed of one or two peptides that are de novo synthesized for a given patient and preferentially represent mutation-bearing neo-epitopes.

Primary endpoints of the study are assessment of safety, feasibility of APVAC manufacturing and biological activity. Composition and manufacturing are ongoing for four patients.

APVAC1 vaccines differ substantially with 31 out of 59 warehouse peptides have been selected at least once, indicating the need for personalization due to tumor heterogeneity even for non-mutated epitopes.

Injection site reactions were the most frequent toxicities so far. One brain edema Grade 3 and one allergic reaction Grade 4 were observed, both potentially related to the vaccinations.

In conclusion, the GAPVAC concept has been successfully translated into the clinics and so far demonstrated to be safe and feasible with its level of personalization matching the observed tumor heterogeneity.

The majority of metastatic cancers remain incurable since the current methods of treatment often fail to target the heterogeneous nature of each individual patient's tumor.

Personalized approaches targeting each individual patient's tumor may therefore bring significant improvements. MERIT combines two personalized treatment concepts: The mRNAs are administered intravenously as a nanoparticulate lipoplex formulation, which specifically targets APCs and consequently induces antigen-specific T cell responses.

MERIT is a multi-center phase I trial NCT conducted in four European countries to assess the feasibility, safety and biological efficacy of this personalized immunotherapy.

During the clinical trial, patients will receive the individualized combination of the RNAs in parallel to standard radiotherapy.

The clinical trial is approved and the study start is planned for Q1 The consortium has built a multi-disciplinary clinical workflow and trial design tailored to this unique therapeutic concept, which covers the whole individualized drug development cycle from target discovery, validation to GMP manufacturing and drug release for each individual patient.

We will present the therapeutic concept and study protocol as well as the methodologies required for this highly innovative phase I trial.

The personalized immunotherapy overcomes the current limitations of fixed, off-the-shelf therapeutics and thus might increase the clinical benefit for TNBC patients.

One of the hallmarks of cancer is the inherent instability of the genome leading to multiple genomic alterations and epigenetic changes that ultimately drive carcinogenesis.

These processes lead to a unique molecular profile of every given tumor and to substantial intratumoral heterogeneity of cancer tissues.

Recently, a series of independent reports revealed that pre-formed neoantigen specific T-cell responses are of crucial relevance for the clinical efficacy of immune checkpoint inhibitors.

Accordingly, only patients with a high burden of mutations profit from currently approved therapies. A phase I study to test this novel concept of an active individualized cancer vaccine for the treatment of malignant melanoma was initiated in NCT Detailed information on the trial, the recruitment and treatment status as well as data on the assessment of vaccine induced immune responses will be presented.

As neoepitopes with strict lack of expression in any healthy tissue, they are expected to be safe and could bypass the central tolerance mechanisms.

Recent advances in nucleic acid sequencing technologies have revolutionized the field of genomics, allowing the readily targeting of mutated neoantigens for personalized cancer vaccination.

Encouraged by these findings we set up a process comprising mutation detection by exome sequencing, selection of vaccine targets by solely bioinformatical prioritization of mutated epitopes predicted to be abundantly expressed and presented on MHC class II molecules.

Synthetic mRNA vaccines encoding multiple of these prioritized mutated epitopes induce potent tumor control and complete rejection of established aggressively growing tumors in mice.

Tadmor, Ozlem Tureci, Ugur Sahin. Towards Patient-Centered Tumor Vaccination. Advances in nucleic acid sequencing technologies have revolutionized the field of genomics, allowing the efficient targeting of mutated neoantigens for personalized cancer vaccination.

Due to their absence during negative selection of T cells and their lack of expression in healthy tissue, tumor mutations are considered as optimal targets for cancer immunotherapy.

Preclinical and early clinical data suggest that synthetic mRNA can serve as potent drug format allowing the cost efficient production of highly efficient vaccines in a timely manner.

In this review, we describe a process, which integrates next generation sequencing based cancer mutanome mapping, in silico target selection and prioritization approaches, and mRNA vaccine manufacturing and delivery into a process we refer to as MERIT mutanome engineered RNA immunotherapy.

An online cancer cell line catalogue integrating HLA type, predicted neo-epitopes, virus and gene expression.

Human cancer cell lines are an important resource for research and drug development. However, the available annotations of cell lines are sparse, incomplete, and distributed in multiple repositories.

Re-analyzing publicly available raw RNA-Seq data, we determined the human leukocyte antigen HLA type and abundance, identified expressed viruses and calculated gene expression of 1, cancer cell lines.

Using the determined HLA types, public databases of cell line mutations, and existing HLA binding prediction algorithms, we predicted antigenic mutations in each cell line.

We integrated the results into a comprehensive knowledgebase. Using the Django web framework, we provide an interactive user interface with advanced search capabilities to find and explore cell lines and an application programming interface to extract cell line information.

The portal is available at http: Electronic supplementary material The online version of this article doi: Individualized vaccines for the treatment of cancer.

Cancer arises from the accumulation of genomic alterations and epigenetic changes that constitute a hallmark of cancer. Owing to the molecular heterogeneity in cancer, only a minor fraction of patients profit from approved therapies.

Available targeted therapies can only address alterations common to a particular type of cancer and induce transient effects due to the generation of resistant sub-clones.

The IVAC MUTANOME approach should be applicable to the majority of patients irrespective of the tumor entity and offers the potential to exploit the whole tumor mutanome of a given patient using a multi-target approach.

The IVAC approach is supported by i the availability of technologies that allow fast discovery and validation of individual mutations based on sequencing of whole exome and ii an innovative vaccine platform based on RNA-technology supporting fast manufacturing and release of patient-specific vaccines targeting multiple immunogenic mutations within weeks.

The phase I study to test the individualized cancer immunotherapeutics for the treatment of malignant melanoma was approved and initiated in NCT Recruitment of a patient in the trial repetitively triggers the IVAC MUTANOME process covering i the receipt of tumor and blood sample specimens, ii the identification, prioritization and confirmation of mutations, iii testing of pre-existing immunity against private tumor mutations, iv the final selection of mutated sequences, iv design, production of a DNA lead structure, v GMP manufacturing and release of the patient-specific mRNA, vi shipment to the clinical trial site, and vii the administration of the IMP to patients.

Bjoern-Philipp Kloke, Cedrik M. Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite.

In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected.

In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction in asthma symptoms, demonstrating the immunosuppressive potency of tick-derived molecules.

Next-generation sequencing NGS enables high-throughput transcriptome profiling using the RNA-Seq assay, resulting in billions of short sequence reads.

Worldwide adoption has been rapid: Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire.

Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient's tumour possesses a unique set of mutations 'the mutanome' that must first be identified.

Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient's individual tumour-specific mutations.

Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex MHC class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines.

We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice.

Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types.

Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced 'just in time'.

Exploiting the Mutanome for Personalized Cancer Immunotherapy. Since the publication of our first book 'Vaccine Design: Innovative Approaches and Novel Strategies' in , the field of vaccinology has advanced significantly.

This has prompted the need for this new volume, which aims to distil the most important new findings to provide a timely overview of the field.

As before the book has been divided into two main parts. The first explores in considerable depth the key innovations that we think are dramatically changing the field; both for preclinical as well as clinical vaccine research fields.

Some of the topics covered include: The second part focuses on diseases for which current medical treatment is not sufficiently effective and that could be either prevented or treated by vaccination.

The examples that we have used comprise very different diseases including infectious diseases e. We believe that these will be the vaccines of the future, the 'vaccines for '.

Cancer cell lines are a tremendous resource for cancer biology and therapy development. Mutations, gene expression, and drug sensitivity have been determined for many cell lines using next-generation sequencing NGS.

However, the human leukocyte antigen HLA type and HLA expression of tumor cell lines, characterizations necessary for the development of cancer vaccines, have remained largely incomplete and, such information, when available, has been distributed in many publications.

Second, we determine HLA expression levels in each cancer cell line, providing insights into HLA downregulation and loss in cancer.

Fourth, we integrate the cancer cell-line specific HLA types and HLA expression with available cell-line specific mutation information and existing HLA binding prediction algorithms to make a catalog of predicted antigenic mutations in each cell line.

The compilation of our results are a fundamental resource for all researchers selecting specific cancer cell lines based on the HLA type and HLA expression, as well as for the development of immunotherapeutic tools for novel cancer treatment modalities.

Translation of genomics-guided RNA-based personalised cancer vaccines: Cancer is a disease caused by DNA mutations. Cancer therapies targeting defined functional mutations have shown clinical benefit.

A rapidly determined patient-specific tumour mutation pattern combined with a flexible mutation-targeting drug platform could generate a mutation-targeting individualised therapy, which would benefit each single patient.

Next-generation sequencing enables the rapid identification of somatic mutations in individual tumours the mutanome. Immunoinformatics enables predictions of mutation immunogenicity.

Integration of these cutting-edge technologies into a clinically applicable process holds the promise of a disruptive innovation benefiting cancer patients.

Here, we describe our translation of the individualised RNA-based cancer vaccine concept into clinic trials.

Mutated tumor alleles are expressed according to their DNA frequency. The transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice.

It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele. We sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction.

Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay.

Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles.

In conclusion, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency.

Genomics Meets Cancer Immunotherapy. Mar Cancer Immunotherapy Meets Oncology. High-throughput cancer genomics and bioinformatics are revolutionizing our ability to profile tumor samples.

With next-generation sequencing NGS and high-performance computing HPC platforms, we have developed the infrastructures to determine and characterize tumor genomes and transcriptomes within days.

Now, we are integrating these platforms into both cancer immunology and patient therapy decision-making. Here, we briefly describe the technology platforms and highlight several emerging applications: These and other concepts will continue to expand the medical impact of NGS.

Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma. Tumor models are critical for our understanding of cancer and the development of cancer therapeutics.

Here, we present an integrated map of the genome, transcriptome and immunome of an epithelial mouse tumor, the CT26 colon carcinoma cell line.

We found that Kras is homozygously mutated at p. G12D, Apc and Tp53 are not mutated, and Cdkn2a is homozygously deleted.

Several known cancer-testis antigens are expressed, including Atad2, Cep55, and Pbk. The highest expressed gene is a mutated form of the mouse tumor antigen gp Of the 1, non-synonymous point variations, are both in expressed genes and in peptides predicted to bind MHC and thus potential targets for immunotherapy development.

CT26 cells share molecular features with aggressive, undifferentiated, refractory human colorectal carcinoma cells.

As CT26 is one of the most extensively used syngeneic mouse tumor models, our data provide a map for the rationale design of mode-of-action studies for pre-clinical evaluation of targeted- and immunotherapies.

Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model.

Combining a conditional mouse model that closely resembles the slow evolution and the mosaic AE expression pattern of human t 8;21 CBF AML with global transcriptome sequencing, we find that disease progression was characterized by two principal pathogenic mechanisms.

Initially, AE expression modified the lineage potential of haematopoietic stem cells HSCs , resulting in the selective expansion of the myeloid compartment at the expense of normal erythro- and lymphopoiesis.

This lineage skewing was followed by a second substantial rewiring of transcriptional networks occurring in the trajectory to manifest leukaemia.

We also find that both HSC and lineage-restricted granulocyte macrophage progenitors GMPs acquired leukaemic stem cell LSC potential being capable of initiating and maintaining the disease.

Finally, our data demonstrate that long-term expression of AE induces an indolent myeloproliferative disease MPD -like myeloid leukaemia phenotype with complete penetrance and that acute inactivation of AE function is a potential novel therapeutic option.

We determine HLA-type and expression for the previously un-typed Illumina Body Map tissues and a cohort of Korean lung cancer patients.

Because the algorithm uses standard RNA-Seq reads and requires no change to lab protocols, it can be used for both existing datasets and future studies, thus adding a new dimension for HLA typing and biomarker studies.

Validation results for mutations with an intermediate FDR. Alignment statistics for all samples. Confidence-based Somatic Mutation Evaluation and Prioritization.

Next generation sequencing NGS has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms.

Here, we developed an algorithm to assign a single statistic, a false discovery rate FDR , to each somatic mutation identified by NGS.

This FDR confidence value accurately discriminates true mutations from erroneous calls. For each identified mutation, our algorithm assigned an FDR.

We selected mutations for validation, including 50 somatic mutations assigned a low FDR high confidence and 44 mutations assigned a high FDR low confidence.

All of the high confidence somatic mutations validated 50 of 50 , none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated.

Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics.

Using the HiSeq , single end 50 nt reads from replicates generate the highest confidence somatic mutation call set. Exploiting the Mutanome for Tumor Vaccination.

Multiple genetic events and subsequent clonal evolution drive carcinogenesis, making disease elimination with single-targeted drugs difficult.

The multiplicity of gene mutations derived from clonal heterogeneity therefore represents an ideal setting for multiepitope tumor vaccination.

Here, we used next generation sequencing exome resequencing to identify nonsynonymous somatic point mutations in B16F10 murine melanoma cells, with of those mutations in expressed genes.

Potential driver mutations occurred in classical tumor suppressor genes and genes involved in proto-oncogenic signaling pathways that control cell proliferation, adhesion, migration, and apoptosis.

Individualized vaccines for the treatment of cancer. Cancer arises from the accumulation of genomic alterations and epigenetic changes that constitute a hallmark of cancer.

Owing to the molecular heterogeneity in cancer, only a minor fraction of patients profit from approved therapies. Available targeted therapies can only address alterations common to a particular type of cancer and induce transient effects due to the generation of resistant sub-clones.

The IVAC MUTANOME approach should be applicable to the majority of patients irrespective of the tumor entity and offers the potential to exploit the whole tumor mutanome of a given patient using a multi-target approach.

The IVAC approach is supported by i the availability of technologies that allow fast discovery and validation of individual mutations based on sequencing of whole exome and ii an innovative vaccine platform based on RNA-technology supporting fast manufacturing and release of patient-specific vaccines targeting multiple immunogenic mutations within weeks.

The phase I study to test the individualized cancer immunotherapeutics for the treatment of malignant melanoma was approved and initiated in NCT Recruitment of a patient in the trial repetitively triggers the IVAC MUTANOME process covering i the receipt of tumor and blood sample specimens, ii the identification, prioritization and confirmation of mutations, iii testing of pre-existing immunity against private tumor mutations, iv the final selection of mutated sequences, iv design, production of a DNA lead structure, v GMP manufacturing and release of the patient-specific mRNA, vi shipment to the clinical trial site, and vii the administration of the IMP to patients.

Bjoern-Philipp Kloke, Cedrik M. Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite.

In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected.

In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction in asthma symptoms, demonstrating the immunosuppressive potency of tick-derived molecules.

Next-generation sequencing NGS enables high-throughput transcriptome profiling using the RNA-Seq assay, resulting in billions of short sequence reads.

Worldwide adoption has been rapid: Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire.

Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient's tumour possesses a unique set of mutations 'the mutanome' that must first be identified.

Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient's individual tumour-specific mutations.

Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex MHC class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines.

We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice.

Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types.

Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced 'just in time'.

Exploiting the Mutanome for Personalized Cancer Immunotherapy. Since the publication of our first book 'Vaccine Design: Innovative Approaches and Novel Strategies' in , the field of vaccinology has advanced significantly.

This has prompted the need for this new volume, which aims to distil the most important new findings to provide a timely overview of the field.

As before the book has been divided into two main parts. The first explores in considerable depth the key innovations that we think are dramatically changing the field; both for preclinical as well as clinical vaccine research fields.

Some of the topics covered include: The second part focuses on diseases for which current medical treatment is not sufficiently effective and that could be either prevented or treated by vaccination.

The examples that we have used comprise very different diseases including infectious diseases e. We believe that these will be the vaccines of the future, the 'vaccines for '.

Cancer cell lines are a tremendous resource for cancer biology and therapy development. Mutations, gene expression, and drug sensitivity have been determined for many cell lines using next-generation sequencing NGS.

However, the human leukocyte antigen HLA type and HLA expression of tumor cell lines, characterizations necessary for the development of cancer vaccines, have remained largely incomplete and, such information, when available, has been distributed in many publications.

Second, we determine HLA expression levels in each cancer cell line, providing insights into HLA downregulation and loss in cancer. Fourth, we integrate the cancer cell-line specific HLA types and HLA expression with available cell-line specific mutation information and existing HLA binding prediction algorithms to make a catalog of predicted antigenic mutations in each cell line.

The compilation of our results are a fundamental resource for all researchers selecting specific cancer cell lines based on the HLA type and HLA expression, as well as for the development of immunotherapeutic tools for novel cancer treatment modalities.

Translation of genomics-guided RNA-based personalised cancer vaccines: Cancer is a disease caused by DNA mutations. Cancer therapies targeting defined functional mutations have shown clinical benefit.

A rapidly determined patient-specific tumour mutation pattern combined with a flexible mutation-targeting drug platform could generate a mutation-targeting individualised therapy, which would benefit each single patient.

Next-generation sequencing enables the rapid identification of somatic mutations in individual tumours the mutanome. Immunoinformatics enables predictions of mutation immunogenicity.

Integration of these cutting-edge technologies into a clinically applicable process holds the promise of a disruptive innovation benefiting cancer patients.

Here, we describe our translation of the individualised RNA-based cancer vaccine concept into clinic trials. Mutated tumor alleles are expressed according to their DNA frequency.

The transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice. It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele.

We sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction.

Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay. Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles.

In conclusion, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency.

Genomics Meets Cancer Immunotherapy. Mar Cancer Immunotherapy Meets Oncology. High-throughput cancer genomics and bioinformatics are revolutionizing our ability to profile tumor samples.

With next-generation sequencing NGS and high-performance computing HPC platforms, we have developed the infrastructures to determine and characterize tumor genomes and transcriptomes within days.

Now, we are integrating these platforms into both cancer immunology and patient therapy decision-making.

Here, we briefly describe the technology platforms and highlight several emerging applications: These and other concepts will continue to expand the medical impact of NGS.

Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma. Tumor models are critical for our understanding of cancer and the development of cancer therapeutics.

Here, we present an integrated map of the genome, transcriptome and immunome of an epithelial mouse tumor, the CT26 colon carcinoma cell line.

We found that Kras is homozygously mutated at p. G12D, Apc and Tp53 are not mutated, and Cdkn2a is homozygously deleted.

Several known cancer-testis antigens are expressed, including Atad2, Cep55, and Pbk. The highest expressed gene is a mutated form of the mouse tumor antigen gp Of the 1, non-synonymous point variations, are both in expressed genes and in peptides predicted to bind MHC and thus potential targets for immunotherapy development.

CT26 cells share molecular features with aggressive, undifferentiated, refractory human colorectal carcinoma cells.

As CT26 is one of the most extensively used syngeneic mouse tumor models, our data provide a map for the rationale design of mode-of-action studies for pre-clinical evaluation of targeted- and immunotherapies.

Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model.

Combining a conditional mouse model that closely resembles the slow evolution and the mosaic AE expression pattern of human t 8;21 CBF AML with global transcriptome sequencing, we find that disease progression was characterized by two principal pathogenic mechanisms.

Initially, AE expression modified the lineage potential of haematopoietic stem cells HSCs , resulting in the selective expansion of the myeloid compartment at the expense of normal erythro- and lymphopoiesis.

This lineage skewing was followed by a second substantial rewiring of transcriptional networks occurring in the trajectory to manifest leukaemia.

We also find that both HSC and lineage-restricted granulocyte macrophage progenitors GMPs acquired leukaemic stem cell LSC potential being capable of initiating and maintaining the disease.

Finally, our data demonstrate that long-term expression of AE induces an indolent myeloproliferative disease MPD -like myeloid leukaemia phenotype with complete penetrance and that acute inactivation of AE function is a potential novel therapeutic option.

We determine HLA-type and expression for the previously un-typed Illumina Body Map tissues and a cohort of Korean lung cancer patients.

Because the algorithm uses standard RNA-Seq reads and requires no change to lab protocols, it can be used for both existing datasets and future studies, thus adding a new dimension for HLA typing and biomarker studies.

Validation results for mutations with an intermediate FDR. Alignment statistics for all samples. Confidence-based Somatic Mutation Evaluation and Prioritization.

Next generation sequencing NGS has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms.

Here, we developed an algorithm to assign a single statistic, a false discovery rate FDR , to each somatic mutation identified by NGS.

This FDR confidence value accurately discriminates true mutations from erroneous calls. For each identified mutation, our algorithm assigned an FDR.

We selected mutations for validation, including 50 somatic mutations assigned a low FDR high confidence and 44 mutations assigned a high FDR low confidence.

All of the high confidence somatic mutations validated 50 of 50 , none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated.

Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics.

Using the HiSeq , single end 50 nt reads from replicates generate the highest confidence somatic mutation call set. Exploiting the Mutanome for Tumor Vaccination.

Multiple genetic events and subsequent clonal evolution drive carcinogenesis, making disease elimination with single-targeted drugs difficult. The multiplicity of gene mutations derived from clonal heterogeneity therefore represents an ideal setting for multiepitope tumor vaccination.

Here, we used next generation sequencing exome resequencing to identify nonsynonymous somatic point mutations in B16F10 murine melanoma cells, with of those mutations in expressed genes.

Potential driver mutations occurred in classical tumor suppressor genes and genes involved in proto-oncogenic signaling pathways that control cell proliferation, adhesion, migration, and apoptosis.

Aim1 and Trrap mutations known to be altered in human melanoma were included among those found. The immunogenicity and specificity of 50 validated mutations was determined by immunizing mice with long peptides encoding the mutated epitopes.

In tumor transplant models, peptide immunization conferred in vivo tumor control in protective and therapeutic settings, thereby qualifying mutated epitopes that include single amino acid substitutions as effective vaccines.

Together, our findings provide a comprehensive picture of the mutanome of B16F10 melanoma which is used widely in immunotherapy studies. In addition, they offer insight into the extent of the immunogenicity of nonsynonymous base substitution mutations.

Lastly, they argue that the use of deep sequencing to systematically analyze immunogenicity mutations may pave the way for individualized immunotherapy of cancer patients.

PDF document containing supplementary figures. Robust analysis of peptide microarray data. Peptide microarrays offer an enormous potential as a screening tool for peptidomics experiments and have recently seen an increased field of application ranging from immunological studies to systems biology.

By allowing the parallel analysis of thousands of peptides in a single run they are suitable for high-throughput settings.

Since data characteristics of peptide microarrays differ from DNA oligonucleotide microarrays, computational methods need to be tailored to these specifications to allow a robust and automated data analysis.

While follow-up experiments can ensure the specificity of results, sensitivity cannot be recovered in later steps.

Providing sensitivity is thus a primary goal of data analysis procedures. We evaluated rapmad in antibody reactivity experiments for several thousand peptide spots and compared it to two existing algorithms for the analysis of peptide microarrays.

Particularly, it shows substantially improved sensitivity for low intensity settings without sacrificing specificity.

It thereby contributes to increasing the effectiveness of high throughput screening experiments. The rapmad R-package as well as the data sets are available from http: Pharmacophores describe the spatial arrangement of essential interactions in a receptor-ligand complex.

Although highly established in ligand-based virtual screening, the application of pharmacophores for in absence of a ligand is more sophisticated.

This article summarizes the recent approaches to derive and evaluate pharmacophore models using only limited information e. Advantages and current limitations of the state-of-the-art methods and future perspectives for development are discussed in this publication.

E-cadherin and HtrA were detected by Western blot. The reaction vials were centrifuged at Fluorescence was measured in a Tecan M spectrometer excitation wavelength: Final concentration of HtrA: A Scaffold of compounds 1, 4, 5 and 6 inhibitory activity , and 7, 11, 13 no inhibitory activity.

B Superposition of docking poses of compounds 1 cyan , 4 pink , 5 blue and 6 magenta. C Same as B including compounds 2 grey and 3 orange.

D Superposition of compounds 7, 11, Structures and activities inhibition of HtrA of the inhibitory compounds, ordered according to falling inhibitory activity.

The Gold docking rank calculated for all 26 ordered compounds as well as the Gold ASP score in brackets is shown in column 5.

Purity analysis of compound 1. Idealized geometric interaction rules used for the calculation of the virtual ligand model 8.

Results of retrospective screening; averaged over all targets. Results of retrospective screening using the UGI database.

Three different dissimilarity metrics were used a Euclidian distance, b Manhattan distance c Cosine similarity.

Results of retrospective screening using the MUV database. The human pathogen Helicobacter pylori H. Increasing bacterial resistance against antibiotics demands for innovative strategies for therapeutic intervention.

We present a method for structure-based virtual screening that is based on the comprehensive prediction of ligand binding sites on a protein model and automated construction of a ligand-receptor interaction map.

Pharmacophoric features of the map are clustered and transformed in a correlation vector 'virtual ligand' for rapid virtual screening of compound databases.

This computer-based technique was validated for 18 different targets of pharmaceutical interest in a retrospective screening experiment. Prospective screening for inhibitory agents was performed for the protease HtrA from the human pathogen H.

Among 22 tested compounds six block E-cadherin cleavage by HtrA in vitro and result in reduced scattering and wound healing of gastric epithelial cells, thereby preventing bacterial infiltration of the epithelium.

This study demonstrates that receptor-based virtual screening with a permissive 'fuzzy' pharmacophore model can help identify small bioactive agents for combating bacterial infection.

Fimbriae of the human uropathogen Proteus mirabilis are the only characterized surface proteins that contribute to its virulence by mediating adhesion and invasion of the uroepithelia.

Comparative protein modeling using the Hia three-dimensional structure as a template predicted that each of these domains would contain four antiparallel beta sheets and that they formed homotrimers.

Inactivation of aipA in P. A aa-long invasin region in the AipA passenger domain was required for this function. AipA and TaaP individually offered advantages to P.

This is the first report characterizing trimeric autotransporters in P. The goal of this paper is to enable investigators to understand and readily implement currently available methods for response determination.

We describe empirical and statistical approaches, identifying the strengths and limitations of each approach to allow readers to rationally select and apply a scientifically sound method appropriate to their specific laboratory setting.

Five representative approaches were applied to data sets from the CIMT Immunoguiding Program and the response detection and false positive rates were compared.

Simulation studies were also performed to compare empirical and statistical approaches. Find Website Traffic Statistics: For the website owner Certified Metrics provide:.

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