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Article ; Online: How to Respond to Misinformation From the Anti-Vaccine Movement

Mike-Andrew Westhoff PhD / Carsten Posovszky MD / Klaus-Michael Debatin MD

Inquiry: The Journal of Health Care Organization, Provision, and Financing, Vol

2023 Volume 60

Abstract: Vaccines are doubtlessly one of the most crucial life-saving medical interventions to date. However, perplexingly, they court more public controversy than their objectively excellent safety profile warrants. While doubts about the safety of vaccines, as ... ...

Abstract	Vaccines are doubtlessly one of the most crucial life-saving medical interventions to date. However, perplexingly, they court more public controversy than their objectively excellent safety profile warrants. While doubts about the safety of vaccines, as well as opposition to vaccine policies, can be traced back at least to the mid-19th century, the modern anti-vaccine movement has come in 3 distinct waves, or generations, each precipitating around distinct key events. Here, we describe the first 2 generations and trace the origins of an emerging third generation anti-vaccine movement. Currently, this third generation is an integral part of the larger anti-COVID movement and in this more libertarian environment propagates the idea of individualism superseding the responsibility for community health. We highlight the need for a better science education of the young, as well as the general public to further enhance overall science literacy and suggests strategies to achieve these goals.
Keywords	Public aspects of medicine ; RA1-1270
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	SAGE Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Lipodystrophy as a Late Effect after Stem Cell Transplantation

Daniel Tews / Ansgar Schulz / Christian Denzer / Julia von Schnurbein / Giovanni Ceccarini / Klaus-Michael Debatin / Martin Wabitsch

Journal of Clinical Medicine, Vol 10, Iss 1559, p

2021 Volume 1559

Abstract: Survivors of childhood cancer are at high risk of developing metabolic diseases in adulthood. Recently, several patients developing partial lipodystrophy following hematopoietic stem cell transplantation (HSCT) have been described. In this review, we ... ...

Abstract	Survivors of childhood cancer are at high risk of developing metabolic diseases in adulthood. Recently, several patients developing partial lipodystrophy following hematopoietic stem cell transplantation (HSCT) have been described. In this review, we summarize the cases described so far and discuss potential underlying mechanisms of the disease. The findings suggest that HSCT-associated lipodystrophies may be seen as a novel form of acquired lipodystrophy.
Keywords	lipodystrophy ; adipose tissue ; stem cells ; Medicine ; R
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: microRNA-27a-3p but Not -5p Is a Crucial Mediator of Human Adipogenesis

Hang Wu / Taner Pula / Daniel Tews / Ez-Zoubir Amri / Klaus-Michael Debatin / Martin Wabitsch / Pamela Fischer-Posovszky / Julian Roos

Cells, Vol 10, Iss 3205, p

2021 Volume 3205

Abstract: MicroRNAs (miRNAs), a class of small, non-coding RNA molecules, play an important role in the posttranscriptional regulation of gene expression, thereby influencing important cellular functions. In adipocytes, miRNAs show import regulatory features and ... ...

Abstract	MicroRNAs (miRNAs), a class of small, non-coding RNA molecules, play an important role in the posttranscriptional regulation of gene expression, thereby influencing important cellular functions. In adipocytes, miRNAs show import regulatory features and are described to influence differentiation as well as metabolic, endocrine, and inflammatory functions. We previously identified miR-27a being upregulated under inflammatory conditions in human adipocytes and aimed to elucidate its function in adipocyte biology. Both strands of miR-27a, miR-27a-3p and -5p, were downregulated during the adipogenic differentiation of Simpson–Golabi–Behmel syndrome (SGBS) cells, human multipotent adipose-derived stem cells (hMADS), and human primary adipose-derived stromal cells (hASCs). Using miRNA-mimic transfection, we observed that miR-27a-3p is a crucial regulator of adipogenesis, while miR-27a-5p did not alter the differentiation capacity in SGBS cells. In silico screening predicted lipoprotein lipase (LPL) and peroxisome proliferator activated receptor γ (PPARγ) as potential targets of miR-27a-3p. The downregulation of both genes was verified in vitro, and the interaction of miR-27-3p with target sites in the 3′ UTRs of both genes was confirmed via a miRNA-reporter-gene assay. Here, the knockdown of LPL did not interfere with adipogenic differentiation, while PPARγ knockdown decreased adipogenesis significantly, suggesting that miR-27-3p exerts its inhibitory effect on adipogenesis by repressing PPARγ. Taken together, we identified and validated a crucial role for miR-27a-3p in human adipogenesis played by targeting the essential adipogenic transcription factor PPARγ. Though we confirmed LPL as an additional target of miR-27a-3p, it does not appear to be involved in regulating human adipogenesis. Thereby, our findings call the conclusions drawn from previous studies, which identified LPL as a crucial regulator for murine and human adipogenesis, into question.
Keywords	microRNA-27a ; adipocytes ; adipogenesis ; PPARγ ; LPL ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Immunostimulatory functions of adoptively transferred MDSCs in experimental blunt chest trauma

Monika Kustermann / Malena Klingspor / Markus Huber-Lang / Klaus-Michael Debatin / Gudrun Strauss

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 12

Abstract: Abstract Myeloid-derived suppressor cells (MDSCs) expand during inflammation and exhibit immunomodulatory functions on innate and adaptive immunity. However, their impact on trauma-induced immune responses, characterized by an early pro-inflammatory ... ...

Abstract	Abstract Myeloid-derived suppressor cells (MDSCs) expand during inflammation and exhibit immunomodulatory functions on innate and adaptive immunity. However, their impact on trauma-induced immune responses, characterized by an early pro-inflammatory phase and dysregulated adaptive immunity involving lymphocyte apoptosis, exhaustion and unresponsiveness is less clear. Therefore, we adoptively transferred in vitro-generated MDSCs shortly before experimental blunt chest trauma (TxT). MDSCs preferentially homed into spleen and liver, but were undetectable in the injured lung, although pro-inflammatory mediators transiently increased in the bronchoalveolar lavage (BAL). Surprisingly, MDSC treatment strongly increased splenocyte numbers, however, without altering the percentage of splenic leukocyte populations. T cells of MDSC-treated TxT mice exhibited an activated phenotype characterized by expression of activation markers and elevated proliferative capacity in vitro, which was not accompanied by up-regulated exhaustion markers or unresponsiveness towards in vitro activation. Most importantly, also T cell expansion after staphylococcal enterotoxin B (SEB) stimulation in vivo was unchanged between MDSC-treated or untreated mice. After MDSC transfer, T cells preferentially exhibited a Th1 phenotype, a prerequisite to circumvent post-traumatic infectious complications. Our findings reveal a totally unexpected immunostimulatory role of adoptively transferred MDSCs in TxT and might offer options to interfere with post-traumatic malfunction of the adaptive immune response.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2019-05-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy

Mike-Andrew Westhoff / Marie Schuler-Ortoli / Daniela Zerrinius / Amina Hadzalic / Andrea Schuster / Hannah Strobel / Angelika Scheuerle / Tiana Wong / Christian Rainer Wirtz / Klaus-Michael Debatin / Aurelia Peraud

Pharmaceuticals, Vol 15, Iss 91, p

2022 Volume 91

Abstract: Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells’ intrinsic ... ...

Abstract	Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells’ intrinsic resistance to therapy-induced cell death should lead to less aggressive and more effective treatment options. In other tumour entities, this has been achieved by modulating the balance between the various pro- and anti-apoptotic members of the Bcl-2 family with small molecule inhibitors. To evaluate the therapeutic benefits of ABT-199 (Venetoclax), a Bcl-2 inhibitor, and ABT-263 (Navitoclax), a dual Bcl-XL/Bcl-2 inhibitor, increasingly more relevant model systems were investigated. Starting from established MB cell lines, progressing to primary patient-derived material and finally an experimental tumour system imbedded in an organic environment were chosen. Assessment of the metabolic activity (a surrogate readout for population viability), the induction of DNA fragmentation (apoptosis) and changes in cell number (the combined effect of alterations in proliferation and cell death induction) revealed that ABT-263, but not ABT-199, is a promising candidate for combination therapy, synergizing with cell death-inducing stimuli. Interestingly, in the experimental tumour setting, the sensitizing effect of ABT-263 seems to be predominantly mediated via an anti-proliferative and not a pro-apoptotic effect, opening a future line of investigation. Our data show that modulation of specific members of the Bcl-2 family might be a promising therapeutic addition for the treatment of MB.
Keywords	medulloblastoma ; apoptosis ; Bcl-2 ; Bcl-XL ; ABT-199 (Venetoclax) ; ABT-263 (Navitoclax) ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	610
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Diisothiocyanate-Derived Mercapturic Acids Are a Promising Partner for Combination Therapies in Glioblastoma

Pengfei Xu / Mike-Andrew Westhoff / Amina Hadzalic / Klaus-Michael Debatin / Lukasz Winiarski / Jozef Oleksyszyn / Christian Rainer Wirtz / Uwe Knippschild / Timo Burster

ACS Omega, Vol 7, Iss 7, Pp 5929-

2022 Volume 5936

Keywords	Chemistry ; QD1-999
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	American Chemical Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comment in Response to “Temozolomide in Glioblastoma Therapy

Mike-Andrew Westhoff / Tim Baisch / Verena J. Herbener / Georg Karpel-Massler / Klaus-Michael Debatin / Hannah Strobel

Biomedicines, Vol 8, Iss 93, p

Role of Apoptosis, Senescence and Autophagy etc. by B. Kaina”

2020 Volume 93

Abstract: It is with great pleasure that we acknowledge the fact that our review on Temozolomide (TMZ) has initiated a discussion [1–3]. [.] ...

Abstract	It is with great pleasure that we acknowledge the fact that our review on Temozolomide (TMZ) has initiated a discussion [1–3]. [.]
Keywords	n/a ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: mRNA Vaccines Enhance Neutralizing Immunity against SARS-CoV-2 Variants in Convalescent and ChAdOx1-Primed Subjects

Dorit Fabricius / Carolin Ludwig / Judith Scholz / Immanuel Rode / Chrysanthi Tsamadou / Eva-Maria Jacobsen / Martina Winkelmann / Aline Grempels / Ramin Lotfi / Aleš Janda / Sixten Körper / Guido Adler / Klaus-Michael Debatin / Hubert Schrezenmeier / Bernd Jahrsdörfer

Vaccines, Vol 9, Iss 918, p

2021 Volume 918

Abstract: To identify the most efficient methods of immunological protection against SARS-CoV-2, including the currently most widespread variants of concern (VOCs)—B.1.1.7, B.1.351 and P.1—a simultaneous side-by-side-comparison of available vaccination regimes is ... ...

Abstract	To identify the most efficient methods of immunological protection against SARS-CoV-2, including the currently most widespread variants of concern (VOCs)—B.1.1.7, B.1.351 and P.1—a simultaneous side-by-side-comparison of available vaccination regimes is required. In this observational cohort study, we compared immunological responses in 144 individuals vaccinated with the mRNA vaccines BNT162b2 or mRNA-1273 and the vector vaccine ChAdOx1-nCoV-19, either alone, in combination, or in the context of COVID-19-convalescence. Unvaccinated COVID-19-convalescent subjects served as a reference. We found that cellular and serological immune responses, including neutralizing capacity against VOCs, were significantly stronger with mRNA vaccines as compared with COVID-19-convalescent individuals or vaccinated individuals receiving the vector vaccine ChAdOx1-nCoV-19. Booster immunizations with mRNA vaccines triggered strong and broadly neutralizing antibody and IFN-γ responses in 100% of vaccinated individuals investigated. This effect was particularly strong in COVID-19-convalescent and ChAdOx1-nCoV-19-primed individuals, who were characterized by comparably moderate cellular and neutralizing antibody responses before mRNA vaccine booster. Heterologous vaccination regimes and convalescent booster regimes using mRNA vaccines may allow enhanced protection against SARS-CoV-2, including current VOCs. Furthermore, such regimes may facilitate rapid (re-)qualification of convalescent plasma donors with high titers of broadly neutralizing antibodies.
Keywords	heterologous vaccination regimes using mRNA vaccines may allow enhanced protection against SARS-CoV-2 ; including current VOCs ; RNA vaccines may facilitate rapid (re-) qualification of convalescent plasma donors with high titers of broadly neutralizing antibodies ; Medicine ; R
Subject code	610
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia

Albert Manzano-Muñoz / Clara Alcon / Pablo Menéndez / Manuel Ramírez / Felix Seyfried / Klaus-Michael Debatin / Lüder H. Meyer / Josep Samitier / Joan Montero

Frontiers in Cell and Developmental Biology, Vol

2021 Volume 9

Abstract: Multiple targeted therapies are currently explored for pediatric and young adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment. However, this new armamentarium of therapies faces an old problem: choosing the right treatment for each ... ...

Abstract	Multiple targeted therapies are currently explored for pediatric and young adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment. However, this new armamentarium of therapies faces an old problem: choosing the right treatment for each patient. The lack of predictive biomarkers is particularly worrying for pediatric patients since it impairs the implementation of new treatments in the clinic. In this study, we used the functional assay dynamic BH3 profiling (DBP) to evaluate two new treatments for BCP-ALL that could improve clinical outcome, especially for relapsed patients. We found that the MEK inhibitor trametinib and the multi-target tyrosine kinase inhibitor sunitinib exquisitely increased apoptotic priming in an NRAS-mutant and in a KMT2A-rearranged cell line presenting a high expression of FLT3, respectively. Following these observations, we sought to study potential adaptations to these treatments. Indeed, we identified with DBP anti-apoptotic changes in the BCL-2 family after treatment, particularly involving MCL-1 – a pro-survival strategy previously observed in adult cancers. To overcome this adaptation, we employed the BH3 mimetic S63845, a specific MCL-1 inhibitor, and evaluated its sequential addition to both kinase inhibitors to overcome resistance. We observed that the metronomic combination of both drugs with S63845 was synergistic and showed an increased efficacy compared to single agents. Similar observations were made in BCP-ALL KMT2A-rearranged PDX cells in response to sunitinib, showing an analogous DBP profile to the SEM cell line. These findings demonstrate that rational sequences of targeted agents with BH3 mimetics, now extensively explored in clinical trials, may improve treatment effectiveness by overcoming anti-apoptotic adaptations in BCP-ALL.
Keywords	pediatric leukemia ; targeted therapies ; resistance ; apoptosis ; BH3 mimetics ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Temozolomide and Other Alkylating Agents in Glioblastoma Therapy

Hannah Strobel / Tim Baisch / Rahel Fitzel / Katharina Schilberg / Markus D. Siegelin / Georg Karpel-Massler / Klaus-Michael Debatin / Mike-Andrew Westhoff

Biomedicines, Vol 7, Iss 3, p

2019 Volume 69

Abstract: The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people ... ...

Abstract	The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 months after presentation. Several key aspects make GB a difficult to treat disease, primarily including the high resistance of tumor cells to cell death-inducing substances or radiation and the combination of the highly invasive nature of the malignancy, i.e., treatment must affect the whole brain, and the protection from drugs of the tumor bulk—or at least of the invading cells—by the blood brain barrier (BBB). TMZ crosses the BBB, but—unlike classic chemotherapeutics—does not induce DNA damage or misalignment of segregating chromosomes directly. It has been described as a DNA alkylating agent, which leads to base mismatches that initiate futile DNA repair cycles; eventually, DNA strand breaks, which in turn induces cell death. However, while much is assumed about the function of TMZ and its mode of action, primary data are actually scarce and often contradictory. To improve GB treatment further, we need to fully understand what TMZ does to the tumor cells and their microenvironment. This is of particular importance, as novel therapeutic approaches are almost always clinically assessed in the presence of standard treatment, i.e., in the presence of TMZ. Therefore, potential pharmacological interactions between TMZ and novel drugs might occur with unforeseeable consequences.
Keywords	temozolomide (TMZ) ; triazene compounds ; alkylating agents ; brain tumor ; glioblastoma ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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