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Article ; Online: Antimicrobial susceptibility profile of clinically relevant Bacteroides, Phocaeicola, Parabacteroides and Prevotella species, isolated by eight laboratories in the Netherlands.

Boiten, K E / Notermans, D W / Rentenaar, R J / van Prehn, J / Bode, L G M / Maat, I / van der Zwet, W / Jansz, A / Siebers, T J H / Rossen, J W A / de Greeff, S C / Hendrickx, A P A / Kuijper, E J / Veloo, A C M

The Journal of antimicrobial chemotherapy

2024 Volume 79, Issue 4, Page(s) 868–874

Abstract: Objectives: Recently, reports on antimicrobial-resistant Bacteroides and Prevotella isolates have increased in the Netherlands. This urged the need for a surveillance study on the antimicrobial susceptibility profile of Bacteroides, Phocaeicola, ... ...

Abstract	Objectives: Recently, reports on antimicrobial-resistant Bacteroides and Prevotella isolates have increased in the Netherlands. This urged the need for a surveillance study on the antimicrobial susceptibility profile of Bacteroides, Phocaeicola, Parabacteroides and Prevotella isolates consecutively isolated from human clinical specimens at eight different Dutch laboratories. Methods: Each laboratory collected 20-25 Bacteroides (including Phocaeicola and Parabacteroides) and 10-15 Prevotella isolates for 3 months. At the national reference laboratory, the MICs of amoxicillin, amoxicillin/clavulanic acid, piperacillin/tazobactam, meropenem, imipenem, metronidazole, clindamycin, tetracycline and moxifloxacin were determined using agar dilution. Isolates with a high MIC of metronidazole or a carbapenem, or harbouring cfiA, were subjected to WGS. Results: Bacteroides thetaiotaomicron/faecis isolates had the highest MIC90 values, whereas Bacteroides fragilis had the lowest MIC90 values for amoxicillin/clavulanic acid, piperacillin/tazobactam, meropenem, imipenem and moxifloxacin. The antimicrobial profiles of the different Prevotella species were similar, except for amoxicillin, for which the MIC50 ranged from 0.125 to 16 mg/L for Prevotella bivia and Prevotella buccae, respectively. Three isolates with high metronidazole MICs were sequenced, of which one Bacteroides thetaiotaomicron isolate harboured a plasmid-located nimE gene and a Prevotella melaninogenica isolate harboured a nimA gene chromosomally.Five Bacteroides isolates harboured a cfiA gene and three had an IS element upstream, resulting in high MICs of carbapenems. The other two isolates harboured no IS element upstream of the cfiA gene and had low MICs of carbapenems. Conclusions: Variations in resistance between species were observed. To combat emerging resistance in anaerobes, monitoring resistance and conducting surveillance are essential.
MeSH term(s)	Humans ; Meropenem ; Moxifloxacin ; Netherlands ; Metronidazole ; Laboratories ; Bacteroides ; Anti-Bacterial Agents/pharmacology ; Carbapenems ; Bacteroides fragilis ; Imipenem ; Anti-Infective Agents ; Microbial Sensitivity Tests ; Piperacillin ; Tazobactam ; Prevotella/genetics ; Amoxicillin ; Clavulanic Acid
Chemical Substances	Meropenem (FV9J3JU8B1) ; Moxifloxacin (U188XYD42P) ; Metronidazole (140QMO216E) ; Anti-Bacterial Agents ; Carbapenems ; Imipenem (71OTZ9ZE0A) ; Anti-Infective Agents ; Piperacillin (X00B0D5O0E) ; Tazobactam (SE10G96M8W) ; Amoxicillin (804826J2HU) ; Clavulanic Acid (23521W1S24)
Language	English
Publishing date	2024-02-21
Publishing country	England
Document type	Journal Article
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkae043
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Zs.A 1197: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 124: Show issues

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Article: An app-based training for adolescents with problematic digital-media use and their parents (Res@t digital): protocol for a cluster-randomized clinical trial.

Paschke, Kerstin / Diestelkamp, Silke / Zapf, Antonia / Busch, Katharina / Arnaud, Nicolas / Prehn-Kristensen, Alexander / Reis, Olaf / Stark, Maria / Cloes, Jan-Ole / Schulz, Anna-Lena / Brauer, Hannah / Krömer, Thomas / Thomasius, Rainer

Frontiers in psychiatry

2024 Volume 14, Page(s) 1245536

Abstract: ... widely missing, leading to a significant clinical gap.: Methods: Res@t digital (Resource-Strengthening ... It comprises separate but content-related modules for adolescents (Res@t-A) and parents (Res@t-P), applying ... multimodal techniques. The effectiveness of Res@t will be evaluated within a multicenter cluster-randomized ...

Abstract	Background: Digital media-use disorders (DMUD) in adolescents are a rising phenomenon associated with psychological distress, comorbid mental disorders, and high burden on affected families. Since the ICD-11 introduced criteria for gaming disorder, these can now be transferred to describe additional DMUD associated with social media platforms and streaming services. Most evidence for effective treatments comes from cognitive-behavioral therapy (CBT). However, interventions based on theoretical models for adolescents and their parents are widely missing, leading to a significant clinical gap. Methods: Res@t digital (Resource-Strengthening Training for Adolescents with Problematic Digital-Media Use and their Parents) is the app-based translation of the first model-based digital intervention for adolescents with DMUD and their parents based on CBT. It comprises separate but content-related modules for adolescents (Res@t-A) and parents (Res@t-P), applying multimodal techniques. The effectiveness of Res@t will be evaluated within a multicenter cluster-randomized controlled evaluator-blinded pre-post follow-up trial with the waitlist control group (CG). In addition to the Res@t program in the intervention group, both groups will receive treatment as usual within primary child and adolescent psychiatric/psychotherapeutic healthcare. The primary outcome addresses DMUD symptom reduction after 10 weeks. Secondary outcomes are related to a reduction in psychological and family-related problems and an increase in parental self-efficacy. All outcomes will be assessed using standardized self-report measures. A total of 1,334 participating adolescent-parent dyads from a large clinical network throughout Germany are planned to be included in the primary analyses based on an intention-to-treat approach, applying linear mixed models. Discussion: Assuming superiority of Res@t over the control condition, the intervention has the potential to provide evidence-based treatment for a significant number of help-seeking families, supporting local healthcare structures and resources. It is a promising program for practicable implementation and flexible use in different settings. Clinical trial registration: https://drks.de, DRKS00031043.
Language	English
Publishing date	2024-01-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564218-2
ISSN	1664-0640
ISSN	1664-0640
DOI	10.3389/fpsyt.2023.1245536
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Article: Association of sex hormones and sex hormone-binding globulin with liver fat in men and women: an observational and Mendelian randomization study.

Cai, Xinting / Thorand, Barbara / Hohenester, Simon / Prehn, Cornelia / Cecil, Alexander / Adamski, Jerzy / Zeller, Tanja / Dennis, Andrea / Banerjee, Rajarshi / Peters, Annette / Yaghootkar, Hanieh / Nano, Jana

Frontiers in endocrinology

2023 Volume 14, Page(s) 1223162

Abstract: ... T), and SHBG with liver fat using complementary observational and Mendelian randomization (MR ... T, dihydrotestosterone (DHT), progesterone and 17α-hydroxyprogesterone (17-OHP) were inversely ... Whereas in women, a positive association of free T with FLI (β = 4.17, 95%CI: 1.35, 6.98) was observed. SHBG was ...

Abstract	Background: Sex hormones and sex hormone-binding globulin (SHBG) may play a role in fatty liver development. We sought to examine the association of various endogenous sex hormones, including testosterone (T), and SHBG with liver fat using complementary observational and Mendelian randomization (MR) analyses. Methods: The observational analysis included a total of 2,239 participants (mean age 60 years; 35% postmenopausal women) from the population-based KORA study (average follow-up time: 6.5 years). We conducted linear regression analysis to investigate the sex-specific associations of sex hormones and SHBG with liver fat, estimated by fatty liver index (FLI). For MR analyses, we selected genetic variants associated with sex hormones and SHBG and extracted their associations with magnetic resonance imaging measured liver fat from the largest up to date European genome-wide associations studies. Results: In the observational analysis, T, dihydrotestosterone (DHT), progesterone and 17α-hydroxyprogesterone (17-OHP) were inversely associated with FLI in men, with beta estimates ranging from -4.23 to -2.30 [p-value <0.001 to 0.003]. Whereas in women, a positive association of free T with FLI (β = 4.17, 95%CI: 1.35, 6.98) was observed. SHBG was inversely associated with FLI across sexes [men: -3.45 (-5.13, -1.78); women: -9.23 (-12.19, -6.28)]. No causal association was found between genetically determined sex hormones and liver fat, but higher genetically determined SHBG was associated with lower liver fat in women (β = -0.36, 95% CI: -0.61, -0.12). Conclusion: Our results provide suggestive evidence for a causal association between SHBG and liver fat in women, implicating the protective role of SHBG against liver fat accumulation.
MeSH term(s)	Male ; Humans ; Female ; Middle Aged ; Sex Hormone-Binding Globulin/genetics ; Sex Hormone-Binding Globulin/analysis ; Mendelian Randomization Analysis ; Dihydrotestosterone ; Fatty Liver/epidemiology ; Fatty Liver/genetics
Chemical Substances	Sex Hormone-Binding Globulin ; Dihydrotestosterone (08J2K08A3Y)
Language	English
Publishing date	2023-10-13
Publishing country	Switzerland
Document type	Observational Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1223162
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Article ; Online: How to: prophylactic interventions for prevention of Clostridioides difficile infection.

Reigadas, Elena / van Prehn, Joffrey / Falcone, Marco / Fitzpatrick, Fidelma / Vehreschild, Maria J G T / Kuijper, Ed J / Bouza, Emilio

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases

2021 Volume 27, Issue 12, Page(s) 1777–1783

Abstract: ... for recurrent CDI (R-CDI) after a thorough evaluation. Faecal microbiota transplantation (FMT) has proved to be ... against R-CDI, mainly in patients with primary episodes and a high risk of relapse.: Implications ... added to standard treatment for patients at high risk for R-CDI. The most promising strategies are ...

Abstract	Background: Clostridioides difficile infection (CDI) remains the leading cause of healthcare-associated diarrhoea, despite existing guidelines for infection control measures and antimicrobial stewardship. The high associated health and economic burden of CDI calls for novel strategies to prevent the development and spread of CDI in susceptible patients. Objectives: We aim to review CDI prophylactic treatment strategies and their implementation in clinical practice. Sources: We searched PubMed, Embase, Emcare, Web of Science, and the COCHRANE Library databases to identify prophylactic interventions aimed at prevention of CDI. The search was restricted to articles published in English since 2012. Content: A toxin-based vaccine candidate is currently being investigated in a phase III clinical trial. However, a recent attempt to develop a toxin-based vaccine has failed. Conventional probiotics have not yet proved to be an effective strategy for prevention of CDI. New promising microbiota-based interventions that bind and inactivate concomitantly administered antibiotics, such as ribaxamase and DAV-132, have been developed. Prophylaxis of CDI with C. difficile antibiotics should not be performed routinely and should be considered only for secondary prophylaxis in very selected patients who are at the highest imminent risk for recurrent CDI (R-CDI) after a thorough evaluation. Faecal microbiota transplantation (FMT) has proved to be a very effective treatment for patients with multiple recurrences. Bezlotoxumab provides protection against R-CDI, mainly in patients with primary episodes and a high risk of relapse. Implications: There are no proven effective, evidenced-based prophylaxis options for primary CDI. As for secondary prevention, FMT is considered the option of choice in patients with multiple recurrences. Bezlotoxumab can be added to standard treatment for patients at high risk for R-CDI. The most promising strategies are those aimed at reducing changes in intestinal microbiota and development of a new effective non-toxin-based vaccine.
MeSH term(s)	Anti-Bacterial Agents/therapeutic use ; Clostridioides difficile ; Clostridium Infections/prevention & control ; Clostridium Infections/therapy ; Fecal Microbiota Transplantation ; Humans ; Recurrence
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2021-07-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1328418-6
ISSN	1469-0691 ; 1470-9465 ; 1198-743X
ISSN (online)	1469-0691
ISSN	1470-9465 ; 1198-743X
DOI	10.1016/j.cmi.2021.06.037
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Zs.A 4541: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 284: Show issues

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Article ; Online: Maternal hyperglycemia induces alterations in hepatic amino acid, glucose and lipid metabolism of neonatal offspring: Multi-omics insights from a diabetic pig model.

Shashikadze, Bachuki / Valla, Libera / Lombardo, Salvo Danilo / Prehn, Cornelia / Haid, Mark / Riols, Fabien / Stöckl, Jan Bernd / Elkhateib, Radwa / Renner, Simone / Rathkolb, Birgit / Menche, Jörg / Hrabĕ de Angelis, Martin / Wolf, Eckhard / Kemter, Elisabeth / Fröhlich, Thomas

Molecular metabolism

2023 Volume 75, Page(s) 101768

Abstract: Objective: To gain mechanistic insights into adverse effects of maternal hyperglycemia on the liver of neonates, we performed a multi-omics analysis of liver tissue from piglets developed in genetically diabetic (mutant INS gene induced diabetes of ... ...

Abstract	Objective: To gain mechanistic insights into adverse effects of maternal hyperglycemia on the liver of neonates, we performed a multi-omics analysis of liver tissue from piglets developed in genetically diabetic (mutant INS gene induced diabetes of youth; MIDY) or wild-type (WT) pigs. Methods: Proteome, metabolome and lipidome profiles of liver and clinical parameters of serum samples from 3-day-old WT piglets (n = 9) born to MIDY mothers (PHG) were compared with those of WT piglets (n = 10) born to normoglycemic mothers (PNG). Furthermore, protein-protein interaction network analysis was used to reveal highly interacting proteins that participate in the same molecular mechanisms and to relate these mechanisms with human pathology. Results: Hepatocytes of PHG displayed pronounced lipid droplet accumulation, although the abundances of central lipogenic enzymes such as fatty acid-synthase (FASN) were decreased. Additionally, circulating triglyceride (TG) levels were reduced as a trend. Serum levels of non-esterified free fatty acids (NEFA) were elevated in PHG, potentially stimulating hepatic gluconeogenesis. This is supported by elevated hepatic phosphoenolpyruvate carboxykinase (PCK1) and circulating alanine transaminase (ALT) levels. Even though targeted metabolomics showed strongly elevated phosphatidylcholine (PC) levels, the abundances of multiple key enzymes involved in major PC synthesis pathways - most prominently those from the Kennedy pathway - were paradoxically reduced in PHG liver. Conversely, enzymes involved in PC excretion and breakdown such as PC-specific translocase ATP-binding cassette 4 (ABCB4) and phospholipase A2 were increased in abundance. Conclusions: Our study indicates that maternal hyperglycemia without confounding obesity induces profound molecular changes in the liver of neonatal offspring. In particular, we found evidence for stimulated gluconeogenesis and hepatic lipid accumulation independent of de novo lipogenesis. Reduced levels of PC biosynthesis enzymes and increased levels of proteins involved in PC translocation or breakdown may represent counter-regulatory mechanisms to maternally elevated PC levels. Our comprehensive multi-omics dataset provides a valuable resource for future meta-analysis studies focusing on liver metabolism in newborns from diabetic mothers.
MeSH term(s)	Infant, Newborn ; Pregnancy ; Female ; Animals ; Humans ; Swine ; Adolescent ; Glucose/metabolism ; Lipid Metabolism ; Amino Acids/metabolism ; Multiomics ; Liver/metabolism ; Diabetes, Gestational ; Hyperglycemia/metabolism
Chemical Substances	Glucose (IY9XDZ35W2) ; Amino Acids
Language	English
Publishing date	2023-07-04
Publishing country	Germany
Document type	Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2023.101768
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Article: The epigenetic instruction manual for the operation of the genome.

Prehn, R T

Medical hypotheses

2002 Volume 58, Issue 2, Page(s) 177–181

Abstract: The factors composing the instruction manual for the operation of the genome are, at least initially, of maternal origin and supplied in the egg; they are postulated to be reproduced only slowly, if at all, during growth. This would insure that, as the ... ...

Abstract	The factors composing the instruction manual for the operation of the genome are, at least initially, of maternal origin and supplied in the egg; they are postulated to be reproduced only slowly, if at all, during growth. This would insure that, as the size of the animal increases, the concentrations of these factors would decline. The progressive decline is postulated to sequentially trigger appropriate master genes, each of which is turned on or off by precise concentrations of these regulatory factors; each master gene in turn specifies a specific pattern of subsidiary gene expression. This formulation can explain how a divided early embryo can grow into two nearly perfect but miniature larvae. The concentration of the regulatory factors would reach a nadir when growth stops and then gradually recover. The increasing concentration after puberty might tend to activate the genome in reverse order and thus contribute to senescence.
MeSH term(s)	Aging ; Animals ; Embryonic and Fetal Development/genetics ; Embryonic and Fetal Development/physiology ; Gene Expression Regulation, Developmental ; Genome ; Humans ; Models, Genetic ; Rotifera/genetics ; Rotifera/growth & development
Language	English
Publishing date	2002-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	193145-3
ISSN	1532-2777 ; 0306-9877
ISSN (online)	1532-2777
ISSN	0306-9877
DOI	10.1054/mehy.2001.1510
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Zs.A 1132: Show issues

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Article ; Online: Laying the foundations of community engagement in Aboriginal health research: establishing a community reference group and terms of reference in a novel research field.

O'Brien, Penny / Prehn, Ryan / Rind, Naz / Lin, Ivan / Choong, Peter F M / Bessarab, Dawn / Coffin, Juli / Mason, Toni / Dowsey, Michelle M / Bunzli, Samantha

Research involvement and engagement

2022 Volume 8, Issue 1, Page(s) 40

Abstract: Background: Community engagement or community involvement in Aboriginal health research is a process that involves partnering, collaborating and involving Aboriginal and Torres Strait Islander people or potential research participants to empower them to ...

Abstract	Background: Community engagement or community involvement in Aboriginal health research is a process that involves partnering, collaborating and involving Aboriginal and Torres Strait Islander people or potential research participants to empower them to have a say in how research with Aboriginal communities is conducted. In the context of Aboriginal health, this is particularly important so that researchers can respond to the priorities of the community under study and conduct research in a way that is respectful of Aboriginal cultural values and beliefs. One approach to incorporating the principals of community engagement and to ensure cultural oversight and guidance to projects is to engage a community reference group. The aim of this study was to describe the process of establishing an Aboriginal community reference group and terms of reference. The community reference group was established to guide the research activities of a newly formed research collaboration aiming to to develop osteoarthritis care that meets the needs of Aboriginal and Torres Strait Islander people in Australia. Methods: Adopting a Participatory Action Research approach, this two-phase study was conducted in Victoria, Australia. In phase one, semi-structured research yarns (a cultural form of conversation used as a data gathering tool) were conducted collaboratively by Aboriginal and non-Aboriginal co-investigators to explore Aboriginal health stakeholder perspectives on establishing a community reference group and terms of reference. In phase two, recommendations in phase one were identified to invite members to participate in the community reference group and to ratify the terms of reference through a focus group. Data were analyzed using a framework analysis approach. Results: Thirteen people (eight female, four male) participated in phase one. Participants represented diverse professional backgrounds including physiotherapy, nursing, general practice, health services management, hospital liaison, cultural safety education, health research and the arts. Three themes were identified in phase one; Recruitment and Representation (trust and relationships, in-house call-outs, broad-spectrum expertise and Aboriginal majority); Purpose (community engagement, research steering, knowledge dissemination and advocacy) and; Function and Logistics (frequency and format of meetings, size of group, roles and responsibilities, authority, communication and dissemination). In phase two, six Aboriginal people were invited to become members of the community reference group who recommended changes which were incorporated into the seven domains of the terms of reference. Conclusion: The findings of this study are captured in a 10-step framework which describes practical strategies for establishing a community reference group and terms of reference in Aboriginal health research.
Language	English
Publishing date	2022-08-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2834246-X
ISSN	2056-7529 ; 2056-7529
ISSN (online)	2056-7529
ISSN	2056-7529
DOI	10.1186/s40900-022-00365-7
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Article ; Online: Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes.

Jäger, Susanne / Cuadrat, Rafael / Wittenbecher, Clemens / Floegel, Anna / Hoffmann, Per / Prehn, Cornelia / Adamski, Jerzy / Pischon, Tobias / Schulze, Matthias B

Nutrients

2020 Volume 12, Issue 12

Abstract: Circulating levels of branched-chain amino acids, glycine, or aromatic amino acids have been associated with risk of type 2 diabetes. However, whether those associations reflect causal relationships or are rather driven by early processes of disease ... ...

Abstract	Circulating levels of branched-chain amino acids, glycine, or aromatic amino acids have been associated with risk of type 2 diabetes. However, whether those associations reflect causal relationships or are rather driven by early processes of disease development is unclear. We selected diabetes-related amino acid ratios based on metabolic network structures and investigated causal effects of these ratios and single amino acids on the risk of type 2 diabetes in two-sample Mendelian randomization studies. Selection of genetic instruments for amino acid traits relied on genome-wide association studies in a representative sub-cohort (up to 2265 participants) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study and public data from genome-wide association studies on single amino acids. For the selected instruments, outcome associations were drawn from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis, 74,124 cases and 824,006 controls) consortium. Mendelian randomization results indicate an inverse association for a per standard deviation increase in ln-transformed tyrosine/methionine ratio with type 2 diabetes (OR = 0.87 (0.81-0.93)). Multivariable Mendelian randomization revealed inverse association for higher log
MeSH term(s)	Adult ; Amino Acids, Aromatic/blood ; Amino Acids, Branched-Chain/blood ; Case-Control Studies ; Diabetes Mellitus, Type 2/genetics ; Female ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Glycine/blood ; Humans ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Prospective Studies ; Tyrosine/blood
Chemical Substances	Amino Acids, Aromatic ; Amino Acids, Branched-Chain ; Tyrosine (42HK56048U) ; Glycine (TE7660XO1C)
Language	English
Publishing date	2020-12-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu12123890
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Article: On the prevention and therapy of prostate cancer by androgen administration.

Prehn, R T

Cancer research

1999 Volume 59, Issue 17, Page(s) 4161–4164

Abstract: It has been widely suggested that elevated androgen levels may be critically involved in the genesis of prostate cancer. Despite the dependency of the normal prostate and of most prostatic cancers upon androgens and the fact that tumors can be produced ... ...

Abstract	It has been widely suggested that elevated androgen levels may be critically involved in the genesis of prostate cancer. Despite the dependency of the normal prostate and of most prostatic cancers upon androgens and the fact that tumors can be produced in some rodent models by androgen administration, I will argue that, contrary to prevalent opinion, declining rather than high levels of androgens probably contribute more to human prostate carcinogenesis and that androgen supplementation would probably lower the incidence of the disease. I will also consider the possibility that the growth of androgen-independent prostate cancers might be reduced by the administration of androgens.
MeSH term(s)	Androgens/physiology ; Androgens/therapeutic use ; Humans ; Male ; Phenotype ; Prostatic Hyperplasia/etiology ; Prostatic Neoplasms/prevention & control ; Prostatic Neoplasms/therapy
Chemical Substances	Androgens
Language	English
Publishing date	1999-09-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
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Uh III Zs.135/5: Show issues

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Article ; Online: Systems analysis of protein signatures predicting cetuximab responses in KRAS, NRAS, BRAF and PIK3CA wild-type patient-derived xenograft models of metastatic colorectal cancer.

Lindner, Andreas U / Carberry, Steven / Monsefi, Naser / Barat, Ana / Salvucci, Manuela / O'Byrne, Robert / Zanella, Eugenia R / Cremona, Mattia / Hennessy, Bryan T / Bertotti, Andrea / Trusolino, Livio / Prehn, Jochen H M

International journal of cancer

2020 Volume 147, Issue 10, Page(s) 2891–2901

Abstract: Antibodies targeting the human epidermal growth factor receptor (EGFR) are used for the treatment of RAS wild-type metastatic colorectal cancer. A significant proportion of patients remains unresponsive to this therapy. Here, we performed a reverse-phase ...

Abstract	Antibodies targeting the human epidermal growth factor receptor (EGFR) are used for the treatment of RAS wild-type metastatic colorectal cancer. A significant proportion of patients remains unresponsive to this therapy. Here, we performed a reverse-phase protein array-based (phospho)protein analysis of 63 KRAS, NRAS, BRAF and PIK3CA wild-type metastatic CRC tumours. Responses of tumours to anti-EGFR therapy with cetuximab were recorded in patient-derived xenograft (PDX) models. Unsupervised hierarchical clustering of pretreatment tumour tissue identified three clusters, of which Cluster C3 was exclusively composed of responders. Clusters C1 and C2 exhibited mixed responses. None of the three protein clusters exhibited a significant correlation with transcriptome-based subtypes. Analysis of protein signatures across all PDXs identified 14 markers that discriminated cetuximab-sensitive and cetuximab-resistant tumours: PDK1 (S241), caspase-8, Shc (Y317), Stat3 (Y705), p27, GSK-3β (S9), HER3, PKC-α (S657), EGFR (Y1068), Akt (S473), S6 ribosomal protein (S240/244), HER3 (Y1289), NF-κB-p65 (S536) and Gab-1 (Y627). Least absolute shrinkage and selection operator and binominal logistic regression analysis delivered refined protein signatures for predicting response to cetuximab. (Phospo-)protein analysis of matched pretreated and posttreated models furthermore showed significant reduction of Gab-1 (Y627) and GSK-3β (S9) exclusively in responding models, suggesting novel targets for treatment.
MeSH term(s)	Animals ; Cell Proliferation/drug effects ; Cetuximab/administration & dosage ; Cetuximab/pharmacology ; Class I Phosphatidylinositol 3-Kinases/genetics ; Cluster Analysis ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Female ; GTP Phosphohydrolases/genetics ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Liver Neoplasms/secondary ; Male ; Membrane Proteins/genetics ; Mice ; Phosphoproteins/drug effects ; Phosphoproteins/metabolism ; Proteomics/methods ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins p21(ras)/genetics ; Unsupervised Machine Learning ; Xenograft Model Antitumor Assays
Chemical Substances	KRAS protein, human ; Membrane Proteins ; Phosphoproteins ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3CA protein, human (EC 2.7.1.137) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; NRAS protein, human (EC 3.6.1.-) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Cetuximab (PQX0D8J21J)
Language	English
Publishing date	2020-08-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.33226
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 478: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 576: Show issues

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