PURPOSE: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. EXPERIMENTAL DESIGN: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. RESULTS: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. CONCLUSIONS: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.

• MeSH
• CD8-pozitivní T-lymfocyty * imunologie   účinky léků   MeSH
• ektopické lymfoidní struktury * imunologie   patologie   MeSH
• hepatocytární jaderný faktor 1-alfa * genetika   metabolismus   MeSH
• inhibitory kontrolních bodů * terapeutické užití   farmakologie   MeSH
• karboplatina aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádorové mikroprostředí * imunologie   účinky léků   MeSH
• nádory vaječníků * farmakoterapie   imunologie   patologie   MeSH
• neoadjuvantní terapie metody   MeSH
• paclitaxel aplikace a dávkování   terapeutické užití   farmakologie   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   farmakologie   MeSH
• serózní cystadenokarcinom farmakoterapie   patologie   imunologie   MeSH
• stres endoplazmatického retikula účinky léků   imunologie   MeSH
• tumor infiltrující lymfocyty imunologie   účinky léků   metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-alfa * MeSH
• inhibitory kontrolních bodů * MeSH
• karboplatina MeSH
• paclitaxel MeSH

Monogenic diabetes is a gateway to precision medicine through molecular mechanistic insight. Hepatocyte nuclear factor 1A (HNF-1A) and HNF-4A are transcription factors that engage in crossregulatory gene transcription networks to maintain glucose-stimulated insulin secretion in pancreatic β cells. Variants in the HNF1A and HNF4A genes are associated with maturity-onset diabetes of the young (MODY). Here, we explored 4 variants in the P2-HNF4A promoter region: 3 in the HNF-1A binding site and 1 close to the site, which were identified in 63 individuals from 21 families of different MODY disease registries across Europe. Our goal was to study the disease causality for these variants and to investigate diabetes mechanisms on the molecular level. We solved a crystal structure of HNF-1A bound to the P2-HNF4A promoter and established a set of techniques to probe HNF-1A binding and transcriptional activity toward different promoter variants. We used isothermal titration calorimetry, biolayer interferometry, x-ray crystallography, and transactivation assays, which revealed changes in HNF-1A binding or transcriptional activities for all 4 P2-HNF4A variants. Our results suggest distinct disease mechanisms of the promoter variants, which can be correlated with clinical phenotype, such as age of diagnosis of diabetes, and be important tools for clinical utility in precision medicine.

• Klíčová slova
• Diabetes, Metabolism, Structural biology, Transcription,
• MeSH
• diabetes mellitus 2. typu * genetika   metabolismus   MeSH
• hepatocytární jaderný faktor 1-alfa * genetika   metabolismus   MeSH
• hepatocytární jaderný faktor 4 * genetika   metabolismus   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• promotorové oblasti (genetika) * genetika   MeSH
• regulace genové exprese MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-alfa * MeSH
• hepatocytární jaderný faktor 4 * MeSH
• HNF1A protein, human MeSH Prohlížeč
• HNF4A protein, human MeSH Prohlížeč

BACKGROUND: HNF1A-MODY is a monogenic form of diabetes caused by variants in the HNF1A gene. Different HNF1A variants are associated with differences in age of disease onset, but other factors are postulated to influence this trait. Here, we searched for genetic variants influencing age of HNF1A-MODY onset. METHODS: Blood samples from 843 HNF1A-MODY patients from Czech Republic, France, Poland, Slovakia, the UK and the US were collected. A validation set consisted of 121 patients from the US. We conducted a genome-wide association study in 843 HNF1A-MODY patients. Samples were genotyped using Illumina Human Core arrays. The core analysis was performed using the GENESIS package in R statistical software. Kinship coefficients were estimated with the KING and PC-Relate algorithms. In the linear mixed model, we accounted for year of birth, sex, and location of the HNF1A causative variant. RESULTS: A suggestive association with age of disease onset was observed for rs2305198 (p = 2.09E-07) and rs7079157 (p = 3.96E-06) in the HK1 gene, rs2637248 in the LRMDA gene (p = 2.44E-05), and intergenic variant rs2825115 (p = 2.04E-05). Variant rs2637248 reached nominal significance (p = 0.019), while rs7079157 (p = 0.058) and rs2825115 (p = 0.068) showed suggestive association with age at diabetes onset in the validation set. CONCLUSIONS: rs2637248 in the LRMDA gene is associated with age at diabetes onset in HNF1A-MODY patients.

• Klíčová slova
• Age at disease onset, Diabetes, GWAS, HNF1A-MODY,
• MeSH
• celogenomová asociační studie * MeSH
• diabetes mellitus 2. typu * diagnóza   genetika   MeSH
• fenotyp MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-alfa MeSH
• HNF1A protein, human MeSH Prohlížeč

• Klíčová slova
• Birthweight, Hepatocyte nuclear factor-4 alpha (HNF4A), Maturity-onset diabetes of the young (MODY), Penetrance,
• MeSH
• diabetes mellitus 2. typu * genetika   MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• kohortové studie MeSH
• lidé MeSH
• mutace MeSH
• penetrance MeSH
• porodní hmotnost genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-alfa MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF4A protein, human MeSH Prohlížeč

BACKGROUND: Maturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now. CASE REPORT: A female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant. CONCLUSION: Digenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed.

• Klíčová slova
• Digenic MODY, HNF1A-MODY, HNF1B-MODY, MODY 3, MODY 5,
• MeSH
• cystická onemocnění ledvin genetika   patologie   MeSH
• diabetes mellitus 2. typu genetika   patologie   MeSH
• dítě MeSH
• fenotyp MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• heterozygot MeSH
• lidé MeSH
• mutace MeSH
• nemoci ledvin genetika   patologie   MeSH
• uterus abnormality   MeSH
• vrozené poruchy tubulárního transportu genetika   patologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-alfa MeSH
• hepatocytární jaderný faktor 1-beta MeSH
• HNF1A protein, human MeSH Prohlížeč
• HNF1B protein, human MeSH Prohlížeč

CONTEXT: While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG) guidelines for variant interpretation, functional studies provide strong evidence to classify a variant as pathogenic. OBJECTIVE: We hypothesized that a functional evaluation can improve the interpretation of the HNF1A variants in our Czech MODY Registry. DESIGN, SETTINGS, AND PARTICIPANTS: We studied 17 HNF1A variants that were identified in 48 individuals (33 female/15 male) from 20 Czech families with diabetes, using bioinformatics in silico tools and functional protein analyses (transactivation, protein expression, DNA binding, and nuclear localization). RESULTS: Of the 17 variants, 12 variants (p.Lys120Glu, p.Gln130Glu, p.Arg131Pro, p.Leu139Pro, p.Met154Ile, p.Gln170Ter, p.Glu187SerfsTer40, p.Phe215SerfsTer18, p.Gly253Arg, p.Leu383ArgfsTer3, p.Gly437Val, and p.Thr563HisfsTer85) exhibited significantly reduced transcriptional activity or DNA binding (< 40%) and were classified as (likely) pathogenic, 2/17 variants were (likely) benign and 3/17 remained of uncertain significance. Functional analyses allowed for the reclassification of 10/17 variants (59%). Diabetes treatment was improved in 20/29 (69%) carriers of (likely) pathogenic HNF1A variants. CONCLUSION: Functional evaluation of the HNF1A variants is necessary to better predict the pathogenic effects and to improve the diagnostic interpretation and treatment, particularly in cases where the cosegregation or family history data are not available or where the phenotype is more diverse and overlaps with other types of diabetes.

• Klíčová slova
• ACMG classification, HNF1A-MODY, functional study, hepatocyte nuclear factor-1 alpha variants, reclassification,
• MeSH
• biologické markery analýza   MeSH
• diabetes mellitus 1. typu genetika   metabolismus   patologie   MeSH
• diabetes mellitus 2. typu genetika   metabolismus   patologie   MeSH
• dospělí MeSH
• fenotyp MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• lidé MeSH
• mutace * MeSH
• následné studie MeSH
• prognóza MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• hepatocytární jaderný faktor 1-alfa MeSH
• HNF1A protein, human MeSH Prohlížeč

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

• MeSH
• ABC transportér z rodiny G, člen 2 genetika   MeSH
• celogenomová asociační studie MeSH
• dna (nemoc) krev   epidemiologie   genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetické lokusy MeSH
• genetické markery * MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• játra metabolismus   patologie   MeSH
• jednonukleotidový polymorfismus * MeSH
• kardiovaskulární nemoci krev   epidemiologie   genetika   MeSH
• kohortové studie MeSH
• kyselina močová krev   MeSH
• ledviny metabolismus   patologie   MeSH
• lidé MeSH
• metabolické nemoci krev   epidemiologie   genetika   MeSH
• nádorové proteiny genetika   MeSH
• orgánová specificita MeSH
• signální transdukce * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABCG2 protein, human MeSH Prohlížeč
• genetické markery * MeSH
• hepatocytární jaderný faktor 1-alfa MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF1A protein, human MeSH Prohlížeč
• HNF4A protein, human MeSH Prohlížeč
• kyselina močová MeSH
• nádorové proteiny MeSH

The discovery of MODY (Maturity-Onset Diabetes of the Young) and the elucidation of its heritability enabled more precise clinical characteristics of different MODY subtypes and led to understanding that glucokinase MODY (GCK-MODY) is not associated with vascular complications in long term follow-up, whereas MODY of transcription factors (e.g. HNF1A-MODY) is in case of bad metabolic control connected with the acceleration of particularly microvascular complications. There is a strong evidence of the needlessness of any specific antidiabetic treatment in prognosticaly favourable GCK-MODY (except for the pregnancy). On the contrary, in MODY of transcription factors, including the most common one - HNF1A-MODY, the treatment, traditionally based on sulphonylurea derivatives (and after their failure on insulin) is required. Due to wider spectrum of available antidiabetic agents offering individualization of the treatment, the question of efficacy of other antidiabetic agents in MODY patients arises. This review article summarizes current knowledge of therapeutic options in patients with MODY.Key words: insulin - MODY - oral hypoglycemic drugs - treatment.

• MeSH
• diabetes mellitus 2. typu * farmakoterapie   genetika   MeSH
• glukokinasa MeSH
• hepatocytární jaderný faktor 1-alfa MeSH
• hypoglykemika * terapeutické užití   MeSH
• lidé MeSH
• mutace MeSH
• těhotenství při diabetu MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glukokinasa MeSH
• hepatocytární jaderný faktor 1-alfa MeSH
• hypoglykemika * MeSH

Hepatocellular adenoma (HA) is a benign neoplasm of the liver, whose aetiopathogenesis is little known. Newest research allowed dividing all cases into three types based on molecular characteristics: inflammatory HA, HA with HNF1A mutation, β-catenin-mutated HA. The clinical significance of HA is chiefly due to the possibility of malignant transformation into hepatocellular carcinoma (HCC). The aim of the present study was to immunohistochemically assess the expression pattern and level of c-MET protein in hepatocellular adenoma (taking into account its status of Wnt/β-catenin pathway functioning) and intertwining the results into a wider pattern of expression in non-neoplastic liver and hepatocellular carcinoma of various histological grades. It was found that expression of c-MET in poorly-differentiated HCC was significantly higher than in non-neoplastic liver and well- to moderately-differentiated HCC. The expression in HA was variable and differed between molecular subtypes of this neoplasm: inflammatory and HNF1A mutation-associated type are characterized by overexpression of c-MET to an extent comparable with poorly-differentiated HCC, whereas Wnt/β-catenin dysfunction-associated type lacks overexpression, and the amount of c-MET protein accumulated in its cells is similar to the levels in non-neoplastic tissue and well- to moderately-differentiated HCC. These findings suggest that c-MET overexpression in HA is not an early event in hepatocarcinogenesis, but constitutes a divergent molecular pathway leading to neoplastic change compared to overexpression observed in the late stages of tumour progression.

• MeSH
• dospělí MeSH
• hepatocelulární karcinom metabolismus   MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• imunohistochemie MeSH
• játra metabolismus   patologie   MeSH
• lidé MeSH
• mutace MeSH
• nádory jater metabolismus   MeSH
• protoonkogenní proteiny c-met metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-alfa MeSH
• HNF1A protein, human MeSH Prohlížeč
• protoonkogenní proteiny c-met MeSH

CONTEXT: Congenital hyperinsulinism of infancy (CHI) represents a group of heterogeneous disorders characterized by oversecretion of insulin from pancreatic β-cells causing severe hypoglycemia. OBJECTIVE: We studied the distribution of genetic causes of CHI in a Czech population. METHODS: Countrywide collection of patients with CHI included 40 subjects (12 females, median age of diagnosis, 1 wk [interquartile range, 1-612 wk]). We sequenced the ABCC8, KCNJ11, GLUD1, GCK, HADH, UCP2, SLC16A1, HNF4A, and HNF1A genes and investigated structural changes in the ABCC8 gene. We functionally tested novel variants in the ABCC8 gene by Rb(86+) efflux assay and novel variants in the HNF1A gene by transcriptional activation and DNA-binding tests. RESULTS: We found causal mutations in 20 subjects (50%): 19 carried a heterozygous mutation while one patient was homozygous for mutation in the ABCC8 gene. Specifically, we detected 11 mutations (seven novel) in ABCC8, one novel mutation in KCNJ11, five mutations (two novel) in HNF1A, two novel mutations in HNF4A, and one in GCK. We showed a decrease of activation by diazoxide in mutant KATP channels with novel ABCC8 variants by 41-91% (median, 82%) compared with wild-type (WT) channels and reduced transcriptional activity of mutant HNF1A proteins (2.9% for p.Asn62Lysfs93* and 22% for p.Leu254Gln) accompanied by no DNA-binding ability compared with WT HNF1A. CONCLUSION: We detected a higher proportion of heterozygous mutations causing CHI compared with other cohorts probably due to lack of consanguinity and inclusion of milder CHI forms. Interestingly, HNF1A gene mutations represented the second most frequent genetic cause of CHI in the Czech Republic. Based on our results we present a genetic testing strategy specific for similar populations.

• MeSH
• aktivace transkripce MeSH
• DNA genetika   MeSH
• dospělí MeSH
• draslíkové kanály dovnitř usměrňující genetika   MeSH
• genetická variace MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• kinázy zárodečného centra MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• mutace genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• protein-serin-threoninkinasy genetika   MeSH
• radioizotopy rubidia MeSH
• receptory sulfonylurey genetika   MeSH
• rodokmen MeSH
• těhotenství MeSH
• vrozený hyperinzulinismus epidemiologie   genetika   MeSH
• Check Tag
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• ABCC8 protein, human MeSH Prohlížeč
• DNA MeSH
• draslíkové kanály dovnitř usměrňující MeSH
• hepatocytární jaderný faktor 1-alfa MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF1A protein, human MeSH Prohlížeč
• HNF4A protein, human MeSH Prohlížeč
• kinázy zárodečného centra MeSH
• Kir6.2 channel MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH
• radioizotopy rubidia MeSH
• receptory sulfonylurey MeSH