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PubMed2024

Epigenetic footprints: Investigating placental DNA methylation in the context of prenatal exposure to phenols and phthalates.

BACKGROUND: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation. METHODS: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed. RESULTS: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben. CONCLUSIONS: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.

Humans↗
PubMed1977

First-neighbor specificities of actinomycin-DNA bindings by circular dichroism.

The circular dichroism spectra of eleven double-stranded DNAs, five natural with known nearest neighbor frequencies and six synthetic polydimers and polytrimers, were measured from 210 to 310 nm in the absence and presence of increasing amounts of actinomycin up to saturation. Based on the fact that the circular dichroism of nucleic acids is a nearest-neighbor frequency-dependent property, matrix analysis of the problem revealed which neighbor sets were perturbed by actinomycin, presumably by intercalation of the planar moiety of the molecule. The intercalation sites can be separated into three families. The first-neighbor units GpC and CpG are very favorable binding sites for actinomycin. ApG, CpC, ApC, TpC, and TpG appear to be less attractive sites, while ApT, TpA, and ApA are unfavorable sites.

Binding Sites↗
PubMed1977

Conformational properties of purine-pyrimidine and pyrimidine-purine dinucleoside monophosphates.

The detailed conformational features and dynamics of heterodinucleoside monophosphates ApU, ApC, GpU, GpC, UpA, CpA, UpG, and CpG have been studied in aqueous solution by high field nuclear magnetic resonance (NMR) spectroscopy. Analysis of the resultant NMR parameters leads to a number of discernible trends throughout the series. Thus the ribose rings of the dimers exist as equilibrium mixtures of C(2')-endo(2E) in equilibrium C(3')-endo(3E) conformers with a proclivity for the 3E pucker in most cases; the C(4')-C(5') bonds of both nucleotidyl units show significant preference (74-96%) for a gg conformation and the dominant conformer (85-89%) about C(5')-O(5') is g'g'. Orientation about the C(3')-O(3') bond is coupled to the ribose conformational equilibrium and the system exists with a bias for the 3Eg- coupled conformation in which the H(3')-C(3')-O(3')-P dihedral angle occupies the narrow range of 33-35 degrees. Dimerization, on the average, causes about 10% increase in gg and g'g' populations and the g-domain becomes increasingly populated about the C(3')-O(3') bond. The ribose equilibrium 2E in equilibrium 3E shifts in favor of 3E upon dimerization, the effect being very conspicuous for the pu-py series (similar to 40 yields 60%) and less noticeable for the py-pu systems (similar to 47 yields 58%), clearly suggesting a correlation between sequence and ribose conformational equilibrium. The temperature and dimerization data for the heterodinucleoside monophosphates show that the transition 2E yields 3E is directly related to XCN changes induced by dimerization and stacking. Analysis of the ribose coupling data shows that the percentage populations of stacked species vary from dimer to dimer with GpC displaying a maximum of 45% stacked population and UpG about 10%. However, in general, the pu-py dimers show a higher preference (27-45%) for stacked conformations than py-pu dimers (10-25%). It is proposed that the pronounced deshielding of H(5') of the 5'-nucleotidyl units upon dimerization is associated with the presence of right-handed stacks (g-g-), whereas the chemical shift trends of H(5') and H(5') of 3'-nucleotidyl units are due to the presence of left-handed stacks (g+g+) in all the dimers. In pu-py dimers, the population of the g-g- species is found to be greater than that of g+g+. Also the population of g-g- stacks in pu-py dimers is generally greater than in their corresponding matched py-pu dimers. Thus the base sequence has not only an explicit effect on the overall populations of stacked species, but also on the handedness of the stacks. The present results further confirm the interdependence of conformational bonds throughout the nucleotidyl framework.

Deuterium↗
PubMed1978

Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia.

Analgesic abuse is a major public health hazard in Australia, and analgesic nephropathy with consequent terminal renal failure is the underlying cause in 20% of the patients requiring dialysis and transplantation. Analgesics are invariably taken in the form of compounds and mixtures. In the aspirin-phenacetin-caffeine (APC) mixture, aspirin appears to be the major nephrotoxic agent and phenacetin appears to play a secondary and synergistic role. The renal disease associated with abuse of analgesics is characteristic and is part of a much wider clinical syndrome, the analgesic syndrome, which includes peptic ulcer disease (35%), anemia (60 to 90%), hypertension (15 to 70%), ischemic heart disease (35%), psychological and psychiatric manifestations, pigmentation, and possible gonadal- and pregnancy-related effects. The primary lesion in analgesic nephropathy is renal papillary necrosis (RPN), and this is a nephrotoxic effect common to all nonsteroid antiinflammatory agents. The most important factor in the management of patients with analgesic nephropathy is the cessation of analgesic abuse, and this leads to improvement and stabilization of renal function. A small proportion of patients will, however, deteriorate in relation to accelerated hypertension, persistent proteinuria, ischemic heart disease, and complications leading to nephrectomy. Patients with analgesic nephropathy are poor risk patients and have a poor prognosis, even after dialysis and transplantation.

Adult↗
PubMed2026

Optimizing GRIDSS for clinical use: A targeted NGS filtering strategy for germline structural variant detection.

Detecting intermediate-sized structural variants (SVs) remains challenging in diagnostics, as tools for single-nucleotide and copy-number variants, particularly read-depth-based methods, are often insufficient. GRIDSS addresses this gap by integrating paired-end mapping, split-read analysis, and assembly-based approaches. However, its use in targeted sequencing and diagnostic workflows remains complex. NGS panel data from 9726 patients with suspected hereditary cancer were analyzed using GRIDSS. A filtering strategy was developed to prioritize clinically relevant germline SVs. Multiple parameter settings were tested to optimize performance. The initial dataset of 1,307,592 variants was reduced to 89 candidates after applying the selected filtering strategy. Of these, 24 had been previously detected by routine callers and were not further analyzed. Among the remaining 65, 13 were considered likely true positives after visual inspection using IGV. Experimental validation was performed by Sanger/Nanopore long-read sequencing for these variants, all of which were confirmed. Eight were classified as (likely) pathogenic, including two frameshift duplications in MSH6, one splicing variant in BARD1, and five mobile element insertions in APC, BRCA2, and PALB2. Altogether, GRIDSS implementation increased diagnostic yield while maintaining feasibility for diagnostic workflows. Comprehensive workflow scheme for germline structural variant detection and results in our diagnostic setting.

Humans↗
PubMed1977

Inhibition of pancreatic ribonuclease by 2'-5' and 3'-5' oligonucleotides.

Forty different oligonucleotides were investigated as possible inhibitors of the depolymerizing activity of RNase A. The strongest inhibitors among the diribonucleoside 2'-5' mono- phosphates were: G2'-5'G, C2'-5'G and U2'-5'G, and among the diribonucleoside 3'-5' monophosphates: ApU, ApC and GpU. Of the eight trinucleotides investigated, ApApUp, ApApCp and ApGpUp were the strongest inhibitors. All four dinucleotides studied (ApUp, ApCp, GpUp and GpCp) were very strong inhibitors, ApUp being the strongest one. The results show that the nature of the various bases in the oligonucleotide has an effect on the degree of inhibition, and that the 3' phosphomonoester group increases the binding of the oligonucleotide to RNase A. These inhibitors can be used in physicochemical and biochemical studies of ribonuclease.

Kinetics↗
PubMed2026

NTRK-positive collision tumor of the gastrointestinal tract: a rare entity case report.

Neurotrophic receptor tyrosine kinase (NTRK) fusion-positive colorectal cancer (CRC) represents a rare molecular subset of CRC. We report an exceptional case of a collision tumor composed of two anatomically adjacent but histologically and genomically distinct primary colorectal carcinomas, each giving rise to a corresponding metastasis. Comprehensive histopathologic and molecular analyses demonstrated that one primary tumor and its matched metastasis consisted predominantly (> 90%) of a solid carcinoma harboring a TPR::NTRK fusion, high microsatellite instability (MSI-H), elevated tumor mutational burden (TMB), and loss of MLH1 and PMS2 expression by immunohistochemistry. In contrast, the second primary tumor and its corresponding metastasis exhibited conventional adenocarcinoma morphology with mucinous differentiation, lacked an NTRK fusion, and carried canonical driver mutations in KRAS, APC, SMAD4, and TP53. This case underscores the importance of integrated histopathologic and molecular evaluation in CRCs with heterogeneous morphology, as the identification of multiple, genomically distinct tumor components may have significant diagnostic, prognostic, and therapeutic implications.

NTRK gene fusion↗
PubMed2025

Molecular alterations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathways in gastric cancer among ethnically heterogeneous cohorts.

BACKGROUND/OBJECTIVES: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, and patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding of ethnicity-specific molecular alterations. This study aims to characterize pathway-specific mutations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS signaling pathways in GC and compare mutation frequencies between H/L and Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact of these alterations on overall survival using publicly available datasets. METHODS: We conducted a bioinformatics analysis using publicly available GC datasets to assess mutation frequencies in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway genes. A total of 800 patients were included in the analysis, comprising 83 H/L patients and 717 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW patients. RESULTS: Significant differences were observed in the TP53 pathway and related genes when comparing GC in H/L patients to NHW patients. TP53 mutations were less prevalent in H/L patients (9.6% vs. 19%, p = 0.03). Borderline significant differences were noted in the WNT pathway when comparing GC in H/L patients to NHW GC patients, with WNT alterations more frequent in H/L GC (8.4% vs. 4%, p = 0.08), and APC mutations significantly higher (3.6% vs. 0.8%, p = 0.05). Although alterations in PI3K, TGF-Beta and RTK/RAS pathways were not statistically significant, borderline significance was observed in genes related to these pathways, including EGFR (p = 0.07), FGFR1 (p = 0.05), FGFR2 (p = 0.05), and PTPN11 (p = 0.05) in the PI3K pathway, and SMAD4 (p = 0.08) in the TGF-Beta pathway. Survival analysis revealed no significant differences among H/L patients. However, NHW patients with TP53 and PI3K pathway alterations exhibited significant differences in overall survival, while those without TGF-Beta pathway alterations also showed a significant survival impact. In contrast, WNT pathway alterations were not associated with significant survival differences. These findings suggest that TP53, PI3K, and TGF-Beta pathway disruptions may have distinct prognostic implications in NHW GC patients. CONCLUSIONS: This study provides one of the first ethnicity-focused analyses of TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway alterations in GC, revealing significant racial/ethnic differences in pathway dysregulation. The findings suggest that TP53 and WNT alterations may play a critical role in GC among H/L patients, while PI3K and TGF-Beta alterations may have greater prognostic significance in NHW patients. These insights emphasize the need for precision medicine approaches that account for genetic heterogeneity and ethnicity-specific pathway alterations to improve cancer care and outcomes for underrepresented populations.

PI3K pathway↗
PubMed2025

The Genetic Basis of Elongated Tails in Birds: Evidence for Sexual Selection as a Driver of Convergent Evolution.

Elongated tails are exaggerated ornaments observed in various bird species, and their functional and evolutionary dynamics have attracted considerable attention. Empirical studies consistently show that sexual selection is a major drive of tail elongation. However, the genetic basis of this trait remains poorly understood. To address this gap, we performed comparative genomic analyses of 23 bird species, including 7 with extremely long tails and 16 with relative short tails. Genes related to feather development exhibited amino acid convergence replacement (e.g., APC) or displayed faster evolutionary rates (e.g., LEF1, WISP3) in the long-tailed species. Importantly, we identified convergence replacements of amino acids and rapid evolution in genes related to reproductive functions (e.g., PAQR7) and immunity (e.g., ADA), suggesting that elongated tails may serve as honest signals of genetic quality. In conclusion, this study provides genomic evidence supporting the role of sexual selection in the evolution of elongated tails, revealing an intricate interplay between sexually selected traits, fitness, and immune competence.

Animals↗
PubMed2026

Molecular profiling of pancreatic acinar cell carcinoma and amphicrine-like carcinoma: high frequency of homologous recombination deficiency and molecular heterogeneity.

BACKGROUND: The 6th edition of the WHO Classification of Digestive System Tumours distinguishes amphicrine-like carcinomas (ALCs) from mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Acinar cell carcinomas (ACCs) with an intimately admixed and not separated neuroendocrine component comprising >30% of the tumour are classified as amphicrine-like ACCs (AL-ACCs). We characterised the genomic landscape of pancreatic ACCs and AL-ACCs to validate current classification and identify therapeutic targets. METHODS: Among 2,151 pancreatic biopsy and resection cases that underwent targeted next-generation sequencing using the OncoPanel AMC v4.3 or v4.5 (DNA-based hybrid capture, targeting 323 genes (v4.3) or 343 genes (v4.5)), eight ACCs, seven AL-ACCs originally diagnosed as MiNENs under the 5th edition of the WHO classification scheme, and four neuroendocrine tumours (NETs) were identified, diagnosed between 2020 and 2026. RESULTS: Homologous recombination deficiency (HRD)-associated alterations, involving BRCA1/2, ATM and FANCD2, were identified in 87.5% (7/8) of ACCs and 29% of AL-ACCs. One ACC had an ATRX nonsense mutation. Genomic heterogeneity was observed in molecular profiling of AL-ACCs; two demonstrated a 'true hybrid' signature with co-occurrence of lineage-specific drivers: MEN1 deletion and splice site mutation (neuroendocrine-associated), APC, SMAD4 and CTNNB1 alterations (exocrine-associated). Two others exhibited 'ACC-like' signatures, including missense BRCA1 and nonsense TP53 mutations and MDM4 and AKT3 amplifications, located on chromosome 1q, despite their neuroendocrine differentiation. CONCLUSIONS: Pancreatic ACCs frequently harbour HRD-related alterations, suggesting potential for PARP-inhibitor therapy. AL-ACCs comprise molecularly heterogeneous groups, including true hybrid and ACC-like patterns. Larger studies are required to elucidate the molecular distinction between true hybrid AL-ACCs and those with single-lineage alterations to refine their classification.

acinar↗
PubMed2026

Spatiotemporal mapping of tertiary lymphoid structure heterogeneity shapes immune niches and clinical outcomes in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy with limited therapeutic options. The spatial architecture and functional diversity of tertiary lymphoid structures (TLSs) in iCCA remain unclear. Here, we present a multimodal spatial atlas of TLSs and identified intratumoral TLSs (iTLSs) as independent prognostic markers. Bulk proteomic profiling of 214 discovery and 155 validation cases identified a four-tier TLS-based tumor microenvironment classification system and supported development of a TLS-predictive random forest classifier. Imaging mass cytometry revealed that iTLS+ tumors harbor structured immune architectures, where M1-like tissue-resident macrophages (RTMs), dendritic cells, and CXCL13+ CD4+ T cells colocalize to form antigen-presenting neighborhoods (apc-CNs) spatially coupled to TLS core regions (TLScore-CNs). Single-cell spatial transcriptomics further resolved 61 TLSs into 14 spatial niches and defined a pseudotemporal maturation continuum: aggregated, activated, and postactivated. Intraniche communication, primarily mediated by ifnCAFs, iCAFs, and CXCL12+ macrophages, evolved dynamically with maturation. Single-nucleus RNA sequencing combined with Tangram-based spatial mapping revealed CXCL12+ macrophages and iCAFs forming a peripheral band in aggregated TLSs, whereas ifnCAFs infiltrated TLS interiors during activation. These findings define TLS heterogeneity and provide insights for stroma-directed immunotherapy.

Cholangiocarcinoma↗
PubMed2026

Heterozygous germline mutations in MSH3, and probably MLH3, act as classical tumour suppressors, leading to excess somatic deletion mutations, signature ID4 and increased colorectal cancer risk.

BACKGROUND: MSH3 and MLH3 are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline MSH3 mutations, and in a very few bi-allelic MLH3 mutation carriers. OBJECTIVES: We hypothesised that germline loss-of-function MSH3 and MLH3 mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations or heterozygous germline mutations after second hits. DESIGN: About 12 000 CRC and multiple polyp cases and 460&#x2009;000 controls were studied. 2023 patients underwent cancer genome sequencing. RESULTS: One CRC/multiple polyp case had bi-allelic MSH3 mutations and another, bi-allelic MLH3 mutations. MSH3 and MLH3 germline heterozygotes had an increased risk of CRC (2.2-fold, p=6.6&#xd7;10-5&#x2009;and 1.6-fold, p=0.028, respectively), owing to somatic 'second hits' that inactivated the wildtype allele. Single second hits sometimes inactivated both MSH3 and the nearby APC gene. All CRCs with MSH3 or MLH3 deficiency were microsatellite-stable but hypermutant. Deletions of &#x2265;2&#x2009;bp were particularly increased (~12-fold) and signature ID4 was usually present (p<0.0001). CRCs from heterozygotes without 'second hits' showed no hypermutation. CONCLUSION: The phenotypes of bi-allelic MSH3 and MLH3 mutation carriers resemble some patients with cMMRd. Heterozygous germline MSH3 and MLH3 alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling PMS2-mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from MSH3 or MLH3 deficiency.

COLONIC POLYPS↗
PubMed2026

The Landscape of Genomic and Socioeconomic Variables in Patients with Colorectal Cancer Based on Genetic Ancestry.

BACKGROUND: Despite differences in tumor alterations across genetic ancestries, investigations of the colorectal cancer molecular landscape have used self-reported ethnicity instead of genetic ancestry. METHODS: We used tumor and matched normal whole-exome sequencing data from 16,388 patients with stage I to IV colorectal cancer to investigate colorectal cancer's germline and somatic molecular landscape and the potential influence of socioeconomic factors (Distressed Communities Index, DCI) across diverse genetic ancestries. Genetic ancestry determined via supervised local ancestry inference included African (AFR, N = 1,697), Native American (AMR, N = 1,291), East Asian (EAS, N = 2,247), European (EUR, N = 9,726), Levantine Middle Eastern (LME, N = 1,192), and South Asian (SAS, N = 184). RESULTS: Microsatellite instability (MSI) was the most common form of hypermutation (80.8%), higher in the EUR genetic ancestry than in the AFR, AMR, and EAS genetic ancestry. Among germline findings, positive results were most common in high-penetrance genes associated with Lynch syndrome. Enrichment patterns included MLH1 (SAS) and PMS2 (AFR). There were significant differences in the frequency of driver mutations in APC, BRAF, KRAS, TP53, and PIK3CA between the EUR and other ancestry groups in both MSI and microsatellite stable tumors. Mutational signatures suggested enrichment of reactive oxygen species and POLE in AFR, colibactin in EAS, and aflatoxin and NTHL1 in SAS. DCI scores differed by ancestry (higher distress in AFR/AMR than in EUR), but driver mutation frequencies did not vary across DCI quintiles. CONCLUSIONS: Genetic ancestry shapes hereditary risk, tumor biology, and environmental exposures. IMPACT: These findings suggest that incorporating ancestry into screening, trials, and precision oncology may improve equity, though outcome-linked prospective studies and implementation research are warranted.

Aged↗
PubMed2026

Origin and evolution of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN).

Colorectal neuroendocrine carcinoma (NEC) is a rare and aggressive cancer and in a subset of patients associated with an adenocarcinoma (AC) component. When both components exceed 30% of the tumour, it is classified as mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), although there is an ongoing debate about whether any presence of two distinct components should be sufficient for a MiNEN diagnosis. This study aimed to investigate the origin and subsequent genetic changes of these two components. Ten colorectal cases suitable for sampling of an AC and a poorly differentiated NEC component were identified from the NORDIC NEC 2 study and sequenced across a 360-cancer gene panel. Mock phylogenetic trees were constructed from the molecular profiles of each sample within a patient. All ten cases revealed a common trunk of shared somatic mutations, including well-known colorectal cancer driver mutations such as BRAF, KRAS, APC, and TP53. In all cases, a single branching point separated the AC and NEC components. Private AC and NEC mutations generally had low variant allele frequencies, indicating that most AC and NEC cells were genetically similar. NEC, when compared with AC samples, demonstrated a higher frequency of private mutations (P = 0.009), indicating a higher mutation rate and greater ploidy (P = 0.012), suggesting an association between genomic duplication and AC-to-NEC transition. Shared mutations indicate a common clonal origin, underscoring the role of established colorectal driver mutations in the early development of these tumours, while the mechanisms underlying NEC differentiation remain poorly understood and may involve non-genetic factors.

Humans↗
PubMed2026

A Functionally Constrained Immune Ecosystem in Microsatellite-stable Colorectal Cancer Resolved by Single-cell and Exome Profiling.

BACKGROUND/AIM: Microsatellite-stable (MSS) colorectal cancer (CRC) generally responds poorly to immune checkpoint blockade, but some MSS tumors are T-cell rich. We examined whether such infiltration reflected effective immunity or functional immune constraint. CASE REPORT: A 77-year-old woman underwent resection of a mismatch repair-proficient (pMMR), MSS, low-mutational-burden CRC with a synchronous adenoma. Whole-exome sequencing of tumor, adenoma and adjacent normal tissue detected no shared high-confidence somatic mutations between tumor and adenoma within the sensitivity of this WES analysis and identified tumor-specific APC, KRAS and TP53 alterations. Tumor single-cell RNA sequencing yielded 7,569 cells, with T-lineage populations comprising 83.5%. Cytotoxic T cells showed cytolytic and dysfunction-associated features, regulatory T cells (Tregs) showed suppressive remodeling, and Th17 cells showed inflammatory/profibrotic programs. CellChat nominated stromal MIF/FN1-CD74/CD44 and extracellular-matrix communication with T-cell compartments. CONCLUSION: This molecular case report shows that T-cell abundance and immune effectiveness can be uncoupled in MSS CRC.

Humans↗
PubMed1979

[Arrhythmias in patients with mitral valve prolapse syndrome. An echo- and electrocardiographic study - (author's transl)].

The echocardiograms and electrocardiograms of 76 patients with mitral valve prolapse syndrome (MVP) were examined and compared with those of 20 normal subjects. 30 patients had a late systolic, 32 a holosystolic MVP, 14 patients had a mixed motion pattern of the MVP. Eighty percent of them had arrhythmias, which were detected in 44% only by 24-hours ECG, in 32% by 24-hours ECG and exercise ECG and in 4% only by exercise ECG. 16% of the patients had only atrial premature contractions (APC), 22% only ventricular premature contractions (VPC), 39% had both ventricular and atrial premature contractions. Multifocal VPC'S WERE MORE COMMON IN PATIENTS WITH LATE SYSTOLIC MVP, salvos of VPC however were detected in 3 patients with holosystolic and in one patient with late systolic MVP. Only less severe arrhythmias, in general isolated, univorm VPCs were found in 40% of the normal subjects.

Adolescent↗
PubMed1975

Cell co-operation and hapten--carrier complexes.

The co-operation of spleen cells of carrier- and hapten--carrier-primed mice in antibody formation against the hapten part of complexes was studied in 550 rad whole body irradiated mice. Hapten--carrier complexes were prepared with the 2,4-dinitrophenyl group (DNP) as a hapten and heterologous bovine serum albumin (BSA) and isologous mouse immunoglobulin (MIg) as carriers. Priming of donor mice with carrier alone did not prepare for a secondary (IgG) response in the recipients of hapten--carrier. Priming of donors and challenge of recipients with the same hapten--carrier complex resulted in high IgG responses. Whereas donor and recipient immunization with complexes differing in the carrier did not give a secondary response, addition of cells of donors immunized with the carrier of the complex used for challenge, resulted in a secondary response. This was only possible when at least one of the complexes had an intermediate hapten:carrier ratio. Only an IgM or a low IgG response was obtained if both complexes had a high hapten:carrier ratio. Three determinants, namely hapten and carrier groups and new antigenic determinant (NAD), are suggested for antibody formation against hapten--protein complexes. In vivo treatment of donor cells with anti-thymocyte serum (ATS) or anti-plasma cell serum (APCS) and complement (C) suggested that: (1) T-cell epitopes are present on the carrier; (2) DNP groups are B-cell epitopes; (3) NAD and possibly DNP are T-cell epitopes; (4) synergism exists in the collaborative antibody response of B cells recongnizing DNP, T cell recognizing carrier and T cells recognizing NAD. Mitomycin treatment of donor cells was used to test whether cell division was mandatory. While the B cells were sensitive to mitomycin treatment, no effect of this drug was found on the helper activity of T cells.

Animals↗