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69 records · Page 4Linked to original sources
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↗
PubMed1975

Gentic properties of an R factor carrying resistance to aminolgycoside antibiotics.

R factor Rms 151 is an fi+ R factor and belongs to a incompatibility group FII. It carries the genes governing resistance to various aminoglycoside antibiotics, i.e., kanamycin (KM), lividomycin (LV), gentamicin C complex (GM), and 3',4'-dideoxykanamycin B (DKB), in addition to those governing to tetracycline (TC), chloramphenicol (CM), sulfanilamide (SA), and ampicillin (APC). Electron microscopy observation disclosed that the Rms151 deoxyribonucleic acid was a circular form with length of 31.2 mum. A probable circular genetic map of Rms151 was proposed by genetic and biochemical studies, the genes being in the order of -tet-tra-amp-aad-sul-aph-cml-, in which aad and aph confer resistance to KM.GM.DKB by adenylytransferase or resistance to KM.LV by phosphotransferase, respectively.

Aminoglycosides↗
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↗
PubMed1976

Pathology, aetiology and pathogenesis of analgesic nephropathy.

1. The initial site of damage in analgesic abuse is the renal medulla and the characteristic lesion is renal papillary necrosis. The papillary necrosis appears to be an ischaemic infarct. The cortical lesion of chronic interstial nephritis is a non-specific change and secondary to obstruction to tubules in the necrotic medulla. 2. Medullary perfusion and the concentration mechanism appear to be important factors in the genesis of renal papillary necrosis. 3. Experimental and clinical studies suggest that abuse of compound analgesics containing aspirin, phenacetin and caffeine result in renal papillary necrosis and the clinical syndrome of analgesic nephropathy. In the APC mixture aspirin appears to be the major nephrotoxic agent while phenacetin plays a synergistic but secondary role in the renal nephrotoxicity.

Animals↗
PubMed1975

[Proceedings: Frequency and form of arrhythmia and changes in ECG in juvenile healthy volunteers. Studies with long-term electrocardiography].

In 35 healthy volunteers with a mean age of 24 years an ECG recording for detection of arrhythmias and ECG changes was made by means of a Holter Avionics tape recording system for an average of 7.5 h. Ventricular and supraventricular premature contractions (VPC'S, APCs) were recorded occasionally in 31% and with greater frequency in 6%. Multifocal VPCs and serial VPCs were found in one person (3%). ST-depressions of greater than or equal to 0.1 mV were seen in 9% and a wandering atrial pacemaker in a further 9%. An intermittent increase in P-wave amplitude (greater than or equal to 0.25 mV) was observed in 17%. A surprising finding was frequent (49%) recording of a sinus arrest of short duration, usually followed by an atrial escape rhythm. In view of the frequency of this phenomenon it must be accepted as a normal variant in young people.

Adult↗
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↗
PubMedDate not supplied

[Optimization of production diagrams in automated control systems for medical technology industries].

An algorhythm for drawing up optimal production schedule graphs covering a shop floor (production area) over a planned period of output, based on the criterion of minimizing the total time for the workpiece treatment that may be applicable in the APCS of biomedical engineering industry, is set forth. In this connection the notions of a critical workpiece, critical equipment and of a conflicting situation are introduced, and the LRT rule, that plays a dominant role in combination with those of the SIO and MIN idle time, is applied. A relation intended to settle the conflicting situation in compiling the optimal schedule graphs is adduced and its solution for computerized programming is given.

Electronic Data Processing↗
PubMed2001

Interaction of Galpha 12 and Galpha 13 with the cytoplasmic domain of cadherin provides a mechanism for beta -catenin release.

The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.

Adenocarcinoma↗
PubMed2026

Phlag: scalable detection of genomics regions with unexplained phylogenetic heterogeneity.

MOTIVATION: Phylogenetic analyses of entire genomes (phylogenomics) have revealed abundant heterogeneity of evolutionary histories. While much has been done to model this heterogeneity and to infer species trees despite it, the current toolkit has a limitation. Most methods assume that gene trees across the genome differ but are all sampled from the same distribution, defined by models such as the multi-species coalescent (MSC), and parametrized consistently across the genome. Empirical data strongly suggest this assumption is often violated because the species tree, its parameters, or the process generating the gene trees can all change across the genome. Errors in the data can further compound this heterogeneity. RESULTS: To address this challenge, we define the problem of detecting what segments of the genome are inconsistent with a putative species tree, even after allowing discordance according to MSC. We model gene trees not as a set, but rather as a series (a realization of a stochastic process) along genomic positions. We propose a Hidden Markov Model (HMM) approach applied to quartet statistics measured from gene trees and tie the model to MSC using simulations. The combined use of these three ideas leads to a scalable method called Phlag. On simulated and real data, we show that Phlag can detect many cases of change in underlying evolutionary processes, including reduced recombination rates, population size changes, and admixture, all using the same algorithm. AVAILABILITY AND IMPLEMENTATION: Phlag is available at github.com/bo1929/phlag. All results and scripts can be found at github.com/bo1929/shared.phlag.

Phylogeny↗
PubMed2026

Phlag: Scalable detection of genomics regions with unexplained phylogenetic heterogeneity.

MOTIVATION: Phylogenetic analyses of entire genomes (phylogenomics) have revealed abundant heterogeneity of evolutionary histories. While much has been done to model this heterogeneity and to infer species trees despite it, the current toolkit has a limitation. Most methods assume that gene trees across the genome differ but are all sampled from the same distribution , defined by models such as the multi-species coalescent (MSC), and parametrized consistently across the genome. Empirical data strongly suggest this assumption is often violated because the species tree, its parameters, or the process generating the gene trees can all change across the genome. Errors in the data can further compound this heterogeneity. RESULTS: To address this challenge, we define the problem of detecting what segments of the genome are inconsistent with a putative species tree, even after allowing discordance according to MSC. We model gene trees not as a set, but rather as a series (a realization of a stochastic process) along genomic positions. We propose a Hidden Markov Model (HMM) approach applied to quartet statistics measured from gene trees and tie the model to MSC using simulations. The combined use of these three ideas leads to a scalable method called Phlag. On simulated and real data, we show that Phlag can detect many cases of change in underlying evolutionary processes, including reduced recombination rates, population size changes, and admixture, all using the same algorithm. AVAILABILITY AND IMPLEMENTATION: Phlag is available at github.com/bo1929/phlag . All results and scripts can be found at github.com/bo1929/shared.phlag .

Journal Article↗