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PubMed2025

Glycolytic activity instructs germ layer proportions through regulation of Nodal and Wnt signaling.

Metabolic pathways can influence cell fate decisions, yet their regulative role during embryonic development remains poorly understood. Here, we demonstrate an instructive role of glycolytic activity in regulating signaling pathways involved in mesoderm and endoderm specification. Using a mouse embryonic stem cell (mESC)-based in vitro model for gastrulation, we found that glycolysis inhibition increases ectodermal cell fates at the expense of mesodermal and endodermal lineages. We demonstrate that this relationship is dose dependent, enabling metabolic control of germ layer proportions through exogenous glucose levels. We further show that glycolysis acts as an upstream regulator of Nodal and Wnt signaling and that its influence on cell fate specification can be decoupled from its effects on growth. Finally, we confirm the generality of our findings using a human gastrulation model. Our work underscores the dependence of signaling pathways on metabolic conditions and provides mechanistic insight into the nutritional regulation of cell fate decision-making.

Glycolysis↗

PubMed1976

The reconstruction of a fragment of primordial genetic information from modern proteins: PGI-FI (AHAP).

In a continuation of earlier studies the connection between a reconstructed ancestral histone IV peptide and various sequences from non-histone proteins was investigated. This peptide, AHAP, was found to be related to partial peptides from the human encephalitogenic protein, immunoglobulin L-chains, fibrinopeptide A, glyceraldehyde-3-phosphate-dehydrogenase, TMV coat protein and several other proteins and protein families; for comparison, nodal sequences were employed wherever possible. The widespread occurrence of genetic information expressed in AHAP caused us to rename the peptide PGI-FI (primordial genetic information-fragment 1) since this peptide is apparently part of a very primitive and ancient genetic information, and may be called "protogene".

Amino Acid Sequence↗

PubMedDate not supplied

[Protein biosynthesis in a cell-free protein synthesis system from nodular euthyroid goiter cells].

Analysis of proteins, synthesized in cell-free system using nodal euthyroid goiter, was carried out by polyacrylamide gel disc electrophoresis. Four protein farctions, incorporating labelled amino acids, were found: "complete" thyroglobulin, two its subunits and thyroalmbumin. This correlates with the concept that malignant cell synthesizes intensively proteins untypical for a normal tissue.

Albumins↗

PubMed2026

Cells and Networks in Flux: Rethinking Ontogenesis and Pathogenesis.

Organ and tissue functions emerge from the coordinated activity of cell networks. Therapeutics that act on pathogenic cell networks, modulating their cellular interplay, follow naturally. Over several decades, our laboratory has developed a series of approaches for rewiring cell networks, culminating in a class of cell surface-directed signal converter proteins (SCPs) that do so by modulating juxtacrine and autocrine signaling in and among their nodal cells. A first such SCP has now produced encouraging clinical data for cancer immunotherapy. Yet, these early network-directed fusion proteins rest on a deliberately simplified picture: discrete end-cell types plugged into graphically tractable networks. That picture is increasingly at odds with what computational cell typing and spatiotemporal analytics, along with epigenetics, now reveal-a hyperdiverse, plastic, experience-shaped cellular landscape embedded in dynamic, multiway networks. Setting the stage for a next generation of network modulators, an extended cell differentiation synthesis is proposed, which formalizes paracell ultradifferentiation and aging-associated differentiation phases. According to this model, cells are ever evolving, and no two cells are alike. A richer cellular ontology forces a more elaborate network ontology, with paralogous networks and their shifting subnetworks opening a concrete design space for next-generation network-directed SCP therapeutics. This exploration calls for a willingness to embrace complexity more fully and borrow freely from conceptual fields close and afar.

Humans↗

PubMed2025

Genomic evolution of EGF-CFC genes in deuterostomes.

BACKGROUND: EGF-CFC proteins are a bilaterian innovation, but they are best known for their roles in Nodal signaling during gastrulation and left-right patterning in vertebrates. Species with multiple family members show evidence of functional specialization. For example, in mouse, Cripto is required for gastrulation, whereas CFC1 is involved in left-right patterning. However, members of the EGF-CFC family across model organisms exhibit limited sequence conservation beyond the EGF-CFC domain, posing challenges for determining their evolutionary history and functional conservation. RESULTS: In this study, we describe the evolutionary history of the EGF-CFC family of proteins across several branches of deuterostomes, with a particular focus on vertebrates. We trace the EGF-CFC gene family from a single gene in the deuterostome ancestor through its expansion and functional specialization in tetrapods, and subsequent gene loss and translocation in eutherian mammals. Mouse Cripto and CFC1, zebrafish Tdgf1, and each Xenopus EGF-CFC gene (Tdgf1, Tdgf1.2 and Cripto.3) are all descendants of the ancestral deuterostome Tdgf1 gene. CONCLUSIONS: We propose that subsequent to EGF-CFC family expansion in tetrapods, Tdgf1B (Xenopus Tdgf1.2) acquired specialization in the left-right patterning cascade, and then after its translocation in eutherians to a different chromosomal location, CFC1 has maintained that specialization.

Animals↗

PubMed2026

High-Fat Diet and a High Amyloid Load Interact to Induce PKC-α Dependent Synaptic Insulin Resistance.

A plethora of studies suggest that a high-fat diet in combination with a high amyloid load causes synaptic insulin resistance and is a risk factor for Alzheimer's disease. Our understanding of the underlying mechanisms is still fragmented. To gain new insights, we conducted integrated proteomic and phosphoproteomic profiling of hippocampal synaptosomes from WT and a transgenic mouse line with a high amyloid load (heterozygous TBA2.1 mice) that show no overt signs of neurodegeneration and dementia. Mice were fed with a regular or high-fat diet. Data-independent acquisition quantified over 5400 proteins, revealing a stable synaptic proteome across conditions. However, the combination of high amyloid load and high-fat diet triggered coordinated remodeling of lipid metabolism pathways, particularly mitochondrial and peroxisomal fatty acid catabolism. Phosphoproteomic analysis showed pronounced activation of lipid- and stress-responsive kinases, including protein kinase C-α, along with increased inhibitory phosphorylation of insulin receptor substrates (IRS1/2). In vitro experiments indicate that blocking protein kinase C-α indeed prevents synaptic insulin resistance in primary neurons. The findings suggest that this proteomic workflow, combined with kinase pathway analysis, can reveal nodal points for interventions in a complex disease state with a trajectory to Alzheimer's disease.

Animals↗

PubMed1977

Molecular evolution of snake venom toxins.

Phylogenetic trees were constructed for 62 venom toxins of snakes of Proteroglyphae suborder using matrix method. The resulting tree from Minimum Spanning Tree-Cluster Analysis technique had the lowest "percent deviation" (8.55). The taxonomic relationship of these toxins agrees very well with zoological opinions. However, the appearance of the tree did not directly provide a plausible evolutionary model for the toxins. A model was derived from nodal ancestral sequence calculations, comparisons between intra- and intergenerical rates of amino acid change, and generally held ideas about protein evolution. According to the model, short neurotoxin is the ancient form of snake venom toxins. The courses of evolution leading to the present intraspecific homologous toxins are explained by gene duplication and allelomorphism.

Amino Acid Sequence↗

PubMed1977

Idiotypy of measles virus nucleocapsid-specific IgGkappa antibody in serum and cerebrospinal fluid in subacute sclerosing panencephalitis.

A gel-precipitating anti-idiotypic antiserum was prepared in a rabbit by immunization with measles virus-specific IgG isolated from the serum of a patient with subacute sclerosing pancencephalitis (SSPE). The idiotypic determinant was associated with an electrophoretically restricted and cathodally migrating IgGkappa protein in serum and cerebrospinal fluid (CSF) with antibody activity to measles nucleocapsids. The anti-idiotypic antiserum did not precipitate with other oligoclonal populations of measles-specific IgG in the patients serum or CSF, nor with serum or CSF from 4 other patients with SSPE and 10 patients with multiple sclerosis.

Antibodies, Viral↗

PubMed1978

On investigating the statistical properties of the populous path algorithm by computer simulation. Counterconclusions to those of Tateno and Nei.

Goodman et al.'s (1974) populous path algorithm for estimating hidden mutational change in protein evolution is designed to be used as an adjunct to the maximum parsimony method. When the algorithm is so used, the augmented maximum parsimony distances, far from being overestimates, are underestimates of the actual number of nucleotide substitutions which occur in Tateno and Nei's (1978) computer simulation by the Poisson process model, even when the simulation is carried out at two and a half times the sequence density. Although underestimates, our evidence shows that they are nevertheless more accurate than estimates obtained by a Poisson correction. In the maximum parsimony reconstruction, there is a bias towards overrepresenting the number of shared nucleotide identities between adjacent ancestral and descendant nodal sequences with the bias being stronger in those portions of the evolutionary tree sparser in sequence data. Because of this particular property of maximum parsimony reconstructed sequences, the conclusions of Tateno and Nei concerning the statistical properties of the populous path algorithm are invalid. We conclude that estimates of protein evolutionary rates by the maximum parsimony--populous path approach will become more accurate rather than less as larger numbers of closely related species are included in the analysis.

Biological Evolution↗

PubMed1978

Impaired antibody response to pneumococcal vaccine after treatment for Hodgkin's disease.

To determine if a normal antibody response can develop after therapy for Hodgkin's disease, we immunized 53 patients and 10 normal controls with dodecavalent pneumococcal vaccine. Antibody concentrations three weeks after immunization (geometric mean of 11 serotypes) were 1566 ng of protein nitrogen per milliliter in controls, 963 ng per milliliter after subtotal radiation (P less than 0.05 compared to controls), 658 ng per milliliter after chemotherapy (P less than 0.05), 377 ng per milliliter after subtotal radiation plus chemotherapy (P less than 0.01) and 283 ng per milliliter after total nodal radiation plus chemotherapy (P less 0.001). Low levels of antibody before immunization correlated with a poor response (r = +0.73, P less than 0.001). The ability to respond to immunization improved significantly but did not return to normal as long as four years after combined therapy. The antibody response to pneumococcal vaccine is profoundly impaired in patients who have received intensive treatment for Hodgkin's disease: the ability of this vaccine to protect them from overwhelming postsplenectomy infections remains in doubt.

Adolescent↗

PubMed1979

Distribution, frequency, and quantitative analysis of estrogen, progesterone, androgen, and glucocorticoid receptors in human breast cancer.

The distribution and frequency of steroid hormone receptors are described 329 patients with breast cancer. The distribution of each of the steroid hormone receptors is unimodal with a progressive increase in the proportion of patients positive at lower receptor values. Receptor values expressed as fmol/mg cytoplasmic protein are well correlated with values expressed as fmol/mg breast tumor. Estrogen receptor was positive in 53% of the patients; progesterone receptor was positive in 38% of the patients; glucocorticoid receptor was positive in 52% of the patients; and androgen receptor was positive in 31% of the patients. The type of tissue assayed did not affect steroid hormone receptor positivity. For primary tumors, there was no correlation between steroid hormone receptor positivity and location of the tumor in the breast, size of the tumor, or extent of the disease. Each of the steroid hormone receptors was positively associated with each of the other steroid hormone receptors. Estrogen receptor was correlated with menopausal status and axillary nodal status, but these correlations did not exist for the other steroid hormone receptors. Estrogen receptor was not correlated with age after adjustment for menopausal status. The other steroid hormone receptors were not correlated with age.

Adult↗

PubMed2026

Comparative transcriptomics reveals hormone signaling and MADS-box genes in divergent development of inflorescences and tendrils in grapevine lateral shoots.

Hormone signaling and MADS-box genes regulate grapevine tendril and inflorescence growth divergence, offering molecular insights for managing tendril growth. Grapevine (Vitis vinifera L.) tendrils and inflorescences are homologous organs; however, their divergent development has important agronomic consequences because excessive tendril growth increases vineyard management costs. To explore the regulatory mechanisms, we compared the inflorescence-prone cultivar 'Einset Seedless' (ENT) with the tendril-prone cultivar 'Pinot Noir' (PN) using anatomical observation, transcriptome analysis of specific tendril nodes, and functional characterization of MADS-box genes. ENT exhibited a higher flowering rate at tendril nodes 1-4 than PN. Transcriptome profiling of specific tendril nodes uncovered 549 differentially expressed genes (DEGs) through an intersection/exclusion strategy, with Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment indicating that hormone and mitogen-activated protein kinase (MAPK) signaling were the primary candidates driving the divergence. To assess the spatiotemporal dynamics of these DEGs, we performed Mfuzz clustering, which revealed that multiple expression trajectories were highly consistent with the flowering gradient across different ENT and PN nodes. Plant hormone signal transduction was the predominantly enriched pathway across all dynamic clusters, highlighting the centrality of phytohormones in this process. Guided by this transcriptional evidence, we measured endogenous zeatin and gibberellin (GA₃) contents in the nodal tissues. Remarkably, the zeatin-to-GA₃ ratio not only paralleled the flowering gradient but also correlated with the cluster expression trajectories, providing physiological evidence for a cytokinin-gibberellin interaction model governing organ divergence. Additionally, we analyzed the differentially expressed transcription factors among the DEGs and identified a MADS-box gene, FRUITFULL-LIKE (VvFUL-L), which was markedly upregulated in PN tendrils. Heterologous overexpression of VvFUL-L in arabidopsis promoted early flowering and reduced inflorescence branching, suggesting its potential role in regulating lateral meristem development and affecting tendril formation. Collectively, these findings establish that Hormone Signaling, particularly cytokinin-GA crosstalk, and MADS-box regulators, such as VvFUL-L, are key regulators of inflorescence versus tendril growth in grapevines, providing a basis for future molecular and breeding studies.

Vitis↗

PubMed1975

Bone marrow histology in monoclonal macroglobulinemia.

Rywlin, Arkadi, M., Civantos, Francisco, Ortega, Rolando S., and Dominguez, Carlos J.: Bone marrow histology in monoclonal macroglobulinemiamam J Clin Pathol 63. 769-778, 1975. Histologic sections and smears of aspirated bone marrow particles in 26 cases of monoclonal macroglobulinemia were studied. The bone marrows did not show uniform histologic features. Twenty-two patients had various degrees of lymphoid infiltration of the marrow, including nodules of malignant lymphoma, diffuse lymphocytic infiltration, nodular lymphoid hyperplasia, and normal lymphoid nodules. Four patients had no demonstrable lymphoid collections in the marrow. Additional histologic features of the marrows are summarized. A variant of a Dutcher body consisting of multiple PAS-positive inclusions that by light microscopy appear intranuclear is described. Even though the average macroglobulin levels were higher in patients with abnormal lymphoid infiltrates than in patients with noraml or no lymphoid collections, there was considerable overlap between individual patients values in the different groups. Similarly, no correlation between macroglobulin levels and other histologic features could be established. Patients with monoclonal macroglobulinemia represent a spectrum including benign monoclonal gammopathy, lymphoproliferative disorders of the marrow, nodal or extranodal lymphomas. The separation of Waldenström's macroglobulinemia by arbitrary criteria does not appear justified. (key words: Bone marrow; Monoclonal macroglobulinemia.

Aged↗

PubMed2025

Low expression of HSP27 and HSP70 predicts poor prognosis in laryngeal squamous cell carcinoma.

PURPOSE: Molecular alterations drive the pathogenesis of laryngeal squamous cell carcinoma (LSCC), yet reliable prognostic biomarkers remain elusive. Heat shock proteins (HSPs), which mediate cellular stress responses, are implicated in cancer progression and treatment resistance. This study aimed to evaluate whether HSP27 and HSP70 expression correlate with clinicopathological features and survival outcomes in LSCC. Specifically, we assessed their potential as prognostic biomarkers in this malignancy. METHODS: Immunohistochemistry was performed on 158 LSCC tissue samples from 40 patients and compared to 30 normal laryngeal tissue samples. Expression levels of HSP27 and HSP70 were correlated with clinicopathological variables. Validation was conducted using transcriptomic and survival data from 112 LSCC cases in The Cancer Genome Atlas (TCGA). Kaplan-Meier and Cox regression analyses were used to assess survival. RESULTS: HSP27 was significantly overexpressed in LSCC tissues compared to controls and was associated with advanced tumor stage, nodal metastasis, alcohol abstinence, and older age. HSP70 expression correlated with higher tumor grade and female sex but did not differ significantly between cancerous and noncancerous tissues. In the TCGA cohort, low expression of HSP27 and HSP70 was significantly associated with worse overall survival. Low HSP27 expression emerged as an independent predictor of shorter survival (hazard ratio 2.28; 95% confidence interval, 1.11-4.67; p = 0.024). CONCLUSION: HSP27 and HSP70 show potential as prognostic biomarkers in LSCC, with high expression linked to favorable outcomes. These findings warrant further investigation into their mechanistic roles in tumor progression, therapy resistance, and their potential utility as therapeutic targets.

Humans↗

PubMed2026

The N6-methyladenosine reader IGF2BP2 in T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) represents a highly heterogeneous and aggressive lymphoid neoplasm that lacks pathogenic biomarkers of RNA modification with therapeutic potential. IGF2BP2 is recognized as an N6-methyladenosine reader critically involved in oncogenesis. In this study, we observed consistently high expression of IGF2BP2 across common nodal PTCL subtypes in 3 independent external cohorts, which was further confirmed in our RNA-sequencing (RNA-seq) data set of 196 patients with newly diagnosed PTCL. Both in vitro and in vivo, IGF2BP2 promoted tumor cell growth and inhibited CD8+ T-cell infiltration within the tumor microenvironment. Mechanistically, IGF2BP2 bound to endosome-related genes (RAB4, VPS35, RAB9, and STAM) to maintain their stability, which resulted in enhanced endocytic activity and increased internalization of membrane proteins, and ultimately induced tumor cell proliferation and inhibition of CD8+ T-cell-mediated tumor cytotoxicity. The relationship between IGF2BP2 and endocytosis-associated genes was confirmed using RNA-seq data from patients with PTCL. IGF2BP2 as an upstream regulator of both tumor growth and immune suppression was further demonstrated in patient-derived xenograft models and a coculture system established using tumor samples from patients with PTCL and peripheral blood mononuclear cells. Notably, therapeutic targeting of IGF2BP2 with CWI1-2 suppressed endocytosis and impeded tumor growth in both cell lines and patient-derived xenograft models. Collectively, our findings highlight IGF2BP2 as a clinically relevant oncogenic driver in PTCL that integrates tumor-intrinsic growth signals with immune evasion through endocytosis-centered regulation, providing a novel therapeutic rationale for RNA modification-based strategies that concurrently target tumor cells and the tumor microenvironment.

Humans↗

PubMed2026

Microsatellite instability in penile cancer: comparative analysis of primary tumors and metastases.

BACKGROUND: Penile cancer (PeCA) presents high morbidity and mortality and is more prevalent in underdeveloped countries. The presence of nodal metastasis at diagnosis or as early recurrence carries a worse prognosis, making it important to determine whether clinically relevant biomarkers are maintained between primary tumors and corresponding lymph node metastases. We aim to describe the presence of DNA microsatellite instability (MSI) in primary PeCA tumors and locoregional lymph nodes affected by metastatic cells, as well as to assess HPV status through p16 expression. METHODS: A total of 116 patients were comparatively evaluated between the primary tumor and lymph node metastases. The evaluation of p16 and mismatch repair proteins was done by immunohistochemistry, and MSI status was assessed using a hexa-plex marker by polymerase chain reaction, followed by fragment analysis. RESULTS: All patients underwent a standard lymphadenectomy (inguinal or pelvic), with a pN0 frequency of 33.6%. MSI-H was found in three patients (2.6%), with correspondence between the presence of the biomarker in the primary tumors and the lymph node metastases. A second validation was performed using IHC for MMR, with MLH1/PMS2 loss in MSI-H cases. 22.8% of patients expressed p16 by immunohistochemistry. p16 positivity was associated with a 55% reduction in the risk of death. All MSI-H patients were p16 positive. CONCLUSION: MSI-H occurs in 2,6% of the sample and is associated predominantly with MLH1/PMS2 loss and p16 positivity. Together, these findings suggest potential interactions between HPV- associated carcinogenesis and genomic instability. Further prospective, biomarker-driven trials are warranted to define their prognostic and therapeutic relevance in PeCA.

HPV↗

PubMed1977

Immunochemotherapy of malignant melanoma with chlorambucil-bound antimelanoma globulins: preliminary results in patients with disseminated disease.

Thirteen consecutive patients with inoperable recurrent malignant melanoma were treated by immunochemotherapy with the use of chlorambucil noncovalently bound to goat or rabbit antihuman melanoma globulins. The next consecutive 11 patients fulfilling the criteria for admission into this study were treated with chemotherapy only, i.e., dimethyltriazenoimidazole carboxamide (DTIC). Follow-up was for a minimum of 29 months or until death. Two patients showing an objective response to immunochemotherapy had disease confined to lymph nodes and cutaneous sites; 5 others showed stabilization of cutaneous, nodal, and visceral disease, and 6 patients showed progression of their disease. The median survival of the responders and stabilizers was 20 months, but only 3.5 months for patients with disease progression. None of the 11 patients treated with DTIC had objective tumor regression, and all died within 11 months of the start of treatment with a median survival of 3 months. Immunochemotherapy significantly prolonged the survival compared to that in the DTIC-treated group (P less than 0.05). No hematologic or renal toxicity was detected after immunochemotherapy, but 2 patients in this group developed anaphylactic reactions. Skin reactivity tests to dinitrochlorobenzene and purified protein derivative were of no prognostic value

Adolescent↗

PubMed1977

Some effects on leukaemic B lymphocytes of antibodies to defined regions of their surface immunoglobulin.

During the growth of the L2C leukaemia in strain 2 guinea-pigs there is excreted in the urine a monoclonal light chain of lambda class. This is believed to arise from synthesis by the leukaemic cells of a small molar excess of the light chains incorporated into their surface IgM. Antibodies to this light chain have been raised in rabbits and separated by immunosorption into those directed against idiotypic determinants (anti-Id), and those against determinants also present on other lambda chains (anti-lambda). Both antibodies react with L2C cells via the surface immunoglobulin. In accord with prediction anti-Id is specific for L2C cells while anti-lambda also reacts with 7 per cent of normal nodal lymphocytes. L2C cells are agglutinated strongly by anti-Id, weakly by anti-lambda. Both antisera inhibit migration of the cells, and both can kill them by invoking complement or K-cell cytotoxic mechanisms. The results emphasize the potential of anti-idiotype sera for identifying and specifically attacking neoplastic B lymphocytes.

Animals↗