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PubMed2004

Ultra-high-frequency acoustic stimulation and tinnitus control: a positron emission tomography study.

Ultra-high-frequency (UHF) external acoustic stimulation with the UltraQuiet device (UQ) has been reported to provide significant relief of severe disabling-type tinnitus. The nuclear medicine imaging technique of positron emission tomography (PET) was selected as a monitoring system to compare objectively metabolic alterations in brain function before and after UHF/UQ and to correlate the PET data with the subjective behavioral response of patients reporting tinnitus relief. PET of brain was completed on 6 patients randomly selected from a cohort of 15 patients included in a protocol to establish long-term tinnitus relief with UHF/UQ. Twelve specific regions of interest (ROI) were selected for PET of brain examination on the basis of results obtained with single-photon emission computed tomography (SPECT) of brain examinations recommended for patients with severe disabling-type tinnitus and demonstrating significant perfusion asymmetries in the right and left brain ROI of the primary auditory cortex; frontal, temporal, parietal, and medial temporal lobes; and cerebellum. PET of brain results included ratios of post- and pre-UHF/UQ stimulation that demonstrated no random response in the selected PET of brain ROI and ratios of post- and pre-UHF/UQ stimulation that demonstrated three categories of response in the selected PET brain ROI for all six patients: hypermetabolism in three patients; hypometabolism in two; and a mixed response in one. Correlation was established for each patient among PET and electrophysiological responses of alteration in minimal masking levels, the residual UHF neuronal response as reflected in the UHF audiogram, and the subjective reported behavioral responses of patients (obtained from outcome questionnaires for tinnitus relief, which focused on tinnitus intensity, annoyance, severity index, and a subjective scale of value of the UHF/UQ device for tinnitus relief. The subjective behavioral response for tinnitus relief with UHF/UQ was found to reflect a dual effect: acoustic stimulation of the residual neuronal function in the UHF range (10-14 kHz) and audiometric thresholds of 40-50 dB sound pressure level (SPL), and the metabolic activity at brain cortex for neuronal reprogramming. The PET of brain categories of response suggested that the UHF/UQ "masking" is predominantly reflective of neuronal reprogramming at the brain cortex. Nuclear medicine PET of brain imaging has provided an objective monitoring system for attempting to establish the efficacy of UHF/UQ for tinnitus relief. No complication of the tinnitus was reported secondary to the PET of brain examination. This limited PET of brain study supports the clinical recommendation of the efficacy of UHF/UQ external acoustic stimulation for a selected population of patients with tinnitus of the severe disabling type.

Acoustic Stimulation↗
PubMed2005

Animal cloning: problems and prospects.

An efficient animal cloning technology would provide many new opportunities for livestock agriculture, human medicine, and animal conservation. Nuclear cloning involves the production of animals that are genetically identical to the donor cells used in a technique known as nuclear transfer (NT). However, at present it is an inefficient process: in cattle, only around 6% of the embryos transferred to the reproductive tracts of recipient cows result in healthy, longterm surviving clones. Of concern are the high losses throughout gestation, during birth and in the post-natal period through to adulthood. Many of the pregnancy losses relate to failure of the placenta to develop and function correctly. Placental dysfunction may also have an adverse influence on postnatal health. These anomalies are probably due to incorrect epigenetic reprogramming of the donor genome following NT, leading to inappropriate patterns of gene expression during the development of clones. Whilst some physiological tests on surviving clones suggest normality, other reports indicate a variety of post-natal clone-associated abnormalities. This variability in outcome may reflect species-specific and/or cloning methodological differences. Importantly, to date it appears that these clone-associated phenotypes are not transmitted to offspring following sexual reproduction. This indicates that they represent epigenetic errors, rather than genetic errors, which are corrected during gametogenesis. Whilst this needs confirmation at the molecular level, it provides initial confidence in the first application of NT in agriculture, namely, the production of small numbers of cloned sires from genetically elite bulls, for natural mating, to effectively disseminate genetic gain. In addition to the animal welfare concerns with the technology, the underlying health of the animals and the consequential effect on food safety are critical aspects that require investigation to gain regulatory and consumer acceptance. Future improvements in animal cloning will largely arise from a greater understanding of the molecular mechanisms of reprogramming.

Animal Welfare↗
PubMed1991

[Hazards of radiotherapy in the presence of a cardiac pacemaker].

A patient with cardiac pacing operated for cancer of the breast received subsequent radiotherapy, first with a linear accelerator, then with a betatron. The pacemaker was found deprogrammed as a sequel to irradiation although care was taken to keep it outside the irradiation field. After reprogramming the pacemaker changed a second time spontaneously the given parameters indicating permanent damage by the irradiation. In such cases the exchange of the pacemaker is recommended. Precautionary measures ranging from surveillance to possibilities for reprogramming and even reanimation or pacemaker replacement should be assured prior to irradiation of patients with cardiac pacing.

Breast Neoplasms↗
PubMed1990

Nuclear protein modifications in vitellogenic rooster liver.

The estrogenic regulation of vitellogenesis in chicken liver provides an unique perspective on cellular reprogramming because males can be induced experimentally. Transient exposure to estradiol (ES) completely alters established patterns of gene expression in rooster hepatocytes within 6 hrs., and triggers major structural and compositional changes in cell nuclei by 24 hrs. Concurrently, the total protein content of nuclei increases nearly 50% and the relative proportion of protein within the nucleoplasmic, chromatin and residual compartments, shifts markedly. These bulk quantitative changes in nuclear composition are accompanied by marked alterations in 2-D electrophoretic patterns of cytoplasmic, nuclear and nuclear matrix polypeptides. Although most individual proteins remain unidentified, several components clearly overlap both the cytoplasmic and nuclear compartments. Reciprocal changes in the 2-D patterns are also evident after ES stimulation, with progressive decline in some and relative increase in other proteins. Among known species, the lamins (La and Lb) decrease in prominence after hormone, while RNP-associated polypeptides become increasingly pronounced in the residual matrix fraction. The results are discussed in relation to other systems where large-scale nuclear reprogramming is known to occur.

Animals↗
PubMed1990

Cardiac pacemaker inhibition by transcutaneous electrical nerve stimulation.

The use of transcutaneous electrical nerve stimulation (TENS) has increased in recent years for the management of chronic pain. One of its few contraindications is the presence of a cardiac pacemaker. Clinicians have recommended that cardiac monitoring be performed for a short interrupted period during the first application of TENS to ensure safety. We present two patients who were given trials of TENS for different chronic pain complaints. In both cases, electrocardiograms during the TENS trial did not reveal cardiac pacemaker dysfunction, but extended cardiac monitoring with the Holter monitor showed interference with pacemaker function. The abnormalities did not recur after reprogramming the sensitivity of the pacemakers. We suggest the use of extended cardiac monitoring for patients with cardiac pacemakers during the prolonged use of TENS to ensure safety and to determine any need for reprogramming of the pacemakers. Patients with cardiac pacemakers should not be excluded from the use of TENS, but careful evaluation and extended cardiac monitoring should be performed.

Aged↗
PubMed1985

[Reevaluation of pacemaker-induced reentry tachycardias: incidence, mechanisms and therapy].

To reassess incidence, mechanisms and therapeutic possibilities in the treatment of pacemaker-induced reentry tachycardias (RT) in patients with the second generation of DDD-pacemakers, 35 consecutive patients were studied prospectively by measuring VA conduction at implant and searching for RT clinically and by repeat 24-hour ECG monitoring. Reprogramming to the VVI mode because of atrial flutter and to the AAI mode because of lead displacement was necessary in 2 and 1 of the patients respectively. RT were detected in 7/32 patients (22%), 4 of whom were symptomatic. The triggering mechanism of RT was premature ventricular contraction in 4 patients, premature atrial contractions in 1, loss of atrial sensing in 1, and remained unclear in 1. Unlike the 30% of patients of an earlier consecutive series with first generation of physiologic PM who had RT and required permanent reprogramming to VVI stimulation in 10% of cases, RT was abolished in all patients maintaining physiologic pacing by prolonging the atrial refractory period, shortening the av delay, adjusting atrial output or atrial sensing, or by antiarrhythmic therapy.

Aged↗
PubMed1979

Long-term atrial pacing for sinus node disease with output-terminal programmagle pacemakers.

Long-term transvenous atrial pacing for symptomatic sinus node disease, in the absence of atrioventricular conduction disease, confers the advantages of increased cardiac performance and probable freedom from systemic thromboembolism. Conventional ventricular pacing has been preferred, however, because of the complications of atrial pacing, mainly those of electrical and mechanical instability of currently available atrial electrodes. These complications have been circumvented with a new pacemaker, programmable for output terminal. This has allowed the institution of atrial pacing in seven patients, with its attendant advantages and the ability to reprogram noninvasively to ventricular pacing should atrial pacing fail. Such reprogramming has been accomplished without difficulty in one patient who developed second-degree atrioventricular block and one with electrode microdisplacement.

Aged↗
PubMed1984

The biological significance of meiosis.

Four possible biological functions of meiosis are considered. First, the conventional view that it generates by recombination and sexual reproduction the genetic diversity on which natural selection can act. Second, that recombination at meiosis plays an important role in the repair of genetic defects in germ line cells. Third, that it is essential, at least in animals, for the reprogramming of gametes which give rise to the fertilized egg. Fourth, that it helps maintain the immortality of the germ line, possible by a process of rejuvenation involving the removal of faulty RNA and protein molecules, or by the elimination of defective meiocytes. A unified hypothesis is proposed which attempts to link these diverse functions. Evidence is now available which strongly indicates that the control of gene activity in higher organisms depends in part on the pattern of cytosine methylation in DNA, and that this pattern is inherited through the activity of a maintenance methylase. Epigenetic defects may arise by the loss of methyl groups which the methylase is unable to replace in somatic and also germ line cells, if de novo methylation cannot occur. There is also evidence that recombination at meiosis is largely confined to structural genes or adjacent DNA. It is proposed that the absence of a functionally important methyl group in a promotor or operater region produces a recombinator or signal for the initiation of recombination. The formation of hybrid DNA in this region then allows the lost methyl groups to be replaced by maintenance methylase activity. The removal of epigenetic defects by recombination during meiosis therefore becomes an essential part of a reprogramming and rejuvenation process. Assuming some epigenetic defects are nevertheless transmitted to the next generation, sexual reproduction and outbreeding would be advantageous because they provide the opportunity for their removal at the next meiosis. Inbreeding would be disadvantageous, because it increases the probability that epigenetic defects would become homozygous and could no longer be removed by recombination.

5-Methylcytosine↗
PubMed1983

[Re-entry tachycardias: a fragment problem during physiologic heart stimulation].

In a prospective study, reentry tachycardias (RT) due to retrograde VA-conduction were sought in 30 patients after implantation of an atrial synchronous (VDD, DDD) pacemaker (PM) by frequent clinical controls and by 24-hour Holter monitoring. At least one RT was detected in 9/30 patients (in 5 during clinical control, in 4 on Holter monitoring only). 6 patients had symptoms due to RT (6 had palpitations, 1 complained of dizziness and 1 of ischemic heart pain). RTs were initiated by VPBs in 6 patients, by sinus bradycardia in 2 (VDD) and by magnet application in 1. Rates of RT varied from 100 bpm to 128 bpm. RT necessitated reprogramming of the PM in 5 patients (in 3 of them reprogramming to VVI-stimulation). RTs are thus a frequent complication after implantation of an atrial synchronous pacemaker.

Adult↗
PubMed1994

Activation of hepatic proliferation-associated transcription factors by lipopolysaccharide.

BACKGROUND: The hepatic acute-phase response is the result of reprogramming of gene expression in the liver. Similar acute-phase responses occur in regenerating liver after partial hepatectomy and are preceded by increases in the expression of a set of transcriptional regulatory proteins that are encoded by "immediate-early" genes. The purpose of this study was to determine whether acute systemic inflammation after lipopolysaccharide injection induces hepatic immediate-early genes that are induced by partial hepatectomy. METHODS: Two- to 4-month-old Balb/c mice received intraperitoneal Escherichia coli lipopolysaccharide (0111:B4; 100 micrograms), and total liver RNA, nuclear protein extracts, or total liver protein lysates were obtained at 0, 1, 3, 12, and 24 hours. RNA blot hybridization analysis was used to determine steady-state messenger RNA levels for c-jun, jun-B, jun-D, c-fos, fos-B, fra-1, nup475, and zif268. Specific nuclear protein-binding activity was determined by gel mobility shift assay. The protein c-Jun was detected by antibody-blocking experiments, and Jun-B was detected by gel supershift assay of the activating protein (AP-1) complex. Steady-state Jun-B levels were determined by immunoblot analysis. RESULTS: Intraperitoneal injection of lipopolysaccharide is followed by induction (from fivefold to 13-fold) of c-jun, jun-B, c-fos, zif268, and nup475 messenger RNAs in the liver. Lipopolysaccharide induced increases in AP-1 and Zif268 consensus DNA-binding activity in mouse liver. The proteins c-Jun and Jun-B are detected in the AP-1 complex after administration of lipopolysaccharide. CONCLUSIONS: The induction of hepatic immediate-early genes after lipopolysaccharide is similar to that that follows partial hepatectomy. These transcription factors likely have important roles in the reprogramming of gene expression that leads to the acute-phase response.

Animals↗
PubMed1993

Models of neoplasia and their diagnostic implications: a historical perspective.

In comparison with normal cells, cancer cells have an enhanced ability to trap both nitrogen and energy; an enhanced operation of the glycolytic and direct oxidative pathways, leading to accumulation of lactate and increased production of NADPH; and a greater content of lysosomal hydrolases. These changes represent a reprogramming of gene expression, which, at its most specific, is accompanied by the reappearance in the cell and ultimately in the body fluids of oncodevelopmental proteins not normally found in mature adult tissues. The most florid stage of this reprogramming leads to the metastatic phenotype, which confers upon the cancer cell the ability to stimulate angiogenesis, invade the bloodstream and lymphatic vessel, and arrest and proliferate in distant tissues. The diagnostic implications of these phenotypic changes are illustrated for cancer of the cervix uteri and cancer of the colon. We also review the classical theories of neoplasia, including the cellular anoxia concept of Warburg, the deletion hypothesis of Potter, and various other mechanisms emphasizing genomic derepression and impaired immunity. The critical steps in chemical carcinogenesis are described, and the Vogelstein-Lane model is presented, emphasizing the stepwise and cumulative genomic changes affecting chromosomes 5q, 17p, 18q, and gene amplification of chromosome 12 as well as genomic instability resulting from reduced DNA methylation. The main consequences of these genomic alterations include overexpression or activation of oncogenes such as c-myc and k-ras, together with mutation or functional inactivation of suppressor genes such as p53. Finally, the implications of these findings for diagnosis and management are illustrated by reference to recent investigations in cancers of the breast, colon, and bladder, in which these genomic alterations can be detected by examination of appropriate cellular material and by detection in serum of antibodies to the p53 gene product.

History, 20th Century↗
PubMed1996

[Implantable cardioverter-defibrillators in patients resuscitated from sudden death and in patients with sustained refractory ventricular tachycardia].

OBJECTIVE: The aim of this study was to evaluate the results of our experience with implantable cardioverter-defibrillator therapy. PATIENT SELECTION: We treated with implantable cardioverter-defibrillator (ICD) 18 patients, 15 male and 3 female, mean age 51 years, ranging from 12 to 76 years, with life threatening ventricular arrhythmias. Eleven patients were resuscitated from cardiac arrest and seven had refractory ventricular tachycardia. The underlying condition was coronary artery disease in 12 patients, dilated cardiomyopathy in two, congenital long QT syndrome in one, mitral regurgitation in one and idiopathic in two patients. METHODS: All patients underwent cardiac catheterization and electrophysiological study before ICD implantation. In the first patient epicardial leads were used, but a transvenous approach was used in the remaining 17 patients. The device was implanted in an abdominal position in all patients. Defibrillation and pacing threshold tests were performed during the implantation procedure and whenever necessary. After implantation, patients were followed up in an outpatient basis, with evaluation of therapy efficacy and reprogramming of the device if required. The mean follow-up time was 16 months, ranging from 1 to 40 months. RESULTS: The implantation was successful and without complications in all patients. Defibrillation threshold was considered within normal range, with an electrode impedance ranging from 40 to 65 Ohms. During the follow-up period no deaths occurred, 8 patients (44%) had episodes of VT or VF that were successfully treated, with shock in six patients, with antitachycardia pacing in one and with both modalities in another patient. Inappropriate shocks were observed in three patients (16%). The device was reprogrammed in five patients. CONCLUSIONS: Our experience with implantable ICD in patients who survived cardiac arrest or with refractory VT has shown a low surgical risk with no mortality. The incidence of ICD discharges was high, with a satisfactory efficacy rate and the number of inappropriate shocks was acceptable. The careful patient selection made possible a good cost/benefit relation.

Adolescent↗
PubMed1995

[Electrophoretic analysis of the protein patterns of the nuclear transplant rabbit embryos].

The qualitative patterns of protein synthesis in nuclear transplant rabbit embryos were examined by SDS-polyacrylamide gel electrophoresis followed by silver staining. The results indicated that the qualitative pattern of several protein synthesis in NT embryos was very different from the protein pattern of donor morulae or recipient oocytes, and also not as the same as the protein pattern obtained from fertilized ova at pronuclear formation stage. After fertilization or nuclear transfer, several maternal proteins were no longer synthesized or decreased in the embryo, and some new bands were observed and several protein synthesis were increased obviously. The most intriguing aspect of this study was the observation that all major changes in the protein pattern took place after fertilization or nuclear transfer and were rather similar. It is suggested that the gene activities of the donor nucleus from rabbit morulae are reprogrammed by the oocyte cytoplasm in current nuclear transfer technology, but the reprogramming is incomplete. This paper stresses on the paternal effect during fertilization on gene expression in nuclear transplant rabbit embryos.

Animals↗
PubMed1997

[The implantable cardioverter-defibrillator: the Portuguese experience].

OBJECTIVE: The aim of this study was to review the Portuguese experience with implantable cardioverter-defibrillator therapy (ICD), in order to evaluate the increase in the number of ICD implanted, the main indications for this kind of therapy, the technical evolution of the procedure and the results of the follow-up of these patients during the last five years. PATIENT SELECTION: The study group consists of 58 patients, 53 male and 5 female, mean age 54 +/- 14 years with ICD implanted in our country since 1992. The ICDs were implanted in 4 Hospitals, namely, Santa Cruz Hospital with 36 patients, Santa Maria Hospital with 11, Santa Marta Hospital with 8 and Coimbra University Hospital with 3 patients. Twenty six patients were resuscitated from cardiac arrest and the other 32 had ventricular tachycardia (VT) not tolerated haemodynamically and refractory to therapy. The diagnosis was coronary artery disease in 31 patients, dilated cardiomyopathy in 8, valvular disease in 4, congenital cardiopathy in 3, right ventricular dysplasia in 2, congenital long QT syndrome in 1, hypertrophic cardiomyopathy in one. Seven patients had idiopathic ventricular fibrillation without structural heart disease and one patient had isolated right ventricular dilatation. METHODS: All patients underwent electrophysiological study before ICD implantation. In 2 patients epicardial leads were used and in the remaining 56 patients a transvenous approach was used. The device was implanted in an abdominal position in 36 patients and in a pectoral position in 22. Defibrillation and pacing thresholds were measured during the implantation procedure and whenever necessary. Patients were followed up on an outpatient basis with evaluation of the number of arrhythmic episodes, therapy efficacy with reprogramming of the device when required. RESULTS: The number of implantations has increased, from 4 devices implanted in 1992, to 32 in 1996. The implantation was successful and without mortality or complications in all patients. Defibrillation threshold was 16 +/- 3 J, with an electrode impedance of 48 +/- 9 Ohms. During a mean follow-up time of 18 +/- 15 months (1 to 56) 5 patients died, one of sudden death and 4 of non cardiac deaths, 15 patients were re-admitted to hospital and in 8 patients the device was replaced due to exhaustion. In this period, 37 patients (64%) had arrhythmic episodes detected by the device, 32 patients (55%) had shocks and 9 (16%) were treated with anti-tachycardia pacing. Inappropriate shocks were observed in 10 patients (17%). The ICD were reprogrammed in 11 patients. CONCLUSIONS: Portuguese experience with IC implantation is increasing and has shown to be a safe procedure with no operative mortality or morbidity. The incidence of appropriate shocks was high with a good efficacy in sudden death reduction.

Adult↗
PubMed2026

Multi-Omics Integration Identifies a Five-Gene Metabolic Signature With Experimental Validation in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is hallmarked by profound metabolic reprogramming; however, its intricate crosstalk with the tumor immune microenvironment (TIME) and its clinical ramifications remain inadequately elucidated. This study aims to systematically decipher the metabolic-immune interplay in ccRCC through multi-omics integration, with the goal of identifying robust prognostic biomarkers and actionable therapeutic vulnerabilities. AIMS: This study aims to systematically decipher the metabolic-immune interplay in clear cell renal cell carcinoma (ccRCC) through multi‑omics integration, and to identify robust prognostic biomarkers and actionable therapeutic vulnerabilities that can inform precision risk stratification and individualized treatment strategies. METHODS: We integrated bulk transcriptomic, genomic, and clinical data from multiple ccRCC cohorts. Differential expression and functional enrichment analyses were performed to characterize metabolic pathway alterations. Mendelian randomization (MR) was employed to infer causal relationships between metabolic disorders and ccRCC risk. A machine learning-based prognostic framework, incorporating SHAP (SHapley Additive exPlanations) for feature interpretability, was constructed and rigorously validated. TIME heterogeneity was dissected using deconvolution algorithms, while drug sensitivity, tumor mutation burden (TMB), and TIDE scores were utilized to assess therapeutic responses and immune evasion. Candidate gene function was evaluated through in vitro gain- and loss-of-function assays, with expression validated via TCGA, HPA, western blot, and qRT-PCR. RESULTS: Enrichment analysis identified coordinated dysregulation in lipid metabolism, energy homeostasis, and hypoxia response pathways. MR analysis confirmed lipid metabolism disorders as a causal risk factor for ccRCC. Our machine-learning model, centered on five core SHAP-identified features (SUCLA2, ACAT1, PC, SUCLG1, and HMGCS2), demonstrated superior predictive accuracy over conventional clinical staging. Immune profiling unveiled dichotomous TIME states: the low-risk group retained active immune surveillance, whereas the high-risk group was enriched with immunosuppressive subsets. Drug sensitivity screening pinpointed LY2109761 and carmustine as high-risk-specific candidate agents. Furthermore, TMB and TIDE analyses stratified high-risk patients displaying genomic instability and immune evasion phenotypes. Functionally, SUCLA2 knockdown significantly enhanced ccRCC cell proliferation and invasion, while its overexpression suppressed these malignant phenotypes, corroborating its tumor-suppressive role. Expression patterns of the hub genes were consistently validated across multi-level datasets and experimental assays. CONCLUSION: This study establishes a precision oncology framework for ccRCC by functionally linking metabolic biomarkers, immunophenotypes, and stratified therapeutic strategies. Importantly, we identify SUCLA2 as a potential functional tumor suppressor and a promising target for further mechanistic and translational investigation.

Humans↗
PubMed2027

Generation of Transgene-Free Naive Human Induced Pluripotent Stem Cells from Somatic Cells Using a Modified Temperature-Sensitive Sendai Virus System.

The Sendai virus (SeV) vector system offers an efficient, nonintegrating approach to reprogram somatic cells into either naive or primed human induced pluripotent stem cells (iPSCs). Here, we describe a protocol to generate transgene-free naive iPSCs from human dermal fibroblasts (HDFs) and peripheral blood mononuclear cells (PBMCs) using a modified, temperature-sensitive SeV system. The method leverages LMYC in place of cMYC and an optional H1FOO-DD factor to enhance efficiency and uniformity, and employs a controlled temperature shift to facilitate vector clearance.

Humans↗
PubMed2025

Integrative multi-omics analysis proposes a metabolic classification of gliomas: distinct metabolic states, immune infiltration, and prognosis.

BACKGROUND: The tumor microenvironment (TME) of glioma harbors diverse cell types; however, cell metabolic heterogeneity remains to be explored. This study aims to characterize the metabolic features of different cell types in the TME by integrating multiple datasets, including genomics, bulk and single-cell transcriptomics, and metabolomics. METHODS: Unsupervised machine learning was used to construct an energy metabolic classifier based on the metabolic pathways identified from bulk RNA-seq of gliomas in the TCGA dataset. The classifier was externally validated using multiple datasets, including genomics, bulk RNA-seq, snRNA-seq, and the metabolomics data. Furthermore, metabolic heterogeneity associated with the classifier was further characterized at single-cell resolution. RESULTS: The energy metabolism-based classifier stratified patients into two prognostic clusters: patients in cluster 1 were characterized by high pathway activity of glycolysis, the pentose phosphate pathway (PPP), and fatty acid oxidation (FAO), whereas patients in cluster 2 exhibited higher activity in glutaminolysis. This metabolic classifier revealed both intratumoral and intertumoral metabolic heterogeneity, and the complexity was further validated by the metabolomics profiling and snRNA-seq data from the CPTAC dataset. Notably, OSMR, highly expressed in cluster 1, showed significant co-expression with key glycolytic enzyme genes. The OSM/OSMR/JAK1/STAT3 axis potently drives malignant progression of glioma cells, specially enhancing their invasive and migratory capabilities. Single-cell resolution analyses demonstrated that tumor metabolic heterogeneity is primarily driven by malignant cells rather than non-malignant components, while tumor microenvironment (TME) factors were also found to modulate malignant cell metabolism. Significantly, glycolytic activity in glioma cells increased during the phenotypic transition from PN (proneural) to MES (mesenchymal), with cluster 1 metabolic phenotypes predominating in the tumor core. Compared to cluster 2, cluster 1 patients exhibited higher mRNA expression of immunosuppressive checkpoint genes, which correlated with pronounced immunosuppression in the TME. Furthermore, various immune cells demonstrated distinct metabolic preferences at single-cell resolution. CONCLUSIONS: This study developed an energy metabolic-based classifier for gliomas with prognostic and therapeutic potential. Metabolic reprogramming was linked with the PN-to-MES transition of glioma cells and immunosuppression in the tumor microenvironment. Multi-omics data, especially snRNA-seq, offered insights into metabolism heterogeneity at single-cell resolution, enabling personalized treatment strategies.

Humans↗
PubMed2026

Integrated single-cell and spatial transcriptomic analyses reveal malignant epithelial glycolytic heterogeneity and spatial niche remodeling during colorectal cancer progression.

Colorectal cancer (CRC) progression is shaped by metabolic reprogramming and complex interactions within the tumor microenvironment. However, the cellular heterogeneity, spatial organization, and clinical relevance of glycolytic activity in CRC remain incompletely understood. In this study, we integrated single-cell RNA sequencing, bulk transcriptomics, and spatial transcriptomics data to systematically characterize glycolytic heterogeneity in CRC. Glycolytic activity was quantified using five independent scoring methods, consistently showing that epithelial cells exhibited the highest glycolytic activity across the two single-cell cohorts. Stratification of CopyKAT-verified aneuploid malignant epithelial cells into high-glycolysis (HG) and low-glycolysis (LG) subgroups by glycolysis scores revealed that HG cells exhibited higher stemness scores and chromosomal copy number variations. Cell-cell communication analysis revealed that, compared with LG cells, HG cells exhibited increased interaction frequency and strength with immune and stromal populations, indicating enhanced malignant epithelial-microenvironment crosstalk. Spatial transcriptomics analyses further revealed that glycolytic activity varied across normal colorectal tissue, primary CRC, and colorectal liver metastases, accompanied by progressive remodeling of epithelial-associated spatial niches and MIF-mediated intercellular communication. Bulk transcriptomic analysis identified a glycolysis-related prognostic signature with robust predictive performance, which served as an independent prognostic factor for overall survival in CRC cohorts. Collectively, these findings indicate that glycolytic heterogeneity is a key feature of CRC malignant epithelial cells and is closely associated with tumor progression, microenvironmental remodeling, and clinical outcomes.

Humans↗