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PubMed2000

Altered E-C coupling in rat ventricular myocytes from failing hearts 6 wk after MI.

Excitation-contraction (E-C) coupling was investigated in rat hearts 6 wk after induction of myocardial infarction (MI) by ligation of the left coronary artery. Heart weight was increased by 74% and left ventricular end-diastolic pressure was 23 +/- 2 mmHg in MI compared with 8 +/- 2 mmHg in sham-operated controls (Sham, P < 0.001). Cell shortening was measured in voltage-clamped myocytes at 36 degrees C. In solutions where Cs(+) had been replaced by K(+), the voltage dependence of contraction was sigmoidal between -20 and +100 mV in Sham and MI cells. Verapamil (20 microM) blocked L-type Ca(2+) current and reduced contraction in Sham cells by approximately 50% (P < 0.01) but did not decrease contraction significantly in MI cells at test potentials above +10 mV. Verapamil-insensitive contractions were blocked by Ni(2+) (5 mM). Na(+)/Ca(2+) exchange current was doubled in MI compared with Sham cells at test potentials between -20 and +80 mV (P < 0.05), whereas mRNA and protein expression increased by 30-40%. Finally, voltage dependence of contraction was bell shaped in Na(+)-free solutions, but contraction was significantly increased in MI cells over a wider voltage range (P < 0.05). The insensitivity to Ca(2+) channel block in MI cells may result from an increased contribution of the Na(+)/Ca(+) exchanger to triggering of E-C coupling. These results suggest significant changes in E-C coupling in the hypertrophy and failure that develop in response to extensive MI.

Animals↗
PubMed2001

Time course of collagen and decorin changes in rat cardiac and skeletal muscle post-MI.

We examined the temporal relationship between messages (type I and type III mRNAs) for the principal fibrillar procollagens and subsequent collagen accretion, cross-linking, and decorin expression in the left ventricle (LV) postmyocardial infarction (post-MI). We sought to determine 1) what role the proteoglycan decorin plays in extracellular matrix (ECM) remodeling known to take place as a consequence of MI and 2) the extent skeletal muscle ECM is altered early post-MI. Therefore, after surgically induced production of small- to moderate-sized infarcts (approximately 20% of LV mass), extent and time course of ECM remodeling was evaluated in remaining viable LV free wall and in slow- [soleus (SOL)] and fast-twitch [gastrocnemius (GAST)] skeletal muscles. Decorin, collagen, and hydroxylysylpyridinium cross-link concentrations and alpha1(I) (type I) and alpha1(III) (type III) procollagen mRNAs were measured in LVs from noninfarcted controls and at 72 h, 1, 2, 5, and 13 wk post-MI. These same data were collected in SOL and GAST muscles at all time points except 13 wk. Type I procollagen mRNA increased at both 72-h and 1-wk time points in LVs. Type III procollagen mRNA was elevated at 1 wk, returning to baseline by 2 wk post-MI. Collagen concentration was significantly increased by 1 wk, more than doubled by 5 wk, and was elevated 129% by 13 wk in the remaining viable LV. LV decorin expression was unaltered at early time points, but increased 38% at 5 wk post-MI and doubled by 13 wk post-MI. In skeletal muscle, procollagen mRNAs were transiently altered in SOL and GAST muscles without any demonstrable effect on the measured ECM parameters. This study reports, for the first time, the upregulation time course of decorin and its relationship to increased HP cross-linking and accumulation of collagen in viable myocardium post-MI.

Animals↗
PubMed2001

Inhibitory effect on natural killer activity of microphthalmia transcription factor encoded by the mutant mi allele of mice.

The mouse mi locus encodes a basic-helix-loop-helix-leucine zipper-type transcription factor, microphthalmia transcription factor (MITF). Mice of mi/mi genotype express a mutant form of MITF (mi-MITF), whereas mice of tg/tg genotype have a transgene in the 5' flanking region of the mi gene and do not express MITF. Although the mi/mi mouse is deficient in natural killer (NK) activity, it was found that the tg/tg mouse was normal in this respect. To know the cause, spleen cells of both genotypes were compared. Although the proportion of spleen cells expressing an NK cell marker, NK1.1, was comparable in both mice, the proportion of large granular lymphocytes decreased only in mi/mi mice. The difference between mi/mi and tg/tg mice was reproducible in the culture supplemented with interleukin-2. Moreover, the perforin gene expression was reduced in mi/mi-cultured spleen cells. Wild-type (+) MITF transactivated, but mi-MITF suppressed, the perforin gene promoter through the NF-P motif, a strong cis-acting element. However, neither +-MITF nor mi-MITF bound the NF-P motif. Instead, 2 nuclear factors that bound the NF-P motif were retained in the cytoplasm of mi/mi-cultured spleen cells. In addition, overexpression of mi-MITF resulted in cytoplasmic retention of the 2 NF-P motif-binding factors in cytotoxic T lymphocytes. The presence of mi-MITF rather than the absence of +-MITF appeared to lead to poor transactivation of the NF-P motif by intercepting NF-P motif-binding factors. This inhibitory effect of mi-MITF may cause the deficient cytotoxicity of NK cells in mi/mi mice. (Blood. 2001;97:2075-2083)

Alleles↗
PubMed1995

Analysis of the Mi-2 autoantigen of dermatomyositis.

OBJECTIVE: To determine the biochemical structure and antigenic components of Mi-2 autoantigen, the target of autoantibodies in 15-20% of dermatomyositis patients. METHODS: Immunoprecipitation from 35S-labeled HeLa cell extract, immunoblotting, and purification from bovine thymus by immunoaffinity chromatography. RESULTS: All 46 sera that had anti-Mi-2 autoantibodies demonstrated by immunodiffusion immunoprecipitated a major protein of approximately 240 kd. Additional proteins of 200, 150, 72, 65, 63, 50, and 34 kd appeared to be part of the antigen. Fractions of purified bovine Mi-2 with antigenic activity showed high molecular weight bands comparable with immunoprecipitated HeLa Mi-2. Twenty-four of 47 anti-Mi-2 positive sera reacted with the 240-kd protein by immunoblot against anti-Mi-2 immunoprecipitates. CONCLUSION: Mi-2 antigen consists of multiple proteins, of which the 240-kd protein appears to be the major reactive component.

Adenosine Triphosphatases↗
PubMed2005

Microspherule protein 1, Mi-2beta, and RET finger protein associate in the nucleolus and up-regulate ribosomal gene transcription.

The nucleolus is the site of ribosomal DNA (rDNA) transcription and ribosome production. In exploring the role of nucleolar protein MCRS1 (microspherule protein1)/MSP58 (58-kDa microspherule protein), we found that Mi-2beta, a component of a nucleosome remodeling and deacetylase (NuRD) complex, RET finger protein (RFP), and upstream binding factor (UBF) were associated with MCRS1. Yeast two-hybrid assays revealed that MCRS1 bound to the ATPase/helicase region of Mi-2beta and the coiled-coil region of RFP. Interestingly, confocal microscopic analyses revealed the co-localization of MCRS1, Mi-2beta, RFP, and the rRNA transcription factor UBF in the nucleoli. We also found that MCRS1, Mi-2beta, and RFP were associated with rDNA using a chromatin immunoprecipitation assay. Finally, we showed that MCRS1, Mi-2beta, and RFP up-regulated transcriptional activity of the rDNA promoter and that ribosomal RNA transcription was repressed when MCRS1, Mi-2beta, and RFP expression was reduced using siRNA. These results indicated that Mi-2beta and RFP, known to be involved in transcriptional repression in the nucleus, co-localize with MCRS1 in the nucleolus and appear to activate the rRNA transcription.

Adenosine Triphosphatases↗
PubMed2003

Establishment of a prostatic small-cell carcinoma cell line (SO-MI).

BACKGROUND: Prostatic small-cell carcinoma is an extremely rare, highly aggressive disease. We established a cell line from this tumor. MATERIALS AND METHODS: Tumor tissue obtained from a 24-year-old Japanese man was used to establish the cell line. Cultured cells and tumors transplanted into nude mice were characterized by histologic, immunohistologic, immunocytologic, and molecular biologic methods. RESULTS: An immortal culture cell line (SO-MI) was successfully established. SO-MI cells adhered weakly to plastic surfaces in vitro, showing a 52- to 72-hr doubling time. SO-MI cells were heterotopically and orthotopically transplantable in nude mice. The cells were immunoreactive for NSE, chromogranin A, and NCAM, but not for ACTH, calcitonin, serotonin, gastrin, insulin, glucagons, LCA, EMA, PAP, PSA, androgen receptor, and p53. SO-MI cells secreted NSE in vitro and in vivo. SO-MI cells at passage 30 contained 50-59 chromosomes with a modal number of 55. PCR suggested that the p53 gene was deleted in SO-MI cells. RT-PCR detected no mRNA encoding androgen receptor in these cells. CONCLUSIONS: SO-MI cells retain the neuroendocrine nature of the original tumor, and should be useful in studying possible etiologies and new treatments.

Adult↗
PubMed2005

IL-1beta and TNF-alpha upregulate angiotensin II type 1 (AT1) receptors on cardiac fibroblasts and are associated with increased AT1 density in the post-MI heart.

Angiotensin (Ang) II plays an important role in post-myocardial infarction (MI) cardiac remodeling. The Ang II type 1 (AT(1)) receptor which mediates most Ang II effects is upregulated on non-myocytes in the post-MI heart. We have shown that pro-inflammatory cytokines increase AT(1) receptor density on cardiac fibroblasts through a mechanism involving NF-kappaB activation. This study examines the in vitro kinetics of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) induced AT(1) receptor upregulation in neonatal rat cardiac fibroblasts and assesses temporal and spatial associations between the appearance of these agents and increased AT(1) receptor density post-MI. The results show that IL-1beta more rapidly induces AT(1) receptor upregulation than does TNF-alpha, an effect that can be mimicked by a NF-kappaB-dependent luciferase reporter gene. Moreover, the effects of these pro-inflammatory cytokines are additive. Using immunohistochemistry in the post-MI rat heart we found strong temporal and spatial correlations between TNF-alpha, IL-1beta and AT(1) receptor proteins in the peri-infarction (PI) zone in fibroblasts and macrophages. Labeling intensity for the cytokines and the AT(1) receptor increased from 1 to 7 days post-MI in the PI zone in conjunction with replacement scar formation. This labeling persisted in non-myocytes bordering the scar for up to 83 days post-MI. These findings suggest that IL-1beta and TNF-alpha act coordinately to increase AT(1) receptor density on non-myocytes in the post-MI heart and that this effect may contribute to extracellular matrix remodeling and fibrosis.

Animals↗
PubMed1998

Osteoblastic cells regulate mi gene expression in cultured bone marrow cells.

The microphthalmia (mi) gene encodes a bHLH-Zip protein and certain mutations in this gene are known to result in osteopetrosis. We examined mi gene expression in murine bone marrow (BM) cells and calvaria-derived osteoblastic (OB) cells. The mi message level in BM cells was three- to four-fold higher than that in OB cells. The mi message level in BM cells alone was not enhanced by 1,25(OH)2 vitamin D3 (vitamin D) which induces TRAP-positive multinucleated cells, but was enhanced two-fold by the addition of conditioned medium obtained from cultures of OB cells. The mi message levels in BM cells were also enhanced by macrophage colony-stimulating factor (M-CSF). The mi message levels in cocultures of BM cells and osteoblastic MC3T3-E1 cells, which do not support osteoclastogenesis, were similar to those in the cocultures of BM cells and OB cells. Cocultures of BM cells with MC3T3-E1 cells did not yield TRAP-positive multinucleated cells, but they did maintain osteoclast progenitor cells. These findings suggest that mi is expressed in BM cells that may be under the control of OB cells.

Animals↗
PubMed2005

Cloning and characterization of the mouse ortholog of mi-er1.

Mi-er1 is a fibroblast growth factor immediate-early gene whose expression is differentially regulated in breast tumours. MI-ER1 functions as a transcriptional repressor of a number of genes, including Sp1 target genes. The Xenopus and human orthologs have been described and here we report the characterization of the mouse gene and its products. Mouse mi-er1 is a single copy gene located on chromosome 4. It has the same intron-exon structure as the human gene with the exception of exon 3A, in which an upstream 3' splice acceptor is utilized. As described in humans, multiple transcripts are produced in the mouse, and we have isolated the mouse orthologs of the human N1-beta, N2-beta and N3-beta, all of, which differ in their N-terminal sequence. Furthermore, we have isolated a novel isoform, N4-beta, containing sequence from an additional exon located between exon 4 and exon 5 that produces an fourth alternate N-terminus. The human mi-er1 transcripts also include isoforms encoding two alternate C-termini, alpha and beta. Like Xenopus, only isoforms containing the beta C-terminus have been detected in the mouse. Expression analysis, using a panel of mouse tissues and embryos, revealed that the N1-beta and N3-beta are ubiquitously expressed while N4-beta is only expressed in testis. N2-beta is expressed in most tissues but was not detected in heart, brain, eye or skeletal muscle. Sequence comparison revealed 95% identity between mouse and human MI-ER1 isoforms and 72% identity between mouse and Xenopus. The most conserved region in the MI-ER1 protein is the SANT domain, which is identical in all three species. Further analysis of the SANT domain using sequences retrieved from the genome databases for rat, cow, chicken, zebrafish, trout and Xenopustropicalis revealed that this domain is highly conserved, with 88% identity among the 9 species. Moreover, an additional 10 residues C-terminal to the published end of this domain are 100% conserved, suggesting that in MI-ER1, the functional domain includes this extended sequence.

Amino Acid Sequence↗
PubMed2003

The root-knot nematode resistance gene Mi-1.2 of tomato is responsible for resistance against the whitefly Bemisia tabaci.

The tomato gene Mi-1.2 confers resistance against root-knot nematodes and some isolates of potato aphid. Resistance to the whitefly Bemisia tabaci previously has been observed in Mi-bearing commercial tomato cultivars, suggesting that Mi, or a closely linked gene, is responsible for the resistance. The response of two biotypes of B. tabaci to tomato carrying the cloned Mi was compared with that of the isogenic untransformed tomato line Moneymaker. Our results indicate that Mi-1.2 is responsible for the resistance in tomato plants to both B- and Q- biotypes. Mi-1.2 is unique among characterized resistance genes in its activity against three very different organisms (root-knot nematodes, aphids, and whiteflies). These pests are among the most important on tomato crops worldwide, making Mi a valuable resource in integrated pest management programs.

Animals↗
PubMed2002

Clonal polymorphism of Borrelia burgdorferi strain B31 MI: implications for mutagenesis in an infectious strain background.

A major obstacle to studying the functions of particular gene products in the mouse-tick infectious cycle of Borrelia burgdorferi has been an inability to knock out genes in pathogenic strains. Here, we investigated conditions for site-directed mutagenesis in B31 MI, the low-passage-number, infectious B. burgdorferi strain whose genome was sequenced. We inactivated several plasmid and chromosomal genes in B31 MI and determined that clones carrying these mutations were not infectious for mice. However, we found extensive heterogeneity among clones and mutants derived from B31 MI based on colony phenotype, growth rate, plasmid content, protein profile, and transformability. Significantly, several B31 MI clones that were not subjected to mutagenesis but that lacked particular plasmids also exhibited defects at various stages in the infectious cycle. Therefore, the high degree of clonal polymorphism within B31 MI complicates the assessment of the contributions of individual genes to the observed phenotypes of the mutants. Our results indicate that B31 MI is not an appropriate strain background for genetic studies in infectious B. burgdorferi, and a well-defined isogenic clone is a prerequisite for targeted mutagenesis. To this end, we derived several wild-type clones from B31 MI that were infectious for mice, and gene inactivation was successful in one of these clones. Due to the instability of the genome with in vitro propagation, careful monitoring of plasmid content of derived mutants and complementation of inactivated genes will be crucial components of genetic studies with this pathogen.

Adaptation, Physiological↗
PubMed2004

Coagulation activation in young survivors of myocardial infarction (MI)--a population-based case-control study.

Formation of an occlusive thrombus by exposure of tissue factor (TF) to circulating blood and subsequent triggering of coagulation by TF-FVIIa complexes on ruptured atherosclerotic plaques is thought to be a key event in acute MI. Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of TF-induced coagulation by neutralizing FXa and inhibiting the TF-FVIIa complex. A case control study was conducted to investigate the role of coagulation activation in MI. Sixty-two patients with verified MI, 40-60 yrs of age, were recruited into the study and examined 1-4 years after the acute coronary event. Thrombin-antithrombin complex (TAT) was significantly increased in MI patients (8.2 +/- 12.9 microg/l vs. 3.9 +/- 2.6 microg/l, p=0.01). In contrast, FVIIa was lower in MI patients (41 +/- 13 mU/ml vs. 48 +/- 15 mU/ml, p=0.003) accompanied by an increase in plasma free TFPI antigen (20.9 +/- 5.0 ng/ml vs. 19.2 +/- 4.9 ng/ml, p=0.03). Significant trends for increase in triglycerides and total cholesterol across quartiles of free TFPI Ag were found in both groups, whereas HDL cholesterol decreased across quartiles of TFPI among control subjects. The compensatory increase in plasma free TFPI with established lipid and haemostatic risk factors were abrogated in the MI patients. An apparent increase in the basal activation of the coagulation system was observed in young patients with MI. Enhanced coagulation activation was accompanied by a decrease in FVIIa and increase in free TFPI Ag, probably reflecting a modest triggering of TF-induced coagulation in these patients.

Adult↗
PubMed1999

Expression of the microphthalmia-associated basic helix-loop-helix leucine zipper transcription factor Mi in avian neuroretina cells induces a pigmented phenotype.

The microphthalmia gene (mi) appears to be required for pigment cell development, based on its mutation in mi mice. The mi gene encodes a basic helix-loop-helix leucine zipper transcription factor (Mi) with tissue-restricted expression. To investigate the role of mi in cell proliferation and pigmentation, we transfected neuroretina (NR) cells with a recombinant virus expressing the murine mi cDNA. The virus induced the proliferation of chicken NR cells in response to fibroblast growth factor 2, which enabled them to form colonies in soft agar. In contrast to control cultures, transfected chicken NR cells or quail NR cells became rapidly pigmented and strongly expressed the QNR-71 mRNA encoding a melanosomal protein. These results demonstrate that Mi not only acts as pigmentation inducer but is also able to modulate the response of cells to growth factors.

Amino Acid Sequence↗
PubMed2005

[Study on the relationship between LOH and MI of FHIT gene and the development of cervical carcinoma].

OBJECTIVE: To explore the relationship of loss of heterozygosity (LOH) and microsatellite instability (MI) of fragile histidine triad (FHIT) gene to the development of cervical carcinoma. METHODS: Two sites of microsatellite polymophism in FHIT gene were selected to detect LOH and MI in 60 cases of primary invasive cervical carcinoma and 35 cases of cervical intra-epithelial neoplasia (CIN). RESULTS: At D3S1234 and D3S1300, the LOH rates of primary invasive cervical carcinomas were 45.0% (27/60) and 38.3% (23/60), the MI rates were 18.3% (11/60) and 11.7% (7/60), respectively. The LOH rates of CINs were 42.9% (15/35) and 37.1% (13/35), the MI rates were 11.4% (4/35), 8.6% (3/35), respectively. There were no significant differences between invasive cervical carcinomas and CINs in respect to their positive rates of LOH and MI at D3S1234 and D3S1300 (P>0.05). There were significant differences in LOH rates at D3S1234 and D3S1300 between the well/moderately differentiated cervical carcinomas and the poorly differentiated invasive cervical carcinomas (P<0.05). Significant differences were noted between the invasive cervical carcinomas with lymph node metastasis and those without lymph node metastasis in regard to their LOH and MI at the two sites (P < 0.05). The positive rates of LOH and MI for CIN III and noninvasive cervical carcinomas were higher than those for CIN I-II. CONCLUSION: The FHIT gene change is a relatively late event in CINs. The detection of the LOH of FHIT gene might be helpful to the early diagnosis and the screening of cervical carcinoma. It might also be useful for predicting the prognosis of cervical carcinoma.

Acid Anhydride Hydrolases↗
PubMed1986

A missense mutation in the oxi-3 gene of the [mi-3] extranuclear mutant of Neurospora crassa.

We have determined the DNA sequence of the oxi-3 gene and its 5' flanking region in the extranuclear [mi-3] mutant of Neurospora crassa. The oxi-3 gene encodes subunit 1 of cytochrome c oxidase, a protein known to be altered in the [mi-3] mutant (Bertrand, H., and Werner, S. (1979) Eur. J. Biochem. 98, 9-18). When the sequence from [mi-3] was compared to previously published sequences of the same region of mtDNA from wild-type N. crassa, a total of five differences was found. Four of these differences can be accounted for as either genetic polymorphisms or previous errors in DNA sequence determination. The remaining difference is a G/C to T/A transversion that changes a codon specifying an aspartic acid residue (GAC) to one that would specify tyrosine (TAC) at amino acid 448 of the 555 amino acid mature subunit 1 protein. This alteration was also found in the mtDNA of two separate heterokaryotic strains that had acquired the [mi-3] phenotype after repeated subculturing of heterokaryons forced between an [mi-3] strain and a strain containing a wild-type cytoplasm. The particular aspartic acid residue that would be affected by the mutation observed in [mi-3] is conserved in a diversity of species as either aspartic acid or glutamic acid, suggesting that an acidic residue at this position is important for the correct function of the subunit 1 protein. For these reasons, we consider it likely that the observed missense mutation is responsible for the [mi-3] phenotype.

Amino Acid Sequence↗
PubMed1996

[Expression of the mutant gene mi in mice: white spotting pattern].

Mice of mi/+ and +/+ genotypes of the mutant stock microphthalmia (mi) were mated inter se and with those of CC57BR/Mv and CBA/J inbred lines. In all types of crosses, the offsprings of mi/+ genotype had unpigmented fingers and distal tail parts (penetrance 100%). This trait is determined mostly by the mutant mi gene, the expression of which is not affected by modifier genes. However, the degree of mi gene expression, white spotting, on other body parts (wrist, foot, ventral body side, and parietal head part) varied widely in mice obtained from different crosses; penetrance ranged from 0 to 100%. The results obtained indicate that in these cases, the expression of mi gene was strongly affected by modifier genes. The different frequency of the mi gene effects, in heterozygote offspring obtained from reciprocal crosses, can result from the imprinting of the modifier genes in maternal and paternal gametes.

Animals↗
PubMed1999

Inhibitory effect of the transcription factor encoded by the mi mutant allele in cultured mast cells of mice.

The mi locus of mice encodes a transcription factor of the basic-helix-loop-helix-leucine zipper protein family (MITF). The MITF encoded by the mutant mi allele (mi-MITF) deletes 1 of 4 consecutive arginines in the basic domain. The mice of mi/mi genotype express mi-MITF, whereas the mice of tg/tg genotype have a transgene at the 5' flanking region of the mi gene and do not express any MITF. To investigate the function of mi-MITF in cultured mast cells (CMCs), we took two approaches. First, mRNA obtained from mi/mi CMCs or tg/tg CMCs was subtracted from complementary (c) DNA library of normal (+/+) CMCs, and the (+/+-mi/mi) and (+/+-tg/tg) subtraction libraries were obtained. When the number of clones that hybridized more efficiently with +/+ CMC cDNA probe than with mi/mi or tg/tg CMC cDNA probe was compared using Southern analysis, the number was larger in the (+/+-mi/mi) library than in the (+/+-tg/tg) library. Second, we compared mRNA expression of six genes between mi/mi and tg/tg CMCs by Northern analysis. The transcription of three genes encoding mouse mast cell proteases was impaired in both mi/mi and tg/tg CMCs. On the other hand, the transcription of three genes encoding c-kit receptor, tryptophan hydroxylase, and granzyme B was markedly reduced in mi/mi CMCs, but the reduction was significantly smaller in tg/tg CMCs. These results indicated the inhibitory effect of mi-MITF on the transactivation of particular genes in CMCs.

Animals↗
PubMed2026

Mutual Information-based Prognostic Biomarker Discovery in Cancer Genomics: Conceptual Framework and Representative Applications of MI-POG.

Mutual information (MI)-based approaches have increasingly been applied to cancer genomics; however, their use for genome-wide prognostic biomarker discovery remains relatively underexplored. The present article summarizes the conceptual workflow of Mutual Information-based Prognostic Omics Gene (MI-POG) based on previously published applications in breast cancer, lower-grade glioma, and other cancer datasets. The framework consists of clinical endpoint discretization, genome-wide MI-based screening, candidate ranking, and downstream validation using conventional survival-analysis approaches. Previous MI-POG applications identified solute carrier family 20 member 1 (SLC20A1) as a prognostic biomarker in hormone receptor-positive breast cancer. Elevated SLC20A1 expression was associated with unfavorable survival outcomes and was independently validated in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. Methodological analyses demonstrated how survival endpoints can be integrated into an information-theoretic framework through fixed-time outcome discretization, enabling model-independent assessment of molecular-clinical dependencies. Applications across multiple cancer datasets suggested the potential applicability of the framework across biologically distinct tumor types, although further validation will be required to establish its robustness and generalizability. In conclusion, MI-POG can be formalized as an information-theoretic framework for genome-wide identification of prognostic biomarkers by quantifying molecular-clinical dependencies using mutual information. Representative applications from previously published studies suggest that MI-POG may complement conventional survival-analysis approaches and provide a useful strategy for biomarker discovery, although additional benchmarking and prospective validation will be required.

Humans↗