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PubMed2026

Plasma cell-CD8+ T cell co-enrichment distinguishes immunotherapy-responsive hepatocellular carcinoma subtypes.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterised by significant racial disparities in incidence and outcomes, yet whether these reflect distinct tumour biology or differential distribution of molecular subtypes among immunotherapy patients remains unclear. METHODS: We characterised molecular heterogeneity among 46 patients with HCC of differing background population from the NCI-CLARITY cohort receiving immune checkpoint inhibitor therapy, using transcriptomic and genomic profiling, with validation across multiple independent cohorts. RESULTS: Differential expression analysis comparing African American versus non-African American patients identified 126 genes, of which 55 demonstrated tumour-specific expression across independent validation cohorts with paired tumour-normal samples. Consensus clustering revealed two molecular subtypes with no significant race association, indicating these clusters capture tumour-intrinsic biology rather than ancestry. The genomic landscape showed minimal differences between subtypes. A prognostic signature derived from these expression profiles demonstrated significant risk stratification in the NCI-CLARITY cohort and TCGA-LIHC, but not in Asian cohorts, suggesting population-specific applicability. Immune deconvolution revealed that the two subtypes represent distinct immune microenvironments: one subtype exhibited markedly elevated plasma cell infiltration with strong plasma cell-CD8+T cell correlation suggesting coordinated adaptive immunity, along with elevated tertiary lymphoid structure signatures. The other subtype showed regulatory T cell-macrophage correlation and enrichment for immune-excluded phenotypes. The immune-enriched subtype trended towards higher immunotherapy response rates. CONCLUSIONS: Molecular heterogeneity in HCC reveals distinct tumour-immune ecosystems that transcend racial classification. Tumour immune heterogeneity in HCC reflects distinct molecular patterns, with immune hot tumours characterised by elevated tertiary lymphoid structure signatures and enriched plasma cell and CD8+T cells. These patterns may serve as prognostic biomarkers for immunotherapy patient stratification and demonstrate the value of diverse cohort representation in identifying clinically relevant therapeutic targets.

Gastrointestinal Cancer↗
PubMed1974

The epidemiological importance of 'ay' and 'ad' subtypes of the HB-Ag.

The distribution of the subtypes ;ay' and ;ad' has been assessed in 159 hepatitis B antigen (HB-Ag) positive subjects with a variety of associated hepatic conditions. A specific subtype could not be correlated with any particular hepatic pathology when the whole group was considered. However, the distribution of these two subtypes did vary according to the geographical origin of the subject or infection, or the presumed route of infection, so that there was an apparent association of one subtype with a certain disease state. Subtyping performed on 10 HB-Ag-positive households showed the subtype to be the same within nine, emphasizing the epidemiological rather than the pathological importance of the ;ay' and ;ad' subtypes of the HB-Ag.

Carrier State↗
PubMed1994

Alpha 1-adrenoceptor subtypes mediating contraction of the femoral artery in spontaneously hypertensive rats.

alpha 1-Adrenoceptors (ARs) were divided into alpha 1H and alpha 1L subtypes by their different affinities for bunazosin or prazosin. alpha 1H-ARs were further subdivided into alpha 1A, alpha 1B, and alpha 1C subtypes. Therefore, this study was undertaken to determine which alpha 1-AR subtypes were involved in the activation of femoral artery preparations by alpha 1-AR agonists in spontaneously hypertensive rats (SHR). For comparison, aortic strips were also incorporated in the present study. In the presence of propranolol, deoxycorticosterone, and desipramine, norepinephrine (NE) contracted the vascular strips in a dose-dependent manner. Negative log EC50 values and maximum responses of NE-induced contraction of the SHR femoral artery were unchanged and increased, respectively, compared with those of Sprague-Dawley and Wistar-Kyoto rats (WKY). Contractile responses of the SHR aortae to NE were similar to those of the normotensive tissues. Schild plot data for alpha 1-AR antagonists indicated that alpha 1-AR subtypes mediating contraction of the aorta were homogeneous and had high affinities for bunazosin (pA2 9.4, alpha 1H subtype) and WB 4101 (pA2 9.3) and a low affinity for 5-methylurapidil (pA2 7.7). In the femoral artery, because Schild plots for bunazosin had slopes of less than 1.0, there were alpha 1H and alpha 1L subtypes. Bunazosin, at 10(-9) M, which could mask the alpha 1H subtype, yielded a Schild plot for bunazosin with a slope not different from unity and decreased the pA2 value for bunazosin (pA2 9.4 vs. 8.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-1 Receptor Agonists↗
PubMed1991

Inhibition of surfactant subtype convertase in radiation model of adult respiratory distress syndrome.

The accompanying paper [Am. J. Physiol. 260 (Lung Cell. Mol. Physiol. 4): L302-L310, 1991] showed that in the radiation pneumonitis model of adult respiratory distress syndrome (ARDS) there was an excess of the proximate, higher buoyant density subtypes of alveolar surfactant, and a decrease in the light buoyant density form. Because the surfactant subtypes normally evolve from the former to the latter a delay in the alveolar metabolism of surfactant could explain this disproportion. Three possible mechanisms of a delay in surfactant metabolism in radiation pneumonitis were explored using an in vitro model of surfactant subtype metabolism called "cycling". The first was that the surfactant of mice with radiation pneumonitis was intrinsically less capable of conversion to the light subtype. It was found, however, that the proximate forms of surfactant of mice with radiation pneumonitis were as capable of generating light subtype as those of control mice. The second was that there was a deficit in the serine protease activity, called "convertase", that mediates the conversion. But it was found that lungs of mice with radiation pneumonitis released convertase activity to the same extent as control lungs. The third was that an inhibitor of convertase activity was present in the alveoli. It was found that the alveolar lavage fluid of mice with radiation pneumonitis inhibited the conversion of exogenous surfactant by exogenous convertase. Moreover, it contained an 18-fold excess of antiprotease activity. The present data are interpreted as suggesting that an inhibitor in the alveolar space is responsible for the delay in surfactant subtype metabolism in radiation pneumonitis, resulting in the disproportion of surfactant subtypes in radiation pneumonitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2.

Major pelvic ganglion electrocautery (MPGE) and spinal cord injury in the rat induce bladder hypertrophy and a change in muscarinic receptor subtypes mediating bladder contraction from predominantly M3 to a combination of M2 and M3. To determine whether this is a result of bladder hypertrophy or denervation, we studied the following groups: sham-operated controls, urinary diversion (DIV), MPGE together with urinary diversion (DIV-DEN), bilateral MPGE (DEN), bladder outlet obstruction (BOO), and MPG decentralization (MPGDEC). The degree of bladder denervation was determined by the maximal carbachol response normalized to the response to electric field stimulation. Receptor subtype density was determined by immunoprecipitation. The affinity of subtype-selective muscarinic antagonists for inhibition of carbachol-induced contractions was used to determine the subtype-mediating contraction. DEN, MPG-DEC, and BOO bladders were hypertrophic whereas DIV bladders were atrophic compared with sham operated. Bladder contraction in sham-operated, DIV, and DIV-DEN was mediated by the M3 receptor subtype, whereas the M2 subtype participated in contraction in the DEN, MPG-DEC, and BOO groups. The hypertrophied bladders had an increase in total and M2 receptor density while all experimental groups showed a reduction in M3 receptor density. Thus bladder hypertrophy, independent from bladder denervation, causes a shift in the muscarinic receptor subtype mediating bladder contraction from M3 toward M2.

Animals↗
PubMed1991

Angiotensin II receptor subtypes in renal cortex of rats and rhesus monkeys.

The angiotensin II (ANG II) receptor has recently been shown to exhibit subtypes with respect to antagonist binding. Of particular interest are the potent nonpeptide antagonists, DUP 753 and PD 121981, which exhibit selectivity for the subtype 1 (AT1) and subtype 2 (AT2) receptors, respectively. We used these high-affinity antagonists in competition with 125I-[Sar1,Ile8]ANG II to determine autoradiographically the distribution of these ANG II-receptor subtypes in the renal cortex of rats and rhesus monkeys. Binding of the radioligand to receptor in sections of rat renal cortex was inhibited by DUP 753; inhibition by PD 121981 was not detected. By contrast, AT1 and AT2 receptors are present in the renal cortex of rhesus monkeys in regionally distinct structures. DUP 753 inhibited binding to the ANG II receptor in glomeruli. PD 121981 inhibited binding to arterial smooth muscle and the juxtaglomerular (JG) apparatus. The JG apparatus also exhibits radioligand binding, which is inhibited by DUP 753. The effect of DUP 753 and PD 123177 (a more water-soluble analogue of PD 121981) on changes in plasma renin activity was examined to determine if one or both of these subtypes participate in the ANG II-mediated negative feedback of control of renin release. Although DUP 753 increased plasma renin activity to the same extent as the angiotensin-converting enzyme inhibitor, enalaprilat, in rats and rhesus monkeys, the AT2 antagonists did not affect renin release in either species. Thus both subtypes of ANG II receptor are present in rhesus monkey cortex, but a function for only the AT1 subtype was demonstrated.

Aldosterone↗
PubMed1993

Glomerular angiotensin II receptor subtypes during development of rat kidney.

We used quantitative autoradiography to investigate distribution of angiotensin II (ANG II) receptor subtypes during development of the kidney in the rat. In fetal, newborn, and 3-day-old rats, immature glomeruli in the form of comma and S-shaped bodies, located in the nephrogenic zone of the renal cortex, expressed only the angiotensin AT2 receptor subtype. Conversely, the juxtamedullary glomeruli, in more advanced developmental stages, expressed only the AT1 subtype. Similarly, maturing and fully developed glomeruli, present in 1-, 2-, and 8-wk-old rats, expressed only AT1 receptors. In the kidney medulla, there was a similar change in ANG II receptor subtype expression, with the AT2 subtype expressed earlier and the AT1 subtype later during development. Our results demonstrate a selective expression of ANG II receptor subtypes during kidney development. We have found glomerular and medullary AT1 receptors only at developmental stages when kidney function has matured. Conversely, AT2 receptors are expressed only in immature structures, suggesting that they may have a role during kidney organogenesis.

Aging↗
PubMed1989

Surfactant subtypes of mice: metabolic relationships and conversion in vitro.

Mouse alveolar surfactant can be separated by equilibrium centrifugation on continuous sucrose gradients into three subtypes which we call "ultraheavy", "heavy", and "light" on the basis of their buoyant densities. We examined their metabolic relationship by in vivo labeling studies and by physical manipulation, cycling the surface area in vitro in an attempt to convert one subtype into another. Labeling studies indicated rapid quantitative progression of surfactant through ultraheavy, heavy, and light subtypes in sequence. To mimic the in vivo conversion of subtypes in vitro we "cycled" the surface area of surfactant in plastic tubes. Newly secreted surfactant obtained from incubated lungs, as well as surfactant obtained by alveolar lavage and lamellar bodies, exhibited conversion of material from heavier to lighter subtypes. The conversion between subtypes was quantal and was dependent on cycling, temperature, and time. We conclude that the three subtypes are discrete forms of alveolar surfactant that evolve from one into another. Cycling may provide a means to study the mechanisms of their interconversion in vitro.

Animals↗
PubMed2000

Prevalence and distribution of hepatitis C subtypes in patients with opioid dependence.

UNLABELLED: AIM AND SETTING: The drug addiction out-patient clinic at the University Hospital for Psychiatry in Vienna performed a study to identify the prevalence of hepatitis C virus (HCV) infections in a group of opiate-dependent patients, to detect the distribution of HCV subtypes and to calculate the comorbidity of human immunodeficiency virus (HIV) and hepatitis B virus (HBV). DESIGN AND PARTICIPANTS: We consecutively investigated unselected patients (n = 173) during an observation period of 2 months with the diagnosis of opioid dependence (DSM-IV: 304.0) and polysubstance dependence (DSM-IV: 304.9). MEASUREMENTS: Blood was investigated focusing on liver enzymes and on viral status including HIV, hepatitis B and hepatitis C, followed by subtyping of the virus. FINDINGS: In 80.3% hepatitis C antibodies were found, 66.5% were HCV RNA (PCR) positive. 3a was the most frequent subtype (35.6%), followed by 1a (28.8%) and 1b (22.0%). Four patients had both subtypes 1a and 1b (6.8%), 3 were 2b positive (5.1%) and 1 patient had subtypes 2a/2c (1.7%). No significant difference in aspartate (AST) and alanine aminotransferases (ALT) concerning the different subtypes (AST: p = 0.290; ALT: p = 0.260) could be calculated; 11.6% showed co-infection with HIV, 2 patients had a chronic infection with hepatitis B. CONCLUSIONS: The rate of HCV infection in substance-dependent patients at our drug addiction out-patient clinic is extremely high. The distribution of subtypes showed a relatively homogeneous distribution of the types 1a, 1b and 3a. The recommended therapy with alpha-interferon should be initiated in drug-dependent patients under considerations of an enrollment in oral maintenance with synthetic opioids.

Adolescent↗
PubMed2004

Long-term prognosis, by stroke subtypes, after a first-ever stroke: a hospital-based study over a 20-year period.

BACKGROUND AND PURPOSE: The influence of stroke subtype on recurrence, and determinants of recurrence-free survival after a first-ever stroke are not fully understood. We aimed to clarify the long-term prognosis by stroke subtypes and to identify determinants for recurrence and death after a first-ever stroke. METHODS: We enrolled 1,732 consecutive patients (men/women = 1,134/598, mean age of 65 years) with a first-ever acute stroke who were admitted to our Stroke Care Unit during a period of 20 years. Stroke subtypes were classified as atherothrombotic brain infarction, lacunar infarction, cardioembolic infarction, other type of infarction, and brain hemorrhage. The prognosis was assessed by stroke subtypes. RESULTS: During the hospital stay (mean 61 days), 99 patients died: 73 died directly from stroke. A total of 198 patients had recurrent strokes, and 286 died within 3 years after the index stroke. The overall recurrence rate within the first year was 6.5%, which was different among stroke subtypes. Patients with cardioembolic infarction (9.0%) as well as other type of infarction (9.1%) had more recurrent strokes within the initial year compared with the other subtypes. A history of transient ischemic attack (relative risk = 1.38), atrial fibrillation (1.52), ischemic heart disease (1.40), and disability at discharge (2.64) were independent predictors for the recurrence and death within 3 years after the first-ever stroke. CONCLUSIONS: The recurrence rate was different among stroke subtypes within 1 year after the index stroke. Atrial fibrillation, ischemic heart disease, history of transient ischemic attack, and disability at discharge were important determinants for stroke recurrence and death.

Acute Disease↗
PubMed1995

Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene.

The serologic heterogeneity of the hepatitis B virus (HBV) has been established from immunodiffusion experiments for a long time. Four serotypes called subtypes of the hepatitis B surface antigen (HBsAg) have been defined by two mutually exclusive determinant pairs, d/y and w/r, and a common determinant a. These subtypes are adw, ayw, adr and ayr. By subdivision of the four major subtypes in the mid-70s, nine different subtypes were identified. Sequencing of viral genomes has now become a major goal of descriptive virology, and sequence data is now used to trace routes of infection, to reconstruct the phylogenetic history of viruses and two delimit genetic subtypes. A genetic classification based on the comparison of complete genomes has defined four genomic groups of HBV, later referred upon as genotypes, which were designated with A-D. However, the interrelation of the nine subtypes to the genotypes, the possible presence of more than four human HBV genotypes as well as their global geographical prevalence remained to be determined. By sequencing the S-gene of HBV the molecular basis was assessed for the serological variations of HBsAg within the major four subtypes. Thereby, also two new genotypes of HBV designated with E and F were identified. Complete genomic sequencing of E and F strains confirmed their status as new genotypes. The F genotype was found to diverge from other HBV genomes sequenced by 14%, thus being the most divergent HBV genome so far characterized. When the worldwide molecular epidemiology of HBV based on the variability of the S-gene was defined, the E and F strains seemed to originate in aboriginal populations of Africa and the New World, respectively. They shared a unique substitution at residue 140 in the second immunodominant loop of their encoded surface antigen when compared to the vaccine strain. Future research will establish whether this substitution may predispose to a vaccine escape mutant at residue 141, that now has been reported to occur in conjunction with the 140 substitution.

Demography↗
PubMed1999

Subtype specific regulation of human vascular alpha(1)-adrenergic receptors by vessel bed and age.

BACKGROUND: alpha(1)-adrenergic receptors (alpha(1)ARs) regulate blood pressure, regional vascular resistance, and venous capacitance; the exact subtype (alpha(1a), alpha(1b), alpha(1 d)) mediating these effects is unknown and varies with species studied. In order to understand mechanisms underlying cardiovascular responses to acute stress and chronic catecholamine exposure (as seen with aging), we tested two hypotheses: (1) human alpha(1)AR subtype expression differs with vascular bed, and (2) age influences human vascular alpha(1)AR subtype expression. METHODS AND RESULTS: Five hundred vessels from 384 patients were examined for alpha(1)AR subtype distribution at mRNA and protein levels (RNase protection assays, ligand binding, contraction assays). Overall vessel alpha(1)AR density is 16+/-2.3fmol/mg total protein. alpha(1a)AR predominates in arteries at mRNA (P<0.001) and protein (P<0.05) levels; all 3 subtypes are present in veins. Furthermore, alpha(1)AR mRNA subtype expression varies with vessel bed (alpha(1a) higher in splanchnic versus central arteries, P<0.05); competition analysis (selected vessels) and functional assays demonstrate alpha(1a) and alpha(1b)-mediated mammary artery contraction. Overall alpha(1)AR expression doubles with age (<55 versus > or = 65 years) in mammary artery (no change in saphenous vein), accompanied by increased alpha(1b)>alpha(1a) expression (P< = 0.001). CONCLUSIONS: Human vascular alpha(1)AR subtype distribution differs from animal models, varies with vessel bed, correlates with contraction in mammary artery, and is modulated by aging. These findings provide potential novel targets for therapeutic intervention in many clinical settings.

Adrenergic alpha-Agonists↗
PubMed1995

Regulation, chamber localization, and subtype distribution of angiotensin II receptors in human hearts.

BACKGROUND: To assess the chamber localization, subtype distribution, and regulation of human myocardial angiotensin II receptors in heart failure, we determined the binding of angiotensin II, Sar1Ile8-angiotensin II, and the subtype-specific antagonists Dup 753 (AT1-specific) and PD 123319 (AT2-specific) in atria from patients with normal (left ventricular ejection fraction > 55%) or moderately impaired (left ventricular ejection fraction 30% to 55%) cardiac function and in atria and ventricles from explanted end-stage failing hearts. Sarcolemmal and combined fractions, the latter including internalized receptors, were studied. In addition, AT1 mRNA content was analyzed by polymerase chain reaction after reverse transcription. METHODS AND RESULTS: The number of angiotensin II binding sites (Bmax) in sarcolemmal fractions was significantly reduced in explanted end-stage failing hearts in comparison with control subjects and moderate heart failure (Bmax 3.9 +/- 0.8 versus 11.2 +/- 1.7 and 9.6 +/- 0.8 fmol/mg protein, respectively). A comparable 65% reduction in receptor numbers was found in combined fractions from end-stage failing hearts, indicating that the loss of binding sites was not due to their internalization. The dissociation constants were comparable in sarcolemmal and combined fractions and in nonfailing and failing hearts, ranging from 0.5 +/- 0.2 to 1.2 +/- 0.5 nmol/L. In nonfailing hearts, 69 +/- 4% of binding sites were blocked by the subtype-2-specific inhibitor PD 123319 and were therefore classified as AT2; 33 +/- 5% were blocked by the subtype-1-specific inhibitor DUP 753 and thus classified as subtype 1. In explanted hearts, comparable ratios of 66 +/- 5% AT2 sites and 34 +/- 5% AT1 sites were found. AT1 cDNA amplification signals by polymerase chain reaction were reduced to about one third of the level in control subjects in end-stage failing hearts. CONCLUSIONS: Angiotensin II receptors in human myocardium are present in relatively low numbers, and AT2 is the predominant subtype. A significant loss of angiotensin II receptors occurs in end stage but not in moderate heart failure. The loss of receptors affects both subtypes to a comparable degree. The data suggest that the decrease in receptor density is due to a decrease in steady-state mRNA abundance.

Binding Sites↗
PubMed1991

Subtype 2 angiotensin receptors mediate prostaglandin synthesis in human astrocytes.

We have identified two distinct cellular responses that occur in human astrocytes in the presence of angiotensin (Ang) peptides and are linked to specific receptor subtypes. Ang II and the N-terminal heptapeptide Ang-(1-7) stimulated release of prostaglandin (PG) E2 and PGI2 (measured as the stable metabolite 6-keto-PGF1 alpha). In contrast, only Ang II but not Ang-(1-7) activated phosphoinositide-specific phospholipase C, leading to mobilization of intracellular calcium. The Ang II-induced PGE2 and PGI2 syntheses were attenuated by [Sar1,Ile8]Ang II but not by [Sar1,Thr8]Ang II. Ang-(1-7)-induced PGE2 and PGI2 syntheses were not inhibited by either of these two classical antagonists. DuP 753, a subtype 1-selective Ang receptor antagonist, blocked the Ang II-induced release of PGE2 but not PGI2. In contrast, CGP 42112A, the subtype 2-selective antagonist, totally blocked the Ang II-induced PGI2 release and partially attenuated the PGE2 release. Ang-(1-7)-induced PGE2 and PGI2 release was not altered by DuP 753; however, CGP 42112A totally blocked the effects of Ang-(1-7) on PG stimulation. Calcium mobilization in response to Ang II was blocked by [Sar1,Thr8]Ang II, [Sar1,Ile8]Ang II, and DuP 753 but not by CGP 42112A. These data suggest that human astrocytes contain both Ang receptor subtypes. The subtype 1 Ang receptor participates both in the release of PGs and in the mobilization of calcium, whereas the subtype 2 receptor is coupled to the release of PGs only. In addition, PG release coupled to subtype 2 Ang II receptors occurs through a calcium-independent mechanism and responds uniquely to Ang-(1-7).

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed2000

Ischemic stroke subtypes : a population-based study of functional outcome, survival, and recurrence.

BACKGROUND AND PURPOSE: There is scant population-based information on functional outcome, survival, and recurrence for ischemic stroke subtypes. METHODS: We identified all residents of Rochester, Minnesota, with a first ischemic stroke from 1985 through 1989 using the resources of the Rochester Epidemiology Project medical records linkage system. After reviewing medical records and imaging studies, we assigned patients to 4 major ischemic stroke categories based on National Institute of Neurological Diseases and Stroke Data Bank criteria: large-vessel cervical or intracranial atherosclerosis with stenosis (ATH, n=74), cardioembolic (CE, n=132), lacunar (LAC, n=72), and infarct of uncertain cause (IUC, n=164). We used the Rankin disability score to assess functional outcome and the Kaplan-Meier product-limit method and Cox proportional hazards regression analysis with bootstrap validation to estimate rates and identify predictors of survival and recurrent stroke among these patients. RESULTS: Rankin disabilities were different across stroke subtypes at the time of stroke and 3 months and 1 year later (P=0.001). LAC was associated with milder deficits compared with other subtypes. Mean follow-up among the 442 patients in the cohort was 3.2 years. Estimated rates of recurrent stroke at 30 days were significantly different (P<0.001): ATH, 18.5% (95% CI 9.4% to 27.5%); CE, 5.3% (95% CI 1.2% to 9.6%); LAC, 1.4% (95% CI 0.0% to 4.1%); and IUC, 3. 3% (95% CI 0.4% to 6.2%). After adjusting for age, sex, and stroke severity, infarct subtype was an independent determinant of recurrent stroke within 30 days (P=0.0006; eg, risk ratio for ATH compared with CE=3.3, 95% CI 1.2 to 9.3) but not long term (P=0.07). Four of 25 recurrent strokes within 30 days were procedure-related, each in patients with ATH. Five-year death rates were significantly different (P<0.001): ATH, 32.2% (95% CI 21.1% to 43.2%); CE, 80.4% (95% CI 73.1% to 87.6%); LAC, 35.1% (95% CI 23.6% to 46.0%); and IUC, 48.6% (95% CI 40.5% to 56.7%). With adjustment for age, sex, cardiac comorbidity, and stroke severity, the subtype of ischemic stroke was an independent determinant of long-term (P=0.018; eg, risk ratio for ATH compared with cardioembolic=0.47, 95% CI 0.29 to 0.77) but not 30-day survival (P=0.2). CONCLUSIONS: Early recurrence rates for ischemic stroke caused by ATH are higher than those for other subtypes and higher than previous non-population-based studies have reported. Some of the increased risk of early recurrence among patients with ATH may be iatrogenic. Patients with LAC have better poststroke functional status than those with other subtypes. Survival is poorest among those with ischemic stroke with a cardiac source of embolism.

Adult↗
PubMed2001

Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank.

BACKGROUND AND PURPOSE: Data on risk factors for etiologic subtypes of ischemic stroke are still scant. The aim of this study was to characterize stroke subtypes regarding risk factor profile, outcome, and current treatment strategies. METHODS: We analyzed data from 5017 patients with acute ischemic stroke (42.4% women, aged 65.9+/-14.1 years) who were enrolled in a large multicenter hospital-based stroke data bank. Standardized data assessment and stroke subtype classification were used by all centers. RESULTS: Sex and age distribution, major risk factors and comorbidities, recurrent stroke, treatment strategies, and outcome were all unevenly distributed among stroke subtypes (P<0.001, respectively). Cardioembolism, the most frequent etiology of stroke (25.6%), was particularly common in the elderly (those aged >70 years) and associated with an adverse outcome, a low rate of early stroke recurrence, and frequent use of thrombolytic therapy and intravenous anticoagulation. Large-artery atherosclerosis (20.9%), the most common cause of stroke in middle-aged patients (those aged 45 to 70 years), showed the highest male preponderance, highest rate of early stroke recurrence, and highest prevalence of previous transient ischemic attack, current smoking, and daily alcohol consumption among all subtypes. The highest prevalence of hypertension, diabetes mellitus, hypercholesterolemia, and obesity was found in small-vessel disease (20.5%), which, in turn, was associated with the lowest stroke severity and mortality. CONCLUSIONS: Our results foster the concept of ischemic stroke as a polyetiologic disease with marked differences between subtypes regarding risk factors and outcome. Therefore, studies involving risk factors of ischemic stroke should differentiate between etiologic stroke subtypes.

Adult↗
PubMed1990

Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung.

Muscarinic receptor subtypes have been localized in human and guinea pig lung sections by an autoradiographic technique, using [3H](-)quinuclidinyl benzilate [( 3H]QNB) and selective muscarinic antagonists. [3H]QNB was incubated with tissue sections for 90 min at 25 degrees C, and nonspecific binding was determined by incubating adjacent serial sections in the presence of 1 microM atropine. Binding to lung sections had the characterization expected for muscarinic receptors. Autoradiography revealed that muscarinic receptors were widely distributed in human lung, with dense labeling over submucosal glands and airway ganglia, and moderate labeling over nerves in intrapulmonary bronchi and of airway smooth muscle of large and small airways. In addition, alveolar walls were uniformly labeled. In guinea pig lung, labeling of airway smooth muscle was similar, but in contrast to human airways, epithelium was labeled but alveolar walls were not. The muscarinic receptors of human airway smooth muscle from large to small airways were entirely of the M3-subtype, whereas in guinea pig airway smooth muscle, the majority were the M3-subtype with a very small population of the M2-subtype present. In human bronchial submucosal glands, M1- and M3-subtypes appeared to coexist in the proportions of 36 and 64%, respectively. In human alveolar walls the muscarinic receptors were entirely of the M1-subtype, which is absent from the guinea pig lung. No M2-receptors were demonstrated in human lung. The localization of M1-receptors was confirmed by direct labeling with [3H]pirenzepine. With the exception of the alveolar walls in human lung, the localization of muscarinic receptor subtypes on structures in the lung is consistent with known functional studies.

Animals↗
PubMed2026

Machine Learning and Metabolomics to Characterize Warburg-Like Metabolic Subtypes in Human Retinal Endothelial Cells Exposed to Risk Factors Associated With Proliferative Diabetic Retinopathy.

PURPOSE: High glucose (HG), hypoxia (Hyp), and their combination are major risk factors for proliferative diabetic retinopathy (PDR). Although these conditions induce features of the Warburg-like metabolic reprogramming in human retinal endothelial cells (HRECs), it remains unclear whether they produce distinct metabolic and angiogenic subtypes. This study aimed to characterize the Warburg-like-associated metabolic heterogeneity induced by these PDR-related risk factors and evaluate the ability of supervised machine-learning models to distinguish these subtypes. METHODS: HRECs were cultured under normoglycemic, HG, Hyp (2% O2), and combined HG-Hyp conditions. Untargeted LC-MS/MS metabolomics quantified metabolites spanning carbohydrates, amino acids, nucleotides, and lipids. Principal component analysis (PCA) assessed overall metabolic variation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified metabolic pathways associated with angiogenesis. In vitro angiogenesis assays measured endothelial tube formation and branching. Nine supervised classifiers (decision tree, logistic regression, na&#xef;ve Bayes, random forest, K-Nearest Neighbors, neural network, gradient boosting, AdaBoost, and Support Vector Machine) were trained on the highest-ranked metabolites selected by the Information Gain Ratio feature-ranking approach. Model performance was evaluated using 10-fold cross-validation, leave-one-out cross-validation (LOOCV), permutation testing, and a classifier stability analysis under biologically meaningful distributional shift using an independent chemically induced hypoxia model (CoCl2). RESULTS: PCA revealed partial separation of metabolic profiles across conditions, indicating different Warburg-like metabolic subtypes. The combined HG-Hyp condition exhibited enhanced angiogenic potential relative to either HG or Hyp alone. KEGG pathway enrichment analysis identified fatty acid biosynthesis and elongation among the most significantly enriched pathways in HRECs under combined HG-Hyp conditions, alongside amino sugar and nucleotide sugar metabolism, glycerophospholipid metabolism, the pentose phosphate pathway, and glycolysis/gluconeogenesis. Supervised machine-learning classifiers distinguished these metabolic subtypes, with AdaBoost and gradient Boosting showing the most balanced, reproducible performance across 10-fold cross-validation, LOOCV, and permutation testing, and remaining the most reliable classifiers under domain-shift testing (area under the curve = 0.88, P = 0.0061). CONCLUSIONS: In this exploratory analysis, HG, Hyp, and their combination drive metabolically and functionally distinct subtypes of Warburg-like metabolic reprogramming in HRECs, with HG-Hyp in combination producing a highly angiogenic phenotype. Boosting-based ensemble classifiers provide a promising framework for detecting these subtypes even under domain-shift conditions, warranting validation in larger independent datasets. TRANSLATIONAL RELEVANCE: Integrating metabolomics with machine-learning classification offers a strategy to identify Warburg-like metabolic subtypes in retinal endothelial cells, providing insights into angiogenic mechanisms and guiding the development of targeted diagnostics or therapeutics for PDR.

Humans↗