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PubMed1989

Differences between negative inotropic and vasodilator effects of calcium antagonists acting on extra- and intracellular calcium movements in rat and guinea-pig cardiac preparations.

In order to get more insight into the utilization of calcium in the mammalian heart and the influence of calcium antagonists on this process we have evaluated the negative inotropic and vasodilator effect of nifedipine, diltiazem, verapamil, bepridil and lidoflazine as well as of the intracellularly acting calcium antagonists ryanodine and TMB-8 in the presence of 0.9 and 1.8 mmol/l calcium in rat Langendorff hearts. The effect of ryanodine was also studied in guinea-pig Langendorff hearts. In addition, in rat and guinea-pig papillary muscles the effect of these drugs on the force of contraction was examined. With the exception of ryanodine and TMB-8 all calcium antagonists induced a pronounced coronary vasodilator effect. The rank order of potency for this effect was: nifedipine greater than verapamil = diltiazem = bepridil = lidoflazine in the presence of 0.9 mmol/l calcium. At a calcium concentration of 1.8 mmol/l nifedipine and verapamil proved more potent, whereas diltiazem was less active. All calcium antagonists completely suppressed the development of the left ventricular pressure. At a calcium concentration of 0.9 mmol/l the potency order for this effect was: ryanodine greater than nifedipine = verapamil greater than diltiazem = bepridil = lidoflazine greater than TMB-8. In the presence of 1.8 mmol/l calcium the concentration-response curves for reduction of the left ventricular pressure by nifedipine, verapamil and diltiazem slightly shifted to the right. In contrast to all calcium antagonists investigated, in guinea-pig Langendorff hearts ryanodine only partially decreased the left ventricular pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

An ultrastructural double-labelling method: immunohistochemical localization of cell adhesion molecule L1 on HRP-labelled developing corticospinal tract axons in the rat.

A double electronmicroscopical (EM) staining was developed which enabled the ultrastructural localization of cell adhesion molecules on the outer axonal membrane of horseradish peroxidase (HRP)-labelled axons in the developing central nervous system (CNS). HRP was used to anterogradely trace outgrowing corticospinal tract (CST) axons in ten-day-old rats. After visualization of HRP using tetramethylbenzidine (TMB) as a chromogen and ammoniumheptamolybdate (AHM) as a stabilizer at pH 6.0 as described previously (Joosten et al. 1987, J Histochem Cytochem 35: 623-626) an additional diaminobenzindine (DAB)-Ni incubation was carried out for further stabilization. Subsequently a preembedding immunoperoxidase (DAB) staining was executed for detection of cell adhesion molecule L1. Using this procedure anterogradely HRP-labelled CST axons were recognizable by a granular black TMB-AHM-DABNi reaction product at the light microscopic (LM) level, which clearly contrasts to the relatively homogeneous brown L1-immunostaining. Electronmicroscopically HRP-labelled CST axons were characterized by the presence of an intracellular crystaloid TMB-AHM-DABNi reaction product which made identification of CST axons rather easy, whereas the L1-DAB precipitate could be noted on the outer axonal membrane of the HRP-labelled CST axons, marking the presence of the L1 cell adhesion molecule. In addition the procedure described in this report preserves ultrastructural details of developing neural tissue. In conclusion, the method presented can be employed in combined HRP-tracing and immunohistochemical electronmicroscopic studies.

Animals↗

PubMed1983

The effect of calmodulin antagonists on amylase release from the rat parotid gland in vitro.

The effect of several calmodulin antagonists on the release of alpha-amylase (EC 3.2.1.1) from rat parotid gland minces was investigated as an approach to determine whether calmodulin has a role in the stimulus-secretion coupling mechanism in this tissue. The phenothiazines, trifluoperazine, chlorpromazine, and thioridazine, failed to inhibit amylase release induced by N6,O2'-dibutyryl adenosine 3':5'-cyclic monophosphate. All three phenothiazines increased basal amylase release at high concentrations. This release was independent of cellular energy, indicating that the release was probably due to the membrane perturbing properties of these compounds rather than their ability to antagonize calmodulin. R24571, a more potent calmodulin antagonist, also failed to inhibit amylase release induced by N6,O2'-dibutyryl adenosine 3':5'-cyclic monophosphate but increased basal amylase release. A different calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, partially inhibited release while 8-(N,N-diethylamino)-octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8) completely blocked the amylase release induced by the cyclic AMP derivative. However, concentrations of TMB-8 inhibiting amylase release drastically reduced the ATP concentration of rat parotid minces, suggesting that the inhibition of secretion was due to toxic effects of TMB-8 on parotid cells rather than the ability of the compound to antagonize calmodulin. The use of calmodulin antagonists has therefore failed to implicate calmodulin as an intermediate in the stimulus-secretion coupling mechanism of the rat parotid gland.

Adenosine Triphosphate↗

PubMed1980

Properties of concanavalin A-elicited granule exocytosis from human polymorphonuclear neutrophils.

Exposure of human neutrophils to concanavalin A (Con A) resulted in a time- and concentration-dependent extracellular release of granule-associated lysozyme but not beta-glucuronidase or cytosolic lactate dehydrogenase. Maximum extrusion of lysozyme occurred 30 min after cell contact with Con A. The percent of total granule enzyme activity discharged is insignificant when cells are not preincubated with cytochalasin B prior to being exposed to Con A (5-50 micrograms/ml). Granule enzyme release from Con A-treated cells is markedly inhibited by alpha-methyl-D-mannoside. Con A-elicited extrusion of lysozyme is reduced significantly, but not abolished, in the absence of extracellular calcium. However, contact between neutrophils and EGTA in calcium-free medium had no effect on Con A-stimulated release of granule enzymes. 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8), an antagonist of intracellular calcium, caused a dose-dependent inhibition of lysozyme discharge from Con A-treated neutrophils. The activity of TMB-8 could be abrogated with the addition of calcium, but not magnesium, to the extracellular medium. Therefore, Con A and TMB-8 should serve as useful tools for elucidating the mechanism of granule enzyme release from neutrophils.

Calcium↗

PubMed2006

High activity of xylose reductase and xylitol dehydrogenase improves xylose fermentation by recombinant Saccharomyces cerevisiae.

Xylose fermentation performance was studied of a previously developed Saccharomyces cerevisiae strain TMB 3057, carrying high xylose reductase (XR) and xylitol dehydrogenase (XDH) activity, overexpressed non-oxidative pentose phosphate pathway (PPP) and deletion of the aldose reductase gene GRE3. The fermentation performance of TMB 3057 was significantly improved by increased ethanol production and reduced xylitol formation compared with the reference strain TMB 3001. The effects of the individual genetic modifications on xylose fermentation were investigated by comparing five isogenic strains with single or combined modifications. All strains with high activity of both XR and XDH had increased ethanol yields and significantly decreased xylitol yields. The presence of glucose further reduced xylitol formation in all studied strains. High activity of the non-oxidative PPP improved the xylose consumption rate. The results indicate that ethanolic xylose fermentation by recombinant S. cerevisiae expressing XR and XDH is governed by the efficiency by which xylose is introduced in the central metabolism.

Aldehyde Reductase↗

PubMed2001

Biodegradation of soluble aromatic compounds of jet fuel under anaerobic conditions: laboratory batch experiments.

Laboratory batch experiments were performed with contaminated aquifer sediments and four soluble aromatic components of jet fuel to assess their biodegradation under anaerobic conditions. The biodegradation of four aromatic compounds, toluene, o-xylene, 1,2,4-trimethylbenzene (TMB), and naphthalene, separately or together, was investigated under strictly anaerobic conditions in the dark for a period of 160 days. Of the aromatic compounds, toluene and o-xylene were degraded both as a single substrate and in a mixture with the other aromatic compounds, while TMB was not biodegraded as a single substrate, but was biodegraded in the presence of the other aromatic hydrocarbons. Substrate interaction is thus significant in the biodegradation of TMB. Biodegradation of naphthalene was not observed, either as a single substrate or in a mixture of other aromatic hydrocarbons. Although redox conditions were dominated by iron reduction, a clear relation between degradation and sulfate reduction was observed. Methanogenesis took place during the later stages of incubation. However, the large background of Fe(II) masked the increase of Fe(II) concentration due to iron reduction. Thus, although microbial reduction of Fe(III) is an important process, the evidence is not conclusive. Our results have shown that a better understanding of the degradation of complex mixtures of hydrocarbons under anaerobic conditions is important in the application of natural attenuation as a remedial method for soil and groundwater contamination.

Anaerobiosis↗

PubMed1984

Inhibition of (H+ + K+)-ATPase and H+ accumulation in hog gastric membranes by trifluoperazine, verapamil and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate.

The mechanism of gastric antisecretory action for trifluoperazine, verapamil and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) has been studied utilizing isolated hog gastric membranes enriched with (H+ + K+)-ATPase. The drugs inhibited the gastric ATPase due to their apparent competition with K+ for the luminal high-affinity K+-site of the ATPase. The dose to inhibit 50% (ID50) of the ATPase in the membranes rendered freely permeable to K+ (20 mM) was 50 microM for trifluoperazine and 1.5 mM for verapamil and TMB-8. In intact hog gastric membranes which develop a pH gradient in the presence of valinomycin, ATP and KCl, however, trifluoperazine at 4 microM, verapamil and TMB-8 at 15 microM inhibited 40 and 30% of the valinomycin-stimulated ATPase activity, respectively, and also blocked the ionophore-dependent intravesicular acidification as measured by aminopyrine accumulation. The enhanced potency of the drugs to inhibit the ATPase in the intact membrane vesicles may be attributed to the accumulation of the drugs as a weak base within the vesicles, where the luminal K+-site of the ATPase is accessible. Calmodulin and Ca2+ had no effect on the extent of H+-accumulation as measured by aminopyrine accumulation in the membrane vesicles which were prepared in the presence of 1 mM EGTA. Since the drugs showed similar potency in interfering with H+ movements either in the membrane vesicles or isolated rabbit gastric glands stimulated by dibutyryl cAMP, it is reasonable to suggest the inhibitory effect of the drugs on (H+ + K+)-ATPase as a primary cause for such interferences in both cases. A trifluoperazine analog and other lipophilic amine drugs similarly inhibited (H+ + K+)-ATPase and H+ accumulation in the membrane vesicles or in the glands. We have concluded that a tertiary amine, the only common functional group among these drugs, is primarily responsible for their ability to interact with the high-affinity K+ site of the gastric ATPase.

Adenosine Triphosphatases↗

PubMed1985

The effects of some non-steroidal anti-inflammatory agents on membrane-associated calcium in rabbit peritoneal neutrophils.

Several non-steroidal anti-inflammatory agents (NSAIAs) (flufenamate, flurbiprofen, indomethacin, phenylbutazone, piroxicam and salicylate), one anti-inflammatory steroid (hydrocortisone) and three compounds known to affect cellular calcium metabolism [nifedipine, calcium ionophore A23187, 8-(diethylamino)octyl 3,4,5,-trimethoxy benzoate hydrochloride (TMB-8)] were tested for their effects on membrane-associated calcium in rabbit peritoneal neutrophils using the fluorescent probe chlortetracycline (CTC). The NSAIAs reduced the level of fluorescence attained by incubating neutrophils with CTC, and caused an immediate reduction in the fluorescence of CTC-loaded neutrophils, both effects being concentration-related. Nifedipine, A23187 and TMB-8 also reduced the fluorescence of CTC-loaded cells. However, these measured reductions in fluorescence were due in whole or in part to a drug-induced drop in the autofluorescence of the neutrophils. After applying a correction factor which took account of this effect there was still an immediate concentration-related reduction in CTC-dependent fluorescence after the addition of all the NSAIAs. A23187 also caused a reduction in CTC fluorescence, but nifedipine, TMB-8 and hydrocortisone were inactive. Flufenamate, indomethacin and piroxicam reduced the drop in fluorescence brought about by N-formyl-methionyl-leucyl-phenylalanine (FMLP). These findings suggest that NSAIAs and A23187 displace membrane-associated calcium. Electron microscopical findings confirm that indomethacin and salicylate both affect membrane-associated calcium. Using the fluorescent probe Quin 2, an attempt was made to determine whether or not the displacement of membrane-associated calcium by NSAIAs was accompanied by changes in cytoplasmic calcium ion concentration. This was unsuccessful, however, since the effects of the NSAIAs on the fluorescence of Quin 2-loaded neutrophils was accounted for almost entirely by their effects on the autofluorescence of the cells.

Aminoquinolines↗

PubMed1993

Basic fibroblast growth factor (bFGF) regulates tyrosine hydroxylase and proenkephalin mRNA levels in adrenal chromaffin cells.

bFGF is a neurotrophic protein expressed in various regions of the adult peripheral and central nervous system. The present study was undertaken to examine the role of bFGF in multihormonal, catecholaminergic and enkephalinergic cells of the adrenal medulla (AM). Western blot analysis revealed the presence of at least three bFGF isoforms (18, 22/23, and 24 kDa) in cultured bovine AM cells. Incubation of AM cells with the exogenous 18 kDa bFGF produced time-dependent increases in tyrosine hydroxylase (TH) and proenkephalin (PEK) mRNA, with maximal changes occurring at 12 h (TH) or 24 h (PEK) of bFGF exposure. Effects of bFGF on TH and PEK mRNA were non-additive with increases induced by exposure of AM cells to nicotine, the depolarizing agent veratridine, or the adenylate cyclase activator forskolin. These data indicate that bFGF effects may occur through intracellular pathways accessed during transsynaptic induction of TH and PEK genes. The increases in PEK mRNA induced by nicotine or bFGF were inhibited by the calcium antagonist TMB-8. TMB-8 also inhibited bFGF-induced increases in TH mRNA as well. However, treatment with TMB-8 increased basal levels of TH mRNA. The addition of bFGF increased endogenous levels of c-fos mRNA, c-Fos and c-Fos-related proteins, suggesting that bFGF may activate TH and PEK gene expression through a calcium-AP1 transcriptional regulatory pathway. Immunohistochemical analysis revealed the presence of bFGF-immunoreactivity (bFGF-IR) in the cytoplasm and in the nucleus of AM cells. Incubation of cells with exogenous bFGF produced time-dependent increases of nuclear bFGF-IR.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗

PubMed1983

Calcium antagonists and calmodulin inhibitors block cytokinin-induced bud formation in Funaria.

The plant hormone cytokinin stimulates nuclear migration followed by an asymmetric cell division in target cells of the protonema of the moss Funaria hygrometrica, leading to bud formation. The role of calcium in this developmental event was investigated by examining the effects of various calcium antagonists on the cytokinin-induced division. Calcium-free medium (buffered with EGTA), the extracellular Ca2+ antagonist La3+ (lanthanum), and the Ca2+ channel inhibitors D 600 and verapamil all block bud formation. These inhibitions are partially reversed by washing the cells or by raising the extracellular [Ca2+]. The Ca2+ ionophore A23187 partially reversed the effects of D 600 and verapamil. Bud formation is also inhibited by the intracellular Ca2+ antagonist TMB-8 (8-diethylamino)octyl 3,4,5-trimethoxybenzoate HCl), and this inhibition is partially reversed by washing or raising the extracellular [Ca2+]. The cross walls of both the filaments and bud initial cells formed during TMB-8 exposure exhibit a distorted morphology. High concentrations of TMB-8 block nuclear migration. The calmodulin inhibitor trifluoperazine stops cytokinin-induced budding more effectively than the related compound chlorpromazine. Low concentrations of these two compounds do not affect nuclear migration; however, the target cell does not enter mitosis. These results support the hypothesis that a rise in intracellular calcium mediates cytokinin-induced bud formation in Funaria. It is concluded that the proposed cytokinin-induced rise in intracellular calcium may be effected in part by the activation of calmodulin. The essential source of Ca2+ appears to be extracellular, because blocking Ca2+ uptake with Ca2+ transport inhibitors can block both nuclear migration and subsequent division.

Calcium↗

PubMed1995

Hypoglycemia-induced cognitive dysfunction in diabetes mellitus: effect of hypoglycemia unawareness.

Hypoglycemia results in cognitive dysfunction. The aim of this study was to assess and compare the degree of cognitive dysfunction experienced by insulin-dependent diabetic patients (IDDM) with hypoglycemia unawareness with patients with normal awareness of hypoglycemia. Cognitive function was examined in 10 patients who had normal awareness of the onset of hypoglycemia and 10 patients who had a history of impaired awareness of hypoglycemia. A hyperinsulinemic glucose clamp was used to manipulate blood glucose concentrations. Cognitive function was assessed using Rapid Visual Information Processing (RVIP), Trial Making B (TMB), Paced Auditory Serial Addition Test (PASAT) and Digit Symbol Substitution Test (DSST). Multivariate analysis of variance demonstrated a significant effect of hypoglycemia on cognitive function (p < 0.01). A trend was observed towards an overall effect of awareness on performance (p = 0.08). There were trends in the effects of awareness on RVIP correct responses across time (p = 0.07) and the interaction of awareness by study by TMB (p = 0.08). During hypoglycemia subjects with impaired awareness were less cautious in their responses (RVIP misses p = 0.03) and on recovery from hypoglycemia, their cognitive function remained abnormal (TMB p = 0.04, RVIP correct responses p = 0.02, RVIP misses p = 0.04). Thus, IDDM patients with hypoglycemia unawareness exhibited more profound cognitive dysfunction during acute hypoglycemia which persisted for longer following blood glucose recovery.

Adult↗

PubMed1987

Calcium dependency of massive postmortem bronchoconstriction in guinea pig lungs.

Calcium antagonists were employed to examine whether or not guinea pig's postmortem bronchoconstriction is calcium dependent. First, a group of 17 young (3-4-week-old) animals were divided in three subgroups: control, nifedipine, and 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8, an intracellular calcium antagonist). A second group of 12 mature (5-7-week-old) animals were divided into two subgroups: control and nifedipine. Baseline pressure-volume (P-V) curves were performed prior to cannulation of the pulmonary artery in the anesthetized, opened chested animal. The lungs of the animal were then perfused and P-V curves were obtained again at intervals for up to 60 min. Nifedipine (10(-6) M) or TMB-8 (5 X 10(-4) M) was added to the perfusate in experimental groups. A temporal decrease in inflation volume (IV, the lung volume between transpulmonary pressure of 0 and 30 cm H2O during inflation) was used as an indicator of bronchoconstriction. In control subgroups, the decrease in IV was significantly greater (P less than 0.05) in the young (29.5 +/- 12.9% baseline at 20 min) than in the mature animals (75.0 +/- 7.0% baseline at 20 min). Nifedipine significantly alleviated (P less than 0.05) the decrease in IV in young animals at 15-30 min (58.6 +/- 8.4% baseline at 20 min) while TMB-8 (90.6 +/- 2.1% baseline at 20 min) prevented the decrease even further. Nifedipine did not have a significant effect on IV in mature animals. These data suggest that the postmortem bronchospasm is much more severe in young animals and that this severe constriction is calcium dependent.

Age Factors↗

PubMed1988

Stimulation of leucine transport by a mitogen through intracellular Ca2+ increase in human peripheral lymphocytes.

The effect of concanavalin A and ionophore A23187 on leucine uptake by human peripheral lymphocytes has been examined. Preincubation of the cells with 32 micrograms/ml concanavalin A or 0.1 microM A23187 increased leucine uptake by 67% and 100%, respectively. Both concanavalin A and A23187 could, within 2 min, induce a more than 2-fold increase in the cytoplasmic free Ca2+ concentration ([Ca2+]i). This increase by concanavalin A was completely blocked by the addition of 0.1 mM 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) to incubation medium; TMB-8 partially blocked the action of A23187. The stimulation of leucine uptake by concanavalin A and A23187 was strongly inhibited by the presence of TMB-8 in the medium, whereas the basal uptake was not affected by this intracellular Ca2+ antagonist. Amiloride did not inhibit the stimulation of leucine uptake by concanavalin A. The concanavalin A- and A23187-induced elevation of [Ca2+]i was accompanied by membrane hyperpolarization. Concanavalin A-stimulated leucine uptake was greatly inhibited by the presence of an excess of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid. These results indicate that the increase in [Ca2+]i may function as a signal of the stimulation by mitogen of leucine uptake mediated by system L, finally inducing membrane hyperpolarization in human lymphocyte.

Amiloride↗

PubMed1981

Electron microscopical identification of 3,3',5,5'-tetramethylbenzidine-reacted horseradish peroxidase after retrograde axoplasmic transport.

Tetramethylbenzidine (TMB) histochemistry for retrogradely transported horseradish peroxidase (HRP) has been successfully applied in electron microscopical preparations in the guinea pig visual cortex. In ultrathin sections, the TMB--HRP reaction product appears as an accumulation of typical electron-dense crystals. These crystals were identified in the cytoplasm of labeled cells in the proximal portions of the dendrites, and in myelinated axons. It is demonstrated that the TMB--HRP method is well suitable to analyze the ultrastructure of labeled cells and their synaptology.

Animals↗

PubMed1992

Studies of the amplification of carbaryl toxicity by various oximes.

The administration of 2-pyridine aldoxime methyl chloride (2-PAM Cl) is a standard part of the regimen for treatment of human overexposure to many organophosphorus pesticides and nerve agents. However, some literature references indicate that poisoning by carbaryl (1-naphthyl N-methyl carbamate), an insecticide in everyday use, is aggravated by the administration of 2-PAM Cl. This effect has been reported in the mouse, rat, dog and man. We have found that the inhibition of both eel acetylcholinesterase (eel AChE, EC 3.1.1.7) and human serum cholinesterase (human BuChE, EC 3.1.1.8) by carbaryl was enhanced by several oximes. Based on 95% confidence limits the rank order of potentiation with eel AChE was TMB-4 = Toxogonin > HS-6 = HI-6 > 2-PAM Cl. By the same criterion, the rank order of potentiation with human BuChE was TMB-4 > Toxogonin > HS-6 = 2-PAM Cl. Carbaryl-challenged mice also reflected a potentiation since TMB-4 exacerbated the toxicity more than 2-PAM Cl. Our hypothesis is that certain oximes act as allosteric effectors of cholinesterases in carbaryl poisoning, resulting in enhanced inhibition rates and potentiation of carbaryl toxicity.

Animals↗

PubMed2004

Langmuir-Blodgett films incorporating redox mediators for molecular recognition of NADH.

We focused our studies on the fabrication of nano-organized systems incorporating redox mediators for NADH. We fabricated gold-modified electrodes of phospholipid layers containing a redox mediator for NADH by means of the Langmuir-Blodgett (LB) technique. We chose tetramethylbenzidine (TMB) which is known to decrease the very large overvoltage involved in the direct oxidation of NADH. The electrochemical characterisation of the films allowed to determine the presence and the electrochemical activity of the mediator in the LB layers. The response of the sensing layer in solutions containing NADH was investigated by means of cyclic voltammetry and fluorescence spectroscopy. We observed that NADH has a strong affinity with the film, and it interacts with the TMB-containing phospholipid layers. In fact, we found that TMB molecules mediate the NADH oxidation reaction, even if the surrounding matrix relatively hinders their mobility.

Benzidines↗

PubMed2006

Increasing the scale of true moving bed electrophoretic separations using filtration to reduce solvent volumetric flows between sections II and III.

Over the past decade the moving bed process has become a commonly used tool for the continuous separation of chiral compounds, and its recent application to electrophoretic separations allows the technique to be used as a model system for moving bed method improvements. Much of the recent research on moving bed separations has focused on improving the technique's efficiency and increasing the maximum attainable throughput. This paper presents a novel method for reducing or reversing the increases in tailing that stem from the addition of the feed stream in a moving bed process by adding a filtration unit which retains the products while removing fluid from the boundary between the sections above and below the feed stream. This filtration-enhanced moving bed process was applied to a true moving bed (TMB) electrophoresis separation in the Vortex Stabilized Electrophoresis Apparatus, and its effect on a homatropine enantiomer separation was studied. Experiments showed that there is a 2.4-fold increase in the homatropine processing rate when 0.5 ml/h of water is removed through a reverse osmosis filter at the boundary between the sections above and below the feed stream. In order to further understand the process, filtration-enhanced TMB (FE-TMB) was also analyzed using a linear model of the system which shows that the 99% purity operating region of the separation is greatly increased even with moderate permeate flowrates.

Adsorption↗

PubMed2026

Integrated Genomic and Immune Profiling of Early Onset Lung Cancer in East Asians Reveals a Distinct Molecular Architecture.

BACKGROUND: The age cut-off for early-onset lung cancer (EOLC) varies across studies (40-50 years). Here, we define EOLC as diagnosis at ≤ 40 years, a threshold identifying a subgroup with distinct clinical characteristics. However, whether EOLC differs fundamentally from late-onset lung cancer (LOLC) at the molecular level and represents a distinct subtype requiring different management remains unclear. METHODS: This integrated analysis included genomic and immune profiling data from 8,021 lung cancer patients, comprising 302 EOLC and 7,719 LOLC cases. Using targeted sequencing, we assessed somatic and germline alterations, mutational signatures, and immune biomarkers including tumor mutational burden (TMB), MSI status, and PD-L1 expression. RESULTS: EOLC patients were more often female, had adenocarcinoma, and earlier-stage disease. Molecular profiling revealed significant enrichment of ERBB2 mutations in EOLC, while KRAS, TP53, and MET mutations were more common in LOLC. Mutational signature analysis indicated tobacco-related signatures predominated in LOLC, whereas endogenous processes contributed more substantially in EOLC. Germline analysis showed a higher burden of pathogenic variants in EOLC (14.57% vs. 8.93%, P < .01), with TP53 and BRCA1 being particularly prominent. Immunologically, LOLC tumors exhibited higher TMB and PD-L1 positivity. CONCLUSION: Integrated profiling establishes EOLC as a distinct molecular subtype, defined by a unique triad: an ERBB2-driven somatic profile, germline susceptibility in DNA damage response pathways, and an endogenous mutagenic process within a low-TMB microenvironment. The findings are specific to the selected threshold and should be interpreted accordingly, while elucidating EOLC pathogenesis and supporting age-specific management strategies.

Humans↗