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PubMed2003

Current controversies in sentinel lymph node biopsy for breast cancer.

Despite the widespread use of sentinel lymph node biopsy (SLNBx) in the surgical management of breast cancer patients, several areas remain controversial. The following controversies are reviewed: Learning curves and validation studies. There clearly is a learning curve, and a completion ALND should be done until adequate proficiency is exhibited, both in terms of identification and false-negative rates. Location of injection. Intradermal injection offers superior identification rates compared with peritumoral injection, with comparable false-negative rates. Subareolar injection is as accurate as peritumoral injection. The value of scintigraphy. Routine scintigraphy does not enhance identification or false-negative rates. Mapping agents. Blue dye and radioactive tracer combined to provide a higher identification rate than either used alone.SLNBx in DCIS. In patients with a high risk of microinvasion, such as large tumors, a mass or high-grade DCIS-SLNBx is justified.SLNBx following neoadjuvant chemotherapy. Although there is evidence that SLNBx after neoadjuvant chemotherapy may be accurate, these data should be applied cautiously. Implications of non axillary SLN, especially internal mammary nodes. Data do not support routine resection of internal mammary sentinel lymph nodes outside a clinical trial. Implications of micrometastases in the sentinel lymph node seen only on immunohistochemistry. Since the significance of such metastases is unclear, decisions regarding treatment of these patients should be individualized. The value of completion axillary lymph node dissection. Is being addressed in clinical trials. Until those studies mature, completion ALND should be performed for patients with SLN metastases, but may be abandoned for patients with a negative SLN.

Breast Neoplasms↗

PubMed2003

Characterization of vigabatrin-associated optic atrophy.

AIMS: To report the discovery of a previously unknown form of optic atrophy associated with use of the anti-epileptic drug vigabatrin. METHODS: We conducted a retrospective analysis of digitally enhanced ocular fundus photographs, kinetic visual field maps and treatment parameters for 25 patients, who were selected to represent a large spectrum of visual field defects. RESULTS: In all, 21 patients (84%) evidenced subtle, diffuse atrophy of the retinal nerve fibre layer, in a pattern accessible to scoring. Atrophy scores correlated with visual field remains and cumulative vigabatrin doses. A pathophysiological model is proposed that involves the lengths of intraocular (unmyelinated) retinal ganglion cell axons. CONCLUSION: Optic atrophy attests to the irreversible nature of vigabatrin's visual toxicity. Ocular fundus imaging should prove useful for objectively monitoring vigabatrin-treated subjects for visual toxicity.

Anticonvulsants↗

PubMed2006

Integration of metabolome data with metabolic networks reveals reporter reactions.

Interpreting quantitative metabolome data is a difficult task owing to the high connectivity in metabolic networks and inherent interdependency between enzymatic regulation, metabolite levels and fluxes. Here we present a hypothesis-driven algorithm for the integration of such data with metabolic network topology. The algorithm thus enables identification of reporter reactions, which are reactions where there are significant coordinated changes in the level of surrounding metabolites following environmental/genetic perturbations. Applicability of the algorithm is demonstrated by using data from Saccharomyces cerevisiae. The algorithm includes preprocessing of a genome-scale yeast model such that the fraction of measured metabolites within the model is enhanced, and thus it is possible to map significant alterations associated with a perturbation even though a small fraction of the complete metabolome is measured. By combining the results with transcriptome data, we further show that it is possible to infer whether the reactions are hierarchically or metabolically regulated. Hereby, the reported approach represents an attempt to map different layers of regulation within metabolic networks through combination of metabolome and transcriptome data.

Algorithms↗

PubMed2026

Locus-specific stratification and prioritization unveil genetic risk mechanism underlying complex diseases.

Although genome-wide association studies have identified thousands of disease-associated loci, the mechanistic understanding and drug target discovery remain challenging, particularly for complex diseases. The multi-signal architecture of complex diseases complicates the interpretation of genetic contributions. To address this challenge, we develop an approach comprising locus-specific stratification (LSS) and gene regulatory prioritization score (GRPS), which uniquely considers multi-signals during fine-mapping and target gene identification. LSS significantly enhances the interpretability of genetic risk associated with complex diseases. For loci associated with serum urate levels, the method identifies candidate causal genes in 34.43% of loci, surpassing the performance of other methods by 5.47% to 25.14%. GRPS considers the regulatory network of LSS-variants comprehensively and successfully nominates under-explored drug targets for hyperuricemia with high confidence such as SLC17A4, which is further validated using epigenetic activation and phenotypic assays. This study introduces an approach to efficiently and comprehensively address the multi-signal challenges in complex diseases.

Humans↗

PubMed2005

Imaging photon-initiated reactions: a study of the Cl(2P(3/2))+CH4-->HCl+CH3 reaction.

The hydrogen or deuterium atom abstraction reactions between Cl((2)P(3/2)) and methane, or its deuterated analogues CD(4) and CH(2)D(2), have been studied at mean collision energies around 0.34 eV. The experiments were performed in a coexpansion of molecular chlorine and methane in helium, with the atomic Cl reactants generated by polarized laser photodissociation of Cl(2) at 308 nm. The Cl-atom reactants and the methyl radical products were detected using (2+1) resonantly enhanced multiphoton ionization, coupled with velocity-map ion imaging. Analysis of the ion images reveals that in single-beam experiments of this type, careful consideration must be given to the spread of reagent velocities and collision energies. Using the reactions of Cl with CH(4), CD(4), and CH(2)D(2), as examples, it is shown that the data can be fitted well if the reagent motion is correctly described, and the angular scattering distributions can be obtained with confidence. New evidence is also provided that the CD(3) radicals from the Cl+CD(4) reaction possess significant rotational alignment under the conditions of the present study. The results are compared with previous experimental and theoretical works, where these are available.

Journal Article↗

PubMed2006

Parity-dependent rotational rainbows in D2-NO and He-NO differential collision cross sections.

The (j', Omega', epsilon') dependent differential collision cross sections of D2 with fully state selected (j = 12, Omega = 12, epsilon = -1) NO have been determined at a collision energy of about 550 cm(-1). The collisionally excited NO molecules are detected by (1+1') resonance enhanced multiphoton ionization combined using velocity-mapped ion-imaging. The results are compared to He-NO scattering results and tend to be more forward scattered for the same final rotational state. Both for collisions of the atomic He and the molecular D2 with NO, scattering into pairs of rotational states with the same value of n = j' - epsilon epsilon'2 yields the same angular dependence of the cross section. This "parity propensity rule" remains present both for spin-orbit conserving and spin-orbit changing transitions. The maxima in the differential cross sections-that reflect rotational rainbows-have been extracted from the D2-NO and the He-NO differential cross sections. These maxima are found to be distinct for odd and even parity pair number n. Rainbow positions of parity changing transitions (n is odd) occur at larger scattering angles than those of parity conserving transitions (n is even). Parity conserving transitions exhibit-from a classical point of view-a larger effective eccentricity of the shell. No rainbow doubling due to collisions onto either the N-end or the O-end was observed. From a classical point of view the presence of a double rainbow is expected. Rotational excitation of the D2 molecules has not been observed.

Journal Article↗

PubMed2002

Evidence for a role of nuclear factor-kappaB in acute hypovolemic hemorrhagic shock.

BACKGROUND: In acute hypovolemic shock, a rapid systemic release of the inflammatory cytokine tumor necrosis factor (TNF-alpha) contributes to vascular failure. Nuclear factor kappaB (NF-kappaB) is an ubiquitous rapid-response transcription factor involved in inflammatory reactions and exerts its effect by expressing cytokines, chemokines, and cell adhesion molecules. The purpose of this study was to evaluate the role of NF-kappaB in acute hypovolemic hemorrhagic shock. METHODS: Hemorrhagic shock was induced in anesthetized male rats by intermittently withdrawing blood from an iliac catheter for 20 minutes (bleeding period) until mean arterial blood pressure (MAP) decreased and stabilized within the range of 20 to 30 mm Hg. Two minutes after bleeding was discontinued the rats received tacrolimus (100 microg/kg), an inhibitor of NF-kappaB activation, or its vehicle. We then evaluated survival rate and survival time, liver NF-kappaB activation by means of electrophoretic mobility shift assay, liver IkappaBalpha protein in the cytoplasm, hepatic TNF-alpha messenger RNA expression, plasma TNF-alpha, arterial blood pressure, and the contractile response of aortic rings to phenylephrine. RESULTS: Rats that underwent hemorrhagic shock died 28+/-2 minutes after bleeding was discontinued, experienced marked hypotension (MAP, 20-30 mm Hg), and had enhanced plasma levels of TNF-alpha (218 +/- 28 pg/mL 20 minutes after bleeding was discontinued). Aortas taken 20 minutes after bleeding was discontinued in rats that underwent hemorrhagic shock showed marked hyporeactivity to phenylephrine (1 nmol/L-10 micromol/L) compared with aortas harvested from sham shocked rats. Rats that underwent hemorrhagic shock also had increased levels of TNF-alpha messenger RNA in the liver. Furthermore, electrophoretic mobility shift assay showed that liver NF-kappaB binding activity increased in the nucleus, and Western blot analysis suggested that the levels of inhibitory IkappaBalpha protein in the cytoplasm decreased. Tacrolimus (100 microg/kg, administered 2 minutes after bleeding was discontinued) inhibited the loss of IkappaBalpha protein from the cytoplasm and prevented NF-kappaB binding activity in the nucleus. Moreover, tacrolimus increased survival time (118 +/- 7 minutes; P <.01) and survival rate (vehicle = 0 and tacrolimus = 90% 240 minutes after bleeding was discontinued), reverted the marked hypotension, decreased liver messenger RNA for TNF-alpha reduced plasma TNF-alpha (35 +/- 6 pg/mL), and restored the hyporeactivity to phenylephrine to control values. CONCLUSIONS: Our results suggest that acute blood loss (50% of the estimated total blood volume during a 20-minute period) causes activation of NF-kappaB and that tacrolimus, by inhibiting this transcription factor, protects against acute hypovolemic shock.

Acute Disease↗

PubMed1997

Cloning and characterization of the type I inositol 1,4,5-trisphosphate receptor gene promoter. Regulation by 17beta-estradiol in osteoblasts.

The inositol 1,4,5-trisphosphate (InsP3) receptor is essential for signal Ca2+ release from intracellular stores and for capacitative Ca2+ entry. We have isolated the promoter and proximal DNA segments of the human type I InsP3 receptor gene. Transcription initiation in human G-292 osteosarcoma and HL-60 promyelocytic leukemia cells was shown to occur predominantly from an adenine residue located 39 base pairs downstream of a consensus TATA box element. Upstream DNA including the TATA box promoted directional transcription of a chloramphenicol acetyltransferase reporter gene when transfected into G-292 cells. A negative regulatory element in the distal promoter and a positive element in the proximal region were identified by deletion mapping and transcription assays. The proximal region enhanced transcription in response to 12-O-tetradecanoylphorbol-13-acetate or serum, but conferred transcriptional repression in response to 1,25-dihydroxyvitamin D3 or 17beta-estradiol. The repressive effect of 17beta-estradiol was mediated by the nuclear estrogen receptor, as estrogen-dependent transcriptional repression was inhibited by the antiestrogen tamoxifen and the estrogen receptor antagonist ICI 182,780. This is the first study of the type I InsP3 receptor gene promoter, and the results suggest a mechanism by which chronic estrogen treatment of osteoblasts affects type I InsP3 receptor gene expression, signal transduction, and secretion.

Base Sequence↗

PubMed2006

Hdm2 nuclear export, regulated by insulin-like growth factor-I/MAPK/p90Rsk signaling, mediates the transformation of human cells.

Insulin-like growth factor (IGF)-I receptor activation leads to enhanced proliferation and cell survival via the MAP kinase and phosphatidylinositol 3-kinase-signaling pathways. Upon stimulation by IGF-I, the Hdm2 oncoprotein is phosphorylated by AKT, leading to its rapid nuclear translocation and subsequent inhibition of p53. We now show that IGF-I stimulation regulates the nuclear export of Hdm2 and p53 via the MAP kinase pathway. Inhibition of p38 MAPK or MEK via pharmacological means or expression of dominant negative proteins inhibited the cytoplasmic accumulation of Hdm2 and increased Hdm2 and p53 protein levels, whereas constitutively active p90Rsk promoted the nuclear export of Hdm2. Expression of constitutively active p90Rsk with E1A, oncogenic H-Ras, and hTERT resulted in the anchorage-independent growth of normal human fibroblasts. Our findings link p90Rsk-mediated modulation of Hdm2 nuclear to cytoplasmic shuttling with the diminished ability of p53 to regulate cell cycle checkpoints that ultimately leads to transformation.

Active Transport, Cell Nucleus↗

PubMed2003

Three-dimensional trabecular alignment model.

Trabecular alignment theory has been used to quantify Wolff's Law of bone remodeling. A three-dimensional finite element scheme was developed to analyze the bone remodeling phenomenon. The mathematical model proposed by Mullender et al. and later modified by Smith et al. was adopted to simulate the surface-based trabecular resorption and formation processes. Enhancements incorporated into the previous model include: mapping into three-dimensions, controlling the remodeling signal's passage through marrow, controlling the finite distance the signal may pass through the bone matrix, and including non-bone material in the finite element model. After the model is explained and thoroughly studied, three-dimensional implant surface geometries are simulated.

Adaptation, Physiological↗

PubMed2001

G-protein-mediated signaling and its control in macrophages and mammalian cells.

G-protein coupled receptor (GPCR) in various cell types exert its effects through heterotrimetic GTP-binding proteins (G-proteins). The interaction of specific ligand or agonists with CPCR transuces signal and enhances gene expression, mitogen activated protein kinase (MAP kinase) activation, and thus regulates cell proliferation, differentation, and motility. Abnormal signaling or prolonged activation of G-protein signaling pathways blocks normal functioning of various cells and tissues of our body. New insights into the mechanisms governing the specificity and temporal regulation of G-protein signaling pathways have been provided by the recent discovery of GTPase-activating proteins (GAPs) and RGS proteins (regulators of G-protein signaling). Different molecular biological approaches are now being employed to study the G-protein-mediated signaling and its control in various mammalian cells. Recent developments on the activation of phagocytic cells, especially macrophages, via ligation or cross-linking of GPCR and their postreceptor ligation effect against several intramacrophage pathogens are also discussed.

Animals↗

PubMed2004

Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis).

Several studies reported linkage between bacterial infections and carcinogenesis. Streptococcus bovis was traditionally considered as a lower grade pathogen frequently involved in bacteremia and endocarditis. This bacterium became important in human health as it was shown that 25-80% of patients who presented a S.bovis bacteremia had also a colorectal tumor. Moreover, in previous experiments, we demonstrated that S.bovis or S.bovis wall extracted antigens (WEA) were able to promote carcinogenesis in rats. The aim of the present study was: (i) to identify the S.bovis proteins responsible for in vitro pro-inflammatory properties; (ii) to purify them; (iii) to examine their ability to stimulate in vitro IL-8 and COX-2 expression by human colon cancer cells; and (iv) to assess in vivo their pro-carcinogenic potential in a rat model of colon carcinogenesis. The purified S300 fraction, as determined by proteomic analysis, contained 72 protein spots in two-dimensional gel electrophoresis representing 12 different proteins able to trigger human epithelial colonic Caco-2 cells and rat colonic mucosa to release CXC chemokines (human IL-8 or rat CINC/GRO) and prostaglandins E2, correlated with an in vitro over-expression of COX-2. Moreover, these proteins were highly effective in the promotion of pre-neoplastic lesions in azoxymethane-treated rats. In the presence of these proteins, Caco-2 cells exhibited enhanced phosphorylation of the three classes of MAP kinases. Our results show a relationship between the pro-inflammatory potential of S.bovis proteins and their pro-carcinogenic properties, confirming the linkage between inflammation and colon carcinogenesis. These data support the hypothesis that colonic bacteria can contribute to cancer development particularly in chronic infection/inflammation diseases where bacterial components may interfere with cell function.

Animals↗

PubMed1997

Structural analysis of mouse rDNA: coincidence between nuclease hypersensitive sites, DNA curvature and regulatory elements in the intergenic spacer.

We have analyzed the chromatin structure of mouse ribosomal RNA genes (rDNA) by partial digestion of genomic DNA with micrococcal nuclease (MNase), DNase I and identified hypersensitive sites by indirect end-labeling. This analysis has revealed defined regions of nuclease hypersensitivity in the intergenic spacer which in turn coincide with regulatory elements. Hypersensitive sites map to the transcription initiation site, the enhancer repeats, the spacer promoter and two sequence elements which coincide with amplification-promoting sequences. Analysis of the DNA curvature by computer modeling uncovered a striking correlation between sequence-directed structural features of regulatory regions and the position of nuclease hypersensitive sites. Moreover, we demonstrate that nucleosomes are specifically positioned upstream and downstream of the transcription start site. In vitro studies using chromatin assembled in the presence of Drosophila embryo extracts show that binding of the transcription termination factor TTF-I to the upstream terminator mediates this specific nucleosome positioning at the rDNA promoter in an ATP- dependent fashion.

3T3 Cells↗

PubMed2000

The three-dimensional structure of a Trichoderma reesei beta-mannanase from glycoside hydrolase family 5.

The crystal structure of the catalytic core domain of beta-mannanase from the fungus Trichoderma reesei has been determined at a resolution of 1.5 A. The structure was solved using the anomalous scattering from a single non-isomorphous platinum complex with two heavy-metal sites in space group P2(1). The map computed with the experimental phases was enhanced by the application of an automated model building and refinement procedure using the amplitudes and experimental phases as observations. This approach is expected to be of more general application. The structure of the native enzyme and complexes with Tris-HCl and mannobiose are also reported: the mannobiose binds in subsites +1 and +2. The structure is briefly compared with that of the homologous beta-mannanase from the bacterium Thermomonospora fusca.

Actinomycetales↗

PubMed2003

Partial NMR assignments and secondary structure mapping of the isolated alpha subunit of Escherichia coli tryptophan synthase, a 29-kD TIM barrel protein.

The alpha subunit of tryptophan synthase (alphaTS) from S. typhimurium belongs to the triosephosphate isomerase (TIM) or the (beta/alpha)(8) barrel fold, one of the most common structures in biology. To test the conservation of the global fold in the isolated Escherichia coli homolog, we have obtained a majority of the backbone assignments for the 29-kD alphaTS by using standard heteronuclear multidimensional NMR methods on uniformly (15)N- and (15)N/(13)C-labeled protein and on protein selectively (15)N-labeled at key hydrophobic residues. The secondary structure mapped by chemical shift index, nuclear Overhauser enhancements (NOEs), and hydrogen-deuterium (H-D) exchange, and several abnormal chemical shifts are consistent with the conservation of the global TIM barrel fold of the isolated E. coli alphaTS. Because most of the amide protons that are slow to exchange with solvent correspond to the beta-sheet residues, the beta-barrel is likely to play an important role in stabilizing the previously detected folding intermediates for E. coli alphaTS. A similar combination of uniform and selective labeling can be extended to other TIM barrel proteins to obtain insight into the role of the motif in stabilizing what appear to be common partially folded forms.

Amino Acid Sequence↗

PubMed1984

Surface iodination of epidermal growth factor receptors in intact cells.

The membranes from epidermoid carcinoma cells (A-431) that were surface iodinated while intact using catalysis by lactoperoxidase and 125I as iodide contain one major labeled protein of Mr = 180,000. This protein is clearly iodinated on the outside of the intact cell because it is not the major protein labeled when isolated membranes are iodinated. This major surface-iodinated protein is almost certainly the epidermal growth factor (EGF) receptor, since both have the same Mr and have identical sensitivity to proteases. Both are nearly quantitatively converted from an Mr = 180,000 form to an Mr = 160,000 form by an endogenous calcium-activated neutral protease when cells are broken in the presence of calcium. Both are degraded by trypsin only if trypsin has access to the inside of the cell. This latter finding implies that the surface-iodinated EGF receptor spans the plasma membrane. Since the EGF receptor is an autophosphorylating kinase whose activity is enhanced in the presence of EGF, the receptor was labeled and identified using [gamma-32P] ATP. While both iodination and EGF-enhanced phosphorylation occur on tyrosine residues, peptide mapping of the iodinated or phosphorylated Mr = 180,000 band showed that different peptides were being labeled. Since the EGF receptor-kinase spans the plasma membrane, the peptide iodinated on the surface of the intact cell must be different from the peptides that are probably autophosphorylated on the cytoplasmic side of the membrane.

Animals↗

PubMed2026

The Role of Artificial Intelligence for Intimate Partner Violence Prevention: A Systematic Review.

INTRODUCTION: Intimate partner violence (IPV), encompassing physical, sexual, emotional and economic abuse, remains a pervasive global health concern. Traditional prevention efforts face obstacles such as underreporting, delayed detection and limited personalised support. Emerging artificial intelligence (AI) approaches offer new opportunities to enhance IPV prevention. AIM: This systematic review maps and synthesises evidence on AI-driven tools in IPV prevention based on studies published between 2004 and 2024. METHODS: Following PRISMA 2020 guidelines and PROSPERO registration, we searched PubMed, Embase, CINAHL, PsycINFO, IEEE Xplore and Web of Science. Eligible studies explicitly evaluated AI technologies targeting IPV prediction, screening, intervention or support delivery. Study quality was appraised using the Mixed Methods Appraisal Tool (MMAT). RESULTS: Of 1304 records initially identified, 41 studies met eligibility criteria. AI applications ranged from machine learning (ML) for risk prediction and natural language processing (NLP) for IPV detection in clinical and social media data, to image analysis for forensic evaluation and chatbot-based support. Predictive modelling demonstrated strong discriminative performance, while NLP-based screening detected IPV with notable sensitivity. Chatbots showed feasibility and user acceptability, but evidence of their direct impact on reducing IPV incidence was limited, with one randomised controlled trial showing a modest reduction. Key challenges identified included algorithmic bias, data privacy risks and barriers to integration across health and social care systems. DISCUSSION: AI-informed interventions show promise for improving IPV detection, risk assessment, and scalable support, but questions remain about long-term effectiveness, ethical fairness, transparency and equitable implementation. Future interdisciplinary research should address these concerns to responsibly deploy AI in IPV prevention. RELEVANCE TO CLINICAL PRACTICE: The findings highlight the importance of trauma-informed, culturally responsive care and provider training in AI applications. Nurse-led innovation and policy advocacy will be crucial for safe, equitable integration of AI in IPV prevention.

Artificial Intelligence↗

PubMed2003

Infrared microspectroscopic imaging maps the spatial distribution of exogenous molecules in skin.

Infrared (IR) microscopic imaging is used, in a series of proof-of-principle experiments to map the spatial distribution of two penetration enhancers, dimethylsulphoxide (DMSO) and propylene glycol, in skin. The current instrumentation utilizes a 64 x 64 array of IR detectors imaged at the focal plane of an IR microscope, each collecting a complete mid-infrared spectrum of the skin section on each pass of the interferometer. The spatial area sampled by each element in the array is approximately 6.3 x 6.3 microm. Any spectral parameter (e.g., arising from lipid or protein vibrational modes of the endogenous tissue or the exogenous component) may be quantitatively analyzed across the entire array of 4096 spectra, thereby generating an IR spectroscopic image of that particular parameter throughout the sample. The images directly reveal the spatial heterogeneity of the protein and lipid distributions. In transverse slices of skin, the depth dependencies of the spatial distribution of triglyceride and protein have been monitored, and compared to those of the exogenous penetration enhancers. Images of both DMSO and propylene glycol suggest that each penetrates the skin to a depth of at least 1 mm (under our experimental protocols), and reveals a spatial distribution that is essentially coincident with the protein constituents of the skin. These results demonstrate that IR microscopic imaging has great potential for mechanistic studies of topical, dermal, and transdermal delivery.

Animals↗