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PubMed2025

Population analysis and immunologic landscape of melanoma in people living with HIV.

PURPOSE: To dissect the clinical and immunological features of people living with HIV (PLWH) diagnosed with melanoma, who have consistently exhibited worse clinical outcomes than HIV-negative individuals (PLw/oH) with the same cancer. EXPERIMENTAL DESIGN: We analyzed electronic health records from 1,019 PLWH and 373,121 PLw/oH diagnosed with melanoma. Demographic and clinical characteristics were compared. Spatial immune transcriptomics (72 immune-related genes) was performed on melanoma tumor samples (n=11), followed by downstream validation using multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH). RESULTS: PLWH were diagnosed with melanoma at a younger age, had a higher representation of Hispanic and Black individuals compared to PLw/oH, and a decreased survival rate. PLWH also showed a markedly increased risk of brain metastases. PLWH experienced significant delays in initiating immune checkpoint inhibitor (ICI) therapy and had worse survival outcomes following ICI, even after balancing for demographic covariates. Spatial transcriptomics revealed a more immunosuppressive tumor microenvironment in PLWH, with upregulation of immune checkpoints (PD1, LAG3) and reduced expression of antigen presentation markers (HLA-DRB, B2M), with distinct spatial distributions in tumors and their microenvironments. Multiplex immunofluorescence confirmed an exhausted CD8+ T cell compartment in PLWH, including enrichment of PD1intLAG3- and PD1intLAG3+ subpopulations, and a significant accumulation of immunosuppressive myeloid-derived suppressor cells (CD11b+ HLA-DR- CD33+). CONCLUSIONS: Our findings suggest chronic HIV infection fosters a permissive tumor microenvironment that might undermine effective immune responses and contribute to poor clinical outcomes for PLWH with melanoma. Targeting the actionable immune pathways identified in this study could inform tailored therapeutic strategies to mitigate these disparities.

HIV↗
PubMed2003

Engineering of a water-soluble plant cytochrome P450, CYP73A1, and NMR-based orientation of natural and alternate substrates in the active site.

CYP73A1 catalyzes cinnamic acid hydroxylation, a reaction essential for the synthesis of lignin monomers and most phenolic compounds in higher plants. The native CYP73A1, initially isolated from Jerusalem artichoke (Helianthus tuberosus), was engineered to simplify purification from recombinant yeast and improve solublity and stability in the absence of detergent by replacing the hydrophobic N terminus with the peptitergent amphipathic sequence PD1. Optimized expression and purification procedures yielded 4 mg engineered CYP73A1 L(-1) yeast culture. This water-soluble enzyme was suitable for 1H-nuclear magnetic resonance (NMR) investigation of substrate positioning in the active site. The metabolism and interaction with the enzyme of cinnamate and four analogs were compared by UV-visible and 1H-NMR analysis. It was shown that trans-3-thienylacrylic acid, trans-2-thienylacrylic acid, and 4-vinylbenzoic acid are good ligands and substrates, whereas trans-4-fluorocinnamate is a competitive inhibitor. Paramagnetic relaxation effects of CYP73A1-Fe(III) on the 1H-NMR spectra of cinnamate and analogs indicate that their average initial orientation in the active site is parallel to the heme. Initial orientation and distances of ring protons to the iron do not explain the selective hydroxylation of cinnamate in the 4-position or the formation of single products from the thienyl compounds. Position adjustments are thus likely to occur during the later steps of the catalytic cycle.

Amino Acid Sequence↗
PubMed1988

PD117302: a selective agonist for the kappa-opioid receptor.

1. A new nonpeptide kappa-opioid compound, a cyclohexyl benzeneacetamide derivative (PD117302), has been synthesized and its affinity for the different types of opioid receptor determined. The ability of PD117302 to modify the activity of the electrically-stimulated guinea-pig ileum and rabbit vas deferens has also been evaluated. 2. In binding studies using guinea-pig brain homogenates, unlabelled PD117302 had a high affinity (Ki = 3.7 nM) at [3H]-etorphine labelled kappa sites and a low affinity at [3H]-[D-Ala2, MePhe4, glyol5]-enkephalin ([3H]-DAGOL) labelled mu sites (Ki = 408 nM) and [3H]-SKF 10047 labelled sigma sites (Ki = 1.8 microM). In bioassay studies, PD117302 was a potent agonist, producing a maximum inhibition of the electrically-evoked contractions of the guinea-pig ileum (IC50 = 1.1 nM) and rabbit vas deferens (IC50 = 45 nM) which was naloxone-reversible. 3. In guinea-pig brain, [3H]-PD117302 bound to a high-affinity opioid binding site with a KD of 2.7 nM and a Bmax of 3.4 pmol g-1 wet weight. The Bmax was found to be less than 50% of the Bmax values for [3H]-etorphine and [3H]-bremazocine suggesting that [3H]-PD117302 may be a specific ligand for a subtype of kappa receptor. [3H]-PD117302 also bound with micromolar affinity to a non-opioid binding site. 4. Kinetic studies found that [3H]-PD117302-specific binding to the high affinity site was saturable, reaching equilibrium within 20 min at 4 degrees C, and reversible, with a half-life of dissociation of 3.9 min. 5. Several unlabelled compounds with high affinities for the ['H]-etorphine labelled K binding site, had comparable affinities when competing for the ['H]-PDl 17302-specific high affinity binding site. In contrast, DAGOL, [D-Ala', D-Leu'] enkephalin (DADLE) and [D-Pen2, D-Pen'] enkephalin (DPDPE) had no significant effect on ['H]-PD 1 17302 binding, suggesting minimal interaction with mu and delta binding sites. 6. In autoradiography studies ['H]-PD1 17302 binding sites were found throughout the brain with the greatest density in the striatum, cerebral cortex (layers V-VI), substantia nigra, and the molecular layer of the cerebellum. Lowest levels were found in the granular layer of the cerebellum, thalamus and cerebral cortex (layers I - IV).

Animals↗
PubMed1990

Opioid receptor ligands in the neonatal rat spinal cord: binding and in vitro depression of the nociceptive responses.

1. Opioid receptors in the neonatal rat spinal cord have been characterized by measurements of ligand binding to crude membrane fractions and by functional tests on the nociceptive spinal response in a spinal cord-tail preparation in vitro. 2. There were high affinity binding sites for [3H]-[D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGOL), [3H]-U69593, and [3H]-ethylketocyclazocine (EKC) on spinal cord membranes from neonatal rats. Hill slopes for binding of [3H]-DAGOL and [3H]-U69593 were close to unity. The Hill slope for binding of [3H]-EKC was less than unity, even after its interactions at mu-receptors had been blocked with 100 nM unlabelled DAGOL. Binding sites for [3H]-[D-Pen2, D-Pen5]enkephalin (DPDPE) could not be detected. 3. In competition assays U50488 was as potent as PD117302 and U69593 in competition for either [3H]-U69593 or [3H]-EKC binding sites. Hill slopes for a range of competing ligands at [3H]-DAGOL or [3H]-U69593 sites were close to unity. Hill slopes for competition at [3H]-EKC sites were less than one. 4. In the spinal cord-tail preparation from neonatal rats, opioid receptor agonists depressed spinal nociceptive responses evoked by application of capsaicin or heat to the tail. The order of potency was DAGOL greater than U69593 = PD117302 greater than morphine greater than U50488 = [D-Pen2, L-Pen5]enkephalin (DPLPE). 5. The antagonist naloxone was about equally potent against DAGOL, morphine and DPLPE, and about ten times less potent against U69593 and PD117302. The effects of U50488 were much less sensitive to blockade by naloxone than the effects of PD11703 or U69593. The Kappa antagonist, nor-binaltorphimine was equipotent against all three Kappa agonists. 6. The absence of delta-binding sites, and the low potency and relatively high sensitivity to naloxone suggest that DPLPE could be working at mu-receptors in the neonatal rat spinal cord. 7. The binding assays show that U50488 has the same affinity as PD1 17302 and U69593 for Kappa-receptors, yet it was less effective in the depression of nociceptive responses. This may be because U50488 has a relatively low efficacy at Kappa-receptors. It is possible that at high concentrations U50488 activates receptors not affected by other Kappa-ligands. These additional receptors may be non-opioid receptors (hence the insensitivity to naloxone), or they could be a subtype of Kappa-opioid receptor.

Animals↗
PubMed1991

Pharmacological profile of various kappa-agonists at kappa-, mu- and delta-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the rat brain.

1. The potency, relative efficacy and selectivity of a series of kappa-opioid receptor agonists at the mu-, delta- and kappa-opioid receptors mediating inhibition of electrically-induced (radiolabelled) neurotransmitter release from superfused rat brain slices was determined. 2. With regard to their potencies at kappa-receptors mediating inhibition of striatal [3H]-dopamine release, the highest pD2 value (8.7) was found for bremazocine and the lowest (7.1) for U50488; the pD2 values for ethylketocyclazocine (EKC), tifluadom, U69593 and PD117302 were between 8.0 and 8.3. There were no marked differences between the relative efficacies of the kappa-agonists (maximum inhibition being 60-70%). In contrast to the other kappa-agonists, at a concentration of 1 microM, PD117302 caused a significant (25-40%) increase of the spontaneous efflux of tritium. 3. None of the kappa-agonists significantly affected striatal [14C]-acetylcholine (ACh) release, with the exception of a slight inhibitory effect of EKC. The delta-receptor-mediated inhibitory effect of [D-Ala2, D-Leu5]enkephalin (DADLE) on [14C]-ACh release was antagonized in a concentration-dependent manner by bremazocine (0.1 and 1.0 microM) and also partially by EKC (1 microM), but not by the other kappa-agonists. The pA2 value for bremazocine as an antagonist at the delta-receptors involved was 8.0, compared to 7.6 for naloxone. 4. None of the kappa-agonists significantly affected cortical [3H]-noradrenaline (NA) release, with the notable exception of tifluadom, which strongly inhibited release by activating mu-receptors. The mu-receptor-mediated inhibitory effect of Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO) on [3H]-NA release was antagonized in a concentration-dependent manner by bremazocine and EKC, but not by the other K-agonists. The pA2 value for bremazocine as an antagonist at the mu-receptors involved was 8.2, compared to 8.6 for naloxone. 5. Thus, whereas U69593 and PD1 17302 display high potency and selectivity towards K-opioid receptors, the potent benzomorphan K-agonists bremazocine and EKC also appear to be strong mu-opioid receptor antagonists.

Acetylcholine↗
PubMed1982

Steady expiratory flow-pressure relationship in a model of the human bronchial tree.

Static pressure differences across a human bronchial tree model were obtained for steady expiratory flows of several gases producing Reynolds numbers (Re1) in the bronchus carrying the entire flow (first bronchus) between 150 and 50,000. The model was constructed from an air-dried lung and was complete to bronchi about 2 mm in diameter. Dimensionless static pressure plotted against Re1 consolidated the data on a single curve, phenomenologically described by an equation of the form: delta Ps/delta Pd1 = A + B Re1 where delta P d1 is a pressure drop for Poiseuille flow, Velocity profile measurements at two sites along the first bronchus for laminar and turbulent flows indicate a dependence on the latter and distance from the first junction. Loss in total pressure was computed and may result from both frictional dissipation and changes in momentum flux associated with development of velocity profiles near the junctions. An average loss in total pressure within a single bronchus was calculated after making several simplifying assumptions, and this result may be useful in modeling both the resistance of the entire bronchial tree and the more complex phenomenon of maximal expiratory flow.

Airway Resistance↗
PubMed1991

A complex regulatory DNA element associated with a major histocompatibility complex class I gene consists of both a silencer and an enhancer.

A novel regulatory element which contributes to the regulation of quantitative, tissue-specific differences in gene expression has been found between -771 and -676 bp upstream of the major histocompatibility complex (MHC) class I gene, PD1. Molecular dissection of this element reveals the presence of two overlapping functional activities: an enhancer and a silencer. Distinct nuclear factors bind to the overlapping enhancer and silencer DNA sequence elements within the regulatory domain. The levels of factors binding the silencer DNA sequence in different cell types are inversely related to levels of class I expression; in contrast, factors binding the enhancer DNA sequence can be detected in all cells. In cultured cell lines, inhibition of protein synthesis leads to the rapid loss of silencer complexes, with a concomitant increase in both enhancer complexes and MHC class I RNA. From these data, we conclude that a labile silencer factor competes with a constitutively expressed, stable enhancer factor for overlapping DNA-binding sites; the relative abundance of the silencer factor contributes to establishing steady-state levels of MHC class I gene expression.

Animals↗
PubMed1993

Primers that amplify inserts in a multicloning site also hybridize to Sorghum bicolor DNA.

One or both members of a pair of primers developed to permit polymerase chain reaction amplification of sorghum DNA fragments cloned into the PstI site of pUC18 were shown to hybridize to sorghum DNA. The presence of the same primer sequences on the ends of amplified inserts posed a problem in using the amplified inserts as hybridization probes because the high signal level of the primer-detected DNA fragments often obscured the segregation patterns of the restriction fragments detected by the insert DNA. Conditions that favor annealing of the insert rather than the primers were experimentally defined, however, so that directly amplified DNA sequences could be used as RFLP probes. Cosegregation analysis of 51 F2 individuals from a cross between BTx 623 and IS 3620C established a linkage group containing the Pd1 locus. Alleles at the locus are revealed as codominant bands on Southern blots of heterozygotes, but the segregation ratio among the F2 progeny deviated significantly from the expected 1:2:1. The distortion favored the allele from parent BTx 623.

Base Sequence↗
PubMed2006

Effective cancer therapy through immunomodulation.

MAbs directed toward tumor cells, tumor neovasculature, and host negative immunoregulatory elements (checkpoints) have emerged as useful immunotherapeutic agents against cancer. However, effective active modulation of the immune response with anticancer vaccines will require identifying appropriate tumor-rejection antigens; optimizing the interactions of peptides, antigen-presenting cells, and T cells; and blockading negative immunological checkpoints that impede an effective immune response. Checkpoints being targeted include CTLA-4 and PD1 that are negative signaling receptors expressed on activated T cells, CD4+CD25+ Foxp3-expressing Tregs (suppressor T cells), IL-2-mediated activation-induced cell death (AICD), and the cytokine TGFbeta.

Antibodies, Monoclonal↗
PubMed2026

Loss of tumor-infiltrating lymphocytes and poor response to immunotherapy in IDH GOF mutant melanoma.

Recent innovations in melanoma treatment with immune checkpoint blockade (ICB) have improved overall outcomes for patients; however, over 50% of patients still develop resistance to treatment. These patients either have intrinsic resistance and never respond to therapy or develop acquired resistance months or years into treatment. The mechanisms underlying ICB resistance remain poorly understood. Our data show that patients with isocitrate dehydrogenase gain-of-function (IDH GOF) mutant melanoma have a worse response to anti-PD1 immunotherapy. IDH mutations have been found to be oncogenic and associated with differential methylation in multiple cancers but are not yet characterized in human melanoma. Here, we investigate the clinical, immune, and transcriptional phenotypes of IDH GOF melanomas through analyses of clinical response, single-cell RNA-seq, bulk RNA-seq, and DNA methylation data. Single-cell data analysis showed decreased immune infiltrate and activity in the IDH GOF tumors. Bulk sequencing data demonstrated the association among IDH mutation, immune exclusion, and disruptions in global DNA methylation. The melanoma-derived genomic data presented support previously described resistance mechanisms of IDH mutation in other cancer types and is the first demonstration to our knowledge of the role of IDH GOF in the human melanoma tumor microenvironment.

Humans↗
PubMed2005

Inhibitors of mitogen-activated protein kinases differentially regulate costimulated T cell cytokine production and mouse airway eosinophilia.

BACKGROUND: T cells play a dominant role in the pathogenesis of asthma. Costimulation of T cells is necessary to fully activate them. An inducible costimulator (ICOS) of T cells is predominantly expressed on Th2 cells. Therefore, interference of signaling pathways precipitated by ICOS may present new therapeutic options for Th2 dominated diseases such as asthma. However, these signaling pathways are poorly characterized in vitro and in vivo. METHODS: Human primary CD4+ T cells from blood were activated by beads with defined combinations of surface receptor stimulating antibodies and costimulatory receptor ligands. Real-time RT-PCR was used for measuring the production of cytokines from activated T cells. Activation of mitogen activated protein kinase (MAPK) signaling pathways leading to cytokine synthesis were investigated by western blot analysis and by specific inhibitors. The effect of inhibitors in vivo was tested in a murine asthma model of late phase eosinophilia. Lung inflammation was assessed by differential cell count of the bronchoalveolar lavage, determination of serum IgE and lung histology. RESULTS: We showed in vitro that ICOS and CD28 are stimulatory members of an expanding family of co-receptors, whereas PD1 ligands failed to co-stimulate T cells. ICOS and CD28 activated different MAPK signaling cascades necessary for cytokine activation. By means of specific inhibitors we showed that p38 and ERK act downstream of CD28 and that ERK and JNK act downstream of ICOS leading to the induction of various T cell derived cytokines. Using a murine asthma model of late phase eosinophilia, we demonstrated that the ERK inhibitor U0126 and the JNK inhibitor SP600125 inhibited lung inflammation in vivo. This inhibition correlated with the inhibition of Th2 cytokines in the BAL fluid. Despite acting on different signaling cascades, we could not detect synergistic action of any combination of MAPK inhibitors. In contrast, we found that the p38 inhibitor SB203580 antagonizes the action of the ERK inhibitor U0126 in vitro and in vivo. CONCLUSION: These results demonstrate that the MAPKs ERK and JNK may be suitable targets for anti-inflammatory therapy of asthma, whereas inhibition of p38 seems to be an unlikely target.

Animals↗
PubMed1988

Identification of a set of calcium-binding proteins in reticuloplasm, the luminal content of the endoplasmic reticulum.

A procedure was developed for the isolation of reticuloplasm, the luminal material of the endoplasmic reticulum (ER). A reticuloplasm-rich extract was prepared from a murine plasmacytoma cell line that contains large amounts of ER, by first extracting the cytoplasmic contents using hypotonic lysis to yield ER-rich 'shells' followed by mechanical lysis to release the ER contents. The extract contains five major proteins with apparent molecular weights of 100, 75, 60, 58 and 55 (X 10(3] Mr by SDS-polyacrylamide gel electrophoresis. The 100, 75 and 58 (X 10(3] Mr species were identified as the known ER proteins endoplasmin, BiP and PD1, respectively. The ER association of the 60 and 55 (X 10(3] Mr proteins was confirmed by confocal fluorescence microscopy with affinity-purified antibodies. Equilibrium dialysis with isolated reticuloplasm gave a calcium-binding capacity of 300 nmoles calcium per mg protein with half-maximal binding at 3 mM-Ca2+. Purified endoplasmin bound 280 nmoles calcium per mg protein at a calcium concentration of 5 mM-Ca2+. A calcium overlay test revealed that, in addition to endoplasmin, reticuloplasm contained at least three other calcium-binding proteins: i.e. BiP, PDI and the 55 X 10(3) Mr protein, respectively, with endoplasmin and the 55 X 10(3) Mr protein (CRP55) accounting for the major proportion of the calcium-binding activity. Treatment of cells with calcium ionophore led to the specific over-expression of the major calcium-binding reticuloplasmins endoplasmin, BiP and CRP55. These studies show that the lumen of the ER contains a family of proteins with the capacity to bind significant amounts of calcium in the millimolar range and thereby to confer upon the ER the ability to perform a calcium storage function analogous to that of the sarcoplasmic reticulum in muscle cells.

Animals↗
PubMed2006

Cell-cell interaction in the transcellular biosynthesis of novel omega-3-derived lipid mediators.

Omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosa-hexaenoic acid (DHA) display beneficial actions in human diseases. The molecular basis for these actions remains of interest. We recently identified novel mediators generated from omega-3 PUFA during cell-cell interactions that displayed potent anti-inflammatory and proresolving actions. Compounds derived from EPA are designated resolvins of the E series (RvE1), and those biosynthesized from DHA are denoted resolvins of the D series (RvD) and docosatriene, such as protectin D1 (PD1), which belongs to the family of protectins. In addition, treatment using aspirin initiates a related epimeric series by triggering endogenous formation of the 17R-RvD series, denoted as aspirin-triggered (AT)-RvDs. These compounds possess potent anti-inflammatory actions in vivo that essentially are equivalent to their counterpart generated without aspirin, namely the 17S-RvDs. In this chapter, we provide an overview and detail protocols of the biosynthesis and bioactions of these newly uncovered pathways and products that include three distinct series: 18R-resolvins of the E series derived from EPA (i.e., RvE1); 17R-resolvins of the D series from DHA (AT-RvD1 through RvD4); and 17S-resolvins of the D series from DHA (RvD1 through RvD4).

Animals↗
PubMed2006

Transcriptional regulation of major histocompatibility complex class I gene by insulin and IGF-I in FRTL-5 thyroid cells.

Increased major histocompatibility complex (MHC) class I gene expression in nonimmune cell 'target tissues' involved in organ-specific diseases may be important in the pathogenesis of autoimmune diseases. This possibility in part evolves from studies of cultured thyrocytes where properties appear relevant to the development of thyroid autoimmune disease. In FRTL-5 rat thyroid cells in continuous culture, hormones and growth factors that regulate cell growth and function specifically decrease MHC class I gene expression. We hypothesized that this could reflect a mechanism to preserve self-tolerance and prevent autoimmune disease. The mechanisms of action of some of these hormones, namely TSH and hydrocortisone, have been already characterized. In this report, we show that IGF-I transcriptionally downregulates MHC class I gene expression and that its action is similar to that of insulin. The two hormones have a complex effect on the promoter of the MHC class I gene, PD1. In fact, they decrease the full promoter activity, but upregulate the activity of deleted mutants that have lost an upstream, tissue-specific regulatory region but still retain the enhancer A region. We show that insulin/IGF-I promotes the interactions of the p50/p65 subunits of NF-kappaB and AP-1 family members with these two regions, and that the tissue-specific region acts as a dominant silencer element on insulin/IGF-I regulation of promoter activity. These observations may be important to understand how MHC class I gene transcription is regulated in the cells.

Animals↗
PubMed2026

Post-vaccination expansion of extrafollicular Th10 and regulatory Tfr cells distinguishes strong from weak influenza vaccine responses in older adults.

Despite the superior efficacy of high-dose influenza vaccines, over one-third of older adults fail to respond. Yet, the mechanisms underlying this impaired vaccine responsiveness remain poorly understood. Here, we performed longitudinal profiling of older adults (n=60) receiving high-dose influenza vaccination to identify immune programs associated with vaccine responsiveness. Strong responders exhibited a primed baseline immune state characterized by elevated plasma cytokines and chemokines, followed by enhanced IFN-γ responses and coordinated transcriptional and epigenetic activation of cDC2 cells at day 1. By day 7, CD4+ T-cell trajectories diverged: strong responders preferentially expanded influenza-specific activated cTfh1 (CXCR5 + CXCR3 + ICOS + CD38 +) and influenza-specific Th10 (CXCR5 - CXCR3 + PD1 + IL10 +) cells, whereas weak responders expanded regulatory cTfr (CXCR5 + FOXP3 +) cells. Th10 expansion correlated with plasmablast and antibody responses and was independently validated in a larger influenza vaccination cohort, including younger adults. Functionally, Th10 cells promoted memory B-cell differentiation into plasmablasts and production of influenza-specific IgGs. TCR analyses revealed minimal clonal overlap between Th10 and cTfh1 cells. Together, these findings identify divergent helper and regulatory CD4+ T cell programs associated with vaccine responsiveness and establish Th10 cells as a previously unrecognized component of vaccine-induced humoral immunity.

Journal Article↗
PubMed2000

Development of the innervation of long bones: expression of the growth-associated protein 43.

It has been known from clinical and experimental observations that the peripheral nervous system is involved in the development of long bones. Expression of growth-associated protein 43 (GAP-43/B-50) was found in axonal growth cones during embryonic and postnatal ontogeny as well as in regenerating axons after nerve injury. The aim of the present study was to examine the occurrence of growing nerve fibers in rat tibia from gestational day 16 (GD 16) to postnatal day 28 (PD28). An indirect immunoenzymatic reaction using antibodies raised against GAP-43 was applied to detect outgrowing nerve fibers penetrating into the developing bone. On GD 16 and GD 17 no GAP-43-immunoreactive (IR) fibers were observed in the close vicinity of bone rudiments. On GD19 GAP-43-IR fibers were scarcely present within the periosteum of the central portion of the diaphysis. In the perichondrium surrounding the proximal epiphysis, nerve fibers were first detected around birth. From PD1 onward, numerous fibers were seen in the fibrous buds of the perichondrium at the epi-metaphyseal junction (Ranvier's grooves), some of them being adjacent to the blood vessels. Nerve fibers penetrating into the bone and located in the bone marrow, predominantly associated with blood vessels, were first observed on GD21 and their number increased with further development. They were initially located in the central portion of the diaphysis and later extended towards the metaphyses. On PD4 an increased number of GAP-43-IR fibers appeared in the perichondrium of proximal and distal epiphyses. In the fibrous strands penetrating into the epiphyses and in the secondary ossification centers, nerve fibers were first observed on PD10. From PD14 onward the pattern of tibial innervation remained unchanged but the intensity of GAP-43 immunostaining visibly decreased. The present study demonstrates that developing long bones of rat hindlimbs are supplied by growing nerve fibers immunoreactive for GAP-43 from GD 19 onward. Time and location of their appearance were at least partially correlated with known events taking place during long bone development, e.g. formation of primary and secondary ossification centers. Decreased expression of GAP-43 immunoreactivity in later developmental stages is believed to reflect nerve fiber maturation.

Aging↗
PubMed2002

[Effect of hepatic arterial infusion chemotherapy for liver metastasis from gastric cancer].

We performed hepatic arterial infusion (HAI) chemotherapy for 4 patients with advanced gastric cancer who had undergone curative resection except for liver metastasis. The main antineoplastic drugs were 5-fluorouracil (5-FU), mitomycin C (MMC) and cisplatin (CDDP). A catheter was inserted into the hepatic artery by interventional radiological techniques in 3 patients and operatively in 1 patient. The response rate for 4 patients was 75% (CR2, PR1, PD1). The adverse events were Grade 3/4 nausea and/or vomiting in 2 cases. The HAI chemotherapy was effective and useful for patients with advanced gastric cancer who had no unresectable lesions except for liver metastasis.

Aged↗
PubMed1992

[11th International Histocompatibility Workshop 1991: Personal data for the Multiple Sclerosis Study].

In our multiple sclerosis (MS) study as a part of the 11th IHWS we HLA-typed 6 MS families with 9 patients and defined the complement polymorphisms (BF, C2, C4) of these families. The aims of the study were the definition of the MS susceptibility gene and the investigation of the involvement of other factors in the etiopathogenesis of MS. The MS study of the IHWS demonstrated a strong association with HLA-DRw15 and -DWw6 in a Caucasian population. The heterozygous C2 deficiency in our family PD1 linked with the haplotype A25 B18 DR2 BFS C4A4 C4B2 confirmed by complement titration may express the participation of complement factors in the etiopathogenesis of MS resulting in immunogenetic heterogeneity of MS. Analysis of the 3 MS pairs of sisters shows the linkage of HLA with the assumed MS susceptibility gene. This could not be confirmed in the whole MS family study of the 11th IHWS.

Chromosome Mapping↗