There is great interest in developing efficient therapeutic cancer vaccines, as this type of therapy allows targeted killing of tumor cells as well as long-lasting immune protection. High levels of ...tumor-infiltrating CD8
T cells are associated with better prognosis in many cancers, and it is expected that new generation vaccines will induce effective production of these cells. Epigenetic mechanisms can promote changes in host immune responses, as well as mediate immune evasion by cancer cells. Here, we focus on epigenetic modifications involved in both vaccine-adjuvant-generated T cell immunity and cancer immune escape mechanisms. We propose that vaccine-adjuvant systems may be utilized to induce beneficial epigenetic modifications and discuss how epigenetic interventions could improve vaccine-based therapies. Additionally, we speculate on how, given the unique nature of individual epigenetic landscapes, epigenetic mapping of cancer progression and specific subsequent immune responses, could be harnessed to tailor therapeutic vaccines to each patient.
BACKGROUND: The aim of this study was to determine the influence of mode of birth and umbilical cord blood (CB) collection before (in utero) or after delivery of the placenta (ex utero) on total ...number of WBCs and CD34+ cells in CB units.
STUDY DESIGN AND METHODS: Consecutively donated, banked CB units were assessed for net volume, WBC concentration, total number of WBCs, proportion of CD34+ cells, and total number of CD34+ cells. These parameters were then correlated with the mode of birth and the mode of CB collection relative to the delivery of the placenta.
RESULTS: A significantly higher CB volume was seen following cesarean section (n = 61) than following vaginal delivery (n = 157; median volume, 76 vs. 63 mL, respectively; p < 0.0001). In contrast, CB from vaginal delivery had a significantly higher WBC concentration compared with CB from cesarean section (medians, 17.1 × 109 and 13.6 × 109 WBCs/L, respectively; p < 0.0001). The mode of birth did not influence the proportion of CD34+ cells. A correlation was demonstrated between the total number of CD34+ cells and the total number of WBCs. As a consequence of the opposing effects on volume and WBC counts by cesarean section and vaginal delivery, there were no significant differences in the total number of WBCs or CD34+ cells for the CB units with mode of delivery in this study. No significant differences were found in CB with mode of CB collection (in utero n = 58 or ex utero n = 99) following vaginal delivery.
CONCLUSIONS: The mode of birth influences the CB WBC concentration and volume collected and should be taken into consideration for establishing any acceptance limits for CB units to be banked. There were no differences in CB with in utero or ex utero collections.
Fibroblast growth factor receptors and their ligands in the adult rat kidney.
Fibroblast growth factors (FGFs) are a family of at least 21 heparin-binding proteins involved in many biological ...processes, both during development and in the adult, including cell proliferation, differentiation, and angiogenesis. FGFs mediate their effects through high-affinity tyrosine kinase receptors (FGFRs), which are encoded by four genes. The aims of the present study were to localize FGFR-1 through FGFR-3 in the normal adult rat kidney and to determine which functional FGFR variants and FGFs were expressed.
Avidin-biotin–enhanced horseradish peroxidase immunohistochemistry was used on paraffin sections of rat kidney to localize FGFR-1 through FGFR-3, whereas reverse transcriptase-polymerase chain reaction was used to examine expression of the receptor variants and also of FGF-1 through FGF-10 in cortex, outer medulla, and inner medulla.
By immunohistochemistry, each receptor was localized to distinct and overlapping nephron segments, such that one or more FGFRs were localized to all nephron and collecting duct epithelia. FGFR-1 and FGFR-3 were localized to glomeruli, FGFR-3 to proximal tubules and FGFR-1 to thin limbs. FGFR-1 through FGFR-3 were localized to distal straight tubules, with FGFR-1 and FGFR-3 localized to distal convoluted tubules. FGFR-1 and FGFR-3 were localized to medullary collecting ducts. In addition, FGFR-1 was localized to the smooth muscle of renal arteries. All seven FGFR variants were expressed in the cortex and outer medulla, with fewer FGFRs in the inner medulla. FGF-1, FGF-2, FGF-7, FGF-8, and FGF-9 were expressed in the kidney, with FGF-10 expression found only in the cortex.
Mapping of these receptors is critical to the determination of the effects of FGF ligands in discrete regions of the kidney. The distributions of the FGFRs in the normal adult kidney and the restricted expression of FGF ligands suggest that specific FGFs have distinct and important roles in the maintenance of normal kidney structure and function.
Purpose To evaluate the relative benefits and to identify any adverse effects of surgical interventions for limbal stem cell deficiency (LSCD). Design Systematic literature review. Methods We ...searched the following electronic databases from January 1, 1989 through September 30, 2006: MEDLINE, EMBASE, Science citation index, BIOSIS, and the Cochrane Library. In addition, reference lists were scanned to identify any additional reports. The quality of published reports was assessed using standard methods. The main outcome measure was improvement in vision of at least two Snellen lines of best-corrected visual acuity (BCVA). Data on adverse outcomes also were collected. Results Twenty-six studies met the inclusion criteria. There were no randomized controlled studies. All 26 studies were either prospective or retrospective case series. For bilateral severe LSCD, keratolimbal allograft was the most common intervention with systemic immunosuppression. Other interventions included eccentric penetrating keratolimbal allografts and cultivated autologous oral mucosal epithelial grafts. An improvement in BCVA of two lines or more was reported in 31% to 67% of eyes. For unilateral severe LSCD, the most common surgical intervention was contralateral conjunctival limbal autograft, with 35% to 88% of eyes gaining an improvement in BCVA of two lines or more. The only study evaluating partial LSCD showed an improvement in BCVA of two lines or more in 39% of eyes. Conclusions Studies to date have not provided strong evidence to guide clinical practice on which surgery is most beneficial to treat various types of LSCD. Standardized data collection in a multicenter LSCD register is suggested.
To quantify the risks for cataract surgery in patients who have previously undergone external beam radiotherapy (EBRT).
Tertiary ophthalmology and oncology hospital.
Retrospective case series.
...Patients treated with orbital EBRT at the Beatson West of Scotland Cancer Centre between 2001 and 2019 were identified, and clinical records were reviewed to identify those who had subsequently undergone cataract surgery. Preoperative and postoperative case records, and operation records, were reviewed to identify demographic data and data regarding complications and surgical outcomes.
46 eyes (of 33 patients) were included. The indications for EBRT included thyroid eye disease, lymphoma, choroidal metastases, and other orbital malignancies. Mean corrected preoperative Snellen visual acuity was 20/100 (range 20/30 to 20/2000) improving to 20/25 (20/12 to 20/160, 1-way analysis of variance P < .01). Mean visual gain was 0.5 logMAR (-0.9 to 1.9). There was 1 case of posterior capsule (PC) rupture with vitreous loss (2%). Dense PC plaque was noted intraoperatively in 19.5% (n = 9). 13% (n = 6) required Nd:YAG laser posterior capsulotomy. There were 6 cases (13%) of cystoid macular edema (CME).
Visual outcomes after cataract surgery in this cohort of patients were similar to those obtained in a nationwide cohort. EBRT seemed to be associated with an increased incidence of intraoperative PC plaque, postoperative CME (which in most cases settled with treatment), and need for posterior capsulotomy.
The fibroblast growth factors (FGFs) are a family of conserved polypeptides known to regulate cell differentiation and proliferation. We have used avidin-biotin-enhanced indirect immunohistochemistry ...to localize FGF-1 and FGF-2 in the rat kidney. The most consistent specific immunostaining pattern is found in paraffin sections from kidneys perfusion-fixed with 4% paraformaldehyde in 0.1 M phosphate buffer. Intracellular immunoreactivity for FGF-1 and FGF-2 is co-localized in visceral (podocytes) and parietal (Bowman's capsule) glomerular epithelial cells, S3 segments of proximal tubules, distal tubules and collecting ducts in the cortex, and thick ascending limbs and collecting ducts in the medulla. Immunoreactivity is also observed within urothelium and the tunica adventitia of large blood vessels. No immunostaining is found in cortical S1 or S2 segments of proximal tubules, in frozen sections prepared from unfixed or 4% paraformaldehyde perfusion-fixed kidneys, or in paraffin sections from Bouin-fixed kidneys. Immersion fixation with 4% paraformaldehyde gives a similar staining pattern in paraffin sections to that achieved with perfusion fixation. However, in paraffin sections fixed with methyl Carnoy's fixative, immunoreactivity is primarily localized to the tunica media of blood vessels, with little tubular or glomerular immunostaining. Thus, variation in immunolocalization patterns for FGFs can be partially attributed to differences in fixative, preparative technique and antibody specificity.
Expression of fibroblast growth factors and their receptors in rat glomeruli. Fibroblast growth factors (FGFs) regulate cell proliferation and differentiation, and are also important regulators of ...extracellular matrix. They are among the most potent angiogenic factors known. Evidence suggests the FGFs play a role in glomerular development and pathology. The aim of the present study was to determine whether FGF-1 (acidic FGF) and FGF-2 (basic FGF) and their receptors (FGFRs) were expressed in normal adult rat glomeruli, using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. For RT-PCR studies, the kidneys of 200g female Sprague-Dawley rats were perfused with buffer and glomeruli isolated using conventional sieving techniques followed by micropipetting. FGF-1 and FGF-2 were expressed in cortex and in glomeruli. All seven receptor isoforms assayed (FGFR1, 2 and 3 IIIb and IIIc splice variants, and FGFR4) were expressed in whole cortex. However, only the IIIc variants and FGFR4 were expressed in glomeruli. The relative levels of glomerular expression of these isoforms were determined using a semiquantitative RT-PCR assay using primers designed against three transmembrane regions: FGFR1 (100%); FGFR2 (0.1%); and FGFR4 (6%). Immunohistochemistry revealed specific immunostaining for all four FGFRs within glomeruli. The differential expression pattern of FGFR isoforms between glomeruli and whole cortex, and the mutually exclusive nature of the expression of IIIc but not IIIb isoforms within glomeruli, indicates that FGFR expression and thereby FGF activity is tightly regulated in glomeruli. These findings have important implications for the roles of the FGFs in glomerular health and disease.
A technique involving the quantitative estimation of globin chains using cellulose acetate electrophoresis is described, and applied to the analysis of fetal globin chain production. When cord blood ...was analyzed, there was poor correlation between the globin chain ratios namely beta/alpha, gamma/alpha and beta/gamma ratios with either age or weight of newborn babies between 36-40 weeks gestation: best correlations were obtained for the beta/gamma ratio against weight (P less than 0.05). However, there was highly significant correlation between the various globin chain ratios and either age or weight of the newborn infant up to 12 weeks of age (P less than 0.001). This technique allows visual demonstration and quantitation of abnormal haemoglobins in a single procedure.
Lymphocyte reactivity assessed by a fluorescent lipophilic probe test of responsiveness to concanavalin A (con A) was shown to differ from normal in early pregnancy. The difference was most marked in ...multiparas. Abnormal reactivity was detected in the earliest pregnancy examined (5 weeks' gestation) and up to about the 20th week; after 20 weeks, reactivity was normal in all of the multiparas and most of the nulliparas studied. However, in pregnancy induced hypertension (PIH), a disorder of late pregnancy, the same responsiveness as in early pregnancy was found. When unstimulated lymphocytes were examined, abnormal reactivity associated with increased fluorescence was observed in early pregnancy and in PIH, compared with normal late pregnancy, reflecting alteration in lymphocyte membrane phospholipids. It is postulated that pregnancy is associated with sequential change in immunity, disturbance of which may result in immunologically-determined obstetric morbidity.
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