T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy.

Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T-cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy.

Persistence of left atrial abnormalities despite left atrial volume normalization after successful ablation of atrial fibrillation.

BACKGROUND: Left atrial volume index (LAVI) of >34 mL/m2 is the cutoff value for identifying an enlarged left atrium. The definition of left atrial (LA) reverse remodeling after atrial fibrillation (AF) ablation is undetermined. We hypothesized that patients with LA dilatation who achieve normal LA volume (LAVI<34 mL/m2) after AF ablation have better long-term outcomes than those who do not. Furthermore, we investigated whether patients with a normal LA volume can also achieve normal LA function with AF ablation. METHODS: We enrolled 140 AF patients with baseline LAVI of ≥34 mL/m2, without AF recurrence for 1 year after the initial AF ablation. We acquired conventional and speckle-tracking echocardiographic parameters within 24 hour and at 1 year after the procedure. To define the normal range of LA function, age- and sex-matched controls without a history of AF were also enrolled. RESULTS: After restoration of sinus rhythm, LA structural and functional parameters significantly improved, and 75 patients (54%) had normal LA volume. During a median follow-up of 44 (31-61) months, 32 patients (23%) experienced a late recurrence of AF (AF recurrence >1 year). Patients who achieved normal LA volume after AF ablation had fewer late recurrences than those who did not (P < .01). However, LA abnormalities, especially LA dysfunction, persisted in AF patients even when the LA volume was normalized compared with controls. CONCLUSION: Patients who achieved normal LA volume had better long-term outcomes of AF ablation than those who did not; however, LA abnormalities persisted even after successful ablation of AF.

Corneal thickness profile and posterior corneal astigmatism in normal corneas.

PURPOSE: To analyze the influence of corneal thickness profile on posterior corneal astigmatism (PA). DESIGN: Prospective, observational study. SUBJECTS: We included 418 normal subjects (213 men and 205 women) ranging in age from 6 to 93 years (49.0 ± 23.4 years, mean ± standard deviation) in this study. METHODS: Anterior and posterior corneal topography were evaluated using 3-dimensional anterior segment optical coherence tomography. Pericentral corneal thickness (PCT) in each quadrant (superior, inferior, nasal, and temporal) was measured, and average PCT in the vertical (superior + inferior) and horizontal (nasal + temporal) directions was calculated. Posterior corneal astigmatism was calculated as (1) assumed PA based on the anterior corneal curvature measurement and the keratometric index and (2) actual PA derived from the direct measurement of posterior corneal curvature. MAIN OUTCOME MEASURES: Corneal thickness distribution and the difference between assumed and actual PA. RESULTS: The PCT was significantly greater in the vertical (546.0 ± 31.8 µm) than in the horizontal direction (542.6 ± 31.7 µm) (P < 0.0001), and the difference between them was significantly correlated with subject age (r = 0.518, P < 0.0001). The difference between assumed and actual PA significantly correlated with the discrepancy between vertical and horizontal PCT (r = 0.819, P < 0.0001), as well as subject age (r = 0.533, P < 0.0001). CONCLUSIONS: Corneal thickness is greater in the vertical than in the horizontal direction, making the PA more against-the-rule pattern than calculated on the basis of the anterior corneal curvature measurement only. Such discrepancy is more prominent in older patients.

Age-related changes in anterior, posterior, and total corneal astigmatism.

PURPOSE: To evaluate age-related changes in anterior, posterior, and total corneal astigmatism by comparing simulated keratometric astigmatism to total corneal astigmatism. METHODS: Corneal topography of the anterior and posterior surfaces was evaluated using three-dimensional optical coherence tomography in 419 patients with normal eyes (218 men and 201 women) with ages ranging from 8 to 93 years (mean ± standard deviation: 49.5 ± 23.1 years). Keratometric astigmatism was calculated using the keratometric index (1.3375) and radius of the anterior corneal curvature; anterior and posterior corneal curvature measurements were used to calculate total corneal astigmatism. RESULTS: The keratometric and total astigmatism were 1.08 ± 0.71 diopters (D) and 1.03 ± 0.69 D, respectively. Vector analysis revealed a mean difference between keratometric and total astigmatism of 0.24 ± 0.09 D, which showed a significant correlation to age (P < .0001). In eyes with with-the-rule astigmatism, keratometric astigmatism overestimated total astigmatism. In eyes with against-the-rule astigmatism, keratometric astigmatism underestimated total astigmatism. CONCLUSIONS: The anterior corneal surface shifts from with-the-rule to against-the-rule astigmatism with aging, whereas the posterior corneal surface remains as against-the-rule astigmatism in most cases. The variation in the anterior astigmatism is the most important factor contributing to this change. Total corneal astigmatism is a better predictor than keratometric astigmatism for selecting toric intraocular lenses.

The pore region of N-methyl-D-aspartate receptors differentially influences stimulation and block by spermine.

The transmembrane and pore-forming regions of N-methyl-D-aspartate receptors containing the NR1 and NR2B subunits were studied by measuring the effects of various NR1 and NR2B mutants on stimulation and block by spermine. Block by spermine was predominantly affected by mutations in the M3 segment of NR1 and especially in the M1 and M3 segments of NR2B. These regions are in the outer vestibule of the channel pore and may contribute to a spermine binding site. Mutations in different regions-predominantly the M3 segment and M2 loop of NR1 and the M3 segment of NR2B-influenced spermine stimulation, a surprising finding because spermine stimulation is thought to involve a spermine binding site in the distal, extracellular regulatory domain. However, some of these mutations also influence sensitivity to ifenprodil and protons, and changes in spermine sensitivity may be secondary to changes in proton sensitivity. The results are consistent with the proposal that the relative positions of the M1 and M3 transmembrane segments and M2 loops are staggered or asymmetric in NR1 and NR2 subunits, and with the idea that stimulation and block by spermine involve separate binding sites and distinct mechanisms, although some residues in the receptor subunits can affect both stimulation and block.

[Continuous infusion of cyclosporine A and C3 monitoring in pediatric stem cell transplantation].

We performed an intravenous cyclosporine (CsA) drip infusion method for 3 hours and C3 monitoring in pediatric hematopoietic stem cell transplantation and examined the internal change and monitoring method of CsA. A total of six cases comprised five cord blood transplantations and one related allogeneic bone marrow transplantation. We started CsA 1.5 mg/kg at the day before transplantation by intravenous drip infusion (twice a day) for three hours. We controlled the dose so that the optimal peak value of C3 reached 800-1000 ng/ml. We recognized the C3 peak occurred three hours after initiation of infusion, and the blood CsA concentration was restored to the baseline value (C0) to (C12) 12 hours after that. We found a strong correlation between the C3 value (r = 0.90), and AUC(0-12). Two patients had grade II acute graft-versus-host disease (GVHD), but one needed no treatment, and the other recovered with short-term dosage of prednisolone. Apart from these instances, no serious complication occurred. In pediatric hematopoietic stem cell transplantation, it seems that regulation of the appropriate blood CsA concentration is enabled by using C3 monitoring at around 3 hours after commencing the intravenous drip infusion method for CsA.

Preferential selection of human T-cell leukemia virus type 1 provirus lacking the 5' long terminal repeat during oncogenesis.

In adult T-cell leukemia (ATL) cells, a defective human T-cell leukemia virus type 1 (HTLV-1) provirus lacking the 5' long terminal repeat (LTR), designated type 2 defective provirus, is frequently observed. To investigate the mechanism underlying the generation of the defective provirus, we sequenced HTLV-1 provirus integration sites from cases of ATL. In HTLV-1 proviruses retaining both LTRs, 6-bp repeat sequences were adjacent to the 5' and 3' LTRs. In 8 of 12 cases with type 2 defective provirus, 6-bp repeats were identified at both ends. In five of these cases, a short repeat was bound to CA dinucleotides of the pol and env genes at the 5' end, suggesting that these type 2 defective proviruses were formed before integration. In four cases lacking the 6-bp repeat, short (6- to 26-bp) deletions in the host genome were identified, indicating that these defective proviruses were generated after integration. Quantification indicated frequencies of type 2 defective provirus of less than 3.9% for two carriers, which are much lower than those seen for ATL cases (27.8%). In type 2 defective proviruses, the second exons of the tax, rex, and p30 genes were frequently deleted, leaving Tax unable to activate NF-kappaB and CREB pathways. The HTLV-1 bZIP factor gene, located on the minus strand, is expressed in ATL cells with this defective provirus, and its coding sequences are intact, suggesting its significance in oncogenesis.

Nephrotic syndrome and aberrant expression of laminin isoforms in glomerular basement membranes for an infant with Herlitz junctional epidermolysis bullosa.

Herlitz junctional epidermolysis bullosa (H-JEB) is a hereditary bullous disease caused by absent expression of laminin-5, a component of anchoring filaments within the dermal-epidermal basement membrane zone. Affected individuals usually die during the first 1 year of life. We studied an infant with H-JEB who presented with nephrotic syndrome, a previously unreported complication that may contribute to early death in this disease. DNA analysis revealed a compound heterozygote for mutations 2379delG and Q995X in the LAMB3 gene. The patient had massive albuminuria, attributable to failure of the glomerular filtration barrier, and high urinary N-acetylglucosaminidase levels, indicating renal tubular involvement. Electron-microscopic examination of the renal tissue revealed diffuse fusion of the foot processes, irregular swelling of the lamina rara interna, and disappearance of endothelial cell fenestrations. Immunohistopathologic analysis of the patient's renal tissue revealed compositional changes in laminin isoforms of the glomerular basement membrane and no detectable laminin-5 in the renal tubular basement membrane, which suggests that laminin-5 may play an important role in renal function. Our findings strongly suggest that H-JEB should be considered in the spectrum of congenital nephrotic syndromes. Combination therapy with meticulous skin care and treatment strategies established for congenital nephrotic syndromes may rescue patients with this disease.

Successful allogeneic bone marrow transplantation in a patient with acute myelogenous leukemia and cytomegalovirus retinitis.

A 1-year-old boy with acute myeloid leukemia with cytomegalovirus (CMV) retinitis that was refractory because of severely impaired cellular immunity underwent bone marrow transplantation from an HLA-matched donor after a conditioning regimen of busulfan, cyclophosphamide, and etoposide. Although we continued administration of ganciclovir from preparation therapy, retinitis worsened after engraftment. Thereafter retinitis improved gradually as the number of CD4+ T-lymphocytes increased. The findings in this case suggest that stem cell transplantation for a leukemia patient with CMV disease may be effective.

[The effectiveness of the long-term treatment with pranlukast in pediatric patients with mild to moderate asthma].

To investigate the efficacy of the long-term treatment with pranlukast, a specific cysteinyl leukotriene receptor antagonist, in pediatric patients with mild to moderate asthma, 77 pediatric asthmatic patients who received pranlukast for up to 36 months (mean duration, 13 months) were evaluated retrospectively. Treatment with pranlukast resulted in improvements from the pretreatment baseline in asthma attacks per month, episodes of hospitalization, and episodes of intravenous amynophiline treatment on emergent clinic visits. The percentage of responders who had marked or moderate improvements in the above-mentioned parameters of asthma control was 79%. In conclusion, pranlukast caused significant improvements in long-term asthma control in pediatric patients with mild to moderate asthma.