Tumor thickness as a novel risk factor for lymph node metastasis by superficial squamous cell carcinoma of head and neck.

Narrow-band imaging combined with magnified endoscopy has enabled the detection of superficial squamous cell carcinoma of the head and neck (SSCCHN) that has been resected with minimally invasive treatment, preserving vocalization and swallowing functions. However, risk factors of lymph node metastasis (LNM) must be identified, as some patients with LNM have a poor prognosis. From an initial 599 patients with 700 lesions who underwent trans-oral surgery in 27 Japanese hospitals (a nationwide registration survey), we enrolled 541 patients with 633 SSCCHNs, as indicated by central pathological diagnoses. All pathological specimens for each patient were examined using 20 pathological factors that are thought to affect the LNM of SSCCHN. In all, 24 (4.4%) of the 568 SSCCHNs exhibited LNM, and all 24 had at least one solitary nest of epithelial neoplastic cells present in the stroma, clearly separated from the intraepithelial carcinoma. Multivariate analysis also showed that tumor thickness (p = 0.0132, RR: 7.85, 95% confidence interval [CI]: 1.54-40.02), and an INFc pattern classified as infiltrating growth (INF) with unclear boundaries between tumor and non-tumor tissues (p = 0.0003, RR: 14.47, 3.46-60.46), and tumor budding (p = 0.0019, RR: 4.35, CI: 1.72-11.01) were significantly associated with LNM. Solitary nests may be indicative of LNM. In addition, tumor thickness was revealed to be a risk factor for LNM in SSCCHNs using pT factors that do not include an invasion depth element because of the anatomical absence of the muscularis mucosae.

Analysis of IgG subclass staining for IgG immunofluorescence-positive IgA nephropathy.

AIMS: The clinicopathological significance of IgG subclass staining is unclear in IgG immunofluorescence (IF)-positive IgA nephropathy (IgAN). This study investigated IgG subclass distribution in IgG IF-positive IgAN by IF staining and examined their clinicopathological significance. MATERIALS AND METHODS: From January 2015 to December 2020, 27 biopsies from 26 patients with IgG IF-positive IgAN who were IF-positive for any IgG subclass staining were collected. We compared the clinicopathological findings between cases with and without IF positivity for each IgG subclass. RESULTS: Of the 27 biopsies with IgG IF-positive IgAN, 20 (74.1%) were IF-positive for IgG1, 10 (37.0%) were positive for IgG2, 7 (25.9%) were positive for IgG3, and none were positive for IgG4. Oxford E and C scores were significantly higher in cases of IgG IF-positive IgAN than IgG IF-negative IgAN. The age at biopsy had a negative correlation with IgG1 IF intensity (γ = -0.604, p = 0.001). The levels of proteinuria and microscopic hematuria as well as Oxford classification score were not significantly different between cases with or without positive staining for each IgG subclass. IgG IF intensity had a positive correlation with IgG1 IF intensity (γ = 0.741, p < 0.001). CONCLUSION: IgG1-positive IF staining intensity was highest among each IgG subclass in IgG IF-positive IgAN biopsies. A negative correlation was revealed between the age at biopsy and IgG1 IF intensity. Oxford E and C scores were higher in patients with IgG IF-positive IgAN than in those with IgG IF-negative IgAN. The Oxford score was not significantly different between the IgG subclasses, but the IF intensity of IgG had a positive correlation with the IF intensity of IgG1 in IgG IF-positive IgAN biopsies. Further studies should assess relationships between IgG subclass IF deposition and examine the pathogenesis of IgAN.

Clinicopathological importance of Bcl-2 and p53 in postmenopausal triple-negative breast carcinoma and association with age.

Appropriate biomarkers are required to predict the clinical outcome of triple-negative breast cancer (TNBC). In this study, we focused on the clinical importance of two representative tumor-associated proteins, Bcl-2 and p53. Bcl-2 expression is usually related to estrogen receptor expression and a favorable outcome in breast cancer. TNBC has been reported to show a high frequency of p53 positivity suggesting TP53 mutations. The expressions of Bcl-2 and p53 were immunohistochemically examined in TNBC involving two age groups of postmenopausal women (≥75 y/o, n = 75; 55-64 y/o, n = 47), who underwent surgery without neoadjuvant therapy. We examined their associations with each other, or with clinicopathological factors including the outcome. Bcl-2 expression was inversely correlated with androgen receptor, apocrine morphology, and p53 expressions, and was an independent predictor of a poor outcome in total or in younger women. p53 positivity was associated with a more favorable outcome than p53 negativity in the younger group. In combined analyzes, none of the twenty Bcl-2-negative/p53-positive cases in the younger group exhibited recurrence, resulting in the independent favorable predictive value of Bcl-2-negative/p53-positive. The anti-apoptotic nature of Bcl-2 may be apparent in TNBC. The excellent outcome of Bcl-2-negative/p53-positive cases in the younger group warrants further combined investigation of Bcl-2/p53 in TNBC.

Prognostic value of the 7-year protocol biopsy of adult kidney allografts: impact of mesangiosclerosis and proteinuria.

AIM: The aim of the present study was to clarify the relationship between the Banff score of the 7-year protocol biopsy and the allograft outcome. METHODS: One-hundred-and-eighty-four patients received kidney transplantation from 2002 to 2008. We excluded patients aged <20 years at transplantation (n = 24), those who did not undergo a 7-year protocol biopsy (n = 66), and those who underwent for-cause biopsy (n = 5). Consequently, 89 patients who underwent a 7-year protocol biopsy were enrolled. We analyzed the relationship between the clinicopathological findings 7 years after transplantation and the estimated glomerular filtration rate (eGFR) change per year and allograft survival. Histological evaluation was performed using the Banff 2015 classification. RESULTS: Among the clinicopathological findings, each Banff mesangial matrix increase (mm) score ≥1 and proteinuria ≥1+ was independently associated with the eGFR decline per year during a median follow-up of 73 months. Furthermore, in the model of the clinicopathological findings including the presence of mm with proteinuria, mm ≥1 alone and mm ≥1 with proteinuria were each independently associated with the eGFR decline. The graft survival was significantly worse for those with mm ≥1 with proteinuria than those with mm ≥1 without proteinuria. CONCLUSION: Among the 7-year protocol biopsy findings, the presence of mm alone and mm with proteinuria were each significant predictors of eGFR decline. The presence of both proteinuria and mm had a negative impact on graft survival. These results underscore the significance of the Banff mm score and proteinuria at the time of the 7-year protocol biopsy to predict the allograft outcome.

Estrogen Receptor-ß Gene Cytosine-Adenine (ESR2-CA) Repeat Polymorphism in Postmenopausal Colon Cancer.

The pathobiological role of estrogen is controversial in colorectal cancer. Cytosine-adenine (CA) repeat in the estrogen receptor (ER)-ß gene (ESR2-CA) is a microsatellite, as well as representative of ESR2 polymorphism. Though its function is unknown, we previously showed that a shorter allele (germline) increased the risk of colon cancer in older women, whereas it decreased it in younger postmenopausal women. ESR2-CA and ER-ß expressions were examined in cancerous (Ca) and non-cancerous (NonCa) tissue pairs from 114 postmenopausal women, and comparisons were made considering tissue types, age/locus, and the mismatch repair protein (MMR) status. ESR2-CA repeats <22/≥22 were designated as 'S'/'L', respectively, resulting in genotypes SS/nSS (=SL&LL). In NonCa, the rate of the SS genotype and ER-ß expression level were significantly higher in right-sided cases of women ≥70 (≥70Rt) than in those in the others. A decreased ER-ß expression in Ca compared with NonCa was observed in proficient-MMR, but not in deficient-MMR. In NonCa, but not in Ca, ER-ß expression was significantly higher in SS than in nSS. ≥70Rt cases were characterized by NonCa with a high rate of SS genotype or high ER-ß expression. The germline ESR2-CA genotype and resulting ER-ß expression were considered to affect the clinical characteristics (age/locus/MMR status) of colon cancer, supporting our previous findings.

Outcome of ABO-incompatible kidney transplantation using a modified desensitization protocol without plasmapheresis.

OBJECTIVES: Several controversies regarding desensitization strategies for successful ABO-incompatible (ABOi) kidney transplantation still exist. This study aimed to investigate whether pretransplant anti-A/B antibody removal is mandatory in an ABOi kidney transplant recipient with low baseline isoagglutinin titers. METHODS: We adopted a modified desensitization protocol with two doses of rituximab (RTX, 100 mg/body) without pretransplant antibody removal for ABOi kidney transplant recipients with a titer of ≤1:64 (group A; n = 35) and investigated the feasibility of this protocol by comparing it with the clinical outcomes of patients undergoing standard pretransplant plasmapheresis (group B; n = 21). RESULTS: There was no significant difference in the rate of antibody-mediated rejection within the first month after transplantation between the two groups (11.4% in group A vs. 2% in group B, p = 0.6019). Moreover, no differences were observed in the short- and long-term graft outcomes between the groups. However, two major critical acute antibody-mediated events occurred in group A; one patient lost the graft due to hyperacute rejection, and the other patient developed thrombotic microangiopathy after surgery. Risk factors predicting these perioperative complications were not identified. CONCLUSIONS: We conclude that not only B-cell depletion using RTX but also pretransplant antibody removal is still recommended even for patients with low isoagglutinin titers. In addition, a new diagnostic tool is needed for accurate risk stratification.

Increased Indoleamine 2,3-Dioxygenase Levels at the Onset of Sjögren's Syndrome in SATB1-Conditional Knockout Mice.

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by dysfunction of salivary and lacrimal glands, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Autoantibodies, such as anti-SSA and anti-SSB antibodies, are hallmarks and important diagnostic factors for SS. In our previous study, we demonstrated that SS-like xerostomia was observed in SATB1 conditional knockout (SATB1cKO) mice, in which the floxed SATB1 gene was specifically deleted in hematopoietic cells as early as 4 weeks of age. In these mice, autoantibodies were not detected until 8 weeks of age in SATB1cKO mice, although exocrine gland function reached its lowest at this age. Therefore, other markers may be necessary for the diagnosis of SS in the early phase. Here, we found that mRNA expression of the interferonγ (IFN-γ) gene and the IFN-responsive indoleamine 2,3-dioxygenase (IDO) gene is upregulated in the salivary glands of SATB1cKO mice after 3 and 4 weeks of age, respectively. We detected l-kynurenine (l-KYN), an intermediate of l-tryptophan (l-Trp) metabolism mediated by IDO, in the serum of SATB1cKO mice after 4 weeks of age. In addition, the upregulation of IDO expression was significantly suppressed by the administration of IFN-γ neutralizing antibodies in SATB1cKO mice. These results suggest that the induction of IFN-dependent IDO expression is an initial event that occurs immediately after the onset of SS in SATB1cKO mice. These results also imply that serum l-KYN could be used as a marker for SS diagnosis in the early phases of the disease before autoantibodies are detectable.

A murine model of acute lung injury identifies growth factors to promote tissue repair and their biomarkers.

Type II alveolar epithelial cells (AEC2s) play a crucial role in the regeneration of type I AECs after acute lung injury. The mechanisms underlying the regeneration of AEC2s are not fully understood. To address this issue, here, we investigated a murine model of acute lung injury using mice expressing human Diphtheria Toxin Receptor (DTR) under the control of Lysozyme M promoter (LysM-DTR). DT injection induced the depletion of AEC2s, alveolar macrophages, and bone marrow (BM)-derived myeloid cells in LysM-DTR mice, and the mice died within 6 days after DT injection. Apoptotic AEC2s and bronchiolar epithelial cells appeared at 24 hr, whereas Ki67-positive proliferating cells appeared in the alveoli and bronchioles in the lung of LysM-DTR mice at 72-96 hr after DT injection. Transfer of wild-type BM cells into LysM-DTR mice accelerated the regeneration of AEC2s along with the up-regulation of several growth factors. Moreover, several metabolites were significantly decreased in the sera of LysM-DTR mice compared with WT mice after DT injection, suggesting that these metabolites might be biomarkers to predict AEC2s injury. Together, LysM-DTR mice might be useful to identify growth factors to promote lung repair and the metabolites to predict the severity of lung injury.

Comparison of live donor predonation and post-transplant kidney volumes and glomerular size in pediatric patients weighing less than 15 kg - a retrospective study.

Renal transplantation of adult-size kidneys presents a size mismatch in small children. This study presents a comparison of live donor predonation and recipient post-transplant kidney volumes (k-vol) and glomerular size at 1 year after transplantation. We analyzed 47 pediatric renal transplant recipients weighing <15 kg between 2009 and 2017. The k-vol before and 1 year after transplantation and glomerular size at implant and 1 year post-transplant were evaluated. We estimated the relationships between these changes and graft function, and the factors associated with k-vol. Pretransplant k-vol was 158.1 ± 25.1 ml, and the k-vol at 1 year post-transplant was significantly reduced by -17.2% to 132.3 ± 27.3 ml (P < 0.001). Implant glomerular size showed the diameter was 165.3 ± 15.1 µm and the area 20 737.1 ± 3230.6 µm2 . One-year post-transplant, the glomerular diameter was 150.6 ± 11.4 µm and the area 17 428.3 ± 2577.9 µm2 , significantly reduced compared with implantation values (both P < 0.001). The change in k-vol was affected by pretransplant abdominal cavity (ml/200 ml cavity volume, partial regression coefficient = 0.029, SE = 0.009, P = 0.004) and recipient's weight gain (ml/5% of weight gain, partial regression coefficient = 0.020, SE = 0.006, P = 0.002). In small pediatric transplants, an adult-size kidney is acceptable with reduction in k-vol. Moreover, the post-transplant k-vol might be regulated by pretransplant physique and post-transplant somatic growth.

Impact of older age on clinicopathological and prognostic features of colon cancer in postmenopausal women.

To clarify the clinicopathological features of colorectal cancer in older people, systematic studies considering age, sex, and the tumor locus is needed. We focused on colon cancer in postmenopausal women (<70 years, n = 68 vs. ≥70 years, n = 85), and examined the effect of age on clinicopathological features. Rates of medullary carcinoma /mucinous carcinoma were higher and pathological stages at diagnosis were less advanced in patients ≥70 years compared with <70 years. Matching pathological stages, no significant difference in disease-free interval was observed according to age; however, disease-specific survival (DSS) was poorer in patients ≥70 years than <70 years, being significantly different in stage IV cases. Regarding post-metastasis/recurrence (met/rec) cases, chemotherapy and surgery for metastasis were less frequent in those aged ≥70 years than <70 years. Post-met/rec DSS was poorer in ≥70 years, those with microsatellite instability, and those without surgery for met/rec than in each counterpart; however, post-met/rec chemotherapy exhibited no effect. Multivariate analyses revealed that an older age and no surgery for metastasis were independent predictors of disease-specific death. These findings remained after excluding stage IV cases. Older age was a potent risk factor of rapid disease-specific death after met/rec.

Expression of CA2 and CA9 carbonic anhydrases in ulcerative colitis and ulcerative colitis-associated colorectal cancer.

Ulcerative colitis (UC) is characterized by chronic inflammation in the colonic mucosa and submucosa with repeating relapse and remission, but the pathogenesis is unknown. Patients with long-standing UC are at high risk of neoplasm development. The aim of the present study was to identify molecules whose expression is associated with UC and UC-associated colorectal cancer (UCCA). Biopsy specimens from UC and normal colonic mucosae were analyzed using a proteomics approach, in which carbonic anhydrase 2 (CA2) was identified as a molecule downregulated in UC mucosae. Immunohistochemically, CA2 expression was detected in normal and diverticulitis mucosal epithelia, and its expression decreased as UC activity increased. CA2 expression was almost undetectable in UCCA. We also analyzed the expression of another carbonic anhydrase, CA9, and its upstream molecule, hypoxia-inducible factor-1α (HIF-1α), both of which are induced under hypoxic conditions. It was revealed that CA9 expression was relatively low in normal, diverticulitis and UC mucosae, and was upregulated in UCCA. HIF-1α expression was consistently low in all tissue types examined. In conclusion, these results suggest that CA2 and CA9 may be possible indicators of UC activity and UCCA development, respectively.

Settlement of Stenotic Site and Enhancement of Risk Factor Load for Atherosclerosis in Left Anterior Descending Coronary Artery by Myocardial Bridge.

OBJECTIVE: The aim of this study was to investigate the influence of a myocardial bridge (MB) on atherosclerosis development in the left anterior descending artery of the normal heart and the importance of traditional risk factors (RFs). An additional objective was to determine the correlation between intimal thickening and luminal narrowing. APPROACH AND RESULTS: The left anterior descending artery from 150 autopsied hearts was treated with formalin perfusion fixation, and each left anterior descending artery was serially cross-sectioned. The intima-media and luminal stenosis ratios were examined using computer-assisted histomorphometry. The luminal stenosis ratio was closely correlated with the intima-media ratio (r=0.792; P<0.001). When an MB was present, the luminal stenosis ratios proximal to the MB in the RF (+) group were significantly greater than those in the RF (-) group (P=0.022 by a multiple comparison test), but there were no differences between the RF (+) and RF (-) groups when an MB was absent. In addition, the site of the greatest stenosis in the MB (+) RF (+) group was 2.5 cm proximal to the MB entrance. Multivariate analyses indicated that age was an independent factor for luminal stenosis ratios ≥50% and 60% (P=0.002 and 0.029, respectively). Furthermore, the presence of an MB plus RFs was an independent factor for a luminal stenosis ratio ≥70% (P=0.037). CONCLUSIONS: An MB enhances left anterior descending artery atherosclerosis development at a site proximal to the MB entrance, particularly in subjects who have some RFs.

Expression of mTOR Signaling Pathway Molecules in Triple-Negative Breast Cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC), which lacks expression of estrogen receptor (ER), progesterone receptor (PgR), and epidermal growth factor receptor 2 (HER2), currently has no effective hormonal or molecular target therapy. OBJECTIVE AND METHODS: To elucidate the role of the mammalian target of rapamycin (mTOR) signaling pathway in TNBC, the expression of molecules involved in mTOR signaling including mTOR, phosphorylated (p)-mTOR, p-4EBP1, GLUT1, GLUT3, HIF-1α, and Ki67 was investigated by immunohistochemistry in 35 TNBC and 81 non-TNBC cases. RESULTS: Expression of p-mTOR, the activated form of mTOR, but not unphosphorylated mTOR, was significantly higher in non-TNBC cases than in TNBC cases. Expression of p-4EBP1, GLUT1, and GLUT3 was higher in TNBC cases than in non-TNBC cases. When the localization of p-mTOR was classified as nuclear, perinuclear, or cytoplasmic, nuclear localization of p-mTOR was observed more frequently in TNBC than in non-TNBC cases and was correlated with the expression of GLUT1 and GLUT3, which was related to proliferation activity examined with Ki67. CONCLUSIONS: mTOR signaling regulates cell proliferation in some cases of TNBC and may be a potential target of molecular therapy for TNBC.

SATB1 Conditional Knockout Results in Sjögren's Syndrome in Mice.

Sjögren's syndrome (SS) is an autoimmune disease in which exocrine tissues are affected by cellular and humoral immunity. As a result, the salivary and lacrimal glands of patients with SS are damaged, leading to xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Because experimental approaches to investigate SS pathogenesis in human patients are limited, development of a mouse model is indispensable for understanding the disease. In this study, we show that special AT-rich sequence binding protein-1 conditional knockout (SATB1cKO) mice, in which the SATB1 gene is specifically deleted from hematopoietic cells, develop SS by 4 wk of age, soon after weaning. Female mice presented an earlier onset of the disease than males, suggesting that female SATB1cKO mice are more susceptible to SS. T cell-dominant immune cell infiltration was observed in the salivary glands of 4 wk old SATB1cKO mice, and the frequency of B cells gradually increased as the mice aged. Consistently, levels of anti-SSA and anti-SSB Abs were increased around 8 wk of age, after salivary production reached its lowest level in SATB1cKO mice. These results suggest that SATB1cKO mice can be a novel SS model, in which the progression and characteristics of the disease resemble those of human SS.

Characteristics of adverse events of endocrine therapies among older patients with breast cancer.

PURPOSE: To clarify the profile of adverse events from endocrine therapies in older patients. METHODS: We surveyed 15 subjective symptoms including hot flashes, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, lethargy, forgetfulness, depressive state, irritated state, genital bleeding, leukorrhea increase, vaginal dryness, bone fracture, and weight gain by a questionnaire among 2044 patients over 55 years old (total number of answered sheets, 8875) and compared the results according to age (56-69 years old vs. ≥ 70 years old) and type of therapy (aromatase inhibitors (AIs) vs. selective estrogen receptor modulators (SERMs)). Among patients 56-69 years old, 6093 and 314 responses were from patients treated with AIs (1477 patients) and SERMs (123 patients), respectively, and 2292 and 176 responses were from those ≥ 70 years old treated with AIs (581 patients) and SERMs (51 patients), respectively. RESULTS: In patients ≥ 70 years old, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, and lethargy were significantly more frequent/severe with AIs than with SERMs. In those aged 56-69, knuckle stiffness and vaginal dryness were significantly more frequent with AIs than with SERMs, but the opposite occurred for hot flashes, leukorrhea increase, genital bleeding, and weight gain. CONCLUSIONS: Among patients ≥ 70 years old, many symptoms were significantly more frequent/severe with AIs than with SERMs, compared with those aged 56-69, which suggests a difference in the profile of adverse events according to the type of endocrine therapy and the patient's age. It is important to consider the benefits and risks of each treatment to optimize endocrine therapy for older patients.

Vasa recta hyalinosis reflects severe arteriolopathy in renal allografts.

AIM: We examined the clinicopathologic significance of hyalinosis in the vasa recta in the medulla of allograft kidney biopsies. METHOD: We analyzed biopsy specimens from January 2010 to December 2015, obtained from both the cortex and medulla (including the vasa recta) ≥ 1 year after living-donor kidney transplantation. We excluded biopsy specimens from recipients who had undergone transplantation due to diabetic nephropathy or who had diabetes mellitus after transplantation. We evaluated hyaline arteriolopathy in the cortex using the aah score determined by the Banff 2007 classification. RESULT: Among 381 biopsy specimens obtained from 248 transplant recipients ≥ 1 year after transplantation, 36 specimens obtained from 34 recipients showed vasa recta hyalinosis (VRH) in the medulla. Among these 36 specimens, 17 had a score of aah3, 16 had a score of aah2, and 3 had a score of aah1. The incidence of VRH was 1.9% at ≥ 1 to < 4 years, 7.1% at ≥ 4 to < 8 years, and 50.0% at ≥ 8 years. The aah scores and the proportion of hyalinosis in the arteriolar media among all muscular arterioles in the cortex were significantly higher in the VRH group at ≥ 8 years in the late-phase biopsy (P < 0.01). The graft survival was worse in the VRH group (P = 0.024), although there was no significant difference in the graft survival between the ≥ aah2 and < aah2 groups at ≥ 8 years in the late-phase biopsy (P = 0.159). CONCLUSION: VRH in renal allografts reflects severe arteriolopathy of the cortex. VRH in the late-phase biopsy may be a prognostic factor for graft survival.

Generation of and characterization of anti-IL-11 antibodies using newly established Il11-deficient mice.

Interleukin (IL)-11 belongs to the members of the IL-6 family of cytokines and is involved in a variety of biological responses, including hematopoiesis, bone development, and carcinogenesis. However, the cellular sources of IL-11 and regulation of IL-11 expression under physiological and pathological conditions are not fully understood. One of the causes to prevent characterization of IL-11 in vivo is due to the lack of reliable antibodies that detect IL-11 by immunohistochemistry. Moreover, although mice lacking Il11ra have been generated and extensively characterized, Il11-deficient mice have not been characterized yet. Here we generated two anti-IL-11 antibodies that blocked biological activities of IL-11 and detected IL-11 by immunohistochemistry, respectively. One clone of anti-IL-11 antibodies blocked IL-11-, but not IL-6-induced cell proliferation and IL-11-induced phosphorylation of STAT3 of an IL-11-dependent cell line. Moreover, we used recently established Il11-deficient mice to test the specificity of anti-IL-11 antibodies for immunohistochemistry. Another clone of anti-IL-11 antibodies stained stromal cells surrounding tumors of the colon of wild-type, but not Il11-deficient mice following treatment with Azoxymethane plus dextran sulfate sodium. Together, these newly developed anti-IL-11 antibodies provide a better understanding of the functions of IL-11 in vivo under various physiological and pathological conditions.

Special AT-rich sequence binding protein 1 is required for maintenance of T cell receptor responsiveness and development of experimental autoimmune encephalomyelitis.

The genome organizer special AT-rich sequence binding protein 1 (SATB1) regulates specific functions through chromatin remodeling in T helper cells. It was recently reported by our team that T cells from SATB1 conditional knockout (SATB1cKO) mice, in which the Satb1 gene is deleted from hematopoietic cells, impair phosphorylation of signaling molecules in response to T cell receptor (TCR) crosslinking. However, in vivo T cell responses upon antigen presentation in the absence of SATB1 remain unclear. In the current study, it was shown that SATB1 modulates T cell antigen responses during the induction and effector phases. Expression of SATB1 was upregulated in response to TCR stimulation, suggesting that SATB1 is important for this antigen response. The role of SATB1 in TCR responses and induced experimental autoimmune encephalomyelitis (EAE) was therefore examined using the myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) and pertussis toxin. SATB1cKO mice were found to be resistant to EAE and had defects in IL-17- and IFN-γ-producing pathogenic T cells. Thus, SATB1 expression appears necessary for T cell function in the induction phase. To examine SATB1 function during the effector phase, a tamoxifen-inducible SATB1 deletion system, SATB1cKO-ER-Cre mice, was used. Encephalitogenic T cells from MOG35-55-immunized SATB1cKO-ER-Cre mice were transferred into healthy mice. Mice that received tamoxifen before the onset of paralysis were resistant to EAE. Furthermore, no disease progression occurred in recipient mice treated with tamoxifen after the onset of EAE. Thus, SATB1 is essential for maintaining TCR responsiveness during the induction and effector phases and may provide a novel therapeutic target for T cell-mediated autoimmune diseases.

Interlobular hyaline arteriopathy reflects severe arteriolopathy in renal allografts.

AIM: The present study was performed to examine the clinicopathological significance of hyaline deposits in the smooth muscle of the interlobular artery (interlobular hyaline arteriopathy [IHA]) in renal allografts. METHODS: Tissue specimens that included the interlobular artery from biopsies performed from January 2012 to December 2015, as well as specimens from biopsies performed ≥1 year after living kidney transplantation were analyzed. Biopsies of recipients with new-onset diabetes mellitus after transplantation were excluded, as well as those of recipients who had undergone transplantation because of diabetic nephropathy. Arteriolopathy was evaluated using the aah score determined by the Banff 2007 classification. RESULTS: In total, 51 specimens with IHA lesions were identified among 381 biopsies obtained from 243 recipients performed ≥1 year after kidney transplantation. Among these 51 biopsies, 18 specimens had a score of aah3, 29 had a score of aah2, and four had a score of aah1. The incidence of IHA lesions was 3.6% at ≥1 to <4 years, 18.5% at ≥4 to <8 years, and 54.1% at ≥8 years. Older kidney grafts exhibited more IHA lesions. Among the biopsy specimens obtained ≥8 years after transplantation, no significant differences in the recipient or donor age, duration after transplantation, or prevalence of hypertension were observed between the IHA and non-IHA groups. The aah scores were significantly higher in the IHA group ≥8 years after transplantation as determined by the mean score test (P < 0.01). CONCLUSION: IHA in renal allografts is associated with severe arteriolopathy.

Basic Fibroblast Growth Factor Induces Angiogenic Properties of Fibrocytes to Stimulate Vascular Formation during Wound Healing.

The role of fibrocytes in wound angiogenesis remains unclear. We therefore demonstrated the specific changes in fibrocyte accumulation for angiogesis in basic fibroblast growth factor (bFGF)-treated wounds. bFGF-treated wounds exhibited marked formation of arterioles and inhibition of podoplanin+ lymph vessels that were lacking in vascular endothelial growth factor-A-treated wounds. Real-time PCR in bFGF-treated wounds manifested enhanced expression of CD34, CD31, and bFGF mRNA and reduced expression of podoplanin and collagen type I, III, and IV mRNA. Double immunofluorescence staining focusing on fibrocyte detection in bFGF-treated wounds showed increased formation of capillary-like structures composed of CD34+/procollagen I+ fibrocytes, with a lack of capillary-like structures formed by CD45+/procollagen I+ or CD11b+/procollagen I+ fibrocytes. However, vascular endothelial growth factor-A-treated wounds lacked capillary-like structures composed of CD34+/procollagen I+ fibrocytes, with increased numbers of CD34+/fetal liver kinase-1+ endothelial progenitor cells. Furthermore, fibroblast growth factor receptor 1 siRNA injection into wounds, followed by bFGF, inhibited the formation of capillary-like structures composed of CD34+/procollagen I+ fibrocytes, together with inhibited mRNA expression of CD34 and CD31 and enhanced mRNA expression of collagen type I, indicating the requirements of bFGF/fibroblast growth factor receptor 1 system for capillary structure formation. This study highlights the angiogenic properties of CD34+/procollagen I+ fibrocytes specifically induced by bFGF, providing new insight into the active contribution of fibrocytes for vascular formation during wound healing.