Objective: To investigate the clinicopathological features of angioimmunoblastic T-cell lymphoma pattern Ⅰ (AITL Pattern Ⅰ). Methods: The clinicopathological data of 11 AITL Pattern Ⅰ cases that were diagnosed at the Beijing Friendship Hospital Affiliated to Capital Medical University (10 cases) and Beijing Lu Daopei Hospital (1 cases) from January 2019 to October 2021 were retrospectively collected. Immunophenotype, Epstein-Barr virus infection status and T cell receptor (TCR) clonality of the tumor cells were tested, and clinicopathological features of cases were analyzed. Results: Among the 11 AITL Pattern Ⅰ cases, the male to female ratio was 1.2∶1.0. The median age was 59 years (range 47-78 years). Seven cases had B symptoms, while eleven cases presented with systemic lymphadenopathy. According to Ann Arbor system staging, two cases were classified as stage Ⅰ-Ⅱ, and 9 cases as stage Ⅲ-Ⅳ. Hepatosplenomegaly was present in two cases (2/11), three cases (3/11) had skin rash and pruritus, and two cases (2/11) had pleural effusion. Previously, 6 cases (6/11) were diagnosed as reactive hyperplasia, 1 case (1/11) as EBV-associated lymphoproliferative disorder, and 4 cases (4/11) as hyperplasia of lymphoid tissue, which was unable to exclude lymphoma. Histologically, all the 11 cases showed hyperplastic follicles in the paracortical regions with well-formed germinal centers. The hyperplastic follicles showed ill-defined borders and attenuated mantle zones in 7 cases. Mantle zones completely disappeared in 4 cases. The follicles were surrounded by a thin layer of atypical lymphocytes with bright or faintly stained cytoplasm. In 2 cases, the clear cells were located between the germinal centers and the thin residual mantle cell layers, showing a circular growth pattern. The cells were medium in size, with irregular karyotype, coarse chromatin and indistinct nucleoli. Immunohistochemically, CD21 staining showed that the meshworks of follicular dendritic cells(FDC)were mainly confined to the follicles. There was a subtle expansion of the meshworks of FDC in 4 cases with ill-defined borders. The atypical cells surrounding the follicles expressed CD3 (11/11), CD4 (11/11), PD-1 (11/11), CXCL13 (6/11), ICOS (10/11) and CD10 (7/11). PD-1 staining showed a strong perifollicular pattern, and a small number of positive cells were scattered around the high endothelial veins in the interfollicular region. CXCL13, ICOS and CD10 showed similar distribution patterns. EBV-encoded small RNA probe (EBER) in situ hybridization showed that EBER positive B lymphocytes were scattered in the interfollicular region (5-20/HPF) in all cases. T cell receptor gene rearrangement was monoclonal in all cases. Conclusions: Diagnosing AITL Pattern Ⅰ may be challenging and requires comprehensive analysis of clinical manifestations, histological morphology, immunophenotype and gene rearrangement results.
Aged ; Epstein-Barr Virus Infections ; Female ; Herpesvirus 4, Human ; Humans ; Hyperplasia ; Immunoblastic Lymphadenopathy/pathology* ; Lymphoma, T-Cell/pathology* ; Male ; Middle Aged ; Neprilysin ; Programmed Cell Death 1 Receptor ; Retrospective Studies

Objective: To investigate the clinicopathological characteristics, immunophenotype, and molecular signatures of oncocytic papillary renal cell carcinoma (OPRCC), and to compare these findings with those in type 1 papillary renal cell carcinoma (PRCC 1). Methods: The clinicopathologic data of 19 patients with OPRCC from the Affiliated Hospital of Qingdao University (16 patients) and the 971 Hospital of People's Liberation Army Navy (3 patients) from October 2003 to February 2021 were collected. Histologic, immunohistochemical (IHC) and molecular analyses, together with a control group of 15 cases of PRCC I diagnosed in the same period, were assessed. Results: The cohort included 15 males and 4 females, with a median age of 61 years (range, 47-78 years). In 13 patients the tumors were found at physical examination; four presented with painless gross hematuria and two with low back pain. As for the pathologic stage, 14 patients were pT1, one patient was pT2a, three patients were pT3a and one patient was pT4. The tumor size ranged from 1.7-14.0 cm, with clear boundary and soft texture. The cut surface was grayish-yellow and grayish-red. Microscopically, the tumor cells were mainly arranged in papillary (10%-100%) and acinar (tubular) patterns, with strongly eosinophilic cytoplasm, round or irregular nuclei, and prominent nucleoli (WHO/ISUP grade Ⅲ). Two cases showed sarcomatoid differentiation. Stromal foamy macrophages were visible in all cases. IHC staining showed diffuse strong positivity for AMACR in all cases. RCC (18/19), CD10 (17/19), vimentin (16/19) and PAX8 (17/19) were positive in most tumors. CK7 was expressed in about 50% of cases. Fluorescence in situ hybridization identified trisomy 7 in eight patients, trisomy 17 in seven patients, and the two aberrations occurred simultaneously in seven cases. Eight of 13 men had Y chromosome deletion. All patients were followed up for 8-120 months. Three patients died of metastases at 8, 62 and 82 months postoperatively, respectively, and one patient relapsed 36 months after surgery. Compared with PRCC1, OPRCC tended to have higher nuclear grade, and stromal foam cell aggregation was more commonly found (P<0.05). The expression of CD10 and EMA were different (P<0.01). There was no significant difference in the survival rate between the two groups (P=0.239). Conclusions: OPRCC has unique morphologic features, and its immunophenotype overlaps but differs from PRCC1. The molecular results support that it belongs to a morphologic variation of PRCC. This tumor has similar biologic behavior to PRCC1, and has a poor prognosis when sarcomatoid differentiation occurs.
Aged ; Biological Products ; Biomarkers, Tumor/analysis* ; Carcinoma, Renal Cell/genetics* ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Kidney Neoplasms/genetics* ; Male ; Middle Aged ; Neprilysin/analysis* ; Vimentin/analysis*

Aminobutyrates ; Angiotensin Receptor Antagonists ; China ; Consensus ; Drug Combinations ; Heart Failure/drug therapy* ; Humans ; Neprilysin ; Stroke Volume ; Tetrazoles ; Valsartan

The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (HF) trial (PARADIGM-HF) showed that adding a neprilysin inhibitor (sacubitril) to a renin-angiotensin system blocker (and other standard therapy) reduced morbidity and mortality in ambulatory patients with chronic HF with reduced ejection fraction (HFrEF). In PARADIGM-HF, valsartan combined with sacubitril (a so-called ARNI) was superior to the current gold standard of an ACEI, specifically enalapril, reducing the risk of the primary composite outcome of cardiovascular (CV) death or first HF hospitalization by 20% and all-cause death by 16%. Following the results of PARADIGM-HF, sacubitril/valsartan was approved by American and European regulatory authorities for the treatment of HFrEF. The burden of HF in Asia is substantial, both due to the huge population of the region and as a result of increasing CV risk factors and disease. Both the prevalence and mortality associated with HF are high in Asia. In the following review, we discuss the development of sacubitril/valsartan, the prototype ARNI, and the available evidence for its efficacy and safety in Asian patients with HFrEF.
Angiotensins ; Asia ; Asian Continental Ancestry Group ; Enalapril ; Heart Failure ; Heart ; Hospitalization ; Humans ; Mortality ; Neprilysin ; Peptidyl-Dipeptidase A ; Prevalence ; Prospective Studies ; Renin-Angiotensin System ; Risk Factors ; Valsartan

OBJECTIVE: To investigate effects of benzo(a)pyrene (BaP) on expressions of insulin-degrading enzyme (IDE) and neprilysin (NEP) which have the ability to degrade β-amyloid (Aβ) in neuroglia cells. METHODS: Primary mix-neuroglia cells were cultured from newborn SD rats. After exposure to BaP, Aβ_1-42 oligomer or Aβ_1-42 fiber individually or jointly for 24 h, the cell survival rate was measured by cell counting kit-8 (CCK-8). Afterwards, the primary mix-neuroglia cells were divided randomly into six groups: Control group, BaP group (2.00 μmol/L), Aβ_1-42 oligomer group (20.00 mg/L), BaP plus Aβ_1-42 oligomer group, Aβ_1-42 fiber group (20.00 mg/L) and BaP plus Aβ_1-42 fiber group, of which BaP was pretreated for 12 h followed by cotreatment with different aggregated Aβ_1-42. The expressions of IDE and NEP were measured by quantitative real-time polymerase chain reaction (qRT-PCR) for mRNA level and Western blotting for protein level. RESULTS: The cell survival rate showed no significant differences after treatment with BaP (≤20.00 μmol/L), Aβ_1-42 oligomer (20.00, 40.00 mg/L), Aβ_1-42 fiber (20.00, 40.00 mg/L) or cotreatment with BaP and Aβ_1-42 oligomer or BaP and Aβ_1-42 fiber. Compared with the control group, expressions of IDE and NEP in BaP-treated alone group had no obvious change; however, exposure to Aβ_1-42 oligomer alone significantly increased the mRNA and protein level of IDE (P<0.05), and the BaP pretreatment could significantly inhibit the up-regulated expressions of IDE by Aβ_1-42 oligomer (P<0.05); on the other hand, exposure either to Aβ_1-42 fiber alone or under the BaP pretreatment did not change the mRNA and protein level of IDE and NEP obviously. CONCLUSION On the premise of no significant change of cell survival rate, BaP pretreatment inhibited the up-regulated expressions of IDE in primary mixed neuroglia cells under cotreatment with Aβ oligomer, indicating that BaP may disturb degradation of Aβ oligomer and cause deposition of β-amyloid and further induce cognitive decline and acceleration of Alzheimer.
Amyloid beta-Peptides ; Animals ; Benzo(a)pyrene ; Blotting, Western ; Insulysin/metabolism* ; Neprilysin/metabolism* ; Neuroglia/metabolism* ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo evaluate the diagnostic value of HGAL and LMO2 expression and compare with CD10 and bcl-6 in follicular lymphoma (FL).

METHODS63 cases of FL were collected from Guangdong General Hospital. The expression of HGAL, LMO2, CD10 and bcl-6 was assessed by immunohistochemistry.

RESULTSThe expression rates of HGAL, LMO2, CD10 and bcl-6 were 98.4% (62/63), 82.5% (52/63), 82.5% (52/63) and 87.3% (55/63), respectively. The expression rate of HGAL was higher than those of LMO2, CD10 and bcl-6, but the differences were not significant (P>0.05). There was no significant difference in HGAL, LMO2 and bcl-6 expression among FL1, FL2 and FL3 cases. The CD10 expression rate of FL1-3A cases was significantly higher than that of FL3B cases(P<0.01).

CONCLUSIONSHGAL and LMO2, especially HGAL, can be used in FL particularly high grade FL as useful germinal center marker.

Adaptor Proteins, Signal Transducing ; metabolism ; Biomarkers, Tumor ; metabolism ; Germinal Center ; Humans ; Immunohistochemistry ; LIM Domain Proteins ; metabolism ; Lymphoma, Follicular ; metabolism ; Neoplasm Proteins ; metabolism ; Neprilysin ; metabolism ; Proto-Oncogene Proteins ; metabolism ; Proto-Oncogene Proteins c-bcl-6 ; metabolism

To investigate the expression of CD10 in tumor-associated fibroblasts (TAF) in colorectal adenomas and its relation to cancerization and recurrence of adenoma.Tissue samples of low-grade adenoma (=50), high-grade adenoma (=50) and colorectal adenocarcinoma (=50) were collected, and tissue samples at the distal margin of corresponding colorectal lesions were taken as controls. The expression of CD10 in the stromal TAFs, and the expressions of β-catenin, Ki-67, p53 and CyclinD1 in tumor cells were detected by immunohistochemistry (Envision). The correlation of CD10 expression in stromal TAFs with the expressions of β-catenin, Ki-67, p53 and CyclinD1 in tumor cells was analyzed by Spearmen. One hundred samples of low-grade colorectal adenoma were collected, including 57 non-recurrent cases and 43 recurrent cases (16 cases of recurrent adenoma and 27 cases of recurrent adenocarcinoma); the expression of stromal TAF CD10 were determined and compared among groups.There was no TAF in normal colorectal mucosa. The expression rates of TAF CD10 in low-grade adenoma, high-grade adenoma and colorectal adenocarcinoma were 22%, 50% and 78%, respectively (all<0.05). The expression of Ki-67 and β-catenin in low-grade adenoma, high-grade adenoma, colorectal adenocarcinoma was on a rising trend (all<0.01). The expression of CyclinD1 in high-grade adenoma was higher than that in colorectal adenocarcinoma and low-grade adenoma (all>0.05). The expression of p53 in colorectal adenocarcinoma and high-grade adenoma was higher than that in low grade adenoma (all<0.01). The expression of TAF CD10 was correlated with the expression of p53, Ki-67 and β-catenin-nucleus(=0.264、0.307、0.320, all<0.01),but not correlated with CyclinD1 and β-catenin-membrane (=0.012、-0.073, all>0.05). The TAF CD10 level was significantly higher in low-grade adenoma with recurrence than that in those without recurrence (<0.05).The expression of CD10 in recurrent colorectal adenocarcinoma was higher than that in recurrent adenoma (<0.05).The expression of TAF CD10 is increased gradually in the process of adenoma-cancer, indicating that it may play an important role in the canceration of adenoma. Adenomas with high expression of CD10 TAF are likely to be recurrent and cancerized, and detection of TAF CD10 combined with p53, Ki-67 and β-catenin may be of value in predicting canceration or recurrence of colorectal adenoma.
Adenocarcinoma ; chemistry ; genetics ; Adenoma ; chemistry ; genetics ; Biomarkers, Tumor ; analysis ; Cancer-Associated Fibroblasts ; chemistry ; Carcinogenesis ; chemistry ; Colorectal Neoplasms ; chemistry ; genetics ; Cyclin D1 ; analysis ; Disease Progression ; Humans ; Immunohistochemistry ; Ki-67 Antigen ; analysis ; Neoplasm Grading ; Neoplasm Recurrence, Local ; chemistry ; Neprilysin ; analysis ; Predictive Value of Tests ; Tumor Suppressor Protein p53 ; analysis ; beta Catenin ; analysis

Impaired angiogenesis is a common pathological characteristic of chronic wounds. Therefore, the regulation of angiogenesis is important for proper tissue repair. It was reported that substance P (SP) accelerates wound healing in a skin injury model. SP is degraded by neutral endopeptidase (NEP). Our study shows that systemic co-treatment of SP and thiorphan, an inhibitor of NEP synergically increased the number of α-smooth muscle actin positive-blood vessels in skin wounds. However, there was no synergic improvement in wound contraction and extracellular matrix deposition. Therefore, inhibition of endogenous NEP activity by thiorphan treatment might modulate the effects of SP treatment specifically on accelerating angiogenesis during wound healing. However, the molecular mechanism(s) of the synergic increase in angiogenesis by SP and thiorphan treatment is still unknown.
Actins ; Extracellular Matrix ; Neprilysin ; Skin ; Substance P* ; Thiorphan* ; Wound Healing* ; Wounds and Injuries*

Angiotensin II Type 1 Receptor Blockers ; pharmacology ; Cardiovascular Agents ; pharmacology ; Clinical Trials as Topic ; Heart Failure ; drug therapy ; Humans ; Neprilysin ; antagonists & inhibitors

Angiotensin Receptor Antagonists ; Heart Failure ; Humans ; Neprilysin ; Receptors, Angiotensin