Evaluación de la expresión de PD-L1 e infiltración linfocitaria intratumoral en carcinoma de mama invasivo triple negativo / Evaluation of PD-L1 expression and intratumoral lym phocytic infiltration in triple-negative invasive breast car cinoma

Resumen Introducción : El endofenotipo de cáncer de mama triple negativo (TNBC) es uno de los menos frecuentes y sin diana terapéutica, por tanto, se plantea estudiar la correlación del punto de control inmunológico PD-L1 con el establecimiento de microambiente tumoral evaluado por la infiltración linfocitaria intratumoral estromal (TILs) y su importancia en la práctica clínica. Métodos : Se realizó un estudio retrospectivo de casos y controles, con 31 casos de carcinoma infiltrante de la mama triple negativo y 57 controles no pareados de endofenotipo Luminal A, Luminal B y HER-2 atendidos en un año. Se evaluaron las variables: tipo y grado his tológico, expresión PD-L1 con el clon 22C3, TILs, invasión linfovascular, tamaño tumoral, compromiso de ganglios linfáticos y metástasis. El análisis estadístico se ejecutó con la prueba de chi cuadrado y prueba de coeficiente de correlación de Spearman. Resultados : Se encontró una correlación negativa estadísticamente significativa entre TILs y PD-L1 (rho - 0.106, p 0.025), indicando que a mayor expresión de PD-L1, es menor la infiltración linfocitaria intratumo ral. En los grupos de TILs B (10-40% TILs) y C (40-90% TILs) donde se presenta marcado infiltrado inflamatorio intratumoral se evidenció mayor número de pacientes negativos para PD-L1 (CPS <10) con 16 y 10 casos res pectivamente. Para los casos TNBC se logró identificar un coeficiente de asociación negativa (rho -0.378) y con significancia estadística (p 0.01). Discusión : Se estableció la asociación de TNBC, TILs y expresión de PDL1, lo cual es importante para la instau ración de terapias diana y el desarrollo de la medicina de precisión.

Abstract Introduction : Triple negative breast cancer endophe notype (TNBC) is one of the least frequent and without therapeutic target; therefore we propose to study the correlation of PD-L1 immune checkpoint with the es tablishment of tumor microenvironment assessed by intratumoral stromal lymphocyte infiltration (TILS) and its importance in clinical practice. Methods : A retrospective case-control study was performed, with 31 cases of triple-negative infiltrat ing breast carcinoma and 57 unmatched controls of Luminal A, Luminal B and HER-2 endophenotype seen in one year. The following variables were evaluated: histologic type and grade, PD-L1 expression with clone 22C3, TILS, lymphovascular invasion, tumor size, lymph node involvement and metastasis. Statistical analysis was performed with the chi-square test and Spearman correlation coefficient test. Results : a statistically significant negative correlation was found between TILS and PD-L1 (rho - 0.106, p 0.025), indicating that the higher the expression of PD-L1, the lower the intratumoral lymphocytic infiltration. In the TILS B (10-40% TILS) and C (40-90% TILS) groups where there was a marked intratumoral inflammatory infiltrate, a greater number of patients were negative for PD-L1 (CPS <10) with 16 and 10 cases, respectively. For TNBC cases a negative association coefficient was identified (rho -0.378) with statistical significance (p 0.01). Discussion : The association between TNBC, TILS and PDL1 expression was established, which is important for the establishment of target therapies and the develop ment of precision medicine.

Síndrome de Sjögren: identificación de nuevos biomarcadores y mecanismos moleculares implicados en su fisiopatogénesis

Introducción: El Síndrome de Sjögren (SS) es una enfermedad autoinmune de carácter sistémico, que afecta principalmente al sistema glandular exocrino, generando un funcionamiento anormal de las glándulas lacrimales y salivales. Objetivo: proporcionar una actualización sobre la identificación de nuevos biomarcadores y mecanismos moleculares implicados en la fisiopatogénesis del SS. Método: Revisión narrativa de la literatura en diferentes bases de datos, mediante la búsqueda de términos descritos incluidos en los tesauros MESH y DeCs, para artículos publicados a partir del año 2018. Resultados: presentamos evidencia que destaca la identificación de nuevos biomarcadores y mecanismos implicados en la fisiopatogénesis del SS, describiendo las vías de: linfocitos B, catepsina S, cistatina C, quimioquina C-X3-C modificada de ligando 1, quimiocina regulada por activación del timo, células T, proteína morfogenética ósea 6, estimulación del receptor de oxitocina, receptor de zinc, calponina-3. Conclusión: los avances en la tecnología facilita el análisis detallado de la genética y fisiopatogénesis del SS, impulsando el desarrollo de terapias específicas. La búsqueda de biomarcadores no invasivos responde a las limitaciones de los métodos existentes y la invasividad de las biopsias salivales, prometiendo mejoras diagnósticas y terapéuticas.

Introduction: Sjögren's Syndrome (SS) is a systemic autoimmune disease that primarily affects the exocrine glandular system, leading to abnormal lacrimal and salivary gland function. Objective: To provide an update on identifying new biomarkers and molecular mechanisms involved in the pathogenesis of SS. Method: Narrative review of the literature in various databases, searching for terms included in the MESH and DeCs thesauri, for articles published since 2018. Results: We present evidence highlighting the identification of new biomarkers and mechanisms involved in the pathogenesis of SS, describing pathways of B lymphocytes, cathepsin S, cystatin C, modified C-X3-C chemokine ligand 1, thymus activation-regulated chemokine, T cells, bone morphogenetic protein 6, oxytocin receptor stimulation, zinc receptor, and calponin-3. Conclusion: Advances in technology facilitate detailed analysis of the genetics and pathogenesis of SS, driving the development of specific therapies. The search for non-invasive biomarkers is driven by the limitations of existing methods and the invasiveness of salivary gland biopsies, promising diagnostic and therapeutic improvements.

Morphological Characteristics of the Results of Experimental Modeling of Septic Peritonitis

SUMMARY: Experimental studies devoted to the study of the mechanisms of the pathogenesis of acute peritonitis and the development of new methods of medical and surgical treatment are becoming increasingly relevant. Today, experimental medicine knows many different ways to modeling septic peritonitis and eliminate it, but the role of the local immune system is underestimated, whereas it takes a direct part in inflammation. The objective of our work to study morphological features of results of experimental modeling of septic peritonitis in white rats. The study included 15 sexually mature white male rats weighing 276.75±6.56 grams. A simulation of septic peritonitis was performed by perforating the upper part of the cecum with four punctures with a G16 injection needle. As a result of the experiment, after examination of the peritoneal cavity, all 15 animals were diagnosed with omentum tamponade of perforated damage to the caecum. In 11 cases, the perforated wall of the caecum was covered by the greater omentum (73.34 %), and in the other 4 animals, tamponade was performed by one of the epididymal omentum (26.66 %). The initial stage of tamponade with the greater or epididymal omentums of a perforated caecum begins on the first day of the experiment and consists of tight interstitial consolidation between them, as well as in the invasion of blood vessels from the omentum side to the focus of infection, which ensure the delivery of the appropriate immunocompetent cells. As a result of this process, intensive lymphoid infiltrates are formed in this area, as well as the growth of adipose tissue, which isolates the inflammatory focus from the peritoneal cavity with a thick layer.

Las investigaciones experimentales dedicadas al estudio de los mecanismos de patogénesis de la peritonitis aguda y el desarrollo de nuevos métodos de tratamiento médico y quirúrgico son cada vez más relevantes. Hoy en día, la medicina experimental conoce muchas formas diferentes de modelar la peritonitis séptica y eliminarla, pero se subestima el papel del sistema inmunológico local, mientras que él participa directamente en la inflamación. El objetivo de nuestro trabajo fue estudiar las características morfológicas de los resultados del modelado experimental de peritonitis séptica en ratas blancas. El estudio incluyó 15 ratas macho blancas, sexualmente maduras que pesaban 276,75 ± 6,56 gramos. Se realizó una simulación de peritonitis séptica perforando la parte superior del ciego con cuatro punciones con una aguja de inyección G16. Como resultado del experimento, después del examen de la cavidad peritoneal, a los 15 animales se les diagnosticó taponamiento del omento o lesión perforada del ciego. En 11 casos, la pared perforada del ciego fue recubierta por el omento mayor (73,34 %), y en los otros 4 animales el taponamiento se realizó por uno de los epidídimos (26,66 %). La etapa inicial del taponamiento con omento mayor o epidídimo de un ciego perforado comienza el primer día del experimento y consiste en una estrecha consolidación intersticial entre ellos, así como en la invasión de los vasos sanguíneos desde el lado del omento hasta el foco de infección, que aseguran la entrega de las células inmunocompetentes apropiadas. Como resultado de este proceso, se forman intensos infiltrados linfoides en esta zona, así como el crecimiento de tejido adiposo, que aísla el foco inflamatorio de la cavidad peritoneal con una gruesa capa.

Predictive value of preoperative NLR and PLR for inguinal lymph node metastasis of penile cancer / 现代泌尿外科杂志

【Objective】 To explore the value of preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in the prediction of inguinal lymph node metastasis of penile cancer to provide a new idea for the clinical evaluation. 【Methods】 A total of 48 patients with penile cancer who received surgical treatment in our hospital during Jan. 2016 and Dec. 2021 were selected and divided into the metastatic group (n=19) and non-metastatic group (n=29). The number of neutrophils, lymphocytes and platelets were recorded, and NLR and PLR were calculated. The value of NLR and PLR in predicting inguinal lymph node metastasis was analyzed with receiver operating characteristic (ROC) curve. The correlation between NLR and PLR was determined with Pearson correlation analysis. 【Results】 The levels of NLR and PLR were significantly higher in the metastatic group than in the non-metastatic group (P<0.05). ROC curve showed that the optimal cut-off value of NLR was 2.39, the area under the ROC curve (AUC) was 0.838 (95%CI:0.730-0.947), with sensitivity of 94.7% and specificity of 58.6%, respectively. The optimal cut-off value of PLR was 113.66, the AUC was 0.755 (95%CI:0.618-0.892), with sensitivity of 89.5% and specificity of 58.6%, respectively. The AUC of the two combined together was 0.851 (95%CI:0.747-0.956), with sensitivity of 89.5% and specificity of 69.0%. The Pearson correlation analysis showed that NLR was positively correlated with PLR in patients in both groups (r=0.504, r=0.645, P<0.05). 【Conclusion】 Preoperative NLR and PLR levels are significantly increased in patients with penile cancer,and the combination of the two indexes can predict the possibility of inguinal lymph node metastasis.

Mechanism of action of follicular helper T cells in autoimmune hepatitis / 临床肝胆病杂志

Autoimmune hepatitis （AIH） is a type of chronic hepatitis caused by the attack of hepatocytes by the autoimmune system， and with the prolongation of disease course， it may gradually progress to liver cirrhosis and even hepatocellular carcinoma. Although great achievements have been made in the understanding and treatment of AIH， its etiology and pathogenesis still remain unclear. T cells play a crucial role in the development and progression of AIH， and by focusing on follicular helper T cells， this article elaborates on the research advances in follicular helper T cells in AIH， in order to provide new ideas and strategies for the clinical treatment of AIH.

Correlation of neutrophil/lymphocyte ratio with cardiac function and prognosis in patients with acute myocardial infarction after percutaneous coronary intervention / 中国基层医药

Objective:To correlate neutrophil/lymphocyte ratio (NLR) with cardiac function in patients with acute myocardial infarction (ACI) after percutaneous coronary intervention (PCI) and investigate its clinical value in predicting major adverse cardiovascular events (MACEs) in patients.Methods:A total of 120 patients with AMI who underwent PCI at Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine from March 2020 to February 2023 were included in this prospective study. The difference in NLR measured 1 day after PCI relative to that measured at 5 days after surgery (?NLR) was correlated with cardiac function ultrasound indicators measured at 3 months after surgery, myocardial injury, and inflammatory biochemical indicators at 1 day after surgery. The MACEs occurring within 3 months after surgery were recorded. The value of ΔNLR recorded during the early stage after PCI for predicting MACEs in patients with AMI was evaluated.Results:At 3 months after surgery, 13 out of 120 patients with AMI (10.83%) had MACEs. The ?NLR in patients with AMI who had MACEs was (3.55 ± 0.47), which was significantly higher than (2.06 ± 0.34) in patients with AMI who had no MACEs ( t = 17.25, P < 0.001). An optimal critical value of ?NLR for predicting MACEs after PCI in patients with AMI was 2.75, with an area under the receiver operating characteristic curve of 0.972, a sensitivity of 90.70%, and a specificity of 91.10%. Conclusion:Increased NLR during the early stage after PCI in patients with AMI is closely related to decreased cardiac function, and worsened myocardial injury and inflammatory reactions. Changes in NLR after PCI in patients with AMI have a highly valuable value for predicting MACEs in these patients.

Value of peripheral blood NLR, PLR and serum LDH for predicting the occurence of radiation pneumonia in patients with small cell lung cancer / 中国基层医药

Objective:To investigate the value of peripheral blood neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and serum lactate dehydrogenase (LDH) levels for predicting the occurrence of radiation pneumonia (RP) in small cell lung cancer.Methods:A total of 84 patients with small cell lung cancer who received image-guided radiotherapy in Xuzhou Cancer Hospital between September 2019 and September 2022 were retrospectively analyzed. They were divided into an RP group ( n = 25) and a non-RP group ( n = 59) according to whether RP occurred. Peripheral blood NLR and PLR and serum LDH levels were compared between the two groups before and after radiotherapy. The receiver operating characteristic curve (ROC curve) was used to analyze the value of peripheral blood NLR, PLR, and serum LDH levels for the diagnosis of RP in small cell lung cancer. Results:Before radiotherapy, there were no significant differences in peripheral blood NLR and PLR between the two groups (both P > 0.05). After radiotherapy, peripheral blood NLR and PLR in the RP group were (3.39 ± 0.81) and (129.06 ± 24.90), respectively, which were significantly higher than those in the non-RP group [(2.54 ± 0.71), (104.76 ± 26.26), t = 3.61, 3.83, both P < 0.05]. The NLR (2.86 ± 0.30) and PLR (110.07 ± 10.05) were the lowest in patients with grade 2 RP and they were highest in patients with grade 4 RP [(4.49 ± 0.63), (168.88 ± 14.11)]. The grade of RP was positively correlated with peripheral blood NLR and PLR. The sensitivity of peripheral blood NLR in the diagnosis of RP was 88.0%, the specificity was 66.1%, and the area under the curve (AUC) was 0.791. The sensitivity of PLR in the diagnosis of RP was 48.0%, the specificity was 94.9%, and the AUC was 0.735. The sensitivity of NLR combined with PLR in the diagnosis of RP was 92.0%, the specificity was 59.3%, and the AUC was 0.801. There was no significant difference in serum LDH levels between the two groups before and after radiotherapy (both P > 0.05). Logistic regression analysis showed that NLR and PLR were risk factors for RP in patients with small cell lung cancer ( OR = 2.309, 1.037; 95% CI: 1.061-5.024, 1.004-1.071). Conclusion:In patients with small cell lung cancer who develop RP, peripheral blood NLR, and PLR are markedly elevated compared with those in patients who do not develop RP, and combined detection of peripheral blood NLR and PLR has a high value for early diagnosis of RP in patients with small cell lung cancer.

Effects of sublingual immunotherapy on Treg/Th17 cell balance and related cytokines in preschool children aged 3-6 years with allergic rhinitis / 中国耳鼻咽喉头颈外科

OBJECTIVE To evaluate the impact of sublingual immunotherapy(SLIT)on the balance of Treg/Th17 cells and related cytokines in preschool children aged 3-6 years with allergic rhinitis(AR).METHODS Seventy preschool children aged 3-6 years with AR were divided into the SLIT group and the medication group,and their clinical data were retrospectively analyzed.The medication group received symptomatic treatment alone,while the SLIT group received a combined treatment of SLIT and symptomatic medication,with a 3-year follow-up period.The Treg/Th17 cell balance,serum levels of TGF-β,IL-10,IL-17,IL-21,as well as the total nasal symptom score(TNSS),total medication score(TMS),and visual analog scale(VAS)scores were compared before and after treatment between the two groups.RESULTS After 3 years of treatment,both groups showed significant improvements(P<0.05)in the percentages of CD4+CD25+Foxp3+Treg and CD4+IL-17+Th17 cells among CD4+T cells,percentages of Treg and Th17 cells,serum levels of TGF-β,IL-10,IL-17,IL-21,TNSS,TMS,and VAS scores.Moreover,the SLIT group exhibited significantly better outcomes compared to the medication group(P<0.05).CONCLUSION SLIT can modulate the balance of Treg/Th17 cells and improve serum levels of TGF-β,IL-10,IL-17,and IL-21.

The analysis of independent factors affecting tissue inflammatory cells changes in recurrent nasal polyps / 中国耳鼻咽喉头颈外科

OBJECTIVE To explore the independent factors affecting tissue inflammatory cells changes in recurrent nasal polyps.METHODS The clinical data of 31 patients with nasal polyps who underwent endoscopic surgery at the Department of Otolaryngology Head and Neck Surgery,Yantai Yuhuanding Hospital from December 2007 to December 2021 were selected and analyzed by stepwise regression logistic analysis.RESULTS The number of tissue inflammatory cells in recurrent nasal polyps changed compared with that in primary nasal polyps,and the number and percentage of neutrophils in recurrent polyps increased(P<0.05).Logistic analysis revealed that smoking was an independent risk factor for eosinophilia in recurrent nasal polyps,increasing age was an independent factor for lowering neutrophils,and the comorbid allergic rhinitis and the time interval of recurrence were independent factors for lowering and increasing lymphocytes,respectively.CONCLUSION The number of tissue-infiltrating cells is altered in recurrent polyps compared with primary polyps.Smoking is an independent risk factor for eosinophilia in recurrent polyps.

The Predictive Value of MMP-9 the and NLR Values for Bleeding Transformation after the Revascularization in Acute Ischemic Stroke / 昆明医科大学学报

Objective To study the correlation between the changes of matrix metalloproteinase-9(MMP-9)and neutrophil/lymphocyte ratio(NLR)before and after the revascularization of acute ischemic stroke(AIS),so as to find biomarkers to predict the bleeding transformation risk of AIS patients.Methods From February 2022 to December 2022,161 patients admitted to the Stroke Center of Qujing Hospital Affiliated to Kunming Medical University with AIS werre divided in to the hemorrhagic transformation group and the non-hemorrhagic transfor-mation groupand treated with revascularization(intravenous thrombolysis,endovascular treatment,combined the intravenous thrombolysis with endovascular treatment).Among them,there were 46 cases in the hemorrhagic transformation group and 115 cases in the non hemorrhagic transformation group.And the general data,NLR value and MMP-9 before and after the revascularization were compared between the two groups.Results There was no statistical difference in general data between the two groups(all P>0.05)except for C-reactive protein in hemorrhagic transformation group and in non-hemorrhagic transformation group(P<0.001).The white blood cells,neutrophils,neutrophil percentage,neutrophil absolute value,lymphocyte absolute value,NLR and MMP-9 value in hemorrhagic transformation group were significantly higher than those in non-hemorrhagic transformation group before the treatment and there was a statistical significance(P<0.05).After revascularization,the indexes of blood routine and MMP-9 were significantly higher than those before the revascularization,and the increase in hemorrhagic transformation group was more obvious than that in non-hemorrhagic transformation group and there was a statistical significance(P<0.001),The ROC curve showed that the area under the curve(AUC)of NLR and MMP-9 predicting bleeding transformation after AIS revascularization were 0.74 and 0.90.Conclusion NLR,MMP-9 are associated with the risk of bleeding transformation in AIS patients after the revascularization and can they can be used as the predictive factors for bleeding transformation risk.

Clinical Immunological Characteristic and Influencing Factors Analysis of HIV/AIDS Patients Infected with EBV and HCMV / 现代检验医学杂志

Objective To investigate the basic information of human immunodeficiency virus/acquired immune deficiency syndrome(HIV/AIDS)patients who infected with Epstein-Barr virus(EBV)or human Cytomegalovirus(HCMV),collect the relevant clinical immunological data and analyze the influencing factors.Method A total of 1 093 HIV/AIDS patients treated in the First Hospital of Changsha from January to December 2022 and underwent EBV and HCMV screening were collected.Flow cytometry was used to detect the CD4+T lymphocytes.Fluorescence quantitative PCR was applied for HIV-RNA,EBV-DNA,and HCMV-DNA testing.Statistical analysis was carried out by using SPSS 27.0,and logistic regression was used to analyze the risk factors of HIV/AIDS patients complicated with viral infection.Results Among 1 093 HIV/AIDS patients,the positive rates of EBV-DNA and HCMV-DNA were 48.22%(527/1 093)and 19.03%(208/1 093),respectively.As the number of CD4+T lymphocytes increased,the positive rates of EBV-DNA and HCMV-DNA decreased,and the differences was statistically significant(χ2=39.50,143.0,all P<0.001).As the level of HIV-RNA increased,the positive rates of EBV-DNA and HCMV-DNA increased,and the differences were statistically significant(χ2=46.18,124.3,all P<0.001).The patients receiving antiretroviral therapy(ART)significantly decreased the positive rates of EBV-DNA and HCMV-DNA(χ2=30.60,96.59,all P<0.001).There was a significant negative correlation between the number of CD4+T lymphocytes and the level of HIV-RNA(r=-0.49,P<0.001).Logistic regression analysis showed that the CD4+T lymphocyte count<200/μl(OR=1.46,95%CI:1.02～2.08,P=0.037),HIV-RNA load>200 copies/ml(OR=1.70,95%CI:1.18～2.44,P=0.004)and the age>30 years old(OR=2.15,95%CI:1.44～3.19,P<0.001)were risk factors for HIV/AIDS patients infected with EBV.Without regularly receiving ART(OR=1.83,95%CI:1.10～3.02,P=0.019),HIV-RNA load>200 copies/ml(OR=2.56,95%CI:1.50～4.35,P<0.001)and the CD4+T lymphocyte count<200/μl(OR=4.61,95%CI:2.57～8.28,P<0.001)were risk factors for HCMV infection in HIV/AIDS patients.Conclusion To reduce the possibility of opportunistic infection in HIV/AIDS patients,the surveillance of EBV and HCMV and regular ART should be strengthened,especially when the number of CD4+T lymphocytes decreases(<200/μl),the level of HIV RNA increases(>200 copies/ml)or the age>30 years old.

Correlation analysis of serum Chemerin with disease activity and Th17/Treg in patients with rheumatoid arthritis / 天津医药

Objective To explore the correlation of serum Chemerin level with disease activity and the ratio of T helper 17/regulatory T cells(Th17/Treg)in patients with rheumatoid arthritis(RA).Methods A total of 180 patients with RA who were admitted to our hospital were regarded as the observation group.According to the DAS28 score,the observation group was divided into the high activity group(60 cases),the moderate activity group(60 cases)and the low activity group(60 cases).Another 180 healthy people who underwent physical examination in our hospital during the same period were regarded as the control group.Enzyme-linked immunosorbent assay(ELISA)was used to detect serum levels of Chemerin,interleukin-9(IL-9),interleukin-10(IL-10)and interleukin-17(IL-17).Flow cytometry was used to detect the Th17/Treg ratio.Spearman correlation analysis was applied to analyze the correlation between serum Chemerin level and DAS28 score.Pearson correlation analysis was used to analyze the correlation between serum Chemerin level and Th17,Treg cell percentage and Th17/Treg ratio.Results The results of this study showed that the serum level of Chemerin was higher in the observation group than that in the control group(P＜0.05).The serum Chemerin level was positively correlated with DAS28 score(P＜0.05).Serum Chemerin levels and DAS28 scores decreased in turn in the high,moderate and low activity groups(P＜0.05).The percentage of Th17 cells and the ratio of Th17/Treg were higher in the observation group than those in the control group,and the percentage of Treg cells was lower in the observation group than that in the control group(P＜0.05).The level of IL-10 was lower in the observation group than that in the control group,while levels of IL-17 and IL-9 were higher in the observation group than those in the control group(P＜0.05).The results of Pearson correlation analysis showed that serum Chemerin level was positively correlated with the percentage of Th17 cells and the ratio of Th17/Treg,and negatively correlated with the percentage of Treg cells(P＜0.05).Conclusion Serum Chemerin level is elevated in patients with RA,which is closely related to disease activity and Th17/Treg ratio.

Clinical features and lymphocyte subtypes in patients with IgG 4-related diseases / 中华内科杂志

Objective:To deepen understanding of IgG 4-related diseases (RDs), we analyzed the associated lymphocyte subtypes, and explored the pathogenesis and potential immunotherapeutic targets. Methods:Eighty-six patients with IgG 4-RDs were enrolled, and their clinical characteristics, peripheral lymphocyte subtypes, and disease course were analyzed. Results:The mean age of the participants was 36-87(62±11) years; 51 were male (59.3%) and 35 were women (40.7%); and 34.9% had a history of allergy. Follow-up lasted 4.8 (0.4, 14.1) months. The most common symptoms were abdominal pain, and submandibular gland and lacrimal gland swelling (each 20.9%). Sixty-five (75.6%) participants had multiple organ involvement, and the most frequently affected organs were the pancreas (52.3%), submandibular gland (51.2%), and lacrimal gland (34.9%). A high eosinophil count; high IgE, IgG, IgG 1, and IgG 4 concentrations; and low complement C3 and C4 concentrations were present in 18.8% (16/85), 30.0% (24/80), 72.9% (62/85), 58.3% (28/48), 89.5% (77/86), 61.2% (52/85), and 50.0% (42/84), respectively, of the participants. In addition, 64.7% (55/85) were positive for autoantibodies, and the most frequent was anti-nuclear antibody (63.5%). The proportion of CD4 +T lymphocytes increased in 25.7% (9/35) of the participants, which was accompanied by an increase in the ratio of CD4 +/CD8 +T lymphocytes (22.9%, 8/35). Importantly, most participants (90.0%, 18/20) had a high proportion of regulatory T (Treg) cells. High interleukin (IL)-2, IL-6, and IL-10 concentrations were present in 50.0% (11/22), 33.3% (10/30), and 16.7% (5/30), respectively, of the participants. Substantial lymphoplasmacytic infiltration, fibrosis, IgG 4-positive plasma cell infiltration, and lymphoid follicle hyperplasia or ectopic formation were present in 79.2% (42/53), 67.9%(36/53), 35.8%(19/53) and 30.2% (16/53), respectively, of the participants. Fifty-three participants with detailed pathologic data were also further evaluated, of whom 24.5% (13/53), 3.8% (2/53), and 67.9% (36/53) had definite, probable, and possible diagnoses; and 3.8% (2/53) could not be diagnosed. Compared with baseline, the percentage of eosinophils and the IgE, IgG, and IgG 4 concentrations decreased significantly; and the complement C3 and C4 concentrations had increased significantly after 6 months of treatment (all P<0.05). The IgG 4 concentration after 6 months of treatment negatively correlated with that of C4, and positively correlated with the baseline concentration of IgE and the IgG 4/IgG ratio. Conclusion:IgG 4-RDs are a group of diseases characterized by male predisposition; multiple organ involvement; a high eosinophil count; high IgE, IgG, IgG 1, and IgG 4 concentrations; and a low C3 concentration. Peripheral CD4 +T cells and Treg cells are also more abundant. The diseases can be controlled with glucocorticoids and immunosuppressive drugs in the majority of instances. The IgG 4 concentration after 6 months of treatment negatively correlates with the baseline complement C4 concentration and positively correlates with the IgE concentration and IgG 4/IgG ratio, which suggests that IgG 4/IgG, IgE, and complement should be closely monitored to evaluate disease activity and the efficacy of treatment in such patients.

Expression of interleukin-37 in patients with diabetic kidney disease and its regulatory activity to the cytotoxic function of CD8 +T lymphocytes / 中华肾脏病杂志

Objective:To investigate interleukin-37 (IL-37) expression in patients with diabetic kidney disease (DKD), and to assess the regulation of exogenous IL-37 on CD8 + T cell function in DKD patients. Methods:A cross-section study was carried out. Twenty healthy controls, thirty-six patients with diabetes mellitus type 2 (T2DM), and forty-seven DKD patients were enrolled in the study. Peripheral blood was collected. Plasma and peripheral blood mononuclear cells were isolated. IL-37 and soluble IL-1 receptor 8 (IL-1R8) levels in the plasma were measured by enzyme-linked immunosorbent assay (ELISA). IL-18 receptor α chain (IL-18Rα), IL-1R8 and immune checkpoint molecules levels in CD8 + T cells were measured by flow cytometry. CD8 + T cells were purified, and were stimulated with recombinant IL-37. CD8 + T cells were co-cultured with HEK293 cells in either direct contact or indirect contact manner. Levels of perforin, granzyme B, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were measured by ELISA. The proportion of target cell death was assessed by measuring lactate dehydrogenase level. Results:Plasma IL-37 levels in DKD patients [(63.42±23.30) ng/L] were significant lower than those in healthy controls [(143.02±50.67) ng/L] and T2DM patients [(87.88±40.62) ng/L] ( t=8.848, P<0.001; t=3.456, P<0.001). Plasma IL-37 level had good predictive values for T2DM in health individuals and for DKD in T2DM patients [the area under the curve was 0.797 (95% CI 0.676-0.917, P<0.001) and 0.691 (95% CI 0.576-0.807, P=0.003), respectively]. Plasma IL-37 level was negatively correlated with urea nitrogen ( r=-0.313, P=0.032) and creatinine ( r=-0.477, P<0.001), and positively correlated with estimated glomerular filtration rate (eGFR) ( r s=0.478, P<0.001) in DKD patients. IL-1R8 + CD8 + cell proportion in DKD patients (33.60%±9.47%) was significantly higher compared to healthy controls (16.29%±5.97%) and T2DM patients (17.13%±4.85%) ( t=7.545, 9.516, both P<0.001), but did not correlate with fast blood glucose, urea nitrogen, creatinine, or eGFR (all P>0.05). There were no statistical differences of IL-18Rα + CD8 + cell proportion, soluble IL-1R8 level, or immune checkpoint molecule proportion in CD8 + T cells among healthy controls, T2DM patients, and DKD patients (all P>0.05). Perforin and granzyme B secretions by CD8 + T cells were significantly elevated in DKD patients compared with healthy controls [(108.78±12.42) ng/L vs. (94.60±10.07) ng/L, t=3.096, P=0.005; (261.34±48.79) ng/L vs. (166.28±30.80) ng/L, t=3.387, P=0.002] and T2DM patients [(108.78±12.42) ng/L vs. (92.58±14.71) ng/L, t=3.263, P=0.003; (261.34±48.79) ng/L vs. (170.66±39.24) ng/L, t=2.627, P=0.014]. There were no significant differences of either IFN-γ or TNF-α secretions by CD8 + T cells among healthy controls, T2DM patients, and DKD patients (all P>0.05). In direct contact co-culture manner, CD8 + T cell-induced HEK293 cell death was down- regulated (13.03%±4.97% vs. 17.88%±5.19%, t=2.235, P=0.037). The levels of perforin [(222.02±25.79) ng/L vs. (294.30±25.58) ng/L, t=6.603, P<0.001], granzyme B [(416.27±90.24) ng/L vs. (524.71±115.53) ng/L, t=2.454, P=0.023], IFN-γ [(23.66±4.20) ng/L vs. (35.18±8.51) ng/L, t=4.026, P<0.001] and TNF-α [(1.62±0.29) μg/L vs. (2.09±0.57) μg/L, t=2.302, P=0.034] were also reduced as well. In indirect contact co-culture manner, there were no significant differences of CD8 + T cell-induced HEK293 cell death, perforin, or granzyme B levels between no stimulation and IL-37 stimulation (all P>0.05). IFN-γ and TNF-α levels in the supernatants were reduced in response to IL-37 stimulation [(23.56±6.24) ng/L vs. (32.56±9.90) ng/L, t=2.550, P=0.019; (1.41±0.31) μg/L vs. (2.10±0.44) μg/L, t=4.011, P<0.001]. Conclusion:IL-37 level is reduced in DKD patients.Exogenous IL-37 suppresses the cytotoxicity of CD8 + T cells in DKD patients.

Predictive value of peripheral blood inflammatory indicators in patients with new-diagnosed multiple myeloma / 中国现代医生

Objective To explore the predictive value of peripheral blood inflammatory indicators such as neutrophil-to-lymphocyte ratio(NLR),monocyte-to-lymphocyte ratio(MLR)and platelet-to-lymphocyte ratio(PLR)on the prognosis of patients with primary diagnosis of multiple myeloma(MM).Methods Using a retrospective method,77 patients with first diagnosis of MM admitted to the Department of Hematology of Baise People's Hospital and 77 healthy medical checkups with peripheral blood NLR,MLR and PLR were collected and compared the differences.Then the patients with primary diagnosis of MM were categorized into high NLR group,low NLR group,high MLR group,low MLR group,high PLR group,low PLR group using the mean value as the critical value,and the prognosis of the patients in each group as well as the relationship with overall survival time(OS)were compared.Results The NLR,MLR,and PLR of patients with initial diagnosis of MM were significantly higher than those of healthy controls,and the differences were statistically significant(all P<0.05).Serum β2-microglobulin(β2-MG)levels were higher in patients with high NLR and high MLR than in the low NLR and low MLR groups,and the difference was statistically significant(P<0.05).Patients in the high NLR,high MLR and high PLR groups had less OS and poorer prognosis than those in the low NLR,low MLR and low PLR groups,and the differences were statistically significant(all P<0.05).Univariate Cox regression analysis showed that international staging system(ISS)stage,creatinine(Cr),β2-MG,albumin(ALB),NLR,MLR and PLR were associated with overall survival(P<0.05);multivariate Cox proportional risk regression analysis showed that NLR,MLR,and PLR were not independent risk factors affecting the prognosis of patients with primary diagnosis of MM,and the difference was not statistically significant(P>0.05).According to the number of inflammatory indexes(high NLR,high MLR,high PLR)that affected the prognosis,the patients were divided into 0 or 1 risk factor group,2 risk factor groups and 3 risk factor groups,and the comparison of OS between the three groups was statistically significant(P=0.001).The greater the number of concomitant risk factors for prognosis,the shorter the OS.Conclusion Elevated inflammatory indicators(NLR,MLR,PLR)in patients with primary diagnosis of MM were associated with less OS and poorer prognosis of the patients,and they may be used as indicators to assess the condition and prognosis of patients with primary diagnosis of MM.

Diagnostic value of HPV-DNA typing combined with serum NLR and DCLK1 for cervical cancer / 中国现代医生

@#Objective To investigate the value of receiver operating curve human papilloma virus(HPV)-DNA typing combined with serum neutrophil lymphocyte ratio(NLR)and bicorticoid kinase 1(DCLK1)levels in the early diagnosis of cervical cancer.Methods A total of 120 patients with early cervical cancer diagnosed in our obstetrics and gynecology department from August 2018 to June 2022 were randomly included as cervical cancer group,and 120 patients with benign lesions were included as benign group.The level of DCLK1 was detected by ELISA;NLR was detected by automatic blood cell analyzer;HPV subtypes in cervical secretions were detected by HPV genotyping gene chip detection system;the cut-off values of serum NLR and DCLK1 levels in the diagnosis of cervical cancer were analyzed by using the receiver operator curve(ROC);four table method was applied to analyze the diagnostic value of HPV-DNA typing,serum NLR,DCLK1 levels alone and in combination for cervical cancer.Results Compared with benign group,the levels of serum NLR and DCLK1 in cervical cancer group were obviously higher(P<0.05).The positive rate of HR-HPV in cervical cancer group was obviously higher than that in benign group(P<0.05).The ROC curve was drawn with serum NLR and DCLK1 levels as test variables,the results showed that the AUC of serum NLR and DCLK1 predicting early cervical cancer was 0.724 and 0.718,respectively,and the cut-off value was 3.08 and 3.32,respectively.HPV-DNA typing combined with serum NLR and DCLK1 detected 18 false positives and 17 false negatives,Kappa value was 0.725,which was consistent with pathological results.The sensitivity,negative predictive value and accuracy of HPV-DNA typing combined with serum NLR and DCLK1 levels in the diagnosis of early cervical cancer were obviously higher than those of HPV-DNA typing,serum NLR and DCLK1 levels alone(P<0.05).Conclusion The results of HPV-DNA typing combined with NLR and DCLK1 in the diagnosis of early cervical cancer are highly consistent with the pathological results,and the sensitivity and accuracy are obviously improved.

Safety of the yellow fever vaccine in people living with HIV: a longitudinal study exploring post-vaccination viremia and hematological and liver kinetics

ABSTRACT Background: Safety data on the yellow fever vaccine 17DD in People Living with HIV (PLWH) are limited. This study explored the occurrence of post-vaccination 17DD viremia and the kinetics of hematological and liver laboratorial parameters in PLWH and HIV-uninfected participants [HIV(-) controls]. Methods: We conducted a secondary analysis of a longitudinal interventional trial (NCT03132311) study that enrolled PLWH and HIV(-) controls to receive a single 17DD dose and were followed at 5, 30 and 365 days after vaccination in Rio de Janeiro, Brazil. 17DD viremia (obtained throughreal-time PCR and plaque forming units' assays), hematological (neutrophils, lymphocytes and platelets counts) and liver enzymes (ALT and AST) results were assessed at baseline and Days 5 and 30 post-vaccination. Logistic regression models explored factors associated with the odds of having positive 17DD viremia. Linear regression models explored variables associated with hematological and liver enzymes results at Day 5. Results: A total of 202 PLWH with CD4 > 200 cells/μL and 68 HIV(-) controls were included in the analyses. 17DD viremia was found in 20.0 % of the participants and was twice more frequent in PLWH than in HIV(-) controls (22.8% vs. 11.8 %, p-value < 0.001). Neutrophils, lymphocytes and platelets counts dropped at Day 5 and returned to baseline values at Day 30. 17DD viremia was associated with lower nadir of lymphocytes and platelets at Day 5. ALT levels did not increase post-vaccination and were not associated with 17DD viremia. Conclusions: 17DD was safe and well-tolerated in PLWH with CD4 > 200 cells/μL. Post-vaccination viremia was more frequent in PLWH than in controls. Transient and self-limited decreases in lymphocytes and neutrophils occurred early after vaccination. 17DD viremia was associated with lower lymphocytes and platelets nadir after vaccination. We did not observe elevations in ALT after 17DD vaccination.

Foxp3+CD39+CD73+ regulatory T-cells are decreased in the peripheral blood of women with deep infiltrating endometriosis

Abstract Endometriosis's pathophysiology remains incompletely understood, with evidence pointing towards a dysregulated immune response. Regulatory T (Treg) cells, pivotal in maintaining self-tolerance, may facilitate the survival of ectopic endometrial cells within the abdominal cavity, thereby contributing to endometriosis development. This study aimed to assess the prevalence of CD39+CD73+ suppressor Treg cell subsets in the peripheral blood of endometriosis patients. This research focuses on the pivotal role of regulatory T-cells (Tregs), which are essential for maintaining immune tolerance and preventing autoimmune diseases. A case-control study was conducted, including 32 women diagnosed with endometriosis and 22 control subjects. The frequency of peripheral blood CD39+CD73+ suppressor Treg cells was quantified using flow cytometry. No significant differences were observed in the frequency of CD3+CD4+CD25High cells (Median [M]: 10.1; Interquartile Range [IQR]: 6.32‒18.3 vs. M: 9.72; IQR: 6.22-19.8) or CD3+CD4+CD25HighCD39+Foxp3+ cells (M: 31.1; IQR: 19.7-44.0 vs. M: 30.55; IQR: 18.5-45.5) between controls and patients. However, a significantly lower frequency of CD3+CD4+CD25HighCD39+CD73+ cells was observed in the endometriosis group compared to controls (M: 1.98; IQR: 0.0377-3.17 vs. M: 2.25; IQR: 0.50-4.08; p = 0.0483), suggesting a reduction in systemic immune tolerance among these patients. This finding highlights the potential role of CD39 and CD73 expression on Treg cells as biomarkers for assessing disease severity and progression. Furthermore, elucidating the mechanisms driving these alterations may unveil new therapeutic strategies to restore immune equilibrium and mitigate endometriosis symptoms.

METTL3-mediated HPV vaccine enhances the effect of anti PD-1 immunotherapy to alleviate the development of cutaneous squamous cell carcinoma

Abstract Background Cutaneous squamous cell carcinoma (cSCC) develops from epithelial keratinocytes by dysregulation of self-renewal and differentiation. Recent studies have found that the size and number of cSCC tumors gradually decrease or even disappear after HPV vaccination. However, the role of the HPV vaccine in the cSCC mechanism is poorly understood. Objective The aim of this study is to investigate the effect and mechanism of the HPV vaccine in cSCC. Methods Immunofluorescence was used to study the immune infiltrating cells in the tumor tissues of patients with cSCC. The effects of the HPV vaccine on cSCC cells and tissues were studied by Cell Culture, Real-time PCR, Western Blot, Cytotoxicity Assay, Enzyme-linked Immunosorbent Assay, m6A Blotting, CCK-8 Assay, m6A Ribonucleic acid Methylation Quantification and tumor transplantation. Results The HPV vaccine enhanced the toxic effect of CD8+T cells on cSCC cells and promoted the secretion of multiple cytokines by CD8+T cells. In addition, HPV vaccines can increase tumor sensitivity to anti-PD-1 therapy by downregulating METTL3 in tumor tissue, with the combination of HPV vaccine and PD-1 monoclonal antibodies producing enhanced immune cell infiltration compared to PD-1 blockade alone. Study limitations It is important to note the limitations of this study, including the small sample size, the construction of the mouse model, and the choice of HPV vaccine and PD-1 monoclonal antibody, which may limit the generalization of our findings to a wider population. Conclusions It is hoped that this research will contribute to a deeper understanding of the role of the HPV vaccine in the treatment of cSCC. HPV vaccine is expected to become an important approach to alleviate the development of cSCC.

Deficiency in infiltration of CD8/CD3 positive lymphocytes and macrophages plays a role in lip carcinogenesis: an immunohistochemical study

Abstract Objective To evaluate the immunoexpression profile for CD8, CD3, CD20 and CD68 in the process and carcinogenesis of Carcinoma of the vermilion lip. Methods Average cell count with positive expression for CD3, CD8, CD20 and CD68. The CD8/CD3 ratio calculated in the region was based on the percentage of positive cells in a total of malignant cells. Kruska-Wallis/Dunn, Mann-Whitney and Spearman correlation tests (SPSS, p< 0.05) were used. Results In the Aquitic Cheilitis samples, there was an increase in intraepithelial CD8+ and CD68+. In LSCCs, there was an increase in peritumoral and intratumoral CD3+, CD8+, CD20+ and CD68+ cells. In peritumoral LSCC, CD3+ and CD8+ showed a direct correlation (p= 0.004), and CD68+ and CD8+ (p= 0.017). In the intraepithelial region, CD8+ correlated with CD20+ (p= 0.014) and CD68+ (p= 0.013). In the CAs, CD3 (p< 0.001) and CD8 (p= 0.025) correlated intraepithelial and subepithelial. In LSCC CD3+ (p= 0.002), CD8+ (p= 0.001) and CD68+ (p= 0.030) had intra and peritumoral correlation. Conclusion CD68+ is the first interacting cell with the greatest capacity to migrate to the tumor and interact with CD3, CD8 and CD20. Apparently, CD20 affects perineural invasion. Level of evidence: Level 2.