[Clinicopathological features of Sjogren's syndrome complicated with liver injury].

Objective: To study the clinicopathological features of Sjogren's syndrome (SS) with liver injury and to improve the understanding of this disease. Methods: Forty-nine patients with SS complicated with liver injury were collected from Beijing Ditan Hospital, Capital Medical University from October 2008 to January 2022. All patients underwent ultrasound-guided liver biopsy, and all specimens were stained with HE. The histopathologic characteristics were observed and the pathologic indexes were graded. Immunohistochemical stains for CK7, CK19, CD38, MUM1 and CD10 were performed by EnVision method; and special histochemical stains for reticulin, Masson's trichrome, Rhodanine, Prussian blue, periodic acid Schiff (PAS) and D-PAS stains were conducted. Results: The age of patients ranged from 31 to 66 years, including 3 males and 46 females. SS combined with drug-induced liver injury was the most common (22 cases, 44.9%), followed by autoimmune liver disease (13 cases, 26.5%, including primary biliary cholangitis in eight cases, autoimmune hepatitis in 3 cases, and PBC-AIH overlap syndrome in 2 cases), non-alcoholic fatty liver disease (NAFLD, 9 cases, 18.4%) and other lesions (5 cases, 10.2%; including 3 cases of nonspecific liver inflammation, 1 case of liver amyloidosis, and 1 case of porto-sinusoidal vascular disease). Among them, 28 cases (57.1%) were associated with obvious interlobular bile duct injury, mainly in SS combined with PBC group and drug-induced liver injury group. Twenty-three cases (46.9%) were associated with hepatocyte steatosis of varying degrees. In SS with autoimmune liver disease group, ISHAK score, degree of fibrosis bile duct injury, bile duct remodeling, lymphocyte infiltration of portal area, and plasma cell infiltration, MUM1 and CD38 expression; serum ALP and GGT, IgM; elevated globulin; positive AMA, proportion of AMA-M2 positive and IgM positive were all significantly higher than those in other groups(all P<0.05). Serum ALT, direct bilirubin and SSA positive ratio in SS combined with drug liver group were significantly higher than those in other groups(all P<0.05). The serum total cholesterol level in SS combined with PBC group (P=0.006) and NALFD group (P=0.011) were significantly higher than those in other groups (P<0.05). Conclusions: The pathologic manifestations of SS patients with liver injury are varied. The inflammatory lesions of SS patients with autoimmune liver disease are the most serious, and the inflammatory lesions of SS patients with non-alcoholic fatty liver disease and non-specific inflammation are mild. Comprehensive analysis of liver histopathologic changes and laboratory findings is helpful for the diagnosis of SS complicated with different types of liver injury.

[Clinicopathological analysis of benign mammary ductal cystic papillomatosis with loss of myoepithelial cells].

Objective: To investigate the histopathological and immunohistochemical characteristics of benign apocrine cystic papillary hyperplasia of the breast with loss of myoepithelial cell layer. Methods: The clinical data, histopathological features and immunohistochemical profile of patients with benign apocrine cystic papillary hyperplasia of breast with loss of myoepithelial cell layer from January 2016 to December 2021 were examined, in which six patients were identified. Results: All six patients were female, aged 36-61 years (median 46 years), who presented with a breast mass; three cases were from the left breast and three cases were from the right breast. Microscopic examination of all cases showed breast hyperplasia with apocrine cysts, accompanied by different degrees of micropapillary and papillary hyperplasia of apocrine cells. One case was associated with lobular carcinoma in situ, and one case was associated with apocrine ductal carcinoma in situ with intraductal dissemination in adenosis. Immunohistochemical staining of CK5/6, p63, SMA, SMMHC, Calponin and CD10 showed complete absence of myoepithelial cell layer surrounding ducts in apocrine cystic papillary hyperplasia. Conclusions: The myoepithelial cells of apocrine cystic papillary hyperplasia of the breast may undergo abnormal changes and may even be completely lost. The diagnosis should be comprehensively considered along with cytomorphological and histological features to avoid overdiagnosis.

[Response characteristics of tislelizumab combined with chemotherapy in first-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer].

Objective: To investigate the response characteristics of patients with locally advanced/metastatic non-squamous non-small cell lung cancer (nsq-NSCLC) treated with tislelizumab in combination with chemotherapy in the first line. Methods: Patients with nsq-NSCLC who achieved complete or partial remission after treatment with tislelizumab in combination with chemotherapy or chemotherapy alone in the RATIONALE 304 study, as assessed by an independent review board, were selected to analyze the response characteristics and safety profile of the responders. Time to response (TTR) was defined as the time from randomization to the achievement of first objective response. Depth of response (DpR) was defined as the maximum percentage of tumor shrinkage compared with the sum of the baseline target lesion length diameters. Results: As of January 23, 2020, 128 patients treated with tislelizumab in combination with chemotherapy achieved objective tumor response (responders), representing 57.4%(128/223) of the intention-to-treat population, with a TTR of 5.1 to 33.3 weeks and a median TTR of 7.9 weeks. Of the responders (128), 50.8%(65) achieved first remission at the first efficacy assessment (week 6), 31.3%(40) at the second efficacy assessment (week 12), and 18.0%(23) at the third and subsequent tumor assessments. The percentages of responders who achieved a depth of tumor response of 30% to <50%, 50% to <70% and 70% to 100% were 45.3%(58/128), 28.1%(36/128) and 26.6%(34/128), respectively, with median progression-free survival (PFS) of 9.0 months (95% CI: 7.7 to 9.9 months), 11.5 months (95% CI: 7.7 months to not reached) and not reached (95% CI: 11.8 months to not estimable), respectively. Tislelizumab plus chemotherapy were generally well tolerated in responders with similar safety profile to the overall safety population. Conclusion: Among responders to tislelizumab in combination with chemotherapy for nsq-NSCLC, 82.0%(105/128) achieves response within the first two tumor assessments (12 weeks) and 18.0%(23/128) achieves response at later (18 to 33 weeks) assessments, and there is a trend toward prolonged PFS in responders with deeper tumor response.

Updating species diversity of Colletotrichum, with a phylogenomic overview.

The genus Colletotrichum includes important plant pathogens, endophytes, saprobes and human pathogens. Even though the polyphasic approach has facilitated Colletotrichum species identification, knowledge of the overall species diversity and host distribution is largely incomplete. To address this, we examined 952 Colletotrichum strains isolated from plants representing 322 species from 248 genera, or air and soil samples, from 87 locations in China, as well as 56 strains from Saudi Arabia, Thailand, Turkey, and the UK. Based on morphological characteristics and multi-locus phylogenetic analyses, the strains were assigned to 107 species, including 30 new species described in this paper and 18 new records for China. The currently most comprehensive backbone tree of Colletotrichum, comprising 16 species complexes (including a newly introduced C. bambusicola species complex) and 15 singleton species, is provided. Based on these analyses, 280 species with available molecular data are accepted in this genus, of which 139 have been reported in China, accounting for 49.6 % of the species. Colletotrichum siamense, C. karsti, C. fructicola, C. truncatum, C. fioriniae, and C. gloeosporioides were the most commonly detected species in China, as well as the species with the broadest host range. By contrast, 76 species were currently found to be associated with a single plant species or genus in China. To date, 33 Colletotrichum species have been exclusively reported as endophytes. Furthermore, we generated and assembled whole-genome sequences of the 30 new and a further 18 known species. The most comprehensive genome tree comprising 94 Colletotrichum species based on 1 893 single-copy orthologous genes was hence generated, with all nodes, except four, supported by 100 % bootstrap values. Collectively, this study represents the most comprehensive investigation of Colletotrichum diversity and host occurrence to date, and greatly enhances our understanding of the diversity and phylogenetic relationships in this genus. Taxonomic novelties: New species: Colletotrichum arecacearum F. Liu, Z.Y. Ma & L. Cai, Colletotrichum bicoloratum F. Liu, W.P. Wu & L. Cai, Colletotrichum bromeliacearum F. Liu & L. Cai, Colletotrichum buxi F. Liu, W.P. Wu & L. Cai, Colletotrichum chamaedoreae F. Liu, W.P. Wu & L. Cai, Colletotrichum crousii F. Liu, Z.Y. Ma & L. Cai, Colletotrichum danxiashanense F. Liu, W.P. Wu & L. Cai, Colletotrichum diversisporum F. Liu, W.P. Wu & L. Cai, Colletotrichum diversum F. Liu & L. Cai, Colletotrichum dolichoconidiophori F. Liu, W.P. Wu & L. Cai, Colletotrichum iris F. Liu & L. Cai, Colletotrichum monsterae F. Liu, W.P. Wu & L. Cai, Colletotrichum multiseptatum F. Liu, W.P. Wu & L. Cai, Colletotrichum nageiae F. Liu, W.P. Wu & L. Cai, Colletotrichum obovoides F. Liu & L. Cai, Colletotrichum parabambusicola F. Liu, W.P. Wu & L. Cai, Colletotrichum paraendophytum F. Liu, W.P. Wu & L. Cai, Colletotrichum reniforme F. Liu, Z.Y. Ma & L. Cai, Colletotrichum schimae F. Liu, W.P. Wu & L. Cai, Colletotrichum shivasii F. Liu & L. Cai, Colletotrichum sinuatum F. Liu, W.P. Wu & L. Cai, Colletotrichum subacidae F. Liu, Z.Y. Ma & L. Cai, Colletotrichum subsalicis F. Liu & L. Cai, Colletotrichum subvariabile F. Liu, W.P. Wu & L. Cai, Colletotrichum syngoniicola F. Liu, Z.Y. Ma & L. Cai, Colletotrichum telosmae F. Liu, W.P. Wu & L. Cai, Colletotrichum tibetense F. Liu & L. Cai, Colletotrichum variabile F. Liu, W.P. Wu & L. Cai, Colletotrichum zhaoqingense F. Liu & L. Cai, Colletotrichum zhejiangense F. Liu, W.P. Wu & L. Cai. Citation: Liu F, Ma ZY, Hou LW, Diao YZ, Wu WP, Damm U, Song S, Cai L (2022). Updating species diversity of Colletotrichum, with a phylogenomic overview. Studies in Mycology 101: 1-56. doi: 10.3114/sim.2022.101.01.

[Expression of PD-L1 and tumor infiltrating lymphocyte markers in uterine cervical carcinoma].

Objective: To investigate the expression of PD-L1, CD4, CD8 and CXCL-13 in cervical carcinoma, and their clinicopathological significance was analyzed. Methods: A total of 77 patients with cervical carcinoma in the Seventh Medical Center, PLA General Hospital from January 2019 to December 2021 were included. All patients received radical surgical resection in the Seventh Medical Center of Chinese PLA General Hospital. The expression of PD-L1, CD4, CD8 and CXCL-13 was detected by immunohistochemical (IHC) method. The correlation between IHC markers and patients' clinicopathological parameters was analyzed. Results: There were 59 cases of squamous cell carcinoma and 18 cases of adenocarcinoma (ranging from 29 to 69 years) with an average of (49.4±9.8) years. PD-L1 was expressed in different degrees in cervical squamous cell carcinoma and adenocarcinoma (χ²=4.975, P=0.026); CD4+, CD8+and CXCL-13+tumor infiltrating lymphocytes (TIL) were observed in the carcinoma cell nests and peritumoral stroma. PD-L1 expression in cervical carcinoma was moderately correlated with the number of CD4+TIL in the carcinoma nests, and the number of CD8+, CXCL-13+TIL infiltration in the carcinoma nests and stroma, but not to the patient's age, histologic differentiation, presence or absence of vascular invasion, presence or absence of lymph node metastasis and FIGO stage (P>0.05). Conclusions: The high expression of PD-L1 in cervical carcinoma tissues is closely related to the number of TIL in the carcinoma nests and peritumor stroma, suggesting that they may have important reference value for predicting the response to immunotherapy in patients with cervical carcinoma.

[Clinicopathological features of malignant mixed mesodermal tumor: analysis of 50 cases].

Objective: To investigate the clinicpathological, immunohistochemical and molecular genetic features of malignant mixed mesodermal tumor (MMMT) in the female reproductive system. Methods: To analyze its histopathological characteristics, we performed a retrospective review of the MMMT cases diagnosed at PLA General Hospital, Beijing, China during 2005-2019 using its surgical and pathological databases. EnVision immunohistochemical staining was used to detect the expression of ER, PR, p16, p53 and MMR proteins. Results: Fifty cases were conformed to the diagnosis, including 29 cases originated in the uterus, 16 cases in ovary, 4 cases of synchronous occurrence in uterus and ovary, 1 case in cervix. The tumor was histologically composed of two components, namely carcinoma and sarcoma ones, with clear borderline or blend mutually. The proportion of cancer component in the whole tumor ranged from 5%-90%. The proportion of carcinoma was more than 50% in 76% of the cases, and less than 50% in 24% of cases, including 2 cases with<10% of carcinoma. In the cases of primary uterine MMMT, the main carcinoma type was high grade endometrioid carcinoma (55%, 16/29). In ovarian MMMT, the main carcinoma type was serous carcinoma (12/16), while that of cervical MMMT was squamous cell carcinoma. The others were clear cell carcinoma or the undifferentiated carcinoma. There was one carcinoma type in most cases, only 7 cases had two carcinoma types. Homologous sarcomas, including stromal sarcoma, leiomyosarcoma and high-grade spindle cell sarcomas, were more commonly found in uterine MMMT (72.4%, 21/29). While heterogenic sarcomas, including chondrosarcoma, osteosarcoma and rhabdomyosarcoma, were more commonly noted in ovarian MMMT (12/16) than MMMT of other sites. There were 10 cases that consisted of two types of sarcomas. The synchronous MMMT of uterus and ovary had similar morphology and the types of carcinoma and sarcoma. The tumor cells that spread or metastasized to lymph node, omentum, intestinal wall or skin were all carcinoma cells, and were morphologically consistent with the original tumors. Immunohistochemically, ER and PR were both negative (23/25 in uterine, 8/10 in ovarian tumors). p16 was strongly positive (11/11 in uterine tumors, and 6/6 in ovarian tumors), with similar expression patterns in the carcinoma and sarcoma components. p53 showed mutant-type staining (64%, 21/33) and expressed synchronously in carcinoma and sarcoma components. p53 mutation was found in 35% cases of endometrial carcinoma and 46.7% cases of non-endometrial carcinoma. p53 mutation was also found in only 31.8% cases of heterogenic sarcomas, but in 50% of non-heterogenic sarcomas. Twenty-eight cases (28/33, 85%) presented intact mismatch repair proteins, while 5 cases (5/33, 15%) presented deficient mismatch repair proteins. Conclusions: MMMT in female reproductive system is a rare high-grade biphasic tumor with complex and diverse morphology. The immunohistochemical features are characterized by negative ER/PR and strongly positive p16, mostly mutant p53 and proficient mismatch repair proteins. The patients with a high FIGO stage have worse prognosis.

[Therapeutic effect of nivolumab on non-small-cell lung cancer patients with brain metastases: a retrospective study].

Objective: To preliminarily explore the treatment effect of nivolumab on Chinese non-small-cell lung cancer (NSCLC) patients with brain metastases, and further enrich the evidences of programmed death-ligand 1 (PD-1) monoclonal antibody in the treatment of NSCLC patients with brain metastases. Methods: The clinical and pathological data of 22 NSCLC patients with brain metastases treated with nivolumab were collected. The electronic imaging data were collected to confirm the treatment effect and time point of disease progression, and the survival data of the patients were obtained through follow-up. Results: Twenty-one patients were evaluated for the intracranial treatment effect. The intracerebral objective response rate (IORR) was 28.6%, the intracranial disease control rate (IDCR) was 47.6%. The median intracranial progression-free-survival (iPFS) of all the 22 patients was 5.2 months. Both the 1-year and 2-year survival rates were 56.7%. Conclusions: The treatment effect of PD-1 monoclonal antibody on NSCLC patients with brain metastases is similar as those without brain metastases.

Glycyrrhizin improves inflammation and apoptosis via suppressing HMGB1 and PI3K/mTOR pathway in lipopolysaccharide-induced acute liver injury.

OBJECTIVE: Acute liver injury (ALI) is mainly characterized by the symptom of metabolic disorders, homeostasis unbalance, and loss of liver function. There are no effective treatment methods at present stage except the liver transplantation. Effective treatment for early ALI is of great significance for the treatment of liver injury thereof. Glycyrrhizin (GL) is a promising inhibitor of the high-mobility group box-1 gene (HMGB1) which is expressed much higher in an inflammatory injury. However, it is not clear whether GL improves ALI via the inhibition of HMGB1. The present study is to probe the function and mechanism of glycyrrhizin on acute liver injury. MATERIALS AND METHODS: The expression of HMGB1 and inflammation in liver macrophages were analyzed. Lipopolysaccharide (LPS) was used in stimulating the macrophages to activate inflammatory response and recombined human HMGB1 was used to resist the function of GL to explore whether GL acted via the target of HMGB1. Then, LPS injection was utilized to induce ALI in mice, and then we evaluated GL treatment in ALI model. RESULTS: The results showed that the expressions of HMGB1 and inflammatory factors were markedly increased in LPS-activated liver macrophages. GL inhibited the progress of macrophages inflammation by restraining HMGB1, and the administration of GL could reverse the effects of LPS-induced ALI in mice. Moreover, PI3K/mTOR pathway was significantly suppressed by GL application. CONCLUSIONS: These results suggest that GL prevents inflammation in liver macrophages via inhibition of HMGB1. GL restrains inflammation and cell apoptosis by inhibiting HMGB1 via PI3K/mTOR signaling pathway in ALI. GL may become a novel drug for the therapy of ALI in the future.

[Comparison of radiological and clinicopathological features of craniofacial fibro-osseous lesions].

Objective: To investigate the clinicopathological and radiological features of benign fibro-osseous lesion (BFOL). Methods: Sixty-five cases of craniofacial BFOL, eight cases of peripheral ossifying fibroma (POF) and one case of low-grade central osteosarcoma diagnosed at Sichuan Provincial People's Hospital between January 2010 and March 2019 were collected. The clinicopathologic features, hematoxylin-eosin and immunohistochemical (IHC) staining and radiographic features were analyzed. MDM2 gene amplification was detected by FISH in difficult borderline cases. Results: This cohort of BFOLs included 50 cases of fibrous dysplasia (FD), 12 cases of ossifying fibroma (OF), and three cases of juvenile psammomatoid ossifying fibroma (JPOF). The average ages of patients with FD,OF and JPOF were 31.7, 39.2 and 26.0 years respectively. The male to female ratio was 1.0∶1.8.The average age of POF was 47.0 years, with male to female ratio of 1∶7. Patient of low-grade central osteosarcoma was a 48-year-old man. Twenty-seven cases of FD were located in the jaw, and 23 cases were in other craniofacial bones. Nine cases of OF were located in the jaw, and three cases were in the nasal cavity. Two cases of JPOF were in the nasal sinus, and one was in the jaw. All POF were located in the gingiva, and low-grade central osteosarcoma was located in the mandible. The imaging features of FD were luffa-like or ground-glass like signal shadows with poorly defined borders with expansion. OF had clear borders or sclerosing margins. Both JOF and low-grade central osteosarcoma were expansile intraosseously and with focally invasive nodular masses with ground-glass like signal shadows; and POF showed soft tissue mass with bone formation. Histological features of BFOLs showed mixed fibrous and irregular osteoid lesions. FD had no clear relationship with the host bone and no osteoblasts surrounded the bone trabeculae. Osteoblasts rimming was found in OF, and the boundaries of the host bone were clear. JPOF and low-grade central osteosarcoma infiltrated the host bone focally, and the latter showed mild cellular atypia. MDM2 amplification was detected in low-grade central osteosarcoma. Conclusions: BFOLs are a group of fibro-osseous lesions with similar morphology in the head and neck and face, but their clinical features and prognosis are different; and their imaging and histological characteristics are also slightly different. Attentions should be given to the combination of clinical, imaging and pathologic features of BFOLs, especially the differential diagnosis between BFOLs and low-grade central osteosarcoma. Molecular detection could be used to assist the diagnosis in difficult cases.

[Effects of heme oxygenase-1 knockdown on proliferation, invasion and metastasis of lung adenocarcinoma A549 cells and its mechanism].

Objective: To investigate the effects of heme oxygenase-1 (HO-1) knockdown on proliferation, invasion and migration of lung adenocarcinoma A549 cells and explore the mechanism. Methods: The expression levels of HO-1 mRNA in human bronchial epithelial cells (HBECs) and human lung cancer cell lines (A549, H1299, H358 and H1993) were detected by real-time quantitative polymerase chain reaction (RT-qPCR), and immunohistochemistry (IHC) was used to detect the expression level of HO-1 in human lung adenocarcinoma specimens. The HO-1 short hairpin RNA (shRNA) was transfected into A549 cells by RNA interference technique. HO-1 stably deleted A549 cells were selected (HO-1 shRNA group) and verified by RT-qPCR and western blot. HO-1 shRNA A549 cells and control shRNA A549 cells were treated with the inducer of autophagy Torin1 or its inhibitor Bafilomycin A1 (Baf A1), respectively. The expressions of autophagic markers LC3B and p62 were determined by western blot. The proliferation, invasion and migration abilities of each group of A549 cells were assessed by cell counting, Transwell and wound healing assays, respectively. Results: The expressions of HO-1 mRNA in lung cancer cell lines (A549, H1299, H358 and H1993) were significantly higher than that of HBECs, and HO-1 upregulated in human lung adenocarcinoma. The expression of p62 protein and the ratio of LC3B-Ⅱ/ LC3B-Ⅰ in no treatment group, Torin1 treatment group and Baf A1 treatment group were significantly higher than those of the corresponding control group (P<0.05). After 11 days of culture, the number of cells in HO-1 shRNA group were 41.8%, 30.4% and 14.0% of the corresponding control group, respectively. The number of lower chamber cells in HO-1 shRNA group were (35.7±2.1), (27.0±1.0) and (38.0±1.0)/field, respectively, which were lower than (66.0±9.2), (39.3±1.2) and (43.0±2.6)/field of the corresponding control group, respectively (P<0.05). The migration distances of HO-1 shRNA group were (7.47±0.91) mm, (4.23±0.82) mm and (5.42±0.24) mm, which were lower than (10.07±1.26) mm, (7.14±0.07) mm and (12.04±0.80) mm of the corresponding control groups, respectively (P<0.05). Conclusion: Knockdown of HO-1 inhibits the proliferation, invasion and migration of A549 cells by impeding autophagy.

[Efficacy of first generation EGFR-TKIs and chemotherapy as first-line therapy in advanced lung adenocarcinoma patients with uncommon EGFR mutations].

Objective: To investigate the clinical effects of first generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) compared with platinum-based chemotherapy as first-line therapy in advanced lung adenocarcinoma patients with uncommon EGFR mutations. Methods: Clinical data of 4 276 patients diagnosed as advanced lung adenocarcinoma (ⅢB/Ⅳ) underwent EGFR gene detection at the Affiliated Cancer Hospital of Zhengzhou University from January 2012 to February 2018 were collected and 99 cases with uncommon EGFR mutations were selected. The clinical pathological features, treatment outcomes, treatment options and prognosis after first-line treatment of the 99 cases were analysed and compared with other patients with common EGFR mutations. Results: The objective response rates of patients with uncommon EGFR mutations receiving EGFR-TKIs or platinum-based chemotherapy were 33.0% and 27.1%, respectively. The disease control rates were 76.5% and 87.5%, respectively. The progression-free survival (PFS) of patients treated with EGFR-TKIs was 7.2 months, significantly superior than 4.9 months of patients receiving chemotherapy (P=0.009). The overall survival of patients treated with EGFR-TKIs was 14.3 months, significantly worse than 20.7 months of patients receiving chemotherapy (P=0.034). Multivariate analysis showed that distant metastases (P=0.001) and smoking history (P=0.013) were independent prognostic factors for OS of lung adenocarcinoma patients with EGFR uncommon mutations. Conclusions: Compared with chemotherapy, the usage of first generation of EGFR-TKIs as first-line therapy can improve the short-term efficacy of advanced lung adenocarcinoma patients with EGFR uncommon mutations. However, platinum-based chemotherapy shows a longer overall survival.

[Clinicopathological features of intestinal mucosal lesions in AIDS patients and their relation with CD4+ T lymphocytes].

Objective: To observe the histopathological features of different opportunistic infections and tumors of the intestinal mucosa in AIDS patients, and to explore the correlation between different lesions and CD4+ T lymphocyte levels. Methods: Colonic mucosal biopsy specimens of 263 patients with clinically diagnosed AIDS and abdominal pain, diarrhea, blood in the stool and other gastrointestinal symptoms were collected from Beijing Ditan Hospital from 2010 to 2018. There were 232 males and 31 females, with age range 10-81 (mean 40±13) years. HE staining, histochemical special staining, immunohistochemical staining, and in-situ hybridization were used to detect the expression of different opportunistic infection pathogens, tumors and CD4+ T lymphocytes. Peripheral blood was also taken for CD4+ T lymphocytes, CD8+ T lymphocytes, HIV viral load and routine indicators. Results: The cohort included 263 intestinal mucosal biopsy specimens. There were 175 cases (66.5%) of non-specific inflammation, and pathogens were detected in 41 cases (15.6%), including 20 cases(7.6%) of cytomegalovirus (CMV) infection, 12 cases (4.6%) of mycobacterial infection, eight cases (3.0%) of amoeba infestation, and one case (0.3%) of talaromycesmarneffei infection; there were also 41 (15.6%) neoplastic lesions including 25 cases (9.5%) of intraepithelial neoplasia, 10 cases (3.8%) of adenocarcinoma and squamous cell carcinoma, six cases (2.3%) of lymphoma; and six cases (2.3%) of ulcerative colitis. The peripheral blood CD4+T lymphocyte levels of patients with CMV, mycobacteria and talaromycesmarneffei were less than 200/µL; the peripheral blood CD4+ T lymphocyte level (P<0.01) and intestinal mucosa CD4+T lymphocytes (P<0.01) were all significantly lower than those in patients with non-specific inflammation. The peripheral red blood cells and hemoglobin levels of patients with CMV and mycobacterial infection (P<0.01), adenocarcinoma and squamous cell carcinoma (P<0.05) were significantly lower than those of non-specific inflammation patients. Conclusions: Pathologic examination of intestinal mucosa can identify specific infections and neoplastic lesions in AIDS patients; the most common lesions are non-specific inflammation, and CMV infection is the most common opportunistic infections; CMV, mycobacteria and talaromycesmarneffei infections are associated with decreased levels of CD4+ T lymphocytes in peripheral blood and intestinal mucosa; entamoeba histolytica infestation and non-HIV-related neoplastic lesions such as intraepithelial neoplasia, adenocarcinoma and squamous cell carcinoma are not associated with changes in AIDS immune function.

Inflammatory cytokines IL-6, IL-10, IL-13, TNF-α and peritoneal fluid flora were associated with infertility in patients with endometriosis.

OBJECTIVE: To investigate the correlations of inflammatory factors, interleukin-6 (IL-6), IL-10, IL-13 and tumor necrosis factor-α (TNF-α), and composition of bacterial flora in the peritoneal fluid with infertility in endometriosis patients. PATIENTS AND METHODS: A total of 55 patients diagnosed with endometriosis and infertility in the Gynecology Clinic of our hospital from June 2014 to July 2017 were selected as observation group, and another 30 non-endometriosis and non-infertility patients were enrolled as control group. The peritoneal fluid was extracted from patients in both groups, and the total white cell count and the percentage of leukocyte subset were determined. The total genome deoxyribonucleic acid (DNA) of microorganisms in peritoneal fluid was extracted, and the composition of microorganisms was analyzed using the Ion Torrent PGM platform (BGI). The levels of IL-6, IL-10, IL-13, and TNF-α in peritoneal fluid were detected via enzyme-linked immunosorbent assay (ELISA). Moreover, the correlations of inflammatory factors in the peritoneal fluid with endometriosis complicated with infertility were analyzed via Logistic regression analysis. RESULTS: The total white cell count, monocytes, neutrophils, eosinophils and basophils in endometriosis patients complicated with infertility were significantly higher than those in control group (p<0.05). Results of ELISA showed that the levels of IL-6, IL-10, IL-13, and TNF-α in peritoneal fluid of endometriosis patients complicated with infertility were significantly higher than those in control group (p<0.05). In peritoneal fluid of patients in both groups, Proteobacteria and Firmicutes were mainly dominated, followed by Actinobacillus, Bacteroidetes, Fusobacteria and Tenericutes, and there was no significant difference in the Eumycota between the two groups (p>0.05). Logistic regression analysis results showed that there were significant correlations of inflammatory factors (IL-6, IL-10, IL-13, and TNF-α) with endometriosis complicated with infertility. CONCLUSIONS: There are many kinds of Eumycota in the peritoneal fluid of endometriosis patients complicated with infertility, but they are not the main pathogenic factors. Inflammatory factors (IL-6, IL-10, IL-13, and TNF-α) can be used as important reference indexes for the diagnosis of endometriosis complicated with infertility.

First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study.

BACKGROUND: Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. PATIENTS AND METHODS: Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety. RESULTS: Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43-0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group. CONCLUSIONS: First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population.

The TrkB+ cancer stem cells contribute to post-chemotherapy recurrence of triple-negative breast cancers in an orthotopic mouse model.

Cancer stem cells (CSCs) are believed to have a crucial role in triple-negative breast cancer (TNBC) recurrence. However, the exact mechanisms that are functionally critical in CSCs-mediated recurrence remain unclear. Here, we showed that CSCs derived from recurrent TNBCs are endowed with increased self-renewal capacity as compared with those from the matched primary lesions. Using patient-derived specimens, we demonstrated the existence of paracrine brain-derived neurotrophic factor (BDNF) signaling between differentiated recurrent TNBC cells and CSCs characterized by the expression of TrkB, the receptor of BDNF. We showed that paclitaxel induced BDNF expression and apoptosis simultaneously in a cell cycle-dependent manner. BDNF promotes the self-renewal potential of the TrkB+CSCs through induction of KLF4. The TrkB+CSCs represent a particular subset indispensable for TNBC relapse. In line with this, TrkB is proved to be a superior predictor for TNBC recurrence. Using a genetically engineered mouse model of TNBC, we observed that ablation of the TrkB+CSCs potentially prevents relapse of malignant tumors. Further preclinical investigation of this promising approach may lead to development of a novel therapeutic strategy to improve the devastating prognosis of TNBC patients.

[Establishment of bisphosphonate-related osteonecrosis of the jaw model in rats and preliminary analysis of its etiological mechanism].

OBJECTIVE: To establish bisphosphonate-related osteonecrosis of the jaw (BRONJ) model in rats and to make preliminary analysis of its etiological mechanisms. METHODS: A BRONJ model was established in rats using pamidronate, dexamethasone combined with alveolar bone trauma (tooth extraction) method, and the ratios of CD4+ and CD90+ lymphocytes in splenocytes were also analyzed by flow cytometry in each group. For in vitro studies, the effects of pamidronate and dexamethasone on the proliferation of human osteosarcoma cell line MG-63 and mouse pre-osteoclasts cell line Raw 264.7 were investigated using CCK-8 assay. RESULTS: The rat BRONJ model was successfully established using the method described above. Flow cytometry results showed that the ratios of CD4+ and CD90+ lymphocytes in splenocytes were much lower in the pamidronate and dexamethasone-treated rats than those in either pamidronte alone- or dexamethasone alone-treated rats. CCK-8 assay results showed that pamidronate could inhibit the proliferation of both MG-63 and Raw 264.7 cell lines, while dexamethasone could enhance the inhibitory effect of pamidronate on Raw 264.7 cells. CONCLUSION: This study successfully established the BRONJ model in rats and verified that dexamethasone could enhance the inhibitory effect of pamidronate on pre-osteoclasts in vitro. At least three factors including alveolar bone trauma, infection and immune response induced by dexamethasone could be involved in the process of BRONJ.

Classification of hypothalamic hamartoma and prognostic factors for surgical outcome.

OBJECTIVES: The main aims of this study were to classify patients with hypothalamic hamartoma (HH) based on neuroimaging features and describe the clinical manifestations of HH. MATERIALS AND METHODS: A retrospective review of 214 consecutive patients with HH treated in Beijing Tiantan Hospital was performed. RESULTS: HH were diagnosed and divided into Types I-IV based on MRI. Types I and II were defined as the HH attached to the floor of the third ventricle with narrow (Type I) or broad (Type II) interfaces. Type III ('straddling') was defined by the HH extending into the third ventricle and interpeduncular cistern. Type IV was defined as the HH located totally within the third ventricle. The percent distribution of patients was 35.9% Type I, 12.1% Type II, 40.7% Type III, and 11.2% Type IV. The percentage of patients with precocious puberty was highest in Type I (81.8%). The percentage of patients with gelastic seizures was highest in Type IV (91.7%). After surgery, 20% (1/5) of patients with Type II HH, 48.8% (20/42) with Type III, and 91.7% (11/12) with Type IV were free of epileptic seizures. Significant prognostic factors for surgical outcome were HH size, surgical approach, and resection level. CONCLUSIONS: The clinical manifestations of HH are correlated with the topology of the HH in relation to the hypothalamus. Our results suggest that patients with Type IV HH have the best outcome from surgery and neurosurgeons should be cautious about performing surgery on patients with Type II and Type III HH.

Role of macrophage migration inhibitory factor in influenza H5N1 virus pneumonia.

The severe and often fatal disease in humans and birds caused by H5N1 influenza viruses has been attributed to aberrant pulmonary inflammatory responses. We investigated the role of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and a pivotal regulator of innate immunity, in H5N1 influenza virus pneumonia in murine model. We found increased MIF mRNA levels in the lungs and MIF protein levels in the serum of infected mice. Although the inhibition of MIF action by isoxazolone-1 (ISO-1) did not render mice more resistant to the lethality of infection, it caused a significant reduction in pulmonary inflammatory cytokines interleukin-1 beta (IL-1beta), IL-6 and tumor necrosis factor alpha (TNF-alphalfa) and chemokine interferon-inducible protein-10 (IP-10). These results indicate the involvement of MIF in inflammatory responses to H5N1 influenza virus infections by induction of pulmonary inflammatory cytokines and chemokines, and suggest that pharmacotherapeutic approaches targeting MIF may hold promise for the treatment of H5N1 influenza virus pneumonia.

4IgB7-H3 is the major isoform expressed on immunocytes as well as malignant cells.

Human B7-H3, a novel member of B7 family, has two isoforms (2IgB7-H3 and 4IgB7-H3). As costimulatory functions of both isoforms are not clarified, there has been much discussion on their expression patterns, T-cell responses, etc. This study generated two specific mouse anti-human 2IgB7-H3 monoclonal antibodies (mAbs) (7D7 and 10F1), whose specificities are quite different from those of the available B7-H3 mAb (21D4) by competition assay. The use of antibodies indicated that B7-H3 was found to have different expression patterns on monocyte-derived dendritic cells, that is the isoform 2IgB7-H3 is tended to express on immature dendritic cells (iDCs), whereas 4IgB7-H3 could be detected in the whole process of maturation of dendritic cells. The isoform 4IgB7-H3 was shown in the immunohistochemistry assay to be more widely expressed than 2IgB7-H3 in human benign and malignant hepatic tissues. Furthermore, flow cytometry and reverse transcription-polymerase chain reaction indicated that 4IgB7-H3 rather than 2IgB7-H3 was the major isoform on many human tumor cell lines. In addition, both 2IgB7-H3- and 4IgB7-H3-transfected cells could promote T-cell proliferation, which could be blocked by 7D7 mAb. These two novel antibodies may shed light on the function of the two B7-H3 isoforms.

Identification of feline MAGE-1 gene product by monoclonal antibodies.

Melanoma antigens (MAGE) are thought to induce a tumor-specific immune response and to be potential therapeutical targets for cancer immunotherapy. We have earlier identified the cDNA of feline melanoma antigen 1 (fMAGE-1), but its product was not characterized in detail. We have expressed the recombinant fMAGE-1 protein and have generated monoclonal antibodies (mAbs) against it, to identify the native fMAGE-1 protein in feline lymphoma cell lines and tumor tissues. The fMAGE-1 protein was found to be approximately 39 kDa in molecular mass on sodium dodecyl-sulphate-polycrylamide gel electrophoresis (SDS-PAGE), and it was found to be located in the cytoplasm of the cells by immunofluorescence. Immunoblotting analysis detected the fMAGE-1 gene product in the fMAGE-1-mRNA-positive cells, but not in the fMAGE-1-mRNA-negative cells. An interesting finding of the present study was the distribution of the fMAGE-1 protein, which was found to have a spindle-like distribution, with filaments twining around the nucleus, suggesting that the fMAGE-1 protein may be associated with or form some cytoplasmic filaments. This type of finding is so far the first report of its kind, and to the best of our knowledge it has not been reported in either human or mouse MAGE proteins until now. It most probably implies the major diversity of the MAGE family genes.