[Effect of Jianpi Shengxue Granule on Fertility and Early Embryo Development Toxicity of Rats].

Objective To assess the effects of Jianpi Shengxue Granule (JSG) on the fertility and early embryo development in rats. Methods Totally 176 SD rats were stratified by sex, and divided into 4 groups, i.e., the control group, low, medium, high dose JSG treatment groups. Rats in the 3 JSG treatment groups were administered with JSG at 0, 1. 16, 3. 48, 5. 80 g/kg per day by gastrogavage, re- spectively. After 2 weeks of administration for females and 4 weeks of administration for males, males and females were caged in the ratio of 1:1. Females were administered to the gestation day 7. Males were administered for 59 -63 days until the day before anatomy. All parental generations were anatomized to observe signs and morphologies. Pathological examination was performed. General toxicity was detected. The testis and epididymis were weighed. Spermatozoa number was counted from epididymis, and repro- duction toxicity of sperm motility was checked. The numbers of corpus luteum, live fetus, dead fetus, and absorbed fetus were counted. The implantation number was calculated to observe early embryo de- velopment toxicity. Results (1) General toxicity: The body weight growth slowed down in male rats of the high dose JSG treatment group. No abnormality was found in low and medium dose JSG treatment groups. (2)Fertility toxicity: There was no obvious toxic effect on testis, epididymis, and spermatozoa number from epididymis sperm in all JSG treatment groups. (3) Early embryo development toxicity: No significant effect on the formation of early embryos was found in all JSG treatment groups. Conclusions Certain gastrointestinal toxicity of JSG might exist to some extent. The dose for non-adverse effect of JSG on fertility and early embryo development was 3. 38 g/kg per day. No obvious fertility or early embryo development toxicity occurred in each JSG treatment group.

[Effective Ingredients of Yangjing Zhongyu Decoction Regulated Androgen Biosyntheses by Mitogen-Activated Protein Kinase Pathway in Porcine Granulose Cells].

OBJECTIVE: To study the molecular mechanism of Yangjing Zhongyu Decoction (YZD) n-butanol extracts (ZDC) and ethyl acetate extracts (YSYZ) in reducing androgen in porcine granulose cells by mitogen-activated protein kinase (MAPK) pathway. METHODS: Porcine granulose cells were isolated and cultured. They were inoculated by MAPK inhibitor PD98059 at different concentrations, and then they were divided into the blank control group (0), 1, 3, 10, and 25 micromol/L groups. After 24-h culture the cytochrome P450c17a (CYP17) mRNA expression level was detected using Real-time fluorescent quantitative PCR. Contents of androgen (testosterone) in the supernate were detected using RIA and optimal PD98059 concentration screened. After intervened by 10 micromol/L PD98059 for 24 h, the culture solution was intervened by effective ingredients of with or without YZD or YSYZ at various concentrations (0, 1 , 5, 25, 50 mg/mL) at various time points (3, 6, 18, 24 h). Expression levels of p-ERK1/2, c-Fos and CYP17 were detected by Western blot. Testosterone content in the supernate was determined by radioimmunoassay (RIA). RESULTS: Ten pLmol/L PD98059 could obviously decrease p-ERK1/2 protein expression and increase CYP17 mRMA expression, and elevate testosterone content in the supernate (P < 0.05). ZDC and YSYZ at 25 ng/mL could increase p-ERK1/2 protein expression and c-Fos levels, and reduce CYP17 protein expression, and lower testosterone content in the supernate after 6-h intervention (P < 0.01). CONCLUSION: Effective ingredients of YZD could reduce androgen production in porcine granulose cells through increasing activities of MAPK.

[Effect of Yangjing Zhongyu Decoction on mRNA and protein expression of PCNA, StAR, and FSHR in ovarian granulosa cells cultured by excess androgen].

OBJECTIVE: To observe the effect of Yangjing Zhongyu Decoction (YZD) on mRNA and protein expression of PCNA, StAR, and FSHR in ovarian granulose cells (GCs) cultured by excess androgen. METHODS: Ovarian GCs from porcine follicles were isolated and cultured in vitro. Follicular stimulating hormone (FSH) or YZD was added in the GCs treated by excess testosterone propionate. Totally 48 h later mRNA and protein expression of PCNA, StAR, and FSHR were detected by RT-PCR and Western blot. RESULTS: Excess androgen inhibited mRNA and protein expression of PCNA, StAR, and FSHR of GCs. FSH and YZD could antagonize inhibition of excess androgens, and promote mRNA and protein expression of PCNA, StAR, and FSHR in GCs. CONCLUSION: YZD could antagonize the inhibition of excess androgen on mRNA and protein expression of PCNA, StAR and FSHR in GCs. Thus, we inferred that YZD could improve the follicle dysplasia by promoting mRNA and protein expression of PCNA, StAR and FSHR in GCs.

Distribution and survival outcomes of primary head and neck hematolymphoid neoplasms in older people: a population-based study.

Primary head and neck hematolymphoid neoplasms (PHNHLN) are defined as a series of hematolymphoid system-derived neoplasms which primarily emanate in head and neck region. Due to the rarity and absence of symptomatic specificity, PHNHLN is easily neglected. The objective of this study is to investigate demographics, pathological subtype distribution, anatomical location, survival outcomes and prognostic factors of PHNHLN among older patients aged ≥ 60. The individual patient information in our study was derived from Surveillance, Epidemiology and End Results database. Descriptive epidemiological methods were used to analyze the distribution of histologic subtypes and primary anatomical sites. Kaplan-Meier survival curves and log-rank test were conducted to evaluate the effect of variables on the prognosis. Cox hazard regression was conducted to identify the independent prognostic factors. The male-to-female ratio in most pathological subtypes was close to 1:1. The most common pathological subtype was diffuse large B-cell lymphoma. The most commonly involved sites outside the lymph nodes were salivary glands, especially parotid gland, followed by tonsil, thyroid gland and tongue. The prognosis of mature T- and NK-cell non-Hodgkin lymphoma (NHL) was bleaker than Hodgkin lymphoma, mature B-cell NHL and plasma cell neoplasm. Age at diagnosis, presence of second primary malignancy (SPM), pathological subtype, Ann-Arbor stage, chemotherapy and radiation were independent prognostic factors of overall survival. Our study comprehensively reported the subtype distribution, anatomical sites and survival outcomes of PHNHLN among older patients, improving understanding of this rare group of cancer entities.

The PARP1 Inhibitor Niraparib Represses DNA Damage Repair and Synergizes with Temozolomide for Antimyeloma Effects.

Purpose: Poly(ADP-ribose) polymerase 1 (PARP1) is necessary for single-strand break (SSB) repair by sensing DNA breaks and facilitating DNA repair through poly ADP-ribosylation of several DNA-binding and repair proteins. Inhibition of PARP1 results in collapsed DNA replication fork and double-strand breaks (DSBs). Accumulation of DSBs goes beyond the capacity of DNA repair response, ultimately resulting in cell death. This work is aimed at assessing the synergistic effects of the DNA-damaging agent temozolomide (TMZ) and the PARP inhibitor niraparib (Nira) in human multiple myeloma (MM) cells. Materials and Methods: MM RPMI8226 and NCI-H929 cells were administered TMZ and/or Nira for 48 hours. CCK-8 was utilized for cell viability assessment. Cell proliferation and apoptosis were detected flow-cytometrically. Immunofluorescence was performed for detecting γH2A.X expression. Soft-agar colony formation assay was applied to evaluate the antiproliferative effect. The amounts of related proteins were obtained by immunoblot. The combination index was calculated with the CompuSyn software. A human plasmacytoma xenograft model was established to assess the anti-MM effects in vivo. The anti-MM activities of TMZ and/or Nira were evaluated by H&E staining, IHC, and the TUNEL assay. Results: The results demonstrated that cotreatment with TMZ and Nira promoted DNA damage, cell cycle arrest, and apoptotic death in cultured cells but also reduced MM xenograft growth in nude mice, yielding highly synergistic effects. Immunoblot revealed that TMZ and Nira cotreatment markedly increased the expression of p-ATM, p-CHK2, RAD51, and γH2A.X, indicating the suppression of DNA damage response (DDR) and elevated DSB accumulation. Conclusion: Inhibition of PARP1 sensitizes genotoxic agents and represents an important therapeutic approach for MM. These findings provide preliminary evidence for combining PARP1 inhibitors with TMZ for MM treatment.

MSC Senescence-Related Genes Are Associated with Myeloma Prognosis and Lipid Metabolism-Mediated Resistance to Proteasome Inhibitors.

Background: Complex carcinogenic mechanisms and the existence of tumour heterogeneity in multiple myeloma (MM) prevent the most commonly used staging system from effectively interpreting the prognosis of patients. Since the microenvironment plays an important role in driving tumour development and MM occurs most often in middle-aged and elderly patients, we hypothesize that ageing of bone marrow mesenchymal stem cells (BM-MSCs) may be associated with the progression of MM. Methods: In this study, we collected the transcriptome data on MM from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Differentially expressed genes in both senescent MSCs and MM tumour cells were considered relevant damaged genes. GO and KEGG analyses were applied for functional evaluation. A PPI network was constructed to identify hub genes. Subsequently, we studied the damaged genes that affected the prognosis of MM. Least absolute shrinkage and selection operator (lasso) regression was used to identify the most important features, and a risk model was created. The reliability of the risk model was evaluated with the other 3 GEO validation cohorts. In addition, ROC analysis was used to evaluate the novel risk model. An analysis of immune checkpoint-related genes, tumour immune dysfunction and exclusion (TIDE), and immunophenotypic scoring (IPS) were performed to assess the immune status of risk groups. pRRophetic was utilized to predict the sensitivity to administration of chemotherapeutic agents. Results: We identified that MAPK, PI3K, and p53 signalling pathways were activated in both senescent MSCs and tumour cells, and we also located hub genes. In addition, we constructed a 14-gene prognostic risk model, which was analysed with the ROC and validated in different datasets. Further analysis revealed significant differences in predicted risk values across the International Staging System (ISS) stage, sex, and 1q21 copy number. A high-risk group with higher immunogenicity was predicted to have low proteasome inhibitor sensitivity and respond poorly to immunotherapy. Lipid metabolism pathways were found to be significantly different between high-risk and low-risk groups. A nomogram was created by combining clinical data, and the optimization model was further improved. Finally, real-time qPCR was used to validate two bortezomib-resistant myeloma cell lines, and the test confirmed that 10 genes were detected to be expressed in resistant cell lines with the same trend as in the high-risk cohort compared to nonresistant cells. Conclusion: Fourteen genes related to ageing in BM-MSCs were associated with the prognosis of MM, and by combining this genotypic information with clinical factors, a promising clinical prognostic model was established.

[Clinical Characteristics and Prognosis of Systemic Anaplastic Large Cell Lymphoma].

OBJECTIVE: To evaluate the clinical characteristics, treatment and prognosis of systemic anaplastic large cell lymphoma(sALCL). METHODS: The clinical data of 90 cases with sALCL treated in the Department of Hematology of the Affiliated Xijing Hospital of Air Force Medical University from November 2018 to October 2021 were retrospectively analyzed. The clinical features, treatment and prognosis were summarized and the prognostic factors were investigated. RESULTS: There were 58 males and 32 females, with a median age of 32 (12-73) years old. 69 (76.7%) patients had Ann Arbor stage Ⅲ-Ⅳ disease and half of the patients had extranodal infiltration. The median age was 27(12-72) years of the 60 ALK+ patients while 53(15-73) years of the 30 ALK- patients, and it was significantly different in the age of onset between the two group(P<0.01). 88 patients received first line chemotherapy, and 50(568%) cases achieved complete remission(CR). IPI score≥3 was an independent risk factor for CR. The median progressive free survival(PFS) and overall survival(OS) of the patients were not reached. Multivariate analysis showed that no achievement of CR after first-line therapy was a significant prognostic factor influencing PFS and OS. CONCLUSION: sALCL mainly occurs in males and most patients were in advanced stage. Half of the patients had extranodal involvement. The CR rate after first-line chemotherapy was 568%, and IPI score≥3 was a significant prognostic factor for CR. No achievement of CR after first-line therapy is poorly prognostic for PFS and OS.

The serum galectin-3 levels are associated with the severity and prognosis of ischemic stroke.

Galectin-3, a microglia/macrophage-derived inflammatory mediator, plays a role in the stroke progression. In this single-center prospective study, we included 288 consecutive patients with a first-ever acute ischemic stroke to assess the association between galectin-3 serum level and clinical severity at admission and outcome at discharge by univariate and multivariate logistic regression. The results were presented as odds ratios (OR) and 95% confidence intervals (CI). Patients with high severity and poor outcomes had higher serum levels of galectin-3 (P<0.001 and P<0.001). Multivariate analysis suggested that a galectin-3 serum level in the highest quartile (The lowest three quartiles[Q1-3] as the reference) was associated with poor functional outcome (OR, 3.15; 95% CI, 2.44-3.87). The AUC (standard error) for the NIHSS and the combined model were 0.764 (0.031) and 0.823 (0.027), corresponding to a difference of 0.059 (0.004). This study shows that higher serum levels of galectin-3 are associated with stroke severity at admission and stroke prognosis at discharge in ischemic stroke.

Clinical Characteristics and Prognostic Analysis of Multiple Myeloma with Extramedullary Disease: A SEER-Based Study.

BACKGROUND: Extramedullary disease (EMD), an infrequent manifestation of multiple myeloma (MM), can present at diagnosis or develop during the disease course. EMD can be clinically divided into bone-related EMD (EMD-B) and soft tissue-related EMD (EMD-S). The purpose of our study is to investigate the clinical characteristics, survival outcomes, and prognostic factors of MM patients with EMD. METHODS: A total of 155 MM patients with EMD were ultimately enrolled in our study by retrieving the Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier survival curves and log-rank test for overall survival (OS) and myeloma-specific survival (MSS) were conducted to compare each potential variable. Variables with a p value <0.1 in the univariate Cox regression were incorporated into the multivariate Cox model to determine the independent prognostic factors, with a hazard ratio (HR) >1 representing adverse prognostic factors. RESULTS: The median age at diagnosis was 63 years old. EMD-B occurred in 99 patients (63.90%), while EMD-S occurred in 56 cases (36.10%). Patients with EMD-S had a significant survival disadvantage in MSS (HR = 1.844, 95% CI 1.117-3.042, p = 0.017) and OS (HR = 1.853, 95% CI 1.166-2.942, p = 0.009) compared to those with EMD-B. Patients with EMD interval ≤24 months were at higher risk of death than those with EMD at diagnosis in MSS (HR = 1.885, 95% CI 1.175-3.346, p = 0.042) and in OS (HR = 1.33, 95% CI 1.119-2.529, p = 0.036). Patients with EMD interval >24 months were at a lower risk of death as opposed to those with EMD at diagnosis. CONCLUSION: Age at MM diagnosis, site of EMD, and time interval from diagnosis to EMD occurrence were independent prognostic factors in MM patients with EMD. EMD-B bore a better prognosis than EMD-S.

Effect of High-Fat Diet on the Intestinal Flora in Letrozole-Induced Polycystic Ovary Syndrome Rats.

AIM: The aim of this study was to explore whether letrozole and high-fat diets (HFD) can induce obese insulin-resistant polycystic ovary syndrome (PCOS) with intestinal flora dysbiosis in a rat model. We compared the changes in the intestinal flora of letrozole-induced rats fed with HFD or normal chow, to explore the effects of HFD and letrozole independently and synergistically on the intestinal flora. METHODS: Five-week-old female Sprague Dawley (SD) rats were divided into four groups: control (C) group fed with regular diet; L1 group administered with letrozole and fed with regular diet; L2 group received letrozole and fed with HFD; and HFD group fed with HFD. At the end of the experiment, ovarian morphology, hormones, metabolism, oxidative stress, and inflammatory status of all rats were studied. 16S rDNA high-throughput sequencing was used to profile microbial communities, and various multivariate analysis approaches were used to quantitate microbial composition, abundance, and diversity. RESULTS: Compared to the C group, the increased plasma fasting insulin and glucose, HOMA-IR, triglyceride, testosterone, and malondialdehyde were significantly higher in the L2 group, while high-density lipoprotein cholesterol was significantly lower in the L1 group and L2 group. The indices of Chao1 and the Abundance-based Coverage Estimator (ACE) (α-diversity) in the L2 and HFD groups were significantly lower than that in the C group. Bray-Curtis dissimilarity based principal coordinate analysis (PCoA) plots and analysis of similarities (ANOSIM) test showed obvious separations between the L2 group and C group, between the HFD group and C group, and between the L2 and HFD groups. At the phylum level, Firmicutes and ratio of Firmicutes and Bacteroidetes (F/B ratio) were increased in the L2 group; Bacteroidetes was decreased in the L2 and HFD groups. No significant differences in bacterial abundance between the C group and L1 group were observed at the phylum level. Based on linear discriminant analysis (LDA) effect size (LEfSe) analysis, the bacterial genera (the relative abundance > 0.1%, LDA > 3, p < 0.05) were selected as candidate bacterial signatures. They showed that the abundance of Vibrio was significantly increased in the L1 group; Bacteroides and Phascolarctobacterium were enriched in the HFD group, and Bacteroides, Phascolarctobacterium, Blautia, Parabacteroides, Akkermansia [Ruminococcus]_torques_group, and Anaerotruncus were enriched in the L2 group. CONCLUSION: The effect of letrozole on intestinal flora was not significant as HFD. HFD could destroy the balance of intestinal flora and aggravate the intestinal flora dysbiosis in PCOS. Letrozole-induced rats fed with HFD have many characteristics like human PCOS, including some metabolic disorders and intestinal flora dysbiosis. The dysbiosis was characterized by an increased Firmicutes/Bacteroidetes ratio, an expansion of Firmicutes, a contraction of Bacteroidetes, and the decreased microbial richness. Beta-diversity also showed significant differences in intestinal microflora, compared with control rats.

Pulmonary Lymphomatoid Granulomatosis With Hemophagocytic Lymphohistiocytosis as the Initial Manifestation.

Lymphomatoid granulomatosis (LYG) is an extremely rare angio-centric and angio-destructive B-cell lymphoproliferative disease. Driven by Epstein-Barr virus (EBV), LYG predominantly involves the bilateral lungs. Commonly presenting as multiple nodules in the lung, pulmonary LYG can masquerade as various infectious diseases, vasculitis, lung cancer, or other metastatic neoplasm. It is difficult to be diagnosed and is always neglected by clinicians. No standardized therapeutic regimens for LYG has been established yet now. Hemophagocytic lymphohistiocytosis (HLH), a life-threatening condition caused by abnormal activation of macrophages and T-cells, is characterized by fever, hepatosplenomegaly, pancytopenia, hypercytokinemia, and the presence of hemophagocytosis within the bone marrow, liver, spleen, or other lymphatic tissue. We herein report a 55-year-old man with recurrent fever, severe jaundice, and multiple high-density opacities and nodules in both lungs, who was finally diagnosed with pulmonary LYG (Grade 3) manifested with secondary HLH. Administration of HLH-1994 protocol led to the rapid control of the symptoms caused by HLH. Rituximab-based combination therapy was useful yet LYG (Grade 3) progressed rapidly. This case demonstrates that tissue biopsy is essential for early pathological diagnosis and effective treatment of LYG.

BRD4 inhibitor nitroxoline enhances the sensitivity of multiple myeloma cells to bortezomib in vitro and in vivo by promoting mitochondrial pathway-mediated cell apoptosis.

BACKGROUND: Multiple myeloma (MM) is the second most common hematological neoplasm. Wide administration of bortezomib significantly improves the survival of MM patients compared with conventional chemotherapy. Bromodomain-containing protein 4 (BRD4) inhibitors also have been demonstrated to retard cell proliferation and induce cellular apoptosis in various cancers. However, it is unclear whether the BRD4 inhibitor nitroxoline plus bortezomib has a synergistic anti-tumor effect on MM. METHODS: Cell viability was determined via 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle and cell apoptosis were assessed via flow cytometry. Protein expression levels were determined via western blotting. The expression of apoptosis-related proteins in xenograft tissue were detected by means of immunohistochemistry. RESULTS: Treatment with nitroxoline or bortezomib suppressed cell proliferation, and caused G0/G1 phase arrest and apoptosis in H929 and RPMI8226 cells. Furthermore, nitroxoline intensified the retardation of cell proliferation, as well as further enhanced the G0/G1 phase arrest and apoptosis induced by bortezomib in H929 and RPMI8226 cells. The western blot analysis revealed that nitroxoline or bortezomib treatment markedly diminished the levels of Bcl-2 and cyclin D1, and increased the levels of p21, Bax, cleaved PARP and cleaved caspase-3. Combination of these two agents was observed to result in further marked changes on these levels compared with nitroxoline or bortezomib treatment alone. What is more, in the xenograft tumor model, combinative treatment markedly inhibited tumor growth compared with the single drug treatment. CONCLUSION: Combination of bortezomib with nitroxoline has a synergistic anti-tumor activity in MM cells and may be a novel treatment method for MM.

Primary lymphoma of bone: a population-based study of 2558 patients.

BACKGROUND: Primary lymphoma of bone (PLB) is an extremely rare malignancy arising in the skeletal system. There is no consensus over the best definition of PLB. Most of the published articles are single-institutional retrospective studies with a limited sample size. The rarity of PLB and discrepancies on diagnostic criteria has resulted in a vague understanding of PLB. METHODS: We retrospectively analyzed the clinical characteristics and prognostic factors of 2558 PLB patients who were registered in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2016. Survival rates were calculated using the Kaplan-Meier method. The effects of various factors on survival outcomes were analyzed by using the log-rank test. Univariate and multivariate analyses were conducted by using the Cox proportional hazards model to determine independent prognostic factors. RESULTS: The median follow-up time of all eligible patients was 58 months. There seemed no sex preponderance in PLB incidence. The most involved sites are axial skeletons. The most common histological subtype was diffuse large B-cell lymphoma. The 3-, 5-, 10-, and 20-year overall survival (OS) rates were 70.70%, 65.70%, 54.40% and 39.50%, respectively. PLB patients whose primary tumor sites were appendicular and craniofacial skeletons had a significant survival advantage [hazard ratio (HR) = 0.694, 95% confidence interval (CI) 0.552-0.872; HR = 0.729, 95% CI 0.597-0.889, respectively] over those with axial skeletons as primary tumor sites. Patients with Hodgkin lymphoma, non-Hodgkin lymphoma (NHL)-mature B-cell lymphoma, and NHL-precursor-cell lymphoblastic lymphoma also had a significant OS advantage (HR = 0.392, 95% CI 0.200-0.771; HR = 0.826, 95% CI 0.700-0.973; and HR = 0.453, 95% CI 0.223-0.923, respectively). Patients with Ann Arbor stage III-IV at diagnosis were at higher risk of death than those with stage I-II (HR = 1.348, 95% CI 1.107-1.641). Chemotherapy was an independent favorable prognostic factor (HR = 0.734, 95% CI 0.605-0.890). CONCLUSIONS: Primary anatomic site, histology type, higher Ann Arbor stage and chemotherapy were independent prognostic factors. Chemotherapy played a pivotal role in PLB treatment.

[Detection of tissue protein biomarkers by surface enhanced laser desorption/ionization-time of flight-mass spectrometry in patients with mycosis fungoides].

OBJECTIVE: To search the tissue biomarker in mycosis fungoides (MF) patients by surface enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS). METHODS: Skin specimens were collected from 12 MF patients and 15 normal controls to prepare solution of protein. CM10 Proteinchip was used to detect the biomarkers for MF. Differentially expressed protein was identified by immuno capturing. RESULTS: The expression intensity levels of 24 proteins were different between the MF patients and controls. By searching in SWISS-PRO database and literature, the 3498 and 10 837 peaks were found to accord with HNP3 and S100A8 proteins respectively. By immuno capturing, 10 837 could be identified as S100A8 with a special antibody against S100A8. CONCLUSION: A quick, easy, and high throughout proteome analytic method, SELDI-TOF-MS can identify the differential expressed proteins from MF tissue, thus offering a unique platform for biomarker detection of MF.

[Study for drug-resistance of epithelial ovarian cancer by serum protein profiling].

OBJECTIVE: To develop the rationales for ovarian cancer-specific protein profiles in serum and to analyze the protein profiles of multidrug resistance P-glucoprotein (MDR1) and multidrug resistance-associated protein (MRP) positive and negative expression sets for a rapid and sensitive serum protein pattern. METHOD: Serum protein profiles from 36 epithelial ovarian cancer cases were compared with 30 healthy controls using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (DELDI-TOF-MS). Blinded test was conducted subsequently for identification of the protein pattern. Expression of MDR and MRP were detected in set of training cases by immunohistochemistry. The spectra were analyzed statistically between positive and negative groups. RESULTS: Twenty-nine peaks were significantly different between ovarian cancer and healthy controls (P < 0.01, 15 peaks up-regulated and 14 down-regulated). A set of three peaks, at 5 486, 6 463 and 8 575 m/z respectively, were selected from 29 sense peaks as an ovarian cancer biomarker. The sensitivity was 100% and specificity 93.33%. Identification by blinded validation indicated a positive predictive value of 90%. MDR1 expression in ovarian cancer was 69.4 %. Twenty peaks were significantly different between positive and negative sets (P < 0.01). MRP expression in ovarian cancer was 63.8%. But one peak was detected (P < 0.01). CONCLUSION: It was an ideal pattern for employing the SELDI mass spectrum approach to diagnose ovarian cancer and select the multidrug resistance cases. Serum biomarkers for detecting drug resistance in ovarian cancer can be established on the basis of MDR1 immunohistochemistry.

[Establishment of endometriosis diagnostic model using plasma protein profiling].

OBJECTIVE: To establish the diagnostic model for endometriosis by screening the plasma biomarkers of endometriosis using surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS)coupled with bioinformatics. METHODS: Plasma samples from 36 patients with endometriosis (endometriosis group) matched with 35 patients with infertility or benign ovarian tumors (control group) before laparoscopy were collected at Peking Union Medical College Hospital from January to October 2007. Plasma protein profiling were detected using SELDI-TOF-MS and protein chip and peak intensities were compared between the two groups. Biomarker Discovery Software was used for data analysis and model was build by classification and regression tree software (CART), sensitivity and specificity of the diagnostic model were verified. RESULTS: There were 14 protein peaks abnormally expressed in endometriosis group compared with those of control group (P < 0.01). The diagnostic model composed of three protein peaks with the molecular weight of 3,956,000, 11,710,000 and 6,986,000 showed a sensitivity of 92% and specificity of 83%. In the blind test the model showed a sensitivity of 88% and specificity of 80%. CONCLUSIONS: SELDI-TOF-MS is a new approach for screening markers of endometriosis. Its clinical value deserves further investigation.

[Screening of serum protein biomarkers by surface-enhanced laser desorption and ionization with time-of-flight detection mass spectrometry in patients with mycosis fungoides].

OBJECTIVE: To screen serum biomarkers in patients with mycosis fungoides (MF) using surface-enhanced laser desorption and ionization with time-of-flight detection mass spectrometry (SELDI-TOF-MS) technique. METHODS: Serum was analyzed from 14 patients with MF and 17 controls using CM10 Protein-chip to capture serum proteins, followed by Biomarker Wizard software analysis. RESULTS: In all specimens, about 131 protein peaks could be detected when the relative molecular weight ranged from 0 to 50 000. When comparing the protein fingerprint between these two groups, 14 differentially expressed protein peaks were found. By searching SWISS-PRO database, we found 7 670Da peaks accord with C-C motif chemokine 22. CONCLUSION: SELDI-TOF-MS technique can be used for screening serum protein biomarkers in patients with MF.

Rituximab-based combination therapy in patients with Waldenström macroglobulinemia: a systematic review and meta-analysis.

BACKGROUND: To evaluate the efficacy and safety of rituximab-based combination therapy for Waldenström macroglobulinemia (WM), we conducted this meta-analysis by pooling the rates of overall response, major response, complete response, and grade ≥3 hematological adverse events. METHODS AND MATERIALS: We searched for relevant studies in the databases of PubMed, Web of Science, Embase, and the Cochrane Library. The qualitative assessment of all the included articles was conducted with reference to the Newcastle-Ottawa Scale. A random-effects model was selected to perform all pooled analyses. RESULTS: We identified altogether 22 studies with a total of 806 symptomatic WM patients enrolled. The pooled analysis indicated that the rituximab-based combination therapy achieved an overall response rate (ORR) of 84% (95% CI: 81%-87%), a major response rate (MRR) of 71% (95% CI: 66%-75%), and a complete response rate (CRR) of 7% (95% CI: 5%-10%). Rituximab plus conventional alkylating agents-containing chemotherapy (subgroup A) yielded an ORR of 86% (95% CI: 81%-89%), an MRR of 74% (95% CI: 69%-79%), and a CRR of 8% (95% CI: 4%-14%). Rituximab plus purine analog (subgroup B) resulted in an ORR of 85% (95% CI: 79%-89%), an MRR of 74% (95% CI: 66%-81%), and a CRR of 9% (95% CI: 4%-15%). Rituximab plus proteasome inhibitor (subgroup C) resulted in an ORR of 86% (95% CI: 81%-90%), an MRR of 68% (95% CI: 58%-77%), and a CRR of 7% (95% CI: 3%-11%). Rituximab plus immunomodulatory drug (subgroup D) attained relatively lower response rates, with an ORR of 67% (95% CI: 51%-81%), an MRR of 56% (95% CI: 27%-83%), and a CRR of 5% (95% CI: 1%-12%). Common grade ≥3 hematological adverse events consisted of neutropenia (33%, 95% CI: 17%-52%), thrombocytopenia (7%, 95% CI: 3%-11%), and anemia (5%, 95% CI: 3%-9%). CONCLUSION: Rituximab in combination with an alkylating agent, purine analog, or proteasome inhibitor is highly effective with tolerable hematological toxicities for WM.

Proteiomic patterns for endometrial cancer using SELDI-TOF-MS.

Serum samples from endometrial cancer (EC) patients and healthy females were analyzed using surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF-MS) to discover the potential diagnostic biomarker for detection of EC. A preliminary training set of spectra derived from 40 EC patients and 30 healthy women were used to develop a proteomic model that effectively discriminated cancer patients from healthy women. The training set had a specificity of 100% and sensitivity of 92.5% in the EC detection. A blind test set, including 20 new cancer cases and 10 healthy women, was used to validate the sensitivity and specificity of this multivariate model, which had a corresponding results of 60% in specificity and 75% in sensitivity, respectively. The combination of SELDI-TOF-MS with bioinformatics tools could help find new biomarkers and establish the detection of EC with high sensitivity and specificity.

An insight into new strategies to combat antifungal drug resistance.

Invasive fungal infections especially in immunocompromised patients represent a dominating cause of mortality. The most commonly used antifungal agents can be divided into three broad categories, including triazoles, echinocandins and polyenes. Antifungal resistance is on the increase, posing a growing threat to the stewardship of immunocompromised patients with fungal infections. The paucity of currently available antifungals leads to the rapid emergence of drug resistance and thus aggravates the refractoriness of invasive fungal infections. Therefore, deep exploration into mechanisms of drug resistance and search for new antifungal targets are required. This review highlights the therapeutic strategies targeting Hsp90, calcineurin, trehalose biosynthesis and sphingolipids biosynthesis, in an attempt to provide clinical evidence for overcoming drug resistance and to form the rationale for combination therapy of conventional antifungals and agents with novel mechanisms of action. What's more, this review also gives a concise introduction of three new-fashioned antifungals, including carboxymethyl chitosan, silver nanoparticles and chromogranin A-N46.