Screening and characterisation of a novel efficient tumour cell-targeting peptide derived from insulin-like growth factor binding proteins.

Targeted delivery of antitumor drugs is particularly important in tumour treatment. Tumour-targeted peptide is a very effective drug carrier for tumour therapy. Here, we screened and characterised a highly efficient targeted peptide named IHP5, which was derived from insulin-like growth factor binding proteins (IGFBPs). IHP5 exhibited preferential binding to the tested tumour cell lines. The delivery efficiency of IHP5 was higher in various tested tumour cells than in normal cells, especially in the human cervical cancer cell line HeLa, which was 11.7-fold higher than in normal human embryonic kidney cells HEK293. Moreover, the penetration efficiency of IHP5 was 13 times higher than that of the classical cell penetrating peptide TAT in HeLa cells. Detail analysis revealed that IHP5 endocytosis was possibly correlated with acetylated heparan sulphate proteoglycans including phosphatidylinositol proteoglycan 3 (GPC3), phosphatidylinositol proteoglycan 5 (GPC5) and syndecan 2 (SDC2). Subsequently, the introduction of IHP5 enhanced the inhibitory effect of trichosanthin (TCS) on tumour cells, resulting in at least 19-fold increase in tumour cells without enhanced cytotoxicity in normal cells HEK293. These results suggested that IHP5, as a novel tumour cell-targeting penetrating peptide with the ability to target tumour cells, has great potential in drug delivery applications.

A systematic review of artificial intelligence chatbots for promoting physical activity, healthy diet, and weight loss.

BACKGROUND: This systematic review aimed to evaluate AI chatbot characteristics, functions, and core conversational capacities and investigate whether AI chatbot interventions were effective in changing physical activity, healthy eating, weight management behaviors, and other related health outcomes. METHODS: In collaboration with a medical librarian, six electronic bibliographic databases (PubMed, EMBASE, ACM Digital Library, Web of Science, PsycINFO, and IEEE) were searched to identify relevant studies. Only randomized controlled trials or quasi-experimental studies were included. Studies were screened by two independent reviewers, and any discrepancy was resolved by a third reviewer. The National Institutes of Health quality assessment tools were used to assess risk of bias in individual studies. We applied the AI Chatbot Behavior Change Model to characterize components of chatbot interventions, including chatbot characteristics, persuasive and relational capacity, and evaluation of outcomes. RESULTS: The database search retrieved 1692 citations, and 9 studies met the inclusion criteria. Of the 9 studies, 4 were randomized controlled trials and 5 were quasi-experimental studies. Five out of the seven studies suggest chatbot interventions are promising strategies in increasing physical activity. In contrast, the number of studies focusing on changing diet and weight status was limited. Outcome assessments, however, were reported inconsistently across the studies. Eighty-nine and thirty-three percent of the studies specified a name and gender (i.e., woman) of the chatbot, respectively. Over half (56%) of the studies used a constrained chatbot (i.e., rule-based), while the remaining studies used unconstrained chatbots that resemble human-to-human communication. CONCLUSION: Chatbots may improve physical activity, but we were not able to make definitive conclusions regarding the efficacy of chatbot interventions on physical activity, diet, and weight management/loss. Application of AI chatbots is an emerging field of research in lifestyle modification programs and is expected to grow exponentially. Thus, standardization of designing and reporting chatbot interventions is warranted in the near future. SYSTEMATIC REVIEW REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO): CRD42020216761 .

Inhibition of tau aggregation and associated cytotoxicity on neuron-like cells by calycosin.

In this study, the in vitro assembly of tau and anti-amyloidogenic properties of one naturally occurring phytoestrogen, calycosin, was investigated by spectroscopic techniques including ThT and ANS fluorescence, CD, Congo red absorbance as well as TEM analysis. Afterwards the cytotoxicity of different amyloid species against SH-SY5Y cells was evaluated by MTT assay. Fluorescence spectroscopic studies revealed that calycosin exerts its anti-amyloidogenic effects through increasing the lag time and reducing the apparent growth rate constant (kapp), the amount of fibrillation, and the exposure of hydrophobic regions. Congo red absorbance and CD studies indicated that calycosin prevented the formation of tau aggregate species and ß-sheets structures, respectively. TEM analysis also determined the capacity of calycosin to inhibit tau fibrillogenesis through formation of large amorphous aggregates. Furthermore, cellular assays disclosed that calycosin mitigated the cell mortality, LDH release, ROS level, and expression of Bax, Bcl-2, and Caspase-3 in both mRNA and protein levels induced by tau amyloid fibrils. In conclusion, this data may suggest that calycosin can prevent tau amyloid fibrillation and the associated cytotoxicity, mainly due to its effects on formation of lower content of oligomeric and fibrillar aggregates with lower solvent-exposed hydrophobic patches compared to those produced in the absence of calycosin.

Changes in the Spectrum of Kidney Diseases: An Analysis of 40,759 Biopsy-Proven Cases from 2003 to 2014 in China.

OBJECTIVES: To evaluate the changing spectrum of kidney diseases over time in China using renal biopsy-proven cases. METHODS: All patients over the age of 14 years who were diagnosed with a kidney disease by renal biopsy in the Renal Biopsy Registry of the National Clinical Research Center of Kidney Diseases in Jinling Hospital, Nanjing, from 2003 to 2014 were included. RESULTS: In total, 40,759 cases of renal biopsy were analyzed. The mean age of the patients was 36.59 ± 14.12 years. 52.0$ of the patients were male. Primary glomerulonephritis (PGN), secondary glomerulonephritis, tubulointerstitial disease, and hereditary renal diseases accounted for 67.1, 26.4, 2.9, and 2.5$, respectively. IgA nephropathy (IgAN), membranous nephropathy (MN), minimal change disease, and focal segmental glomerulosclerosis were the leading PGN diagnoses. The frequency of MN increased significantly (p < 0.001) by doubling from 2003 to 2014. An analysis by age category indicated that the frequency of MN increased significantly over time (p < 0.001) in all age categories and increased by more than 2 times in the 14-24 age category. Lupus nephritis (LN) and Henoch-Schönlein purpura nephritis (HSPN) decreased significantly (p < 0.001), diabetic nephropathy (DN) increased nearly twice (p < 0.001), monoclonal immunoglobulin deposition disease (MIDD) tripled (p < 0.001), and hypertensive nephropathy (HT) (p < 0.001) and renal amyloidosis (AMY) (p < 0.05) showed an upward trend. An analysis by age category showed that hepatitis B-related nephritis has significantly decreased in the 14-24 age category (p < 0.001). CONCLUSION: PGN continued to be the predominant kidney disease in China with IgAN being the most common PGN. The frequency of MN increased significantly, with a maximum increase in young adults. LN and HSPN decreased significantly, DN and MIDD increased significantly, and HT and AMY also showed an increasing trend. The kidney disease trends presented in this study serve as a reference point for patient care, disease prevention, and public health interventions.

The association of early life socioeconomic position on breast cancer incidence and mortality: a systematic review.

OBJECTIVES: We conducted a systematic review of the literature relating early life socioeconomic position (SEP) to breast cancer incidence and mortality from a critical period and life-course trajectory perspective. METHODS: PubMed, EMBASE and Web of Science were searched to identify cohort studies that evaluated the impact of early life SEP indicators on the incidence and/or mortality from breast cancer in adulthood. RESULTS: Nine distinct studies evaluated the relationship between early life SEP and breast cancer between 1990 and 2016. Five reports assessed breast cancer incidence and five assessed breast cancer mortality as outcomes; one study assessed both incidence and mortality. While lower early life SEP was associated with reduced breast cancer incidence and increased breast cancer mortality in the US, studies conducted in Europe were unable to establish a consistent association. CONCLUSIONS: We found moderate support for the association between early life SEP and incidence and mortality from breast cancer. The impact of early life SEP on breast cancer incidence and mortality appeared to vary between countries. We urge further investigation of the role of lifelong SEP trajectories in breast cancer outcomes.

Treatment and clinicopathological characteristics of lupus nephritis with anti-neutrophil cytoplasmic antibody positivity: a case-control study.

OBJECTIVE: To assess the clinical features, pathological presentations, treatments and outcomes of lupus nephritis (LN) with anti-neutrophil cytoplasmic antibody (ANCA) positivity. DESIGN: A case-control study. METHODS: Patients (n=49) were retrospectively included from Jinling Hospital in China if presenting with biopsy-proven ANCA-positive LN between 1985 and 2008. Clinicopathological characteristics and outcomes were analysed and compared with those of a control group (n=1279). We further compared treatment responses and outcomes of ANCA-positive LN patients based on the treatment issued. RESULTS: The study included 40 women and 9 men (median age 33 years at biopsy): 38 with myeloperoxidase (MPO)-ANCA, 7 with proteinase 3 (PR3)-ANCA and 4 with double positivity. ANCA-positive LN patients exhibited higher haematuria, serum creatinine levels and systemic lupus erythematosus disease activity index scores. On pathological evaluation, class IV LN was predominant, accounting for 61.22% of cases. Light microscopy revealed significantly higher activity index and chronicity index scores, including cellular crescents, interstitial inflammation, tubular atrophy and interstitial fibrosis. ANCA-positive LN patients receiving mycophenolate mofetil as induction therapy had a higher remission rate and better renal outcomes than those receiving cyclophosphamide. During follow-up, end-stage renal disease developed in seven (14.29%) ANCA-positive LN patients, all of them were MPO-ANCA positive. CONCLUSIONS: The characteristics of ANCA-positive LN were massive haematuria and advanced renal insufficiency. We observed a higher remission rate and better prognoses when using mycophenolate mofetil than when using cyclophosphamide as induction therapy.

Mycophenolate Mofetil Combined With Prednisone Versus Full-Dose Prednisone in IgA Nephropathy With Active Proliferative Lesions: A Randomized Controlled Trial.

BACKGROUND: Observational studies suggest that patients with immunoglobulin A nephropathy (IgAN) with active proliferative lesions show a good response to immunosuppressive treatment. STUDY DESIGN: Multicenter, prospective, randomized, controlled trial. SETTING & PARTICIPANTS: 176 patients with IgAN with active proliferative lesions (cellular and fibrocellular crescents, endocapillary hypercellularity, or necrosis), proteinuria with protein excretion ≥ 1.0g/24h, and estimated glomerular filtration rate > 30mL/min/1.73m2. INTERVENTION: Mycophenolate mofetil (MMF) group: MMF, 1.5g/d, for 6 months and prednisone, 0.4 to 0.6mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months; prednisone group: prednisone, 0.8 to 1.0mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months. All patients were followed up for another 6 months. OUTCOMES: The primary end point was complete remission rate at 6 and 12 months. RESULTS: At baseline, median estimated glomerular filtration rates were 90.2 and 94.3mL/min/1.73m2 and mean proteinuria was protein excretion of 2.37 and 2.47g/24h in the MMF and prednisone groups, respectively. At 6 months, complete remission rates were 37% (32 of 86 patients) and 38% (33 of 88 patients); the between-group difference was not statistically significant (P=0.9). At 12 months, complete remission rates were 48% (35 of 73 patients) and 53% (38 of 72 patients) in the MMF and prednisone groups, respectively; the between-group difference was not statistically significant (P=0.6). Incidences of Cushing syndrome and newly diagnosed diabetes mellitus were lower in the MMF group than in the prednisone group. LIMITATIONS: Not all participants were treated with renin-angiotensin system blockers, relatively short follow-up. CONCLUSIONS: MMF plus prednisone versus full-dose prednisone did not differ in reducing proteinuria, but patients treated with the former had fewer adverse events in patients with IgAN with active proliferative lesions.

Primary care providers' cancer genetic testing-related knowledge, attitudes, and communication behaviors: A systematic review and research agenda.

BACKGROUND: Primary care providers (PCPs) can play a critical role in helping patients receive the preventive health benefits of cancer genetic risk information. Thus, the objective of this systematic review was to identify studies of US PCPs' knowledge, attitudes, and communication-related behaviors regarding genetic tests that could inform risk-stratification approaches for breast, colorectal, and prostate cancer screening in order to describe current findings and research gaps. METHODS: We conducted a systematic search of six electronic databases to identify peer-reviewed empirical articles relating to US PCPs and genetic testing for breast, colorectal, or prostate cancer published in English from 2008 to 2016. We reviewed these data and used narrative synthesis methods to integrate findings into a descriptive summary and identify research needs. RESULTS: We identified 27 relevant articles. Most focused on genetic testing for breast cancer (23/27) and colorectal cancer risk (12/27); only one study examined testing for prostate cancer risk. Most articles addressed descriptive research questions (24/27). Many studies (24/27) documented PCPs' knowledge, often concluding that providers' knowledge was incomplete. Studies commonly (11/27) examined PCPs' attitudes. Across studies, PCPs expressed some concerns about ethical, legal, and social implications of testing. Attitudes about the utility of clinical genetic testing, including for targeted cancer screening, were generally favorable; PCPs were more skeptical of direct-to-consumer testing. Relatively fewer studies (9/27) examined PCPs' communication practices regarding cancer genetic testing. DISCUSSION: This review indicates a need for investigators to move beyond descriptive research questions related to PCPs' knowledge and attitudes about cancer genetic testing. Research is needed to address important gaps regarding the development, testing, and implementation of innovative interventions and educational programs that can improve PCPs' genetic testing knowledge, assuage concerns about the appropriateness of cancer genetic testing, and promote open and effective patient-provider communication about genetic risk and genetic testing.

Expressions and clinical significance of autophagy-related markers Beclin1, LC3, and EGFR in human cervical squamous cell carcinoma.

PURPOSE: We aimed to investigate the expression of EGFR and the autophagy-related markers Beclin1 and LC3 in cervical cancer. METHODS: Beclin1, LC3, and EGFR expression were analyzed in 80 samples of cervical squamous cell carcinoma (SCC), 40 samples of high-grade cervical intraepithelial neoplasia (CIN), and 40 samples of normal cervical tissues by immunohistochemistry. The protein expression rates were analyzed with χ (2) and Fisher's exact tests. Differences in overall survival (OS) were determined using the Kaplan-Meier method and log-rank tests. RESULTS: Cervical cancer, high-grade CIN, and normal cervical epithelial cells expressed Beclin1 in 26.2%, 77.5%, and 82.5% of patients, respectively, and expressed LC3 in 28.8%, 70.0%, and 75.0% of patients, respectively. There was a significant difference between cervical SCC and high-grade CIN or normal cervical epithelial cells (P=0.000). Cervical cancer cells, high-grade CIN cells, and normal cervical epithelial cells expressed EGFR in 68.8%, 62.5%, and 12.5% of patients, respectively. There was a significant difference between cervical SCC or high-grade CIN and normal cervical epithelial cells (P=0.000). No significant association between Beclin1 or LC3 or EGFR expression and various clinicopathological parameters was observed in cervical SCC. There was no significant correlation between Beclin1, LC3, EGFR expression, and 5-year OS rates of cervical SCC patients. Beclin1- or LC3-negativity with EGFR-positivity in cervical SCC was associated with a higher Federation International of Gynecology and Obstetrics (FIGO) stage (P=0.011 and P=0.013, respectively) and pelvic lymph node metastasis (P=0.036 and P=0.092, respectively). The 5-year OS rates did not significantly differ between Beclin1- or LC3-positive and -negative patients with positive EGFR. CONCLUSION: Autophagy was downregulated and EGFR was upregulated in cervical SCC. Autophagy downregulation combined with EGFR upregulation promotes the progression of cervical SCC.

Reversal of active glomerular lesions after immunosuppressive therapy in patients with IgA nephropathy: a repeat-biopsy based observation.

BACKGROUND: Reversal of active glomerular lesions after immunosuppressive treatment in patients with IgA nephropathy (IgAN) and their association with prognosis have not been well established. METHODS: Sixty patients with IgAN who received repeat biopsies after immunosuppressive treatment were recruited. Reversal of renal pathological lesions was evaluated between the first and second biopsy. The end-point was defined as a 30% reduction in estimated glomerular filtration rate (eGFR) or end-stage renal disease after the second biopsy. RESULTS: Active glomerular lesions, i.e. endocapillary hypercellularity (E), crescents (C) and necrosis (N) were markedly decreased at the second biopsy after immunosuppressive therapy (36.7 vs. 8.3%, p < 0.001; 85.0 vs. 25.0%, p < 0.001; and 51.7 vs. 3.3%, p < 0.001). Patients with E, C or N at the first biopsy but reversed at the second biopsy showed significantly decreased median levels of proteinuria and hematuria. Such clinical changes were not observed in those with active lesions at both biopsies. After a median follow-up of 32 months, 25.0% of patients reached the end-point. Repeat biopsy confirmed that only tubular atrophy/interstitial fibrosis was associated with the renal outcome. CONCLUSIONS: Active glomerular lesions can be reversed by immunosuppressive treatment in patients with IgAN. The reversal is accompanied by improvement in proteinuria and hematuria. The reversal of these lesions during the disease process may explain the lack of significant correlation of these lesions with clinical outcomes in the present study as well as in previous evaluation studies of the Oxford classification of IgAN.

Importance of glycolysis and oxidative phosphorylation in advanced melanoma.

Serum lactate dehydrogenase (LDH) is a prognostic factor for patients with stage IV melanoma. To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma. Our data demonstrate that high serum LDH is associated with a significant increase in LDH isoenzymes 3 and 4, and a decrease in LDH isoenzymes 1 and 2. Since LDH isoenzymes play a role in both glycolysis and oxidative phosphorylation (OXPHOS), we subsequently determined using tissue microarray (TMA) analysis that the levels of proteins associated with mitochondrial function, lactate metabolism, and regulators of glycolysis were all elevated in advanced melanomas compared with nevic melanocytes. To investigate whether in advanced melanoma, the glycolysis and OXPHOS pathways might be linked, we determined expression of the monocarboxylate transporters (MCT) 1 and 4. Analysis of a nevus-to-melanoma progression TMA revealed that MCT4, and to a lesser extend MCT1, were elevated with progression to advanced melanoma. Further analysis of human melanoma specimens using the Seahorse XF24 extracellular flux analyzer indicated that metastatic melanoma tumors derived a large fraction of energy from OXPHOS. Taken together, these findings suggest that in stage IV melanomas with normal serum LDH, glycolysis and OXPHOS may provide metabolic symbiosis within the same tumor, whereas in stage IV melanomas with high serum LDH glycolysis is the principle source of energy.

A rare presentation of conjunctival myxoma with pain and redness: case report and literature review.

BACKGROUND: Conjunctival myxoma is a type of rare, benign tumor of mesenchymal cells, with fewer than 30 reported cases in the English literature. It is mostly an isolated occurrence but can sometimes be associated with systemic diseases such as Carney complex or Zollinger-Ellison syndrome. It is necessary in clinical practice to differentiate it from other similar lesions, such as amelanotic nevus, lymphangioma, myxoid liposarcoma, spindle-cell lipoma, myxoid neurofibroma, and rhabdomyosarcoma. CASE PRESENTATION: The usual presentation of conjunctival myxoma is a translucent, well-circumscribed, and painless conjunctival mass, but in this report we discuss an unusual case of conjunctival myxoma in a 47-year-old Taiwanese woman who presented initially with pain and redness. This atypical presentation complicated the diagnosis and the management at first. Surgical excision of the mass was performed. The mass was found to be a conjunctival myxoma. The patient subsequently underwent extensive evaluation but was found not to have any systemic diseases with known association with conjunctival myxoma. CONCLUSIONS: In summary, we present a case of conjunctival myxoma in a 47-year-old Taiwanese woman. The initial presentation with pain and redness was atypical for conjunctival myxoma. The lesion was successfully managed with complete excisional biopsy.

Synergism between curdlan and GM-CSF confers a strong inflammatory signature to dendritic cells.

A simultaneous engagement of different pathogen recognition receptors provides a tailor-made adaptive immunity for an efficient defense against distinct pathogens. For example, cross-talk of TLR and C-type lectin signaling effectively shapes distinct gene expression patterns by integrating the signals at the level of NF-κB. In this study, we extend this principle to a strong synergism between the dectin-1 agonist curdlan and an inflammatory growth factor, GM-CSF. Both together act in synergy in inducing a strong inflammatory signature that converts immature dendritic cells (DCs) to potent effector DCs. A variety of cytokines (IL-1ß, IL-6, TNF-α, IL-2, and IL-12p70), costimulatory molecules (CD80, CD86, CD40, and CD70), chemokines (CXCL1, CXCL2, CXCL3, CCL12, CCL17), as well as receptors and molecules involved in fugal recognition and immunity such as Mincle, dectin-1, dectin-2, and pentraxin 3 are strongly upregulated in DC treated simultaneously with curdlan and GM-CSF. The synergistic effect of both stimuli resulted in strong IκBα phosphorylation, its rapid degradation, and enhanced nuclear translocation of all NF-κB subunits. We further identified MAPK ERK as one possible integration site of both signals, because its phosphorylation was clearly augmented when curdlan was coapplied with GM-CSF. Our data demonstrate that the immunomodulatory activity of curdlan requires an additional signal provided by GM-CSF to successfully initiate a robust ß-glucan-specific cytokine and chemokine response. The integration of both signals clearly prime and tailor a more effective innate and adaptive response against invading microbes and fungi.

GM-CSF signalling boosts dramatically IL-1 production.

GM-CSF is mostly known for its capacity to promote bone marrow progenitor differentiation, to mobilize and mature myeloid cells as well as to enhance host immune responses. However the molecular actions of GM-CSF are still poorly characterized. Here we describe a new surprising facet of this "old" growth factor as a key regulator involved in IL-1ß secretion. We found that IL-1ß release, a pivotal component of the triggered innate system, is heavily dependent on the signaling induced by GM-CSF in such an extent that in its absence IL-1ß is only weakly secreted. GM-CSF synergizes with LPS for IL-1ß secretion mainly at the level of pro-IL-1ß production via strengthening the NF-κB signaling. In addition, we show that expression of Rab39a, a GTPase required for caspase-1 dependent IL-1ß secretion is greatly augmented by LPS and GM-CSF co-stimulation suggesting a potential GM-CSF contribution in enhancing IL-1ß exocytosis. The role of GM-CSF in regulating IL-1ß secretion is extended also in vivo, since GM-CSF R-/- mice are more resistant to LPS-mediated septic shock. These results identify GM-CSF as a key regulator of IL-1ß production and indicate GM-CSF as a previously underestimated target for therapeutic intervention.

Soluble Fas ligand is another good diagnostic marker for tuberculous pleurisy.

Soluble Fas ligand (sFasL) is abundant in effusions of tuberculous (TB) pleurisy; however, its diagnostic value has not been scrutinized. We collected pleural effusions from 79 patients, including 23 with TB pleurisy and 56 without TB, and measured sFasL, adenosine deaminase (ADA), and interferon-γ (IFN-γ) concentrations of each specimen. The median of the sFasL concentration of the TB group was 57.3 pg/mL, which was significantly higher than that of the non-TB group (27.4 pg/mL) (P < 0.001). When cutoff value was 39.85 pg/mL, the sensitivity and specificity of sFasL were 95.7% and 80.4%, respectively. The area under the receiver operating characteristic curve for sFasL was not significantly different from those of ADA and IFN-γ. Soluble FasL concentrations of TB patients were significantly higher than those of parapneumonic effusion subgroup (P = 0.039). In conclusion, pleural effusion sFasL is another good diagnostic marker for TB pleurisy.

Cutting edge: granulocyte-macrophage colony-stimulating factor is the major CD8+ T cell-derived licensing factor for dendritic cell activation.

During priming, CD8(+) T lymphocytes can induce robust maturation of dendritic cells (DCs) in a CD40-independent manner by secreting licensing factor(s). In this study, we isolate this so-far elusive licensing factor and identify it, surprisingly, as GM-CSF. This provides a new face for an old factor with a well-known supporting role in DC development and recruitment. Signaling through the GM-CSFR in ex vivo-purified DCs upregulated the expression of costimulatory molecules more efficiently than did any tested TLR agonist and provided a positive feedback loop in the stimulation of CD8(+) T cell proliferation. Combined with a variety of microbial stimuli, GM-CSF supports the formation of potent "effector" DCs capable of secreting a variety of proinflammatory cytokines that guide the differentiation of T cells during the immune response.

Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis.

The mammalian brain exhibits diverse types of neural plasticity, including activity-dependent neurogenesis in the adult hippocampus. How transient activation of mature neurons leads to long-lasting modulation of adult neurogenesis is unknown. Here we identify Gadd45b as a neural activity-induced immediate early gene in mature hippocampal neurons. Mice with Gadd45b deletion exhibit specific deficits in neural activity-induced proliferation of neural progenitors and dendritic growth of newborn neurons in the adult hippocampus. Mechanistically, Gadd45b is required for activity-induced DNA demethylation of specific promoters and expression of corresponding genes critical for adult neurogenesis, including brain-derived neurotrophic factor and fibroblast growth factor. Thus, Gadd45b links neuronal circuit activity to epigenetic DNA modification and expression of secreted factors in mature neurons for extrinsic modulation of neurogenesis in the adult brain.

A randomized comparison of ovulation induction and hormone profile between the aromatase inhibitor anastrozole and clomiphene citrate in women with infertility.

BACKGROUND: IN the present study we evaluated and compared the effects of ovulation and hormonal dynamics induced by anastrozole and clomiphene citrate in women with infertility. MATERIALS AND METHODS: Thirty-three infertile patients, aged 25-41 years, were enrolled. Patients received either anastrozole 1 mg daily (AI group) or clomiphene citrate 100 mg daily (CC group) from cycle day 3 to day 7. Number of mature follicles (> or =18 mm), endometrial thickness, pregnancy rate and serial hormone profiles (follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E(2)), testosterone and progesterone) were measured on cycle day 3, day 8, day 10, the day of intrauterine insemination (IUI), day 7 after IUI and day 14 after IUI. RESULTS: Baseline parameters were similar in the two groups, including age, body mass index, infertility duration and day-3 serum hormones except FSH. The mean FSH value on day 3 was significantly different (4.3 mIU/ml in the AI group vs. 6.3 mIU/ml in the CC group; p < 0.05). The women receiving anastrozole had fewer ovulatory follicles (1.2 in the AI group vs. 1.8 in the CC group; p < 0.05) and a thicker endometrium (10.6 mm in the AI group vs. 7.8 mm in the CC group; p < 0.05). The levels of progesterone and testosterone were similar during ovulation stimulation cycles in both groups. On the other hand, the AI group had a significantly higher LH level but a significantly lower E(2) level in the stimulation cycle. CONCLUSION: Anastrozole has a high pregnancy rate, although it induces fewer ovulatory follicles compared with clomiphene citrate. The two drugs gave different responses of FSH, LH and E2 during stimulation cycles.

Microglia/macrophages responses to kainate-induced injury in the rat retina.

The present study was aimed to elucidate how retinal microglia/macrophages would respond to neuronal death after intravitreal kainate injection. An increased expression of the complement receptor type 3 (CR3) and an induction of the major histocompatibility complex (MHC) class II and ED-1 antigens were mainly observed in the inner retina after kainate injection. Prominent cell death revealed by Fluoro Jade B (FJB) staining and ultrastructural examination appeared at the inner border of the inner nuclear layer (INL) at 1 day post-injection. Interestingly, some immunoreactive cells appeared at the outer segment of photoreceptor layer (OSPRL) at different time intervals. Our quantitative analysis further showed that CR3 immunoreactivity was drastically increased peaking at 7 days but subsided thereafter. MHC class II and ED-1 immunoreactivities showed a moderate but steady increase peaking at 3 days and declined thereafter. Double labeling study further revealed that retinal microglia/macrophages expressed concurrently CR3 and ED-1 antigens (OX-42+/ED-1+) or MHC class II molecules (OX-42+/OX-6+) and remained branched in shape at early stage of kainate challenge. By electron microscopy, microglia/macrophages with CR3 immunoreactivity displayed abundant cytoplasm containing a few vesicles and phagosomes. Other cells ultrastructurally similar to Müller cells or astrocytes could also engulf exogenous substances. In conclusion, retinal microglia/macrophages responded vigorously to kainate-induced neuronal cell death that may also trigger the recruitment of macrophages from neighboring tissues and induce the phagocytotic activity of cells other than retinal microglia/macrophages.

Clinical study on treatment of primary hepatocellular carcinoma by Shenqi mixture combined with microwave coagulation.

OBJECTIVE: To observe the short-term efficacy and safety of Shenqi mixture (SQM) combined with microwave coagulation in treating primary hepatocellular carcinoma (HCC). METHODS: Seventy-two patients with primary HCC of stage II-III, Karnofsky scoring > or = 50 scores and predicted survival period > or = 3 months were selected and randomly assigned into two groups, the treated group and the control group, 36 in each. Microwave therapy was applied to both groups by double leads, 60 W, 800 sec once a week for two weeks. To the treated group, SQM was given additionally through oral intake of 20 ml, three times a day for 1 month. The changes in tumor size, main symptoms, serum level of alpha-fetoprotein (AFP), immune function and adverse reaction were observed after treatment and the immune parameters of the patients were compared with 30 healthy persons in the normal control group. RESULTS: (1) In the SQM treated group, after treatment 3 patients got completely remitted (CR), 24 partial remitted (PR), 4 unchanged (NC) and 5 progressively deteriorated (PD), the effective rate being 75.00%; while in the control group, 1 got CR, 19 PR, 9 NC and 7 PD, the effective rate being 55.56%. Comparison of the effective rate between the two groups showed significant difference (P < 0.05). (2) AFP level decreased after treatment in both groups, but the decrement in the treated group was significantly higher than that in the control group (P < 0.01). (3) After treatment, in the treated group, CD3(+), CD4(+), CD4(+)/CD8(+) and NK activity were improved, Karnofsky scores increased and liver function bettered, with these improvements significantly superior to those in the control group (P < 0.01). (4) The improvement in symptoms such as hepatic region pain, fever, weakness, poor appetite and jaundice in the treated group after treatment was also superior to that in the control group (P < 0.01). (5) The 12-month, 18-month and 24-month survival rates were higher and the recurrence rate was lower in the treated group than those in the control group, showing significant difference (P < 0.05). CONCLUSION: Combined therapy with SQM and microwave coagulation could not only kill the tumor and residue tumor cells to prevent recurrence, but also enhance the cellular immunity of organism. It is one of the effective therapies for patients with middle-advanced hepatocarcinoma, who have lost the chance of surgical operation. It could improve clinical symptoms, elevate the quality of life, prolong the survival period of patients, but shows no evident adverse reaction.