Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis.

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.

An intelligent "chemical tongue" for high-order monitoring ATP-related physiological phosphates and ATP hydrolysis through diverse transduction principles.

For discriminating diverse analytes and monitoring a specific chemical reaction, the emerging multi-channel "chemical nose/tongue" is challenging multi-material "chemical nose/tongue". The former contributes greatly to integrating different transduction principles from a single sensing material, avoiding the need for complex design, high cost, and tedious operation involved with the latter. Therefore, this high-order sensing puts a particular emphasis on the effects of encapsulation. Herein, the plasmonic gold nanoparticles (Au NPs) are encapsulated as a core into the fluorescent guanine monophosphate-Tb3+ infinite coordination polymer nanoparticles (GMP-Tb ICPs) to obtain a core-shell nanocomposite named Au NPs@GMP-Tb ICPs. Hence, a dual-channel "chemical tongue" based on Au NPs@GMP-Tb ICPs is present to realize high-order sensing of adenosine triphosphate (ATP)-related physiological phosphates and the monitoring of ATP hydrolysis. Considering the affinity of Tb3+ towards P-O bonds, four inorganic phosphates and three nucleotide phosphates with different phosphate group numbers and steric hindrance effect directly regulate two stimulus responses (fluorescence intensity and UV-vis absorbance) of Au NPs@GMP-Tb ICPs. Robust statistical methods, such as linear discriminant analysis and hierarchical cluster analysis, are used to recognize each phosphate by the developed sensor array either in the aqueous solution or in complex media such as serum, together with efficiently monitored ATP hydrolysis at different intervals. These findings and blind test clarify that the designed "chemical tongue" guarantees interference resistance and strengthens analytical capacity, together with offering valuable insight into "lab-on-a-nanoparticle" development for monitoring specific chemical reactions.

ZNRF2 as an oncogene is transcriptionally regulated by CREB1 in breast cancer models.

E3 ubiquitin ligase Zinc and Ring Finger 2 (ZNRF2) has been demonstrated to be engaged in the development of multiple cancers. Nevertheless, the function of ZNRF2 in breast cancer (BC) still unclear. In this work, we firstly analyzed the differentially expressed genes in BC by bioinformatics and found that ZNRF2 was highly expressed in BC. Consistently, we further confirmed that ZNRF2 was upregulated in BC tissues compared with adjacent normal tissues, and this was positively correlated with the poor prognosis and the higher pathological grades of patients with BC. Functional assays performed on HCC1937 and MCF-7 cells indicated that silencing of ZNRF2 suppressed cell proliferation, as evidenced by the decrease in the expression of cyclin A, PCNA and cyclin D1. Flow cytometry and Hoechst staining showed that knockdown of ZNRF2 induced cell apoptosis, which was verified by the upregulation of apoptosis genes such as Bax, cleaved PARP and Bim. ZNRF2 knockdown also inhibited in vivo tumor growth. But, instead, ZNRF2-overexpressed BC cells exhibited obvious malignant phenotypes. Additionally, we observed that cAMP response element binding protein 1 (CREB1) directly bound to the promoter sequence of ZNRF2 and thus activating its transcription, suggesting that ZNRF2 is transcriptionally regulated by CREB1. Additionally, ZNRF2 knockdown could reverse the proliferation-promoting action of CREB1 on BC cells, Hence, this study demonstrated that ZNRF2 might serve as a prospective therapeutic target for BC.

Role of synaptotagmin 13 (SYT13) in promoting breast cancer and signaling pathways.

PURPOSE: Breast cancer is one of the leading causes of tumor death worldwide in female, and the five-year overall survival of breast cancer patients remains poor. It is an urgent need to seek novel target for its treatment. Synaptotagmin 13 (SYT13) is a synaptic vesicle transporting protein that regulates the malignant phenotypes of various cancers. However, its role in breast cancer is still unclear. The current study aimed to investigate the effects of SYT13 on the progression of breast cancer. METHODS: Twenty-five pairs of breast cancer tissues and non-tumor tissues were obtained to assess the expression of SYT13. We manually modified the expression of SYT13 in MCF-7 and MDA-MB-231 cells. CCK-8 assay, EdU staining, and cell cycle analysis were carried out to measure the proliferated ability of cells. Annexin V/PI and TUNEL assays were used to detect the apoptotic ability of cells. Wound healing and transwell assays were employed to evaluate the migrated and invasive ability of breast cancer cells. RESULTS: The results revealed that the mRNA and protein levels of SYT13 were higher in breast cancer tissues and cell lines. Knockdown of SYT13 inhibited the cell proliferation and induced cell cycle arrest in G1 phase of MCF-7 cells by downregulating cyclin D1 and CDK4, as well as upregulating p21. The migration and invasion of MCF-7 cells were repressed by the loss of SYT13 via the gain of E-cadherin and the loss of vimentin. Overexpression of SYT13 in MDA-MB-231 cells led to the opposite effects. Silencing of SYT13 induced the apoptosis ability of MCF-7 cells by the upregulation of bax and the downregulation of bcl-2. Moreover, we found that SYT13 depletion suppressed the FAK/AKT signaling pathway. PF573228 (a FAK inhibitor) and MK2206 (an AKT inhibitor) reversed the SYT13 overexpression-induced promotion of proliferation, migration, and invasion of MDA-MB-231 cells. CONCLUSION: The results indicated that SYT13 promoted the malignant phenotypes of breast cancer cells by the activation of FAK/AKT signaling pathway.

[Study on the central mechanism of acupuncture for post-stroke spasticity based on the Na+/K+-ATPase-EAATs-Glu pathway].

OBJECTIVE: To observe the effect of acupuncture at "Yanglingquan" (GB34) and "Baihui" (GV20) on Na+/K+-ATPase, excitatory amino acid transporters (EAATs) and glutamate (Glu) in hippocampus of post-stroke spasticity rats, so as to explore the central mechanism in anti-spasticity. METHODS: In a total of 48 healthy SD rats, 12 rats were randomly selected to be included into sham operation group, and the remaining rats were used to make a middle cerebral artery occlusion (MCAO) model using a suture method. On the 3rd day after modeling, MCAO limb spasticity rats were screened by neurological deficit symptoms and muscle tension scores, and randomly divided into the model, GB34 (Hui-puncture at GB34) and GB34+GV20 (Hui-puncture at GB34 and horizontal insertion at GV20) groups (n=12 rats in each group), and the treatment was lasted for 7 conse-cutive days. The neurological symptoms and muscle tension score were observed with the Zea Longa score and modified Ashworth scale (MAS). The levels of Glu, EAAT1 (GLAST) and EAAT2 (GLT-1) in the ischemic area of cerebral hippocampus were detected by ELISA, the expression of Na+/K+-ATPase α1 (ATP1α1) was detected by Western blot, the expression of ATP1α1 mRNA was detected by real-time PCR, and the expression of GLAST, GLT-1 and ATP1α1 was detected by immunofluorescence. RESULTS: After modeling, Zea Longa score and MAS score were increased (P<0.01), the level of Glu in the ischemic area of cerebral hippocampus was increased (P<0.01), while the expression levels of GLAST, GLT-1, ATP1α1 protein and mRNA were all decreased (P<0.01) in the model group relevant to the sham operation group. After 7 days' treatment, all the increased and decreased levels of the indexes mentioned above were reversed in the two acupuncture groups relevant to the model group (P<0.01, P<0.05), and the effects of acupuncture at GB34+GV20 were obviously superior to that of acupuncture at GB34 (P<0.05, P<0.01). CONCLUSION: Acupuncture can alleviate post-stroke spasticity effectively, which may be related to its effect in up-regulating the expressions of Na+/K+-ATPase and EAATs in hippocampus. The anti-spastic effect of acupuncture at GB34+GV20 is superior to GB34 alone.

[Effect of different acupuncture and moxibustion methods on uterine contraction and microcirculation in cold congealing dysmenorrhea rats].

OBJECTIVE: To observe and compare the effects of different acupuncture and moxibustionmethods at "San-yinjiao" (SP6) on uterine contraction and microcirculation in cold congealing dysmenorrhea rats, so as to explore its mechanism underlying treatment of dysmenorrhea. METHODS: A total of 140 female SD rats were randomly divided into normal control, mo-del, perpendicular needling, transverse needling and moxibustion groups, with 28 rats in each group. The cold congealing dysme-norrhea rat model was prepared by exposure in a freezer (25 ℃) for 4 h, once daily for 5 days, and subcutaneous injection of estradiol benzoate (once daily for 10 days) and intra-abdominal injection of oxytocin (once). For rats in three intervention groups, acupuncture needles were inserted into bilateral SP6 perpendicularly or transversely to a depth of 4~5 mm and retained for 20 min, or moxibustion was applied to SP6 for 20 min. The uterine contraction degree and the uterine microcirculation were recorded. The expression levels of transient receptor potential vanilloid 1 (TRPV1) and heat shock protein 70 (HSP70) in local tissues of SP6 area were detected by immunohistochemistry. The expression levels of µopioid receptor and endothelin 1 (ET1) mRNA in the uterus were assessed by quantitative real time-PCR. RESULTS: After modeling and compared with the normal control group, the number and peak-to-peak values of uterine contraction waves, and uterine motility were significantly increased (P<0.01,P<0.05), while the speed of blood flow in the microvessels was slowed down (P<0.01), diameters of the uterine microvessels and capillaries (cap) shrank obviously (P<0.01) in the model group. After the intervention, all indexes of uterine contraction and microcirculation were improved in three intervention groups (P<0.01, P<0.05), while transverse needling and moxibustion showed better effects compared to perpendicular needling (P<0.05, P<0.01). The expression of TRPV1 and HSP70 in SP 6 area had no significant changes (P>0.05), while the uterine µopioid receptor mRNA expression decreased (P<0.01), and ET1 mRNA expression increased (P<0.01) in the model group relevant to the normal control group. Following the intervention, the expression levels of TRPV1 and HSP70 in SP6 area were increased (P<0.05, P<0.01), and expression levels of uterine µopioid receptor mRNA increased (P<0.05, P<0.01) and uterine ET1 mRNA decreased (P<0.05, P<0.01) in the three intervention groups. The effect of moxibustion was considerably better than those of two acupuncture groups in up-regulating TRPV1 expression (P<0.05). Both transverse needling and moxibustion showed better effects of down-regulating uterine ET1 mRNA expression than perpendicular needling (P<0.01). CONCLUSION: Transverse needling and moxibustion at SP6 have a better effect of relieving ute-rine contraction and improving uterine microcirculation than perpendicular needling, which may be related to their effects in up-re-gulating the expression of TRPV1 and HSP70 in SP6 area, thereby modulating the mRNA expression of µ opioid receptor and ET1 in uterine tissue.

Preoperative prediction of axillary lymph node metastasis in patients with breast cancer based on radiomics of gray-scale ultrasonography.

BACKGROUND: To investigate the performance of a radiomics model based on gray-scale ultrasonography (US) for the preoperative non-invasive prediction of ipsilateral axillary lymph node (ALN) metastasis in patients with breast cancer (BC). METHODS: A total of 192 pathologically confirmed BC patients were included in this study. The training set was comprised of 132 patients from hospital 1 and the test set was comprised of 60 patients from hospital 2. All patients underwent US before percutaneous core biopsy and the results of ALN status reported by a radiologist with 12 years of experience were recorded. Radiomic features were extracted from the gray-scale US images. Max-relevance and min-redundancy (MRMR) and least absolute shrinkage and selection operator (LASSO) were used for data dimension reduction and feature selection. A radiomics model was constructed using LASSO and was validated using the leave group out cross-validation (LGOCV) method. The performance of the model was validated with receiver operating characteristic (ROC), calibration curve, and decision curve analysis. RESULTS: A total of 860 features were extracted from the gray-scale US images of each breast lesion, and 9 radiomic features were selected for model construction. The area under the curve (AUC), sensitivity, and specificity of the model for predicting ALN metastasis were 0.85, 78.9%, and 77.3% in the training set and 0.65, 68.0%, and 79.4% in the test set, respectively. The prediction performance of the model was significantly higher than that of the radiologist (AUC: 0.85 vs. 0.59, P<0.01) in the training set and was slightly higher than that of the radiologist (AUC: 0.65 vs. 0.63, P>0.05) in the test set. CONCLUSIONS: The non-invasive radiomics model has the ability to predict ALN metastasis for patients with breast cancer and may outperform US-reported ALN status performed by the radiologist.

Can measuring perilesional tissue stiffness and stiff rim sign improve the diagnostic performance between benign and malignant breast lesions?

PURPOSE: To evaluate tissue stiffness values around breast lesions and stiff rim sign for the differentiation of benign and malignant lesions. METHODS: A total of 192 patients (mean age, 44.6 ± 13.6 years) with 199 breast lesions were included in this retrospective study. All lesions were pathologically proven by US-guided core needle biopsy (CNB), Mammotome biopsy, or surgery. We first observed the presence or absence of a stiff rim sign, which was defined as a red or orange halo around the breast lesion. The shell around the breast lesion on SWE was then automatically drawn by machine, with a width of 1 mm, 2 mm, and 3 mm. The elasticity moduli of the lesion and surrounding tissue were recorded, including maximum elasticity (Emax), mean elasticity (Emean), minimum elasticity (Emin), and elasticity ratio (shell/lesion ratio). The optimal thresholds of elasticity moduli were calculated according to the receiver operating characteristic (ROC) curve. RESULTS: There were 75 malignant lesions and 124 benign ones. The average Emax and Emean of lesions and shell were significantly higher in the malignant group than in the benign group (P < 0.05). The optimal cut-off value of Emax for diagnosing malignant lesions was 101.7 kPa, with a sensitivity of 66.3% and specificity of 87.9%. The optimal cut-off value of Emean was 29.1 kPa, with a sensitivity of 65.3% and specificity of 79.8%. The stiff rim sign had the highest diagnostic performance for malignancy as compared with other elastic parameters, with an accuracy of 88.4%. However, measuring peritumoral tissue stiffness can achieve relatively high sensitivity, whereas specificity was not improved significantly. CONCLUSIONS: The stiffness of tissue surrounding breast malignancies was significantly higher than the surrounding benign lesions. Stiff rim sign has the potential to improve the diagnostic performance of breast lesions.

Role of SOCS3 in enhanced acute-phase protein genes by neonatal macrophages in response to IL-6.

BACKGROUND: Interleukin 6 (IL-6) induce the inflammatory response directly related with the morbidity and mortality of neonatal. Here we aimed to explore the mechanism of IL-6 in neonatal inflammatory response by studying the IL-6/STAT3 signaling pathway. METHODS: Cord blood samples from health term neonatal and peripheral venous blood from health volunteers were collected. The monocytes of adults and cord blood were isolated and induced into macrophages. Then the macrophages were pretreated with or without MG132 before IL-6 stimulation. Proteins were analyzed by Western blot, mRNA by real time PCR and membrane molecule by flow cytometry. RESULTS: The acute phase protein gene expression in neonatal macrophages after stimulated with IL-6 were higher than that in adult. Significantly enhanced phosphorylation of STAT3 was seen in neonatal macrophages. Both mRNA and protein expression of SOCS3 in neonatal macrophages were lower than that in adult. After pretreated with MG132, the expression of SOCS3 protein was increased which lead to attenuate the STAT3 phosphorylation and APP gene expression. CONCLUSION: Neonatal exhibit an enhanced expression of downstream target genes and IL-6/STAT3 signal pathway which is related with the diminished SOCS3. This provides a new sight into inflammatory responses in neonatal.

Ophthalmological outcomes of unilateral coronal synostosis in young children.

BACKGROUND: To report refractive outcomes, describe types of strabismus and evaluate the outcomes of surgical intervention for unilateral coronal synostosis (UCS) in paediatric patients. METHODS: This study retrospectively included 30 UCS cases. Patients aged from 3 months to 6 years (median: 1.8 years) were enrolled from January 2018 to December 2019 at Shanghai Children's Hospital. Sixteen patients had all types of strabismus; 15 of these patients underwent surgery. RESULTS: Refractive errors of 30 cases were included. In 60% of patients, astigmatism of 1.00D or more existed in not less than one eye at last record. Twenty (66.7%) patients had the larger amount of astigmatism in the contralateral eye. Fifteen patients received strabismus surgery, of whom 6 patients with monocular elevation deficiency (MED) underwent the standard Knapp procedure, with or without a horizontal deviation procedure. Fifteen cases were horizontally aligned within 5 prism dioptres (Δ). Six patients with MED (100%) had attained ≥25% elevation improvement after surgery, and the vertical deviation decreased from 25.83 Δ ± 4.92 Δ (range, 20 Δ-30 Δ) to 0.83 Δ ± 4.92 Δ after surgery (range, 0 Δ-10 Δ), for an improvement of 26.67 Δ ± 4.08 Δ (t = 16 P < 0.05). In 1 patient with esotropia, the horizontal deviation decreased from + 80 Δ to + 5 Δ after surgery. One patient was diagnosed with trichiasis and one with contralateral lacrimal duct obstruction. CONCLUSIONS: Contralateral MED was also the main type of strabismus in UCS. Superior oblique muscle palsy was still the most common, as previously reported. There is a risk of developing a higher astigmatism and anisometropia in the contralateral eye to synostosis. Other ophthalmic disorders should be treated in a timely manner. TRIAL REGISTRATION: The study was approved by the Institutional Review Board of Shanghai Children's Hospital (approval No. 2020R023-E01) and adhered to the tenets of the Declaration of Helsinki. Ethics approval was procured on March 30, 2020. This was a retrospective study. Written informed consent was sought from the patients' parents or legal guardians. Clinical Trials Registry number: ChiCTR2000034910 . Registration URL: http://www.chictr.org.cn/showproj.aspx?proj=56726 .

DKK1 inhibits breast cancer cell migration and invasion through suppression of ß-catenin/MMP7 signaling pathway.

BACKGROUND: DKK1 has been reported to act as a tumor suppressor in breast cancer. However, the mechanism of DKK1 inhibits breast cancer migration and invasion was still unclear. METHODS: Western blot and real time PCR was used to detect the expression of DKK1, ß-catenin and MMP7 in breast cancer cells. Wound scratch assay and transwell assay was employed to examine migration and invasion of breast cancer cell. RESULTS: DKK1 overexpression dramatically inhibits breast cancer cell migration and invasion. Knockdown of DKK1 promotes migration and invasion of breast cancer cells. DKK1 suppressed breast cancer cell migration and invasion through suppression of ß-catenin and MMP7 expression. XAV-939, an inhibitor of ß-catenin accumulation could reverse DKK1 silencing-induced MMP7 expression in breast cancer cells. Meanwhile, XAV-939 also could reverse the increase in the cell number invaded through Matrigel when DKK1 was knockdown. Furthermore, depletion of MMP7 also could reverse DKK1 knockdown-induced increase in the cell number invaded through Matrigel. CONCLUSIONS: DKK1 inhibits migration and invasion of breast cancer cell through suppression of ß-catenin/MMP7 pathway, our findings offered a potential alternative for breast cancer prevention and treatment.

Suppression of epidermal growth factor receptor-mediated ß-catenin nuclear accumulation enhances the anti-tumor activity of phosphoinositide 3-kinase inhibitor in breast cancer.

Phosphoinositide 3-kinase (PI3K) signaling is frequently deregulated in breast cancer and plays a critical role in tumor progression. However, resistance to PI3K inhibitors in breast cancer has emerged, which is due to the enhanced ß-catenin nuclear accumulation. Until now, the mechanisms underlying PI3K inhibition-induced ß-catenin nuclear accumulation remains largely unknown. In the present study, we found inhibition of PI3K with LY294002 promoted ß-catenin nuclear accumulation in MCF-7 and MDA-MB-231 breast cancer cells. Combining PI3K inhibitor LY294002 with XAV-939, an inhibitor against ß-catenin nuclear accumulation, produced an additive anti-proliferation effect against breast cancer cells. Subsequent experiments suggested ß-catenin nuclear accumulation induced by PI3K inhibition depended on the feedback activation of epidermal growth factor receptor (EGFR) signaling pathway in breast cancer cells. Inhibition of EGFR phosphorylation with Gefitinib enhanced anti-proliferation effect of PI3K inhibitor LY294002 in MCF-7 and MDA-MB-231 cells. Taken together, our findings may elucidate a possible mechanism explaining the poor outcome of PI3K inhibitors in breast cancer treatment.

Role of Zc3h12a in enhanced IL-6 production by newborn mononuclear cells in response to lipopolysaccharide.

BACKGROUND: The uncontrolled inflammatory response following infection is closely related to the morbidity and mortality of neonates. Interleukin 6 (IL-6) plays an important role in the pathogenesis and prognosis of this process. To better elucidate the secretion of IL-6 following infection in neonates, we investigated the IL-6 level and mechanism of IL-6/TLR4 signaling pathways. METHODS: We compared the IL-6, procalcitonin (PCT), and CRP levels between septic neonates and toddlers. In vitro cord blood samples from healthy term neonates and peripheral venous blood from healthy adult volunteers were collected. Protein expression was analyzed by Western blotting, mRNA expression by real-time PCR and membrane molecule expression by flow cytometry. RESULTS: The IL-6 concentrations were significantly higher in the neonate group than in the toddler group (p < 0.05). In the toddler group, the IL-6 concentrations were correlated positively with both PCT and CRP (PCT: r = 0.451, p = 0.001; CRP: r = 0.243, p = 0.023). In vitro, the secretion of IL-6 increased with the rising concentrations of LPS; at 1000 ng/ml LPS, IL-6 secretion from the monocytes of neonates was significantly higher than that of adults. There was a marked decreased level of MyD88 in neonate monocytes compared with that in adult monocytes. Additionally, the mRNA levels of Zc3h12a in neonate monocytes were significantly lower than those in adult monocytes following LPS stimulation. CONCLUSION: Neonates displayed enhanced IL-6 production after infection. Our study, for the first time, reported a significant decrease in the expression of Zc3h12a in neonates. Thus, Zc3h12a may be a key factor for the aberrant increase in IL-6 after neonate infection.

[Effect of Qishen Yiqi droplet on adenylate contents in myocardium of cor pulmonale rats].

Cor pulmonale rat models were induced by a single intraperitoneal injection of monocrotaline(MCT), and the sham group received a single intraperitioneal injection of normal saline. After the model rats received intragastric administration of Qishen Yiqi droplet(QS) for 6 weeks, the contents of adenylate(ATP, ADP and AMP) in right myocardial tissues were measured by HPLC, and then the metabolism changes in myocardium of cor pulmonale rats with QS were investigated. The results showed that ATP, ADP, and AMP were well separated, with a good linearity within a certain range of concentration; and the recovery rates were within the range of 90%-108%. As compared with model group, the level of ATP was significantly elevated in high-dose treatment group; ADP contents showed an increasing trend and AMP contents showed a decreasing trend, indicating that QS could significantly improve energy metabolism system in myocardium. By using the HPLC, a qualitative and quantitative analysis method was given for the determination of ATP, ADP and AMP contents in myocardium, providing a method for energy metabolism measurement in biological samples.

Clinical Features and Genetic Analysis of 48 Patients with Chronic Granulomatous Disease in a Single Center Study from Shanghai, China (2005-2015): New Studies and a Literature Review.

Chronic Granulomatous Disease (CGD) is a rare inherited primary immunodeficiency, which is characterized by recurrent infections due to defective phagocyte NADPH oxidase enzyme. Nowadays, little is known about Chinese CGD patients. Here we report 48 CGD patients in our single center study, which is the largest cohort study from Mainland China. The ratio of male to female was 11 : 1. The mean onset age was 0.29 years old, and 52% patients had an onset within the 1st month of life. The mean diagnosis age was 2.24 years old. 11 patients (23%) had died with an average age of 2.91 years old. 13 patients (28%) had positive family histories. The most prevalent infectious sites were the lungs (77%), followed by gastrointestinal tract (54%), lymph nodes (50%), and skin (46%). In addition, septicopyemia, thrush, and hepatosplenomegaly were also commonly observed, accounting for 23%, 23%, and 40% of the cases. Lesions due to BCG vaccination occurred in more than half of the patients. X-linked CGD due to CYBB gene mutations accounted for 75% of the cases, and 11 of them were novel mutations. Autosomal recessive inheritance accounted for 6% patients, including 1 patient with CYBA, 1 with NCF1, and 1 with NCF2 gene mutations.

Malignant Pelvic Tumors Involving the Sacrum: Surgical Approaches and Procedures Based on a New Classification.

OBJECTIVE: To introduce a new classification of Enneking type IV pelvic tumors involving the sacrum and a corresponding system of standardized surgical approaches and procedures for resection of such tumors, and to investigate the feasibility and therapeutic effect of the new system. METHODS: Data on 59 patients treated between February 2003 and February 2013 by standardized surgical approaches and procedures were retrospectively reviewed. The study subjects comprised 28 male and 31 female patients with a mean age at diagnosis of 36 years (range, 2-72 years). There are four subtypes in the new classification: (i) subtype IVa, neoplasms invading the ipsilateral sacral wing; (ii) subtype IVb, neoplasms invading the ipsilateral sacral foramina; (iii) subtype IVc, neoplasms invading the contralateral sacral foramina; and (iv) subtype IVd, neoplasms invading the whole of the sacrum. Standardized surgical approaches and procedures were devised for en-bloc resection for each subtype with adequate margins. RESULTS: Adequate margins were achieved in 43/59 patients (72.9%). The mean operation time was 5.0 h and the mean intraoperative blood loss 2157 mL. At the final follow-up, 27/53 patients (50.9%) who had been followed up were alive and in complete remission. The mean Musculoskeletal Tumor Society 93 score was 17.4 (58%) of a possible 30 points. The mean functional score for patients who had undergone a pelvic zone II resection was 15.2, compared with 19.0 for those with an intact pelvic zone II. CONCLUSIONS: The proposed standardized protocols should help orthopaedic surgeons to achieve adequate margins, manage risk, achieve better oncologic and functional outcomes, and minimize perioperative complications when treating massive pelvic tumors involving the sacrum.

Temporal and spatial characterization of mononuclear phagocytes in circulating, lung alveolar and interstitial compartments in a mouse model of bleomycin-induced pulmonary injury.

The mononuclear phagocyte system, including circulating monocytes and tissue resident macrophages, plays an important role in acute lung injury and fibrosis. The detailed dynamic changes of mononuclear phagocytes in the circulating, lung alveolar and interstitial compartments in bleomycin-induced pulmonary injury model have not been fully characterized. The present study was designed to address this issue and analyzed their relationships with pulmonary pathological evolution after bleomycin challenge. A total of 100 male C57BL/6 mice were randomly divided to receive bleomycin (2.5mg/kg, n=50) or normal saline (n=50) via oropharyngeal approach, and were sacrificed on days 1, 3, 7, 14 and 21. Circulating monocyte subsets, polarization state of bronchoalveolar lavage fluid (BALF)-derived alveolar macrophages (AMφ) and lung interstitial macrophages (IMφ, derived from enzymatically digested lung tissue) were analyzed by flow cytometry. There was a rapid expansion of circulating Ly6C(hi) monocytes which peaked on day 3, and its magnitude was positively associated with pulmonary inflammatory response. Moreover, an expansion of M2-like AMφ (F4/80+CD11c+CD206+) peaked on day 14, and was positively correlated with the magnitude of lung fibrosis. The polarization state of IMφ remained relatively stable in the early- and mid-stage after bleomycin challenge, expect for an increase of M2-like (F4/80+CD11c-CD206+) IMφ on day 21. These results support the notion that there is a Ly6C(hi)-monocyte-directed pulmonary AMφ alternative activation. Our result provides a dynamic view of mononuclear phagocyte change in three compartments after bleomycin challenge, which is relevant for designing new treatment strategies targeting mononuclear phagocytes in this model.

Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis.

OBJECTIVE: The aryl hydrocarbon receptor interacting protein gene (AIP) is associated with pituitary adenoma (PA). AIP has not been sequenced in East Asian PA populations, so we performed this study in a Han Chinese cohort. DESIGN: Our study included six familial PA pedigrees comprising 16 patients and 27 unaffected relatives, as well as 216 sporadic PA (SPA) patients and 100 unrelated healthy controls. METHODS: AIP sequencing was carried out on genomic DNA isolated from blood samples. Multiplex ligation-dependent probe amplification and microsatellite marker analyses on DNA from the paired tumor tissues were performed for loss of heterozygosity analysis. RESULTS: We identified three common and four rare single nucleotide polymorphisms (SNPs), one intron insertion, one novel synonymous variant, four novel missense variants, and a reported nonsense mutation in three familial isolated PA (FIPA) cases from the same family. Large genetic deletions were not observed in the germline but were seen in the sporadic tumor DNA from three missense variant carriers. The prevalence of AIP pathogenic variants in PA patients here was low (3.88%), but was higher in somatotropinoma patients (9.30%), especially in young adults (≤30 years) and pediatric (≥18 years) paients (17.24% and 25.00% respectively). All AIP variant patients suffered from macroadenomas. However, the AIP mutation rate in FIPA families was low in this cohort (16.67%, 1/6 families). CONCLUSION: AIP gene mutation may not be frequent in FIPA or SPA from the Han Chinese population. AIP sequencing and long-term follow-up investigations should be performed for young patients with large PAs and their families with PA predisposition.

Clinical characteristics and genetic profiles of 44 patients with severe combined immunodeficiency (SCID): report from Shanghai, China (2004-2011).

Severe combined immunodeficiency (SCID), a rare type of genetic associated immune disorder, is poorly characterized in mainland China. We retrospectively reviewed 44 patients with SCID who received treatment from 2004 to 2011 in Shanghai, China, and herein summarize their clinical manifestations and immunological and preliminary genetic features. The male-to-female ratio was 10:1. Twenty five patients presented with X-SCID symptoms. Only one patient was diagnosed before the onset of symptoms due to positive family history. The mean time of delay in the diagnosis of X-SCID was 2.69 months (range, 0.5-8.67). Thirty-seven of the 44 patients died by the end of 2011 with the mean age of death being 7.87 months (range, 1.33-31). Six patients received hematopoietic stem cell transplantation (HSCT); only one of them survived, who was transplanted twice. The time between onset and death was shorter in the HSCT-treated group compared with the untreated group (2.87 ± 1.28 and 3.34 ± 0.59 months, respectively), probably due to active infections during transplantation. Bacillus Calmette-Guérin (BCG) complications occurred in 14 of the 34 patients who received BCG vaccination. Transfusion-induced graft-versus-host disease occurred in 5 patients. Total 20 mutations in interleukin-2 receptor subunit gamma (IL2RG) were identified in 22 patients, including 11 novel mutations. Most patients were misdiagnosed before referred to our SCID Center. Therefore, establishing more diagnostic centers dedicated to the care of PID and accessible by primary immunodeficiency patients will facilitate early, correct diagnosis and better care of SCID in China.

[Aryl hydrocarbon receptor interacting protein gene and familial isolated pituitary adenomas].

Familial isolated pituitary adenoma (FIPA) is an autosomal dominant disease, characterized by low penetrance, early-onset disease, more invasive tumor growth, as well as somatotroph and lactotroph adenomas in most cases. It has been indicated that the aryl hydrocarbon receptor interacting protein (AIP) gene is a tumor suppressor gene. Many heterozygous mutations have been discovered in AIP in about 20% of FIPA families. However, the exact molecular mechanism by which its disfunction promotes tumorigenesis of pituitary is unclear.