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This article discusses a case of a 2-year-old boy with Langerhans cell histiocytosis (LCH), a rare neoplastic disorder characterized by a clonal proliferation of Langerhans cells. The boy presented with recurrent fevers, abdominal distension, an eroded skin lesion, and dystrophic nails. The diagnosis was confirmed through histopathological examination of the skin lesion, which showed infiltration of histiocytes with large nuclei. The boy was treated with a combination of vincristine and prednisone, followed by azathioprine, cytosine arabinoside chemotherapy, and targeted therapy with vemurafenib. The nail deformities improved with treatment, but the hepatosplenomegaly showed minimal improvement. LCH involvement of the nail is rare, and nail changes are most likely caused by direct infiltration of Langerhans cells. Treatment for patients with only skin and nail involvement is limited, with few reported cases in the literature. LCH is driven by genetic changes, such as the BRAF V600E mutation, and is associated with more severe disease and higher treatment resistance. The article emphasizes the importance of considering LCH as a differential diagnosis in cases with hepatosplenomegaly and nail changes. [Extracted from the article]

The emulsifying properties of phosvitin were stronger than those of other food proteins. In this study, phosvitin was subjected to ball-milling treatment for 20, 40 and 60 min, and the physicochemical, rheological and emulsifying properties were investigated. After the treatment, phosvitin possessed an unfolded and stretched structure, with a higher surface hydrophobicity and thermal stability. The morphology spectrum showed that the protein micelles tended to collapse into coarse particles with irregular and rigid structures. The rheological data illustrated that the treated phosvitin dispersion possessed an increased apparent viscosity. Correspondingly, the emulsifying ability of phosvitin was enhanced by 3.0, 2.9 and 2.5 folds for 20, 40 and 60 min of treatment, while the emulsifying stability decreased by 40.0%, 34.0% and 34.5%, respectively. These findings explored the relationship between structure and function of proteins in industrial processing, and indicated that ball-milling process could be applied to improve emulsifying properties of food proteins. Image 1058394 • Ball-milling treatment modified surficial, electrical and thermal properties of phosvitin. • Milling treatment altered rheological properties of phosvitin via increasing its apparent viscosity and viscoelasticity. • Milling treatment enhanced emulsifying ability of phosvitin but decreased its emulsifying stability. [ABSTRACT FROM AUTHOR]

Introduction: Burns are a very frequent injury type in the battlefield, comprising 5-20% of combat casualties in the recent conflicts. Almost 80% of the burns occur to the face, in part because the face is often not protected. Immediate treatment is critical in the first hours after severe burn injury in order to prevent infection and wound progression. Immediate treatment in the battlefield can be a serious challenge especially if the injury occurs in a remote area with limited transport options. Therefore, novel treatment modalities for prolonged field care when transport to the definitive care is delayed are needed. The purpose of this study was to utilize the platform wound device (PWD) with negative pressure capabilities for the immediate and definitive treatment of porcine full-thickness head burns.Materials and Methods: Full-thickness burn wounds were created on foreheads of seven Yorkshire pigs. Burns were created on day 0, immediately enclosed with the PWD and treated topically with minocycline and lidocaine. On day 3, the burns were surgically debrided. Subsequently, new PWDs were placed on the wounds and continuous negative pressure wound therapy was initiated with either -50 mmHg or -80 mmHg. On day 7, the animals were euthanized and wounds were harvested for analyses. Control wounds were treated with silver sulfadiazine cream.Results: The PWD treatment with negative pressure significantly reduced erythema and edema in the injured tissue and promoted granulation tissue and neocollagen formation by day 7 in comparison to control wounds. In addition, the PWD with both topical minocycline and negative pressure (-80 mmHg or -50 mmHg) reduced bacterial counts in the wounds similar to the current standard of care.Conclusion: This study demonstrates that the PWD is an effective platform for delivery of antibiotics and negative pressure wound therapy for the treatment of full-thickness burns. Therefore, the PWD may be utilized for both prolonged field care and definitive treatment of burn- and blast-injured warfighters. [ABSTRACT FROM AUTHOR]

Background: EGFR‐tyrosine kinase inhibitors (TKIs) combined with TS‐1 might overcome EGFR‐TKI resistance, which has been indicated by several preclinical studies. We investigated the synergistic efficacy and safety of the combination therapy of EGFR‐TKIs and TS‐1 in non‐small cell lung cancer (NSCLC) patients with acquired resistance to previous EGFR‐TKI therapy. Methods: This was a phase II, single‐arm and single‐center prospective study. Stage IIIB–IV NSCLC patients with acquired resistance to prior EGFR‐TKI treatment were enrolled. All patients were administered combination therapy of TS‐1 and continuing EGFR‐TKIs in this study. The primary endpoints were progression‐free survival (PFS), while overall survival (OS), disease control rate (DCR), and safety were secondary endpoints. Results: A total of 42 patients with acquired resistance to EGFR‐TKIs were eligible for this study. The median PFS for all patients was five months (95% confidence interval [CI] 3.6–5.4). The OS and DCR were 31.9 (95% CI 17.8–46.0) months and 69.0% (29/42), respectively. No grade 4 toxicity or grade 3 hematologic toxicity was observed in this study. One patient (2%) experienced grade 3 elevated total serum bilirubin. Conclusion: The combination treatment of TS‐1 and EGFR‐TKIs was effective and well tolerated by patients who had experienced prior EGFR‐TKI treatment failure. Our results need to be validated by larger prospective clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: To compare the efficacy and safety between tadalafil once-a-day and tadalafil on-demand dosing regimen in patients with ED. Materials and Methods: A systematic search of Medline, Embase, and Cochrane Library was performed to identify all randomized controlled trials (RCTs) that compared tadalafil used a once-a-day with an on-demand dosing regimen for erectile dysfunction. A secondary hand-search was performed in relevant journals, references, and the grey literature. Meta-analyses were performed using Review Manager version 5.3.0. Results: Six RCTs involving a total of 1,534 patients were included in this review. All studies reported the International Index of Erectile Function- Erectile Function domain score and the results of the metaanalysis showed no difference between the groups. The overall pooled estimated weighted mean differences (WMD) was 0.97 (95% CI -0.37 to 2.32; p = 0.16). Meta-analyses of Sexual Encounter Profile questions 2 and 3 (SEP-2 and SEP-3) showed that the once-a-day dosing regimen was superior to the on-demand regimen with statistical significance. The WMD of SEP-2 and SEP-3 were 10.32 (95% CI 3.16-17.48; p = 0.005) and 11.07 (95% CI 2.57-19.56; p = 0.01), respectively. Both dosing regimens of tadalafil showed similar complication rates. The meta-analyses of adverse events showed no significant differences. Conclusions: The efficacy rates of tadalafil once-a-day and on-demand were similar. No significant difference in safety was found between the 2 dose regimens of tadalafil. [ABSTRACT FROM AUTHOR]

Background: Clinical studies evaluating the effectiveness and safety of phosphodiesterase type 5 inhibitors (PDE5is) for female sexual dysfunction have reported conflicting results.Objectives: To systematically review evidence from studies comparing PDE5is with placebo in the treatment of female sexual dysfunction.Search Strategy: Searches of PubMed, the Cochrane Library, and Embase databases were performed using the MeSH terms "females/female/women", "sexual", and "sildenafil/tadalafil/vardenafil/PDE5/PDE5i".Selection Criteria: All randomized controlled trials, available in English, published no later than January 28, 2015 comparing the effectiveness of PDE5is, or PDE5is in combination with other agents, with placebo in improving female sexual function were included.Data Collection and Analysis: The inclusion criteria were met by 14 studies, which were analyzed by two reviewers.Main Results: The randomized controlled trials included in the present study adopted different questionnaires for measuring sexual function; consequently, most of the data had to be considered separately rather than pooled. Generally, the use of PDE5is resulted in significant improvements in sexual function compared with placebo, with some studies demonstrating negative results. Pooled data regarding adverse events demonstrated significantly higher rates of headache, flushing, and changes in vision in PDE5i-treated patients.Conclusions: PDE5is could be an effective treatment modality for female sexual dysfunction. Although there were significant increases in adverse events in comparison with placebo, PDE5is were still relatively safe. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The aim of this study was to investigate whether the DOR agonist BW373U86 conferred neuroprotection following ACA when given after resuscitation and to determine the long-term effects of chronic BW373U86 treatment on ACA-elicited brain injury. Methods: Animals were divided into acute and chronic treatment groups. Each group consisted of four sub-groups, including Sham, ACA, BW373U86 (BW373U86+ACA), and Naltrindole groups (Naltrindole and BW373U86+ACA). The DOR antagonist Naltrindole was used to confirm the possible receptor-dependent effects of BW373U86. ACA was induced by 8min of asphyxiation followed by resuscitation. All drugs were administered either immediately after the restoration of spontaneous circulation (ROSC) in acute-treatment groups or over 6 consecutive days in chronic-treatment groups. Alterations of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) were analyzed by western blot and immunohistochemistry. Neurological functions were assessed by neurological deficit score (NDS) and Morris Water Maze performance. Neurodegeneration was monitored by immunofluorescence and Nissl staining. Results: ACA induced massive neuron loss and serious neurological function deficits. BW373U86 significantly reduced both of these negative effects and increased CREB and pCREB expression in the hippocampus; these effects were reversed with acute Naltrindole treatment. The protective effects of BW373U86 persisted until 28d post-ROSC with chronic treatment, but these effects were not reversed by Naltrindole. Conclusions: BW373U86 attenuates global cerebral ischemic injury induced by ACA through both DOR-dependent and DOR-independent mechanisms. CREB might be an important molecule in mediating these neuroprotective effects. [Copyright &y& Elsevier]

Objective: This systematic review was performed to evaluate the efficacy and safety of tramadol in patients with premature ejaculation (PE). Methods: A systematic search of PubMed®, Embase® and the Cochrane Library was performed to identify all randomized controlled trials (RCTs) that compared the effects of tramadol with placebo or no drug for patients with PE. The outcomes included post-therapeutic intravaginal ejaculation latency time (IELT), increases in IELT, satisfaction with sexual intercourse, control over ejaculation and side effects (SEs). The Cochrane Collaboration Review Manager software (RevMan 5.1.4) was used for statistical analysis. Results: A total of 5 trials, involving 715 patients, met the inclusion criteria. The synthesized data from these RCTs indicated that compared with the control, tramadol significantly increased IELT values post-therapeutically (SMD 3.51, 95% CI 2.14-4.88, p < 0.00001) and changes in IELT values were more pronounced in the tramadol group (SMD 2.87, 95% CI 2.63-3.10, p < 0.00001). Satisfaction with sexual intercourse and the ability to control ejaculation were both improved in patients in the tramadol group (p < 0.05). The incidence of SEs in the tramadol group were significantly higher than in the control group (RR 3.55, 95% CI 1.34-9.40, p = 0.01), however most SEs were mild or moderate and transient. Conclusions: Tramadol may be effective in PE treatment, especially when patients have failed therapies, like selective serotonin reuptake inhibitors. However, the possibility of drug addiction and SEs should still be considered before initial use or after chronic use of this agent. More high-quality (clear randomization sequences, allocation concealment and blinding introduction), long-term, RCTs with a large number of PE patients are expected. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: We evaluated differences in cytokine responses and T-lymphocyte subsets following retroperitoneal laparoscopic and conventional open radical nephrectomies for localized renal cell carcinoma (RCC). Methods: A total of 62 patients with T1N0M0 staged RCC were randomized to either retro-laparoscopic (n = 31) or open (n = 31) radical nephrectomy. Plasma levels of interleukin-1β (IL-1β), IL-6, and tumour necrosis factor-alpha (TNF-α) were measured separately by enzyme linked immunosorbent assay (ELISA) preoperatively and on postoperative days 1 and 5. Levels of CD3+, CD4+ and CD8+ as well as the CD4+:CD8+ ratio were acquired by flow cytometry at the same time points. Results: Levels of IL-1β, IL-6 and TNF-α increased significantly compared to preoperative values in both groups (p < 0.05) on postoperative day 1, and all the parameters in the open group were significantly higher than those in the retro-laparoscopy group (p < 0.05). On postoperative day 1, the levels of CD3+ and CD4+ and the CD4+:CD8+ ratio decreased markedly compared to preoperative values for both groups (p < 0.05). Elevations of the CD4+:CD8+ ratio in the retro-laparoscopy group (p < 0.05) and the CD8+ level in the open group (p < 0.05) were observed when compared with the other group. On postoperative day 5, the levels of CD3+ and CD4+ and the CD4+:CD8+ ratio in the retro-laparoscopy group, as well as the level of CD8+ in the open group, returned to about preoperative levels (p < 0.05). Follow-up ranged from 4 to 14 months postoperatively in all 62 patients with a 100% cancerspecific survival rate in both groups. Conclusions: Retroperitoneal laparoscopic radical nephrectomy is associated with the milder cytokine responses caused by trauma and inflammation and the better preserved distribution of T-lymphocytes. [ABSTRACT FROM AUTHOR]

Abstract: Ursolic acid (UA), a triterpenoid compound isolated previously from Oldenlandia diffusa, which is a Traditional Chinese Medicine used to treat cancer, was found to inhibit the proliferation of doxorubicin-resistant human hepatoma cell line (R-HepG2) through apoptosis as shown by externalization of phosphatidyl serine, morphological changes and loss of mitochondrial membrane potential. UA could activate Bak but not Bax, which implied that Bak may play an important role in UA-induced apoptosis. Furthermore, the death of R-HepG2 cells induced by UA was found to be mainly through the caspase-independent apoptosis-inducing factor (AIF) signaling pathway which was evidenced by: (a) the pan-caspase inhibitor and the specific caspase inhibitor had only modest protective effect against UA; (b) UA treatment caused the nuclear translocation of AIF, which is retained in the mitochondria in untreated R-HepG2 cells; (c) cells that had been treated with human AIF-specific siRNA could resist cell death induced by UA. In addition, a further animal study showed that UA was effective against R-HepG2 cells in vivo with negligible body weight loss and damage towards the liver, heart and spleen. Most importantly, immunohistochemical staining in animal tissues also suggested that UA also significantly inhibited the growth of R-HepG2 cells in nude mice through the AIF signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Despite recent significant advances in the treatment of human carcinoma (HCC), the results of chemotherapy to date remain unsatisfactory. 5-Fluorouracil (5-FU) still represents the cornerstone of treatment of carcinoma, and resistance to the actions of 5-FU is a major obstacle to successful chemotherapy. More effective treatment strategies may involve combinations of agents with activity against HCC. Andrographolide (ANDRO), a natural bicyclic diterpenoid lactone isolated from Andrographis paniculata, has been shown to suppress the growth of HCC cells and trigger apoptosis in vitro. To assess the suitability of ANDRO as a chemotherapeutic agent in HCC, its cytotoxic effects have been evaluated both as a single agent and in combination with 5-FU. ANDRO potentiates the cytotoxic effect of 5-FU in HCC cell line SMMC-7721 through apoptosis. ANDRO alone induces SMMC-7721 apoptosis with p53 expression, Bax conformation and caspase-3,8,9 activation. Surprisingly, the addition of ANDRO to 5-FU induces synergistic apoptosis, which could be corroborated to the increased caspase-8, p53 activity and the significant changes of Bax conformation in these cells, resulting in increased losses of mitochondrial membrane potential, increased release of cytochrome c, and activation of caspase-9 and caspase-3. Suppression of caspase-8 with the specific inhibitor z-IETD-fmk abrogates largely ANDRO/5-FU biological activity by preventing mitochondrial membrane potential disappearance, caspase-3,9 activation and subsequent apoptosis. The results suggest that ANDRO may be effective in combination with 5-FU for the treatment of HCC cells SMMC-7721. [Copyright &y& Elsevier]

Liver-directed gene therapy can be aimed at replacing a missing gene product, overexpressing or ectopically expressing a gene product in the liver, generating proteins that are normally not produced in the liver (e.g. hormones, vaccines), down-regulating specific gene expression and targeted repair of genetic mutations. A common critical requirement for achieving these goals is the availability of efficient methods for transferring DNA and RNA into target organin vivo. Both recombinant viruses and non-viral vectors are being explored for transferring nucleic acids to cellsin vitroandin vivo. This review compares the characteristics of these vectors in the context of their potential application in liver-directed gene therapy for various inherited or acquired disorders. [ABSTRACT FROM AUTHOR]

Surgical resection is one of the most common radical treatments for cancers. However, tumors may be compressed or the local intravascular pressure may be increased during surgical manipulation, causing the shedding and entry of tumor cells into the blood circulation and hence distant recurrence and metastasis of tumors. We have preliminarily established a method of riboflavin photosensitization treatment (RPT) for inactivation of circulating tumor cells. This technology promises to solve the problems of shedding and entry of solid tumor cells into blood circulation before surgical manipulation, and almost unavoidable hematogenous dissemination of tumor cells during surgical resection. In the present study, apoptosis detection and tumorigenicity experiment in immunodeficient mice were conducted to evaluate the effect of RPT for inactivation of circulating tumor cells respectively. Next, functional evaluation was carried out for the immune cells through detecting apoptosis rate and cytokine secretion of lymphocyte. Finally, thromboelastography (TEG) and free hemoglobin were detected to assess peripheral blood coagulation and red blood cell damage. The results showed that RPT (50 μmol/L riboflavin, 10.8 J/cm2 UV) could effectively make tumor cell lose the ability of proliferation in the peripheral blood. In the meantime, the damage caused to peripheral blood coagulation, immune cell function and red blood cells was generally acceptable. The results of the study showed that RPT had huge potential in addressing the problems of shedding and entry of solid tumor cells into blood circulation before surgical manipulation, and almost unavoidable hematogenous dissemination of tumor cells during surgical resection. This therapy is expected to be an auxiliary and supportive method to reduce the risk of hematogenous metastasis and recurrence of cancers, and to increase the surgical success rate of malignant solid tumors. • HCT116 cells are more vulnerable to RPT than lymphocytes. • RPT under certain conditions can inactivate HCT116 cells and maintain the RBC, the function of coagulation and immune. 3. RPT is expected to be used in inactivation of CTCs. [ABSTRACT FROM AUTHOR]

Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent at the 9-position might be beneficial for potency. Among them, compound 2d exhibited most potent activities with IC50 values of 7.12–14.8 μM, similar to that of BBR. The effect of 2d was further confirmed in a dose-dependent manner both in RNA and protein level. The mechanism revealed that 2d could inhibit the activation of MEK/ERK signaling pathway. Meanwhile, it could suppress the EV71-induced autophagy by activating AKT and inhibiting the phosphorylation of JNK and PI3KIII proteins. We consider BBR derivatives to be a new family of anti-EV71 agents through targeting host components, with an advantage of broad-spectrum anti-EV71 potency. [ABSTRACT FROM AUTHOR]

Effective cancer therapy is one of the biggest global challenges. Conventional cancer therapies have been at the forefront of combating cancers, but more evidence showed considerable side effects, limiting their use. There are various new therapies in development, but combined approaches for treating cancer are much expected. Natural herbs had been traditionally in use for cancer therapy in most parts of the world. In this review, we have examined ten commonly used Chinese herbs that have, for centuries, shown effectiveness in treating cancers. They demonstrated the abilities to promote the apoptosis of cancer cells, inhibit their metastasis, activate the patient's anticancer immunity, and synergistically increase the efficacy of conventional chemotherapy and radiation therapy when used in combination. Clinical experiences had proved that these herbs and their bioactive compounds were effective against a plethora of cancers through a variety of mechanisms, effectively improving patients' quality of life without significant side effects. These advantages indicate that there are huge potentials in the development of Chinese herbs into cancer medicine as part of a promising, holistic cancer treatment modality. [ABSTRACT FROM AUTHOR]

The increasing usage of general anesthetics on young children and infants has drawn extensive attention to the effects of these drugs on cognitive function later in life. Recent animal studies have revealed improvement in hippocampus-dependent performance after lower concentrations of sevoflurane exposure. However, the long-term effects of low-dose sevoflurane on the developing brain remain elusive. On postnatal day (P) 7, rats were treated with 1.2% sevoflurane (1.2% sevo group), 2.4% sevoflurane (2.4% sevo group), and air control (C group) for 6 h. On P35-40, rats’ hippocampus-dependent learning and memory was tested using the Morris water maze. Cognition-related and synapse-related proteins in the hippocampus were measured using Western blotting on P35. On the same day, neurogenesis and synapse ultrastructure were evaluated using immunofluorescence and transmission electron microscopy (TEM). On P35, the rats neonatally exposed to 1.2% sevoflurane showed better behavioral results than control rats, but not in the 2.4% sevo group. Exposure to 1.2% sevoflurane increased the number of 5′-bromo-2-deoxyuridine (BrdU)-positive cells in the dentate gyrus and improved both synaptic number and ultrastructure in the hippocampus. The expression levels of BDNF, TrkB, postsynaptic density (PSD)-95, and synaptophysin in the hippocampus were also increased in the 1.2% sevo group. In contrast, no significant changes in neurogenesis or synaptic plasticity were observed between the C group and the 2.4% sevo group on P35. These results showed that exposure of the developing brain to a low concentration of sevoflurane for 6 h could promote spatial learning and memory function, along with increased hippocampal neurogenesis and synaptic plasticity, in later life. [ABSTRACT FROM AUTHOR]

The effects of chronic EtOH consumption, associated or not with thiamine deficiency (TD), on cognitive impairment, oxidative damage, and β-amyloid (Aβ) peptide accumulation in the brain were investigated in male C57BL/6 mice. We established an alcoholic mouse model by feeding an EtOH liquid diet, a TD mouse model by feeding a thiamine-depleted liquid diet, and an EtOH treatment associated with TD mouse model by feeding a thiamine-depleted EtOH liquid diet for 7 weeks. The learning and memory functions of the mice were detected through the Y-maze test. Biochemical parameters were measured using corresponding commercial kits. The Aβ expression in the hippocampus was observed by immunohistochemical staining. Several results were obtained. First, EtOH significantly reduced cognitive function by significantly decreasing the Glu content in the hippocampus; increasing the AChE activity in the cortex; and reducing the thiamine level, and superoxide dismutase (SOD), glutathione peroxidase (GPx), and choline acetyltransferase (ChAT) activities in both the hippocampus and cortex. The treatment also increased the levels of malondialdehyde (MDA), protein carbonyl, 8-hydroxydeoxyguanosine (8-OHdG), and nitric oxide (NO) and the activities of total nitric oxide synthase (tNOS), inducible nitric oxide synthase (iNOS), and monoamine oxidase B (MAO-B). Furthermore, EtOH enhanced the expression levels of Aβ 1–42 and Aβ 1–40 in the hippocampus. Second, TD induced the same dysfunctions caused by EtOH in the biochemical parameters, except for learning ability, 8-OHdG content, and GPx, tNOS, and AChE activities in the cortex. Third, the modification of MDA, protein carbonyl and NO levels, and GPx, iNOS, ChAT, and MAO-B activities in the brain induced by chronic EtOH treatment associated with TD was greater than that induced by EtOH or TD alone. The synergistic effects of EtOH and TD on Aβ 1–40 and Glu release, as well as on SOD activity, depended on their actions on the hippocampus or cortex. These findings suggest that chronic EtOH consumption can induce TD, cognitive impairment, Aβ accumulation, oxidative stress injury, and neurotransmitter metabolic abnormalities. Furthermore, the association of chronic EtOH consumption with TD causes dramatic brain dysfunctions with a severe effect on the brain. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated that various traditional Chinese medicines (TCMs) exhibit potent anti-inflammatory effects against inflammatory diseases mediated through macrophage polarization and metabolic reprogramming. The objective of this review was to assess and consolidate the current understanding regarding the pathogenic mechanisms governing macrophage polarization in the context of regulating inflammatory diseases. We also summarize the mechanism action of various TCMs on the regulation of macrophage polarization, which may contribute to facilitate the development of natural anti-inflammatory drugs based on reshaping macrophage polarization. We conducted a comprehensive review of recently published articles, utilizing keywords such as "macrophage polarization" and "traditional Chinese medicines" in combination with "inflammation," as well as "macrophage polarization" and "inflammation" in conjunction with "natural products," and similar combinations, to search within PubMed and Google Scholar databases. A total of 113 kinds of TCMs (including 62 components of TCMs, 27 TCMs as well as various types of extracts of TCMs and 24 Chinese prescriptions) was reported to exert anti-inflammatory effects through the regulation of key pathways of macrophage polarization and metabolic reprogramming. In this review, we have analyzed studies concerning the involvement of macrophage polarization and metabolic reprogramming in inflammation therapy. TCMs has great advantages in regulating macrophage polarization in treating inflammatory diseases due to its multi-pathway and multi-target pharmacological action. This review may contribute to facilitate the development of natural anti-inflammatory drugs based on reshaping macrophage polarization. [Display omitted] • Macrophage types M1/M2 dictate inflammation outcome via phenotypic shift. • Macrophage polarization pathways are vital targets for treating inflammation-related diseases. • Modulating macrophage metabolism is a novel approach for inflammation-related diseases. • Traditional Chinese medicine aids inflammation by regulating macrophage polarization through multi-pathway, multi-target effects. [ABSTRACT FROM AUTHOR]

Objective: To clarify the efficacy of phosphodiesterase-5 inhibitor (PDE5i) in men with premature ejaculation (PE).Methods: We searched the PubMed, Embase, and Cochrane Library databases to identify all randomized controlled trials and compared results, including intravaginal ejaculation latency time, satisfaction, side effects, and others, after treatment with PDE5i vs placebo, PDE5i vs selective serotonin reuptake inhibitor (SSRI), or combined use of PDE5i with SSRI vs SSRI alone for treating PE.Results: The study inclusion criteria were met by 10 studies (10 randomized controlled trials with 3 crossover studies) involving 775 patients. The data synthesized from these studies indicated that the efficacy of PDE5i was better than that of placebo; however, more patients had side effects while taking PDE5i. The efficacy of PDE5i was better than that of SSRIs, and no significant difference was observed in the frequency of side effects. The efficacy of the combined treatment was significantly better than that of SSRI alone; however, more patients had side effects from the combined treatment. The major limitations of this meta-analysis were that there is no universally agreed definition of PE, and the types of medications differed among the studies evaluated.Conclusion: PDE5i was significantly more effective than a placebo or SSRI for treating PE; however, it had more side effects than placebo. The combined treatment of PDE5i and SSRI had better efficacy but more side effects than the use of SSRI alone. [ABSTRACT FROM AUTHOR]

Background: Type I interferonopathies are a group of rare autoimmune diseases characterised by excessive activation of type I interferon that leads to disturbances in immune function. Three prime repair exonuclease 1 (TREX1) is an important exonuclease and plays an important role in DNA damage repair. TREX1 mutations are associated with many type I interferonopathies. Studies have been published on the effectiveness of tofacitinib in the treatment of type I interferonopathies. The aim of this study is to identify the pathogenic variation in a Chinese family with type I interferonopathies and to observe the therapeutic effects of tofacitinib. Methods: A Chinese family with two members with type I interferonopathies was investigated. Whole exome sequencing and Sanger sequencing were applied for mutation screening using peripheral blood DNA of the patient and her family members. Sequencing results were analysed using bioinformatics software tools including VarCards and PolyPhen-2. Close clinical follow-up and observation were used to record changes in the disease before and after treatment with tofacitinib. Results: Compound heterozygous variants of TREX1 were observed in the patient's genome. One was a missense variant (NM_016381; c.C227T; p.Ala76Val) from the patient's father, and the other was a frameshift variant (NM_016381; c.458dupA; p.Gln153Glnfs*3) from the patient's mother. One of the proband's elder brothers with similar skin lesions also carried these two variants. This brother of the proband had more serious cutaneous involvement with the comorbidity of cerebral palsy. These TREX1 variants have not been reported in previous studies and are predicted to be highly pathogenic. The proband was given tofacitinib that led to a marked improvement. Conclusions: We identified two novel complex heterozygous variants in the TREX1 gene, which may underlie the molecular pathogenesis of the type I interferonopathies observed in members of this family. Tofacitinib could be an alternative treatment for this disease. [ABSTRACT FROM AUTHOR]

Innovations and discoveries in cancer therapeutics have improved survival rates in patients with various types of malignancies. At the same time, physicians are identifying an increased number of patients with treatment-related cardiotoxicity. It is imperative that physicians recognize early treatment-related adverse effects to determine the safest therapeutic options for patients with cancer. This manuscript evaluates the role of cardiovascular imaging and biomarkers in identifying cardiotoxicity trigged by various chemotherapeutic agents and summarizes expert consensus statements regarding cardiotoxicity monitoring. [ABSTRACT FROM AUTHOR]

Background: For localized prostate cancer (PCa), radical prostatectomy (RP) and radiotherapy (RT) are two standard interventions to decrease PCa mortality. Contemporary studies contained the elderly people; analyses focusing on patients over 75 years of age were still lacking. Method: In the Surveillance Epidemiology and End Results (SEER) database (2004‐2015), people over 75 years of age with cT2 stage were selected in our research. Multivariable Cox proportional hazard models were used to analyze cancer‐specific mortality (CSM) and overall mortality (OM) after adjustment. The propensity score matching was performed to assume the randomization. An instrument variate (IVA) was used to calculate the unmeasured confounders. Results: Radical prostatectomy is superior to RT in OM and CSM after adjustment for covariates (HR = 0.54, 95% CI = 0.47‐0.62, P < 0.001 and HR = 0.30, 95% CI = 0.20‐0.45, P < 0.001, respectively). The cox model after matching indicated similar consequence (OM: HR = 0.53, 95% CI = 0.46‐0.62, P < 0.001; CSM: HR = 0.27, 95% CI = 0.17‐0.43, P < 0.001). In the IVA‐adjusted model, the effect of treatment changed slightly (OM: HR = 0.65, 95% CI = 0.54‐0.78, P < 0.001; CSM: HR = 0.21, 95% CI = 0.12‐0.37, P < 0.001). Subgroup analyses showed that for patients with GS = 7, those received RP obtained the highest risk decline for overall death (HR = 0.41, 95% CI = 0.32‐0.52); and for patients with younger age, those received RP obtained the highest risk decline for CSM (HR = 0.11, 95% CI = 0.01‐0.52). Conclusion: Patients over 75 years of age with cT2 stage will obtain more benefit from RP compared with RT, especially for patients with GS = 7 and younger age. [ABSTRACT FROM AUTHOR]

We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way. [ABSTRACT FROM AUTHOR]

The present study was designed to compare the effect of indocyanine green (ICG)-enhanced laser (810 nm) thermocoagulation method and photodynamic therapy (PDT) on circumscribed choroidal hemangioma (CCH). A total of 36 patients (36 pair of eyes) diagnosed with CCH in the Ocular Fundus Disease Center of The Affiliated Hospital of Medical College of Ningbo University from June 2010 to January 2016 were selected and randomly divided into two groups. ICG-enhanced thermocoagulation was used to treat 18 patients (18 pair of eyes), and PDT was used to treat the remaining 18 patients (18 pair of eyes). The best corrected visual acuity of the affected eyes was observed before and after treatment, and changes in the tumor were observed through ocular fundus photochromes under the ophthalmoscope. The changes in tumor size and height were examined through B-scan ultrasonography. The changes in serous retinal fluid were examined by optical coherence tomography (OCT). A total of 36 patients were followed-up for 3, 7, 11 and 24 weeks after laser therapy with an average of 18 weeks. It was seen that the subretinal serous exudation disappeared in 36 patients through the fundus examination after treatment, and B-scan ultrasonography showed that the tumor size was reduced. Among 18 patients undergoing ICG-enhanced thermocoagulation treatment, the visual acuity of 72.2% of them was improved, while that of the remaining 27.8% was stable, and there were no patients with decreased visual acuity; the fundus observation showed that when tumor atrophy occurred, the tumor turned white accompanied with mild pigment disorders, but retinal and choroidal normal vessels were not damaged. Among 18 patients undergoing PDT treatment, the visual acuity of 44.4% was increased, that of 50% was stable, and that of 5.6% of the patients was decreased; through fundus observation, tumor atrophy scars and alignment, a large number of hyperplasia or pigment loss and partial vascular occlusion could be seen. The results indicated that in the treatment of CCH, ICG-enhanced laser (810 nm) thermocoagulation and PDT can lead to tumor atrophy and promote the absorption of exudation. However, the damage of ICG-enhanced laser thermocoagulation to normal fundus tissues is significantly smaller than that of PDT, and the former has higher safety. [ABSTRACT FROM AUTHOR]

The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC-overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers. [ABSTRACT FROM AUTHOR]

Background: Although blinatumomab, a bispecific T cell engaging antibody, exhibits high clinical response rates in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL) and B cell non-Hodgkin's lymphoma (B-NHL), it still has some limitations because of its short half-life. Mesenchymal stromal cells (MSCs) represent an attractive approach for delivery of therapeutic agents to cancer sites owing to their tropism towards tumors, but their immunosuppression capabilities, especially induced by indoleamine 2,3-dioxygenase (IDO), should also be taken into consideration. Methods: Human umbilical cord-derived MSCs (UC-MSCs) were genetically modified to secrete Tandab (CD3/CD19), a tetravalent bispecific tandem diabody with two binding sites for CD3 and two for CD19. The tropism of MSCs towards Raji cells in vitro was determined by migration assays, and the homing property of MSCs in vivo was analyzed with firefly luciferase-labeled MSCs (MSC-Luc) by bioluminescent imaging (BLI). The cytotoxicity of T cells induced by MSCsecreting Tandab (CD3/CD19) was detected in vitro and in vivo in combination with D-1-methyl-tryptophan (D-1MT), an IDO pathway inhibitor. Results: The purified Tandab (CD3/CD19) was functional with high-binding capability both for CD3-positive cells and CD19-positive cells and was able to induce specific lysis of CD19-positive cell lines (Raji, Daudi, and BJAB) in the presence of T cells. Additionally, results from co-culture killing experiments demonstrated that Tandab (CD3/CD19) secreted from MSCs was also effective. Then, we confirmed that D-1MT could enhance the cytotoxicity of T cells triggered by MSC-Tandab through reversing T cell anergy with down-regulation of CD98 and Jumonji and restoring the proliferation capacity of T cells. Furthermore, MSC-Luc could selectively migrate to tumor site in a BALB/c nude mouse model with Raji cells. And mice injected with MSC-Tandab in combination with D-1MT significantly inhibited the tumor growth. Conclusions: These results suggest that UC-MSCs releasing Tandab (CD3/CD19) is an efficient therapeutic tool for the treatment of B cell lymphoma when combined with D-1MT. [ABSTRACT FROM AUTHOR]

Purpose: We aimed at evaluating the efficacy of extracorporeal shockwave lithotripsy (SWL) for treating distal ureteral calculi performed in supine vs. prone position. Materials and Methods: Eligible studies were identified by 2 reviewers using PubMed, Embase, and Web of Science databases. Outcomes included stone-free rate after the first and the final SWL session, the mean number of shocks per SWL session, the mean percentage of power used in the first SWL session, and the mean number of SWL sessions per patient. Results: Pooled data among the 647 included patients showed that supine SWL was associated with a significantly higher stonefree rate than prone SWL. This difference was consistent for both the first SWL session (OR 4.17; 95% CI 2.53-6.87; p < 0.00001) and the final session (OR 3.02; 95% CI 1.96-4.67; p < 0.00001). No differences in the mean number of shocks per SWL session, the mean percentage of power used in the first SWL session, and the mean number of SWL sessions per patient were observed between the positions. SWL complications were infrequent and the incidence was insufficient for further analysis. Conclusion: SWL is safe and effective for the management of distal ureteral calculi, and supine SWL is more effective than prone SWL for achieving a stone-free status. [ABSTRACT FROM AUTHOR]

Background/Aims: Stroke is among the top causes of death worldwide. Neuroprotective agents are thus considered as potentially powerful treatment of stroke. Methods: Using both HT22 cells and male Sprague-Dawley rats as in vitro and in vivo models, we investigated the effect of NaHS, an exogenous donor of H2S, on the focal cerebral ischemia-reperfusion (I/R) induced brain injury. Results: Administration of NaHS significantly decreased the brain infarcted area as compared to the I/R group in a dose-dependent manner. Mechanistic studies demonstrated that NaHS-treated rats displayed significant reduction of malondialdehyde content, and strikingly increased activity of superoxide dismutases and glutathione peroxidase in the brain tissues compared with I/R group. The enhanced antioxidant capacity as well as restored mitochondrial function are NaHS-treatment correlated with decreased cellular reactive oxygen species level and compromised apoptosis in vitro or in vivo in the presence of NaHS compared with control. Further analysis revealed that the inhibition of PARP-1 cleavage and AIF translocation are involved in the neuroprotective effects of NaHS. Conclusion: Collectively, our results suggest that NaHS has potent protective effects against the brain injury induced by I/R. NaHS is possibly effective through inhibition of oxidative stress and apoptosis. [ABSTRACT FROM AUTHOR]

Background The aim of this study was to investigate the distribution of epidermal growth factor receptor ( EGFR)vIII mutation in Chinese non-small cell lung cancer ( NSCLC) patients and to explore the likely relationship between EGFRvIII mutation and response to EGFR-tyrosine kinase inhibitors ( TKIs) in squamous cell carcinoma ( SCC). Methods Samples were derived from two patient cohorts: (i) 114 early-stage NSCLC who received surgical resection; and (ii) 31 advanced-stage SCC who received EGFR-TKI EGFRvIII. EGFR and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS) mutations were detected by reverse transcription polymerase chain reaction ( RT-PCR), denaturing high-performance liquid chromatography, and PCR-restriction fragment length polymorphism, respectively. The associations of EGFRvIII, EGFR, and KRAS mutations with clinical outcome of EGFR- TKI treatment were evaluated using the Kaplan- Meier method, descriptive analysis, and multi-variable Cox regression analysis. Results In the first cohort, EGFRvIII mutation was detected in eight of 114 (7.0%) patients, including 11.1% (6/54) SCC and 3.6% (2/55) adenocarcinomas ( ADC) ( P = 0.269). In the second cohort, five (16.1%) and 10 out of 31 advanced SCC presented EGFRvIII and EGFR mutations, respectively. No appreciable discrepancy of progression-free survival or disease control rate was detected between the patients with and without EGFRvIII mutation ( P > 0.05). However, longer median overall survival ( OS) was observed in patients harboring EGFRvIII compared to those without EGFRvIII, although the difference did not reach statistical significance. Conclusion The frequency of EGFRvIII mutation in SCC was higher than in ADC. SCC patients harboring EGFRvIII mutations had a tendency for prolonged OS. [ABSTRACT FROM AUTHOR]

One-dimensional (1-D) nanostructures have attracted enormous research interest due to their unique physicochemical properties and wide application potential. These 1-D nanofibers are being increasingly applied to biomedical fields owing to their high surface area-to-volume ratio, high porosity, and the ease of tuning their structures, functionalities, and properties. Many biomedical nanofiber reviews have focused on tissue engineering and drug delivery applications but have very rarely discussed their use as wound dressings. However, nanofibers have enormous potential as wound dressings and other clinical applications that could have wide impacts on the treatment of wounds. Herein, the authors review the main fabrication methods of nanofibers as well as requirements, strategies, and recent applications of nanofibers, and provide perspectives of the challenges and opportunities that face multifunctional nanofibers for active therapeutic applications. [ABSTRACT FROM AUTHOR]

Purpose After radical nephroureterectomy (RNU), approximately 22% to 47% of patients with upper tract urothelial carcinoma (UTUC) develop a subsequent intravesical recurrence (IVR). Considering this high incidence of occurrence, several risk factors were reported as predictive of IVR after RNU. Until recently, most of the risk factors were still under debate. The aim of study was to conduct a meta-analysis based on the recent literature to explore the risk factors for IVR after RNU for UTUC. Patients and methods An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was performed to identify relevant studies published before May 2013. The studies were included if they reported risk factors related to bladder or IVR after RNU for UTUC. Results Overall, 40 studies, with 12,010 patients, were included in our meta-analysis. Our study indicated that a statistically significant difference in IVR after RNU was found in the male vs. female patients (odds ratio [OR] = 0.72, 95% CI: 0.59–0.85), ureteral vs. renal pelvis (OR = 1.18, 95% CI: 1.00–1.36), T2–4 vs. Tis, Ta, and T1 (OR = 0.53, 95% CI: 0.40–0.66), larger vs. smaller tumor size (OR = 1.02, 95% CI: 1.01–1.03), and previous/synchronous bladder cancer vs. the absence of bladder cancer (OR = 1.59, 95% CI: 1.26–1.9). No significant differences in IVR after RNU were found in the younger vs. older age groups, multifocal tumors vs. single tumor, G3 vs. G1 and G2, high vs. low grade, N0 vs. N+, concomitant carcinoma in situ vs. the absence of carcinoma in situ, positive vs. negative lymphovascular invasion, open vs. laparoscopic nephroureterectomy, and endoscopic vs. transvesical technique. Conclusions Our study showed that female patient; ureteral tumor; larger tumor; Tis, Ta, and T1; and the history of bladder cancer were significant risk factors related to IVR after RNU. [ABSTRACT FROM AUTHOR]

Background Multiple prospective studies have demonstrated that epidermal growth factor receptor ( EGFR) exon 19 and exon 21 mutations are the most powerful predictive biomarkers of response to EGFR tyrosine kinase inhibitors ( TKIs) in advanced non-small-cell lung cancer ( NSCLC). However, there are few studies focused on patients with double mutations compared with a single mutation. Methods We retrospectively screened 1,525 samples of Chinese patients with advanced NSCLC who underwent EGFR mutation detections in tumor tissues at Peking University Cancer Hospital between February 2006 and March 2011. Thirty-two cases harboring double mutations were included in this study. The Kaplan- Meier univariate analysis for prognostic factors of survival was applied. Results Patients with double mutations accounted for 2.1% (32/1525) of the overall tested samples. Double mutations were more common in female, adenocarcinoma, non-smokers, Eastern Cooperative Oncology Group ( ECOG0)-1 and stage IV patients. Twenty-one patients with double mutations were treated with EGFR- TKIs. The objective response rate ( ORR) was 23.8%, and the disease control rate ( DCR) was 76.2%. In the first-line therapy, the ORR was 16.7%, and the DCR was 66.7%. In univariate analysis, gender, smoking-status, TKI type and TKI response were correlated with progression-free survival, and patients with ECOG 0-1 had longer overall survival. Conclusions Patients with double mutations had a low objective response rate when treated with EGFR- TKIs compared with single EGFR exon 19 or exon 21 mutations. [ABSTRACT FROM AUTHOR]

Although advances in understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) have suggested attractive treatment strategies, delivery of agents to motor neurons embedded within the spinal cord is problematic. We have designed a strategy based on the specificity of botulinum toxin, to direct entry of viral vectors carrying candidate therapeutic genes into motor neurons. We have engineered and expressed fusion proteins consisting of the binding domain of botulinum toxin type A fused to streptavidin (SAv). This fusion protein will direct biotinylated viral vectors carrying therapeutic genes into motor nerve terminals where they can enter the acidified endosomal compartments, be released and undergo retrograde transport, to deliver the genes to motor neurons. Both ends of the fusion proteins are shown to be functionally intact. The binding domain end binds to mammalian nerve terminals at neuromuscular junctions, ganglioside GT1b (a target of botulinum toxin), and a variety of neuronal cells including primary chick embryo motor neurons, N2A neuroblastoma cells, NG108-15 cells, but not to NG CR72 cells, which lack complex gangliosides. The streptavidin end binds to biotin, and to a biotinylated Alexa 488 fluorescent tag. Further studies are in progress to evaluate the delivery of genes to motor neurons in vivo, by the use of biotinylated viral vectors. [ABSTRACT FROM AUTHOR]