Search

Xiang She, Jia Chen, Yu-Neng Zhou, Jun Guo, Feng-Hua Zhao, Cong Yi Department of Pediatrics, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People’s Republic of ChinaCorrespondence: Cong Yi, Department of Pediatrics, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People’s Republic of China, Email congyi6649@126.comObjective: To summarize the clinical features and treatment experiences of patients with Kawasaki disease (KD)-associated acute abdomen (KD-AA).Methods: We conducted a retrospective case-control study of patients with KD-AA treated at our hospital between January 2006 and November 2022.Results: Of the 917 children with KD, 43 (4.7%) presented with AA. Of these, 33 with complete information were included in the KD-AA group. Patients with KD-AA were significantly older, with higher neutrophil rate, C‐reactive protein, procalcitonin, and alanine transaminase levels and lower hemoglobin, albumin, and serum sodium levels. Additionally, more patients with KD-AA presented with aseptic meningitis and KD shock syndrome than those with KD alone (all p< 0.05). The two groups did not differ in the incidence of intravenous immunoglobulin (IVIG) resistance, incomplete KD, or coronary artery abnormalities. All patients received aspirin and IVIG therapy, with nine receiving a second dose of IVIG and 11 receiving corticosteroids. Only two patients with KD-AA underwent surgery, and the prognosis of all patients with KD-AA was good.Conclusion: KD-AA should be suspected in febrile children with abdominal symptoms. Prompt diagnosis of KD-AA is important for early effective treatment to avoid unnecessary surgical harm. KD, complicated by acute abdomen, has a good prognosis.Keywords: Kawasaki disease, acute abdomen, clinical manifestation, treatment

Abstract Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.

This semi-analytical study is presented examining the quasi-steady creeping flow caused by a soft (composite) spherical particle, which is a hard (impermeable) sphere core covered by a porous (permeable) layer, translating in an incompressible Newtonian fluid within a non-concentric spherical cavity along the line joining their centers. To solve the Brinkman and Stokes equations for the flow fields inside and outside the porous layer, respectively, general solutions are constructed in two spherical coordinate systems attached to the particle and cavity individually. The boundary conditions at the cavity wall and particle surface are fulfilled through a collocation method. Numerical results of the normalized drag force exerted by the fluid on the particle are obtained for numerous values of the ratios of core-to-particle radii, particle-to-cavity radii, the distance between the centers to the radius difference of the particle and cavity, and the particle radius to porous layer permeation length. For the translation of a soft sphere within a concentric cavity or near a small-curvature cavity wall, our drag results agree with solutions available in the literature. The cavity effect on the drag force of a translating soft sphere is monotonically increasing functions of the ratios of core-to-particle radii and the particle radius to porous layer permeation length. While the drag force generally rises with an increase in the ratio of particle-to-cavity radii, a weak minimum (surprisingly, smaller than that for an unconfined soft sphere) may occur for the case of low ratios of core-to-particle radii and of the particle radius to permeation length. This drag force generally increases with an increase in the eccentricity of the particle position, but in the case of low ratios of core-to-particle radii and particle radius to permeation length, the drag force may decrease slightly with increasing eccentricity.

Cryo-EM structures of E. coli F1Fo ATP synthase highlight the role of the inhibitory ε subunit in regulating the torsional movement of the central stalk within the Fo motor and central stalk flexibility in coupling the F1 and Fo motors.

Xiang She, Yu-Neng Zhou, Jun Guo, Cong Yi Department of Pediatrics, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People’s Republic of ChinaCorrespondence: Cong Yi, Department of Pediatrics, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People’s Republic of China, Tel +8613980130553, Email congyi6649@126.comObjective: To summarize our clinical experience with the diagnosis and treatment of children with acute suppurative thyroiditis (AST).Methods: We retrospectively reviewed the clinical data of 18 children with AST treated at our hospital between January 2009 and May 2022.Results: There were 8 boys and 10 girls, aged 7.8 ± 3.8 years at admission. The main clinical manifestations were fever (88.9%), neck pain (100%), and neck mass (100%). Blood and pus cultures were performed in 9 and 15 patients, respectively. All blood cultures were negative, while positive pus cultures were noted in eight cases (six Streptococcus spp., one Staphylococcus spp., and one Streptococcus spp. and Staphylococcus spp. mixed infection). Additionally, all patients received antibiotic treatment: three received antibiotics alone, seven received antibiotics and ultrasound (US)-guided needle aspiration, seven received antibiotics as well as surgical incision and drainage, and one received antibiotics, US-guided needle aspiration in addition to surgical incision and drainage. Consequently, the average length of hospital stay in patients who received antibiotics and US-guided needle aspiration was 9.1± 2.9 days compared to 14.0± 2.0 days in patients in the antibiotics alone group and 13.0 ± 2.2 days in patients in the antibiotics and surgical incision and drainage group. Follow-up was conducted in 15 of the 18 patients. Three patients relapsed, and the prognosis of the other patients was good.Conclusion: AST has atypical clinical symptoms at the early stage. Regular monitoring of the thyroid gland using ultrasonography is strongly advised in unsure cases. Antibiotics combined with US-guided aspiration is a safe, effective, and minimally invasive treatment for AST in children and can reduce hospital stay. However, surgery may be necessary, particularly in the presence of complications. It is strongly recommended that patients with recurrence be examined for anatomical abnormalities and undergo radical treatment.Keywords: children, acute suppurative thyroiditis, clinical manifestation, treatment

Qian Ren,1 Caixia Yi,2 Jun Pan,1 Xin Sun,2 Xiao Huang2,3 1Key Laboratory for Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People’s Republic of China; 2School of Sports and Health Science, Tongren University, Tongren, People’s Republic of China; 3School of Physical Education, Guangxi University of Science and Technology, Guangxi, People’s Republic of ChinaCorrespondence: Jun Pan; Xiao Huang, Tel/Fax +86023-65102507, Email panj@cqu.edu.cn; humphrey8531@hotmail.comPurpose: Photodynamic therapy (PDT) is a non-invasive therapeutic modality that is used for several types of cancer and involves three essential elements (light, photosensitizer (PS), and oxygen). However, clinical PS is limited by the low yield of reactive oxygen species (ROS) and a long retention time. Therefore, developing a low-cost PS that can significantly increase ROS yield in a short time is of utmost importance.Methods: In this study, brusatol (Bru) was loaded on the surface of ultraviolet A (UVA)-responsive zinc oxide (ZnO)-coated magnetic nanoparticles (Fe3O4@ZnO-Bru). The PS was well characterized by transmission electron microscopy (TEM), Fourier Transform infrared spectroscopy (FTIR), a superconducting quantum interference device, and dynamic light scattering (DLS). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and Hoechst staining were used to determine the inhibitory effect of Fe3O4@ZnO-Bru on squamous cell carcinoma cells (SCC) with or without UVA radiation. Intracellular ROS levels and expression of the Nrf2 signaling pathway were also determined.Results: FTIR showed that Bru was successfully loaded on Fe3O4@ZnO. Fe3O4@ZnO-Bru was superparamagnetic, and the zeta potential was 8.86 ± 0.77 mV. The Bru release behavior was controlled by UVA. Fe3O4@ZnO-Bru with UVA irradiation induced an increase of 48% ROS productivity compared to Fe3O4@ZnO-Bru without UVA irradiation, resulting in a strong inhibitory effect on SCC. Furthermore, Fe3O4@ZnO-Bru nanocomposites (Fe3O4@ZnO-Bru NCs) had nearly no toxic effect on healthy cells without UVA radiation. The released Bru could significantly inhibit the Nrf2 signaling pathway to reduce the activity of scavenging excess ROS in SCC.Conclusion: In this study, Fe3O4@ZnO-Bru was successfully synthesized. PDT was combined with photochemotherapy, which exhibited a higher inhibitory effect on SCC. It can be inferred that Fe3O4@ZnO-Bru holds great potential for skin SCC therapy.Keywords: UVA-triggered chemotherapy, photodynamic therapy, reactive oxygen species, magnetic targeting

Xiliu Zhang,1 Hongyu Li,1,* Chen Yi,1,* Guosheng Chen,2 Ye Li,1 Ying Zhou,1 Guanhui Chen,1 Yiming Li,1 Yi He,1 Dongsheng Yu1 1Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, People’s Republic of China; 2MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongsheng YuGuanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, People’s Republic of ChinaEmail yudsh@mail.sysu.edu.cnIntroduction: With the innovation of photosensitizers, photodynamic therapy is now widely used in antitumor detection and treatment. Graphene quantum dots (GQDs) are proposed as a promising alternative photosensitizer due to their high biocompatibility, specific photoactivity, and strong tumor concentration. However, the changes in host immunity triggered by GQDs have only rarely been reported.Methods: In this work, GQDs as photosensitizers were conjugated to polyethylene glycol (PEG) to enhance solubility and blood circulation. The phototoxicity of the resulting GQD-PEG nanomaterials was then detected in vitro and in vivo. The antitumor immunity triggered by GQD-PEG under irradiation was further evaluated in an oral squamous cell carcinoma animal model.Results: The obtained GQD-PEG nanomaterials exhibited low cytotoxicity, good solution stability, and excellent endocytosis. Both in vitro and in vivo, all demonstrated strong ablation for oral squamous cell carcinoma under irradiation. Meanwhile, host-immunity-related CD8+ T cells (cytotoxic T lymphocytes) and proinflammatory cytokines, including IFN-γ and TNF-α, were significantly increased after photo-activated antitumor activity.Conclusion: These results highlight the dominant role of GQD-PEG in photodynamic therapy and could have significant implications for further combination therapy as a promising antitumor immune response strategy triggered by nanomaterials.Keywords: graphene quantum dots, photodynamic therapy, host immunity, oral squamous cell carcinoma

F1Fo ATP synthase consists of two coupled rotary molecular motors: the soluble ATPase F1 and the transmembrane Fo. Here, the authors present cryo-EM structures of E. coli ATP synthase in four discrete rotational sub-states at 3.1-3.4 Å resolution and observe a rotary sub-step of the Fo motor cring that reveals the mechanism of elastic coupling between the two rotary motors, which is essential for effective ATP synthesis.

Background: Primary cardiac angiosarcomas, especially those originating in the pericardium, are extremely rare and aggressive tumors with poor prognosis. These types of malignant tumors have diverse clinical presentations and are often masked by other comorbidities.Case Summary: Our hospital reported a 59-year-old woman who initially presented with pulmonary thromboembolism (PTE) and was subsequently treated with low-molecular-weight heparin. However, she experienced acute pericardial tamponade after anticoagulation therapy, where no obvious mass was primarily identified upon imaging, both in the pericardium or within the heart. Emergency pericardiocentesis and drainage were performed, where a total of 210 mL of bloody effusion was drained. Four months later, she was hospitalized with progressive hemoptysis and dyspnea. A large mixed mass occupying the right pericardium was later identified by coronary computed tomography angiography (CCTA). The mass was consistent with the right atrium, with heterogeneous thickened pericardium and localized moderate pericardial effusion. CCTA and positron emission tomography scans later showed metastases in both lungs and bilateral pleura. Nodules in hilar and mediastinal lymph nodes were also significant. Ultrasound-guided biopsy was performed, and the patient was ultimately diagnosed with an angiosarcoma based on final positive results for both CD31 and CD34 markers. The patient refused chemotherapy and passed away while waiting for her pathology results. The patient survived for 6 months since the first reported episode of PTE.Conclusions: Our case indicates that patients presenting with both embolism and hemorrhage should urgently be channeled to a clinical specialist to confirm any malignant etiology. This would be beneficial to confirm an early diagnosis and lengthen the duration of patient survival. However, the diagnosis of primary cardiac angiosarcoma is still challenging and requires multiple imaging modalities and biopsies in order to assist the accurate diagnosis of disease and achieve effective patient management.

Background: Patient satisfaction is one of the essential indicators for assessing the quality of healthcare services being delivered, including pharmacy ambulatory care service, as it determines the practicability and sustainability of the service provided. As such, pharmaceutical care services provided during medication therapy adherence clinic (MTAC) sessions need to be assessed to maximise its effectiveness and benefits to the patients. Objective: This study aimed to assess the association between patient satisfaction and socio-demographic characteristics, as well as the predictors for patient satisfaction. Methods: This was a cross-sectional study conducted at the medical outpatient department in Hospital Port Dickson from January until October 2019. Convenience sampling method was used to recruit potential study participants. Patient satisfaction was measured using Validated Patient Satisfaction with Pharmacist Services Questionnaire (PSPSQ2.0), consisted of quality of care and interpersonal relationship between pharmacist and patient domains. Descriptive data were presented as mean and standard deviation or numbers and percentages, while Independent Sample t-test, ANOVA and post-hoc analysis, and multiple linear regression were used for inferential data analysis. Results: There were 37 (25%) diabetes MTAC, 36 (24.3%) respiratory MTAC, and 75 (50.7%) warfarin MTAC patients recruited. On average, the mean overall satisfaction score was 3.30(SD=0.43). The mean satisfaction score in the interpersonal relationship domain [3.35(SD=0.44)] was higher than the quality of care domain [3.26(SD=0.45)]. There was a significant association between gender, education level, and patient satisfaction towards pharmaceutical care service (p

Julie Savelloni,1 Heather Gunter,2 Kelly C Lee,3 Chih Hsu,1 Cassia Yi,2 Kyle P Edmonds,4 Timothy Furnish,5 Rabia S Atayee1 1Department of Pharmacy, UC San Diego Health, San Diego, CA, USA; 2Department of Nursing, UC San Diego Health, San Diego, CA, USA; 3Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA; 4Department of Medicine, UC San Diego Health Sciences, San Diego, CA, USA; 5Department of Anesthesiology, UC San Diego Health, San Diego, CA, USA Introduction: The combination of opioids and central nervous system depressants such as benzodiazepines and barbiturates has an additive effect on the frequency of oversedation and respiratory depression requiring naloxone use in hospitalized patients. Gabapentinoids (gabapentin and pregabalin) are frequently prescribed with opioids for their opioid-sparing and adjuvant analgesic effects. There is limited literature on the risk of respiratory depression due to the combination of opioids and gabapentinoids requiring naloxone administration. Methods: This retrospective study evaluated patients who were prescribed opioids and at least one dose of naloxone between March 1, 2014 and September 30, 2016. The primary objective of this study was to compare the frequency of respiratory depression among patients who received naloxone and opioids (non-gabapentinoid group) with those who received naloxone, opioids, and gabapentinoids (gabapentinoid group). Secondary objectives included comparing the association of oversedation, using the Pasero Opioid-induced Sedation Scale, and various risk factors with those in the gabapentinoid group. Results: A total of 153 patient episodes of naloxone administration (102 in the non-gabapentinoid and 51 in the gabapentinoid groups) in 125 unique patients were included in the study. For the primary objective, there were 33 episodes of respiratory depression associated with the non-gabapentinoid group (33/102=32.4%) versus 17 episodes of respiratory depression with the gabapentinoid group (17/51=33.3%) (p=0.128). Secondary objectives showed a significant association between respiratory depression and surgery in the previous 24 hours (p=0.036) as well as respiratory depression and age >65 years (p=0.031) for patients in the non-gabapentinoid group compared to the gabapentinoid group. Conclusion: There was no significant association of respiratory depression in the gabapentinoid group versus the non-gabapentinoid group. There was an increased risk of respiratory depression in the gabapentinoid group, specifically in patients who had surgery within the previous 24 hours. Keywords: naloxone, opioid analgesics, respiratory depression, gabapentin, pregabalin, POSS

Yong-Jiang Li, Xi Yang, Wen-Biao Zhang, Cheng Yi, Feng Wang, Ping Li Department of Oncology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: Cancer-related systemic inflammation responses have been correlated with cancer development and progression. The prognostic significance of several inflammatory indicators, including neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), Glasgow Prognostic Score (GPS), C-reactive protein to albumin ratio (CRP/Alb ratio), lymphocyte–monocyte ratio (LMR), and neutrophil–platelet score (NPS), were found to be correlated with prognosis in several cancers. However, the prognostic role of these inflammatory biomarkers in Ewing sarcoma has not been evaluated. This study enrolled 122 Ewing patients. Receiver operating characteristic (ROC) analysis was generated to determine optimal cutoff values; areas under the curves (AUCs) were assessed to show the discriminatory ability of the biomarkers; Kaplan–Meier analysis was conducted to plot the survival curves; and Cox multivariate survival analysis was performed to identify independent prognostic factors. The optimal cutoff values of CRP/Alb ratio, NLR, PLR, and LMR were 0.225, 2.38, 131, and 4.41, respectively. CRP/Alb ratio had a significantly larger AUC than NLR, PLR, LMR, and NPS. Higher levels of CRP/Alb ratio (hazard ratio [HR] 2.41, P=0.005), GPS (HR 2.27, P=0.006), NLR (HR 2.07, P=0.013), and PLR (HR 1.85, P=0.032) were significantly correlated with poor prognosis. As the biomarkers had internal correlations, only the CRP/Alb ratio was involved in the multivariate Cox analysis and remained an independent prognostic indicator. The study demonstrated that CRP/Alb ratio, GPS, and NLR were effective prognostic indicators for patients with Ewing sarcoma, and the CRP/Alb ratio was the most robust prognostic indicator with a discriminatory ability superior to that of the other indicators; however, PLR, LMR, and NPS may not be suitable as prognostic indicators in Ewing sarcoma. Keywords: Ewing sarcoma, inflammatory biomarkers, prognosis, survival, CRP/Alb ratio

Ling Gao,1,* Li Wang,2,* Zhen Sun,3 Haiyan Li,3 Qiaoping Wang,3 Cheng Yi,1 Xiujie Wang3 1Department of Abdominal Cancer, 2Laboratory of Lung Cancer, Lung Cancer Center, 3Laboratory of Experimental Oncology, West China Hospital, West China Clinical Medical School, Sichuan University, Chengdu, People’s Republic of China *These authors contributed equally to this work Abstract: Hepatocellular carcinoma (HCC) is one of the most aggressive cancers with high mortality worldwide. Research and development of novel agents for HCC therapy is in demand, urgently. Morusin has been reported to exhibit potential cytotoxic activity in several cancer cell lines. However, whether it has potential antiangiogenic activity especially in HCC remains unclear. In the current study, we found that morusin exerted growth inhibition effects on human HCC cells (HepG2 and Hep3B) in vitro and human HCC cell (HepG2) xenografts in vivo. Moreover, apoptosis induction was observed in a dose-dependent manner after morusin treatment along with an increase in the expression of active caspase-3 and the Bax/Bcl-2 expression ratio. More importantly, morusin inhibited proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and downregulated angiogenic proteins in HCC cells and HUVECs. In vivo, tumor angiogenesis was also attenuated after morusin treatment. In addition, morusin suppressed constitutive as well as IL-6-induced STAT3 phosphorylation in HCC cells and corresponding tumor tissues. Overall, morusin has a potential anticancer effect on human HCC cells in vitro and in vivo by inducing apoptosis and inhibiting anti-angiogenesis. The corresponding mechanism might be associated with the attenuation of the IL-6/STAT3 signaling pathway. Morusin might serve as a promising novel anticancer agent in HCC therapy, and requires further study. Keywords: morusin, human hepatocellular carcinoma, apoptosis, angiogenesis, IL-6, STAT3

Ning Wang, Zhihan Wang,* Shihong Nie,* Linjiang Song, Tao He, Suleixin Yang, Xi Yang, Cheng Yi, Qinjie Wu, Changyang Gong State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China *These authors contributed equally to this work Abstract: The combination of chemotherapy drugs attracts more attention in clinical cancer trials. However, the poor water solubility of chemotherapeutic drugs restricts their anticancer application. In order to improve antitumor efficiency and reduce side effects of free drugs, we prepared paclitaxel (PTX) and honokiol (HK) combination methoxy poly(ethylene glycol)–poly(caprolactone) micelles (P–H/M) by solid dispersion method against breast cancer. The particle size of P–H/M was 28.7±2.5 nm, and transmission electron microscope image confirmed that P–H/M were spherical in shape with small particle size. After being encapsulated in micelles, the release of PTX or HK showed a sustained behavior in vitro. In addition, both the cytotoxicity and the cellular uptake of P–H/M were increased in 4T1 cells, and P–H/M induced more apoptosis than PTX-loaded micelles or HK-loaded micelles, as analyzed by flow cytometry assay and Western blot. Furthermore, the antitumor effect of P–H/M was significantly improved compared with PTX-loaded micelles or HK-loaded micelles in vivo. P–H/M were more effective in inhibiting tumor proliferation, inducing tumor apoptosis, and decreasing the density of microvasculature. Moreover, bioimaging analysis showed that drug-loaded polymeric micelles could accumulate more in tumor tissues compared with the free drug. Our results suggested that P–H/M may have potential applications in breast cancer therapy. Keywords: paclitaxel, honokiol, micelles, codelivery, breast cancer

We describe an easy-to-assemble and robust design of a ConFlat (CF) iris diaphragm device installed in a vacuum environment with its aperture size directly adjustable by users outside the vacuum. This design involves commercially available vacuum equipment, 3D-printed but vacuum-compatible components and a minimal need of professional machining to be straightforwardly taken advantage by a wide range of research groups. The iris diaphragm is centered in a 4.5 in. o.d. double-sided CF flange with user-customizable mounting orientation to allow a maximum range of aperture opening from 0.5 mm to 15 mm in diameter. Installation of this device does not require an additional pump for differential pumping across the iris diaphragm. The functionality of this device is examined at a pressure of ∼7 ×10−9 Torr to provide continuous control on the cross section of a light beam passed through the aperture.

The nasal mucosa provides first line defense against inhaled pathogens while creating a unique microenvironment for bacterial communities. Studying the impact of microbiota in the nasal cavity has been difficult due to limitations with current models including explant cultures, primary cells, or neoplastic cell lines. Most notably, none have been shown to support reproducible colonization by bacterial communities from human donors. Therefore, to conduct controlled studies of the human nasal ecosystem, we have developed a novel ex vivo mucosal model that supports bacterial colonization of a cultured host mucosa created by immortalized human nasal epithelial cells (NEC). For this model, immortalized NEC established from 5 male and 5 female donors were cultured with an air-interfaced, apical surface on a porous transwell membrane. NEC were grown from nasal turbinate tissues harvested from willed bodies or from discarded tissue collected during sinonasal procedures. Immortalized cells were evaluated through molecular verification of cell type, histological confirmation of tissue differentiation including formation of tight junctions, NEC multilayer viability, metabolism, physiology and imaging of the luminal surface by scanning electron microscopy. Results showed proper differentiation and multilayer formation at seven to 10 days after air interface that was maintained for up to 3 weeks. The optimized mucosal cultures created an environment necessary to sustain colonization by nasal microbiomes (NMBs) that were collected from healthy volunteers, cryogenically preserved and characterized with customized quantitative polymerase chain reaction (qPCR) arrays. Polymicrobial communities of nasal bacteria associated with healthy and inflamed states were consistently reproduced in matured NEC co-cultures by transplant of NMBs from multiple community types. The cultured NMBs were stable after an initial period of bacterial replication and equilibration. This novel ex vivo culture system is the first model that supports controlled cultivation of NMBs, allowing for lab-based causation studies and further experimentation to explore the complexities of host-microbe and microbe-microbe interactions.

Human induced pluripotent stem cells (iPSCs) can be differentiated in vitro into bona fide cardiomyocytes for disease modelling and personalized medicine. Mitochondrial morphology and metabolism change dramatically as iPSCs differentiate into mesodermal cardiac lineages. Inhibiting mitochondrial fission has been shown to promote cardiac differentiation of iPSCs. However, the effect of hydrazone M1, a small molecule that promotes mitochondrial fusion, on cardiac mesodermal commitment of human iPSCs is unknown. Here, we demonstrate that treatment with M1 promoted mitochondrial fusion in human iPSCs. Treatment of iPSCs with M1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. The pro-fusion and pro-cardiogenic effects of M1 were not associated with changes in expression of the α and β subunits of adenosine triphosphate (ATP) synthase. Our findings demonstrate for the first time that hydrazone M1 is capable of promoting cardiac differentiation of human iPSCs, highlighting the important role of mitochondrial dynamics in cardiac mesoderm lineage specification and cardiac development. M1 and other mitochondrial fusion promoters emerge as promising molecular targets to generate lineages of the heart from human iPSCs for patient-specific regenerative medicine.

BAFF, an activator of the noncanonical NFκB pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NFκB family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric IκBsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of IκBsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NFκB network states during B cell biology, which causes BAFF to have context-dependent functional consequences.

Savelloni J, Gunter H, Lee KC, et al. J Pain Res. 2017;10: 2635–2641. Page 2640, References, the references 13 and 14 are in the incorrect order and should read as shown below. 13. Keskinbora K, Pekel AF, Aydinli I. Gabapentin and an opioid combinationversus opioid alone for the management of neuropathic cancer pain:a randomized open trial. J Pain Symptom Manage. 2007;34(2):183–189. 14. Meisenberg B, Ness J, Rao S, Rhule J, Ley C. Implementation of solutionsto reduce opioid-induced oversedation and respiratory depression.Am J Health Syst Pharm. 2017;74(3):162–169. Read the original article.

Chengxue Yi,* Hui Zhong,* Shanshan Tong,* Xia Cao,* Caleb K Firempong, Hongfei Liu, Min Fu, Yan Yang, Yingshu Feng, Huiyun Zhang, Ximing Xu, Jiangnan Yu Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, People's Republic of China*These authors contributed equally to this workPurpose: To investigate the growth inhibition activity of Flammulina velutipes sterol (FVS) against certain human cancer cell lines (gastric SGC and colon LoVo) and to evaluate the optimum microemulsion prescription, as well as the pharmacokinetics of encapsulated FVS.Methods: Molecules present in the FVS isolate were identified by gas chromatography/mass spectrometry analysis. The cell viability of FVS was assessed with methyl thiazolyl tetrazolium (MTT) bioassay. Based on the solubility study, phase diagram and stability tests, the optimum prescription of F. velutipes sterol microemulsions (FVSMs) were determined, followed by FVSMs characterization, and its in vivo pharmacokinetic study in rats.Results: The chemical composition of FVS was mainly ergosterol (54.8%) and 22,23-dihydroergosterol (27.9%). After 72 hours of treatment, both the FVS (half-maximal inhibitory concentration [IC50] = 11.99 µg • mL-1) and the standard anticancer drug, 5-fluorouracil (IC50 = 0.88 µg • mL-1) exhibited strong in vitro antiproliferative activity against SGC cells, with IC50 > 30.0 µg • mL-1; but the FVS performed poorly against LoVo cells (IC50 > 40.0 µg • mL-1). The optimal FVSMs prescription consisted of 3.0% medium chain triglycerides, 5.0% ethanol, 21.0% Cremophor EL and 71.0% water (w/w) with associated solubility of FVS being 0.680 mg • mL-1 as compared to free FVS (0.67 µg • mL-1). The relative oral bioavailability (area-under-the-curve values of ergosterol and 22,23-dihydroergosterol showed a 2.56-fold and 4.50-fold increase, respectively) of FVSMs (mean diameter ~ 22.9 nm) as against free FVS were greatly enhanced.Conclusion: These results indicate that the FVS could be a potential candidate for the development of an anticancer drug and it is readily bioavailable via microemulsion formulations.Keywords: Flammulina velutipes sterol, microemulsions, pharmacokinetics, bioavailability

Small cell lung cancer (SCLC) is characterized by rapid progression and low survival rates. Therefore, novel therapeutic agents are urgently needed for this disease. Capsaicin, the active ingredient of chilli peppers, displays anti-proliferative activity in prostate and epidermoid cancer in vitro. However, the anti-proliferative activity of capsaicin has not been studied in human SCLCs. The present manuscript fills this void of knowledge and explores the anti-proliferative effect of capsaicin in SCLC in vitro and in vivo.BrdU assays and PCNA ELISAs showed that capsaicin displays robust anti-proliferative activity in four human SCLC cell lines. Furthermore, capsaicin potently suppressed the growth of H69 human SCLC tumors in vivo as ascertained by CAM assays and nude mice models. The second part of our study attempted to provide insight into molecular mechanisms underlying the anti-proliferative activity of capsaicin. We found that the anti-proliferative activity of capsaicin is correlated with a decrease in the expression of E2F-responsive proliferative genes like cyclin E, thymidylate synthase, cdc25A and cdc6, both at mRNA and protein levels. The transcription factor E2F4 mediated the anti-proliferative activity of capsaicin. Ablation of E2F4 levels by siRNA methodology suppressed capsaicin-induced G1 arrest. ChIP assays demonstrated that capsaicin caused the recruitment of E2F4 and p130 on E2F-responsive proliferative promoters, thereby inhibiting cell proliferation.Our findings suggest that the anti-proliferative effects of capsaicin could be useful in the therapy of human SCLCs.