Description: PALLD is an actin cross-linker supporting cellular mechanical tension. However, its involvement in the regulation of phagocytosis, a cellular activity essential for innate immunity and physiological tissue turnover, is unclear. We report that PALLD is highly induced along with all- trans -retinoic acid–induced maturation of myeloid leukemia cells, to promote Ig- or complement-opsonized phagocytosis. PALLD mechanistically facilitates phagocytic receptor clustering by regulating actin polymerization and c-Src dynamic activation during particle binding and early phagosome formation. PALLD is also required at the nascent phagosome to recruit phosphatase oculocerebrorenal syndrome of Lowe, which regulates phosphatidylinositol-4,5-bisphosphate hydrolysis and actin depolymerization to complete phagosome closure. Collectively, our results show a new function for PALLD as a crucial regulator of the early phase of phagocytosis by elaborating dynamic actin polymerization and depolymerization.

Description: Objective To identify the reasons for low adherence among patients with diabetic retinopathy (DR) in southern China using a qualitative method. Methods Exploratory indepth interviews were conducted in 27 diabetic patients with proliferative diabetic retinopathy who required vitrectomy surgery at Zhongshan Ophthalmic Centre, Sun Yat-sen University, from March to August 2015. Qualitative data analysis and research software (ATLAS.ti7) was used for data processing and analysis. Results Factors influencing the occurrence of timely visits included lack of DR related knowledge, fear and worries about insulin, interactions between patients and society combined with the complexity of emotions and social culture, and the economic burden of treatment. Conclusions Although the reasons for low adherence involved social, emotional, cultural and economic factors, the key issue was the lack of awareness and knowledge of DR. Our findings have several practical implications for health policymakers and programme planners in China.

Description: Long intergenic noncoding RNAs (lincRNAs) are long noncoding transcripts (〉200 nt) from the intergenic regions of annotated protein-coding genes. One of the most highly induced lincRNAs in macrophages upon TLR ligation is lincRNA-Cox2, which was recently shown to mediate the activation and repression of distinct classes of immune genes in innate immune cells. We report that lincRNA-Cox2 , located at chromosome 1 proximal to the PG-endoperoxide synthase 2 ( Ptgs2/Cox2 ) gene, is an early-primary inflammatory gene controlled by NF-B signaling in murine macrophages. Functionally, lincRNA-Cox2 is required for the transcription of NF-B–regulated late-primary inflammatory response genes stimulated by bacterial LPS. Specifically, lincRNA-Cox2 is assembled into the switch/sucrose nonfermentable (SWI/SNF) complex in cells after LPS stimulation. This resulting lincRNA-Cox2/SWI/SNF complex can modulate the assembly of NF-B subunits to the SWI/SNF complex, and ultimately, SWI/SNF-associated chromatin remodeling and transactivation of the late-primary inflammatory-response genes in macrophages in response to microbial challenge. Therefore, our data indicate a new regulatory role for NF-B–induced lincRNA-Cox2 as a coactivator of NF-B for the transcription of late-primary response genes in innate immune cells through modulation of epigenetic chromatin remodeling.

Description: Radiolabeled somatostatin analog therapy has become an established treatment method for patients with well to moderately differentiated unresectable or metastatic neuroendocrine tumors (NETs). The most frequently used somatostatin analogs in clinical practice are octreotide and octreotate. However, both peptides showed suboptimal retention within tumors. The aim of this first-in-humans study is to explore the safety and dosimetry of a long-acting radiolabeled somatostatin analog, 177 Lu-1, 4, 7, 10-tetra-azacyclododecane-1, 4, 7, 10-tetraacetic acid-Evans blue-octreotate ( 177 Lu-DOTA-EB-TATE). Methods: Eight patients (6 men and 2 women; age range, 27–61 y) with advanced metastatic NETs were recruited. Five patients received a single dose, 0.35–0.70 GBq (9.5–18.9 mCi), of 177 Lu-DOTA-EB-TATE and underwent serial whole-body planar and SPECT/CT scans at 2, 24, 72, 120, and 168 h after injection. The other 3 patients received intravenous injection of 0.28–0.41 GBq (7.5–11.1 mCi) of 177 Lu-DOTATATE for the same imaging acquisition procedures at 1, 3, 4, 24, and 72 h after injection. The dosimetry was calculated using the OLINDA/EXM 1.1 software. Results: Administration of 177 Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms being noticed or reported in any of the patients. Compared with 177 Lu-DOTATATE, 177 Lu-DOTA-EB-TATE showed extended circulation in the blood and achieved a 7.9-fold increase of tumor dose delivery. The total-body effective doses were 0.205 ± 0.161 mSv/MBq for 177 Lu-DOTA-EB-TATE and 0.174 ± 0.072 mSv/MBq for 177 Lu-DOTATATE. Significant dose delivery increases to the kidneys and bone marrow were also observed in patients receiving 177 Lu-DOTA-EB-TATE compared with those receiving 177 Lu-DOTATATE (3.2 and 18.2-fold, respectively). Conclusion: By introducing an albumin-binding moiety, 177 Lu-DOTA-EB-TATE showed remarkably higher uptake and retention in NETs as well as significantly increased accumulation in the kidneys and red marrow. It has great potential to be used in peptide receptor radionuclide therapy for NETs with lower dose and less frequency of administration.

Description: Cancer-initiating/sustaining stem cell subsets (CSCs) have the potential to regenerate cancer cell populations and are resistant to routine therapeutic strategies, thus attracting much attention in anticancer research. In this study, an innovative framework of endogenous microenvironment-renewal for addressing such a dilemma has been just developed. CSCs in three-dimensional multipotent spheroid-engineered biologics were prepared with 150 Gy radiation and inoculated into 15-mo-old BALB/c and C57BL/6 mice bearing diverse advanced tumors covering Mammary 4T1, liver Hepa, lung LL/2, and colon C26 tumors and distant metastases. Subsequently, the systematic microenvironment of tumor-bearing hosts was rapidly remodeled to resettle thymic cortex and medulla rudiment as an endogenous foxn1-thymosin reprogramming TCR-repertoire for resetting MHC-unrestricted multifunction renewal. Postrenewal V4T-subsets would bind and lead migrating CSCs into apoptosis. Moreover, TCR repertoire multifunction renewal could reverse tumor metastases from tumoricidal resistance into eventual regression as a blockade of cancer-sustaining Bmi-1/Nanog-Oct4-Sox2 renewal loop with sequent multivalent depletion of both migrating/in situ CSCs and non–stem terminal cancer cell subsets. This study represents a promising start to set up a generalizable strategy of three-dimensional biologics evoking an endogenous integral microenvironment into pluripotent renewal versus advanced cancer.

Description: Low-dose IL-2 represents an immunotherapy to selectively expand regulatory T cells (Tregs) to promote tolerance in patients with autoimmunity. In this article, we show that a fusion protein (FP) of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, has greater in vivo efficacy than rIL-2 at Treg expansion and control of autoimmunity. Biochemical and functional studies support a model in which IL-2 interacts with CD25 in the context of this FP in trans to form inactive head-to-tail dimers that slowly dissociate into an active monomer. In vitro, IL-2/CD25 has low sp. act. However, in vivo IL-2/CD25 is long lived to persistently and selectively stimulate Tregs. In female NOD mice, IL-2/CD25 administration increased Tregs within the pancreas and reduced the instance of spontaneous diabetes. Thus, IL-2/CD25 represents a distinct class of IL-2 FPs with the potential for clinical development for use in autoimmunity or other disorders of an overactive immune response.

Description: Cryptosporidium is an important opportunistic intestinal pathogen for immunocompromised individuals and a common cause of diarrhea in young children in developing countries. Gastrointestinal epithelial cells play a central role in activating and orchestrating host immune responses against Cryptosporidium infection, but underlying molecular mechanisms are not fully understood. We report in this paper that C. parvum infection causes significant alterations in long noncoding RNA (lncRNA) expression profiles in murine intestinal epithelial cells. Transcription of a panel of lncRNA genes, including NR_045064 , in infected cells is controlled by the NF-B signaling. Functionally, inhibition of NR_045064 induction increases parasite burden in intestinal epithelial cells. Induction of NR_045064 enhances the transcription of selected defense genes in host cells following C. parvum infection. Epigenetic histone modifications are involved in NR_045064-mediated transcription of associated defense genes in infected host cells. Moreover, the p300/MLL-associated chromatin remodeling is involved in NR_045064-mediated transcription of associated defense genes in intestinal epithelial cells following C. parvum infection. Expression of NR_045064 and associated genes is also identified in intestinal epithelium in C57BL/6J mice following phosphorothioate oligodeoxynucleotide or LPS stimulation. Our data demonstrate that lncRNAs, such as NR_045064, play a role in regulating epithelial defense against microbial infection.

Description: APCs are essential for the orchestration of antitumor T cell responses. Batf3-lineage CD8α + and CD103 + dendritic cells (DCs), in particular, are required for the spontaneous initiation of CD8 + T cell priming against solid tumors. In contrast, little is known about the APCs that regulate CD8 + T cell responses against hematological malignancies. Using an unbiased approach, we aimed to characterize the APCs responsible for regulating CD8 + T cell responses in a syngeneic murine leukemia model. We show with single-cell resolution that CD8α + DCs alone acquire and cross-present leukemia Ags in vivo, culminating in the induction of leukemia-specific CD8 + T cell tolerance. Furthermore, we demonstrate that the mere acquisition of leukemia cell cargo is associated with a unique transcriptional program that may be important in regulating tolerogenic CD8α + DC functions in mice with leukemia. Finally, we show that systemic CD8α + DC activation with a TLR3 agonist completely prevents their ability to generate leukemia-specific CD8 + T cell tolerance in vivo, resulting instead in the induction of potent antileukemia T cell immunity and prolonged survival of leukemia-bearing mice. Together, our data reveal that Batf3-lineage DCs imprint disparate CD8 + T cell fates in hosts with solid tumors versus systemic leukemia.

Description: Objectives To estimate prevalence and clustering of cardiovascular risk factors (CRFs), and investigate the association between relevant characteristics and CRF clustering among adults in eastern China. Design Community-based cross-sectional study. Setting Data were collected by interview survey, physical measurements and laboratory examinations from the 2011 Nanjing Chronic Disease and Risk Factor Surveillance. Participants A representative sample of 41 072 residents aged ≥18 years volunteered to participate in the survey, with a response rate of 91.3%. We excluded 1232 subjects due to missing data or having a history of cardiovascular diseases; a total of 39 840 participants were included in the analysis. Outcome measures Prevalence and clustering of five major CRFs including hypertension, diabetes, dyslipidaemia, overweight or obesity and current smoking. Results Of 39 840 participants (mean age 47.9±16.2 years), 17 964 (45.1%) were men and 21 876 (54.9%) were women. The weighted prevalence of CRFs ranged between 6.2% for diabetes and 35.6% for overweight or obesity. The proportion of CRFs tended to be higher in men, the elderly, participants who lost a life partner, or lived in rural areas, or had lower level of education and total annual income. Overall, 30.1% and 35.2% of participants had one and at least two CRFs, respectively. Multivariate logistic regression revealed that men, older age, loss of a life partner, lower level of socioeconomic status, rural areas, insufficient physical activity or unhealthy diets were positively associated with CVD risk factor clustering, compared with their counterparts. Conclusions High regional prevalence of hypertension, dyslipidaemia, overweight or obesity and their clustering are present in Nanjing. The Nanjing government should develop effective public health policies at the regional level especially for high-risk groups, such as enhancing the public’s health awareness, organising health promotion programmes, implementing smoke-free law, producing healthy nutrient foods, providing free or low-cost public sports and fitness facilities.

Description: This study presents the preparation and measurement of a novel environmentally friendly konjac glucomannan (KGM)-based composite aerogels enhanced with wheat straw (WS) via a sol–gel and freeze-drying progress. With the addition of WS, the porosity of aerogels could be increased from 50 to 88.13%, the filtration resistance of aerogels could be reduced from 500 to 205 Pa, and the filtration efficiency could be improved to 90.38%. The addition of WS also enhances the mechanical properties of composite aerogels with compression modulus of 2000.66 Pa, compressive strength of 501.56 Pa and elasticity of 0.603. The results demonstrate the high potential of KGM-based composite aerogels enhanced with WS for applications in air filtering.