Photodynamic therapy is an emerging treatment modality that is under intensive preclinical and clinical investigations for many types of disease including cancer. Despite the promise, there is a lack of a reliable drug delivery vehicle that can transport photosensitizers (PSs) to tumors in a site-specific manner. Previous efforts have been focused on polymer- or liposome-based nanocarriers, which are usually associated with a suboptimal PS loading rate and a large particle size. We report herein that a RGD4C-modified ferritin (RFRT), a protein-based nanoparticle, can serve as a safe and efficient PS vehicle. Zinc hexadecafluorophthalocyanine (ZnF 16 Pc), a potent PS with a high 1 O 2 quantum yield but poor water solubility, can be encapsulated into RFRTs with a loading rate as high as ∼60 wt % (i.e., 1.5 mg of ZnF 16 Pc can be loaded on 1 mg of RFRTs), which far exceeds those reported previously. Despite the high loading, the ZnF 16 Pc-loaded RFRTs (P-RFRTs) show an overall particle size of 18.6 ± 2.6 nm, which is significantly smaller than other PS-nanocarrier conjugates. When tested on U87MG subcutaneous tumor models, P-RFRTs showed a high tumor accumulation rate (tumor-to-normal tissue ratio of 26.82 ± 4.07 at 24 h), a good tumor inhibition rate (83.64% on day 12), as well as minimal toxicity to the skin and other major organs. This technology can be extended to deliver other metal-containing PSs and holds great clinical translation potential.
Objective With the growing number of childhood cancer survivors in the US, it is important to assess the well-being of these individuals, particularly during the transitional phase of adolescence. Data about adolescent survivors' overall health and quality of life will help identify survivor subgroups most in need of targeted attention to successfully transition to adulthood. Participants and methods This ancillary study to the Childhood Cancer Survivor Study focused on children 15-19 years of age who had been diagnosed with cancer before the age of 4 years. A cohort of siblings of pediatric cancer survivors of the same ages served as a comparison sample. Adolescent health was assessed using the Child Health and Illness Profile-Adolescent Edition (CHIP-AE) survey. Results The teen survey was sent to 444 survivor teens and 189 siblings. Of these, 307(69%) survivors and 97 (51%) siblings completed and returned the survey. The overall health profiles of siblings and survivors were similar. Among survivors, females scored significantly below males on satisfaction, discomfort, and disorders domains. Survivors diagnosed with central nervous system tumors scored less favorably than leukemia survivors in the global domains of satisfaction and disorders. Conclusion In general, adolescent survivors fare favorably compared to healthy siblings. However, identification of the subset of pediatric cancer survivors who are more vulnerable to medical and psychosocial disorders in adolescence provides the opportunity for design and implementation of intervention strategies that may improve quality of life.
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of polyglutamine (polyQ) tract that leads to motor, cognitive and psychiatric impairment. Currently there is no cure for HD. A transgenic HD nonhuman primate (HD-NHP) model was developed with progressive development of clinical and pathological features similar to human HD, which suggested the potential preclinical application of the HD-NHP model. Elevated expression of miR-196a was observed in both HD-NHP and human HD brains. Cytotoxicity and apoptosis were ameliorated by the overexpression of miR-196a in HD-NHP neural progenitor cells (HD-NPCs) and differentiated neural cells (HD-NCs). The expression of apoptosis related gene was also down regulated. Mitochondrial morphology and activity were improved as indicated by mitotracker staining and the upregulation of CBP and PGC-1α in HD-NPCs overexpressing miR-196a. Here we demonstrated the amelioration of HD cellular phenotypes in HD-NPCs and HD-NCs overexpressing miR-196a. Our results also suggested the regulatory role of miR-196a in HD pathogenesis that may hold the key for understanding molecular regulation in HD and developing novel therapeutics.
It is highly desirable to develop novel approaches to improve patient survival rate of pancreatic cancer through early detection. Here, we present such an approach based on photoacoustic and fluorescence molecular imaging of pancreatic tumor using a miniature multimodal endoscope in combination with targeted multifunctional iron oxide nanoparticles (IONPs). A novel fan-shaped scanning mechanism was developed to minimize the invasiveness for endoscopic imaging of pancreatic tumors. The results show that the enhancements in photoacoustic and fluorescence signals using amino-terminal fragment (ATF) targeted IONPs were ~four to six times higher compared to that using non-targeted IONPs. Our study indicates the potential of the combination of the multimodal photoacoustic-fluorescence endoscopy and targeted multifunctional nanoparticles as an efficient tool to provide improved specificity and sensitivity for pancreatic cancer detection.
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Kimberly M. Ramonell;
Wenxiao Zhang;
Annette Hadley;
Ching-wen Chen;
Katherine T. Fay;
John D. Lyons;
Nathan J. Klingensmith;
Kevin McConnell;
Craig Coopersmith;
Mandy L Ford
Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi-organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis. Results indicate that CXCR4 is selectively upregulated on naïve CD4 + and CD8 + T cells and CD4 + central memory T cells following the induction of sepsis, and that CXCR4 antagonism resulted in a significant decrease in sepsis-induced mortality. We probed the mechanistic basis for these findings and found that CXCR4 antagonism significantly increased the number of peripheral CD4 + and CD8 + T cells following sepsis. Moreover, mice treated with the CXCR4 antagonist contained fewer PD-1+ LAG-3+ 2B4+ cells, suggesting that blockade of CXCR4 mitigates CD4 + T cell exhaustion during sepsis. Taken together, these results characterize CXCR4 as an important pathway that modulates immune dysfunction and mortality following sepsis, which may hold promise as a target for future therapeutic intervention in septic patients.
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Bidisha Paul;
Kendra J. Royston;
Yuanyuan Li;
Matthew L. Stoll;
Christine F. Skibola;
Landon S. Wilson;
Stephen Barnes;
Casey D. Morrow;
Trygve O. Tollefsbol
Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients’ intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients’ post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth.
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Kazuhito Kawata;
Masanobu Tsuda;
Guo-Xiang Yang;
Weici Zhang;
Hajime Tanaka;
Koichi Tsuneyama;
Patrick Leung;
Xiao-Song He;
Stuart Knechtle;
Aftab A Ansari;
Ross L. Coppel;
M. Eric Gershwin
Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, with the most highly directed and specific autoantibody in both murine and human autoimmunity, the anti-mitochondrial autoantibody (AMA). However, therapeutic advances in this disease have lagged behind. Herein we have taken advantage of our unique model of murine PBC in which mice immunized with 2-octynoic acid coupled to BSA (2OA-BSA), a compound identified by quantitative structure activity relationships (QSAR) of human AMA binding, develop an intense inflammatory cholangitis with striking similarities to humans with PBC. In particular, we have constructed several unique gene-deleted mice, including mice deleted of IL-12p40, IL-12p35, IFN-γ, IL-23p19, IL-17A, IL-17F and IL-22, immunized these animals with 2OA-BSA and followed the natural history of immunopathology to identify key pathways that might provide clues for successful therapy. Our data indicate that whereas both IL-12/Th1 and IL-23/Th17 are involved in cholangitis, it is the IL-12/Th1 signaling pathway that elicits pathology. In fact, deletion of IFN-γ prevents disease and suppresses autoantibodies. Importantly, deletion of the Th17 cytokines IL-17A and IL-22, but not IL-17F, reduces biliary damage; IL-17A-knockout mice have reduced levels of anti-mitochondrial antibody. We further demonstrate that the production of IFN-γ is significantly decreased in the liver of IL-23p19(-/-), IL-17A(-/-) and IL-22(-/-) mice compared with controls. However, the ability of T cells to produce IFN-γ was not affected in Th17 cytokine-deficient mice. Our data indicate that a deficient Th17 pathway suppresses the accumulation of IFN-γ producing cells in liver during the early phase of cholangitis. In conclusion, whereas IFN-γ has a pivotal role in the early events involved in the pathogenesis of autoimmune cholangitis induced by 2OA-BSA, the IL-23/Th17 pathway potentiates the effects of IL-12/IFN-γ-mediated immunopathology.
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Emanuel Krebs;
Benjamin Enns;
Linwei Wang;
Xiao Zang;
Dimitra Panagiotoglou;
Carlos Del Rio;
Julia Dombrowski;
Daniel J. Feaster;
Matthew Golden;
Reuben Granich;
Brandon Marshall;
Shruti H. Mehta;
Lisa Metsch;
Bruce R. Schackman;
Steffanie A. Strathdee;
Bohdan Nosyk
Background Dynamic HIV transmission models can provide evidence-based guidance on optimal combination implementation strategies to treat and prevent HIV/AIDS. However, these models can be extremely data intensive, and the availability of good-quality data characterizing regional microepidemics varies substantially within and across countries. We aim to provide a comprehensive and transparent description of an evidence synthesis process and reporting framework employed to populate and calibrate a dynamic, compartmental HIV transmission model for six US cities. Methods We executed a mixed-method evidence synthesis strategy to populate model parameters in six categories: (i) initial HIV-negative and HIV-infected populations; (ii) parameters used to calculate the probability of HIV transmission; (iii) screening, diagnosis, treatment and HIV disease progression; (iv) HIV prevention programs; (v) the costs of medical care; and (vi) health utility weights for each stage of HIV disease progression. We identified parameters that required city-specific data and stratification by gender, risk group and race/ethnicity a priori and sought out databases for primary analysis to augment our evidence synthesis. We ranked the quality of each parameter using context- and domain-specific criteria and verified sources and assumptions with our scientific advisory committee. Findings To inform the 1,667 parameters needed to populate our model, we synthesized evidence from 59 peer-reviewed publications and 24 public health and surveillance reports and executed primary analyses using 11 data sets. Of these 1,667 parameters, 1,517 (91%) were city-specific and 150 (9%) were common for all cities. Notably, 1,074 (64%), 201 (12%) and 312 (19%) parameters corresponded to categories (i), (ii) and (iii), respectively. Parameters ranked as best- to moderate-quality evidence comprised 39% of the common parameters and ranged from 56%-60% across cities for the city-specific parameters. We identified variation in parameter values across cities as well as within cities across risk and race/ethnic groups. Conclusions Better integration of modelling in decision making can be achieved by systematically reporting on the evidence synthesis process that is used to populate models, and by explicitly assessing the quality of data entered into the model. The effective communication of this process can help prioritize data collection of the most informative components of local HIV prevention and care services in order to reduce decision uncertainty and strengthen model conclusions.
Medulloblastoma, which is the most common malignant paediatric brain tumour, has a 70% survival rate, but standard treatments often lead to devastating life-long side effects and recurrence is fatal. One of the emerging strategies in the search for treatments is to determine the roles of tumour microenvironment cells in the growth and maintenance of tumours. The most attractive target is tumour-associated macrophages (TAMs), which are abundantly present in the Sonic Hedgehog (SHH) subgroup of medulloblastoma. Here, we report an unexpected beneficial role of TAMs in SHH medulloblastoma. In human patients, decreased macrophage number is correlated with significantly poorer outcome. We confirm macrophage anti-tumoural behaviour in both ex vivo and in vivo murine models of SHH medulloblastoma. Taken together, our findings suggest that macrophages play a positive role by impairing tumour growth in medulloblastoma, in contrast to the pro-tumoural role played by TAMs in glioblastoma, another common brain tumour.
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Panagiotis Vagenas;
Alexei Zelenev;
Frederick L. Altice;
Angela Di Paola;
Alison O. Jordan;
Paul A. Teixeira;
Paula Frew;
Anne Spaulding;
Sandra A. Springer
The US HIV/AIDS epidemic is concentrated among men who have sex with men (MSM). Black men are disproportionately affected by incarceration and Black MSM experience higher infection rates and worse HIV-related health outcomes compared to non-Black MSM. We compared HIV treatment outcomes for Black MSM to other HIV-infected men from one of the largest cohorts of HIV-infected jail detainees (N = 1270) transitioning to the community. Of the 574 HIV-infected men released, 113 (19.7%) self-identified as being MSM. Compared to other male subgroups, young Black MSM (<30 years old, N = 18) were significantly less likely: (1) before incarceration, to have insurance, access to an HIV healthcare provider, and use cocaine; (2) during incarceration, to receive a disease management intervention; and (3) in the 6 months post-release, to link to HIV care. Interventions that effectively link and retain young HIV-infected Black MSM in care in communities before incarceration and post-release from jail are urgently needed.