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Remodeling Tumor Immune Microenvironment by Using Polymer-Lipid-Manganese Dioxide Nanoparticles with Radiation Therapy to Boost Immune Response of Castration-Resistant Prostate Cancer

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Research 2024年第3期2023卷 83-96页

作者： Abdulmottaleb E.Zetrini HoYin Lip Azhar Z.Abbasi Ibrahim Alradwan Taksim Ahmed Chunsheng He Jeffrey T.Henderson Andrew M.Rauth Xiao Yu Wu Advanced Pharmaceutics and Drug Delivery Laboratory Leslie Dan Faculty of PharmacyUniversity of TorontoM5S 3M2TorontoONCanada. Departments of Medical Biophysics and Radiation Oncology University of TorontoM5G 1L7TorontoONCanada.

Despite substantial progress in the treatment of castration-resistant prostate cancer (CRPC), including radiation therapy and immunotherapy alone or in combination, the response to treatment remains poor due to the hypoxic and immunosuppressive nature of the tumor microenvironment. Herein, we exploited the bioreactivity of novel polymer–lipid manganese dioxide nanoparticles (PLMDs) to remodel the tumor immune microenvironment (TIME) by increasing the local oxygen levels and extracellular pH and enhancing radiation-induced immunogenic cell death. This study demonstrated that PLMD treatment sensitized hypoxic human and murine CRPC cells to radiation, significantly increasing radiation-induced DNA double-strand breaks and ultimately cell death, which enhanced the secretion of damage-associated molecular patterns, attributable to the induction of autophagy and endoplasmic reticulum stress. Reoxygenation via PLMDs also polarized hypoxic murine RAW264.7 macrophages toward the M1 phenotype, enhancing tumor necrosis factor alpha release, and thus reducing the viability of murine CRPC TRAMP-C2 cells. In a syngeneic TRAMP-C2 tumor model, intravenous injection of PLMDs suppressed, while radiation alone enhanced recruitment of regulatory T cells and myeloid-derived suppressor cells. Pretreatment with PLMDs followed by radiation down-regulated programmed death-ligand 1 and promoted the infiltration of antitumor CD8+ T cells and M1 macrophages to tumor sites. Taken together, TIME modulation by PLMDs plus radiation profoundly delayed tumor growth and prolonged median survival compared with radiation alone. These results suggest that PLMDs plus radiation is a promising treatment modality for improving therapeutic efficacy in radioresistant and immunosuppressive solid tumors.

关键词： RAW264.7 alone treatment

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An emerging terpolymeric nanoparticle pore former as an internal recrystallization inhibitor of celecoxib in controlled release amorphous solid dispersion beads:Experimental studies and molecular dynamics analysis

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2669-2684页

作者： Jamie Anne Lugtu-Pe Xuning Zhang Sako Mirzaie Hao Han R.Chang Nour AL-Mousawi Kuan Chen Yongqiang Li Anil Kane daniel Bar-Shalom Xiao Yu Wu Advanced Pharmaceutics and Drug Delivery Laboratory Leslie Dan Faculty of PharmacyUniversity of TorontoToronto M5S 3M2Canada Candoo Pharmatech Company Inc. Mississauga L5N 5M1Canada Department of pharmacy University of CopenhagenCopenhagen DK-2100Denmark Patheon by Thermo Fisher Scientific Toronto Region Operations(TRO)Mississauga L5N 3X4Canada

Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution ***,most new chemical entities exhibit poor water solubility,and hence are exempt from such *** combining drug amorphization with controlled release formulation is promising to elevate drug solubility,like other supersaturating systems,the problem of drug recrystallization has yet to be resolved,particularly within the dosage ***,we explored the potential of an emerging,non-leachable terpolymer nanoparticle(TPN)pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion(CRASD)beads comprising a poorly soluble drug(celecoxib)reservoir and insoluble polymer(ethylcellulose)*** to conventional pore former,polyvinylpyrrolidone(PVP),TPN-containing membranes exhibited superior structural integrity,less crystal formation at the CRASD bead surface,and greater extent of celecoxib ***-atom molecular dynamics analyses revealed that in the presence of TPN,intra-molecular bonding,crystal formation tendency,diffusion coefficient,and molecular flexibility of celecoxib were reduced,while intermolecular H-bonding was increased as compared to *** work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.

关键词： Controlled release amorphous solid dispersion Poorly soluble drug Internal recrystallization Membrane-reservoir coated beads Molecular dynamics simulation Effect of pore formers Terpolymer nanogel Drug-polymer interactions

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SARS-CoV-2 RBD and Its Variants Can Induce Platelet Activation and Clearance:Implications for Antibody Therapy and Vaccinations against COVID-19

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Research 2024年第3期2023卷 1-15页

作者： Xiaoying Ma Jady Liang Guangheng Zhu Preeti Bhoria Aron A.Shoara daniel T.MacKeigan Christopher J.Khoury Sladjana Slavkovicl Lisha Lin danielle Karakas Ziyan Chen Viktor Prifti Zhenze Liu Chuanbin Shen Yuchong Li Cheng Zhang Jiayu Dou Zack Rousseau Jiamin Zhang Tiffany Ni Xi Lei Pingguo Chen Xiaoyu Wu Hamed Shaykhalishahi Samira Mubareka Kim AConnelly Haibo Zhang Ori Rotstein Heyu Ni Department of Laboratory Medicine and Pathobiology University of TorontoTorontoONCanada Department of Laboratory Medicine Keenan Research Centre for Biomedical Science of St.Michael’s HospitalTorontoONCanada Toronto Platelet Immunobiology Group TorontoONCanada Department of Physiology University of TorontoTorontoONCanada CCOA Therapeutics Inc. TorontoONCanada Canadian Blood Services Centre for Innovation TorontoONCanada The State Key Laboratory of Respiratory Disease Guangzhou Institute of Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina Department of Laboratory Medicine The Second Affliated Hospital of Guangzhou University of Chinese MedicineGuangzhouChina Advanced Pharmaceutics&Drug Delivery Laboratory Leslie Dan Faculty of PharmacyUniversity of TorontoTorontoONCanada Department of Medical Microbiology and Infectious Disease Sunnybrook Health Science CentreToronto ONCanada Department of Medicine University of TorontoTorontoONCanada Division of Cardiology.St.Michael's Hospital TorontoONCanada Department of Anesthesiology and Pain Medicine and Division of Critical Care Medicine University of TorontoTorontoONCanada interdepartmental Division of Critical Care Medicine University of TorontoTorontoONCanada Department of Surgery University of Toronto TorontoONCanada.

The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health *** cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia(VITT)are both associated with thrombosis and thrombocytopenia;however,the underlying mechanisms remain inadequately *** infection and vaccination utilize the spike protein receptor-binding domain(RBD)of *** found that intravenous injection of recombinant RBD caused significant platelet clearance in *** investigation revealed the RBD could bind platelets,cause platelet activation,and potentiate platelet aggregation,which was exacerbated in the Delta and Kappa *** RBD–platelet interaction was partially dependent on theβ3 integrin as binding was significantly reduced inβ3−/−***,RBD binding to human and mouse platelets was significantly reduced with relatedαIIbβ3 antagonists and mutation of the RGD(arginine-glycine-aspartate)integrin binding motif to RGE(arginine-glycine-glutamate).We developed anti-RBD polyclonal and several monoclonal antibodies(mAbs)and identified 4F2 and 4H12 for their potent dual inhibition of RBD-induced platelet activation,aggregation,and clearance in vivo,and SARS-CoV-2 infection and replication in Vero E6 *** data show that the RBD can bind platelets partially thoughαIIbβ3 and induce platelet activation and clearance,which may contribute to thrombosis and thrombocytopenia observed in COVID-19 and *** newly developed mAbs 4F2 and 4H12 have potential not only for diagnosis of SARS-CoV-2 virus antigen but also importantly for therapy against COVID-19.

关键词： Antibody diagnosis vaccine

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Crosslinked hydrogels--a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs

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Acta Pharmaceutica Sinica B 2014年第1期4卷 26-36页

作者： Dajun D.Sun Ping I.Lee Department of Pharmaceutical Sciences Leslie Dan Faculty of PharmacyUniversity of TorontoToronto M5S 3M2OntarioCanada

Water-insoluble materials containing amorphous solid dispersions(ASD)are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble *** based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble *** example,solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate)(PHEMA)can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble *** creation of both immediate-and controlled-release ASD dosage forms is also achievable with the PHEMA based *** far,ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical *** review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers,and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.

关键词： Amorphous solid dispersions Crosslinked hydrogels Poly(2-hydroxyethylmethacrylate) Supersaturation Kinetic solubility

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Orotidine Monophosphate Decarboxylase——A Fascinating Workhorse Enzyme with Therapeutic Potential

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Journal of Genetics and Genomics 2015年第5期42卷 221-234页

作者： Masahiro Fujihashi Jagjeet S.Mnpotra Ram Kumar Mishra Emil F.Pai Lakshmi P.Kotra Department of Chemistry Graduate School of Science Kyoto University Department of Chemistry & Biochemistry The University of North Carolina at Greensboro Center for Molecular Design and Preformulations and Toronto General Research Institute University Health Network Department of Biochemistry University of Toronto Department of Medical Biophysics University of Toronto Department of Molecular Genetics University of Toronto Princess Margaret Cancer Center University Health Network Department of Pharmaceutical Sciences Leslie Dan Faculty of Pharmacy University of Toronto

Orotidine 5＇-monophosphate decarboxylase （ODCase） is known as one of the most proficient enzymes. The enzyme catalyzes the last reaction step of the de novo pyrimidine biosynthesis, the conversion from orotidine 5＇-monophosphate （OMP） to uridine 5＇-mono- phosphate. The enzyme is found in all three domains of life, Bacteria, Eukarya and Archaea. Multiple sequence alignment of 750 putative ODCase sequences resulted in five distinct groups. While the universally conserved DxKxxDx motif is present in all the groups, depending on the groups, several characteristic motifs and residues can be identified. Over 200 crystal structures of ODCases have been determined so far. The structures, together with biochemical assays and computational studies, elucidated that ODCase utilized both transition state stabilization and substrate distortion to accelerate the decarboxylation of its natural substrate. Stabilization of the vinyl anion intermediate by a conserved lysine residue at the catalytic site is considered the largest contributing factor to catalysis, while bending of the carboxyl group from the plane of the aromatic pyrimidine ring of OMP accounts for substrate distortion. A number of crystal structures of ODCases complexed with potential drug candidate molecules have also been determined, including with 6-iodo- uridine, a potential antimalarial agent.

关键词： Pyrimidine biosynthesis Orotidine monophosphate decarboxylase Ligand-enzyme interactions Antimalarial agents

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Large-scale frequent testing and tracing to supplement control of Covid-19 and vaccination rollout constrained by supply

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Infectious Disease Modelling 2021年第1期6卷 955-974页

作者： Lia Humphrey Edward W.Thommes Roie Fields Laurent Coudeville Naseem Hakim Ayman Chit Jianhong Wu Monica G.Cojocaru Department of Mathematics and Statistics University of GuelphGuelphOntarioCanada Vaccine Epidemiology and Modeling Sanofi PasteurCanada Founder ***Canada Sanofi Pasteur&leslie dan School of pharmacy University of TorontoCanada Department of Mathematics and Statistics York UniversityCanada

Non-pharmaceutical interventions(NPI)were implemented all around the world in the fight against COVID-19:Social distancing,shelter-in-place,mask wearing,*** mitigate transmission,together with testing and contact-tracing to identify,isolate and treat the *** majority of countries have relied on the former measures,followed by a ramping up of their testing and tracing *** present here the cases of South Korea,Italy,Canada and the United States,as a look back to lessons that can be drawn for controlling the pandemic,specifically through the means of testing and *** fitting a disease transmission model to daily case report data in each of the four countries,we first show that their combination of social-distancing and testing/tracing have had a significant impact on the evolution of their first wave of pandemic *** then consider the hypothetical scenario where the only NPI measures implemented past the first pandemic wave consisted of isolating individuals due to repeated,country-scale testing and contact tracing,as a mean of lifting social distancing measures without a resurgence of *** give estimates on the average isolation rates needed to occur in each *** find that testing and tracing each individual of a country,on average,every 4.5 days(South Korea),5.7 days(Canada),6 days(Italy)and 3.5 days(US),would have been sufficient to mitigate their second pandemic *** also considered the situation in Canada to see how a frequent large-scale asymptomatic testing and contact tracing could have been used in combination with vaccination rollout to reduce the infection in the *** could offer an alternative approach towards preventing and controlling an outbreak when vaccine supply is limited,while testing capacity has been increasingly enhanced.

关键词： Pandemic modelling Pandemic evolution scenarios Testing frequency policy modelling

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Aggressive surgical approach in patients with adrenal-only metastases from hepatocellular carcinoma enables higher survival rates than standard systemic therapy

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Hepatobiliary & Pancreatic Diseases International 2021年第1期20卷 28-33页

作者： Sorin T Alexandrescu Adina E Croitoru Razvan T Grigorie dana R Tomescu Gabriela Droc Mugur C Grasu Irinel Popescu dan Setlacec Centre of General Surgery and Liver Transplantation Fundeni Clinical InstituteBucharest 022328Romania Carol Davila University of Medicine and pharmacy Bucharest 020021Romania Department of Oncology Fundeni Clinical InstituteBucharest 022328Romania faculty of Medicine Titu Maiorescu UniversityBucharest 031593Romania dan Tulbure Centre of Anesteziology and Intensive Care Fundeni Clinical InstituteBucharest 022328Romania Department of Radiology Fundeni Clinical InstituteBucharest 022328Romania

Background:Although guidelines recommend systemic therapy even in patients with limited extrahepatic metastases from hepatocellular carcinoma(HCC),a few recent studies suggested a potential benefit for resection of extrahepatic ***,the benefit of adrenal resection(AR)for adrenal-only metastases(AOM)from HCC was not proved *** is the first study to compare long-term outcomes of AR to those of sorafenib in patients with AOM from ***:The patients with adrenal metastases(AM)from HCC were identified from the electronic records of the institution between January 2002 and December *** who presented AM and other sites of extrahepatic disease were ***,the patients with AOM who received other therapies than AR or sorafenib were ***:A total of 34 patients with AM from HCC were *** of these,22 patients had AOM,6 receiving other treatment than AR or ***,8 patients with AOM underwent AR(AR group),while 8 patients were treated with sorafenib(SOR group).The baseline characteristics of the two groups were not significantly different in terms of age,sex,number and size of the primary tumor,timing of AM diagnosis,Child-Pugh and ECOG *** a median follow-up of 15.5 months,in the AR group,the 1-,3-,and 5-year overall survival rates(85.7%,42.9%,and 0%,respectively)were significantly higher than those achieved in the SOR group(62.5%,0%and 0%at 1-,3-and 5-year,respectively)(P=0.009).The median progression-free survival after AR(14 months)was significantly longer than that after sorafenib therapy(6 months,P=0.002).Conclusions:In patients with AOM from HCC,AR was associated with significantly higher overall and progression-free survival rates than systemic therapy with *** results could represent a starting-point for future phase II/III clinical trials.

关键词： Adrenal metastases Hepatocellular carcinoma Adrenal resection Sorafenib Survival

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Deliberate external pancreatic fistula after pancreaticoduodenectomy performed in the setting of acute pancreatitis, and its internalization through fistula-jejunostomy

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Hepatobiliary & Pancreatic Diseases International 2020年第1期19卷 94-96页

作者： Sorin T Alexandrescu Andrei C Zlate Razvan T Grigorie Mihnea Ionescu Irinel Popescu Fundeni Clinical Institute Dan Setlacec Centre of General Surgery and Liver TransplantationSos.Fundeni nr.258sector 2BucharestRomania Carol Davila University of Medicine and pharmacy BucharestRomania Titu Maiorescu University Faculty of MedicineBucharestRomania

To the Editor:Many patients with tumors of the pancreatic head or of the ampulla of Vater require endoscopic manipulation of the duodenal papilla in order to achieve tumor biopsy or for common bile duct *** interventional endoscopy approaches may lead to acute *** iatrogenic acute pancreatitis will influence the surgical strategy in patients scheduled for pancreaticoduodenectomy(PD).Due to the small number of cases,the surgical strategy in patients who require PD in the context of acute pancreatitis has not been standardized.

关键词： pancreatitis acute Vater

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AD-16 Protects Against Hypoxic-Ischemic Brain Injury by Inhibiting Neuroinflammation

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Neuroscience Bulletin 2022年第8期38卷 857-870页

作者： Zhihua Huang Zhengwei Luo Andrea Ovcjak Jiangfan Wan Nai-hong Chen Wenhui Hu Hong-Shuo Sun Zhong-Ping Feng Department of Physiology Temerty Faculty of MedicineUniversity of TorontoTorontoONM5S 1A8Canada Department of Surgery Temerty Faculty of MedicineUniversity of TorontoTorontoONM5S 1A8Canada State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaNeuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China Key Laboratory of Molecular Target and Clinical Pharmacology State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou511436GuangdongChina leslie dan faculty of pharmacy University of TorontoTorontoONM5S 3M2Canada

Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal ***-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic *** this study,we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation(OGD)in vitro and in mice with neonatal HI brain injury in *** demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell *** dose post-treatment with AD-16(1 mg/kg)improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 *** administration reduced the mortality rate and preserved whole-brain morphology following neonatal *** in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.

关键词： Neuroinflammation Neonatal hypoxic-ischemic brain injury Neuroprotection AD-16

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Real-time sono-elastography in the diagnosis of diffuse liver diseases

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World Journal of Gastroenterology 2010年第14期16卷 1720-1726页

作者： dan Ionut Gheonea Adrian S ǎftoiu Tudorel Ciurea Florin Gorunescu Sevastita Iordache Gabriel Lucian Popescu Smaranda Belciug Marina Gorunescu Larisa Sǎndulescu Research Center of Gastroenterology and Hepatology University of Medicine and Pharmacy Craiova 200349 Romania Department of Biostatistics and Informatics University of Medicine and Pharmacy Craiova 200349 Romania IT Department University of Medicine and Pharmacy Craiova 200349 Romania faculty of Mathematics of Computer Science University of Craiova Craiova 200585 Romania

AIM: To analyze whether computer-enhanced dynamic analysis of elastography movies is able to better characterize and differentiate between different degrees of liver fibrosis. METHODS: The study design was prospective. A total of 132 consecutive patients with chronic liver diseases and healthy volunteers were examined by transabdominal ultrasound elastography. All examinations were done by two ***: Due to the limitations of the method, we obtained high-quality elastography information in only 73.48% of the patients. The κ-means clustering method was applied to assess the inter-observer diagnosis varia- bility, which showed good variability values in accordance with the experience of ultrasound examination of every observer. Cohen’sκ test indicated a moderate agreement between the study observers (κ = 0.4728). Furthermore, we compared the way the two observers clustered the patients, using the test for comparing two proportions (t value, two-sided test). There was no statistically significant difference between the two physicians, regardless of the patients’ real status. CONCLUSION: Transabdominal real-time elastography is certainly a very useful method in depicting liver hard- ness, although it is incompletely tested in large multicenter studies.

关键词： Elastography Ultrasonography Liver steato- sis Viral hepatitis Liver cirrhosis

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