Medicine and Health Sciences Commons^™

C-Terminal Binding Protein 2 Is A Novel Tumor Suppressor Targeting The Myc-Irf4 Axis In Multiple Myeloma, Coty Hing Yau Cheung, Chi Keung Cheng, Kam Tong Leung, Chi Zhang, Chi Yan Ho, Xi Luo, Angel Yuet Fong Kam, Tian Xia, Thomas Shek Kong Wan, Herbert Augustus Pitts, Natalie Pui Ha Chan, Joyce Sin Cheung, Raymond Siu Ming Wong, Xiao-Bing Zhang, Margaret Heung Ling Ng

Journal Articles

Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation targets IRF4 for proliferation and survival. MYC and IRF4 are still considered "undruggable," as most small-molecule inhibitors suffer from low potency, suboptimal pharmacokinetic properties, and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM. Here, we uncovered an unappreciated tumor-suppressive role of C-terminal binding protein 2 (CTBP2) in MM via strong inhibition of the MYC-IRF4 axis. In contrast to epithelial cancers, CTBP2 is frequently downregulated in MM, in association with shortened survival, hyperproliferative features, and adverse clinical outcomes. Restoration of CTBP2 exhibited potent …

Topographical And Cell Type-Specific Connectivity Of Rostral And Caudal Forelimb Corticospinal Neuron Populations, Lina Marcela Carmona, Eric D Thomas, Kimberly Smith, Bosiljka Tasic, Rui M Costa, Anders Nelson

Journal Articles

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse assortment of cells with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, the full diversity of spinal neurons targeted by CFA and RFA CSNs is uncharted. Here, we use anatomical and RNA sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal neuron types, …

Mir-574-5p Activates Human Tlr8 To Promote Autoimmune Signaling And Lupus, Tao Wang, Dan Song, Xuejuan Li, Yu Luo, Dianqiang Yang, Xiaoyan Liu, Xiaodan Kong, Yida Xing, Shulin Bi, Yan Zhang, Tao Hu, Yunyun Zhang, Shuang Dai, Zhiqiang Shao, Dahan Chen, Jinpao Hou, Esteban Ballestar, Jianchun Cai, Feng Zheng, James Y Yang

Journal Articles

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling …

Influenza Incidence, Lineages, And Vaccine Effectiveness Estimates In Lima, Peru, 2023, Juan Gonzalo Acevedo-Rodriguez, Carlos Zamudio, Noah Kojima, Fiorella Krapp, Pablo Tsukayama, Victor Giancarlo Sal Y Rosas Celi, Dante Baldeon, Carmen Stefany Neciosup-Vera, Carlos Medina, Elsa Gonzalez-Lagos, Laura Castro, Ashley Fowlkes, Eduardo Azziz-Baumgartner, Eduardo Gotuzzo

Journal Articles

No abstract provided.

Amino Acid Formula Induces Microbiota Dysbiosis And Depressive-Like Behavior In Mice, Ji Hu, Kaixin He, Yifei Yang, Chuan Huang, Yiping Dou, Hao Wang, Guorong Zhang, Jingyuan Wang, Chaoshi Niu, Guoqiang Bi, Lan Zhang, Shu Zhu

Journal Articles

Amino acid formula (AAF) is increasingly consumed in infants with cow's milk protein allergy; however, the long-term influences on health are less described. In this study, we established a mouse model by subjecting neonatal mice to an amino acid diet (AAD) to mimic the feeding regimen of infants on AAF. Surprisingly, AAD-fed mice exhibited dysbiotic microbiota and increased neuronal activity in both the intestine and brain, as well as gastrointestinal peristalsis disorders and depressive-like behavior. Furthermore, fecal microbiota transplantation from AAD-fed mice or AAF-fed infants to recipient mice led to elevated neuronal activations and exacerbated depressive-like behaviors compared to that …

Cd69 Signaling In Eosinophils Induces Il-10 Production And Apoptosis Via The Erk1/2 And Jnk Pathways, Respectively, Dan Van Bui, Linh Manh Nguyen, Akira Kanda, Hanh Hong Chu, Nhi Kieu Thi Le, Yasutaka Yun, Yoshiki Kobayashi, Kensuke Suzuki, Akitoshi Mitani, Akihiro Shimamura, Kenta Fukui, Shunsuke Sawada, David Dombrowicz, Hiroshi Iwai

Journal Articles

INTRODUCTION: Eosinophils contribute to the pathogenesis of allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis. We previously reported that human tissue eosinophils have high CD69 expression compared to blood eosinophils, and its expression is correlated with disease severity and the number of infiltrated eosinophils. However, biological CD69 signaling activity in eosinophils remains unclear.

METHODS: CD69 expression on lung tissue eosinophils obtained from mice with ovalbumin-induced asthma was measured using flow cytometry. CD69 crosslinking was performed on eosinophils purified from the spleen of IL-5 transgenic mice to investigate CD69 signaling and its function in eosinophils. Then, qPCR, Western blot, enzyme-linked …

The Effects Of Supplemental Dietary Chitosan On Broiler Performance And Myopathic Features Of White Striping, Jessie Lee, Yifei Shan, Angelique Wong, Elizabeth A Brown, Mitchell Callahan, Robert A Hernandez, Michael J Mienaltowski

Journal Articles

White striping (WS) is a common myopathy seen in fast-growing broilers. Studies have demonstrated that chitosan is effective as an antioxidant and has antiobesity and fat-absorption reduction properties. We hypothesized that the dietary supplementation of chitosan would have similar effects when fed to fast-growing broilers and would thus lower WS incidence and improve meat quality. One hundred twenty-six broilers were fed corn-soy diets. The grower and finisher diets contained either 0, 0.2, or 0.4% chitosan. After a 6 wk growth period, birds were euthanized, and then WS and gross pathology scores were assessed. Pectoralis major tissues were collected to evaluate …

Protecting Human And Animal Health: The Road From Animal Models To New Approach Methods, Barbara L F Kaplan, Alan M Hoberman, William Slikker, Mary Alice Smith, Emanuela Corsini, Thomas B Knudsen, M Sue Marty, Sonya K Sobrian, Suzanne C Fitzpatrick, Marcia H Ratner, Donna L Mendrick

Journal Articles

Animals and animal models have been invaluable for our current understanding of human and animal biology, including physiology, pharmacology, biochemistry, and disease pathology. However, there are increasing concerns with continued use of animals in basic biomedical, pharmacological, and regulatory research to provide safety assessments for drugs and chemicals. There are concerns that animals do not provide sufficient information on toxicity and/or efficacy to protect the target population, so scientists are utilizing the principles of replacement, reduction, and refinement (the 3Rs) and increasing the development and application of new approach methods (NAMs). NAMs are any technology, methodology, approach, or assay used …

Fluvoxamine Inhibits Th1 And Th17 Polarization And Function By Repressing Glycolysis To Attenuate Autoimmune Progression In Type 1 Diabetes, Yuan Zou, Jing Zhang, Fei Sun, Qianqian Xu, Longmin Chen, Xi Luo, Ting Wang, Qing Zhou, Shu Zhang, Fei Xiong, Wen Kong, Ping Yang, Qilin Yu, Shiwei Liu, Cong-Yi Wang

Journal Articles

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed.

METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune …

Antiviral Potency Of Long-Acting Islatravir Subdermal Implant In Shiv-Infected Macaques, Fernanda P Pons-Faudoa, Nicola Di Trani, Simone Capuani, Ilaria Facchi, Anthony M Wood, Bharti Nehete, Ashley Delise, Suman Sharma, Kathryn A Shelton, Lane R Bushman, Corrine Ying Xuan Chua, Michael M Ittmann, Jason T Kimata, Peter L Anderson, Pramod N Nehete, Roberto C Arduino, Alessandro Grattoni

Journal Articles

Treatment nonadherence is a pressing issue in people living with HIV (PLWH), as they require lifelong therapy to maintain viral suppression. Poor adherence leads to antiretroviral (ARV) resistance, transmission to others, AIDS progression, and increased morbidity and mortality. Long-acting (LA) ARV therapy is a promising strategy to combat the clinical drawback of user-dependent dosing. Islatravir (ISL) is a promising candidate for HIV treatment given its long half-life and high potency. Here we show constant ISL release from a subdermal LA nanofluidic implant achieves viral load reduction in SHIV-infected macaques. Specifically, a mean delivery dosage of 0.21 ± 0.07 mg/kg/day yielded …

Transmembrane Stem Factor Nanodiscs Enhanced Revascularization In A Hind Limb Ischemia Model In Diabetic, Hyperlipidemic Rabbits, Eri Takematsu, Miles Massidda, Gretchen Howe, Julia Goldman, Patricia Felli, Lei Mei, Gregory Callahan, Andrew D Sligar, Richard Smalling, Aaron B Baker

Journal Articles

Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. …

Fecal Pharmacokinetics And Gut Microbiome Effects Of Oral Omadacycline Versus Vancomycin In Healthy Volunteers, Jinhee Jo, Chenlin Hu, Khurshida Begum, Weiqun Wang, Thanh M Le, Samantha Agyapong, Blake M Hanson, Hossaena Ayele, Chris Lancaster, M Jahangir Alam, Anne J Gonzales-Luna, Kevin W Garey

Journal Articles

BACKGROUND: Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults.

METHODS: This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations …

Examining The Potential Of Vitamin C Supplementation In Tissue-Engineered Equine Superficial Digital Flexor Tendon Constructs, Michael J Mienaltowski, Mitchell Callahan, Nicole L Gonzales, Angelique Wong

Journal Articles

Because equine tendinopathies are slow to heal and often recur, therapeutic strategies are being considered that aid tendon repair. Given the success of utilizing vitamin C to promote tenogenesis in other species, we hypothesized that vitamin C supplementation would produce dose-dependent improvements in the tenogenic properties of tendon proper (TP) and peritenon (PERI) cells of the equine superficial digital flexor tendon (SDFT). Equine TP- and PERI-progenitor-cell-seeded fibrin three-dimensional constructs were supplemented with four concentrations of vitamin C. The gene expression profiles of the constructs were assessed with 3'-Tag-Seq and real-time quantitative polymerase chain reaction (RT-qPCR); collagen content and fibril ultrastructure …

Increased Igfbp2 Levels By Placenta-Derived Mesenchymal Stem Cells Enhance Glucose Metabolism In A Taa-Injured Rat Model Via Ampk Signaling Pathway, Dae-Hyun Lee, Hyeri Park, Jun-Hyeong You, Jin Seok, Dong-Wook Kwon, Young-Ran Kim, Gi-Jin Kim

Journal Articles

The insulin resistance caused by impaired glucose metabolism induces ovarian dysfunction due to the central importance of glucose as a source of energy. However, the research on glucose metabolism in the ovaries is still lacking. The objectives of this study were to analyze the effect of PD-MSCs on glucose metabolism through IGFBP2-AMPK signaling and to investigate the correlation between glucose metabolism and ovarian function. Thioacetamide (TAA) was used to construct a rat injury model. PD-MSCs were transplanted into the tail vein (2 × 10

Interplay Of Hypoxia-Inducible Factors And Oxygen Therapy In Cardiovascular Medicine, Yafen Liang, Wei Ruan, Yandong Jiang, Richard Smalling, Xiaoyi Yuan, Holger K Eltzschig

Journal Articles

Mammals have evolved to adapt to differences in oxygen availability. Although systemic oxygen homeostasis relies on respiratory and circulatory responses, cellular adaptation to hypoxia involves the transcription factor hypoxia-inducible factor (HIF). Given that many cardiovascular diseases involve some degree of systemic or local tissue hypoxia, oxygen therapy has been used liberally over many decades for the treatment of cardiovascular disorders. However, preclinical research has revealed the detrimental effects of excessive use of oxygen therapy, including the generation of toxic oxygen radicals or attenuation of endogenous protection by HIFs. In addition, investigators in clinical trials conducted in the past decade have …

Evaluation Of The Effectiveness Of Foot-And-Mouth Disease Vaccination Of Animals In The Buffer Zone Of The Republic Of Armenia In 2016–2020, Satenik Kharatyan, Khachik Sargsyan, Hasmik Elbakyan, Tigran Markosyan, Pertsh Tumanyan, Varduhi Hakobyan, Vazgen Sargsyan, Manvel Badalyan, Gayane Chobanyan, Jenna E Achenbach

Journal Articles

BACKGROUND: Foot-and-mouth disease (FMD) is a high impact viral disease of livestock for which vaccines are extensively used for limiting the spread of infection. Armenia shares a border with both Turkey and Iran where FMD is endemic, making vaccination an important component of Armenia's control strategy. Additionally, Armenian veterinary services utilize both passive and active monitoring for prevention control.

METHODS: We sought to determine the immune status of animals vaccinated against FMD and to evaluate the effectiveness of our vaccination policy in Armenia. This was conducted in three regions including Shirak, Armavir, and Ararat Region which are located in the …

Tmem27 Suppresses Tumor Development By Promoting Ret Ubiquitination, Positioning, And Degradation, Qianjin Guo, Zi-Ming Cheng, Hector Gonzalez-Cantú, Matthew Rotondi, Gabriela Huelgas-Morales, Purushoth Ethiraj, Zhijun Qiu, Jonathan Lefkowitz, Wan Song, Bethany N Landry, Hector Lopez, Cynthia M Estrada-Zuniga, Shivi Goyal, Mohammad Aasif Khan, Timothy J Walker, Exing Wang, Faqian Li, Yanli Ding, Lois M Mulligan, Ricardo C T Aguiar, Patricia L M Dahia

Journal Articles

The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell …

Enhanced Cerebroprotection Of Xenon-Loaded Liposomes In Combination With Rtpa Thrombolysis For Embolic Ischemic Stroke, Tao Peng, Keith Booher, Melanie R Moody, Xing Yin, Jaroslaw Aronowski, David D Mcpherson, Sean I Savitz, Hyunggun Kim, Shao-Ling Huang

Journal Articles

Xenon (Xe) has shown great potential as a stroke treatment due to its exceptional ability to protect brain tissue without inducing side effects. We have previously developed Xe-loaded liposomes for the ultrasound-activated delivery of Xe into the cerebral region and demonstrated their therapeutic efficacy. At present, the sole FDA-approved thrombolytic agent for stroke treatment is recombinant tissue plasminogen activator (rtPA). In this study, we aimed to investigate the potential of combining Xe-liposomes with an intravenous rtPA treatment in a clinically relevant embolic rat stroke model. We evaluated the combinational effect using an in vitro clot lysis model and an in …

Adenosine Metabolized From Extracellular Atp Ameliorates Organ Injury By Triggering A2br Signaling, Taha Kelestemur, Zoltán H Németh, Pal Pacher, Jennet Beesley, Simon C Robson, Holger K Eltzschig, György Haskó

Journal Articles

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A

METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A

RESULTS: T/HS upregulated the expression of CD39, CD73, and the A

CONCLUSION: In conclusion, the CD39-CD73-A

Free Ferrous Ions Sustain Activity Of Mammalian Stearoyl-Coa Desaturase-1, Jiemin Shen, Gang Wu, Brad S Pierce, Ah-Lim Tsai, Ming Zhou

Journal Articles

Mammalian stearoyl-CoA desaturase-1 (SCD1) introduces a double-bond to a saturated long-chain fatty acid in a reaction catalyzed by a diiron center. The diiron center is well-coordinated by conserved histidine residues and is thought to remain with the enzyme. However, we find here that SCD1 progressively loses its activity during catalysis and becomes fully inactive after about nine turnovers. Further studies show that the inactivation of SCD1 is due to the loss of an iron (Fe) ion in the diiron center and that the addition of free ferrous ions (Fe

Prolylcarboxypeptidase Alleviates Hypertensive Cardiac Remodeling By Regulating Myocardial Tissue Angiotensin Ii, Binh Y Nguyen, Fangchao Zhou, Pablo Binder, Wei Liu, Susanne S Hille, Xiaojing Luo, Min Zi, Hongyuan Zhang, Antony Adamson, Fozia Z Ahmed, Sam Butterworth, Elizabeth J Cartwright, Oliver J Müller, Kaomei Guan, Elizabeth M Fitzgerald, Xin Wang

Journal Articles

Background Prolonged activation of angiotensin II is the main mediator that contributes to the development of heart diseases, so converting angiotensin II into angiotensin 1-7 has emerged as a new strategy to attenuate detrimental effects of angiotensin II. Prolylcarboxypeptidase is a lysosomal pro-X carboxypeptidase that is able to cleave angiotensin II at a preferential acidic pH optimum. However, insufficient attention has been given to the cardioprotective functions of prolylcarboxylpeptidase. Methods and Results We established a CRISPR/CRISPR-associated protein 9-mediated global prolylcarboxylpeptidase-knockout and adeno-associated virus serotype 9-mediated cardiac prolylcarboxylpeptidase overexpression mouse models, which were challenged with the angiotensin II infusion (2 mg/kg …

Targeting Myocardial Equilibrative Nucleoside Transporter Ent1 Provides Cardioprotection By Enhancing Myeloid Adora2b Signaling., Wei Ruan, Jiwen Li, Seungwon Choi, Xinxin Ma, Yafen Liang, Ragini Nair, Xiaoyi Yuan, Tingting W Mills, Holger K Eltzschig

Journal Articles

Previous studies implicate extracellular adenosine signaling in attenuating myocardial ischemia and reperfusion injury (IRI). This extracellular adenosine signaling is terminated by its uptake into cells by equilibrative nucleoside transporters (ENTs). Thus, we hypothesized that targeting ENTs would function to increase cardiac adenosine signaling and concomitant cardioprotection against IRI. Mice were exposed to myocardial ischemia and reperfusion injury. Myocardial injury was attenuated in mice treated with the nonspecific ENT inhibitor dipyridamole. A comparison of mice with global Ent1 or Ent2 deletion showed cardioprotection only in Ent1-/- mice. Moreover, studies with tissue-specific Ent deletion revealed that mice with myocyte-specific Ent1 deletion (Ent1loxP/loxP …

Changes In Local Tissue Microenvironment In Response To Subcutaneous Long-Acting Delivery Of Tenofovir Alafenamide In Rats And Non-Human Primates, Fernanda P Pons-Faudoa, Nicola Di Trani, Simone Capuani, Nathanael Hernandez, Anthony M Wood, Bharti Nehete, Jean Niles, Kathryn A Shelton, Sarah Kezar, Lane R Bushman, Corrine Ying Xuan Chua, Michael M Ittmann, Peter L Anderson, Pramod N Nehete, Roberto C Arduino, Joan E Nichols, Alessandro Grattoni

Journal Articles

Several implantable long-acting (LA) delivery systems have been developed for sustained subcutaneous administration of tenofovir alafenamide (TAF), a potent and effective nucleotide reverse transcriptase inhibitor used for HIV pre-exposure prophylaxis (PrEP). LA platforms aim to address the lack of adherence to oral regimens, which has impaired PrEP efficacy. Despite extensive investigations in this field, tissue response to sustained subcutaneous TAF delivery remains to be elucidated as contrasting preclinical results have been reported in the literature. To this end, here we studied the local foreign body response (FBR) to sustained subdermal delivery of three forms of TAF, namely TAF free base …

Co-Delivery Of Therapeutics And Bioactive Gas Using A Novel Liposomal Platform For Enhanced Treatment Of Acute Arterial Injury, Shao-Ling Huang, Melanie R Moody, Xing Yin, David D Mcpherson, Hyunggun Kim

Journal Articles

Atherosclerosis is a complex, multi-stage disease characterized by pathological changes across the vascular wall. Endothelial dysfunction, inflammation, hypoxia, and vascular smooth muscle cell proliferation contribute to its progression. An effective strategy capable of delivering pleiotropic treatment to the vascular wall is essential to limit neointimal formation. Echogenic liposomes (ELIP), which can encapsulate bioactive gases and therapeutic agents, have the potential to deliver enhanced penetration and treatment efficacy for atherosclerosis. In this study, liposomes loaded with nitric oxide (NO) and rosiglitazone, a peroxisome proliferator-activated receptor agonist, were prepared using hydration, sonication, freeze-thawing, and pressurization. The efficacy of this delivery system was …

Heartworm Adulticide Treatment: A Tropical Perspective, Filipe Dantas-Torres, Jennifer Ketzis, Gabriela Pérez Tort, Andrei Daniel Mihalca, Gad Baneth, Domenico Otranto, Malaika Watanabe, Bui Khanh Linh, Tawin Inpankaew, Pablo Borrás, Sangaran Arumugam, Barend Louis Penzhorn, Adrian Patalinghug Ybañez, Peter Irwin, Rebecca J Traub

Journal Articles

Dirofilaria immitis (the canine heartworm) is widespread in the tropics, with prevalence surpassing 30% in high-risk areas. In addition to the suitable climatic conditions that favour mosquito abundance and filarial larva development, there is low compliance with the recommended year-round use of preventives in these transmission hotspots. This represents a major concern, considering that melarsomine (first-line heartworm adulticide) is unavailable in several tropical countries, resulting in the so-called slow-kill protocol being the only available adulticide treatment option. In this article, the members of TroCCAP (Tropical Council for Companion Animal Parasites) review the current distribution of heartworm in the tropics and …

Loss-Of-Function Variants In Mycbp2 Cause Neurobehavioural Phenotypes And Corpus Callosum Defects, Lama Alabdi, Muriel Desbois, Domniţa-Valeria Rusnac, Raashda A Sulaiman, Jill A Rosenfeld, Seema Lalani, David R Murdock, Lindsay C Burrage, Ping Yee Billie Au, Shelley Towner, William G Wilson, Lawrence Wong, Theresa Brunet, Gertrud Strobl-Wildemann, Jennifer E Burton, George Hoganson, Kirsty Mcwalter, Amber Begtrup, Yuri A Zarate, Elyse L Christensen, Karla J Opperman, Andrew C Giles, Rana Helaby, Artur Kania, Ning Zheng, Brock Grill, Fowzan S Alkuraya

Journal Articles

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions …

Initiating And Imaging Cavitation From Infused Echo Contrast Agents Through The Ekosonic Catheter, Sonya R Kennedy, Maxime Lafond, Kevin J Haworth, Daniel Suarez Escudero, Dan Ionascu, Brion Frierson, Shaoling Huang, Melvin E Klegerman, Tao Peng, David D Mcpherson, Curtis Genstler, Christy K Holland

Journal Articles

Ultrasound-enhanced delivery of therapeutic-loaded echogenic liposomes is under development for vascular applications using the EkoSonic Endovascular System. In this study, fibrin-targeted echogenic liposomes loaded with an anti-inflammatory agent were characterized before and after infusion through an EkoSonic catheter. Cavitation activity was nucleated by Definity or fibrin-targeted, drug-loaded echogenic liposomes infused and insonified with EkoSonic catheters. Passive cavitation imaging was used to quantify and map bubble activity in a flow phantom mimicking porcine arterial flow. Cavitation was sustained during 3-min infusions of Definity or echogenic liposomes along the distal 6 cm treatment zone of the catheter. Though the EkoSonic catheter was …

Cd73-Dependent Adenosine Signaling Through Adora2b Drives Immunosuppression In Ductal Pancreatic Cancer, Erika Y Faraoni, Kanchan Singh, Vidhi Chandra, Olivereen Le Roux, Yulin Dai, Ismet Sahin, Baylee J O'Brien, Lincoln N Strickland, Le Li, Emily Vucic, Amanda N Warner, Melissa Pruski, Trent Clark, George Van Buren, Nirav C Thosani, John S Bynon, Curtis J Wray, Dafna Bar-Sagi, Kyle L Poulsen, Lana A Vornik, Michelle I Savage, Shizuko Sei, Altaf Mohammed, Zhongming Zhao, Powel H Brown, Tingting Mills, Holger K Eltzschig, Florencia Mcallister, Jennifer M Bailey-Lundberg

Journal Articles

UNLABELLED: The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin-dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar …

Cd73-Dependent Adenosine Signaling Through Adora2b Drives Immunosuppression In Ductal Pancreatic Cancer., Erika Y Faraoni, Kanchan Singh, Vidhi Chandra, Olivereen Le Roux, Yulin Dai, Ismet Sahin, Baylee J O'Brien, Lincoln N Strickland, Le Li, Emily Vucic, Amanda N Warner, Melissa Pruski, Trent Clark, George Van Buren, Nirav C Thosani, John S Bynon, Curtis J Wray, Dafna Bar-Sagi, Kyle L Poulsen, Lana A Vornik, Michelle I Savage, Shizuko Sei, Altaf Mohammed, Zhongming Zhao, Powel H Brown, Tingting Mills, Holger K Eltzschig, Florencia Mcallister, Jennifer M Bailey-Lundberg

Journal Articles

UNLABELLED: The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin-dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar …

Clonal Haematopoiesis And Risk Of Chronic Liver Disease, Waihay J Wong, Connor Emdin, Alexander G Bick, Seyedeh M Zekavat, Abhishek Niroula, James P Pirruccello, Laura Dichtel, Gabriel Griffin, Md Mesbah Uddin, Christopher J Gibson, Veronica Kovalcik, Amy E Lin, Marie E Mcconkey, Amelie Vromman, Rob S Sellar, Peter G Kim, Mridul Agrawal, Joshua Weinstock, Michelle T Long, Bing Yu, Rajarshi Banerjee, Rowan C Nicholls, Andrea Dennis, Matt Kelly, Po-Ru Loh, Steve Mccarroll, Eric Boerwinkle, Ramachandran S Vasan, Siddhartha Jaiswal, Andrew D Johnson, Raymond T Chung, Kathleen Corey, Daniel Levy, Christie Ballantyne, Benjamin L Ebert, Pradeep Natarajan

Journal Articles

Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, …