As perinatally HIV-infected (PHIV) women reach reproductive age, there is an increasing number who become pregnant. This is a retrospective cohort study of HIV-infected women who delivered from June 2007 to July 2012 at our institution. Maternal demographics, HIV characteristics, and obstetric and neonatal outcomes were compared. 20 PHIV and 80 SHIV pregnancies were reviewed. The groups had similar CD4+ counts, prevalence of AIDS, and use of antiretrovirals (ARV) at initiation of obstetrical care. PHIV women were significantly more likely to be younger, have a detectable viral load (35% versus 74%, P < 0.01), and have HIV-genotype resistance (40% versus 12%, P < 0.01) than the SHIV women. The median gestational age at delivery (38 weeks) and rates of obstetrical and neonatal complications were similar between the groups. While the overall rate of cesarean delivery (CD) was similar, the rates for CD due to HIV were higher in the PHIV group (64% versus 22%, P < 0.01). There was one case (5.3%) of mother-to-child transmission in the PHIV group versus two cases (2.6%) in the SHIV group. In our population, PHIV pregnant women have a higher rate of HIV-genotype resistance and higher rate of detectable viral load leading to a higher rate of CD secondary to HIV.
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Giada Zurlo;
Xijuan Liu;
Mamoru Takada;
Cheng Fan;
Jeremy M. Simon;
Travis S. Ptacek;
Javier Rodriguez;
Alex von Kriegsheim;
Juan Liu;
Jason W. Locasale;
Adam Robinson;
Jing Zhang;
Jessica M. Holler;
Baek Kim;
Marie Zikanova;
Jorgen Bierau;
Ling Xie;
Xian Chen;
Mingjie Li;
Charles M. Perou;
Qing Zhang
Protein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.
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Fernando Val;
Kim Machado;
Lisiane Barbosa;
Jorge Salinas;
Andre Machado Siqueira;
Maria Gracas Costa Alecrim;
Hernando del Portillo;
Quique Bassat;
Wuelton Marcelo Monteiro;
Marcus Vinicus Guimaraes Lacerda
Malaria, amajor global public health problem, ismainly caused by Plasmodium falciparum and Plasmodium vivax, and is responsible for nearly half a million deaths annually. Although P. vivax malaria was not believed to cause severe disease, recent robust studies have proved otherwise. However, the clinical spectrum and pathogenesis of severe vivax malaria and, especially, its respiratory complications remain poorly understood. A systematic search for articles reporting respiratory complications associated with vivax malaria was performed in Lilacs, Cochrane, Scielo, Web of Science, and Medline databases irrespective of publication date. Prevalence of acute respiratory distress syndrome (ARDS) and associated mortality among vivax patients were calculated from cross-sectional and longitudinal studies, whereas factors associated with mortality were calculated from data pooled from case reports and series of cases. Atotal of 101 studies were included (49 cross-sectional or longitudinal and 52 case reports or series of cases). Prevalence of ARDS was 2.8% and 2.2% in children and adults, respectively, with nearly 50% mortality. Moreover, female sex (P =0.013), having any comorbidity (P =0.036), lower body temperature (P =0.032), lower hemoglobin (P =0.043), and oxygen saturation (P =0.053) values were significantly associated with mortality. Plasmodium vivax malaria respiratory complications included ARDS and were associated with high mortality. Demographics and clinical characteristics upon presentation to hospital were associated with mortality among patients with respiratory complications in vivax malaria. This study reaffirms the evidence of severe and fatal complications of P. vivax malaria and its associated respiratory complications.
The colonic mucosal tissue provides a vital barrier to luminal antigens. This barrier is composed of a monolayer of simple columnar epithelial cells. The colonic epithelium is dynamically turned over and epithelial cells are generated in the stem cell containing crypts of Lieberkühn. Progenitor cells produced in the crypt-bases migrate toward the luminal surface, undergoing a process of cellular differentiation before being shed into the gut lumen. In order to study these processes at the molecular level, we have developed a simple method for the microdissection of two spatially distinct regions of the colonic mucosa; the proliferative crypt zone, and the differentiated surface epithelial cells. Our objective is to isolate specific crypt and surface epithelial cell populations from mouse colonic mucosa for the isolation of RNA and protein.
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Cindy L. Schwartz;
Lu Chen;
Kathleen McCarten;
Suzanne Wolden;
Louis S. Constine;
Robert E. Hutchison;
Pedro A. de Alarcon;
Frank G. Keller;
Kara M. Kelly;
Tanya A. Trippet;
Stephan D. Voss;
Debra L. Friedman
Background: Early response to initial chemotherapy in Hodgkin lymphoma (HL) measured by computed tomography (CT) and/or positron emission tomography (PET) after two to three cycles of chemotherapy may inform therapeutic decisions. Risk stratification at diagnosis could, however, allow earlier and potentially more efficacious treatment modifications. Patients and Methods: We developed a predictive model for event-free survival (EFS) in pediatric/adolescent HL using clinical data known at diagnosis from 1103 intermediate-risk HL patients treated on Children’s Oncology Group protocol AHOD0031 with doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy and radiation. Independent predictors of EFS were identified and used to develop and validate a prognostic score (Childhood Hodgkin International Prognostic Score [CHIPS]). A training cohort was randomly selected to include approximately half of the overall cohort, with the remainder forming the validation cohort. Results: Stage 4 disease, large mediastinal mass, albumin ( < 3.5), and fever were independent predictors of EFS that were each assigned one point in the CHIPS. Four-year EFS was 93.1% for patients with CHIPS = 0, 88.5% for patients with CHIPS = 1, 77.6% for patients with CHIPS = 2, and 69.2% for patients with CHIPS = 3. Conclusions: CHIPS was highly predictive of EFS, identifying a subset (with CHIPS 2 or 3) that comprises 27% of intermediate-risk patients who have a 4-year EFS of < 80% and who may benefit from early therapeutic augmentation. Furthermore, CHIPS identified higher risk patients who were not identified by early PET or CT response. CHIPS is a robust and inexpensive approach to predicting risk in patients with intermediate-risk HL that may improve ability to tailor therapy to risk factors known at diagnosis.
Self assembly between cations and anions is ubiquitous throughout nature. Important biological structures such as chromatin often use polyvalent assembly between a polycation and a polyanion. The biomedical importance of synthetic polycations arises from their affinity to polyanions such as nucleic acid and heparan sulfate. However, the limited biocompatibility of synthetic polycations hampers the realization of their immense potential. By examining biocompatible cationic peptides, we hypothesize that a biocompatible polycation should be biodegradable and made from endogenous cations. We design an arginine-based biodegradable polycation and demonstrate that it is more compatible by several orders of magnitude than conventional polycations in vitro and in vivo. This biocompatibility diminishes when L-arginine is substituted with D-arginine or when the biodegradable ester linker is changed to a biostable ether linker. We believe that this design can lead to many biocompatible polycations that can significantly advance a wide range of applications including controlled release, tissue engineering, biosensing, and medical devices. The design of PAGS and the control polymers that probe the importance of endogenous cations and their degradability in terms of biocompatibility is studied. The biocompatibility is shown to diminish when L-arginine is substituted with D-arginine or when the biodegradable ester linker is changed to a biostable ether linker.
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Khalid Alhasan;
Malik Sallam;
Fadi Aljamaan;
Tariq Ali;
Ahmed Al-jedai;
Ahmed Nazmi;
Aziza Ajlan;
Hassan Aleid;
Enaam Karar;
Moheeb Al-Awwami;
Hamad Almojalli;
Yaser Z Shah;
Amir Eltayeb Ismail Mohammed;
Mazin Barry;
Sarah Alsubaie;
Abdulrahman Altheaby;
Reem S Almaghrabi;
Sumayah Askandarani;
Ziad Memish;
Jaffar A Al-Tawfiq;
Dieter C Broering;
Mohamad H Temsah
Background: In response to the global Mpox outbreaks, this survey aimed to assess the knowledge, perceptions, and advocacy of Mpox vaccines among solid organ transplant healthcare workers (HCWs) in Saudi Arabia. Methods: A cross-sectional survey was conducted among solid organ transplant HCWs in Saudi Arabia from 15 August to 5 September 2022. A total of 199 responses were received from participants primarily working in the kidney (54.8%) and liver (14.6%) transplant units. Results: The survey found that most participants were aware of the 2022 Mpox outbreak, but the majority were more concerned about COVID-19 than Mpox. While the majority of participants thought laboratory personnel and HCWs in direct contact with Mpox patients should receive the vaccine, less than 60% believed that all HCWs should be vaccinated. Additionally, over half of the participants lacked knowledge of animal–human transmission of the virus. Conclusion: The results highlight the need for increased education on Mpox among transplant HCWs in Saudi Arabia, particularly regarding the virus’s transmission dynamics and vaccines. This education is crucial to improve HCWs’ understanding of this emerging disease, especially given their vulnerability during the COVID-19 pandemic.
Cancer genomic, transcriptomic, and proteomic profiling has generated extensive data that necessitate the development of tools for its analysis and dissemination. We developed UALCAN to provide a portal for easy exploring, analyzing, and visualizing these data, allowing users to integrate the data to better understand the gene, proteins, and pathways perturbed in cancer and make discoveries. UALCAN web portal enables analyzing and delivering cancer transcriptome, proteomics, and patient survival data to the cancer research community. With data obtained from The Cancer Genome Atlas (TCGA) project, UALCAN has enabled users to evaluate protein-coding gene expression and its impact on patient survival across 33 types of cancers.
The web portal has been used extensively since its release and received immense popularity, underlined by its usage from cancer researchers in more than 100 countries. The present manuscript highlights the task we have undertaken and updates that we have made to UALCAN since its release in 2017. Extensive user feedback motivated us to expand the resource by including data on a) microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and promoter DNA methylation from TCGA and b) mass spectrometry-based proteomics from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). UALCAN provides easy access to pre-computed, tumor subgroup-based gene/protein expression, promoter DNA methylation status, and Kaplan-Meier survival analyses. It also provides new visualization features to comprehend and integrate observations and aids in generating hypotheses for testing. UALCAN is accessible at http://ualcan.path.uab.edu
Although there is evidence linking hematopoietic chimerism-induction and solid organ transplant tolerance, the mechanistic requirements for chimerism-induced tolerance are not clearly elucidated. To address this, we used an MHC-defined primate model to determine the impact of impermanent, T cell-poor, mixed-chimerism on renal allograft survival. We compared two cohorts: one receiving a bone marrow + renal transplant (“BMT/renal”) and one receiving only a renal transplant. Both cohorts received maintenance immunosuppression with CD28/CD40-directed costimulation blockade and sirolimus. As previously demonstrated, this transplant strategy consistently induced compartmentalized donor chimerism, (significant whole-blood chimerism, lacking T cell chimerism). This chimerism was not sufficient to prolong renal allograft acceptance: the BMT/renal mean survival time (MST, 76 days) was not significantly different than the renal transplant alone MST (85 days, p= 0. 46), with histopathology documenting T-cell mediated rejection. Flow cytometric analysis revealed significant enrichment for CD28-/CD95+ CD4+ and CD8+ Tem cells in the rejected kidney, suggesting a link between CD28-negative Tem and costimulation blockade-resistant rejection. These results suggest that in some settings, transient T cell-poor chimerism is not sufficient to induce tolerance to a concurrently placed renal allograft and that the presence of this chimerism per se is not an independent biomarker to identify tolerance.
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Miguel Quiros;
Hikaru Nishio;
Philipp A Neumann;
Dorothee Siuda;
Jennifer Brazil;
Veronica Azcutia;
Roland Hilgarth;
Monique N. O'Leary;
Vicky Garcia Garcia-Hernandez;
Giovanna Leoni;
Mingli Feng;
Gabriela Bernal;
Holly Williams;
Priya H. Dedhia;
Christian Gerner-Smidt;
Jason Spence;
Charles A. Parkos;
Timothy L. Denning;
Asma Nusrat
In response to injury, epithelial cells migrate and proliferate to cover denuded mucosal surfaces and repair the barrier defect. This process is orchestrated by dynamic crosstalk between immune cells and the epithelium; however, the mechanisms involved remain incompletely understood. Here, we report that IL-10 was rapidly induced following intestinal mucosal injury and was required for optimal intestinal mucosal wound closure. Conditional deletion of IL-10 specifically in CD11c-expressing cells in vivo implicated macrophages as a critical innate immune contributor to IL-10-induced wound closure. Consistent with these findings, wound closure in T cell- and B cell-deficient Rag1-/- mice was unimpaired, demonstrating that adaptive immune cells are not absolutely required for this process. Further, following mucosal injury, macrophage-derived IL-10 resulted in epithelial cAMP response element-binding protein (CREB) activation and subsequent synthesis and secretion of the pro-repair WNT1-inducible signaling protein 1 (WISP-1). WISP-1 induced epithelial cell proliferation and wound closure by activating epithelial pro-proliferative pathways. These findings define the involvement of macrophages in regulating an IL-10/CREB/WISP-1 signaling axis, with broad implications in linking innate immune activation to mucosal wound repair.