José M. Lora

Cornell University

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Amal Al‐Garawi

Takeda (United States)

José A. Pintor‐Toro

Centro Andaluz de Biología Molecular y Medicina Regenerativa

Carl Blobel

Hospital for Special Surgery

Anna Sokolovska

Synlogic (United States)

Thomas M. Li

Icahn School of Medicine at Mount Sinai

Antonio Llobell

Instituto de Bioquímica Vegetal y Fotosíntesis

Theresa Lu

Hospital for Special Surgery

Anthony J. Coyle

Pfizer (United States)

James G. Krueger

Rockefeller University

William Shipman

Cornell University

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Harvard University

103

Brigham and Women's Hospital

Millennium Engineering and Integration (United States)

La Roche College

Cornell University

Constellation Pharmaceuticals (United States)

Synlogic (United States)

Rockefeller University

Massachusetts Institute of Technology

Howard Hughes Medical Institute

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Iron deficiency anemia in young animals.

Veterinaria (1947)

José M. Lora

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Cysteinyl Leukotrienes Regulate Th2 Cell-Dependent Pulmonary Inflammation

The Journal of Immunology (2006)

Daniel C. Kim Florence Ida Hsu Nora A. Barrett Daniel S. Friend Roland Grenningloh

Abstract The Th2 cell-dependent inflammatory response is a central component of asthma, and the ways in which it is regulated is a critical question. The cysteinyl leukotrienes (cys-LTs) are 5-lipoxygenase pathway products implicated in asthma, in particular, by their function as smooth muscle constrictors of airways and microvasculature. To elucidate additional roles for cys-LTs in the pathobiology of pulmonary inflammation, we used an OVA sensitization and challenge protocol with mice lacking leukotriene C4 synthase (LTC4S), the terminal enzyme for cys-LT generation. Ag-induced pulmonary inflammation, characterized by eosinophil infiltration, goblet cell hyperplasia with mucus hypersecretion, and accumulation and activation of intraepithelial mast cells was markedly reduced in LTC4Snull mice. Furthermore, Ag-specific IgE and IgG1 in serum, Th2 cell cytokine mRNA expression in the lung, and airway hyperresponsiveness to methacholine were significantly reduced in LTC4Snull mice compared with wild-type controls. Finally, the number of parabronchial lymph node cells from sensitized LTC4Snull mice and their capacity to generate Th2 cell cytokines ex vivo after restimulation with Ag were also significantly reduced. In contrast, delayed-type cutaneous hypersensitivity, a prototypic Th1 cell-dependent response, was intact in LTC4Snull mice. These findings provide direct evidence of a role for cys-LTs in regulating the initiation and/or amplification of Th2 cell-dependent pulmonary inflammation.

Goblet cell

Allergic Inflammation

10.4049/jimmunol.176.7.4440

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Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity

Nature Communications (2020)

Daniel S. Leventhal Anna Sokolovska Ning Li Christopher Plescia Starsha Kolodziej

Abstract Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine.

Synthetic Biology

Cancer Immunotherapy

10.1038/s41467-020-16602-0

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Cutting Edge: Modulation of Intestinal Autoimmunity and IL-2 Signaling by Sphingosine Kinase 2 Independent of Sphingosine 1-Phosphate

The Journal of Immunology (2007)

Eileen T. Samy Claas A. Meyer Patrick Caplazi Claire L. Langrish José M. Lora

Abstract Sphingosine kinase (Sphk) phosphorylates sphingosine into sphingosine-1-phosphate (S1P), but its recently identified isoform Sphk2 has been suggested to have distinct subcellular localization and substrate specificity. We demonstrate here that, surprisingly, Sphk2−/− CD4+ T cells exhibit a hyperactivated phenotype with significantly enhanced proliferation and cytokine secretion in response to IL-2 as well as reduced sensitivity to regulatory T cell-mediated suppression in vitro, apparently independent of effects upon S1P. Such findings appear to reflect a requirement for Sphk2 to suppress IL-2 signaling because, in Sphk2−/− CD4+ T cells, IL-2 induced abnormally accentuated STAT5 phosphorylation and small interfering RNA knockdown of STAT5 abrogated their hyperactive phenotype. This pathway physiologically modulates autoinflammatory responses, because Sphk2−/− T cells induced more rapid and robust inflammatory bowel disease in scid recipients. Thus, Sphk2 regulates IL-2 pathways in T cells, and the modulation of Sphk2 activity may be of therapeutic utility in inflammatory and/or infectious diseases.

Sphingosine Kinase

Sphingosine kinase 1

STAT5

Sphingolipid

10.4049/jimmunol.179.9.5644

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BET bromodomain inhibition suppresses TH17-mediated pathology

The Journal of Experimental Medicine (2013)

Deanna A. Mele Andrés Salmerón Srimoyee Ghosh Hon-Ren Huang Barbara M. Bryant

Interleukin (IL) 17-producing T helper (T(H)17) cells have been selected through evolution for their ability to control fungal and bacterial infections. It is also firmly established that their aberrant generation and activation results in autoimmune conditions. Using a characterized potent and selective small molecule inhibitor, we show that the bromodomain and extra-terminal domain (BET) family of chromatin adaptors plays fundamental and selective roles in human and murine T(H)17 differentiation from naive CD4(+) T cells, as well as in the activation of previously differentiated T(H)17 cells. We provide evidence that BET controls T(H)17 differentiation in a bromodomain-dependent manner through a mechanism that includes the direct regulation of multiple effector T(H)17-associated cytokines, including IL17, IL21, and GMCSF. We also demonstrate that BET family members Brd2 and Brd4 associate with the Il17 locus in T(H)17 cells, and that this association requires bromodomains. We recapitulate the critical role of BET bromodomains in T(H)17 differentiation in vivo and show that therapeutic dosing of the BET inhibitor is efficacious in mouse models of autoimmunity. Our results identify the BET family of proteins as a fundamental link between chromatin signaling and T(H)17 biology, and support the notion of BET inhibition as a point of therapeutic intervention in autoimmune conditions.

BRD4

BET inhibitor

10.1084/jem.20130376

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L-type (Loaf) Cervical Secretion Crystallization Directionality Biomarker Study

Clinical and Experimental Obstetrics & Gynecology (2023)

José M. Lora María Luisa Esparza Encina Cristina Reig Óscar Martínez Martínez Jennifer Simoni

Background: Cervical discharge is considered a hydrogel, which is part liquid and part solid. Under physiological conditions, the characteristic “fern-leaf” arborization is proportional to the circulating estradiol concentration and maximal in the preovulatory phase. Crystallization of the cervical secretion is a process of dehydration with the arrangement of sodium and potassium chloride crystals around a main axis composed of mucin. L-type (Loaf) (L) is proportional to the circulating estradiol concentration and is higher in the Fertile Window (FW). Currently, most studies comparing the FW with cervical discharge include the biophysical fertile window (BFW) which is 6 days before the estimated day of ovulation (EDO). Methods: Samples were taken from the vulvovaginal region within the FW using the Creighton Model System for Fertility Care (CrMS). Optical images of the samples were digitized to perform a binarization, skeletonization, and crystallization directionality study of the scanned branches. These samples taken from the vulvovaginal secretion were not collected from the endocervix. They were recorded by the Vaginal Secretion Recording System (VDRS) using CrMS. The FW was taken into account from 6 days before the peak (P) day according to CrMS. A statistical study was performed by comparing vulvovaginal crystallization samples including –6 day EDO in FW. Results: Out of 29 samples, 58.6% deemed true positives, 34% were true negatives, 6.8% represented 2 false positives, and no cases were false negatives (p < 0.001). Conclusions: Our analysis of the statistical distribution of the branching angles of the crystallization of cervical secretions allowed us to detect a significant contribution of 90-degree frecuencies, indicating, the existence of an L-type pattern in the FW samples that we studied. The skeletonization of the studied images together with a FW indicator allowed us to identify this crystallization pattern. We therefore propose this feature detection mechanism as a novel biomarker of fertility.

10.31083/j.ceog5006127

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Naprotecnología: ciencia y persona en la infección por el virus del papiloma humano (VPH) en mujeres y preadolescencentes

Persona y Bioética (2017)

José M. Lora María Luisa Esparza Encina Juan Luis Alcázar Zambrano

En la actualidad hay suficiente evidencia científica que relaciona directamente adquisición, exposición y prevalencia del virus del papiloma humano (VPH) con el cáncer del cuello de uterino. Por ello, el artículo aborda el VPH en la mujer teniendo en cuenta la naprotecnología, que permite conjugar evidencia científica y planteamientos éticos. Se busca que se tengan en cuenta tanto el aspecto biológico de la sexualidad como la capacidad de hacerse persona en su núcleo sexual. De ahí que se analicen programas dirigidos a la educación sexual, basados tanto en la prevención sanitaria como en la antropología de la sexualidad, y apoyados por las instituciones familiares, que han demostrado una mejor acogida ante los riesgos de las enfermedades de transmisión sexual, y entre ellas la infección por el VPH.

Persona

10.5294/pebi.2017.21.1.3

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Carbon source control on β-glucanases, chitobiase and chitinase from Trichoderma harzianum

Archives of Microbiology (1993)

Jesús de la Cruz Manuel Rey José M. Lora Antonio Hidalgo-Gallego Fernándo Domínguez

Chitinase

Trichoderma harzianum

Glucanase

Trichoderma

Laminarin

10.1007/bf00290913

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Citations (94)

Mechanisms of allergy FcεRI-dependent gene expression in human mast cells is differentially controlled by T helper type 2 cytokines

José M. Lora Michael D. Pickard Kursteen S. Price Savita Bagga Jaclyn Sicoli

Background: Mast cells (MCs) proliferate in response to TH2 cytokines and express genes de novo after activation. Limited information is available concerning the interplay between these events. Objective: We explored the potential for TH2 cytokines to alter activation-dependent gene expression by MCs. Methods: Cord blood–derived human (h)MCs maintained in stem cell factor (SCF) alone were compared with replicates treated with IL-4, IL-5, or IL-9, respectively, for their patterns of FceRI-dependent gene induction using microarray technology. Results: Activation of SCF-treated hMCs upregulated their expression of roughly 140 transcripts at 2 hours, including genes involved in cell cycle progression and arrest. Each cytokine substantially modified this profile; ~800 inducible genes apiece were controlled by IL-5 or IL-9, whereas 169 inducible genes were controlled by IL-4. IL-4 favored the induction of cytokines and of genes associated with cell growth arrest (GADD34, GAS-1, CIDE-A, INK4D, and BAX) and completely abolished the enhanced proliferation observed in the other 3 groups after activation. Conversely, IL-5 priming induced preferential upregulation of genes involved in cell proliferation and did not abolish thymidine incorporation. Conclusions: TH2 cytokines differentially modulate gene induction in hMCs after FceRI cross-linkage. IL-4 uniquely controls cytokine gene expression by hMCs and might also limit their activation-driven proliferation. (J Allergy Clin Immunol 2003;112:1119-26.)

Interleukin 9

Proinflammatory cytokine

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Multidisciplinary Fertility Window Assessment for Ovulation Diagnosis

Academia Letters (2021)

José M. Lora

Introduction: The purpose of this article was to test biomarkers signals in subfertile women in the fertile phase of the cycle to get pregnancy. The fertile window signals can improve prediction, detection and diagnosis of the fertile phase in subfertlie women. Incorporating fertility biomarkers may improve prediction and detection of the fertile phase. The effectiveness of the use of such signs, in subfertile women it would help to get pregnancy. Material and Method: This report includes 30 sub-fertile woman with an average age of 34.3 years (sem 0.96); range: (26 - 46 years old) in which integrates biomarkers in relation to the fertile window at the follicular phase. This study focused primarily on couples planning to increase efficiency in estimating the time in the fertile window to get pregnancy with a basic work-up of sterility negative. It was take an individual approach by teaching the evolution of biophysical parameters of viscoelasticity and transparency of the cervical secretion, when approaching to the fertile window. Biomarkers progression was located into the window fertile in relation to identify the best time, and maximum peak day of biophysical properties of the cervical mucus. Results: The pregnancy was obtained in 33% of the cases, in which 27% (8/30) was evidenced in patients under 35 years of age. Pregnancy was obtained in two cases, 6% of the group of patients over 35 years old. Within the risk factors in women; age was the main factor that was taken into account. It was possible to identify cycles and a fertile window in both age groups, although the success rate to achieve a pregnancy was greater in the group of women under 35 years of age. Ten cases of patients with oligoteratozospermia were included, of which in two cases a pregnancy equivalent to 6.6% of the sample was achieved in the group of patients under 35 years of age. The acceptance was 100% to detect the left kurtosis curve of the fertile window to estimate cervical mucus changing parameters. The fertile period was possible to detect by looking biophysical parameters of the cervical secretion, for the cervical mucus evolution, since the observation of the left kurtosis fertile period, until the end of to the fertile window. Conclusion: In sub-fertile couples the left kurtosis curve of the fertile window may be tested using biophysical reproducible methods of fertility, by checking changing pattern at the fertile window

10.20935/al3980

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