tbuckley/cabot-search huggingface dataset:
Repurposing <sup>18</sup>F-FMISO as a PET tracer for translational imaging of nitroreductase-based gene directed enzyme prodrug therapy
Authors: Gorka Ruiz de Garibay, Elvira García de Jalón, Endre Stigen, Kjetil B Lund, Mihaela Popa, Ben Davidson, Mireia Mayoral Safont, Cecilie B. Rygh, Heidi Espedal, Torill M Barrett, Bengt Erik Haug, Emmet McCormack
Journal: Theranostics (2021)

Nitroreductases (NTR) are a family of bacterial enzymes used in gene directed enzyme prodrug therapy (GDEPT) that selectively activate prodrugs containing aromatic nitro groups to exert cytotoxic effects following gene transduction in tumours.The clinical development of NTR-based GDEPT has, in part, been hampered by the lack of translational imaging modalities to assess gene transduction and drug cytotoxicity, non-invasively.This study presents translational preclinical PET imaging to validate and report NTR activity using the clinically approved radiotracer, 18 F-FMISO, as substrate for the NTR enzyme.Methods: The efficacy with which 18 F-FMISO could be used to report NfsB NTR activity in vivo was investigated using the MDA-MB-231 mammary carcinoma xenograft model.For validation, subcutaneous xenografts of cells constitutively expressing NTR were imaged using 18 F-FMISO PET/CT and fluorescence imaging with CytoCy5S, a validated fluorescent NTR substrate.Further, examination of the non-invasive functionality of 18 F-FMISO PET/CT in reporting NfsB NTR activity in vivo was assessed in metastatic orthotopic NfsB NTR expressing xenografts and metastasis confirmed by bioluminescence imaging. 18F-FMISO biodistribution was acquired ex vivo by an automatic gamma counter measuring radiotracer retention to confirm in vivo results.To assess the functional imaging of NTR-based GDEPT with 18 F-FMISO, PET/CT was performed to assess both gene transduction and cytotoxicity effects of prodrug therapy (CB1954) in subcutaneous models.Results: 18 F-FMISO retention was detected in NTR + subcutaneous xenografts, displaying significantly higher PET contrast than NTR -xenografts (p < 0.0001).Substantial 18 F-FMISO retention was evident in metastases of orthotopic xenografts (p < 0.05).Accordingly, higher 18 F-FMISO biodistribution was prevalent ex vivo in NTR + xenografts. 18F-FMISO NfsB NTR PET/CT imaging proved useful for monitoring in vivo NTR transduction and the cytotoxic effect of prodrug therapy.Conclusions: 18 F-FMISO NfsB NTR PET/CT imaging offered significant contrast between NTR + and NTR -tumours and effective resolution of metastatic progression.Furthermore, 18 F-FMISO NfsB NTR Ivyspring International
Effects of stably altered stathmin expression on microtubule dynamic instability in breast cancer cells
Authors: Chitose Nakao, Elizabeth Alli, William N. Hait, Leslie Wilson, Mary Ann Jordan
Journal: Cancer Research (2006)

3209  Taxanes, Vinca alkaloids, and a number of other cancer chemotherapeutic agents target microtubules and suppress cancer cell proliferation and metastasis by suppressing microtubule dynamics. Stathmin is a major cellular phosphoprotein that appears to play an important role in the regulation of microtubule dynamics, by sequestering tubulin and increasing the catastrophe frequencies at microtubule ends in purified microtubule systems in vitro. Stathmin is expressed at high levels in a wide variety of human cancers and appears to affect drug sensitivity, G2 arrest, and cell migration. In our stably transfected cell system, we are elucidating the effects of stathmin on intracellular microtubule dynamics and drug sensitivity. We use BT549 human breast cancer cells in which we have stably knocked down stathmin by shRNA or stably overexpressed stathmin for measurement of the dynamic instability of individual microtubules in the living cells. Cells were microinjected with an EGFP-tagged tubulin expression vector, observed by time-lapse fluorescence microscopy, and microtubule dynamic instability of the fluorescent microtubules was quantitated during interphase. Results thus far are that the growth rate and catastrophe frequency were suppressed by approximately 50 % and 40 %, respectively, in cells with reduced stathmin expression. The shortening rate was increased. Interestingly, stathmin overexpression showed similar effects on microtubule dynamic instability. Determination of the effects of stathmin on taxane suppression of microtubule dynamics is currently being investigated. Supported by NIH CA57291.
Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial
Authors: Sanjay Ramakrishnan, Dan V Nicolau, Beverly Langford, Mahdi Mahdi, Helen Jeffers, Christine Mwasuku, Karolina Krassowska, Robin Fox, Ian Binnian, Victoria Glover, Stephen Bright, Christopher Butler, Jennifer L Cane, Andreas Halner, Philippa C Matthews, Louise E Donnelly, Jodie L Simpson, Jonathan R Baker, Nabil T Fadai, Stefan Peterson, Thomas Bengtsson, Peter J Barnes, Richard E K Russell, Mona Bafadhel
Journal: The Lancet Respiratory Medicine (2021)
Abstract 467: ATF6B and ATF6A Play Complimentary Roles in Mediating Adaptive and Maladaptive Signaling in Cardiac Myocytes
Authors: Shivsmriti Koul, Jung-kang Jin, Clifford M Hogan, Christopher C Glembotski
Journal: Circulation Research (2017)

Rationale: ATF6α and ATF6β are endoplasmic reticulum (ER) transmembrane proteins that sense the accumulation of toxic misfolded proteins in the ER of cardiomyocytes, which can be brought about by ER stresses as ischemia. Upon ER stress, ATF6α is proteolytically cleaved into a transcription factor that binds to ER stress response elements (ERSEs) and increases expression of cardioprotective genes that restore ER protein folding. If ER proteostasis is not restored, maladaptive signaling is initiated. ATF6β is also proteolytically cleaved during ER stress, binds to the same ERSEs as ATF6α, but does not induce transcription. Hence it is clear from the above studies done in cancer cells that there are some marked similarities and differences between ATF6α and ATF6β. However, the relative roles of ATF6α and ATF6β have not been studied in the heart, where they might work in concert to mediate the dynamic switch from adaptive to maladaptive gene programing during myocardial pathology. Methods: We used neonatal rat ventricular myocytes (NRVMs) to explore the effects of ATF6α or ATF6β loss-of-function in cells treated with the ER stressor, thapsigargin (TG), which mimics ischemic heart disease. Results: In NRVM treated with TG, knockdown of ATF6β resulted in much more pronounced cell death in isolated myocytes than knockdown of ATF6α. Consistent with this finding, transcriptome analyses showed that compared to knocking down ATF6α, knockdown of ATF6β upregulated much more maladaptive, cell death-inducing genes and downregulated more cardioprotective genes. Surprisingly, knockdown of either ATF6α or ATF6β downregulated some common adaptive ER stress response genes, such as GRP78 and Derlin while also upregulating common maladaptive ER stress response genes, such as CHOP, Bcl2, Bax. Conclusion: These data indicate that both ATF6α and ATF6 β are needed for optimal viability of NRVM subjected to ER stress. There is a common, as well as differential gene regulation program controlled by these two isoforms of ATF6. Importantly, this study demonstrates a novel mechanism by which these two isoforms of ATF6 interact to govern the progression from adaptive to maladaptive ER stress signaling during chronic misfolding of ER proteins that occurs in ischemic heart disease.
CAR T cells Targeting Human Immunoglobulin Light Chains Eradicate Mature B-cell Malignancies While Sparing a Subset of Normal B Cells
Authors: Raghuveer Ranganathan, Peishun Shou, Sarah Ahn, Chuang Sun, John West, Barbara Savoldo, Gianpietro Dotti
Journal: Clinical Cancer Research (2021)

CD19-redirected chimeric antigen receptor (CAR.CD19) T cells promote clinical responses in patients with relapsed/refractory B-cell non-Hodgkin lymphomas and chronic lymphocytic leukemia (CLL). However, patients showing sustained clinical responses after CAR.CD19-T treatment show increased infection risk due to compromised B-lymphocyte recovery. Mature B cell-derived malignancies express monoclonal immunoglobulins bearing either κ- or λ-light chains. We initially constructed CAR-T targeting the κ-light-chain (CAR.κ) and established a clinical study with it. After optimizing the CAR molecule, cells developed CAR-T targeting the λ-light chain (CAR.λ) and we explored their antitumor activity.Using Igλ+ lymphoma cell lines and patient-derived Igλ+ CLL cells, we evaluated the in vitro tumor cytotoxicity and cytokine profiles of CAR.λ. We also assessed the in vivo efficacy of CAR.λ in xenograft Igλ+ lymphoma models including a patient-derived xenograft (PDX) of mantle cell lymphoma, and the effects of λ- or κ-light chain-specific CAR-T on normal B lymphocytes in a humanized murine model.CAR.λ demonstrated antitumor effects against Igλ+ lymphoma cells and patient-derived CLL cells in vitro, and in vivo in xenograft and PDX Igλ+ lymphoma murine models. Antitumor activity of CAR.λ was superimposable to CAR.CD19. Furthermore, we demonstrated in the humanized murine model that λ- or κ-light chain-specific CAR-T cells only depleted the corresponding targeted light chain-expressing normal B cells, while sparing the reciprocal light chain carrying B cells.Adoptive transfer of CAR.λ and CAR.κ-T cells represents a useful and alternative modality to CAR.CD19-T cells in treating mature B-cell malignancies with minimal impact on humoral immunity.See related commentary by Jain and Locke, p. 5736.
Abstract PR-002: SIRT2 promotes BRCA1-BARD1 heterodimerization through deacetylation
Authors: Elizabeth V. Minten, Priya Kappor-Vazirani, Chunyang Li, Hui Zhang, Kamakshi Balakrishnan, David S. Yu
Journal: Clinical Cancer Research (2021)

Abstract The breast cancer type I susceptibility protein (BRCA1) and BRCA1-associated RING domain protein I (BARD1) heterodimer promotes genome integrity through pleiotropic functions, including DNA double-strand break (DSB) repair by homologous recombination (HR). BRCA1-BARD1 heterodimerization is required for their mutual stability, HR function, and role in tumor suppression; however, the upstream signaling events governing BRCA1-BARD1 heterodimerization are unclear. Here, we show that SIRT2, a sirtuin deacetylase and breast tumor suppressor, promotes BRCA1-BARD1 heterodimerization through deacetylation. SIRT2 complexes with BRCA1-BARD1 and deacetylates conserved lysines in the BARD1 RING domain, interfacing BRCA1, which promotes BRCA1-BARD1 heterodimerization and consequently BRCA1-BARD1 stability, nuclear retention, and localization to DNA damage sites, as well as efficient HR. Our findings define a mechanism for regulation of BRCA1-BARD1 heterodimerization through SIRT2 deacetylation, elucidating a critical upstream signaling event directing BRCA1-BARD1 heterodimerization, which facilitates HR and tumor suppression, and delineating a role for SIRT2 in directing DSB repair by HR. Citation Format: Elizabeth V. Minten, Priya Kappor-Vazirani, Chunyang Li, Hui Zhang, Kamakshi Balakrishnan, David S. Yu. SIRT2 promotes BRCA1-BARD1 heterodimerization through deacetylation [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PR-002.
Biochemical Urine Testing of Medication Adherence and Its Association With Clinical Markers in an Outpatient Population of Type 2 Diabetes Patients: Analysis in the DIAbetes and LifEstyle Cohort Twente (DIALECT)
Authors: Jelle M. Beernink, Milou M. Oosterwijk, Kamlesh Khunti, Pankaj Gupta, Prashanth Patel, Job F.M. van Boven, Hiddo J. Lambers Heerspink, Stephan J.L. Bakker, Gerjan Navis, Roos M. Nijboer, Gozewijn D. Laverman
Journal: Diabetes Care (2021)

To assess adherence to the three main drug classes in real-world patients with type 2 diabetes using biochemical urine testing, and to determine the association of nonadherence with baseline demographics, treatment targets, and complications.
Chinese expert consensus on diagnosis and treatment of trauma-induced hypercoagulopathy
Authors: Jing-Chun Song, Li-Kun Yang, Wei Zhao, Feng Zhu, Gang Wang, Yao-Peng Chen, Wei-Qin Li
Journal: Military Medical Research (2021)

Abstract Trauma-induced coagulopathy (TIC) is caused by post-traumatic tissue injury and manifests as hypercoagulability that leads to thromboembolism or hypocoagulability that leads to uncontrollable massive hemorrhage. Previous studies on TIC have mainly focused on hemorrhagic coagulopathy caused by the hypocoagulable phenotype of TIC, while recent studies have found that trauma-induced hypercoagulopathy can occur in as many as 22.2–85.1% of trauma patients, in whom it can increase the risk of thrombotic events and mortality by 2- to 4-fold. Therefore, the Chinese People’s Liberation Army Professional Committee of Critical Care Medicine and the Chinese Society of Thrombosis, Hemostasis and Critical Care, Chinese Medicine Education Association jointly formulated this Chinese Expert Consensus comprising 15 recommendations for the definition, pathophysiological mechanism, assessment, prevention, and treatment of trauma-induced hypercoagulopathy.
γ-Hydroxybutyric Acid
Authors: O. Carter Snead, K. Michael Gibson
Journal: New England Journal of Medicine (2005)

The short-chain fatty acid γ-hydroxybutyric acid (GHB), which is synthesized as an analogue of γ-aminobutyric acid (GABA) that would cross the blood–brain barrier, has found limited clinical use as an anesthetic agent and as treatment for narcolepsy and alcoholism. However, during the past decade, GHB has emerged as a major recreational drug in the United States. This review article discusses the mechanisms of action and presents an approach to the treatment of overdose, abuse, and addiction.
Trends in Racial and Ethnic Disparities in COVID-19 Hospitalizations, by Region — United States, March–December 2020
Authors: Sebastian D. Romano, Anna J. Blackstock, Ethel V. Taylor, Suad El Burai Felix, Stacey Adjei, Christa-Marie Singleton, Jennifer Fuld, Beau B. Bruce, Tegan K. Boehmer
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Investigators analyzed data on in-school COVID-19 testing among 594 students who were exposed to 33 index patients at 13 elementary schools. Compared with non-Hispanic White students, participation in the program was higher among students identifying as Hispanic/Latino White or members of another racial minority group.
Glucose deprivation–induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma
Authors: Jane H.C. Loong, Tin-Lok Wong, Man Tong, Rakesh Sharma, Lei Zhou, Kai-Yu Ng, Hua-Jian Yu, Chi-Han Li, Kwan Man, Chung-Mau Lo, Xin-Yuan Guan, Terence K. Lee, Jing-Ping Yun, Stephanie K.Y. Ma
Journal: Journal of Clinical Investigation (2021)

Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK/eIF2α/ATF4 signaling axis to drive fucosyltransferase 1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal, and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR, and EPHA2 are glycoprotein targets of FUT1, in which such fucosylation would consequently converge on deregulated AKT/mTOR/4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecularly targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR, and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.
Abstract 13581: Prognostic Value of the Patterns of Non-adherence to Anti-platelet Regimen in Stented Patients (PARIS) Bleeding Risk Score for Long Term All-cause and Cardiac Mortalities After Percutaneous Coronary Intervention
Authors: Joh Akama, Takeshi Shimizu, Takuya Ando, Fumiya Anzai, Yuuki Muto, Yusuke Kimishima, Takatoyo Kiko, Akiomi YOSHIHISA, Takayoshi Yamaki, Hiroyuki Kunii, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2020)

Background: The Patterns of non-Adherence to Anti-Platelet Regimen in Stented Patients (PARIS) bleeding risk score has been proposed to predict the risk of bleeding events after percutaneous coronary intervention (PCI). However, the prognostic value of the PARIS bleeding risk score for long term all-cause and cardiac mortalities has not been evaluated. Therefore, we aimed to evaluate the predictive value of the PARIS bleeding risk score for all-cause and cardiac mortalities after PCI. Methods and Results: Consecutive 1061 patients, who had admitted to our hospital and performed or undergone PCI, were divided into 3 groups based on PARIS bleeding risk score: low (n = 113), intermediate (n = 420) and high risk groups (n = 528). We compared comorbidities and characteristics of patients among 3 groups. Furthermore, we prospectively followed up all-cause and cardiac mortalities. Clinical characteristics of 3 groups were as follows: mean age (low, intermediate and high risk groups; 56.5, 65.6 and 73.9 years, P &lt; 0.001, respectively), prevalence of chronic kidney disease (2.7%, 24.2% and 67.8%, P &lt; 0.001), atrial fibrillation (8.2%, 8.9% and 21.6%, P &lt; 0.001) and peripheral artery disease (3.1%, 9.1% and 22.1%, P &lt; 0.001). During the mean follow-up period of 1809 days, there were 205 deaths and 64 cardiac deaths. The Kaplan-Meier analysis revealed that both all-cause and cardiac mortalities were highest in high risk group among 3 groups (P &lt; 0.001 and P &lt; 0.001, respectively, Figure). In multivariable Cox proportional hazard analysis adjusted for confounding factors, PARIS bleeding score was an independent predictor of both all-cause and cardiac mortalities (adjusted hazard ratio 1.27 and 1.21 per 1 point increase, P &lt; 0.001 and P = 0.004, respectively). Conclusion: The PARIS bleeding risk score showed significant prognostic values for all-cause and cardiac mortalities in patients after PCI.
Abstract 12893: Impact of Sinus Node Recovery Time on the Outcome of Radiofrequency Catheter Ablation in Patients With Persistent Atrial Fibrillation: A Systematic Review and Meta-Analysis
Authors: Mohamed Elmassry, Wasawat Vutthikraivit, Saif El Nawaa, Pablo Paz, Ahmed M. Souka, Pattara Rattanawong, Prapaipan Putthapiban, Haneen Mallah, Barbara Mantilla, M Rubayat Rahman, Mohammad M Ansari, Scott W Shurmur
Journal: Circulation (2019)

Background: Atrial Fibrillation (AF) is the most common arrhythmia seen in the current clinical practice and is associated with morbidity and mortality. Radiofrequency catheter ablation (RFA) of AF...
Neonatal airway immune profiles and asthma and allergy endpoints in childhood
Authors: Bo L. Chawes, Helene M. Wolsk, Christian J. Carlsson, Morten A. Rasmussen, Nilofar Følsgaard, Jakob Stokholm, Klaus Bønnelykke, Susanne Brix, Ann‐Marie M. Schoos, Hans Bisgaard
Journal: Allergy (2021)

Abstract Background The immune system plays a key role in the pathogenesis of asthma and allergy, but the role of the airway cytokine and chemokine composition in vivo in early life prior to symptom development has not been described previously. Here, we aimed to examine whether the neonatal airway immune composition associates with development of allergy and asthma in childhood. Methods We measured unstimulated levels of 20 immune mediators related to the Type 1, Type 2, Type 17, or regulatory immune pathways in the airway mucosal lining fluid of 620 one‐month‐old healthy neonates from the COPSAC 2010 birth cohort. Allergy and asthma were diagnosed at our research clinic by predefined algorithms and objective assessments at age 6 years. Principal component analyses were used to describe the airway cytokine and chemokine composition. Results A neonatal airway immune profile particularly characterized by enhanced IL‐1β and reduced CCL26 was significantly associated with later development of elevated specific IgE to inhaled allergens, a positive skin prick test, and allergic rhinitis, but not with food sensitization. Conversely, reduced Type 17 immune‐associated markers, including IL‐1β and CXCL8, showed trend of association with development of early asthma endpoints. Conclusions Development of early asthma endpoints and inhalant allergy during the first 6 years of life seems associated with distinctly perturbed airway immune profiles in neonatal life, which is suggestive of an early origin and different pathogenesis of childhood asthma and allergy. These exploratory findings suggest pre‐ and perinatal life as an important window of opportunity for prevention of asthma and inhalant allergy.
An Ethical Debate: In vitro fertilisation is rarely successful in older women
Authors: S. Bewley
Journal: BMJ (1995)

The two most extreme views of infertility are that (a) it is an unfortunate circumstance but not a medical disorder worthy of treatment and (b) it is a distressing physical malfunction leaving people unable to fulfil a fundamental human potential. Disease or not, infertility is associated with distress and is currently widely investigated and treated. The disagreement thus seems to be not whether doctors have an obligation to infertile women but the extent of that obligation.

Debates on infertility, as on abortion, are clouded by different ethical value systems and deep prejudices about “deserving women” and “potential children.” Age is not an issue unless doctors have a prior obligation to help. If they do then very good reasons, apart from prejudice, have to exist to deny treatment to a particular …
A novel therapeutic modality using CRISPR-engineered dendritic cells to treat allergies
Authors: Byoungjae Kim, Young Eun Lee, Ji Woo Yeon, Ga-Yeon Go, Junhyoung Byun, Kijeong Lee, Hyomin K. Lee, Junho K. Hur, Mihue Jang, Tae Hoon Kim
Journal: Biomaterials (2021)