tbuckley/cabot-search huggingface dataset:
Statins use and peripheral blood progenitor cells mobilization in patients with multiple myeloma.
Authors: Ioannis Voutsadakis, Athina Stravodimou
Journal: Journal of Clinical Oncology (2012)

e17007 Background: Statin drugs have beneficial effects in patients after myocardial infarction and at least part of the benefit is believed to result from mobilization of marrow endothelial progenitors to repopulate damage myocardial tissues. This study examines if statins may have the same effect in mobilizing marrow progenitors to be harvested and subsequently used in high dose chemotherapy with progenitor cell rescue in patients with multiple myeloma. Methods: From 2006 to 2009, 22 consecutive patients with multiple myeloma were mobilized with the use of G-CSF and were retrospectively analyzed. Patients with other malignancies or mobilized with the use of chemotherapy or with plerixafor were excluded from this analysis. Results: The median age of the patients was 60 years-old. Fifteen patients had received one line of chemotherapy, six patients two lines and one patient three lines of chemotherapy. Thirteen patients were taking statins at the time of the harvest while nine patients were not. In the group of patients taking statins in only two of 13 (15%) the target number of 4x10 6 CD34+ cells /kg could not be obtained with a single apheresis session while in the group not taking statins four of nine patients (44.5%) required more than one session to obtain this target (including one patient in whom the target number could not be obtained even with the additional sessions). Nevertheless due to the low number of patients in the study this difference did not attain statistical significance (x 2 =0.13). The median number of cells harvested was 8x10 6 CD34+ cells /kg in the group taking statins and 6.3x10 6 CD34+ cells /kg in the control group. Conclusions: This retrospective analysis of 22 patients discloses a numerically important difference in the success of peripheral blood progenitors harvest in patients taking statins which did not attain statistical significance. Larger studies would be required to clarify the issue. If their effectiveness is confirmed statins could be a safe and cheaper addition to chemotherapy and plerixafor for peripheral hematopoietic stem cell mobilization.
Effects of Selonsertib in Patients with Diabetic Kidney Disease
Authors: Glenn M. Chertow, Pablo E. Pergola, Fang Chen, Brian J. Kirby, John S. Sundy, Uptal D. Patel
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Findings in animal models of diabetic kidney disease identified selonsertib, a selective inhibitor of apoptosis signal–regulating kinase 1 (ASK1), as a potential therapeutic agent. In a randomized, dose-ranging, placebo-controlled phase 2 trial evaluating selonsertib’s safety and efficacy in patients with moderate-to-advanced diabetic kidney disease, the authors found that selonsertib appeared safe, with no dose-dependent adverse effects over 48 weeks, including for the 18-mg daily dose thought to maximally inhibit ASK1. Although the trial did not meet its primary efficacy end point of change in eGFR from baseline to week 48, acute effects related to inhibition of creatinine secretion by selonsertib confounded differences in eGFR. Exploratory post hoc analyses accounting for these effects suggest that selonsertib resulted in a dose-dependent reduction in kidney function decline and merits further study. Background Apoptosis signal-regulating kinase 1 (ASK1) activation in glomerular and tubular cells resulting from oxidative stress may drive kidney disease progression. Findings in animal models identified selonsertib, a selective ASK1 inhibitor, as a potential therapeutic agent. Methods In a phase 2 trial evaluating selonsertib’s safety and efficacy in adults with type 2 diabetes and treatment-refractory moderate-to-advanced diabetic kidney disease, we randomly assigned 333 adults in a 1:1:1:1 allocation to selonsertib (oral daily doses of 2, 6, or 18 mg) or placebo. Primary outcome was change from baseline eGFR at 48 weeks. Results Selonsertib appeared safe, with no dose-dependent adverse effects over 48 weeks. Although mean eGFR for selonsertib and placebo groups did not differ significantly at 48 weeks, acute effects related to inhibition of creatinine secretion by selonsertib confounded eGFR differences at 48 weeks. Because of this unanticipated effect, we used piecewise linear regression, finding two dose-dependent effects: an acute and more pronounced eGFR decline from 0 to 4 weeks (creatinine secretion effect) and an attenuated eGFR decline between 4 and 48 weeks (therapeutic effect) with higher doses of selonsertib. A post hoc analysis (excluding data for 20 patients from two sites with Good Clinical Practice compliance–related issues) found that between 4 and 48 weeks, rate of eGFR decline was reduced 71% for the 18-mg group relative to placebo (difference 3.11±1.53 ml/min per 1.73 m 2 annualized over 1 year; 95% confidence interval, 0.10–6.13; nominal P =0.043). Effects on urine albumin-to-creatinine ratio did not differ between selonsertib and placebo. Conclusions Although the trial did not meet its primary endpoint, exploratory post hoc analyses suggest that selonsertib may slow diabetic kidney disease progression.
FRI0144 Tuberculosis in patients with systemic lupus erythematosus: increased frequency of extrapulmonary localization
Authors: M Sayarlioglu, M Inanç, S Kamali, Ö Karaman, A Çefle, A Gül, L Öcal, O Aral, M Koniçe
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To investigate the frequency and characteristics of tuberculosis (TB) in patients with systemic lupus erythematosus (SLE). <h3>Methods</h3> We reviewed the charts of 556 patients with SLE who were followed-up between 1978–2001 in our lupus clinic. Sixteen patients who developed tuberculosis after the diagnosis of SLE were identified and included into the study. Clinical characteristics of patients recorded according to a predefined protocol. <h3>Results</h3> Demographic characteristics of patients were as follows: Male/female ratio:3/13, age at disease onset: 32.7 ± 9.1 (23–52), median follow-up time: 83 ± 75 months (3–260), mean time elapsed from the diagnosis of SLE to onset of TB: 54 ± 50 months (2–174), mean duration of follow-up after the diagnosis of TB: 47 ± 43 months (6–163). Diagnosis of TB was confirmed microbiologically in 68% of patients. Eight of 16 patients (50%) had extrapulmonary TB (vertebral involvement in 3, meningeal in 2 and skin and soft tissue in 3). All patients had been treated with prednisolon (PRD) (cumulative dose of; 19.7 ± 16.2 g) before the diagnosis of TB. Seven of 16 (44%) patients were additionally treated with pulse PRD, 6 of 16 (38%) with cyclophosphamide and 1 of 16 (0.6%) with azathioprine. <h3>Conclusion</h3> TB infection occurred in 2.9% of patients with SLE in the early or late period after the diagnosis and initiation of immunosuppresive treatment. Extrapulmonary localization of TB was strikingly more than expected and a search for TB should be undertaken in SLE patients who developed novel neurological, musculoskeletal, skin and soft tissue manifestations. The precise role of immunosuppresive regimes and the place of prophylaxis in the development of TB in SLE remain to be determined.
Do framing effects debunk moral beliefs?
Authors: Kelsey McDonald, Siyuan Yin, Tara Weese, Walter Sinnott-Armstrong
Journal: Behavioral and Brain Sciences (2019)

May argues that framing effects do not undermine moral beliefs, because they affect only a minority of moral judgments in small ways. We criticize his estimates of the extent of framing effects on moral judgments, and then we argue that framing effects would cause trouble for moral judgments even if his estimates were correct.
ATF4 destabilizes RET through nonclassical GRP78 inhibition to enhance chemosensitivity to bortezomib in human osteosarcoma
Authors: Jie Luo, Yuanzheng Xia, Yong Yin, Jun Luo, Mingming Liu, Hao Zhang, Chao Zhang, Yucheng Zhao, Lei Yang, Lingyi Kong
Journal: Theranostics (2019)

Rationale: Activating transcription factor 4 (ATF4) is a central regulator of the cellular stress response and reduces tumor burden by controlling the expression of target genes implicated in the induction of apoptosis. Evidence shows ATF4 activation is responsible for proteasome inhibitor bortezomib (BTZ)-induced osteosarcoma (OS) cell death. However, it remains unclear how such suppressive function is impaired during prolonged therapeutic interventions. Methods: Stable cells and in vivo xenograft models were generated to reveal the essential role of ATF4 in cell apoptosis and tumor growth. Fluorescence in situ hybridization (FISH) and immunohistochemistry were employed to detect the expression and significance of ATF4 in the specimens from osteosarcoma patients. Biochemical differences between chemoresistant and chemosensitive cancer cells were determined by proliferation, apoptosis, real-time PCR, immunoblotting and immunofluorescence. Promoter activity was analysed using the luciferase reporter assay. Immunoprecipitation was used to explore the interaction of proteins with other proteins or DNAs. Results: ATF4 significantly inhibited OS tumorigenesis, whereas knockdown of ATF4 prevented the antitumor effects of BTZ. Normal osteoblasts are supposed to preferentially express ATF4, but ATF4 silencing was detected in both OS clinical samples and BTZ-resistant sublines (OS/BTZ). We found that ATF4 downregulation was tightly linked to the aberrant expression of RET, primarily due to RET stabilization in OS/BTZ cells. Loss of RET upregulated ATF4 and potentiated the apoptotic response to BTZ. ATF4 recognized the TK domain of RET by recruiting its transactivated E3 ligase Cbl-c to accelerate RET proteasomal turnover, which in turn prevented BTZ resistance. In contrast, the chaperone GRP78 bound to RET and interfered with ATF4/RET interactions, promoted RET stabilization. Intriguingly, ATF4 repressed GRP78 transcription in OS/BTZ cells via the first ERSE, instead of transactivating GRP78 in wild-type OS via classical CRE element, revealing a dual targeting of RET and GRP78 to overcome chemoresistance. Conclusion: The results uncover a crucial role for ATF4 in blocking the progression and resistance response in RET/GRP78-positive human osteosarcoma.
Effect of Corticosteroid-Sparing Treatment With Mycophenolate Mofetil vs Methotrexate on Inflammation in Patients With Uveitis
Authors: S. R. Rathinam, John A. Gonzales, Radhika Thundikandy, Anuradha Kanakath, S. Bala Murugan, R. Vedhanayaki, Lyndell L. Lim, Eric B. Suhler, Hassan A. Al-Dhibi, Thuy Doan, Jeremy D. Keenan, Maya M. Rao, Caleb D. Ebert, Hieu H. Nguyen, Eric Kim, Travis C. Porco, Nisha R. Acharya
Journal: JAMA (2019)

Methotrexate and mycophenolate mofetil are commonly used immunomodulatory therapies for achieving corticosteroid-sparing control of noninfectious uveitis, but there is uncertainty about which drug is more effective.To compare the effect of methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis.The First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial screened 265 adults with noninfectious uveitis requiring corticosteroid-sparing immunosuppressive therapy from 9 referral eye centers in India, the United States, Australia, Saudi Arabia, and Mexico between August 22, 2013, and August 16, 2017. Follow-up ended on August 20, 2018.Patients were randomized to receive oral methotrexate, 25 mg weekly (n = 107), or oral mycophenolate mofetil, 3 g daily (n = 109).The primary outcome was treatment success at 6 months, which was defined as having control of inflammation in both eyes, no more than 7.5 mg prednisone daily and less than or equal to 2 drops of prednisolone acetate 1%, and no treatment failure due to safety or intolerability. Patients underwent follow-up to 12 months while receiving the same treatment or switched to the other antimetabolite, depending on their 6-month outcome.Among 216 patients who were randomized (median age, 38 years; 135 (62.5%) women), 194 (89.8%) completed follow-up through 6 months. Treatment success occurred in 64 (66.7%) patients in the methotrexate group vs 56 (57.1%) in the mycophenolate group (difference, 9.5% [95% CI, -5.3% to 21.8%]; odds ratio [OR], 1.50 [95% CI, 0.81 to 2.81]; P = .20). Among patients with posterior uveitis or panuveitis, treatment success was achieved in 58 (74.4%) in the methotrexate group vs 42 (55.3%) in the mycophenolate group (difference, 19.1% [95% CI, 3.6% to 30.6%]; OR, 2.35 [95% CI, 1.16 to 4.90]; P = .02); whereas among patients with intermediate uveitis treatment success occurred in 6 (33.3%) in the methotrexate group vs 14 (63.6%) in the mycophenolate group (difference, -30.3% [95% CI, -51.6% to 1.1%]; OR, 0.29 [95% CI, 0.08 to 1.05]; P = .07; P for interaction = .004). Elevated liver enzymes were the most common nonserious laboratory adverse event, occurring in 14 patients (13.0%) in the methotrexate group and 8 patients (7.4%) in the mycophenolate group.Among adults with noninfectious uveitis, the use of mycophenolate mofetil compared with methotrexate as first-line corticosteroid-sparing treatment did not result in superior control of inflammation. Further research is needed to determine if either drug is more effective based on the anatomical subtype of uveitis.ClinicalTrials.gov Identifier: NCT01829295.
Positive Impact of Social Media on Disease Awareness and Management in Patients with Inherited Bleeding Disorders: Saudi Experience from a Tertiary Care Hospital
Authors: Mahsen AlSaleh, Tarek Owaidah, Hazzaa Alzahrani, Tahani Bin Ali, Huda ElFaraidi, Mahmoud Abu Riash, Zikra Alkhayal, AbdulKareem Al Momen, Viqaruddin Mohammed, Azzah AlZahrani
Journal: Blood (2017)
Feasibility, Tolerability, and Patient-Reported Outcomes with Pharmacokinetic (PK)-Directed Dosing of Evomela® (propylene glycol free melphalan) for Multiple Myeloma and AL Amyloidosis Patients Undergoing Autologous Hematopoietic Stem Cell Transplant (AHCT)
Authors: Gunjan L. Shah, Andrew Lin, Ryan Schofield, Caitlin Sarubbi, Elaina V. Preston, Sean M. Devlin, Valkal Bhatt, Stephen J. Harnicar, Elizabeth Hoover, David J. Chung, Parastoo B. Dahi, Guenther Koehne, Roni Tamari, Dean Carlow, Sergio A. Giralt, Heather Landau
Journal: Blood (2017)
Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion
Authors: Mahsa Zarei, Heng Du, Amin H. Nassar, Rachel E. Yan, Krinio Giannikou, Sneha H. Johnson, Hilaire C. Lam, Elizabeth P. Henske, Yubao Wang, Tinghu Zhang, John Asara, David J. Kwiatkowski
Journal: The Journal of Experimental Medicine (2019)

Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces glutathione levels and increases reactive oxygen species due to reduced expression of NRF2 and glutathione biosynthesis genes. Treatment of both Tsc2+/− mice and a TSC1-null bladder cancer xenograft model with a CDK7 inhibitor showed marked reduction in tumor volume and absence of regrowth in the xenograft model. These results suggest that CDK7 inhibition is a promising therapeutic approach for treatment of TSC-associated tumors and cancers with mutations in either TSC1 or TSC2.
Archaeal Ribosomal Proteins Possess Nuclear Localization Signal-Type Motifs: Implications for the Origin of the Cell Nucleus
Authors: Sergey Melnikov, Hui-Si Kwok, Kasidet Manakongtreecheep, Antonia van den Elzen, Carson C Thoreen, Dieter Söll
Journal: Molecular Biology and Evolution (2019)

Eukaryotic cells are divided into the nucleus and the cytosol, and, to enter the nucleus, proteins typically possess short signal sequences, known as nuclear localization signals (NLSs). Although NLSs have long been considered as features unique to eukaryotic proteins, we show here that similar or identical protein segments are present in ribosomal proteins from the Archaea. Specifically, the ribosomal proteins uL3, uL15, uL18, and uS12 possess NLS-type motifs that are conserved across all major branches of the Archaea, including the most ancient groups Microarchaeota and Diapherotrites, pointing to the ancient origin of NLS-type motifs in the Archaea. Furthermore, by using fluorescence microscopy, we show that the archaeal NLS-type motifs can functionally substitute eukaryotic NLSs and direct the transport of ribosomal proteins into the nuclei of human cells. Collectively, these findings illustrate that the origin of NLSs preceded the origin of the cell nucleus, suggesting that the initial function of NLSs was not related to intracellular trafficking, but possibly was to improve recognition of nucleic acids by cellular proteins. Overall, our study reveals rare evolutionary intermediates among archaeal cells that can help elucidate the sequence of events that led to the origin of the eukaryotic cell.
Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury
Authors: Dylan Laug, Teng-Wei Huang, Navish A. Bosquez Huerta, Anna Yu-Szu Huang, Debosmita Sardar, Joshua Ortiz-Guzman, Jeffrey C. Carlson, Benjamin R. Arenkiel, Chay T. Kuo, Carrie A. Mohila, Stacey M. Glasgow, Hyun Kyoung Lee, Benjamin Deneen
Journal: Journal of Clinical Investigation (2019)

Reactive astrocytes are associated with every form of neurological injury. Despite their ubiquity, the molecular mechanisms controlling their production and diverse functions remain poorly defined. Because many features of astrocyte development are recapitulated in reactive astrocytes, we investigated the role of nuclear factor I-A (NFIA), a key transcriptional regulator of astrocyte development whose contributions to reactive astrocytes remain undefined. Here, we show that NFIA is highly expressed in reactive astrocytes in human neurological injury and identify unique roles across distinct injury states and regions of the CNS. In the spinal cord, after white matter injury (WMI), NFIA-deficient astrocytes exhibit defects in blood-brain barrier remodeling, which are correlated with the suppression of timely remyelination. In the cortex, after ischemic stroke, NFIA is required for the production of reactive astrocytes from the subventricular zone (SVZ). Mechanistically, NFIA directly regulates the expression of thrombospondin 4 (Thbs4) in the SVZ, revealing a key transcriptional node regulating reactive astrogenesis. Together, these studies uncover critical roles for NFIA in reactive astrocytes and illustrate how region- and injury-specific factors dictate the spectrum of reactive astrocyte responses.
Keep the cat, change the care pathway: A transformational approach to managing Fel d 1, the major cat allergen
Authors: Ebenezer Satyaraj, Harold James Wedner, Jean Bousquet
Journal: Allergy (2019)

Allergies to cats are the most common animal-origin allergy, and affect approximately 1 in 5 adults worldwide. The prevalence of allergy to furry animals has been increasing, and allergy to cats is a major risk factor for the development of asthma and rhinitis. The diagnosis of cat allergy is now well established. The exact significance of component-resolved diagnosis in the diagnosis of cat allergy remains to be fully understood. Allergen avoidance is effective but often has a psychologic impact. Allergen immunotherapy is not well demonstrated. There is a need for innovative approaches to better manage cat allergens. Next-generation care pathways for asthma and rhinitis will define the place of cat allergen avoidance.This manuscript, based on content presented at the European Academy of Allergy and Clinical Immunology Congress 2019, provides information on the prevalence and impact of cat allergies and the molecular biology of Fel d 1, the major cat allergen.The authors present the scientific basis of a novel care pathway that utilizes anti-Fel d 1 IgY antibodies to safely and effectively neutralize Fel d 1 after its production by the cat but before human exposure.Efficacy of a feline diet with an egg product ingredient containing anti-Fel d 1 IgY antibodies was demonstrated in vitro, ex vivo, and in vivo, and further validated by a pilot exposure study involving cat-allergic human participants.
Macrophages facilitate post myocardial infarction arrhythmias: roles of gap junction and KCa3.1
Authors: Yu-Dong Fei, Qian Wang, Jian-Wen Hou, Wei Li, Xing-Xing Cai, Yu-Li Yang, Liu-Hui Zhang, Zhi-Xing Wei, Tai-Zhong Chen, Yue-Peng Wang, Yi-Gang Li
Journal: Theranostics (2019)

Effective therapeutic targets against post-myocardial infarction (MI) arrhythmias remain to be discovered. We aimed to investigate the role of macrophages in post-MI arrhythmias. Methods: Mononuclear cell accumulation, macrophage polarization from M0 to M1 subset, and gap junction formation were analyzed in MI patients and MI mice by flow cytometry, immunofluorescence and patch clamping. Differentially expressed genes were identified by RNA sequencing. Macrophages and cardiomyocytes were cocultured in vitro, and the effects of gap junction and KCa3.1 on electrophysiological properties were assessed by patch clamping. The effects of KCa3.1 inhibition on post-MI arrhythmias were assessed by intracardiac stimulation and ambulatory electrocardiograms in vivo. Results: Percentage of pro-inflammatory mononuclear cells were significantly elevated in patients with post-MI arrhythmias compared with MI patients without arrhythmias and healthy controls (p<0.001). Macrophages formed gap junction with cardiomyocytes in MI border zones of MI patient and mice, and pro-inflammatory macrophages were significantly increased 3 days post-MI (p<0.001). RNA sequencing identified Kcnn4 as the most differentially expressed gene encoding ion channel, and the upregulation is mainly attributed to macrophage accumulation and polarization into pro-inflammatory subset. In vitro coculture experiments demonstrated that connection with M0 macrophages via gap junction slightly shortened the action potential durations (APDs) of cardiomyocytes. However, the APD90 of cardiomyocytes connected with M1 macrophages were significantly prolonged (p<0.001), which were effectively attenuated by gap junction inhibition (p=0.002), KCa3.1 inhibition (p=0.008), KCa3.1 silencing (p<0.001) and store-operated Ca2+ channel inhibition (p=0.005). In vivo results demonstrated that KCa3.1 inhibition significantly decreased the QTc durations (p=0.031), intracardiac stimulation-induced ventricular arrhythmia durations (p=0.050) and incidence of premature ventricular contractions (p=0.030) in MI mice. Conclusion: Macrophage polarization leads to APD heterogeneity and post-MI arrhythmias via gap junction and KCa3.1 activation. The results provide evidences of a novel mechanism of post-MI heterogeneous repolarization and arrhythmias, rendering macrophages and KCa3.1 to be potential therapeutic targets.