bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction between NSMCE4A and GPS1 links the SMC5/6 complex to the COP9 signalosome
Authors: Horváth András , Rona Gergely , Pagano Michele , Jordan Philip W.
Published: May 2020

Background

The SMC5/6 complex, cohesin and condensin are the three mammalian members of the structural maintenance of chromosomes (SMC) family, large ring-like protein complexes that are essential for genome maintenance. The SMC5/6 complex is the least characterized complex in mammals; however, it is known to be involved in homologous recombination repair (HRR) and chromosome segregation.

Results

In this study, a yeast two-hybrid screen was used to help elucidate novel interactions of the kleisin subunit of the SMC5/6 complex, NSMCE4A. This approach discovered an interaction between NSMCE4A and GPS1, a COP9 signalosome (CSN) component, and this interaction was further confirmed by co-immunoprecipitation. Additionally, GPS1 and components of SMC5/6 complex colocalize during interphase and mitosis. CSN is a cullin deNEDDylase and is an important factor for HRR. Depletion of GPS1, which has been shown to negatively impact DNA end resection during HRR, caused an increase in SMC5/6 levels at sites of laser-induced DNA damage. Furthermore, inhibition of the dennedylation function of CSN increased SMC5/6 levels at sites of laser-induced DNA damage.

Conclusion

Taken together, these data demonstrate for the first time that the SMC5/6 and CSN complexes interact and provides evidence that the CSN complex influences SMC5/6 functions during cell cycle progression and response to DNA damage.
The nurse anesthetist perioperative dialog
Authors: Abelsson Anna , Nygårdh Annette
Published: May 2020

Background

In the perioperative dialogue, pre-, intra- and postoperatively, the patient shares their history. In the dialogue, the nurse anesthetist (NA) gets to witness the patient’s experiences and can alleviate the patients’ suffering while waiting for, or undergoing surgery. The aim of this study was to describe the nurse anesthetist’s experiences of the perioperative dialogue.

Methods

The study had a qualitative design. Interviews were conducted with 12 NA and analyzed with interpretive content analysis. The methods were conducted in accordance with the COREQ guidelines.

Results

In the result, three categories emerge: A mutual meeting (the preoperative dialogue) where the patient and the NA through contact create a relationship. The NA is present and listens to the patient, to give the patient confidence in the NA. In the category, On the basis of the patient’s needs and wishes (the intraoperative dialogue), the body language of the NA, as well as the ability to read the body language of the patient, is described as important. In the category, To create a safe situation (the postoperative dialogue) the NA ensures that the patient has knowledge of what has happened and of future care in order to restore the control to the patient.

Conclusion

The patient is met as a person with their own needs and wishes. It includes both a physical and a mental meeting. In a genuine relationship, the NA can confirm and unreservedly talk with the patient. When the patients leave their body and life in the hands of the NA, they can help the patients to find their inherent powers, which allows for participation in their care. Understanding the patient is possible when entering in a genuine relationship with the patient and confirm the patient. The perioperative dialogue forms a safety for the patients in the operating environment.
Establishing a community advisory group (CAG) for partnership defined quality (PDQ) towards improving primary health care in a peri-urban setting in KwaZulu-Natal, South Africa
Authors: Ndaba Thoko , Taylor Myra , Mabaso Musawenkosi
Published: May 2020

Background

Community advisory groups (CAGs) have been shown to be catalysts who bridge the gap between communities and primary health care facilities by sustaining good working relationships through community engagement to improve the quality of the health care services. This study aimed to explore the establishment, operation, and accomplishments of a CAG towards building a strong partnership between the health facilities and local communities in support of the Partner Defined Quality (PDQ) process, to improve the delivery of quality maternal and neonatal care in a peri-urban setting in the province of KwaZulu-Natal, South Africa.

Methods

The study used a qualitative exploratory research design. Recruitment followed a purposive sampling approach. The study targeted leadership representatives from the community, potential beneficiaries, and health care providers in the selected catchment areas. Participants were identified during community mobilization events that took place during the preparatory stage to ensure key stakeholder support. A participatory research approach was used to discuss membership, composition, the selection criteria, including formulation, and agreement on terms of reference of the CAG membership, roles and responsibilities. A rapid assessment method was used for data collection and analysis of establishment of the CAG, its activities and accomplishments.

Results

The community nominated 24 CAG members during the consultative meetings and the organogram provides clear terms of reference, roles and responsibilities. Immediately after inception, the CAG used four indicators (weaknesses, threats and risks, strengths, and opportunities) to review the community and primary health care challenges that affect their communities. These CAG activities were linked with the phases of the PDQ process. The CAG committed itself going forward to continue to create an enabling environment for all stakeholders working to improve the well-being of the community, especially the PDQ teams working on improving the care of pregnant mothers and their babies pre- and post-delivery.

Conclusion

This work shows that developing community relationships and infrastructure are critical initial stages before embarking on PDQ planning and implementation. Empowerment, local ownership, funding, technical resources and ongoing support are critical elements for sustainability of CAG activities.
FluA-p score: a novel prediction rule for mortality in influenza A-related pneumonia patients
Authors: Chen Liang , Han Xiudi , Li Yan Li , Zhang Chunxiao , Xing Xiqian
Published: May 2020

Background

The pneumonia severity index (PSI) and the CURB-65 (confusion, urea, respiratory rate, blood pressure, age ≥ 65 years) score have been shown to predict mortality in community-acquired pneumonia. Their ability to predict influenza-related pneumonia, however, is less well-established.

Methods

A total of 693 laboratory-confirmed FluA-p patients diagnosed between Jan 2013 and Dec 2018 and recruited from five teaching hospitals in China were included in the study. The sample included 494 patients in the derivation cohort and 199 patients in the validation cohort. The prediction rule was established based on independent risk factors for 30-day mortality in FluA-p patients from the derivation cohort.

Results

The 30-day mortality of FluA-p patients was 19.6% (136/693). The FluA-p score was based on a multivariate logistic regression model designed to predict mortality. Results indicated the following significant predictors (regression statistics and point contributions toward total score in parentheses): blood urea nitrogen > 7 mmol/L (OR 1.604, 95% CI 1.150–4.492, p = 0.040; 1 points), pO2/FiO2 ≤ 250 mmHg (OR 2.649, 95% CI 1.103–5.142, p = 0.022; 2 points), cardiovascular disease (OR 3.967, 95% CI 1.269–7.322, p < 0.001; 3 points), arterial PH < 7.35 (OR 3.959, 95% CI 1.393–7.332, p < 0.001; 3 points), smoking history (OR 5.176, 95% CI 2.604–11.838, p = 0.001; 4 points), lymphocytes < 0.8 × 109/L (OR 8.391, 95% CI 3.271–16.212, p < 0.001; 5 points), and early neurominidase inhibitor therapy (OR 0.567, 95% CI 0.202–0.833, p = 0.005; − 2 points). Seven points was used as the cut-off value for mortality risk stratification. The model showed a sensitivity of 0.941, a specificity of 0.762, and overall better predictive performance than the PSI risk class (AUROC = 0.908 vs 0.560, p < 0.001) and the CURB-65 score (AUROC = 0.908 vs 0.777, p < 0.001).

Conclusions

Our results showed that a FluA-p score was easy to derive and that it served as a reliable prediction rule for 30-day mortality in FluA-p patients. The score could also effectively stratify FluA-p patients into relevant risk categories and thereby help treatment providers to make more rational clinical decisions.
RETRACTED ARTICLE: LncRNA BCRT1 promotes breast cancer progression by targeting miR-1303/PTBP3 axis
Authors: Liang Yiran , Song Xiaojin , Li Yaming , Chen Bing , Zhao Wenjing , Wang Lijuan , Zhang Hanwen , Liu Ying , Han Dianwen , Zhang Ning , Ma Tingting , Wang Yajie , Ye Fangzhou , Luo Dan , Li Xiaoyan , Yang Qifeng
Published: May 2020

Background

Long noncoding RNAs (lncRNAs) play crucial roles in tumor progression and are aberrantly expressed in various cancers. However, the functional roles of lncRNAs in breast cancer remain largely unknown.

Methods

Based on public databases and integrating bioinformatics analyses, the overexpression of lncRNA BCRT1 in breast cancer tissues was detected and further validated in a cohort of breast cancer tissues. The effects of lncRNA BCRT1 on proliferation, migration, invasion and macrophage polarization were determined by in vitro and in vivo experiments. Luciferase reporter assay and RNA immunoprecipitation (RIP) were carried out to reveal the interaction between lncRNA BCRT1, miR-1303, and PTBP3. Chromatin immunoprecipitation (ChIP) and RT-PCR were used to evaluate the regulatory effect of hypoxia-inducible factor-1α (HIF-1α) on lncRNA BCRT1.

Results

LncRNA BCRT1 was significantly upregulated in breast cancer tissues, which was correlated with poor prognosis in breast cancer patients. LncRNA BCRT1 knockdown remarkably suppressed tumor growth and metastasis in vitro and in vivo. Mechanistically, lncRNA BCRT1 could competitively bind with miR-1303 to prevent the degradation of its target gene PTBP3, which acts as a tumor-promoter in breast cancer. LncRNA BCRT1 overexpression could promote M2 polarization of macrophages, mediated by exosomes, which further accelerated breast cancer progression. Furthermore, lncRNA BCRT1 was upregulated in response to hypoxia, which was attributed to the binding of HIF-1α to HREs in the lncRNA BCRT1 promoter.

Conclusions

Collectively, these results reveal a novel HIF-1α/lncRNA BCRT1/miR-1303/PTBP3 pathway for breast cancer progression and suggest that lncRNA BCRT1 might be a potential biomarker and therapeutic target for breast cancer.
CHARGE syndrome: genetic aspects and dental challenges, a review and case presentation
Authors: Chetty Manogari , Roberts Tina Sharon , Elmubarak Mona , Bezuidenhout Heidre , Smit Liani , Urban Mike
Published: May 2020

Background

CHARGE syndrome (CS) is a rare genetic condition (OMIM #214800). The condition has a variable phenotypic expression. Historically, the diagnosis of CHARGE syndrome was based on the presence of specific clinical criteria. The genetic aetiology of CS has since been elucidated and attributed to pathogenic variation in the CHD7 gene (OMIM 608892) at chromosome locus 8q12.

Case presentation

A South African female of mixed ancestry heritage, aged 4 years, was referred for dental assessment to the Faculty of Dentistry, University of the Western Cape, in 2018. She had a diagnosis of CHARGE syndrome confirmed by a Medical Geneticist from the Division of Molecular Biology and Human Genetics at the University of Stellenbosch.

The patient had a long prior history of health and developmental problems, with the correct diagnosis becoming apparent over time. She presented with many oral and craniofacial features warranting consideration by the dentist including micrognathia, hypoplastic nasal bones, cranial nerve dysfunction, bruxism, craniofacial anomalies and compromised sensory perception. The treatment was mainly preventive and, although she fed through a percutaneous endoscopic gastrostomy tube (PEG), maintenance of her oral hygiene was necessitated.

Conclusion: CS is a multisystem condition and the optimal care for an individual is with a specialist multidisciplinary team. The numerous systemic problems affecting these individuals take precedence in their care, and often there is neglect of their dental concerns. Given the abnormalities frequently present in the oral and craniofacial region, the authors recommend that a team of dental and other medical specialists be involved in the management of individuals with CS.
Successful COVID-19 rescue therapy by extra-corporeal membrane oxygenation (ECMO) for respiratory failure: a case report
Authors: Firstenberg Michael S. , Stahel Philip F. , Hanna Jennifer , Kotaru Chakradhar , Crossno Joseph , Forrester Joseph
Published: May 2020

Background

The value of extracorporeal membrane oxygenation (ECMO) for patients suffering from novel coronavirus disease 2019 (COVID-19) as a rescue therapy for respiratory failure remains controversial and associated with high mortality rates of 50 to 82% in early reports from Wuhan, China. We hypothesized that patient outcomes would be improved at our tertiary cardiothoracic surgery referral center with a protocolized team-approach for ECMO treatment of patients with severe COVID-19 disease.

Case presentation

A 51-year-old healthy female developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) bilateral pneumonia while vacationing in Colorado with her family. She was transferred to our facility for a higher level of care. Her respiratory status continued to deteriorate despite maximized critical care, including prone positioning ventilation and nitric oxide inhalation therapy. Veno-venous ECMO was initiated on hospital day 7 in conjunction with a 10-day course of compassionate use antiviral treatment with remdesivir. The patient’s condition improved significantly and she was decannulated from ECMO on hospital day 17 (ECMO day 11). She was successfully extubated and eventually discharged to rehabilitation on hospital day 28.

Conclusion

This case report demonstrates a positive outcome in a young patient with COVID-19 treated by the judicious application of ECMO in conjunction with compassionate use antiviral treatment (remdesivir). Future prospective multi-center studies are needed to validate these findings in a larger cohort of patients.
Foot exercise plus education versus wait and see for the treatment of plantar heel pain (FEET trial): a protocol for a feasibility study
Authors: Franettovich Smith Melinda M. , Collins Natalie J. , Mellor Rebecca , Grimaldi Alison , Elliott James , Hoggarth Mark , Weber Kenneth A. , Vicenzino Bill
Published: May 2020

Background

Plantar heel pain (PHP) is present in a wide range of individuals and creates significant burden to quality of life and participation in physical activity. The high recurrence rates and persistence of PHP suggests current management options may not address all potentially modifiable factors associated with the condition. Reports of intrinsic foot muscle (IFM) atrophy in individuals with PHP, together with biomechanical evidence of their important contribution to optimal foot function, suggests that an intervention focused on IFM training may be beneficial in managing PHP. We will test the feasibility of a prospective, assessor‐blinded, parallel‐group, randomised clinical trial that compares foot exercise plus education to brief advice in individuals with PHP.

Methods

Twenty participants with PHP will be randomly allocated to one of two groups for a 12‐week intervention period: (i) foot exercise plus education, or (ii) brief advice. The foot exercise plus education group will attend eight sessions with a physiotherapist and receive detailed education on self‐management strategies as well as a progressive exercise program for the IFMs. The brief advice group will attend one session with a physiotherapist and receive brief information about self‐management strategies and reassurance. Outcome measures will be obtained at baseline and the primary end‐point of 12 weeks. Primary outcomes will be the feasibility of conducting a full‐scale randomised clinical trial (RCT), and the credibility and acceptability of the foot exercise plus education intervention. Secondary outcomes will explore treatment effects, which will consist of pain, physical function, physical activity level, pain self‐efficacy, perceived treatment effect, magnetic resonance and ultrasound image measurement of IFM morphology, ultrasound imaging measurement of plantar fascia thickness, IFM motor performance, foot posture, foot mobility, ankle dorsiflexion range of motion, toe flexor and plantar flexor strength/endurance.

Discussion

To reduce the burden of PHP on individuals and society, there is a need to establish effective treatments that are feasible and accepted by patients and health professionals. This trial will be the first to evaluate the feasibility of conducting a full‐scale RCT, as well as the credibility, acceptability, and treatment effects, of education and foot exercise for PHP. The findings of this study will inform the development of a full‐scale RCT.

Trial registration

The trial protocol was prospectively registered with the Australia and New Zealand Clinical Trial Registry (ACTRN12619000987167) on 11th July 2019.
Anopheles gambiae (s.l.) exhibit high intensity pyrethroid resistance throughout Southern and Central Mali (2016–2018): PBO or next generation LLINs may provide greater control
Authors: Sovi Arthur , Keita Chitan , Sinaba Youssouf , Dicko Abdourhamane , Traore Ibrahim , Cisse Moussa B. M. , Koita Ousmane , Dengela Dereje , Flatley Cecilia , Bankineza Elie , Mihigo Jules , Belemvire Allison , Carlson Jenny , Fornadel Christen , Oxborough Richard M.
Published: May 2020

Background

Millions of pyrethroid LLINs have been distributed in Mali during the past 20 years which, along with agricultural use, has increased the selection pressure on malaria vector populations. This study investigated pyrethroid resistance intensity and susceptible status of malaria vectors to alternative insecticides to guide choice of insecticides for LLINs and IRS for effective control of malaria vectors.

Methods

For 3 years between 2016 and 2018, susceptibility testing was conducted annually in 14–16 sites covering southern and central Mali. Anopheles gambiae (s.l.) were collected from larval sites and adult mosquitoes exposed in WHO tube tests to diagnostic doses of bendiocarb (0.1%) and pirimiphos-methyl (0.25%). Resistance intensity tests were conducted using CDC bottle bioassays (2016–2017) and WHO tube tests (2018) at 1×, 2×, 5×, and 10× the diagnostic concentration of permethrin, deltamethrin and alpha-cypermethrin. WHO tube tests were conducted with pre-exposure to the synergist PBO followed by permethrin or deltamethrin. Chlorfenapyr was tested in CDC bottle bioassays at 100 µg active ingredient per bottle and clothianidin at 2% in WHO tube tests. PCR was performed to identify species within the An. gambiae complex.

Results

In all sites An. gambiae (s.l.) showed high intensity resistance to permethrin and deltamethrin in CDC bottle bioassay tests in 2016 and 2017. In 2018, the WHO intensity tests resulted in survivors at all sites for permethrin, deltamethrin and alpha-cypermethrin when tested at 10× the diagnostic dose. Across all sites mean mortality was 33.7% with permethrin (0.75%) compared with 71.8% when pre-exposed to PBO (4%), representing a 2.13-fold increase in mortality. A similar trend was recorded for deltamethrin. There was susceptibility to pirimiphos-methyl, chlorfenapyr and clothianidin in all surveyed sites, including current IRS sites in Mopti Region. An. coluzzii was the primary species in 4 of 6 regions.

Conclusions

Widespread high intensity pyrethroid resistance was recorded during 2016–2018 and is likely to compromise the effectiveness of pyrethroid LLINs in Mali. PBO or chlorfenapyr LLINs should provide improved control of An. gambiae (s.l.). Clothianidin and pirimiphos-methyl insecticides are currently being used for IRS as part of a rotation strategy based on susceptibility being confirmed in this study.
Alzheimer’s disease progression characterized by alterations in the molecular profiles and biogenesis of brain extracellular vesicles
Authors: Gallart-Palau Xavier , Guo Xue , Serra Aida , Sze Siu Kwan
Published: May 2020

Background

The contributions of brain intercellular communication mechanisms, specifically extracellular vesicles (EV), to the progression of Alzheimer’s disease (AD) remain poorly understood.

Methods

Here, we investigated the role(s) of brain EV in the progressive course of AD through unbiased proteome-wide analyses of temporal lobe-derived EV and proteome-label quantitation of complementary remaining brain portions. Furthermore, relevant proteins identified were further screened by multiple reaction monitoring.

Results

Our data indicate that EV biogenesis was altered during preclinical AD with the genesis of a specific population of EV containing MHC class-type markers. The significant presence of the prion protein PrP was also manifested in these brain vesicles during preclinical AD. Similarly, sequestration of amyloid protein APP in brain EV coincided with the observed PrP patterns. In contrast, active incorporation of the mitophagy protein GABARAP in these brain vesicles was disrupted as AD progressed. Likewise, disrupted incorporation of LAMP1 in brain EV was evident from the initial manifestation of AD clinical symptoms, although the levels of the protein remained significantly upregulated in the temporal lobe of diseased brains.

Conclusions

Our findings indicate that impaired autophagy in preclinical AD coincides with the appearance of proinflammatory and neuropathological features in brain extracellular vesicles, facts that moderately remain throughout the entire AD progression. Thus, these data highlight the significance of brain EV in the establishment of AD neuropathology and represent a further leap toward therapeutic interventions with these vesicles in human dementias.
On the axiomatic foundation of carbon and energy footprints
Authors: Kuhn Thomas , Pestow Radomir , Zenker Anja
Published: May 2020

Background

A wide variety of footprint concepts is proposed in the scientific literature giving rise to a selection problem.

Method

The objective of this paper is to provide an axiomatic foundation to the concept of ecological footprint indices, in particular carbon and energy footprints. For this purpose, we define five axioms representing general properties which any ecological footprint measure should fulfill.

Results

It can be shown that there exists a unique index which is characterized by the given set of axioms. Its functional form is determined, and an economic interpretation is given. The most prominent empirical application is discussed.

Conclusion

We find that the proposed index as a generalization of more specific indices like carbon and energy footprint indices may confirm some important issues discussed in the literature. First, it incorporates a trade component indicating the ecological footprint of economic activities embodied in the trade pattern of a country or region. Moreover, the productivity of land use in production as a means to mitigate the pressure on the ecological system is reflected. But, most importantly, from a methodological point of view, there is no longer the need for designing ecological footprint indices ad hoc, in particular for the sake of empirical application.
Soil-plant co-stimulation during forest vegetation restoration in a subtropical area of southern China
Authors: Chen Chan , Fang Xi , Xiang Wenhua , Lei Pifeng , Ouyang Shuai , Kuzyakov Yakov
Published: May 2020

Background

Soil and vegetation have a direct impact on the process and direction of plant community succession, and determine the structure, function, and productivity of ecosystems. However, little is known about the synergistic influence of soil physicochemical properties and vegetation features on vegetation restoration. The aim of this study was to investigate the co-evolution of soil physicochemical properties and vegetation features in the process of vegetation restoration, and to distinguish the primary and secondary relationships between soil and vegetation in their collaborative effects on promoting vegetation restoration in a subtropical area of China.

Methods

Soil samples were collected to 40 cm in four distinct plant communities along a restoration gradient from herb (4–5 years), to shrub (11–12 years), toPinus massonianaconiferous and broadleaved mixed forest (45–46 years), and to evergreen broadleaved forest (old growth forest). Measurements were taken of the soil physicochemical properties and Shannon–Wiener index (SD), diameter at breast height (DBH), height (H), and biomass. Principal component analysis, linear function analysis, and variation partitioning analysis were then performed to prioritize the relative importance of the leading factors affecting vegetation restoration.

Results

Soil physicochemical properties and vegetation features showed a significant trend of improvement across the vegetation restoration gradient, reflected mainly in the high response rates of soil organic carbon (SOC) (140.76%), total nitrogen (TN) (222.48%), total phosphorus (TP) (59.54%), alkaline hydrolysis nitrogen (AN) (544.65%), available phosphorus (AP) (53.28%), species diversity (86.3%), biomass (2906.52%), DBH (128.11%), andH(596.97%). The soil properties (pH, SOC, TN, AN, and TP) and vegetation features (biomass, DBH, andH) had a clear co-evolutionary relationship over the course of restoration. The synergistic interaction between soil properties and vegetation features had the greatest effect on biomass (55.55%–72.37%), and the soil properties contributed secondarily (3.30%–31.44%). The main impact factors of biomass varied with the restoration periods.

Conclusions

In the process of vegetation restoration, soil and vegetation promoted each other. Vegetation restoration was the cumulative result of changes in soil fertility and vegetation features.
Imaging-AMARETTO: An Imaging Genomics Software Tool to Interrogate Multiomics Networks for Relevance to Radiography and Histopathology Imaging Biomarkers of Clinical Outcomes
Authors: Gevaert Olivier , Nabian Mohsen , Bakr Shaimaa , Everaert Celine , Shinde Jayendra , Manukyan Artur , Liefeld Ted , Tabor Thorin , Xu Jishu , Lupberger Joachim , Haas Brian J. , Baumert Thomas F. , Hernaez Mikel , Reich Michael , Quintana Francisco J. , Uhlmann Erik J. , Krichevsky Anna M. , Mesirov Jill P. , Carey Vincent , Pochet Nathalie
Published: May 2020

PURPOSE

The availability of increasing volumes of multiomics, imaging, and clinical data in complex diseases such as cancer opens opportunities for the formulation and development of computational imaging genomics methods that can link multiomics, imaging, and clinical data.

METHODS

Here, we present the Imaging-AMARETTO algorithms and software tools to systematically interrogate regulatory networks derived from multiomics data within and across related patient studies for their relevance to radiography and histopathology imaging features predicting clinical outcomes.

RESULTS

To demonstrate its utility, we applied Imaging-AMARETTO to integrate three patient studies of brain tumors, specifically, multiomics with radiography imaging data from The Cancer Genome Atlas (TCGA) glioblastoma multiforme (GBM) and low-grade glioma (LGG) cohorts and transcriptomics with histopathology imaging data from the Ivy Glioblastoma Atlas Project (IvyGAP) GBM cohort. Our results show that Imaging-AMARETTO recapitulates known key drivers of tumor-associated microglia and macrophage mechanisms, mediated by STAT3, AHR, and CCR2, and neurodevelopmental and stemness mechanisms, mediated by OLIG2. Imaging-AMARETTO provides interpretation of their underlying molecular mechanisms in light of imaging biomarkers of clinical outcomes and uncovers novel master drivers, THBS1 and MAP2, that establish relationships across these distinct mechanisms.

CONCLUSION

Our network-based imaging genomics tools serve as hypothesis generators that facilitate the interrogation of known and uncovering of novel hypotheses for follow-up with experimental validation studies. We anticipate that our Imaging-AMARETTO imaging genomics tools will be useful to the community of biomedical researchers for applications to similar studies of cancer and other complex diseases with available multiomics, imaging, and clinical data.
SAT-094 Evaluation of IGF-1 as a Biomarker to Inform Phase 3 Clinical Trial Design and Dose Selection in Patients Born Small for Gestational Age Who Fail to Demonstrate Catch-Up Growth by Age 2–4 Years
Authors: Liu Tao , Penzenstadler Justin , Cicali Brain , Zemskova Marina S , Vaidyanathan Jayabharathi , Sahajwalla Chandrahas
Published: May 2020

Insulin-like growth factor-1 (IGF-1) is a key hormone in mediating the physiological response to endogenous and exogenous growth hormone (GH). Current clinical guidelines suggest use of IGF-1 for dose titration in adults with GH deficiency and for safety monitoring in adults and pediatric patients. Several GH drug development programs for pediatric indications have collected IGF-1, height standard deviation score (HSDS), and height velocity (HV), to support dose selection in Phase 3 clinical trials. In this analysis, patients born small for gestational age (SGA) who fail to demonstrate catch-up growth by age 2–4 years from different growth hormone product development programs were included. A total of 663 patients from 8 clinical trials were included in this analysis, with 7 placebo arms and 15 growth hormone treated arms. The growth hormone dosing regimen ranged from 33 ug/kg/day to 100 ug/kg/day. Both boys and girls throughout a wide range of ages (3 to 7 years old on average) were represented in this analysis. The average patient was 3 to 4 standard deviations below the age- and sex- adjusted mean height at baseline. IGF-1 was collected and standardized according to age and sex, so called the IGF-1 standard deviation score (IGF-1 SDS). At baseline, the average patient had normal IGF-1 (-1 to 0 on average). Based on preliminary findings, IGF-1 SDS change from baseline (CFB) at 6 months was correlated with HSDS CFB at 12 months. HSDS CFB at 3 months and 6 months were also correlated with HSDS CFB at 12 months, respectively. These findings were consistent across the three GH products included in the analysis, as well as age and gender. However, IGF-1 SDS CFB had much larger variability than HSDS CFB. Both HSDS CFB at 3 months and 6 months precisely and accurately predicted HSDS CFB at 12 months. IGF-1 SDS was more variable and did not add any further contribution in the prediction of HSDS at 12 months and therefore IGF-1 may not be sufficient in informing Phase 3 dose selection in such trials.

Reference: 1. Shoshana Yakar, Clifford J. Rosen, Wesley G. Beamer, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest. 2002 Sep 15; 110(6): 771–781. 2. Locatelli V, Bianchi VE. Effect of GH/IGF-1 on Bone Metabolism and Osteoporosis. Int J Endocrinol. 2014;2014:235060 Nothing to Disclose: TL, JP, BC, MZ, JV, CS
SUN-248 Estradiol Changes Angiotensin II-Induced ERK1/2 Phosphorylation by Different Pathways in the Hypothalamus and Lamina Terminalis
Authors: Almeida-Pereira Gislaine , Elias Lucila Leico Kagohara , Antunes-Rodrigues José
Published: May 2020

Female gonadal hormones, especially 17β-estradiol (E2), are known to mediate hydromineral homeostasis and blood pressure mainly by attenuating renin-angiotensin system (RAS) actions. The RAS plays an essential role in the maintenance of hydromineral and cardiovascular homeostasis via angiotensin II (ANGII), a key component of the RAS. However, the cellular mechanisms of the interaction between E2 and ANGII and its physiological role are not fully elucidated. Recently, our group showed that ERK1/2 is involved in sodium intake and vasopressin release induced by ANGII in female rats. In addition, E2 decreases ERK1/2 phosphorylation induced by ANGII in the hypothalamus and in structures of the lamina terminalis (LT). Thus, the goal of the present study was evaluated some mechanisms that could be involved in ERK1/2 dephosphorylation induced by E2 in response to ANGII, such as MAPK phosphatase 1 (MKP-1) and GRK5. For this, Wistar female rats (~250g) were submitted to ovariectomy and on the following day they were treated with estradiol cypionate (10µg/rat, sc) or vehicle (corn oil, 0.1mL/rat, sc) for eight days. On the eighth day, the rats received an intracerebroventricular (icv, lateral ventricle) injection of angiotensin II (25ng/2μL/rat) or vehicle (0.9% saline, 2μL/rat). After five min of ANGII injection the animals were decapitated for brain collection for MKP-1 and GRK5 expression analysis by western blot. Data were analyzed using ANOVA two or three-way, followed by Newman-Keuls post-test and the level of significance was set at 5%. It was observed that E2 increased MKP-1 expression only in hypothalamus (F1,18=24.3, p<0.001) in ovariectomized rats, independent of ANGII stimulus. Because the inhibitory effect of E2 on vasopressin release induced by ANGII was reversed by PKC inhibition, it was analyzed the role of PKC on MKP-1 expression and it was observed that PKC inhibition (Chelerythrine, 100µM/2µL/rat) reversed the positive effect of E2 on MKP-1 expression (F1,30=4.7, p<0.05) in the hypothalamus. In addition, E2 decreased GRK5 expression only in the LT (F1,21=12.7, p<0.01) in response to ANGII. Taken together, these results suggest that E2 requires PKC/MKP-1 pathway to decrease ERK1/2 phosphorylation in the hypothalamus and consequent vasopressin release induced by ANGII. While in the LT, the inhibitory effect of E2 involves decreasing GRK5 expression compromising ERK1/2 phosphorylation and sodium intake induced by ANGII. A significant contribution of this work is the identification of some steps of ANGII signaling modulated by E2, which can explain, at least in part, its regulation on the central ANGII effects.
MON-484 Thyroid Nodules: Not so Simple to Manage
Authors: Cruz Alegyari Figueroa , Torres Yineli Ortiz , Carlo Chévere Victor J , Garcia-Mateo Jose M
Published: May 2020

Thyroid Nodules: Not So Simple to Manage

Thyroid nodules diagnosis and malignancy risk stratification remains a challenge for decision making between conservative vs invasive management. The development of the clinical guidelines provides alternatives for evaluation and management for thyroid nodules, but can be used for all patients?

A 43 y/o female without known past medical history is referred to the endocrine service by her primary care physician for evaluation of a thyroid nodule. She was presenting with 1 month history of mild discomfort on the neck and was evaluated with thyroid US that was relevant for multiple bilateral solid nodules measuring <1.0cm and a one spongiform measuring 1.7 x 1.2 x 1.3cm in the right lobe extending minimally to the capsule laterally and to the carotid artery wall. Patient denies cough, hoarseness, odynophagia, shortness of breath, family history of thyroid cancer or radiation exposure. On examination there were no goiter nor palpable thyroid nodules, as well as no clinical signs and symptoms of thyroid disease. Patient is clinically and biochemically euthyroid with a very low suspicion thyroid nodule (3% estimated malignancy risk). Despite nodule is below the 2.0cm cutoff point for fine needle aspiration biopsy (FNAB) according to American Association of Clinical Endocrinologist (AACE) and American Thyroid Association (ATA) guidelines, it was done based on additional suspicious sonographic features detect by the endocrinologist on evaluation of ultrasound images. FNAB was performed and reveals Atypia of undetermined significance/Follicular Lesion of undetermined significance (AUS/FLUS) Bethesda system category III with a risk of malignancy of 5–15%. Patient was reluctant to surgery given the very low risk nodule and biopsy results of AUS/FLUS. In order to further manage this patient with undetermined significance thyroid nodule, Gene Expression Classifier (GEC) Molecular Analysis (AFIRMA) was performed. AFIRMA test was done with a second FNAB that also reveals AUS/FLUS but was found positive for BRAFv600, Bethesda system category IV: Suspicious of Papillary Thyroid Carcinoma. BRAFv600 is the only mutation that have high specificity (99%) for papillary thyroid carcinoma and is associated with increased disease-specific mortality, aggressive histologic phenotypes, lymph node metastases, extrathyroidal extension and risk of recurrence. Based on this data patient now have 95% risk of malignancy and requires surgical therapy. Patient preferred total thyroidectomy over lobectomy; pathology results shows 2.0cm Papillary Thyroid Carcinoma Stage I (T1N0M0).

Despite very low risk nodule finding, malignancy was diagnosed. As depicted in this case, thyroid nodules aren’t so simple to manage, and their management should involve imaging and pathology findings along with clinical judgement and patient individualization in decision making process.
SAT-421 Novel Role of Chloroquine and Hydroxychloroquine in Graves’ Orbitopathy Therapy by Targeting Orbital Fibroblasts
Authors: Guo Yan , Li Hai , Chen Xueying , Guan Hongyu , He Xiaoying , Chen Yuxin , Xiao Haipeng , Li Yanbing
Published: May 2020

Abstract: Context: Graves’ orbitopathy (GO) presents with infiltrative exophthalmos due to excessive proliferation, adipogenesis and glycosaminoglycans production of orbital fibroblasts (OFs). There are few therapies potent for proptosis. Intervention in autophagy of OFs could be a potential therapy. Objectives: Here, our purpose was to evaluate the effects of chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), as autophagy inhibitors commonly used in clinical practice, on GO-OFs from human orbit in vitro. Design/Setting/Participants: OFs isolated from patients with GO (n = 10) or control persons (non-GO) (n = 8) were allowed to proliferate in the proliferation medium (PM) or differentiate into adipocytes in the differentiation medium (DM), co-treated with CQ of different concentrations, and subsequently examined in vitro. Main Outcome Measures: CCK-8, EdU incorporation and flow cytometry were used to assess cellular viability. Adipogenesis was assessed by Western blot, real time-PCR, and Oil Red O staining. Hyaluronan was determined by real time-PCR and ELISA. Autophagy flux was detected using RFP-GFP-LC3 fluorescent staining and Western blot. Results: CQ (10μM) or HCQ (10μM) treatment for 48h was sufficient to block autophagy flux without exhibiting cell toxicity in OFs from either GO or non-GO participants. Cellular proliferation of GO-OFs was halted by both CQ and HCQ. Also CQ and HCQ exerted an inhibitory action on lipid accumulation of GO-OFs during differentiation as well as expression of adipogenetic markers such as PPARγ and c/EBP-α/β. Moreover, hyaluronan secretion, concurrent with expression of hyaluronan synthase 2 (HAS2), was obviously decreased by CQ and HCQ. Conclusions: We reported the efficacies of CQ and HCQ on proliferation, adipogenesis and hyaluronan generation of GO-OFs via inhibiting autophagy, providing proof of concept that quinoline-based antimalarial (QBA) drugs like CQ and HCQ have potential to be a new treatment for GO as autophagy inhibitors.
SAT-118 Rapid Decompensation from Complications of Severe Hypercortisolism in an Unusual Presentation of an Ectopic ACTH-Secreting Neuroendocrine Tumor
Authors: Sumal Amit Kartar Singh , Liao Charles , Chen Julie
Published: May 2020

Background: Ectopic Cushing’s syndrome from an ACTH-secreting neuroendocrine tumor (NET) is a rare condition whose onset and disease progression is often more aggressive than other forms of Cushing’s syndrome due to complications from severe hypercortisolism.

Clinical Case: A 75-year old woman presented with profound proximal muscle weakness, severe hypokalemia, Cushingoid features, and biopsy-proven Candida esophagitis. Initial testing was consistent with ACTH-dependent Cushing syndrome: elevated 24 hour urinary cortisol excretion (1,310.54 mcg/24h; n <50 mcg/24h), abnormal 1 mg dexamethasone suppression test (68.3 ug/dL), and elevated ACTH level (200 pg/mL; n: 7.2–63.3 pg/mL). MRI was negative for a pituitary lesion but abdominal CT revealed an 8.8 cm liver mass with biopsy consistent with a well-differentiated neuroendocrine tumor, WHO Grade 2. Subsequent 68Ga-DOTATATE-PET/CT noted DOTATATE uptake in the liver lesion, a 0.9 cm right pulmonary nodule, and the pancreatic tail without CT correlate. Initially, the patient was prescribed mifepristone and spironolactone for hypokalemia. Given her NET of unknown primary, metastatic disease, and immunocompromised state due to hypercortisolism, the patient was not a candidate for surgical resection of her NET but was instead referred for bilateral adrenalectomy. However, she rapidly decompensated from complications of her hypercortisolism prior to surgery. Her weakness progressed to immobility, and she developed acute psychosis manifested as agitation and mutism. The patient was immediately admitted to the hospital where she developed new-onset atrial flutter and myelosuppression requiring multiple transfusions. She underwent urgent bilateral adrenalectomy, but despite surgery, her post-operative course was complicated by hypoxemic respiratory failure and shock. The patient shortly thereafter expired from pulseless electrical activity arrest.

Conclusion: This atypical case of an ectopic ACTH-secreting NET highlights the life-threatening complications associated with severe hypercortisolism, including: opportunistic infection, severe metabolic abnormalities, psychosis, myopathy, and critical illness that can incite myelosuppression and unstable arrhythmias. These patients can quickly deteriorate and are at high risk for mortality. Early diagnosis and swift reversal of their hypercortisolism with bilateral adrenalectomy are oftentimes needed to prevent these potentially fatal complications.
SAT-153 PTHrP Mediated Hypercalcemia
Authors: Arguello Mingxue
Published: May 2020

PTHrp mediated hypercalcemia

Introduction:

PTHrp is a normal gene product, which helps tooth eruption and mammary gland development. However, PTHrp production in an adult is mostly related to solid tumor malignancy. The homology of PTHrp to PTH from the 1st to 13th amino acids decided the similar mechanism of acting at PTH-1 receptor on increasing bone resorption and calcium reabsorption at the distal renal tubule. Lung cancer is known to secrete PTHrp and PTHrp secreting hepatic cellular carcinoma (HCC) is exceedingly rare. It’s only been documented in case reports. Two cases of PTHrp secreting atypical HCC are included in this case report.

Case presentation:

67 year old with history of alcohol abuse with 17.8 x 8.8 cm mass in the left hepatic lobe presented with acute encephalopathy and calcium of 14.4 mg/dl. Patient was treated with zolendronic acid 4mg, IV fluid and calcitonin. Patient has a PTH level of 7 pg/ml and PTHrp level of 335 pg/ml. Bone turnover marker Beta crosslaps of 1595 pg/ml. 25-hydroxy vitD of 25 ng/ml and 1,25 dihydroxy vitD of 42 pg/ml. Liver biopsy demonstrated moderately differentiated hepatocellular carcinoma. The undifferentiated portion was positive with CD56, CAM 5.2 suggestive of neuroendocrine differentiation and epithelial lineage. Patient had negative metastatic bone scan and no pathologic fractures. Second case is a 63 year old male with NASH cirrhosis was admitted for hypercalcemia of 13.2 mg/dl. Patient was found to have metastatic atypical hepatocellular carcinoma and L4 vertebral lesion. PTHrp was 30 pg/ml and PTH 14 pg/ml. Bone turnover marker Beta crosslaps of 405 pg/ml. 25-hydroxy vitD of 48 ng/ml and 1,25 dihydroxy vitD of 9 pg/ml. Patient expired prior to biopsy.

Discussion:

4 cases of similar HCC were found in the literature. The treatment approach was resection of tumor, chemo or ablation. Hypercalcemia is controlled with reduction of the tumor burden and rarely by zolendronic acid alone. Both of presented cases were too advanced for surgery or chemo treatment. When tumor was not amendable for treatment, the hypercalcemia was not controllable long term. A small size study in japan administering 10mg alendronate via hepatic artery rather than IV route for patients with HCC showed enhancement of the apoptosis of HCC in addition to controlling hypercalcemia. An animal study on anti-PTHrp monoclonal murine antibody showed improved mortality of PTHrp producing pancreatic carcinoma (FA-6) in transplanted nude mice.

Conclusion:

Most of the patients with PTHrp mediated hypercalcemia have advance cancer that is not amendable for surgery or chemotherapy. A non-invasive treatment approach other than alendronate should be investigated to control PTHrp mediated hypercalcemia.
MON-611 Using Machine Learning on Electronic Health Records to Predict Inpatient Glucose Levels and Physicians’ Insulin Dosing
Authors: Jankovic Ivana , Liu Xiran , Chen Jonathan H
Published: May 2020

The current optimal inpatient diabetes management schema involves administration of basal, prandial, and correctional insulin to maintain blood glucose (BG) within a target range. Nonetheless, practical management often fails to reach the ideal in both insulin dosing regimens and patients’ BG outcomes. Given the challenges of achieving adequate BG control for hospitalized patients using guidelines and expert knowledge alone, we attempted to use machine learning methods to predict (1) individual BGs, (2) average daily BGs, and (3) physician-ordered insulin doses based on data in an electronic health record-based repository between January 2014 and December 2018. We considered inpatients on subcutaneous insulin having a BG ≥ 200 mg/dL or ≤ 70 mg/dL or with an A1c percentage ≥ 6.5%. We excluded those missing critical data (such as weight), with fewer than five BG checks in 72 hours, or those on hemodialysis, resulting in a cohort of 3,461 patients with 175,934 BG checks among them. In this cohort, the average age was 61.4 years, the average A1c was 7.1%, and the average BG was 171.6 mg/dL, with approximately 25% of BGs ≥ 200 mg/dL and 1.7% of BGs < 70 mg/dL. Using linear regression, we identified features that contributed most to prediction of each of the outcomes. For all three outcomes, the average glucose in the past 24 hours was the most important feature. For prediction of glucose levels, previous BG, BG at the same time the previous day, A1c, BG variance, recent long-acting insulin dose, and glucocorticoid dose were all in the top 10 features. Similar features were important for predicting physician-ordered insulin doses. Surprisingly, neither weight nor creatinine were identified as top features for any outcome. Using these features in our predictive model, we found that individual BGs were highly erratic and could not be predicted precisely (R2 0.24). Similarly, and perhaps unsurprisingly, how physicians would order insulin for patients was also difficult to predict (R2 0.25). However, average daily glucose levels were predicted more reliably (R2 0.36), as was prediction of frank hyperglycemia (BG ≥ 200 mg/dL) in the next day (sensitivity 0.73, specificity 0.79). Given the typical practice pattern of a clinician evaluating the previous day’s insulin regimen performance and adjusting it by anticipating BGs for the next day, prediction of hyperglycemia in the next 24 hours can support decision-making for inpatient BG management.