bluuebunny/crossref_metadata_2025 huggingface dataset:
Protective effects of new aryl sulfone derivatives against radiation-induced hematopoietic injury
Authors: Cao Jian , Li Hongyan , Yuan Renbin , Dong Yinping , Wu Jing , Wang Meifang , Li Deguan , Tian Hongqi , Dong Hui
Published: February 2020

The hematopoietic system is sensitive to radiation. In this research, new aryl sulfone derivatives (XH-201 and XH-202) containing a nitrogen heterocycle were designed and synthesized and their radio-protective efficacies with regard to the hematopoietic system were evaluated. XH-201 administration significantly increased the survival rate of mice after 8.0 Gy total body irradiation (TBI). The results showed that XH-201 treatment not only increased the white blood cells, platelets counts and the percentage of hematopoietic progenitor cells and hematopoietic stem cells in mice exposed to 4.0 Gy TBI but also decreased DNA damage, as determined by flow cytometric analysis of histone H2AX phosphorylation. In addition, our data demonstrated that XH-201 decreased the mitochondrial reactive oxygen species (ROS) levels in hematopoietic cells. Overall, these data suggest that XH-201 is beneficial for the protection of the hemoatopoietic system against radiation-induced injuries.
Comparison of rectal dose reduction by a hydrogel spacer among 3D conformal radiotherapy, volumetric-modulated arc therapy, helical tomotherapy, CyberKnife and proton therapy
Authors: Saito Masahide , Suzuki Toshihiro , Sugama Yuya , Marino Kan , Sano Naoki , Komiyama Takafumi , Aoki Shinichi , Maehata Yoshiyasu , Yoshizawa Kazuya , Ashizawa Kazunari , Suzuki Hidekazu , Ueda Koji , Miyasaka Yosuke , Araya Masayuki , Takahashi Hiroshi , Onishi Hiroshi
Published: February 2020

This study aimed to evaluate the rectal dose reduction with hydrogel spacer in 3D conformal radiotherapy (3DCRT), volumetric modulated arc therapy (VMAT), helical tomotherapy (HT), CyberKnife (CK) and proton therapy. Twenty patients who had hydrogel spacer for prostate radiotherapy were retrospectively enrolled. Computed tomography (CT) images with or without hydrogel spacer were used to evaluate rectal dose reduction. In total, 200 plans (20 patients × 2 CT images × 5 techniques) were created using the following criteria: 3DCRT, VMAT and HT [76 Gy/38 fractions (Fr), planning target volume (PTV) D50%], CK (36.25 Gy/5 Fr, PTV D95%) and proton therapy (63 GyE/21 Fr, PTV D50%). Rectal dose reduction was evaluated using low-/middle-dose (D20%, D50% and D80%) and high-dose (D2%) ranges. Rectal dose reduction of each dose index was compared for each technique. Significant rectal dose reduction (P < 0.001) between the treatment plans on pre- and post-CT images were achieved for all modalities for D50%, D20% and D2%. In particular, the dose reduction of high-dose (D2%) ranges were −40.61 ± 11.19, −32.44 ± 5.51, −25.90 ± 9.89, −13.63 ± 8.27 and −8.06 ± 4.19%, for proton therapy, CK, HT, VMAT and 3DCRT, respectively. The area under the rectum dose–volume histogram curves were 34.15 ± 3.67 and 34.36 ± 5.24% (P = 0.7841) for 3DCRT with hydrogel spacer and VMAT without hydrogel spacer, respectively. Our results indicated that 3DCRT with hydrogel spacer would reduce the medical cost by replacing the conventional VMAT without spacer for prostate cancer treatment, from the point of view of the rectal dose. For the high-dose gradient region, proton therapy and SBRT with CK showed larger rectal dose reduction than other techniques.
The effect of high nitrogen pressures on the habitable zone and an appraisal of greenhouse states
Authors: Ramirez Ramses M
Published: February 2020

The habitable zone (HZ) is the main tool that mission architectures utilize to select potentially habitable planets for follow-up spectroscopic observation. Given its importance, the precise size and location of the HZ remains a hot topic, as many studies, using a hierarchy of models, have assessed various factors including: atmospheric composition, time, and planetary mass. However, little work has assessed how the HZ changes with variations in background nitrogen pressure, which is directly connected to the habitability and life-bearing potential of planets. Here, I use an advanced energy balance model with clouds to show that our Solar system's HZ is ∼0.9–1.7 au, assuming a 5-bar nitrogen background pressure and a maximum 100 per cent cloud cover at the inner edge. This width is ∼20 per cent wider than the conservative HZ estimate. Similar extensions are calculated for A–M stars. I also show that cooling clouds/hazes and high background pressures can decrease the runaway greenhouse threshold temperature to ∼300 K (or less) for planets orbiting any star type. This is because the associated increase in planetary albedo enables stable climates closer to the star, where rapid destabilization can be triggered from a lower mean surface temperature. Enhanced longwave emission for planets with very high stratospheric temperatures also permits stable climates at smaller orbital distances. The model predicts a runaway greenhouse above ∼330 K for planets orbiting the Sun, which is consistent with previous work. However, moist greenhouses only occur for planets orbiting A-stars.
TERT, a promoter of CNS malignancies
Authors: Patel Bhuvic , Taiwo Rukayat , Kim Albert H , Dunn Gavin P
Published: February 2020

As cells replicate their DNA during mitosis, telomeres are shortened due to the inherent limitations of the DNA replication process. Maintenance of telomere length is critical for cancer cells to overcome cellular senescence induced by telomere shortening. Telomerase reverse transcriptase (TERT) is the rate-limiting catalytic subunit of telomerase, an RNA-dependent DNA polymerase that lengthens telomeric DNA to maintain telomere homeostasis. TERT promoter mutations, which result in the upregulation of TERT transcription, have been identified in several central nervous system (CNS) tumors, including meningiomas, medulloblastomas, and primary glial neoplasms. Furthermore, TERT promoter hypermethylation, which also results in increased TERT transcription, has been observed in ependymomas and pediatric brain tumors. The high frequency of TERT dysregulation observed in a variety of high-grade cancers makes telomerase activity an attractive target for developing novel therapeutics. In this review, we briefly discuss normal telomere biology, as well as the structure, function, and regulation of TERT in normal human cells. We also highlight the role of TERT in cancer biology, focusing on primary CNS tumors. Finally, we summarize the clinical significance of TERT promoter mutations in cancer, the molecular mechanisms through which these mutations promote oncogenesis, and recent advances in cancer therapies targeting TERT.
Olive oil consumption and its repercussions on lipid metabolism
Authors: Tomé-Carneiro João , Crespo María Carmen , López de las Hazas María Carmen , Visioli Francesco , Dávalos Alberto
Published: February 2020

Consumption of highly processed foods, such as those high in trans fats and free sugars, coupled with sedentarism and chronic stress increases the risk of obesity and cardiometabolic disorders, while adherence to a Mediterranean diet is inversely associated with the prevalence of such diseases. Olive oil is the main source of fat in the Mediterranean diet. Data accumulated thus far show consumption of extra virgin, (poly)phenol-rich olive oil to be associated with specific health benefits. Of note, recommendations for consumption based on health claims refer to the phenolic content of extra virgin olive oil as beneficial. However, even though foods rich in monounsaturated fatty acids, such as olive oil, are healthier than foods rich in saturated and trans fats, their inordinate use can lead to adverse effects on health. The aim of this review was to summarize the data on olive oil consumption worldwide and to critically examine the literature on the potential adverse effects of olive oil and its main components, particularly any effects on lipid metabolism. As demonstrated by substantial evidence, extra virgin olive oil is healthful and should be preferentially used within the context of a balanced diet, but excessive consumption may lead to adverse consequences.
End-of-Therapy Echocardiography May Not Be Needed in All in Patients With Endocarditis
Authors: Virk Abinash , Schutte Kirsten M , Steckelberg James M , Wilson Walter R , Sinak Lawrence J , Baddour Larry M
Published: February 2020

Background

The American Heart Association (AHA) guidelines for infective endocarditis (IE) management recommend end-of-therapy (EOT) echocardiography (ETE) to “establish a new baseline” and based on “expert opinion.”

Methods

Medical records of IE patients treated between January 2005 and December 2011 were reviewed. Utilization of ETE and cumulative incidence of re-treatment with antimicrobials or cardiovascular surgery (re-Rx/CVS) within 1 year after EOT were evaluated.

Results

A total of 243 patients completed clinical follow-up at EOT and 170 at 1 year after EOT. One hundred seventy-seven of 243 (72.8%) underwent ETE, the majority (51.4%) transthoracic echocardiography. One hundred thirty-three of 177 (75.1%) were without new/worsened signs or symptoms (new/w-SSx). One hundred forty-one of 177 (79.7%) overall and 117/133 (87.9%) patients without new/w-SSx had no new ETE findings as compared with initial echocardiography. Among 36/177 (20.3%) with new ETE findings, 20/36 (55.6%) had new/w-SSx; ETE findings were more likely in patients with new/w-SSx (39.2% vs 8.3%; P < 0.001) at EOT. Patients were at increased risk of re-Rx/CVS with either new ETE findings (hazard ratio [HR], 25.86; 95% confidence interval [CI], 7.64–87.56; P < .001) or new/w-SSx (HR, 5.35; 95% CI, 2.87–9.95; P < .001). The highest risk of re-Rx/CVS was in patients with both new/w-SSx and new ETE findings (HR, 45.94; 95% CI, 19.07–110.71). Conversely, only 7/187 (3.4%) patients without new/w-SSx who had an ETE required re-Rx/CVS.

Conclusions

The majority of patients without new/w-SSx at EOT will not have new ETE findings or need re-Rx/CVS within 1 year after EOT. EOT new/w-SSx is associated with new ETE findings and predicts the need for re-Rx/CVS. Further study is needed to determine whether patients without new/w-SSx need ETE.
Giant right atrium: a long-term complication of rheumatic heart disease
Authors: Abugroun Ashraf , Taha Mohamed , Daoud Hussein , Ibrahim Walid
Published: February 2020

Giant right atrium (RA) is a rare entity often seen during childhood due to congenital anomalies. Limited literature has reported such finding in patients with rheumatic valvular heart disease. Here we present a case of a 68-year-old female with a history of rheumatic valve disease treated with a Starr Edwards mechanical ball-in-cage mitral valve replacement and tricuspid valve annuloplasty ring procedures. The patient developed heart failure and had multiple hospital admissions over three decades for heart failure exacerbations mostly triggered by medication and dietary non-compliance. She eventually developed a giant RA that filled most of her thorax. This case demonstrates an extreme form of cardiac remodeling caused by long-term rheumatic valvular heart disease.
An a3-Anterior Inferior Cerebellar Artery to p3-Posterior Inferior Cerebellar Artery Bypass With Thrombectomy and Trapping of an Anterior Inferior Cerebellar Artery Aneurysm: 3-Dimensional Operative Video
Authors: Mascitelli Justin R , Gandhi Sirin , Baranoski Jacob F , Lang Michael J , Lawton Michael T
Published: February 2020

In situ bypasses to the anterior inferior cerebellar artery (AICA) are unusual because, with only one artery in the cerebellopontine angle (CPA), no natural intracranial donors parallel its course. In rare cases, the posterior inferior cerebellar artery (PICA) may have the tortuosity or redundancy to be mobilized to the AICA to serve as a donor. This video demonstrates this p3 PICA-to-a3 AICA in situ side-to-side bypass. A 75-yr-old woman presented with ataxia and hemiparesis from a large thrombotic right AICA aneurysm compressing the brainstem. Strategy consisted of bypass, trapping, and brainstem decompression. Written informed consent for surgery was obtained from the patient. A hockey-stick incision was made to harvest the occipital artery as a backup donor, but its diminutive caliber precluded its use. The bypass was performed through an extended retrosigmoid craniotomy. The aneurysm was trapped completely and thrombectomized to relieve the pontine mass effect. Indocyanine green videoangiography confirmed patency of the bypass, retrograde filling of the AICA to supply pontine perforators, and no residual aneurysmal filling. This unusual in situ bypass is possible when redundancy of the AICA and PICA allow their approximation in the CPA. The anastomosis is performed lateral to the lower cranial nerves in a relatively open and superficial plane. The extended retrosigmoid approach provides adequate exposure for both the bypass and aneurysm trapping. In situ AICA-PICA bypass enables anterograde and retrograde AICA revascularization with side-to-side anastomosis. The occipital artery-to-AICA bypass and the V3 vertebral artery-to-AICA interpositional bypass are alternatives when intracranial anatomy is unfavorable for this in situ bypass.
1–6
Used with permission from Barrow Neurological Institute, Phoenix, Arizona.
Opiate of the Masses? Inequality, Religion, and Political Ideology in the United States
Authors: Schnabel Landon
Published: February 2020

This study considers the assertion that religion is the opiate of the masses. Using a special module of the General Social Survey, I first demonstrate that religion functions as a compensatory resource for structurally disadvantaged groups—women, racial minorities, those with lower incomes, and, to a lesser extent, sexual minorities. I then demonstrate that religion—operating as both compensatory resource and values-shaping schema—suppresses what would otherwise be larger group differences in political ideology. This study provides empirical support for the general “opiate” claim that religion is the “sigh of the oppressed creature” and suppressor of emancipatory political values. I expand and refine the theory, however, showing how religion provides (1) compensatory resources for lack of social, and not just economic, status, and (2) traditional-values-oriented schemas that, rather than just distracting people, shape their politics in accordance with the content of religious belief systems.
Neurosensory Screening and Symptom Provocation in Pediatric Mild Traumatic Brain Injury
Authors: Mayer Andrew R. , Wertz Christopher J. , Robertson-Benta Cidney R. , Pabbathi Reddy Sharvani , Stephenson David D. , Dodd Andrew B. , Oglesbee Scott J. , Bedrick Edward J. , Master Christina L. , Grady Mathew , Shaff Nicholas A. , Hanlon Faith M. , Campbell Richard A. , Phillips John P. , Zemek Roger L. , Yeates Keith Owen , Meier Timothy B. , Mannix Rebekah , Leddy John J. , Arbogast Kristy B. , Park Grace
Published: February 2020

Objective:

To evaluate diagnostic/prognostic implications of neurosensory testing during the subacute stage in patients with pediatric mild traumatic brain injury (pmTBI).

Setting:

Recruitment from pediatric emergency department and urgent care clinics, assessment in a controlled environment.

Participants:

In total, 146 pmTBI patients evaluated 7.4 ± 2.3 days and approximately 4 months postinjury; 104 age/sex-matched healthy controls (HCs) at equivalent time points.

Design:

Prospective cohort study.

Main Measures:

Neurosensory examination based on sequence of 10 established tests of vestibular-ocular, oculomotor, vestibulospinal, and visual functioning.

Results:

The amount of symptom provocation (positive change from pretest symptomatology) was significantly increased in pmTBI relative to HCs on every subtest 1 week postinjury, as were deficits in monocular accommodative amplitude and King-Devick Test errors. However, symptom provocation did not meaningfully alter diagnostic sensitivity/specificity relative to more easily obtained pretest symptom ratings. Evidence of clinically significant symptom provocation 1 week postinjury improved sensitivity (Δ = +12.9%) of identifying patients with persistent postconcussive symptoms 4 months postinjury on an independent symptom measure.

Conclusions:

The diagnostic sensitivity/specificity of neurosensory testing in acutely concussed youth may be limited at 1 week postinjury as a function of natural recovery occurring in most emergency department cohorts. Neurosensory screening may have greater utility for identifying patients who experience delayed recovery.
The Association Between Community Participation and Social Internet Use Among Adults With Traumatic Brain Injury
Authors: Ketchum Jessica M. , Sevigny Mitch , Hart Tessa , O'Neil-Pirozzi Therese M. , Sander Angelle M. , Juengst Shannon B. , Bergquist Thomas F. , Dreer Laura E. , Whiteneck Gale G.
Published: February 2020

Objective:

To examine the association between social Internet use and real-world societal participation in survivors of moderate-severe traumatic brain injury.

Design:

Prospective cross-sectional observational study.

Setting:

Ten Traumatic Brain Injury Model Systems Centers.

Participants:

A total of 331 participants in the Traumatic Brain Injury Model Systems, interviewed at any follow-up year between April 2014 and March 2015.

Main Measures:

Survey on Internet use, including social media and other online socialization; Participation Assessment with Recombined Tools—Objective with separate analyses of Productivity, Social Relations, Out and About subscales; covariates included demographics, injury variables, and functional and emotional status at follow-up.

Results:

Participants were classified as social Internet users (N = 232) or nonusers (N = 99). Users had significantly higher Participation Assessment with Recombined Tools—Objective Social Relations scores than nonusers. A similar finding pertained to Out and About scores, with the between-group difference significantly greater for those with greater depressive symptoms severity. Users and nonusers did not differ significantly on Productivity subscale.

Conclusions:

The positive association between social Internet use and real-world social participation suggests that people with traumatic brain injury do not use social media as an alternative to real-world socialization. Rather, it is likely that similar barriers and facilitators affect both online and real-world social participation following traumatic brain injury. Emotional function should be considered as a moderating factor in further studies.
An exceptional case of severe combined inherited thrombophilia successfully treated with rivaroxaban
Authors: Krumb Evelien , Hermans Cédric
Published: February 2020

We herein report the case of a young patient who presented with premature thromboembolic venous disease secondary to combined heterozygous G20210A prothrombin mutation, dual homozygosity for Factor V Leiden, and severe protein S deficiency. This association has never been reported to date and is likely to be exceptional, even in populations wherein these thrombophilia traits are more common. Long-term antithrombotic prophylaxis with rivaroxaban has proven successful in preventing clinical recurrence under prolonged treatment.
Emergency Department Care of the Post-Metabolic and Bariatric Surgery Patient
Authors: Sacchetti Alfred
Published: February 2020

Metabolic and bariatric surgical procedures have increased in the pediatric-age population over the past decade. Three operations, laparoscopic adjustable gastric banding, vertical sleeve gastrectomy, and Roux-en Y gastric bypass, are the most commonly performed procedures for weight reduction. This article will examine the specifics of each procedure along with the complications associated with any metabolic or bariatric surgery. Complications unique to each operation will be reviewed as well as recommendations for the management of these patients.
Changes in Emotional Vitality as a Predictor of Levels and Change in Allostatic Load: Longitudinal Results From the Whitehall II Cohort Study
Authors: Deen Laura , Dich Nadya , Head Jenny , Clark Alice Jessie
Published: February 2020

Objective

Increasing evidence has shown an association between reduced psychological well-being and long-term morbidity. However, longitudinal studies addressing potential biobehavioral mechanisms, such as physiological function, are lacking. The aim of this study is to examine the association between changes in emotional vitality on levels and changes in allostatic load (AL), a measure of multisystem physiological dysregulation, as well as its composite risk markers.

Methods

Participants comprised 5919 British civil servants from phases 3, 5, and 7 of the Whitehall II study. Psychological well-being was operationalized as emotional vitality. AL was measured using nine biomarkers of the cardiovascular, metabolic, and immune system. Linear mixed-effect models were used to determine the association between changes in emotional vitality between phases 3 and 5 and subsequent levels and change in AL from phases 5 to 7. Generalized linear models were used to address the association between changes in emotional vitality and individual risk markers.

Results

Increase in emotional vitality was associated with a lower mean level of AL, whereas the AL slope was not markedly affected. Among the included risk markers, only interleukin-6 was weakly associated with changes in emotional vitality, with a 7% reduced risk of high levels of interleukin-6 per one-unit increase in emotional vitality.

Conclusion

This study found that an increase in emotional vitality was associated with subsequent lower levels, but not rate of change, of AL over time. Further research is needed to address the relationship between trajectories of psychological well-being and physiological dysregulation.
Quality and Safety in Healthcare, Part LXIV
Authors: Harolds Jay A.
Published: February 2020

Burnout and other causes of a lack of well-being among radiology residents are a major problem. The American College of Radiology has developed a “Well-being Curriculum for Radiology Residency Programs,” which has many suggestions that should be helpful to residents in multiple specialties. The American College of Radiology is also collecting data on well-being in order to get benchmarking data and try to find out why some programs have more problems with decreased well-being than other programs. Wellness newsletters, providing social opportunities, insisting on professional behavior for all, fairness in work distribution, night float schedules, willingness to be flexible with work schedules, and retreats have also been advocated.
FDG Uptake in the Basal Forebrain as Measured by Digital High-Resolution PET Is a Promising Marker of Basal Forebrain Degeneration in the Lewy Body Disease Spectrum
Authors: Özden Cansu , Frings Lars , Apostolova Ivayla , Lange Catharina , Klutmann Susanne , Adam Gerhard , Bannas Peter , Meyer Philipp T. , Grothe Michel J. , Buchert Ralph
Published: February 2020

Purpose

Cognitive decline in diseases of the Lewy body spectrum (LBS) is linked to dysfunction/degeneration of the basal forebrain (BF). Assessment of glucose metabolism in the BF by FDG PET is hampered by the small size of the BF and limited spatial resolution of conventional PET. This pilot study tested the feasibility of assessing BF glucose metabolism by high-resolution digital PET (dPET).

Patients and Methods

The retrospective study included 12 LBS patients (61–86 years, 5 demented). Whole-brain stereotactic normalization to anatomical standard space was followed by local stereotactic normalization of a 7 × 7 × 7-cm3 box around the BF to a custom-made 1 × 1 × 1-mm3 FDG dPET template. FDG uptake was scaled voxelwise to mean FDG uptake in the pons. Scaled FDG uptake in the BF was compared between demented and nondemented LBS patients and tested for correlation with cortical FDG uptake.

Results

Scaled FDG uptake in the BF was significantly lower in demented compared with nondemented patients (1.14 ± 0.09 vs 1.25 ± 0.06, P = 0.031). Brain-wide voxel-based testing for correlations with scaled FDG uptake in the BF revealed a large cluster comprising medial and ventrolateral frontal cortex, anterior cingulate cortex, insular cortex, and striatum as well as smaller clusters in motor cortex and occipital cortex (P < 0.001, uncorrected).

Conclusions

These results suggest that dementia-associated BF degeneration in LBS can be sensitively measured as reduced BF FDG uptake on dPET. More accurate delineation of the BF based on individual high-resolution MRI might be useful to make optimal use of improved spatial resolution of dPET and to correct for possible disease- and age-dependent partial volume effects.
Myelodysplastic Syndrome Presenting With Diffuse Bone Marrow Uptake on 68Ga-PSMA PET/CT
Authors: Arslan İpek , Demirci Emre , Özkara Selvinaz , Taşdelen Neslihan , Alan Selçuk Nalan
Published: February 2020

We present the case of a 67-year-old man with prostate cancer who had no findings of recurrence, except diffuse radiotracer uptake in the bone marrow in 68Ga-PSMA PET/CT. Bone marrow uptake was also represented as multiple focal increased spots without any corresponding lytic or sclerotic lesions in CT. MRI revealed a high and homogeneous T2 signal within the bone marrow, without any contrast-enhanced or diffusion-restricted lesions. Further workup, including a bone marrow biopsy, revealed the diagnosis of myelodysplastic syndrome.
FLT-PET At 6 Weeks Predicts Response Assessed by CT at 12 Weeks in Melanoma Patients Treated With Pembrolizumab
Authors: Yeh Randy , Trager Megan H. , Rizk Emanuelle M. , Finkel Grace G. , Barker Luke W. , Carvajal Richard D. , Geskin Larisa J. , Schwartz Gary K. , Schwartz Lawrence , Dercle Laurent , Saenger Yvonne M.
Published: February 2020

Purpose

Investigate the ability of 18F-fluorothymidine (FLT) PET combined with CT at 6 weeks to predict treatment response at 12 weeks after treatment with pembrolizumab.

Methods

Five patients with unresectable stage IV melanoma were included in this single-institution pilot study. Patients underwent FLT-PET/CT (baseline and 6 weeks) and CT (baseline and 12 weeks). FLT-PET/CT response and CT response were assessed using PET Response Criteria in Solid Tumors and immune Response Evaluation Criteria in Solid Tumors, respectively. Patients were categorized as responders (complete response, partial response) and nonresponders (stable disease, progressive disease). Agreement between 6-week FLT-PET/CT and 12-week CT was calculated using Cohen kappa's agreement. Eight baseline FLT-PET/CT parameters were extracted: SUVmax, SUVpeak, SUVSD, SUVmean, proliferative tumor volume, total lesion proliferation, bone marrow–to–liver SUVmax ratio, and spleen-to-liver SUVmax ratio. Eight delta-parameters were extracted at 6 weeks by calculating variation in FLT uptake as percentage change from baseline.

Results

Agreement between 6-week FLT-PET/CT and 12-week CT was kappa = 0.615, P = 0.025. Three of 5 patients were categorized as responders on CT by immune Response Evaluation Criteria in Solid Tumors. At baseline, responders had a lower mean proliferative tumor volume and a higher bone marrow–to–liver SUVmax ratio. At 6 weeks, responders demonstrated a decrease in tumor volume and tumor proliferation.

Conclusions

Our study illustrates the potential for FLT-PET/CT as an early predictor of response for patients with metastatic melanoma on anti-PD1 immunotherapy. Larger studies are indicated to confirm these findings.
Generation of GGTA1−/−β2M−/−CIITA−/− Pigs Using CRISPR/Cas9 Technology to Alleviate Xenogeneic Immune Reactions
Authors: Fu Rui , Fang Minghui , Xu Kai , Ren Jilong , Zou Jun , Su Long , Chen Xinxin , An PeiPei , Yu Dawei , Ka Meina , Hai Tang , Li Ziyi , Li Wei , Yang Yongguang , Zhou Qi , Hu Zheng
Published: February 2020

Background.

Xenogeneic organ transplantation has been proposed as a potential approach to fundamentally solve organ shortage problem. Xenogeneic immune responses across species is one of the major obstacles for clinic application of xeno-organ transplantation. The generation of glycoprotein galactosyltransferase α 1, 3 (GGTA1) knockout pigs has greatly contributed to the reduction of hyperacute xenograft rejection. However, severe xenograft rejection can still be induced by xenoimmune responses to the porcine major histocompatibility complex antigens swine leukocyte antigen class I and class II.

Methods.

We simultaneously depleted GGTA1, β2-microglobulin (β2M), and major histocompatibility complex class II transactivator (CIITA) genes using clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins technology in Bamma pig fibroblast cells, which were further used to generate GGTA1
−/−
β2M
−/−
CIITA
−/− triple knockout (GBC-3KO) pigs by nuclear transfer.

Results.

The genotype of GBC-3KO pigs was confirmed by polymerase chain reaction and Sanger sequencing, and the loss of expression of α-1,3-galactose, SLA-I, and SLA-II was demonstrated by flow cytometric analysis using fluorescent-conjugated lectin from bandeiraea simplicifolia, anti-β2-microglobulin, and swine leukocyte antigen class II DR antibodies. Furthermore, mixed lymphocyte reaction assay revealed that peripheral blood mononuclear cells from GBC-3KO pigs were significantly less effective than (WT) pig peripheral blood mononuclear cells in inducing human CD3+CD4+ and CD3+CD8+ T-cell activation and proliferation. In addition, GBC-3KO pig skin grafts showed a significantly prolonged survival in immunocompetent C57BL/6 mice, when compared with wild-type pig skin grafts.

Conclusions.

Taken together, these results demonstrate that elimination of GGTA1, β2M, and CIITA genes in pigs can effectively alleviate xenogeneic immune responses and prolong pig organ survival in xenogenesis. We believe that this work will facilitate future research in xenotransplantation.
Identification of potential biomarkers in subtypes of epithelial ovarian cancer
Authors: Singh Rinki , Som Anup
Published: February 2020

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Due to the lack of specific symptoms, ∼80% of epithelial ovarian cancer is diagnosed at an advanced stage and often metastasize to the distant organ. Epithelial ovarian cancer is a heterogeneous disease that is classified into four major histological subtypes namely, serous carcinoma (SC), endometrioid carcinoma (EC), mucinous carcinoma (MC), and clear cell carcinoma (CCC). Ovarian cancer treatment is complicated due to the heterogeneity of the tumors. Patients with different subtypes respond differently to the same treatment and also have different prognoses. This diversity extends to various clinical outcomes of the disease. Thus, identifying new reliable potential biomarkers irrespective of their subtypes is an urgent need for the diagnosis and prognosis of epithelial ovarian cancer. In this study, we performed comparative gene expression analysis for identifying potential biomarkers in four histological subtypes of epithelial ovarian cancer (EOC) that include serous, endometrioid, mucinous, and clear cell carcinomas. Differentially expressed genes (DEGs) between cancerous and normal tissue samples were identified by considering the criteria of absolute logarithmic fold change |log2fc|>1 and adjusted p (padj) value<0.05. Pathway enrichment analysis of the DEGs showed that pathways in cancer, PI3K-AKT signaling pathway, RAP1 signaling pathway, cell cycle, cell adhesion molecules, and proteoglycans in cancer were common among the selected cancer subtypes. Further, we constructed the co-expression network of DEGs and identified 15 candidate genes. Finally, based on the survival analysis of the candidate genes, a total of nine genes namely ASPM, CDCA8, CENPM, CEP55, HMMR, RACGAP1, TPX2, UBE2C, and ZWINT with significant prognostic value was proposed as the potential biomarker.
IL-6 signalling protects zebrafish larvae duringStaphylococcus epidermidisinfection in a novel bath immersion model
Authors: Dhanagovind PT , Kujur Prabeer K. , Swain Rajeeb K. , Banerjee Sanjita
Published: February 2020

Host immune responses toStaphylococcus epidermidis, a frequent cause of nosocomial infections, are not well understood. We have established a novel bath immersion model of this infection in zebrafish larvae.S.epidermidisinfection activates Tlr-2 signalling pathway by upregulation oftlr-2. Macrophages play a primary role in the host immune response and are involved in clearance of infection in the larvae. There is marked inflammation characterised by heightened NF-κB signalling and elevation of several pro-inflammatory cytokines. Infected larvae show rapid upregulation ofil-1bandtnf-atranscripts and relatively slower elevation ofil-6transcription. The IL-6 signalling pathway is additionally subject to amplification by elevation of IL-6 signal transducer (il-6st) levels, which negatively correlates with miRNA dre-miR-142-5p expression. Enhanced IL-6 signalling is protective to the host in this model as inhibition of the signalling pathway resulted in increased mortality uponS.epidermidisinfection. Our study describes the host immune responses toS.epidermidisinfection, identifies a likely role for miR-142-5p –il-6stinteraction in modulating this response and establishes the importance of IL-6 signalling in this infection model.
Reducing monocarboxylate transporter MCT1 worsens experimental diabetic peripheral neuropathy
Authors: Jha Mithilesh Kumar , Ament Xanthe Heifetz , Yang Fang , Liu Ying , Polydefkis Michael J. , Pellerin Luc , Morrison Brett M.
Published: February 2020

Diabetic peripheral neuropathy (DPN) is one of the most common complications in diabetic patients. Though the exact mechanism for DPN is unknown, it clearly involves metabolic dysfunction and energy failure in multiple cells within the peripheral nervous system (PNS). Lactate is an alternate source of metabolic energy that is increasingly recognized for its role in supporting neurons. The primary transporter for lactate in the nervous system, monocarboxylate transporter-1 (MCT1), has been shown to be critical for peripheral nerve regeneration and metabolic support to neurons/axons. In this study, MCT1 was reduced in both sciatic nerve and dorsal root ganglia in wild-type mice treated with streptozotocin (STZ), a common model of type-1 diabetes. Heterozygous MCT1 null mice treated with STZ developed a more severe DPN compared to wild-type mice, as measured by greater axonal demyelination, decreased peripheral nerve function, and increased numbness to innocuous low-threshold mechanical stimulation. Given that MCT1 inhibitors are being developed as both immunosuppressive and chemotherapeutic medications, our results suggest that clinical development in patients with diabetes should proceed with caution. Collectively, our findings uncover an important role for MCT1 in DPN and provide a potential lead toward developing novel treatments for this currently untreatable disease.
Sp8regulatory function in the limb bud ectoderm
Authors: Pérez-Gómez Rocío , Fernández-Guerrero Marc , Campa Víctor , Lopez-Gimenez Juan F. , Rada-Iglesias Alvaro , Ros Maria A.
Published: February 2020

Sp8 and Sp6 are two closely related Sp genes expressed in the limb ectoderm where they regulate proximo-distal and dorso-ventral patterning. Mouse genetics revealed that they act together in a dose-dependent manner but with Sp8 making a much greater contribution. Here, we combine ChIP-seq and RNA-seq genome-wide analyses to investigate the Sp8 regulatory network and mechanism of action. We find that Sp8 predominantly binds to putative distal enhancers to activate crucial limb patterning genes, includingFgf8, En1, Sp6andRspo2. Sp8 exerts its regulatory function by directly binding DNA at Sp consensus sequences or indirectly through Dlx5 interaction. Overall, our work underscores Sp8 master regulatory functions and supports a model in which it cooperates with other Dlx and Sp cofactors to regulate target genes. We believe that this model could help to properly understand the molecular basis of congenital malformations.

Impact Sentence

In the limb ectoderm, Sp8 regulates master genes through a dual mechanism: directly binding DNA at Sp consensus sequences and indirectly engaging through Dlx5 interaction.
Genetic variance in fitness and its cross-sex covariance predict adaptation during experimental evolution
Authors: Koch Eva L. , Sbilordo Sonja H. , Guillaume Frédéric
Published: February 2020

In presence of rapid environmental changes, it is of particular importance to assess the adaptive potential of populations, which is mostly determined by the additive genetic variation (VA) in fitness. In this study we usedTribolium castaneum(red flour beetles) to investigate its adaptive potential in three new environmental conditions (Dry, Hot, Hot-Dry). We tested for potential constraints that might limit adaptation, including negative genetic covariance between female and male fitness. Based on VAestimates for fitness, we expected the highest relative fitness increase in the most stressful condition Hot-Dry and similar increases in single stress conditions Dry and Hot. High adaptive potential in females in Hot was reduced by a negative covariance with male fitness. We tested adaptation to the three conditions after 20 generations of experimental evolution and found that observed adaptation mainly matched our predictions. Given that body size is commonly used as a proxy for fitness, we also tested how this trait and its genetic variance (including non-additive genetic variance) were impacted by environmental stress. In both traits, variances were sex and condition dependent, but they differed in their variance composition, cross-sex and cross-environment genetic covariances, as well as in the environmental impact on VA.
Hypoxia-inducible lipid droplet-associated interacts with DGAT1 and promotes lipid storage in hepatocytes
Authors: de la Rosa Rodriguez Montserrat A. , Gemmink Anne , van Weeghel Michel , Aoun Marie Louise , Warnecke Christina , Singh Rajat , Borst Jan Willem , Kersten Sander
Published: February 2020

Lipid droplets (LD) are dynamic organelles that can expand and shrink, driven by fluctuations in the rate of triglyceride synthesis and degradation. Triglyceride synthesis, storage in LD, and degradation are governed by a complex set of LD-associated proteins. One of these LD-associated proteins, hypoxia-inducible lipid droplet-associated (HILPDA), was found to impair LD breakdown by inhibiting adipose triglyceride lipase. Here we characterized the physiological role and mechanism of action of HILPDA in hepatocytes. Expression of HILPDA was induced by fatty acids in several hepatoma cell lines. Hepatocyte-specific deficiency of HILPDA in mice modestly but significantly reduced hepatic triglycerides in mice with non-alcoholic fatty liver disease. Similarly, deficiency of HILPDA in mouse precision-cut liver slices and primary hepatocytes reduced lipid storage and accumulation of fluorescently-labelled fatty acids in LD, respectively, which was independent of adipose triglyceride lipase. Fluorescence microscopy showed that HILPDA partly colocalizes with LD and with the endoplasmic reticulum, is especially abundant in perinuclear areas, and mainly associates with newly added fatty acids. Real-time fluorescence live-cell imaging further revealed that HILPDA preferentially localizes to LD that are being remodelled. Mechanistically, HILPDA overexpression increased lipid storage in human hepatoma cells concomitant with an increase in DGAT activity and DGAT1 protein levels. Finally, confocal microscopy and Förster resonance energy transfer-fluorescence lifetime imaging microscopy analysis indicated that HILPDA colocalizes and physically interacts with DGAT1. Overall, our data indicate that HILPDA physically interacts with DGAT1 and increases DGAT activity. These findings suggest a novel mechanism in hepatocytes that links elevated fatty acid levels to stimulation of triglyceride synthesis and storage.
Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
Authors: Huoh Yu-San , Wu Bin , Park Sehoon , Yang Darren , Bansal Kushagra , Greenwald Emily , Wong Wesley P. , Mathis Diane , Hur Sun
Published: February 2020

Aggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, is known to form large aggregate-like assemblies visualized as nuclear foci. We demonstrate that Aire utilizes Caspase Activation Recruitment Domain (CARD) to form filamentous homo-multimersin vitro, and this assembly mediates foci formation and transcriptional activity. However, CARD-mediated multimerization is a double-edged sword as it also makes Aire susceptible to interaction with PML bodies, sites of many nuclear processes including protein quality control of nuclear aggregates. Several loss-of-function Aire mutants, including those causing autoimmune polyendocrine syndrome type-1, form foci with increased PML body association. Directing Aire to PML bodies impairs Aire’s transcriptional activity, while dispersing PML bodies with a viral antagonist restores it. Thus, our study reveals a new regulatory role of PML bodies in Aire function and highlights the interplay between nuclear aggregate-like assemblies and PML-mediated quality control.
Network analysis of workshop activities reveals increasing transdisciplinarity of German biodiversity research community
Authors: Geschke Jonas , Lutz Martina , Vohland Katrin
Published: February 2020

Boundary spanning activities in the biodiversity science-policy interface are urgently needed. Effective science communication and uptake of scientific findings by policymakers is crucial for a successful, cross-scale policy implementation. For this, national platforms promoting knowledge exchange between different stakeholder groups are key. Established in 2009, the Network-Forum on Biodiversity Research Germany (NeFo) until 2018 has organized more than 40 workshops bringing together actors from science, policy and society. In this paper, we present a network and cluster analysis of these NeFo workshops. Based on this, we discuss the importance of science-policy interface projects and networks as knowledge brokers and boundary organizations, as well as challenges in using network analysis as a tool for evaluating workshop impacts. Based on the network analysis outcomes as well as experiences in the conduction of workshops, recommendations to strengthen the innovation impact of networking efforts are drawn.
Chemical and structural investigation of the paroxetine-human serotonin transporter complex
Authors: Coleman Jonathan A. , Navratna Vikas , Antermite Daniele , Yang Dongxue , Bull James A. , Gouaux Eric
Published: February 2020

Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand the binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation. Such modifications to SERT have led to questions about the relationships of these structures to thebona fideconformation and inhibitor binding poses of the wild-type transporter. To address these concerns, we characterized wild-type SERT with truncated N- and C-termini and thermostabilized variants of SERT bound with paroxetine using x-ray crystallography, single particle cryo-EM and biochemical techniques. Moreover, using a C–H functionalization approach to synthesize enantiopure analogues, we replaced the halide of the fluorophenyl group in paroxetine with either bromine or iodine. We then exploited the anomalous scattering of Br and I to define the pose of the respective paroxetine analog. These structures provide mutually consistent insights into how paroxetine and its analogs bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.
FL-QSAR: a federated learning based QSAR prototype for collaborative drug discovery
Authors: Chen Shaoqi , Xue Dongyu , Chuai Guohui , Yang Qiang , Liu Qi
Published: February 2020

Motivation

Quantitative structure-activity relationship (QSAR) analysis is commonly used in drug discovery. Collaborations among pharmaceutical institutions can lead to a better performance in QSAR prediction, however, intellectual property and related financial interests remain substantially hindering inter-institutional collaborations in QSAR modeling for drug discovery.

Results

For the first time, we verified the feasibility of applying the horizontal federated learning (HFL), which is a recently developed collaborative and privacy-preserving learning framework to perform QSAR analysis. A prototype platform of federated-learning-based QSAR modeling for collaborative drug discovery, i.e, FL-QSAR, is presented accordingly. We first compared the HFL framework with a classic privacy-preserving computation framework, i.e., secure multiparty computation (MPC) to indicate its difference from various perspective. Then we compared FL-QSAR with the public collaboration in terms of QSAR modeling. Our extensive experiments demonstrated that (1) collaboration by FL-QSAR outperforms a single client using only its private data, and (2) collaboration by FL-QSAR achieves almost the same performance as that of collaboration via cleartext learning algorithms using all shared information. Taking together, our results indicate that FL-QSAR under the HFL framework provides an efficient solution to break the barriers between pharmaceutical institutions in QSAR modeling, therefore promote the development of collaborative and privacy-preserving drug discovery with extendable ability to other privacy-related biomedical areas.

Availability and implementation

The source codes of the federated learning simulation and FL-QSAR are available on the GitHub:https://github.com/bm2-lab/FL-QSAR
Bidirectional sex-dependent regulation of α6 and β3 nicotinic acetylcholine receptors by protein kinase Cε
Authors: Moen Janna K. , DeBaker Margot C. , Myjak Julia E. , Wickman Kevin , Lee Anna M.
Published: February 2020

Nicotine and alcohol are the most commonly abused substances worldwide, and comorbid nicotine and alcohol addiction is highly prevalent. Nicotinic acetylcholine receptors (nAChRs) containing the α6 and β3 subunits are expressed in neural reward circuits and are critical for both nicotine and alcohol reward. nAChRs are dynamically regulated by signaling molecules such as protein kinase C epsilon (PKCε), which impact transcription of α6 and β3 subunit mRNA (Chrna6andChrnb3, respectively). Previous work found decreased expression ofChrna6andChrnb3transcripts in the ventral midbrain of male PKCε−/−mice, who also consume less nicotine and alcohol compared to wild-type (WT) littermates. Here, we show that female PKCε−/−mice have enhanced expression ofChrna6andChrnb3transcripts in the ventral midbrain, which functionally impacts nAChR-dependent behavior, as female but not male PKCε−/−mice exhibit locomotor hypersensitivity to nicotine. Female PKCε−/−mice show no differences in alcohol-induced sedation compared to WT littermates, while male PKCε−/−have enhanced sedation compared to WT mice, a phenotype that has previously been reported in α6−/−mice. Female PKCε−/−mice also show reduced depression-like behavior in response to systemic injections of varenicline compared to WT littermates, and this effect was absent in male mice. Additionally, we found that female PKCε−/−mice show altered alcohol and nicotine consumption patterns in chronic voluntary two bottle choice assays. Our data reveal a bidirectional effect of sex in the transcriptional regulation of nicotinic receptors by PKCε, and highlight the importance of studying both sexes in preclinical animal models.