bluuebunny/crossref_metadata_2025 huggingface dataset:
Fenestration Improves Acellular Dermal Matrix Biointegration: An Investigation of Revascularization with Photoacoustic Microscopy
Authors: Cottler Patrick S. , Olenczak J. Bryce , Ning Bo , Seaman Scott A. , Thuman Jenna M. , Sun Naidi , Piñeros-Fernandez Angela , Hu Song , DeGeorge Brent R. , Campbell Chris A.
Published: February 2019

Background:

Acellular dermal matrices have revolutionized alloplastic breast reconstruction. Furthering our knowledge of their biointegration will allow for improved design of these biomaterials. The ideal acellular dermal matrix for breast reconstruction would provide durable soft-tissue augmentation while undergoing rapid biointegration to promote physiologic elasticity and reduced infectious complications. The inclusion of fenestrations in their design is thought to promote the process of biointegration; however, the mechanisms underlying this theory have not been evaluated.

Methods:

Biointegration of standard and fenestrated acellular dermal matrices was assessed with serial photoacoustic microscopic imaging, in a murine dorsal skinfold window chamber model specifically designed to recapitulate the microenvironment of acellular dermal matrix–assisted alloplastic breast reconstruction. Photoacoustic microscopy allows for a serial, real-time, noninvasive assessment of hemoglobin content and oxygen saturation in living tissues, generating high-resolution, three-dimensional maps of the nascent microvasculature within acellular dermal matrices. Confirmatory histologic and immunohistochemical assessments were performed at the terminal time point.

Results:

Fenestrated acellular dermal matrices demonstrated increased fibroblast and macrophage lineage host cell infiltration, greater mean percentage surface area vascular penetration (21 percent versus 11 percent; p = 0.08), and greater mean oxygen saturation (13.5 percent versus 6.9 percent; p < 0.05) than nonfenestrated matrices by 2 weeks after implantation. By 21 days, host cells had progressed nearly 1 mm within the acellular dermal matrix fenestrations, resulting in significantly more vascularity across the top of the fenestrated matrix (3.8 vessels per high-power field versus 0.07 vessels per high-power field; p < 0.05).

Conclusions:

Inclusion of fenestrations in acellular dermal matrices improves the recellularization and revascularization that are crucial to biointegration of these materials. Future studies will investigate the optimal distance between fenestrations.
External and Internal Diameters of the Facial Artery Relevant to Intravascular Filler Injection
Authors: Lee Shin-Hyo , Ha Tae-Jun , Koh Ki-Seok , Song Wu-Chul
Published: February 2019

Background:

Vision loss and skin necrosis caused by an accidental intraarterial embolism or vascular compression are rare but devastating complications when injecting filler materials into the face.

Methods:

The external and internal diameters and wall thicknesses of the facial artery and its branches were measured from 41 formalin-embalmed cadavers after removing connective tissues attached to the arterial wall.

Results:

The diameter and thickness of the facial artery exhibited significant interregional differences. The external and internal diameters of the facial artery were 1.9 ± 0.4 and 1.2 ± 0.3 mm (mean ± SD), respectively, at the inferior border of the mandible; 1.7 ± 0.3 and 1.2 ± 0.3 mm in the vicinity of the inferior labial artery; 1.5 ± 0.3 and 1.0 ± 0.3 mm at the mouth corner; 1.4 ± 0.3 and 0.9 ± 0.2 mm in the vicinity of the superior labial artery; and 1.1 ± 0.2 and 0.7 ± 0.2 mm in the vicinity of the lateral nasal artery. The external and internal diameters at the proximal parts of the inferior labial artery, superior labial artery, and lateral nasal artery were 1.0 ± 0.3 and 0.6 ± 0.2 mm, 0.9 ± 0.3 and 0.6 ± 0.2 mm, and 0.8 ± 0.2 and 0.5 ± 0.2 mm, respectively.

Conclusion:

Morphometric examinations of the facial artery under stereomicroscope observation as performed in the present study are expected to be more accurate than direct measurements obtained during cadaveric dissection or conventional histologic evaluations.
Fat Grafting into Younger Recipients Improves Volume Retention in an Animal Model
Authors: Chung Natalie N. , Ransom Ryan C. , Blackshear Charles P. , Irizarry Dre M. , Yen Derek , Momeni Arash , Lee Gordon K. , Nguyen Dung H. , Longaker Michael T. , Wan Derrick C.
Published: February 2019

Background:

Soft-tissue deficits associated with various craniofacial anomalies can be addressed by fat grafting, although outcomes remain unpredictable. Furthermore, consensus does not exist for timing of these procedures. Whereas some advocate approaching soft-tissue reconstruction after the underlying skeletal foundation has been corrected, other studies have suggested that earlier grafting may exploit a younger recipient niche that is more conducive to fat graft survival. As there is a dearth of research investigating effects of recipient age on fat graft volume retention, this study compared the effectiveness of fat grafting in younger versus older animals through a longitudinal, in vivo analysis.

Methods:

Human lipoaspirate from three healthy female donors was grafted subcutaneously over the calvaria of immunocompromised mice. Volume retention over 8 weeks was evaluated using micro–computed tomography at three experimental ages: 3 weeks, 6 months, and 1 year. Histologic examination was performed on explanted grafts to evaluate graft health and vascularity. Recipient-site vascularity was also evaluated by confocal microscopy.

Results:

The greatest retention of fat graft volume was noted in the youngest group compared with both older groups (p < 0.05) at 6 and 8 weeks after grafting. Histologic and immunohistochemical analyses revealed that improved retention in younger groups was associated with greater fat graft integrity and more robust vascularization.

Conclusion:

The authors’ study provides evidence that grafting fat into a younger recipient site correlates with improved volume retention over time, suggesting that beginning soft-tissue reconstruction with fat grafting in patients at an earlier age may be preferable to late correction.
Application of Hydroxycholesterols for Alveolar Cleft Osteoplasty in a Rodent Model
Authors: Bakshi Reena , Hokugo Akishige , Zhou Situo , Zhang Zheyu , Wang Lixin , Rezzadeh Kameron , Segovia Luis Andres , Jarrahy Reza
Published: February 2019

Background:

Bone morphogenetic proteins (BMPs) have played a central role in the regenerative therapies for bone reconstruction, including alveolar cleft and craniofacial surgery. However, the high cost and significant adverse effect of BMPs limit their broad application. Hydroxycholesterols, naturally occurring products of cholesterol oxidation, are a promising alternative to BMPs. The authors studied the osteogenic capability of hydroxycholesterols on human mesenchymal stem cells and the impact of hydroxycholesterols on a rodent alveolar cleft model.

Methods:

Human mesenchymal stem cells were treated with control medium or osteogenic medium with or without hydroxycholesterols. Evaluation of cellular osteogenic activity was performed. A critical-size alveolar cleft was created and one of the following treatment options was assigned randomly to each defect: collagen sponge incorporated with hydroxycholesterols, BMP-2, or no treatment. Bone regeneration was assessed by means of radiologic and histologic analyses and local inflammation in the cleft evaluated. Moreover, the role of the hedgehog signaling pathway in hydroxycholesterol-mediated osteogenesis was examined.

Results:

All cellular osteogenic activities were significantly increased on human mesenchymal stem cells treated with hydroxycholesterols relative to others. The alveolar cleft treated with collagen sponge with hydroxycholesterols and BMP-2 demonstrated robust bone regeneration. The hydroxycholesterol group revealed histologically complete bridging of the alveolar defect with architecturally mature new bone. The inflammatory responses were less in the hydroxycholesterol group compared with the BMP-2 group. Induction of hydroxycholesterol-mediated in vitro osteogenesis and in vivo bone regeneration were attenuated by hedgehog signaling inhibitor, implicating involvement of the hedgehog signaling pathway.

Conclusion:

Hydroxycholesterols may represent a viable alternative to BMP-2 in bone tissue engineering for alveolar cleft.
How Can Programs Better Support Female Sex Workers to Avoid HIV Infection in Zimbabwe? A Prevention Cascade Analysis
Authors: Fearon Elizabeth , Phillips Andrew , Mtetwa Sibongile , Chabata Sungai T. , Mushati Phillis , Cambiano Valentina , Busza Joanna , Napierala Sue , Hensen Bernadette , Baral Stefan , Weir Sharon S. , Rice Brian , Cowan Frances M. , Hargreaves James R.
Published: February 2019

Background:

“HIV prevention cascades” have been proposed to support programs by identifying gaps in demand for, access to, and capability to adhere to HIV prevention tools, but there are few empirical examples to guide development. We apply a prevention cascade framework to examine prevention coverage and factors associated with condoms and/or PrEP adherence among female sex workers.

Setting:

Seven sites across Zimbabwe.

Methods:

Seven respondent-driven sampling surveys from the intervention sites of a pragmatic cluster-randomized trial in Zimbabwe in 2016 were analyzed, and 611/1439 women testing HIV-negative included. We operationalized key components of an HIV prevention cascade including demand, supply, and capability to adhere to 2 tools for HIV prevention: condoms and pre-exposure prophylaxis (PrEP). We used adjusted logistic regression to identify determinants of adherence to condoms and PrEP in turn, examining the effect of adherence to one tool on adherence to the other.

Results:

There were 343/611, 54.7%, women reporting adherence to condoms and/or PrEP, leaving almost half uncovered. Although women were aware that condoms prevented HIV and reported good access to them, only 45·5% reported full adherence to condom use. For PrEP, a new technology, there were gaps along all 3 domains of demand, supply, and adherence. Alcohol use decreased adherence to PrEP and condoms. Younger and newer entrants to sex work were less likely to take PrEP every day.

Conclusions:

HIV prevention programming among female sex workers in Zimbabwe could consider increasing awareness of PrEP alongside supply, alcohol use interventions, and approaches to engaging younger women.
Insomnia as an Independent Predictor of Incident Cardiovascular Disease in HIV: Data From the Veterans Aging Cohort Study
Authors: Polanka Brittanny M. , Kundu Suman , So-Armah Kaku A. , Freiberg Matthew S. , Gupta Samir K. , Bedimo Roger J. , Budoff Matthew J. , Butt Adeel A. , Chang Chung-Chou H. , Gottlieb Stephen S. , Marconi Vincent C. , Womack Julie A. , Stewart Jesse C.
Published: February 2019

Background:

Insomnia is associated with increased cardiovascular disease (CVD) risk in the general population and is highly prevalent in people with HIV. The CVD risk conferred by insomnia in the HIV population is unknown.

Methods:

Using the Veterans Aging Cohort Study Survey Cohort, insomnia symptoms were measured and dummy coded with the item, “Difficulty falling or staying asleep?” (5-point scale from no difficulty to bothers a lot). Incident CVD eventICD-9codes (acute myocardial infarction, stroke, or coronary artery revascularization) were identified with the Department of Veterans Affairs (VA) and Medicare administrative data and VA fee-for-service data. Those with baseline CVD were excluded.

Results:

HIV-infected (N = 3108) veterans had a median follow-up time of 10.8 years, during which 267 CVD events occurred. Compared to HIV-infected veterans with no difficulty falling or staying asleep, HIV-infected veterans bothered a lot by insomnia symptoms had an increased risk of incident CVD after adjusting for demographics [hazard ratio (HR) = 1.64, 95% confidence interval (CI): 1.16 to 2.31,P= 0.005], CVD risk factors (HR = 1.62, 95% CI: 1.14 to 2.30,P= 0.007), additional potential confounders (hepatitis C infection, renal disease, anemia, alcohol use, and cocaine use; HR = 1.70, 95% CI: 1.19 to 2.43,P= 0.003), and HIV-specific factors (HIV-1 RNA, CD4+T-cell count, and antiretroviral therapy; HR = 1.66, 95% CI: 1.16 to 2.37,P= 0.005). Additional adjustment for nonbenzodiazepine sleep medication (HR = 1.62, 95% CI: 1.13 to 2.32,P= 0.009) did not attenuate the association; however, it fell short of significance atP< 0.01 after adjustment for depressive symptoms (HR = 1.51, 95% CI: 0.98 to 2.32,P= 0.060) or antidepressant medication (HR = 1.51, 95% CI: 1.04 to 2.19,P= 0.031).

Conclusions:

Highly bothersome insomnia symptoms were significantly associated with incident CVD in HIV-infected veterans, suggesting that insomnia may be a novel, modifiable risk factor for CVD in HIV.
Elevated Microparticle Tissue Factor Activity Is Associated With Carotid Artery Plaque in HIV-Infected Women
Authors: Lin Juan , Xue Xiaonan , Anastos Kathryn , Cohen Mardge H. , Gange Stephen J. , Lazar Jason M. , Liu Chenglong , Mack Wendy J. , Tien Phyllis C. , Tilley Cathy , Hodis Howard N. , Landay Alan L. , Tracy Russell P. , Kaplan Robert C. , Hanna David B.
Published: February 2019

Background:

Expression of tissue factor (TF) on the surface of activated monocytes may trigger thrombosis, leading to clotting risk, inflammation, and atherosclerosis. TF-positive microparticles (MP-TF) represent a functionally active form of TF that may be promulgated by long-term HIV infection. We hypothesized that greater MP-TF activity is associated with carotid artery plaque in HIV+ women.

Setting:

In a case–control study nested within the Women's Interagency HIV Study (WIHS), eligible HIV+ participants underwent B-mode carotid artery ultrasound at 2 study visits occurring 7 years apart. Cases were defined by the presence of at least 1 carotid artery plaque assessed at either visit. Cases were matched 1:2 to controls who were found not to have carotid artery plaques.

Methods:

Conditional logistic regression estimated the association of MP-TF activity with the presence of carotid artery plaque, adjusting for demographic and behavioral characteristics, HIV-related factors, cardiometabolic risk factors, and serum inflammation biomarkers (high-sensitivity C-reactive protein, IL-6, sCD14, sCD163, Gal-3, and Gal-3BP).

Results:

Elevated MP-TF activity (>0.537 pg/mL) was found to be significantly associated with greater odds of plaque (adjusted odds ratio 3.86, 95% confidence interval: 1.06 to 14.07,P= 0.04). The association was attenuated after further adjustment for IL-6 but was unaffected by adjustment for other biomarkers including those denoting monocyte activation.

Conclusions:

Our findings suggest a link among HIV infection, innate immune system perturbation, coagulation, and atherosclerosis.
18F-Choline PET/CT Imaging for Intracranial Hemangiopericytoma Recurrence
Authors: Jehanno Nina , Cassou-Mounat Thibaut , Mammar Hamid , Luporsi Marie , Huchet Virginie
Published: February 2019

We report the case of a 50-year-old man, with previous history of grade 3 intracranial hemangiopericytoma with initial complete surgical resection, addressed for local recurrence. Surgical revision performed 18 months after initial surgery allowed only partial resection, leaving residual disease along the optic nerve. Complementary radiotherapy with proton was decided. 18F-FDG PET/CT and 18F-choline PET/CT were both performed for treatment planning. 18F-FDG PET showed no uptake of the residual tumor, whereas 18F-choline depicted highly metabolic residual disease uptake with excellent delineation of local recurrence. 18F-choline PET/CT appears as a useful PET tracer for hemagiopericytoma imaging.
Metastatic Insulinoma Controlled by Targeted Radionuclide Therapy With 177Lu-DOTATATE in a Patient With Solitary Kidney and MEN-1 Syndrome
Authors: Novruzov Fuad , Mehmetbeyli Leyla , Aliyev Jamil A. , Abbasov Bahadur , Mehdi Elnur
Published: February 2019

A 54-year-old man with multiple endocrine neoplasia type 1 had previous history of parathyroid surgery and left thyroid lobectomy 5 years earlier, and was referred for recurrent hypoglycemic episodes. 68Ga-DOTATATE PET/CT had showed multiple lesions in the right lung, liver, and pancreas. Biopsy from pancreas revealed low-grade neuroendocrine neoplasia. After 2 fractions of 177Lu-DOTATATE therapy, the size of lesions and its activity reduced on the 68Ga-DOTATATE scan and the hypoglycemic episodes manifested every day have scaled down to 1 time over 1-year follow-up. Herein, we report a case of malignant insulinoma successfully treated with radiolabeled somatostatin receptor therapy using 177Lu-DOTATATE.
Recommendations for the Development and Reform of Microtia and Atresia Services
Authors: Mazeed Ahmed S. , Saied Samia , Abulezz Tarek , Youssef Gamal , Bulstrode Neil W.
Published: February 2019

Background:

The initial step in setting up standardized microtia-atresia service is investigating the current status of the service and comparing this to internationally recognized guidelines or care standards. In many countries, documented information about microtia care is lacking. This study is an initiative to guide reform efforts of national microtia service in any country. The UK care standards for microtia-atresia can be a useful model to help set up a comprehensive microtia-atresia service.

Methods:

The authors conducted a survey to investigate different aspects of microtia service in Egypt. The major plastic surgery centers (n = 22) were surveyed by a structured questionnaire. The results were compared with the UK care standards for microtia-atresia to identify the aspects that need improvement. Thorough analysis of the main problems in microtia-atresia service is presented.

Results:

The authors found that microtia service is fragmented between the surveyed centers with 65% of the centers treating less than 10 microtia cases annually. Multiple surgeons are responsible for ear reconstruction in 90% of centers and only 25% of them practise a multidisciplinary team approach. None of the centers uses validated tools of aesthetic or psychological patient-reported outcome measures.

Recommendations:

These 5 recommendations are the keys to reforming microtia service in any country:

(1) Establishing nationally designated centers to concentrate the required expertise.

(2) Assigning fewer high-volume surgeons to optimize the surgical outcomes.

(3) Providing treatment by experienced multidisciplinary teams.

(4) Using validated tools of patient-reported outcome measures.

(5) Collecting and keeping standardized records for regular audit and intercenter studies.
Clinical and Radiological Comparison of Effects of Platelet-Rich Plasma, Hyaluronic Acid, and Corticosteroid Injections on Temporomandibular Joint Osteoarthritis
Authors: Gokçe Kutuk Sinem , Gökçe Gökçen , Arslan Muhammet , Özkan Yasemin , Kütük Mustafa , Kursat Arikan Osman
Published: February 2019

There are few studies in the literature that comparatively evaluate the use of intra-articular orticosteroids (CS), hyaluronic acid (HA), and platelet-rich plasma (PRP). In this study, the authors aimed to compare the clinical results of intra-articular CS, HA, and PRP injections in patients who presented to the authors’ clinic with temporomandibular joint (TMJ) pain and clinically diagnosed with TMJ-osteoarthritis. Patients were evaluated in 2 groups as those patients who felt pain on lateral (n = 31), and posterior (n = 43) palpation. Patients who were evaluated in the study were randomly assigned to 3 different treatment groups as Group 1 (PRP), Group 2 (HA), and Group 3 (CS). Pain felt on the TMJ on lateral and posterior palpation was assessed before treatment and every month for 3 months using a 5-point pain scale. Presence of crepitation, loss of function, and loss of strength were assessed before treatment and every month for 3 months. Significant changes were observed in the PRP and HA groups when the patients were evaluated according to the VAS scores evaluated at different follow-up times for TMJ pain on lateral palpation. Significant changes were observed in the PRP, HA, and CS groups when VAS scores were evaluated according to the patients’ follow-up times for TMJ pain on lateral palpation. In conclusion, the findings of this study have shown that intra-articular PRP injections decreased TMJ palpation pain more effectively compared with the HA and CS groups.
Use of Porous Implants for the Prosthetic Rehabilitation of Fibula Free Flap Reconstructed Patients
Authors: Brauner Edoardo , Di Carlo Stefano , Ciolfi Alessandro , Pompa Giorgio , Jamshir Sara , De Angelis Francesca , Della Monaca Marco , Valentini Valentino
Published: February 2019

Vascularized free flaps represent today the gold standard in Maxillo-Facial reconstructive treatment of the upper and lower compromised maxillas.

The aim of this study is to perform the advantages and disadvantages of the vascularized fibula free flap and the available rehabilitation options with porous implants.

In this study the authors analyzed 45 patients with 211 inserted implants treated and reconstructed with vascularized fibula flaps. The authors compared the use of 103 titanium tapered implants (with micro rough surface) versus 108 tantalum-titanium porous implants to evaluate the bone reabsorption and implant survival. Immediate implant stability, the peri-implant reabsorption, and the survival were evaluated. The follow-up was after 3, 6, 12, and 24 months.

The authors found that for the 108 Zimmer TM they had an average bone loss of 1 mm ± 0.2 mm after 1 year of follow-up, compared with the other implants where the average bone loss was 2.27 mm ± 0.4.

This study demonstrated that the problems caused by different fibula flaps level, compared with the mandibula or, with adjacent teeth in the maxilla, can be solved using TM porous implants that almost duplicate the fixture surface and guarantees long life prognosis to the authors’ prosthetic devices.
Donepezil's Effects on Brain Functions of Patients With Alzheimer Disease: A Regional Homogeneity Study Based on Resting-State Functional Magnetic Resonance Imaging
Authors: Cheng Jianan , Yang Hua , Zhang Jiangtao
Published: February 2019

Purpose

Donepezil is known to increase cholinergic synaptic transmission in Alzheimer disease (AD), although how it affects cortical brain activity and how it consequently affects brain functions need further clarification. To investigate the therapeutic mechanism of donepezil underlying its effect on brain function, regional homogeneity (ReHo) technology was used in this study.

Patients and methods

This study included 11 mild-to-moderate AD patients who completed 24 weeks of donepezil treatment and 11 matched healthy controls. All participants finished neuropsychological assessment and resting-state functional magnetic resonance imaging scanning to compare whole-brain ReHo before and after donepezil treatment.

Results

Significantly decreased Alzheimer's Disease Assessment Scale–Cognitive Subscale scores (P = 0.010) and increased Mini-Mental State Examination scores (P = 0.043) were observed in the AD patients. In addition, in the right gyrus rectus (P = 0.021), right precentral gyrus (P = 0.026), and left superior temporal gyrus (P = 0.043) of the AD patients, decreased ReHo was exhibited.

Conclusion

Donepezil-mediated improvement of cognitive function in AD patients is linked to spontaneous brain activities of the right gyrus rectus, right precentral gyrus, and left superior temporal gyrus, which could be used as potential biomarkers for monitoring the therapeutic effect of donepezil.
Effect of Duloxetine for the Treatment of Chronic Central Poststroke Pain
Authors: Kim Na Young , Lee Sang Chul , Kim Yong Wook
Published: February 2019

Objectives

Central poststroke pain (CPSP) is the neuropathic pain in areas of the body corresponding to stroke lesions. It is often refractory to treatment, reduces quality of life, and impedes rehabilitation. The pharmacological treatment of CPSP is challenging. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is known to be effective against neuropathic pain. The current study describes the efficacy of duloxetine in reducing pain severity in CPSP patients.

Subjects and Methods

For the purpose of this study, CPSP was defined as spontaneous pain within an area of the body corresponding to the brain lesion that emerged at or after stroke onset. Any previously prescribed medical therapy for the patients was not changed or stopped; duloxetine 30 mg was added to their ongoing treatment. Pain was assessed at baseline and thereafter at 1 and 3 weeks using Numeric Rating Scale (NRS) and Short-form MC Gill Pain Questionnaire scores. At the first follow-up, scores were reviewed and dose was doubled if no improvement or adverse effects were observed.

Results

From a total of 37 patients, 4 were withdrawn because of adverse effects including nausea, agitation, and somnolence. The mean elapsed time of observed symptoms since stroke onset was 3.1 ± 4.1 years. There was a significant difference between the mean values of Short-form MC Gill Pain Questionnaire and NRS scores at baseline and those at the follow-up assessment. Twenty-six (70.3%) of the patients showed at least 30% reduction of NRS compared with baseline at the third week.

Conclusions

Our findings suggest that duloxetine can be effective for managing CPSP.
Spatial Correlation and Breast Cancer Risk
Authors: Fowler Erin E. E. , Hathaway Cassandra , Tillman Fabryann , Weinfurtner Robert , Sellers Thomas A. , Heine John
Published: February 2019

We present a novel method for evaluating the spatial correlation structure in two-dimensional (2D) mammograms and evaluate its merits for risk prediction. Two matched case-control studies were analyzed. Study 1 included women (N = 588 pairs) with mammograms acquired with either Hologic Selenia full field digital mammography (FFDM) units or Hologic Dimensions digital breast tomosynthesis units. Study 2 included women (N =180 pairs) with mammograms acquired with a General Electric Senographe 2000D FFDM unit. Matching variables included age, HRT usage/duration, screening history, and mammography unit. The local autocorrelation function was determined with Fourier analysis and compared with template defined as 2D double-sided exponential function with one spatial extent parameter: n = 4, 12, 24, 50, 74, 100, and 124 defined in pixel widths. The difference between local correlation and template was gauged within a kernel with an adjustable parameter and summarized, producing two measures: the mean (mn+1), and standard (sn+1). Both adjustable parameters were varied in Study 1. Select measures that produced significant associations with breast cancer were translated to Study 2. Breast cancer associations were evaluated with conditional logistic regression, adjusted for body mass index and ethnicity. Odds ratios (ORs) were estimated as per standard increment with 95% confidence intervals (CIs).

Two measures were selected for breast cancer association analysis in Study 1: m75 and s25. Both measures revealed significant associations with breast cancer: OR = 1.45 (1.23, 1.66) for m75 and OR = 1.30 (1.14, 1.49) for s25. When translating to Study 2, these measures also revealed significant associations: OR = 1.49 (1.12, 1.96) for m75 and OR = 1.34 (1.06, 1.69) for s25.

Novel correlation metrics presented in this work revealed significant associations with breast cancer risk. This approach is general and may have applications beyond mammography.
SLCs contribute to endocrine resistance in breast cancer: role of SLC7A5 (LAT1)
Authors: Sevigny Catherine M. , Sengupta Surojeet , Luo Zhexun , Liu Xiaoyi , Hu Rong , Zhang Zhen , Jin Lu , Pearce Dominic , Demas Diane , Shajahan-Haq Ayesha N. , Clarke Robert
Published: February 2019

Resistance to endocrine therapies remains a major challenge for the successful management of patients with estrogen receptor-positive (ER+) breast cancers. Central to the development of resistance is the adaptive reprogramming of cellular metabolism in response to treatment. Solute carriers (SLCs) play a key role in metabolic reprogramming by transporting sugars, amino acids, and other nutrients and regulating their abundance within the cell and its subcellular organelles. We found 109 SLC mRNAs to be differentially expressed between endocrine sensitive and resistant breast cancer cells. In univariate analyses, 55 of these SLCs were associated with poor outcome in ER+ breast cancer patients. Data from TMT and SILAC studies then led us to focus on SLC7A5 (LAT1). In complex with SLC3A2 (CD98), LAT1 is the primary transporter of large, neutral amino acids including leucine and tyrosine. LAT1 expression is estrogen-regulated in endocrine sensitive cells but this regulation is lost in resistant cells. Pharmacologic inhibition or genetic depletion of LAT1 each suppressed growth in two models of endocrine resistant breast cancer. Autophagy was activated with LAT1 inhibition, but cells failed to degrade p62 showing that flux was blocked. Overexpression of the LAT1 cDNA increased protein synthesis and high LAT1 expression correlated with poor disease-free survival in ER+ breast cancer patients. This study uncovers a novel LAT1 mediated adaptive response that contributes to the development of endocrine resistance. Blocking LAT1 function may offer a new avenue for effective therapeutic intervention against endocrine resistant ER+ breast cancers.
Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease
Authors: Vogel Jacob W. , Iturria-Medina Yasser , Strandberg Olof T. , Smith Ruben , Evans Alan C. , Hansson Oskar ,   for the Alzheimer’s Disease Neuroimaging Initiative, and the Swedish BioFinder Study
Published: February 2019

Tau is one of the two pathological hallmarks of Alzheimer’s disease, and bears a much closer relationship to local neurodegeneration and cognitive impairment than the other hallmark, β-amyloid. Cell and rodent models have shown evidence that tau spreads from cell to cell through anatomical neuronal connections, and that this process is facilitated by the presence of β-amyloid. We test this hypothesis in humans by using an epidemic spreading model (ESM) to simulate the spread of tau over human neuronal connections, and we compare the simulated pattern of progression to the observed pattern measured in the brains of 312 individuals on the Alzheimer’s disease spectrum, using PET. Fitting our model, we found that the majority of variance in the overall pattern of tau progression could be explained by diffusion of an agent through the human connectome, measured using either functional connectivity or diffusion tractography. These models far exceeded chance, and outperformed models testing the extracellular spread of tau over Euclidian space. Surprisingly, the ESM predicted the spatial patterns of tau irrespective of whether subjects demonstrated evidence for brain β-amyloid. In addition, in β-amyloid-positive subjects only, regions with greater amyloid burden showed greater tau than predicted by connectivity patterns, suggesting a role of amyloid in accelerating the spread of tau in certain isocortical regions. Altogether, our results provide strong evidence that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain β-amyloid.
Left-handedness is associated with greater fighting success in humans
Authors: Richardson Thomas , Gilman R. Tucker
Published: February 2019

Left-handedness is a costly, sexually dimorphic trait found at low frequencies in all human populations. How the handedness polymorphism is maintained is unclear. The fighting hypothesis argues that left-handed men have a negative frequency-dependent advantage in violent intrasexual competition giving them a selective advantage. In support of this, many studies have found that left-handed men are overrepresented among modern professional fighters, but studies typically find no difference in fighting success between left and right-handed fighters. We studied over 13,800 professional boxers and mixed martial artists of varying abilities in three of the largest samples to test this hypothesis to date, finding robust evidence that left-handed fighters have greater fighting success. This held for both male and female fighters, and for both percentage of fights won and an objective measure of fighting ability. We replicated previous results showing that left-handed fighters are strongly overrepresented in professional combat sports, but left-handed fighters did not show greater variance in fighting ability, a hypothesis suggested in previous studies. Overall we find strong evidence consistent with the fighting hypothesis.
Oxidation state dependent conformational changes of HMGB1 regulates the formation of the CXCL12/HMGB1 heterocomplex
Authors: Fassi Enrico M. A. , Sgrignani Jacopo , D’Agostino Gianluca , Cecchinato Valentina , Garofalo Maura , Grazioso Giovanni , Uguccioni Mariagrazia , Cavalli Andrea
Published: February 2019

High-mobility Group Box 1 (HMGB1) is an abundant protein present in all mammalian cells and involved in several processes. During inflammation or tissue damage, HMGB1 is released in the extracellular space and, depending on its redox state, can form a heterocomplex with CXCL12. The heterocomplex acts exclusively on the chemokine receptor CXCR4 enhancing leukocyte recruitment.

Here, we used multi-microsecond molecular dynamics (MD) simulations to elucidate the effect of the disulfide bond on the structure and dynamics of HMGB1.

The results of the MD simulations show that the presence or lack of the disulfide bond between Cys23 and Cys45 modulates the conformational space explored by HMGB1, making the reduced protein more suitable to form a complex with CXCL12.
Microfluidic protein isolation and sample preparation for high-resolution cryo-EM
Authors: Schmidli Claudio , Albiez Stefan , Rima Luca , Righetto Ricardo , Mohammed Inayatulla , Oliva Paolo , Kovacik Lubomir , Stahlberg Henning , Braun Thomas
Published: February 2019

High-resolution structural information is essential to understand protein function. Protein-structure determination needs a considerable amount of protein, which can be challenging to produce, often involving harsh and lengthy procedures. In contrast, the several thousands to a few million protein particles required for structure-determination by cryogenic electron microscopy (cryo-EM) can be provided by miniaturized systems. Here, we present a microfluidic method for the rapid isolation of a target protein and its direct preparation for cryo-EM. Less than 1 μL of cell lysate is required as starting material to solve the atomic structure of the untagged, endogenous human 20S proteasome. Our work paves the way for high-throughput structure determination of proteins from minimal amounts of cell lysate and opens new opportunities for the isolation of sensitive, endogenous protein complexes.
Sox6: A new modulator of renin expression during physiological conditions
Authors: Saleem Mohammad , Hodgkinson Conrad P. , Contreras Ela W. , Xiao Liang , Gimenez-Bastida Juan A. , Foss Jason , Payne Alan J. , Mirotsou Maria , Gama Vivian , Dzau Victor J. , Gomez Jose A.
Published: February 2019

Juxtaglomerular (JG) cells, major sources of renin, differentiate from metanephric mesenchymal cells which give rise to JG cells or a subset of smooth muscle cells of the renal afferent arteriole. During periods of dehydration and salt deprivation JG cells undergo expansion. Gene expression profiling comparing resident renal Mesenchymal Stromal Cells (MSCs) with JG cells indicate that the transcription factor Sox6 is highly expressed in JG cells in the adult kidney. In vitro, loss of Sox6 expression reduces differentiation of renal MSCs to renin producing cells. In vivo, Sox6 expression is up-regulated during JG cell expansion. Importantly, knockout of Sox6 in Ren1d+ cells halts the increase in renin expressing cells normally seen during JG cell expansion as well as the typical increase in renin. These results support a previously undefined role for Sox6 in renin expression during normal and pathophysiological conditions.
U.S. imperiled species are most vulnerable to habitat loss on private lands
Authors: Eichenwald Adam J. , Evans Michael J. , Malcom Jacob W.
Published: February 2019

To stem the ongoing loss of biodiversity, there is an urgent need to distinguish between effective and ineffective approaches for protecting species habitats. Using Google Earth Engine and 30 years of Landsat images, we quantify habitat change for 24 vertebrates on the U.S. Endangered Species List (ESA) and IUCN Red List across different categories of land ownership (e.g., federal, state, and private) that are subject to different conservation-focused legal restrictions. These estimates exclude changes due to agricultural conversion and burned areas. Imperiled species evaluated lost the least habitat (3.6%) on federal lands, while losses on private lands without conservation easements were more than twice as great (8.1%). Differences in annual percent loss before and after species were placed on the Endangered Species List, and between ESA and Red List species suggest that the ESA limited habitat loss and was most effective on federal lands. These results emphasize the importance of federal lands for protecting habitat for imperiled species and highlight the need to improve habitat protection on private lands for long-term conservation.
SIPA1L2 controls trafficking and signaling of TrkB-containing amphisomes at presynaptic terminals
Authors: Andres-Alonso Maria , Ammar Mohamed Raafet , Butnaru Ioana , Gomes Guilherme M. , Sanhueza Gustavo Acuna , Raman Rajeev , Yuanxiang PingAn , Borgmeyer Maximilian , Lopez-Rojas Jeffrey , Raza Syed Ahsan , Brice Nicola , Hausrat Torben J. , Macharadze Tamar , Diaz-Gonzalez Silvia , Carlton Mark , Failla Antonio Virgilio , Stork Oliver , Schweizer Michaela , Gundelfinger Eckart D. , Kneussel Matthias , Spilker Christina , Karpova Anna , Kreutz Michael R.
Published: February 2019

Amphisomes are transient organelles that derive from fusion of autophagosomes with late endosomes. They rapidly transform into degradative autolysosomes, whereas non-degradative roles of the autophagic pathway have been barely described. Here we show that in neurons BDNF/TrkB receptor bearing Rab7 / Light chain 3 (LC3) - positive amphisomes signal at presynaptic boutons during retrograde trafficking to the soma. Local signaling and inward transport essentially require the Rap GTPase-activating (RapGAP) protein SIPA1L2, which directly binds to TrkB and Snapin to connect TrkB-containing amphisomes to dynein. Association with LC3 regulates the RapGAP activity of SIPA1L2 and thereby retrograde trafficking. Following induction of presynaptic plasticity amphisomes dissociate from dynein at boutons, and this enables local signaling and promotes transmitter release. Accordingly,sipa1l2knockout mice show impaired BDNF-dependent presynaptic plasticity. Collectively, the data suggest that TrkB-signaling endosomes are in fact amphisomes that during retrograde transport have local signaling capacity in the context of presynaptic plasticity.
Myc instructs and maintains pancreatic adenocarcinoma phenotype
Authors: Sodir Nicole M. , Kortlever Roderik M. , Barthet Valentin J.A. , Pellegrinet Luca , Campos Tania , Kupczak Steven , Swigart Lamorna Brown , Soucek Laura , Arends Mark J. , Littlewood Trevor D. , Evan Gerard I.
Published: February 2019

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its dismal prognosis and its signature fibroinflammatory phenotype. We show that activation of Myc in PanIN epithelial cells is alone sufficient to instruct and maintain immediate transition of indolent PanINs to PDACs phenotypically identical to the spontaneous human disease. Myc does this by inducing a distinct, tissue-specific ensemble of instructive signals that, together, coordinate changes in multiple, stromal and inflammatory cell types to generate the signature PDAC stroma. We also demonstrate that the Myc PDAC switch is completely reversible and that Myc deactivation immediately triggers meticulous disassembly of both PDAC tumor and stroma. Hence, both the formation and deconstruction of the complex PDAC phenotype may be mediated by a single, reversible molecular switch.

SIGNIFICANCE

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and lacks effective therapies. We show that Myc is a single molecular switch that directly and immediately instructs transition from indolent KRasG12D-induced PanIN to the characteristic complex, multi-cell-type fibroinflammatory and immune-cold PDAC phenotype through the release of a distinct, tissuespecific set of instructive signals. The same combination of KRasG12Dand Myc drives a very different phenotype in lung, indicating that the principal phenotypes of adenocarcinomas are dictated by tissue of origin not specific oncogenes. We also show that the Myc switch is immediately and completely reversible: blocking Myc function triggers meticulous disassembly of the entire PDAC tumor-stromal edifice demonstrating that phenotypic complexity is not a barrier to effective treatment of cancers.
Noradrenergic signaling in wakeful states inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex
Authors: Stowell Rianne D. , Sipe Grayson O. , Dawes Ryan P. , Batchelor Hanna N. , Lordy Katheryn A. , Bidlack Jean M. , Brown Edward , Sur Mriganka , Majewska Ania K.
Published: February 2019

Microglia are the innate immune cells of the brain with roles in neuroimmunology and synaptic plasticity. Microglial processes continuously survey the brain parenchyma interacting with synaptic elements and maintaining tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamicsin vivohave been primarily studied in anesthetized animals, where slow-wave neural activity resembles sleep-like states. We report that microglial surveillance and injury response in awake animals are reduced compared to when animals are anesthetized, suggesting that arousal state profoundly modulates microglial roles in the physiological brain. Stimulating β2-adrenergic receptors recapitulated these observations and also disrupted experience-dependent plasticity only when intact β2-adrenergic receptors were present in microglia specifically. These results indicate that microglial roles in surveillance and synaptic plasticity in the healthy brain are modulated by noradrenergic fluctuations between arousal states and raises new considerations for sleep/wake disruption in neurodevelopment and neuropathology.
3D cell culture stimulates the secretion of in vivo like extracellular vesicles
Authors: Thippabhotla Sirisha , Zhong Cuncong , He Mei
Published: February 2019

For studying cellular communications ex-vivo, a two-dimensional (2D) cell culture model is currently used as the “gold standard”. 2D culture models are also widely used in the study of RNA expression profiles from tumor cells secreted extracellular vesicles (EVs) for tumor biomarker discovery. Although the 2D culture system is simple and easily accessible, the culture environment is unable to represent in vivo extracellular matrix (ECM) microenvironment. Our study observed that 2D culture-derived EVs showed significantly different profiles in terms of secretion dynamics and essential signaling molecular contents (RNAs and DNAs), when compared to the three-dimensional (3D) culture-derived EVs. By performing small RNA next-generation sequencing (NGS) analysis of cervical cancer cells and their EVs compared with cervical cancer patient plasma EV-derived small RNAs, we observed that 3D culture-derived EV small RNAs differ from their parent cell small RNA profile which may indicate a specific sorting process. Most importantly, the 3D culture derived EV small RNA profile exhibited a much higher similarity (~96%) to in vivo circulating EVs derived from cervical cancer patient plasma. However, 2D culture derived EV small RNA profile correlated better with only their parent cells cultured in 2D. On the other hand, DNA sequencing analysis suggests that culture and growth conditions do not affect the genomic information carried by EV secretion. This work also suggests that tackling EV molecular alterations secreted into interstitial fluids can provide an alternative, non-invasive approach for investigating 3D tissue behaviors at the molecular precision. This work could serve as a foundation for building precise models employed in mimicking in vivo tissue system with EVs as the molecular indicators or transporters. Such models could be used for investigating tumor biomarkers, drug screening, and understanding tumor progression and metastasis.
A cellular taxonomy of the bone marrow stroma in homeostasis and leukemia demonstrates cancer-crosstalk with stroma to impair normal tissue function
Authors: Ninib Baryawno , Dariusz Przybylski , Kowalczyk Monika S. , Youmna Kfoury , Nicolas Severe , Karin Gustafsson , Francois Mercier , Marcin Tabaka , Matan Hofree , Danielle Dionne , Ani Papazian , Dongjun Lee , Orit Rozenblatt-Rosen , Aviv Regev , Scadden David T
Published: February 2019

Stroma is a poorly defined non-parenchymal component of virtually every organ with key roles in organ development, homeostasis and repair. Studies of the bone marrow stroma have defined individual populations in the stem cell niche regulating hematopoietic regeneration and capable of initiating leukemia. Here, we use single-cell RNA-seq to define a cellular taxonomy of the mouse bone marrow stroma and its perturbation by malignancy. We identified seventeen stromal subsets expressing distinct hematopoietic regulatory genes, spanning new fibroblastic, and osteoblastic subpopulations. Emerging acute myeloid leukemia resulted in impaired osteogenic differentiation and reduced production of hematopoietic regulatory molecules necessary for normal hematopoiesis. Thus, cancer can affect tissue stroma in which they reside to disadvantage normal parenchymal cells. Our taxonomy of the regulatory stromal compartment provides experimental support for a model where malignant clone is not a destroyer of normal tissue but an architect of it, remodeling tissue stroma to enable emergent cancer.
Protective role of the deSUMOylating enzyme SENP3 in myocardial ischaemia-reperfusion injury
Authors: Rawlings Nadiia , Lee Laura , Nakamura Yasuko , Wilkinson Kevin A. , Henley Jeremy M
Published: February 2019

Interruption of blood supply to the heart is a leading cause of death and disability. However, the molecular events that occur during heart ischaemia, and how these changes prime consequent cell death upon reperfusion, are poorly understood. Protein SUMOylation is a post-translational modification that has been strongly implicated in the protection of cells against a variety of stressors, including ischaemia-reperfusion. In particular, the SUMO2/3-specific protease SENP3 has emerged as an important determinant of cell survival after ischaemic infarct. Here, we used the Langendorff perfusion model to examine changes in the levels and localisation of SUMOylated target proteins and SENP3 in whole heart. We observed a 50% loss of SENP3 from the cytosolic fraction of hearts after preconditioning, a 90% loss after ischaemia and an 80% loss after ischaemia-reperfusion. To examine these effects further, we performed ischaemia and ischaemia-reperfusion experiments in the cardiomyocyte H9C2 cell line. Similar to whole hearts, ischaemia induced a decrease in cytosolic SENP3. Furthermore, shRNA-mediated knockdown of SENP3 led to an increase in the rate of cell death upon reperfusion. Together, our results indicate that cardiac ischaemia dramatically alter levels of SENP3 and suggest that this may a mechanism to promote cell survival after ischaemia-reperfusion in heart.