Publications by authors named "David Muller"

462 Publications

Coronary artery embolism and culture-negative endocarditis post Bentall's procedure.

J Surg Case Rep 2021 Oct 5;2021(10):rjab438. Epub 2021 Oct 5.

Department of Cardiology, St Vincent's Hospital, Sydney, NSW, Australia.

Infective endocarditis is an important cause of morbidity and mortality, which classically presents with fevers and nonspecific symptoms. Afebrile infective endocarditis with negative blood cultures makes diagnosis more challenging and delays in treatment can occur increasing the likelihood of complications. The presence of prosthetic heart valves places patients at an increased risk of infective endocarditis and the case described below highlights the importance of considering this diagnosis even if classic clinical features such as fever and raised inflammatory markers are not present, as well as discussing an unusual complication of infective endocarditis; coronary artery embolism leading to myocardial infarction.
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http://dx.doi.org/10.1093/jscr/rjab438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496241PMC
October 2021

Extremely anisotropic van der Waals thermal conductors.

Nature 2021 Sep 29;597(7878):660-665. Epub 2021 Sep 29.

Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.

The densification of integrated circuits requires thermal management strategies and high thermal conductivity materials. Recent innovations include the development of materials with thermal conduction anisotropy, which can remove hotspots along the fast-axis direction and provide thermal insulation along the slow axis. However, most artificially engineered thermal conductors have anisotropy ratios much smaller than those seen in naturally anisotropic materials. Here we report extremely anisotropic thermal conductors based on large-area van der Waals thin films with random interlayer rotations, which produce a room-temperature thermal anisotropy ratio close to 900 in MoS, one of the highest ever reported. This is enabled by the interlayer rotations that impede the through-plane thermal transport, while the long-range intralayer crystallinity maintains high in-plane thermal conductivity. We measure ultralow thermal conductivities in the through-plane direction for MoS (57 ± 3 mW m K) and WS (41 ± 3 mW m K) films, and we quantitatively explain these values using molecular dynamics simulations that reveal one-dimensional glass-like thermal transport. Conversely, the in-plane thermal conductivity in these MoS films is close to the single-crystal value. Covering nanofabricated gold electrodes with our anisotropic films prevents overheating of the electrodes and blocks heat from reaching the device surface. Our work establishes interlayer rotation in crystalline layered materials as a new degree of freedom for engineering-directed heat transport in solid-state systems.
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http://dx.doi.org/10.1038/s41586-021-03867-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481126PMC
September 2021

Implications of Dengue Virus Maturation on Vaccine Induced Humoral Immunity in Mice.

Viruses 2021 Sep 15;13(9). Epub 2021 Sep 15.

School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia.

The use of dengue virus (DENV) vaccines has been hindered by the complexities of antibody dependent enhancement (ADE). Current late-stage vaccine candidates utilize attenuated and chimeric DENVs that produce particles of varying maturities. Antibodies that are elicited by preferentially exposed epitopes on immature virions have been linked to increased ADE. We aimed to further understand the humoral immunity promoted by DENV particles of varying maturities in an AG129 mouse model using a chimeric insect specific vaccine candidate, bDENV-2. We immunized mice with mature, partially mature, and immature bDENV-2 and found that immunization with partially mature bDENV-2 produced more robust and cross-neutralizing immune responses than immunization with immature or mature bDENV-2. Upon challenge with mouse adapted DENV-2 (D220), we observed 80% protection for mature bDENV-2 vaccinated mice and 100% for immature and partially mature vaccinated mice, suggesting that protection to homotypic challenge is not dependent on maturation. Finally, we found reduced in vitro ADE at subneutralising serum concentrations for mice immunized with mature bDENV-2. These results suggest that both immature and mature DENV particles play a role in homotypic protection; however, the increased risk of in vitro ADE from immature particles indicates potential safety benefits from mature DENV-based vaccines.
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http://dx.doi.org/10.3390/v13091843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473161PMC
September 2021

The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.

PLoS Med 2021 Sep 20;18(9):e1003786. Epub 2021 Sep 20.

Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.

Background: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).

Methods And Findings: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.

Conclusions: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.
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http://dx.doi.org/10.1371/journal.pmed.1003786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496779PMC
September 2021

Uptake and Release of Aroma Compounds by an Ethylene Propylene Diene Monomer Rubber Sealing Polymer: Investigating Aroma Carryover in a Model Wine System.

J Agric Food Chem 2021 Sep 17;69(38):11382-11394. Epub 2021 Sep 17.

Dienstleistungszentrum Ländlicher Raum (DLR) Rheinpfalz, Institute for Viticulture and Oenology, Breitenweg 71, Neustadt an der Weinstraße 67435, Germany.

Aromatized wines and regular table wines are often filled on the same bottling line. Sealing polymers in the filling line absorb volatiles from aromatized wines and may migrate due to insufficient cleaning into the subsequently bottled regular wine. Unintentional carryover of volatiles may lead to accusation of illegal aromatization of wine. Absorption, cleaning efficacy, and migration of volatiles into ethylene propylene diene monomer rubber were investigated in a model system. Direct thermal desorption-gas chromatography-mass spectrometry analysis of seven aroma compounds monitored variation in the polymer (μg/g). Absorption of volatiles was mostly driven by their octanol/water partition coefficients. Cleaning of polymers removed 11 to 62% of the absorbed volatiles. Subsequent immersion of cleaned polymers into model wine revealed migration of 20 to 57% of the remaining volatiles. Sensory tests suggested the impact of transferred volatiles into subsequent model wine. For α-ionone, an odor activity value of 1.03 indicated a potential sensory impact.
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http://dx.doi.org/10.1021/acs.jafc.1c04565DOI Listing
September 2021

2021 CSANZ and ANZSCTS Position Statement on the Operator and Institutional Requirements for a Transcatheter Aortic Valve Implantation (TAVI) Program in Australia.

Heart Lung Circ 2021 Sep 2. Epub 2021 Sep 2.

Department of Cardiology, St. Vincent's Hospital Sydney, Sydney, NSW, Australia.

This document establishes the minimum standard for accreditation of institutions and operators as endorsed by the Cardiac Society of Australia and New Zealand (CSANZ) and the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS). The original Joint Society Position Statement was ratified in August 2014. This 2021 update replaces the original and serves as a consensus within which the Conjoint Committee for Trancatheter Aortic Valve Implantation (TAVI) Accreditation will function, as recommended by Medical Services Advisory Committee (MSAC) Determination for TAVI. This is not a Guideline Statement but takes into consideration regional, legislative, and health system factors important to establishing requirements for TAVI accreditation in Australia.
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http://dx.doi.org/10.1016/j.hlc.2021.07.017DOI Listing
September 2021

Atomically Thin, Optically Isotropic Films with 3D Nanotopography.

Nano Lett 2021 09 20;21(17):7291-7297. Epub 2021 Aug 20.

James Franck Institute, University of Chicago, Chicago, Illinois 60637, United States.

Flat optics aims for the on-chip miniaturization of optical systems for high-speed and low-power operation, with integration of thin and lightweight components. Here, we present atomically thin yet optically isotropic films realized by using three-dimensional (3D) topographic reconstruction of anisotropic two-dimensional (2D) films to balance the out-of-plane and in-plane optical responses on the subwavelength scale. We achieve this by conformal growth of monolayer transition metal dichalcogenide (TMD) films on nanodome-structured substrates. The resulting films show an order-of-magnitude increase in the out-of-plane susceptibility for enhanced angular performance, displaying polarization isotropy in the off-axis absorption, as well as improved photoluminescence emission profiles, compared to their flat-film counterparts. We further show that such 3D geometric programming of optical properties is applicable to different TMD materials, offering spectral generalization over for the entire visible range. Our approach presents a powerful platform for advancing the development of atomically thin flat optics with custom-designed light-matter interactions.
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http://dx.doi.org/10.1021/acs.nanolett.1c02478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431725PMC
September 2021

Transapical Transcatheter Mitral Valve Implantation in Heart Failure: Haemodynamic Challenges for a New Frontier.

Heart Lung Circ 2021 Aug 10. Epub 2021 Aug 10.

Department of Cardiology, St Vincent's Hospital, Sydney, NSW, Australia; The University of New South Wales, Sydney, NSW, Australia; Victor Chang Cardiac Research Institute, Sydney, NSW, Australia.

Secondary mitral regurgitation (MR) and heart failure are mutually dependent. Secondary MR occurs as a consequence of heart failure in patients with impaired left ventricular (LV) function, decreasing cardiac efficiency, accelerating a decline in contractility and worsening the already dismal prognosis of these patients. Advances in transcatheter techniques have now given promise to improved survival, outcomes, and quality of life for patients with advanced heart failure and secondary MR. Although transcatheter edge-to-edge repair is well established, transapical transcatheter mitral valve implantation (TMVI) may represent a more durable solution for correction of secondary MR without the need for cardiopulmonary bypass. Correction of MR, however, is thought to acutely increase LV afterload due to the elimination of low afterload regurgitant flow. In high-risk patients, this may cause acute decompensated heart failure. Off-pump TMVI on a beating heart poses a number of unique challenges, but also the opportunity to study invasive haemodynamic indices in high-risk heart failure patients for the first time. In the following discussion, we review the acute haemodynamic changes during off-pump TMVI in patients with heart failure in order to better guide optimal patient selection and management.
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http://dx.doi.org/10.1016/j.hlc.2021.07.014DOI Listing
August 2021

Ageing, Hypertension and Aortic Valve Stenosis: A Conscious Uncoupling.

Heart Lung Circ 2021 Nov 14;30(11):1627-1636. Epub 2021 Jul 14.

Department of Cardiology, St Vincent's Hospital, Sydney, NSW, Australia; The University of New South Wales, Sydney, NSW, Australia; Victor Chang Cardiac Research Institute, Sydney, NSW, Australia.

Aortic valve stenosis (AS) is no longer considered to be a disease of fixed left ventricular (LV) afterload (due to an obstructive valve), but rather, functions as a series circuit with important contributions from both the valve and ageing vasculature. Patients with AS are frequently elderly, with hypertension and a markedly remodelled aorta. The arterial component is sizable, and yet, the contribution of ventricular afterload has been difficult to determine. Arterial stiffening increases the speed of propagation of the blood pressure wave along the central arteries (estimated as the pulse wave velocity), which results in an earlier return of reflected waves. The effect is to augment blood pressure in the proximal aorta during systole, increasing the central pulse pressure and, in turn, placing even greater afterload on the heart. Elevated global LV afterload is known to have adverse consequences on LV remodelling, function and survival in patients with AS. Consequently, there is renewed focus on methods to estimate the relative contributions of local versus global changes in arterial mechanics and valvular haemodynamics in patients with AS. We present a review on existing and upcoming methods to quantify valvulo-arterial impedance and thereby global LV load in patients with AS.
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http://dx.doi.org/10.1016/j.hlc.2021.05.108DOI Listing
November 2021

Operator and Institutional Requirements for Transcatheter Mitral Valve Therapies in Australia: a CSANZ and ANZSCTS Position Statement.

Heart Lung Circ 2021 Jul 12. Epub 2021 Jul 12.

Alfred and Epworth Hospital, Melbourne, Vic, Australia.

The expert Position Statement is a description of the requirements for Accreditation for transcatheter mitral valve therapy (TMVT) in Australia. The requirements include the need for a multidisciplinary Heart Team review of individual cases, mandatory reporting of outcome data to a national TMVT Registry, and accreditation of individuals and institutions by the Conjoint Accreditation Committee, the assigned accreditation authority.
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http://dx.doi.org/10.1016/j.hlc.2021.07.001DOI Listing
July 2021

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.

Sci Rep 2021 07 5;11(1):13805. Epub 2021 Jul 5.

Duke - NUS Medical School, Singapore, Singapore.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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http://dx.doi.org/10.1038/s41598-021-93214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257595PMC
July 2021

Asian Pacific Society of Cardiology Consensus Recommendations on the Use of MitraClip for Mitral Regurgitation.

Eur Cardiol 2021 Feb 1;16:e25. Epub 2021 Jun 1.

Sendai Kousei Hospital Sendai, Japan.

Transcatheter mitral valve repair with the MitraClip, a catheter-based percutaneous edge-to-edge repair technique to correct mitral regurgitation (MR), has been demonstrated in Western studies to be an effective and safe MR treatment strategy. However, randomised clinical trial data on its use in Asian-Pacific patients is limited. Hence, the Asian Pacific Society of Cardiology convened an expert panel to review the available literature on MitraClip and to develop consensus recommendations to guide clinicians in the region. The panel developed statements on the use of MitraClip for the management of degenerative MR, functional MR, and other less common indications, such as acute MR, dynamic MR, hypertrophic obstructive cardiomyopathy, and MR after failed surgical repair. Each statement was voted on by each panel member and consensus was reached when 80% of experts voted 'agree' or 'neutral'. This consensus-building process resulted in 10 consensus recommendations to guide general cardiologists in the evaluation and management of patients in whom MitraClip treatment is being contemplated.
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http://dx.doi.org/10.15420/ecr.2021.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218170PMC
February 2021

A versatile reverse genetics platform for SARS-CoV-2 and other positive-strand RNA viruses.

Nat Commun 2021 06 8;12(1):3431. Epub 2021 Jun 8.

School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, Australia.

The current COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that despite the large size of the viral RNA genome (~30 kb), infectious full-length cDNA is readily assembled in vitro by a circular polymerase extension reaction (CPER) methodology without the need for technically demanding intermediate steps. Overlapping cDNA fragments are generated from viral RNA and assembled together with a linker fragment containing CMV promoter into a circular full-length viral cDNA in a single reaction. Transfection of the circular cDNA into mammalian cells results in the recovery of infectious SARS-CoV-2 virus that exhibits properties comparable to the parental virus in vitro and in vivo. CPER is also used to generate insect-specific Casuarina virus with ~20 kb genome and the human pathogens Ross River virus (Alphavirus) and Norovirus (Calicivirus), with the latter from a clinical sample. Additionally, reporter and mutant viruses are generated and employed to study virus replication and virus-receptor interactions.
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http://dx.doi.org/10.1038/s41467-021-23779-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187723PMC
June 2021

Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Nutrients 2021 May 28;13(6). Epub 2021 May 28.

Office of the Director, International Agency for Research on Cancer, CEDEX 08, 69372 Lyon, France.

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992-2000 and December 2013-December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.
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http://dx.doi.org/10.3390/nu13061843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228096PMC
May 2021

Micrometer-sized electrically programmable shape-memory actuators for low-power microrobotics.

Sci Robot 2021 Mar;6(52)

Laboratory of Atomic and Solid-State Physics, Cornell University, Ithaca, NY 14853, USA.

Shape-memory actuators allow machines ranging from robots to medical implants to hold their form without continuous power, a feature especially advantageous for situations where these devices are untethered and power is limited. Although previous work has demonstrated shape-memory actuators using polymers, alloys, and ceramics, the need for micrometer-scale electro-shape-memory actuators remains largely unmet, especially ones that can be driven by standard electronics (~1 volt). Here, we report on a new class of fast, high-curvature, low-voltage, reconfigurable, micrometer-scale shape-memory actuators. They function by the electrochemical oxidation/reduction of a platinum surface, creating a strain in the oxidized layer that causes bending. They bend to the smallest radius of curvature of any electrically controlled microactuator (~500 nanometers), are fast (<100-millisecond operation), and operate inside the electrochemical window of water, avoiding bubble generation associated with oxygen evolution. We demonstrate that these shape-memory actuators can be used to create basic electrically reconfigurable microscale robot elements including actuating surfaces, origami-based three-dimensional shapes, morphing metamaterials, and mechanical memory elements. Our shape-memory actuators have the potential to enable the realization of adaptive microscale structures, bio-implantable devices, and microscopic robots.
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http://dx.doi.org/10.1126/scirobotics.abe6663DOI Listing
March 2021

Electron ptychography achieves atomic-resolution limits set by lattice vibrations.

Science 2021 05;372(6544):826-831

School of Applied and Engineering Physics, Cornell University, Ithaca, NY 14853, USA.

Transmission electron microscopes use electrons with wavelengths of a few picometers, potentially capable of imaging individual atoms in solids at a resolution ultimately set by the intrinsic size of an atom. However, owing to lens aberrations and multiple scattering of electrons in the sample, the image resolution is reduced by a factor of 3 to 10. By inversely solving the multiple scattering problem and overcoming the electron-probe aberrations using electron ptychography, we demonstrate an instrumental blurring of less than 20 picometers and a linear phase response in thick samples. The measured widths of atomic columns are limited by thermal fluctuations of the atoms. Our method is also capable of locating embedded atomic dopant atoms in all three dimensions with subnanometer precision from only a single projection measurement.
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http://dx.doi.org/10.1126/science.abg2533DOI Listing
May 2021

Genomic evolutionary trajectory of metastatic squamous cell carcinoma of the lung.

Transl Lung Cancer Res 2021 Apr;10(4):1792-1803

Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: The extent of inter- and intratumoral genomic heterogeneity and the clonal evolution of metastatic squamous cell carcinoma of the lung (LUSC) are poorly understood. Genomic studies of LUSC are challenged by their low tumor cell content. We sought to define the genomic landscape and evolutionary trajectories of metastatic LUSC combining nuclei-flow sorting and whole exome sequencing.

Methods: Five patients with primary LUSC and six matched metastases were investigated. Tumor nuclei were sorted based on ploidy and expression of cytokeratin to enrich for tumor cells for whole exome sequencing.

Results: Flow-sorting increased the mean tumor purity from 26% (range, 12-50%) to 73% (range, 42-93%). Overall, primary LUSCs and their matched metastases shared a median of 79% (range, 67-85%) of copy number aberrations (CNAs) and 74% (range, 65-94%) of non-synonymous mutations, including in tumor suppressor genes such as . Furthermore, the ploidy of the tumors remained unchanged between primary and metastasis in 4/5 patients over time. We found differences in the mutational signatures of shared mutations compared to the private mutations in the primary or metastasis.

Conclusions: Our results demonstrate a close genomic relationship between primary LUSCs and their matched metastases, suggesting late dissemination of the metastases from the primary tumors during tumor evolution.
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http://dx.doi.org/10.21037/tlcr-21-48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107762PMC
April 2021

A chimeric dengue virus vaccine candidate delivered by high density microarray patches protects against infection in mice.

NPJ Vaccines 2021 May 7;6(1):66. Epub 2021 May 7.

Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia.

Dengue viruses (DENV) cause an estimated 390 million infections globally. With no dengue-specific therapeutic treatment currently available, vaccination is the most promising strategy for its control. A wide range of DENV vaccines are in development, with one having already been licensed, albeit with limited distribution. We investigated the immunogenicity and protective efficacy of a chimeric virus vaccine candidate based on the insect-specific flavivirus, Binjari virus (BinJV), displaying the structural prM/E proteins of DENV (BinJ/DENV2-prME). In this study, we immunized AG129 mice with BinJ/DENV2-prME via a needle-free, high-density microarray patch (HD-MAP) delivery system. Immunization with a single, 1 µg dose of BinJ/DENV2-prME delivered via the HD-MAPs resulted in enhanced kinetics of neutralizing antibody induction when compared to needle delivery and complete protection against mortality upon virus challenge in the AG129 DENV mouse model.
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http://dx.doi.org/10.1038/s41541-021-00328-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105366PMC
May 2021

Prostate cancer patient-derived organoids: detailed outcome from a prospective cohort of 81 clinical specimens.

J Pathol 2021 Aug 2;254(5):543-555. Epub 2021 Jun 2.

Department of Urology, University Hospital Basel, Basel, Switzerland.

Patient-derived organoids (PDOs) represent promising preclinical models in various tumor types. In the context of prostate cancer (PCa), however, their establishment has been hampered by poor success rates, which impedes their broad use for translational research applications. Along with the necessity to improve culture conditions, there is a need to identify factors influencing outcomes and to determine how to assess success versus failure in organoid generation. In the present study, we report our unbiased efforts to generate PDOs from a cohort of 81 PCa specimens with diverse pathological and clinical features. We comprehensively analyzed histological features of each enrolled sample (Gleason score, tumor content, proliferation index) and correlated them with organoid growth patterns. We identified improved culture conditions favoring the generation of PCa organoids, yet no specific intrinsic tumor feature was broadly associated with sustained organoid growth. In addition, we performed phenotypic and molecular characterization of tumor-organoid pairs using immunohistochemistry, immunofluorescence, fluorescence in situ hybridization, and targeted sequencing. Morphological and immunohistochemical profiles of whole organoids altogether provided a fast readout to identify the most promising ones. Notably, primary samples were associated with an initial take-rate of 83% (n = 60/72) in culture, with maintenance of cancer cells displaying common PCa alterations, such as PTEN loss and ERG overexpression. These cancer organoids were, however, progressively overgrown by organoids with a benign-like phenotype. Finally, out of nine metastasis samples, we generated a novel organoid model derived from a hormone-naïve lung metastasis, which displays alterations in the PI3K/Akt and Wnt/β-catenin pathways and responds to androgen deprivation. Taken together, our comprehensive study explores determinants of outcome and highlights the opportunities and challenges associated with the establishment of stable tumor organoid lines derived from PCa patients. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361965PMC
August 2021

Dimensionality-Induced Change in Topological Order in Multiferroic Oxide Superlattices.

Phys Rev Lett 2021 Apr;126(15):157601

School of Applied and Engineering Physics, Cornell University, Ithaca, New York 14853, USA.

We construct ferroelectric (LuFeO_{3})_{m}/(LuFe_{2}O_{4}) superlattices with varying index m to study the effect of confinement on topological defects. We observe a thickness-dependent transition from neutral to charged domain walls and the emergence of fractional vortices. In thin LuFeO_{3} layers, the volume fraction of domain walls grows, lowering the symmetry from P6_{3}cm to P3c1 before reaching the nonpolar P6_{3}/mmc state, analogous to the group-subgroup sequence observed at the high-temperature ferroelectric to paraelectric transition. Our study shows how dimensional confinement stabilizes textures beyond those in bulk ferroelectric systems.
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http://dx.doi.org/10.1103/PhysRevLett.126.157601DOI Listing
April 2021

A Prospective Diet-Wide Association Study for Risk of Colorectal Cancer in EPIC.

Clin Gastroenterol Hepatol 2021 Apr 24. Epub 2021 Apr 24.

Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background & Aims: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk.

Methods: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci.

Results: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04-1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04-1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93-0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90-0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90-0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92-0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93-0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons.

Conclusions: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.
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http://dx.doi.org/10.1016/j.cgh.2021.04.028DOI Listing
April 2021

Soft Drink and Juice Consumption and Renal Cell Carcinoma Incidence and Mortality in the European Prospective Investigation into Cancer and Nutrition.

Cancer Epidemiol Biomarkers Prev 2021 06 13;30(6):1270-1274. Epub 2021 Apr 13.

International Agency for Research on Cancer (IARC-WHO), Lyon, France.

Background: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991-2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks.

Results: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97-1.09), total soft drinks (HR = 1.01; 95% CI, 0.98-1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94-1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96-1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97-1.16; 1.03, 0.98-1.09; 0.97, 0.89-1.07; and 1.06, 0.99-1.14, respectively).

Conclusions: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity.

Impact: Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611361PMC
June 2021

Interaction of Alkali Ions with Flavins: Infrared and Optical Spectra of Metal-Riboflavin Complexes.

J Phys Chem A 2021 Apr 8;125(15):3146-3158. Epub 2021 Apr 8.

Institut für Optik und Atomare Physik, Technische Universität Berlin, Hardenbergstr. 36, D-10623 Berlin, Germany.

Flavin compounds are of great interest in biochemistry because of their diverse functions in catalytic and photochemical processes. The intrinsic optical properties of flavins depend sensitively on their environment such as complexation with metal ions. Herein, we characterize the interaction of alkali metal ions (M) with riboflavin (RF, vitamin B). To this end, two different experimental spectroscopic approaches are employed to determine the structural, vibrational, energetic, and optical properties of MRF complexes by comparison with density functional theory (DFT) calculations at the PBE0/cc-pVDZ level. First, infrared multiple photon dissociation (IRMPD) spectra recorded at room temperature demonstrate that M binds to one of the two available nucleophilic carbonyl groups (CO2, CO4) of RF, denoted O2 and O4+ isomers, as revealed by characteristic shifts of the CO stretch modes upon metalation. Second, the optical spectrum of KRF is recorded between 428 and 529 nm in a cryogenic ion trap held at 6 K by visible photodissociation (VISPD). Analysis of the VISPD spectrum by time-dependent DFT calculations coupled to Franck-Condon simulations demonstrates that in fact only the O2 isomer of MRF is formed by electrospray ionization, while the spectroscopic signatures of the O4+ isomer are absent. The VISPD spectrum is attributed to the S ← S (ππ*) transition of the O2 isomer, which is calculated to be much more stable than the O4+ isomer because of additional multiple interactions of M with the OH groups of the ribityl (sugar) side chain attached at N10 of RF. In contrast, there is no evidence for the presence of the O4+ isomer, in which M forms a chelate complex, with M binding to both O4 and N5. A comparison between RF (ribityl at N10) and lumiflavin (LF and CH at N10) reveals the drastic effects of the side chain on the structural, energetic, and optical properties of the flavin interaction with metal ions. While for MLF the O2 and O4+ isomers are close in energy and both observed experimentally, for MRF the O2 isomer is strongly favored due to the additional interaction with the side chain. Although the S energies of MRF(O2) and MLF(O2) are quite similar, because the ππ* transition is localized on the same isoalloxazine chromophore for both flavins, the vibrational structures are strongly different because the soft bending potential for the M···flavin interaction is strongly affected by the ribityl side chain at N10. In contrast to HRF, which prefers protonation at N1, steric repulsion of the larger M ions with the ribityl side chain prevents metalation at N1, leading to the formation of the O2 global minimum.
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http://dx.doi.org/10.1021/acs.jpca.1c01846DOI Listing
April 2021

A comparison of complementary measures of vitamin B6 status, function, and metabolism in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Am J Clin Nutr 2021 07;114(1):338-347

Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.

Background: Vitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5'-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health.

Objectives: We explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics.

Medthods: Dietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP.

Results: In total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers.

Conclusions: We found that 5 different markers, capturing different aspects of vitamin B6-related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors.
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http://dx.doi.org/10.1093/ajcn/nqab045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246608PMC
July 2021

Paced or sensed conduction time to determine programming with cardiac resynchronization therapy: The PASED-CRT Trial.

Pacing Clin Electrophysiol 2021 Jun 7;44(6):967-972. Epub 2021 May 7.

Deborah Heart & Lung Center, Browns Mills, New Jersey, USA.

Background: Cardiac resynchronization therapy (CRT) is a well-established treatment for patients with drug refractory heart failure.

Objectives: This study sought to compare the longest RV to LV activation time (sLAT) versus the longest RV to LV activation time (pLAT) as the programmed site for left ventricular (LV) pacing in CRT patients with quadripolar LV leads at 3 months.

Methods: This single site, double-blinded, prospective trial, randomized patients 1:1 into the sLAT or pLAT group to determine response. LV pacing was programmed at implant and maintained through 3 months of follow-up. The 6-minute hall walk (6MHW) test, NYHA, Minnesota living with heart failure, and clinical composite score (CCS) at the 3 months was compared.

Results: N = 92 patients (73M:19F age 66 ± 11.3 years) were randomized implanted and programmed per protocol. Baseline characteristics were comparable. N = 39 sLAT and N = 34 pLAT completed the 3-month visit for final analysis. Significant improvement from baseline to 3 months was seen in the sLAT group from 253.9 (+/-11.5) to 323.1 (+/-11.9) P = .001. Similarly, the pLAT group improved from 274.9 (+/-16.15) to 343.9 (+/-15.9) P = .003. The difference between these groups, however, did not reach significance (P = .86). The pLAT group demonstrated a higher responder rate of (71%) versus the sLAT group (64%) based on the CCS although not reaching significance (P = .56).

Conclusions: Use of both the pLAT and sLAT method of programming demonstrated significant improvement in 6MHW distance at 3 months with pLAT demonstrating a slightly higher responder rate based on CCS (P = .56). pLAT should be considered at minimum as equivalent in patients with no intrinsic conduction.
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http://dx.doi.org/10.1111/pace.14212DOI Listing
June 2021

Phosphorylation of the MNK1 substrate eIF4E is not required for response to acute pancreatitis.

Pancreatology 2021 Jun 19;21(4):677-681. Epub 2021 Feb 19.

INSERM UMR-1037, Université de Toulouse, Centre de Recherches en Cancérologie de Toulouse (CRCT), Equipe Labellisée Ligue Contre le Cancer, Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Toulouse, France. Electronic address:

Background: The MNK1 protein kinase is directly activated by the MAPK pathway and is specifically expressed in pancreatic acinar cells. Both the MNK1 kinase and the MAPK pathway are required for response to pancreatitis, suggesting that their pharmacological targeting would be of therapeutic interest. Because the mRNA cap-binding protein and translation initiation factor eIF4E is the major known MNK1 substrate, one could anticipate that the protective function of MNK1 in pancreatitis is mediated by eIF4E phosphorylation.

Methods: Acute pancreatitis was induced by the intraperitoneal administration of cerulein in wild-type mice and in transgenic mice carrying two non-phosphorylatable Eif4e alleles. The expression and phosphorylation of proteins of the MNK1-eIF4E pathway was visualized by western-blotting. The severity of pancreatitis was monitored by the measure of serum amylase levels and by histopathology and immunohistochemistry using apoptosis and immune infiltrate markers.

Results: Despite a strong induction in MNK1 kinase activity in both wild-type and transgenic mice, precluding eIF4E phosphorylation has no impact on the severity of acute pancreatitis. Serum amylase is equally induced in both mouse genotypes and neither acinar cell apoptosis nor immune infiltrate is exacerbated.

Conclusion: eIF4E phosphorylation is not required for response to pancreatitis indicating that the acinar-cell-specific MNK1 kinase acts in acute pancreatitis via another substrate.
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http://dx.doi.org/10.1016/j.pan.2021.02.013DOI Listing
June 2021

An all-epitaxial nitride heterostructure with concurrent quantum Hall effect and superconductivity.

Sci Adv 2021 Feb 19;7(8). Epub 2021 Feb 19.

Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA.

Creating seamless heterostructures that exhibit the quantum Hall effect and superconductivity is highly desirable for future electronics based on topological quantum computing. However, the two topologically robust electronic phases are typically incompatible owing to conflicting magnetic field requirements. Combined advances in the epitaxial growth of a nitride superconductor with a high critical temperature and a subsequent nitride semiconductor heterostructure of metal polarity enable the observation of clean integer quantum Hall effect in the polarization-induced two-dimensional (2D) electron gas of the high-electron mobility transistor. Through individual magnetotransport measurements of the spatially separated GaN 2D electron gas and superconducting NbN layers, we find a small window of magnetic fields and temperatures in which the epitaxial layers retain their respective quantum Hall and superconducting properties. Its analysis indicates that in epitaxial nitride superconductor/semiconductor heterostructures, this window can be significantly expanded, creating an industrially viable platform for robust quantum devices that exploit topologically protected transport.
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http://dx.doi.org/10.1126/sciadv.abf1388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895435PMC
February 2021

Large Single Crystals of Two-Dimensional π-Conjugated Metal-Organic Frameworks via Biphasic Solution-Solid Growth.

ACS Cent Sci 2021 Jan 8;7(1):104-109. Epub 2020 Dec 8.

Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

Two-dimensional (2D) π-conjugated metal-organic frameworks (πMOFs) are a new class of designer electronic materials that are porous and tunable through the constituent organic molecules and choice of metal ions. Unlike typical MOFs, 2D πMOFs exhibit high conductivity mediated by delocalized π-electrons and have promising applications in a range of electrical devices as well as exotic physical properties. Here, we develop a growth method that generates single-crystal plates with lateral dimensions exceeding 10 μm, orders of magnitude bigger than previous methods. Synthesis of large single crystals eliminates a significant impediment to the fundamental characterization of the materials, allowing determination of the intrinsic conductivity and mobility along the 2D plane of πMOFs. A representative 2D πMOF, Ni-CAT-1, exhibits a conductivity of up to 2 S/cm, and Hall measurement reveals the origin of the high conductivity. Characterization of crystalline 2D πMOFs creates the foundation for developing electronic applications of this promising and highly diverse class of materials.
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http://dx.doi.org/10.1021/acscentsci.0c01488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844853PMC
January 2021

Sexual dimorphism in cancer: insights from transcriptional signatures in kidney tissue and renal cell carcinoma.

Hum Mol Genet 2021 04;30(5):343-355

Section of Genetics, International Agency for Research on Cancer (IARC-WHO), 69372 Lyon, France.

Sexual dimorphism in cancer incidence and outcome is widespread. Understanding the underlying mechanisms is fundamental to improve cancer prevention and clinical management. Sex disparities are particularly striking in kidney cancer: across diverse populations, men consistently show unexplained 2-fold increased incidence and worse prognosis. We have characterized genome-wide expression and regulatory networks of 609 renal tumors and 256 non-tumor renal tissues. Normal kidney displayed sex-specific transcriptional signatures, including higher expression of X-linked tumor suppressor genes in women. Sex-dependent genotype-phenotype associations unraveled women-specific immune regulation. Sex differences were markedly expanded in tumors, with male-biased expression of key genes implicated in metabolism, non-malignant diseases with male predominance and carcinogenesis, including markers of tumor infiltrating leukocytes. Analysis of sex-dependent RCC progression and survival uncovered prognostic markers involved in immune response and oxygen homeostasis. In summary, human kidney tissues display remarkable sexual dimorphism at the molecular level. Sex-specific transcriptional signatures further shape renal cancer, with relevance for clinical management.
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http://dx.doi.org/10.1093/hmg/ddab031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098110PMC
April 2021
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