bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of Curvature Improvement in Men with Peyronie's Disease Treated with Intralesional Collagenase Clostridium Histolyticum
Authors: Flores Jose M. , Nascimento Bruno , Punjani Nahid , Salter Carolyn A. , Bernie Helen L. , Taniguchi Hisanori , Miranda Eduardo , Terrier Jean-Etienne , Schofield Elizabeth , Jenkins Lawrence , Mulhall John P.
Published: September 2022

Introduction

Penile curvature is the most common abnormality that is observed by men with Peyronie's disease (PD). Collagenase Clostridium histolyticum (CCH) has become a standard treatment for PD patients.

Aim

To identify predictor factors associated with improvements of penile curvature outcomes in men with PD treated with CCH.

Methods

We retrospectively collected the data of patients with PD treated with CCH up to 8 injections divided into 4 cycles between January 2014 and July 2020. Per protocol, penile curvature was assessed at baseline, and after the second and ford CCH cycle. If after cycle 2, curvature demonstrated no improvement, or penile curvature was significantly improved and the patient was happy, no further treatment was recommended. However, if penile curvature was significantly improved and the patient remained dissatisfied, 4 cycles were completed. Three categories of response were evaluated: improvement (≥10 degrees or ≥20%, either 1 happens), unchanged (±10 degrees or ±20%) or worsened (≥10 degrees or ≥20%, either 1 happens). Logistic regression analyses were performed to evaluate predictive factors associated with penile curvature improvements.

Outcomes

Degrees of the curvature changes between the baseline and after the cycles of CCH.

Results

A total of 114 patients underwent CCH treatment. Median age was 57 years. Median PD duration was 11 months. At baseline, mean curvature was 47 degrees, 65% had dorsal curvature, 53% mid-shaft location, and 15% calcification. After CCH treatment, the mean final curvature was 40 degrees. A total of 44% improved the curvature, 39% had no change while 17% worsened after CCH treatment. Of men who had penile curvature improvement with CCH treatment, the mean curvature decreasing in degrees and percentage were 22 degrees and 41%, respectively. Men with baseline curvature ≤ 30, 31–59, and ≥ 60 degrees, the percentage curvature improvement were 29%, 43%, and 60%, respectively. Baseline curvature was the only significant predictor of penile curvature improvement after CCH (OR 1.33, 95% CI = 1.1, 1.7).

Clinical Implications

We confirmed baseline penile curvature is the most important predictive factor, and this is the first report describing proportions of penile curvature improvement with CCH treatment.

Strengths and Limitations

This study has several strengths, including the use of validated instruments. Nonetheless, there are limitations: the retrospective nature of the study, a single institution; and modelling device was not controlled.

Conclusion

Penile curvature improvement was significantly more common in patients with greater baseline curvature, reaching up to 60% for patients with ≥ 60 degrees.
The International Law of Energy
Authors: Viñuales Jorge E.
Published: September 2022

The world's energy structure underpins the global environmental crisis and changing it will require regulatory change at a massive level. Energy is highly regulated in international law, but the field has never been comprehensively mapped. The legal sources on which the governance of energy is based are plentiful but they are scattered across a vast legal expanse. This book is the first single-authored study of the international law of energy as a whole. Written by a world-leading expert, it provides a comprehensive account of the international law of energy and analyses the implications of the ongoing energy transformation for international law. The study combines conceptual and doctrinal analysis of all the main rules, processes and institutions to consider the past, present and likely future of global energy governance. Providing a solid foundation for teaching, research and practice, this book addresses both the theory and real-world policy dimension of the international law of energy.
Reimagining the Court of Protection
Authors: Lindsey Jaime
Published: September 2022

As one of the first researchers authorised to observe hearings and access court files at the Court of Protection, Jaime Lindsey offers an original account and analysis of the workings of this court. Using data collected with the approval from the senior judiciary of the Court of Protection and the Ministry of Justice, this innovative book combines empirical data with theoretical and normative analysis. It takes a socio-legal approach to understanding how the Mental Capacity Act operates in practice to achieve access to justice and situates current debates within an international context, showing how other jurisdictions have been guided by the United Nations Convention on the Rights of Persons with Disabilities. Furthering scholarship across several fields including access to justice, healthcare law and procedural justice theory, this is a timely and pioneering book that argues for a reimagining of the Court of Protection.
Resolution Sensitivity of the GRIST Nonhydrostatic Model From 120 to 5 km (3.75 km) During the DYAMOND Winter
Authors: Zhang Yi , Li Xiaohan , Liu Zhuang , Rong Xinyao , Li Jian , Zhou Yihui , Chen Suyang
Published: September 2022

We investigated the resolution sensitivity of the Global‐to‐Regional Integrated forecast SysTem global nonhydrostatic model characterized by explicit dynamics–microphysics coupling using varying uniform resolutions (120, 60, 30, 15, and 5 km). The experiments followed the DYnamics of the Atmospheric general circulation Modeled On Non‐hydrostatic Domains (DYAMOND) winter protocol, which covers a 40‐day integration. These simulations did not activate parameterized convection. One 120 km test with parameterized convection was performed as a coarse‐resolution reference. Other model configurations for different simulations were kept as consistent as possible. Our results showed that the model gradually improved its representation of the fine‐scale features as the resolution increased. The 5 km simulation was overall close to a 3.75 km simulation during the first 12 days of the DYAMOND winter. With respect to the mean climate, the 5 km simulation had a more realistic rainfall distribution than the lower resolution explicit convection simulations. Cloud water and the related physical fields (e.g., shortwave cloud radiative forcing) had a large resolution sensitivity. The tropical rainfall frequency–intensity spectra became more realistic in the 5 km explicit convection simulation, but the 120 km run with parameterized convection showed a more realistic mean climate. As the resolution increases, the mean bulk effect of finely resolved model convection gradually converges to that of parameterized convection. The mean climate of this storm‐resolving model has slightly higher rainfall biases than a parameterized convection coarse‐resolution model, highlighting the importance of balancing resolved‐ and under‐resolved model convection for developing a unified multiscale global model.
Early Life Learned to Love Oxygen Long Before It Was Cool
Authors: Schmidt Jennifer
Published: September 2022

Laboratory experiments show that earthquakes may have helped early life evolve in an oxygen-free world.
Protecting the Mountain Water Towers of Spain’s Sierra Nevada
Authors: Biddanda Bopaiah , Villar-Argaiz Manuel , Medina-S�nchez Juan
Published: September 2022

Students and community members monitor the health of mountain water reserves, which capture and release water, evening out wet and dry periods downstream.
The Contribution of Vegetation‐Climate Feedback and Resultant Sea Ice Loss to Amplified Arctic Warming During the Mid‐Holocene
Authors: Chen Jie , Zhang Qiong , Kjellström Erik , Lu Zhengyao , Chen Fahu
Published: September 2022

Understanding influence of vegetation on past temperature changes in the Arctic region would help isolate uncertainty and build understanding of its broader climate system, with implications for paleoclimate reconstructions and future climate change. Using an Earth system model EC‐Earth, we conduct a series of simulations to investigate the impact of vegetation‐climate feedback on the Arctic climate during the mid‐Holocene. Results show Arctic greening induced by the warming resulting from stronger orbital forcing, further amplifies the Arctic warming. The increased vegetation contributes 0.33°C of Arctic warming and 0.35 × 106 km2 of Arctic sea ice loss. Increased Arctic vegetation leads to reduced land surface albedo and increased evapotranspiration, both of which cause local warming in spring and summer. The resultant sea ice loss causes warming in the following seasons, with atmospheric circulation anomalies further amplifying the warming. Our results highlight the significant contribution of vegetation‐climate feedback to Arctic climate under natural conditions.
Northward Shift of the Northern Hemisphere Westerlies in the Early to Late Miocene and Its Links to Tibetan Uplift
Authors: Tang Yi , Wan Shiming , Clift Peter D. , Zhao Debo , Xu Zhaokai , Zhang Jin , Song Zehua , Jin Hualong , Li Mengjun , Shi Xuefa , Li Anchun
Published: September 2022

Despite the importance of the westerlies to the global climate system, we still know little about their long‐term evolution and possible orographic controls during the late Cenozoic because of the lack of sedimentary records with precise chronological control. Eolian deposition in the North Pacific preserved past information about the westerlies, the major wind system delivering Asian dust to the Pacific. A continuous, high‐resolution eolian flux record since 23 Ma was reconstructed from sediments at Deep Sea Drilling Project Site 296 in the North Pacific. Combined with dust flux at Ocean Drilling Program Site 1208, variations in their difference indicated a northwards shift of the westerlies during 23‒9 Ma and a relatively stable state since then. We suggest that Tibetan uplift since the early Miocene began to drive the poleward shift of the westerlies until 9 Ma, after which the westerlies remained relatively stable over Asia on million‐year timescales.
Response of Anthropogenic Volatile Organic Compound Emissions to Urbanization in Asia Probed With TROPOMI and VIIRS Satellite Observations
Authors: Pu Dongchuan , Zhu Lei , De Smedt Isabelle , Li Xicheng , Sun Wenfu , Wang Dakang , Liu Song , Li Juan , Shu Lei , Chen Yuyang , Sun Shuai , Zuo Xiaoxing , Fu Weitao , Xu Peng , Yang Xin , Fu Tzung‐May
Published: September 2022

Emissions of air pollutants and their precursors in urban air closely relate to urbanization involving economic development, population growth, and industrialization. Here we use formaldehyde (HCHO) columns from the TROPOspheric Monitoring Instrument (TROPOMI), night‐time light (NTL) radiance from the Visible Infrared Imaging Radiometer Suite, and population density data as respective proxies to explore how anthropogenic non‐methane volatile organic compound (NMVOC) emissions evolve with urbanization in Asia. HCHO columns correlate moderately to highly (0.64 ≤ r ≤ 0.99) with the NTL radiance within most major Asian countries. On both national (across Asia) and provincial scales (within China), HCHO columns increase monotonically with NTL radiance or population density with a log‐linear pattern, implying anthropogenic NMVOC emissions in Asia may similarly respond to urbanization with no apparent turnover yet. Our study confirms TROPOMI HCHO columns as a proxy of anthropogenic NMVOC emissions.
Hysteresis Behaviors in East Asian Extreme Precipitation Frequency to CO2 Pathway
Authors: Jo Seo‐Young , Seong Min‐Gyu , Min Seung‐Ki , Kug Jong‐Seong , Yeh Sang‐Wook , An Soon‐Il , Son Seok‐Woo , Shin Jongsoo
Published: September 2022

Understanding regional hydro‐climatic extreme responses to CO2 pathways is fundamental to climate change mitigation and adaptation. This study evaluates responses of extreme precipitation frequency (R30mm: days with precipitation ≥30 mm) over East Asia to idealized CO2 forcing using the Community Earth System Model (CESM1). Under a symmetric increase (ramp‐up, +1% per year until quadrupling level) and decrease (ramp‐down, about −1% per year back to the present level) of CO2 concentrations, East Asian R30mm shows an asymmetric response with higher frequency during the ramp‐down period. This hysteresis behavior is found to be due to a northwestward propagating wave response to the El Niño‐like warming, which induces a three‐cell (positive‐negative‐positive) R30mm difference pattern from central equatorial Pacific to East Asia. Monthly analysis further reveals that this asymmetry has a seasonal locking, occurring during July–September only, constrained by the background precipitation climatology over the sub‐tropical western Pacific.
A Scalable Framework for Post Fire Debris Flow Hazard Assessment Using Satellite Precipitation Data
Authors: Orland Elijah , Kirschbaum Dalia , Stanley Thomas
Published: September 2022

Wildfire is a global phenomenon that has dramatic effects on erosion and flood potential. On steep slopes, burned areas are more likely to experience significant overland flow during heavy rainfall leading to post fire debris flows (PFDFs). Previous work establishes methods for PFDF hazard assessment, often relying on regional‐scale parameterizations with in‐situ rainfall measurements to categorize hazard as a function of meteorological and surface properties. We present a globally scalable approach to extend the benefit these models provide to new areas. Our new model relies on publicly available satellite‐based inputs with a global extent to provide first order hazard assessments of recently burned areas. Our results show it is possible to identify the conditions relevant for PFDF‐initiation processes across a variety of physiographic settings. Improvements to satellite‐borne rainfall intensity data and increased availability of PFDF occurrence data worldwide are expected to enhance model skill and applicability further.
Determining Variability in Arctic Sea Ice Pressure Ridge Topography With ICESat‐2
Authors: Duncan K. , Farrell S. L.
Published: September 2022

We investigate the characteristics and distribution of pressure ridges in Arctic sea ice using a novel algorithm applied to ICESat‐2 surface heights. We derive the frequency and height of individual pressure ridges and map surface roughness and ridging intensity at the basin scale over three winters between 2019 and 2021. Comparisons with near‐coincident airborne lidar data show that not only can we detect individual ridges 5.6 m wide, but also measure sail height more accurately than the existing ICESat‐2 sea ice height product. We find large regional variability in ridge morphology not only related to parent ice type but also geographic location. Ridge sails are best represented by log‐normal distributions while surface roughness is well fit by an exponential normal function. Our results reveal that high‐resolution satellite altimetry is valuable for characterizing sea ice deformation at short length‐scales and delivers observations that will advance ridging parameterizations in sea ice models.
First Lidar Profiling of Meteoric Ca+ Ion Transport From ∼80 to 300 km in the Midlatitude Nighttime Ionosphere
Authors: Jiao Jing , Chu Xinzhao , Jin Han , Wang Zelong , Xun Yuchang , Du Lifang , Zheng Haoran , Wu Fuju , Xu Jiyao , Yuan Wei , Yan Chunxiao , Wang Jihong , Yang Guotao
Published: September 2022

We report a world record of lidar profiling of metallic Ca+ ions up to 300 km in the midlatitude nighttime ionosphere during geomagnetic quiet time. Ca+ measurements (∼80–300 km) were made over Beijing (40.42°N, 116.02°E) with an Optical‐Parametric‐Oscillator‐based lidar from March 2020 through June 2021. Main Ca+ layers (80–100 km) persist through all nights, and high‐density sporadic Ca+ layers (∼100–120 km) frequently occur in summer. Thermosphere‐ionosphere Ca+ (TICa+) layers (∼110–300 km) are likely formed via Ca+ uplifting from these sporadic layers. The lidar observations capture the complete evolution of TICa+ layers from onset to ending, revealing intriguing features. Concurrent ionosonde measurements show strong sporadic E layers developed before TICa+ and spread F onset. Neutral winds can partially account for observed vertical transport but enhanced electric fields are required to explain the results. Such lidar observations promise new insights into E‐ and F‐region coupling and plasma inhomogeneities.
A 2D Kaleidoscope of Electron Heat Fluxes Driven by Auroral Electron Precipitation
Authors: Khazanov George V. , Gabrielse Christine , Glocer Alex , Chu Mike , Nishimura Yukitoshi , Reyes Pablo
Published: September 2022

Electron heat flux is an important value for ionospheric space weather modeling networks. Utilizing the 2D array of Time History of Events and Macroscale Interactions during Substorms all‐sky‐imager (ASI) observations, Gabrielse et al. (2021, https://doi.org/10.3389/fphy.2021.744298) described a new method that estimates the auroral scale sizes of intense precipitating electron energy fluxes and their mean energies during two substorms on 16 February 2010. These parameters in combination with SuperThermal Electron Transport code were used to develop a new methodology to calculate electron thermal fluxes from data inputs in 2D during one of the substorms at 09:40:00 UT across Canada and Alaska. To test the effect of various precipitation lifetimes on electron heat flux values, boxcar averages ranging from 0 to 900 s were applied to the ASI data. These data are then combined with the newly developed kinetic simulation to determine the thermal fluxes associated with the observed diffuse and discrete precipitation.
Evidence of Strong Upper Oceanic Crustal Hydration Outboard the Alaskan and Sumatran Subduction Zones
Authors: Acquisto Tanner , Bécel Anne , Singh Satish C. , Carton Hélène
Published: September 2022

The hydration state of subducting oceanic crust has been proposed to influence subduction zone processes like seismic coupling at the megathrust interface and arc magmatism downdip. Plate bending in the outer rise region is thought to help rehydrate the incoming oceanic lithosphere before subduction. Although numerous seismic refraction studies provide constraints on the amount of water stored in the lower crust and uppermost mantle, little information exists about how much free water is present in the upper 1–2 km of oceanic crust. Here, we present results from the application of advanced techniques to long‐offset multi‐channel seismic data acquired outboard the Alaskan and South Sumatran subduction zones. Our results show that the incoming upper crustal seismic layer, layer 2A, is significantly hydrated in both areas. Favorable conditions offshore the Alaska Peninsula promote the creation of a dense system of bending‐related faults, facilitating the infiltration of fluids that increases average water estimates to ∼3.9 wt.% H2O in the outer rise. As the crust subducts and temperature increases, some free water may react with the host rocks to form mineral‐bound water that is carried to greater depths, in agreement with elevated water contents found in arc lavas of Shumagin Gap volcanoes. Offshore Sumatra, we propose that similar layer 2A water estimates (∼3.2 wt.% H2O average) and heterogeneous hydration within 2B are associated with the ongoing, slow, complex deformation occurring in the Wharton Basin and thus potentially contribute to the presence of a long‐lived slow slip event recently inferred there at seismogenic depths.
Investigation of the Convection‐Allowing Prediction Error of an Extreme Precipitation Event of China Using CRTM‐Simulated Brightness Temperature
Authors: Yang Nan , Zhu Kefeng , Xue Ming
Published: September 2022

An extreme rainfall case occurred on 20 July 2016 in northern China, producing over 600 mm of maximum 24 hr accumulated rainfall. The case is characterized by low‐echo centroid (LEC) based on radar observations. It is simulated by Weather Research and Forecasting model at 4 km grid spacing using the Morrison two‐moment microphysics scheme. Infrared brightness temperature (BT) simulated using a radiative transfer model together with simulated reflectivity are used to evaluate the simulated cloud structures. In general, the model predicts the rainfall amount, location, and propagation well. However, it fails to accurately predict the three‐dimensional cloud structures. The predicted convective cores (>35 dBZ) are higher than the freezing level, suggesting the presence of active cold‐cloud processes while the observed LEC suggests that warm‐cloud processes dominate. The simulation also produces too many upper level clouds and over‐predicts the fractions of overshooting clouds, resulting great over‐prediction of cloud top height (CTH). Additionally, the sensitivity of simulated BT to predicted cloud properties including CTH, cloud species and hydrometeor effective radii are examined to better understand the sources of error in simulated BT. Among those factors, CTH is found to be most critical to BT simulation. For every kilometer of CTH over‐prediction, there is about 6.431 K of negative BT bias owing to the lapse rate and the absorption and scattering effects of cloud particles. For most cloudy regions, cloud ice dominates the effect on simulated BT. Using diagnosed effective radii of simulated hydrometeors within the radiative transfer model results in small improvement to the BT simulation.
Determination of Broadband Complex EM Parameters of Powdered Materials: 1. MCMC‐Based Two‐Port Transmission Line Measurements
Authors: Boivin A. L. , Tsai C.‐A. , Hickson D. C. , Ghent R. R. , Daly M. G.
Published: September 2022

We propose a Bayesian Markov Chain Monte Carlo parameter estimation technique to determine frequency‐dependent complex dielectric permittivity and permeability of powdered planetary regolith analog materials from coaxial transmission line measurements. The technique uses either a flat (non‐dispersive) or a generalized dielectric response model to simultaneously determine the complex permittivity and permeability from measured scattering parameters. By exploring the parameter space, the technique reduces the dependence on good initial model parameters required by typical optimization methods. The technique can be used with either two‐port measurements or shorted measurements, where an additional one‐port shorted sample is measured. We find the technique is able to accurately determine electromagnetic parameters of low‐loss, high dielectric, and magnetic materials. The technique is also robust to half‐wavelength resonances in the sample as well as the presence of higher order modes.
Tectono‐Stratigraphic Evolution of the Foreland Fold‐and‐Thrust Belt of the United Arab Emirates
Authors: Abdelmaksoud A. , Ali M. Y. , Searle M. P.
Published: September 2022

The subsurface and surface structural geometries of the United Arab Emirates (UAE) fold‐and‐thrust belt (FTB) and foreland basins are interpreted from seismic, well data, and surface geology. Twelve horizons ranging in age from Miocene to Lower Jurassic were interpreted and mapped. Additionally, we outlined subsurface extent of Sumeini and Hawasina allochthonous nappes. The tectonic subsidence curves suggest that the final major passive margin rifting event occurred in the early Aalenian and lasted till Oxfordian. Loading of the Semail ophiolite thrust sheet and accompanying allochthonous thrust sheets resulted in uplift at ca. 95 Ma and rapid subsidence at ca. 83 Ma, indicating the transition of the Arabian margin from a rifted passive margin to a foreland basin. The region witnessed an accelerated subsidence during the late Oligocene‐Miocene, attributed to the initial collision of the Central Iran and Arabian plates. The Permian‐Jurassic NW‐SE oriented rift faults were reactivated as thrust faults during the Late Cretaceous ophiolite obduction and late Oligocene‐Miocene continental collision. Two different tectonic regimes are identified in the FTB. The northern regime is characterized by major inversion of the rift faults with up to 3,700 m throw, whereas the southern regime has a major pop‐up structure with possible basement origin. Four major west‐verging and east‐dipping thrusts, which cross the northern area, form fault‐propagation folds and dissect the entire stratigraphy. Moreover, the Hawasina décollement, together with the inverted basement structures formed the Jabal Hafit anticline as a backthrust structure.
PFKFB4 interacts with FBXO28 to promote HIF-1α signaling in glioblastoma
Authors: Phillips Emma , Balss Jörg , Bethke Frederic , Pusch Stefan , Christen Stefan , Hielscher Thomas , Schnölzer Martina , Fletcher Michael N. C. , Habel Antje , Tessmer Claudia , Brenner Lisa-Marie , Göttmann Mona , Capper David , Herold-Mende Christel , von Deimling Andreas , Fendt Sarah-Maria , Goidts Violaine
Published: September 2022

Glioblastoma is a highly aggressive brain tumor for which there is no cure. The metabolic enzyme 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is essential for glioblastoma stem-like cell (GSC) survival but its mode of action is unclear. Understanding the role of PFKFB4 in tumor cell survival could allow it to be leveraged in a cancer therapy. Here, we show the importance of PFKFB4 for glioblastoma growth in vivo in an orthotopic patient derived mouse model. In an evaluation of patient tumor samples of different cancer entities, PFKFB4 protein was found to be overexpressed in prostate, lung, colon, mammary and squamous cell carcinoma, with expression level correlating with tumor grade. Gene expression profiling in PFKFB4-silenced GSCs revealed a downregulation of hypoxia related genes and Western blot analysis confirmed a dramatic reduction of HIF (hypoxia inducible factor) protein levels. Through mass spectrometric analysis of immunoprecipitated PFKFB4, we identified the ubiquitin E3 ligase, F-box only protein 28 (FBXO28), as a new interaction partner of PFKFB4. We show that PFKFB4 regulates the ubiquitylation and subsequent proteasomal degradation of HIF-1α, which is mediated by the ubiquitin ligase activity of FBXO28. This newly discovered function of PFKFB4, coupled with its cancer specificity, provides a new strategy for inhibiting HIF-1α in cancer cells.
Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective
Authors: Yang Yang , Li Shuo , Wang Yujiao , Zhao Yi , Li Qiu
Published: September 2022

Protein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation of PTKs caused by various factors can deviate cell function from the expected trajectory to an abnormal growth state, leading to carcinogenesis. Inhibiting the aberrant PTK function could inhibit tumor growth. Therefore, tyrosine kinase inhibitors (TKIs), target-specific inhibitors of PTKs, have been used in treating malignant tumors and play a significant role in targeted therapy of cancer. Currently, drug resistance is the main reason for limiting TKIs efficacy of cancer. The increasing studies indicated that tumor microenvironment, cell death resistance, tumor metabolism, epigenetic modification and abnormal metabolism of TKIs were deeply involved in tumor development and TKI resistance, besides the abnormal activation of PTK-related signaling pathways involved in gene mutations. Accordingly, it is of great significance to study the underlying mechanisms of TKIs resistance and find solutions to reverse TKIs resistance for improving TKIs efficacy of cancer. Herein, we reviewed the drug resistance mechanisms of TKIs and the potential approaches to overcome TKI resistance, aiming to provide a theoretical basis for improving the efficacy of TKIs.
Risk of developing a second primary cancer in male breast cancer survivors: a systematic review and meta-analysis
Authors: Allen Isaac , Hassan Hend , Sofianopoulou Eleni , Eccles Diana , Turnbull Clare , Tischkowitz Marc , Pharoah Paul , Antoniou Antonis C.
Published: September 2022

Background

With increasing survival after cancer diagnoses, second primary cancers (SPCs) are becoming more prevalent. We investigated the incidence and site of non-breast SPC risks following male breast cancer (BC).

Methods

PubMed, Embase and Web of Science were systematically searched for studies reporting standardised incidence ratios (SIRs) for SPCs published by March 2022. Meta-analyses used the generic inverse-variance method, assuming a random-effects model. We evaluated SIRs for overall SPCs, site-specific risks, by age at BC onset, time since BC onset and geographic region. We assessed study quality using routine techniques.

Results

Eight population-based retrospective cohort studies were identified. SIRs ranged from 1.05 to 2.17. The summary SIR estimate was 1.27 (95% CI: 1.03–1.56,I2: 86%), and there were increased colorectal (SIR: 1.29, 95% CI: 1.03–1.61), pancreatic (SIR: 1.64, 95% CI: 1.05–2.55) and thyroid (SIR: 5.58, 95% CI: 1.04–30.05) SPC risks. When an outlying study was excluded, the summary SIR for men diagnosed with BC before age 50 was 1.50 (95% CI: 1.21–1.85), significantly higher than men diagnosed at older ages (SIR: 1.14, 95% CI: 0.98–1.33).

Conclusions

Male BC survivors are at elevated risks of developing second primary colorectal, pancreatic and thyroid cancers. The estimates may assist their clinical management and guide decisions on genetic testing.
Sensitisation of cancer cells to radiotherapy by serine and glycine starvation
Authors: Falcone Mattia , Uribe Alejandro Huerta , Papalazarou Vasileios , Newman Alice C. , Athineos Dimitris , Stevenson Katrina , Sauvé Charles-Etienne Gabriel , Gao Yajing , Kim Jin K. , Del Latto Michael , Kierstead Maria , Wu Chao , Smith J. Joshua , Romesser Paul B. , Chalmers Anthony J. , Blyth Karen , Maddocks Oliver D. K.
Published: September 2022

Background

Cellular metabolism is an integral component of cellular adaptation to stress, playing a pivotal role in the resistance of cancer cells to various treatment modalities, including radiotherapy. In response to radiotherapy, cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism, we hypothesised that controlling the exogenous availability of the non-essential amino acids serine and glycine would radiosensitise cancer cells.

Methods

We exposed colorectal, breast and pancreatic cancer cell lines/organoids to radiation in vitro and in vivo in the presence and absence of exogenous serine and glycine. We performed phenotypic assays for DNA damage, cell cycle, ROS levels and cell death, combined with a high-resolution untargeted LCMS metabolomics and RNA-Seq.

Results

Serine and glycine restriction sensitised a range of cancer cell lines, patient-derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic and transcriptomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only antioxidant response and nucleotide synthesis but had a marked inhibitory effect on the TCA cycle.

Conclusion

Dietary restriction of serine and glycine is a viable radio-sensitisation strategy in cancer.
CircSEMA4B inhibits the progression of breast cancer by encoding a novel protein SEMA4B-211aa and regulating AKT phosphorylation
Authors: Wang Xuehui , Jian Wei , Luo Qifeng , Fang Lin
Published: September 2022

PI3K/AKT signaling pathway plays an important role in regulating the tumorigenesis, recurrence, and metastasis of breast cancer (BC). In this study, we discovered a circRNA with protein-coding potential, which we named circSEMA4B. CircSEMA4B could encode a novel protein, SEMA4B-211aa. Both circSEMA4B and SEMA4B-211aa were remarkably downregulated in BC tissues and cell lines. Low expression of circSEMA4B was positively associated with TNM stage, tumor size, lymph node metastasis, and distant metastasis of BC patients. The functional investigation showed that circSEMA4B and SEMA4B-211aa could significantly inhibit the proliferation and migration of BC in vivo and in vitro. Of note, SEMA4B-211aa inhibited the generation of PIP3 by binding to p85, thereby inhibiting the phosphorylation of AKT (Thr308). CircSEMA4B inhibited the phosphorylation of AKT (Ser473) through miR-330-3p/PDCD4 axis. Taken together, circSEMA4B is a novel negative regulator of PI3K/AKT signaling pathway, providing novel mechanistic insights into the underlying mechanisms of BC.
The speckle-type POZ protein (SPOP) inhibits breast cancer malignancy by destabilizing TWIST1
Authors: Wei Chunli , Liu Yun , Liu Xiaoyan , Cheng Jingliang , Fu Jiewen , Xiao Xiuli , Moses Robb E. , Li Xiaotao , Fu Junjiang
Published: September 2022

Epithelial-mesenchymal transition (EMT) inducing transcription factor TWIST1 plays a vital role in cancer metastasis. How the tumor-suppressive E3 ligase, speckle-type POZ protein (SPOP), regulates TWIST1 in breast cancer remains unknown. In this study, we report that SPOP physically interacts with, ubiquitinates, and destabilizes TWIST1. SPOP promotes K63-and K48-linked ubiquitination of TWIST1, predominantly at K73, thereby suppressing cancer cell migration and invasion. Silencing SPOP significantly enhances EMT, which accelerates breast cancer cell migration and invasiveness in vitro and lung metastasis in vivo. Clinically, SPOP is negatively correlated with the levels of TWIST1 in highly invasive breast carcinomas. Reduced SPOP expression, along with elevated TWIST1 levels, is associated with poor prognosis in advanced breast cancer patients, particularly those with metastatic triple-negative breast cancer (TNBC). Taken together, we have disclosed a new mechanism linking SPOP to TWIST1 degradation. Thus SPOP may serve as a prognostic marker and a potential therapeutic target for advanced TNBC patients.
Oocyte Casein kinase 1α deletion causes defects in primordial follicle formation and oocyte loss by impairing oocyte meiosis and enhancing autophagy in developing mouse ovary
Authors: Zhang Di , Jiang Ying , Luo Xuan , Liu Hui , Zhou Yewen , Cui Sheng
Published: September 2022

Casein kinase 1α is a member of CK1 family, which is ubiquitously expressed and plays multiple functions, including its potential roles in regulating cell division. But the functions of CK1α in mammalian oogenesis and folliculogenesis remain elusive. In this study, we assayed the cell type of CK1α expression in the developing mouse ovary and confirmed that CK1α was highly expressed in ovaries after birth. The oocyte-specific CK1α knockout (cKO) mouse model was then established by crossing Ddx4-Cre mice with Csnk1a1-floxp mice, and the effects of CK1α deletion on oogenesis and folliculogenesis were identified. The results showed that oocyte CK1α deletion impaired the progression of oocyte meiosis and primordial follicle formation during meiotic prophase I, which subsequently caused oocyte loss and mouse infertility. Further, the in vivo CK1α deletion and in vitro inhibition of CK1 activity resulted in the defects of DNA double-strand break (DSB) repair, whereas apoptosis and autophagy were enhanced in the developing ovary. These may contribute to oocyte loss and infertility in cKO mice. It is thus concluded that CK1α is essential for mouse oogenesis and folliculogenesis by involving in regulating the processes of oocyte meiosis and DNA DSB repair during meiotic prophase I of mouse oocytes. However, the related signaling pathway and molecular mechanisms need to be elucidated further.
Quantitative fragmentomics allow affinity mapping of interactomes
Authors: Gogl Gergo , Zambo Boglarka , Kostmann Camille , Cousido-Siah Alexandra , Morlet Bastien , Durbesson Fabien , Negroni Luc , Eberling Pascal , Jané Pau , Nominé Yves , Zeke Andras , Østergaard Søren , Monsellier Élodie , Vincentelli Renaud , Travé Gilles
Published: September 2022

Human protein networks have been widely explored but most binding affinities remain unknown, hindering quantitative interactome-function studies. Yet interactomes rely on minimal interacting fragments displaying quantifiable affinities. Here, we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer. We calculate interactomic distances, identify hot spots for viral interference, generate binding profiles and specificity logos, and explain selected cases by crystallographic studies. Mass spectrometry experiments on cell extracts and literature surveys show that quantitative fragmentomics effectively complements protein interactomics by providing affinities and completeness of coverage, putting a full human interactome affinity survey within reach. Finally, we show that interactome hijacking by the viral PBM of human papillomavirus E6 oncoprotein substantially impacts the host cell proteome beyond immediate E6 binders, illustrating the complex system-wide relationship between interactome and function.
Scaling behavior of electron decoherence in a graphene Mach-Zehnder interferometer
Authors: Jo M. , Lee June-Young M. , Assouline A. , Brasseur P. , Watanabe K. , Taniguchi T. , Roche P. , Glattli D. C. , Kumada N. , Parmentier F. D. , Sim H. -S. , Roulleau P.
Published: September 2022

Over the past 20 years, many efforts have been made to understand and control decoherence in 2D electron systems. In particular, several types of electronic interferometers have been considered in GaAs heterostructures, in order to protect the interfering electrons from decoherence. Nevertheless, it is now understood that several intrinsic decoherence sources fundamentally limit more advanced quantum manipulations. Here, we show that graphene offers a unique possibility to reach a regime where the decoherence is frozen and to study unexplored regimes of electron interferometry. We probe the decoherence of electron channels in a graphene quantum Hall PN junction, forming a Mach-Zehnder interferometer1,2, and unveil a scaling behavior of decay of the interference visibility with the temperature scaled by the interferometer length. It exhibits a remarkable crossover from an exponential decay at higher temperature to an algebraic decay at lower temperature where almost no decoherence occurs, a regime previously unobserved in GaAs interferometers.
Mechanistic understanding of human SLFN11
Authors: Metzner Felix J. , Wenzl Simon J. , Kugler Michael , Krebs Stefan , Hopfner Karl-Peter , Lammens Katja
Published: September 2022

Schlafen 11 (SLFN11) is an interferon-inducible antiviral restriction factor with tRNA endoribonuclease and DNA binding functions. It is recruited to stalled replication forks in response to replication stress and inhibits replication of certain viruses such as the human immunodeficiency virus 1 (HIV-1) by modulating the tRNA pool. SLFN11 has been identified as a predictive biomarker in cancer, as its expression correlates with a beneficial response to DNA damage inducing anticancer drugs. However, the mechanism and interdependence of these two functions are largely unknown. Here, we present cryo-electron microscopy (cryo-EM) structures of human SLFN11 in its dimeric apoenzyme state, bound to tRNA and in complex with single-strand DNA. Full-length SLFN11 neither hydrolyses nor binds ATP and the helicase domain appears in an autoinhibited state. Together with biochemical and structure guided mutagenesis studies, our data give detailed insights into the mechanism of endoribonuclease activity as well as suggestions on how SLFN11 may block stressed replication forks.
A randomized controlled trial of heterologous ChAdOx1 nCoV-19 and recombinant subunit vaccine MVC-COV1901 against COVID-19
Authors: Chen Chih-Jung , Yang Lan-Yan , Chang Wei-Yang , Huang Yhu-Chering , Chiu Cheng-Hsun , Shih Shin-Ru , Huang Chung-Guei , Huang Kuan-Ying A.
Published: September 2022

Heterologous prime-boost COVID-19 vaccine strategy may facilitate mass COVID-19 immunization. We reported early immunogenicity and safety outcomes of heterologous immunization with a viral vector vaccine (ChAdOx1) and a spike-2P subunit vaccine (MVC-COV1901) in a participant-blinded, randomized, non-inferiority trial (NCT05054621). A total of 100 healthy adults aged 20–70 years having the first dose of ChAdOx1 were 1:1 randomly assigned to receive a booster dose either with ChAdOx1 (n = 50) or MVC-COV1901 (n = 50) at an interval of 4–6 or 8–10 weeks. At day 28 post-boosting, the neutralizing antibody geometric mean titer against wild-type SARS-CoV-2 in MVC-COV1901 recipients (236 IU/mL) was superior to that in ChAdOx1 recipients (115 IU/mL), with a GMT ratio of 2.1 (95% CI, 1.4 to 2.9). Superiority in the neutralizing antibody titer against Delta variant was also found for heterologous MVC-COV1901 immunization with a GMT ratio of 2.6 (95% CI, 1.8 to 3.8). Both spike-specific antibody-secreting B and T cell responses were substantially enhanced by the heterologous schedule. Heterologous boosting was particularly prominent at a short prime-boost interval. No serious adverse events occurred across all groups. The findings support the use of heterologous prime-boost with ChAdOx1 and protein-based subunit vaccines.
Structural mechanism of tapasin-mediated MHC-I peptide loading in antigen presentation
Authors: Jiang Jiansheng , Taylor Daniel K. , Kim Ellen J. , Boyd Lisa F. , Ahmad Javeed , Mage Michael G. , Truong Hau V. , Woodward Claire H. , Sgourakis Nikolaos G. , Cresswell Peter , Margulies David H. , Natarajan Kannan
Published: September 2022

Loading of MHC-I molecules with peptide by the catalytic chaperone tapasin in the peptide loading complex plays a critical role in antigen presentation and immune recognition. Mechanistic insight has been hampered by the lack of detailed structural information concerning tapasin–MHC-I. We present here crystal structures of human tapasin complexed with the MHC-I molecule HLA-B*44:05, and with each of two anti-tapasin antibodies. The tapasin-stabilized peptide-receptive state of HLA-B*44:05 is characterized by distortion of the peptide binding groove and destabilization of the β2-microglobulin interaction, leading to release of peptide. Movements of the membrane proximal Ig-like domains of tapasin, HLA-B*44:05, and β2-microglobulin accompany the transition to a peptide-receptive state. Together this ensemble of crystal structures provides insights into a distinct mechanism of tapasin-mediated peptide exchange.
The immune landscape of human thymic epithelial tumors
Authors: Xin Zhongwei , Lin Mingjie , Hao Zhixing , Chen Di , Chen Yongyuan , Chen Xiaoke , Xu Xia , Li Jinfan , Wu Dang , Chai Ying , Wu Pin
Published: September 2022

Human thymic epithelial tumors (TET) are common malignancies in the anterior mediastinum with limited biological understanding. Here we show, by single cell analysis of the immune landscape, that the developmental pattern of intra-tumoral T-cells identify three types within TETs. We characterize the developmental alterations and TCR repertoires of tumor-infiltrating T cells in the context of the distinguishing epithelial tumor cell types. We demonstrate that a subset of tumor cells, featuring medullary thymic epithelial cell (TEC) phenotype and marked by KRT14/GNB3 expression, accumulate in type 1 TETs, while T-cell positive selection is inhibited. Type 2 TETs are dominated by CCL25+ cortical TEC-like cells that appear to promote T-cell positive selection. Interestingly, the CHI3L1+ medullary TEC-like cells that are the characteristic feature of type 3 TETs don’t seem to support T-cell development, however, they may induce a tissue-resident CD8+ T cell response. In summary, our work suggests that the molecular subtype of epithelial tumour cells in TETs determine their tumour immune microenvironment, thus GNB3 and CHI3L1 might predict the immunological behavior and hence prognosis of these tumours.
Growth of bilayer MoTe2 single crystals with strong non-linear Hall effect
Authors: Ma Teng , Chen Hao , Yananose Kunihiro , Zhou Xin , Wang Lin , Li Runlai , Zhu Ziyu , Wu Zhenyue , Xu Qing-Hua , Yu Jaejun , Qiu Cheng Wei , Stroppa Alessandro , Loh Kian Ping
Published: September 2022

Abstract

The reduced symmetry in strong spin-orbit coupling materials such as transition metal ditellurides (TMDTs) gives rise to non-trivial topology, unique spin texture, and large charge-to-spin conversion efficiencies. Bilayer TMDTs are non-centrosymmetric and have unique topological properties compared to monolayer or trilayer, but a controllable way to prepare bilayer MoTe2 crystal has not been achieved to date. Herein, we achieve the layer-by-layer growth of large-area bilayer and trilayer 1T′ MoTe2 single crystals and centimetre-scale films by a two-stage chemical vapor deposition process. The as-grown bilayer MoTe2 shows out-of-plane ferroelectric polarization, whereas the monolayer and trilayer crystals are non-polar. In addition, we observed large in-plane nonlinear Hall (NLH) effect for the bilayer and trilayer Td phase MoTe2 under time reversal-symmetric conditions, while these vanish for thicker layers. For a fixed input current, bilayer Td MoTe2 produces the largest second harmonic output voltage among the thicker crystals tested. Our work therefore highlights the importance of thickness-dependent Berry curvature effects in TMDTs that are underscored by the ability to grow thickness-precise layers.
Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia
Authors: Lee Seung Hyun , Kim Nayoung , Kim Minkyu , Woo Sang-Ho , Han Inhee , Park Jisu , Kim Kyeongdae , Park Kyu Seong , Kim Kibyeong , Shim Dahee , Park Sang-eun , Zhang Jing Yu , Go Du-Min , Kim Dae-Yong , Yoon Won Kee , Lee Seung-Pyo , Chung Jongsuk , Kim Ki-Wook , Park Jung Hwan , Lee Seung Hyun , Lee Sak , Ann Soo-jin , Lee Sang-Hak , Ahn Hyo-Suk , Jeong Seong Cheol , Kim Tae Kyeong , Oh Goo Taeg , Park Woong-Yang , Lee Hae-Ock , Choi Jae-Hoon
Published: September 2022

Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.