bluuebunny/crossref_metadata_2025 huggingface dataset:
The transseptal puncture experience: Safety insights from FDA MAUDE database
Authors: Morcos Ramez , Megaly Michael , Desai Anand , Alkhouli Mohamed , Saad Marwan , Luna Michael , Garcia Santiago , Khalili Houman , Maini Brijeshwar
Published: May 2021

Background

There is a paucity of literature on safety and efficacy of various transseptal puncture (TSP) needles.

Objectives

To assess the reported mechanisms of failure, complications, and outcomes among the most frequently used transseptal needles in the United States.

Methods

We queried the Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database between January 2011 and January 2021 for reports on the most commonly used transseptal needles: NRG (Baylis Medical, Montreal, Canada), and BRK (St. Jude, Saint Paul, MN)]. The primary outcome was the mechanism of failure. Secondary outcomes included clinical consequences of device failure.

Results

The final analysis included 306 reports of failure/complication with TSP needles (NRG n = 70, BRK n = 236). The most commonly reported mode of failure was detachment of the needle component (i.e., clip, hub, stopcock, shaft, spring, or needle tip) (14.7% overall; 17.8% BRK; and 4.3% NRG). Among these reports, cardiac perforation was the most common complication (69.9% overall; 69.1% for BRK; and 72.9% for NRG). Pericardiocentesis was the second most commonly reported complication (45.1% overall; 48.3% for BRK; and 34.3% for NRG). The procedure was successfully completed in 33.3% of all cases (36.4% for BRK and 22.9% for NRG), while surgical conversion was needed in (13.4% overall; 14% for BRK and 11.4% for NRG) of the reports. Death occurred in 3.9% of all cases overall (3.4% for BRK and 5.7% for NRG).

Conclusions

Needle detachment was the most common mode of failure, and cardiac perforation was the most common complication reported with TSP needles. Future efforts should focus on innovative TSP needle design, best practice guidelines, including role of imaging guidance, and increased TSP training.
Asymmetric Catalytic Approach to Multilayer 3D Chirality
Authors: Wu Guanzhao , Liu Yangxue , Rouh Hossein , Ma Liulei , Tang Yao , Zhang Sai , Zhou Peng , Wang Jia‐Ying , Jin Shengzhou , Unruh Daniel , Surowiec Kazimierz , Ma Yanzhang , Li Guigen
Published: May 2021

Invited for the cover of this issue is Guigen Li and co‐workers at Texas Tech University and Nanjing University. The cover artwork shows that chirality phenomena exists in the universe and in nature, including at micro and molecular levels. Read the full text of the article at 10.1002/chem.202100700.
Design and Synthesis of Sulfanilamide Aminophosphonates as Novel Antibacterial Agents towards Escherichia coli
Authors: Wang Juan , Ansari Mohammad Fawad , Lin Jian‐Mei , Zhou Cheng‐He
Published: May 2021

Main observation and conclusion

The limit ability of traditional antibiotics to treat drug resistant bacteria calls for new therapeutic alternatives. A class of unique sulfanilamide aminophosphonates as new potential agents against microbes was synthesized by one‐pot three‐component reaction. Noticeably, fluorobenzyl derivative 5d (MIC = 2 μg/mL) was active against drug resistant E. coli infection and exerted no obvious toxicity towards human mammalian cells. Compound 5d also displayed good anti‐biofilm activity and low possibility to induce drug resistance. Mechanism investigation elucidated that molecule 5d could disrupt E. coli membrane through generation of reactive oxygen (ROS) and then intercalate into deoxyribonucleic acid (DNA) to form a steady 5d‐DNA complex, which led to bacterial death. These results indicated that sulfanilamide aminophosphonates would shed light on developing novel potential antibacterial agents.
Flexible Transparent Near‐Infrared Photodetector Based on 2D Ti3C2 MXene‐Te Van Der Waals Heterostructures†
Authors: Hu Chuqiao , Li La , Shen Guozhen
Published: May 2021

Main observation and conclusion

Ti3C2 MXene serving as superior electrical conductors presents more specific performance such as transparency, conductivity than gold (Au), and even could form a heterostructure with active materials of the functional devices. Here, a Ti3C2 MXene‐Te microplate van der Waals heterostructure based transparent near‐infrared photodetector (PD) is exploited. Compared with Au‐Te PD, the on‐off ratio of the Ti3C2‐Te PD is improved by seven orders of magnitude and reaches 9.51 × 107 under 1064 nm laser illuminations. Benefiting from the utilization of flexible PET substrate and Ti3C2 conductors in manufacturing PD devices, the Ti3C2‐Te PD exhibits excellent flexibility with no noticeable response change after being bent for different states and times. Moreover, 63% transmittance of the fabricated PD devices over the 500—1000 nm wavelength range is obtained. All the above results demonstrate the tremendous potential in wearable optoelectronics.
Use of the prostate‐specific antigen (PSA) test in the United States for men age ≥65, 1999–2015: Implications for practice interventions
Authors: Shahangian Shahram , Fan Lin , Sharma Krishna P. , Siegel David A.
Published: May 2021

Background

Various professional organizations have issued recommendations on use of the PSA test to screen for prostate cancer in different age groups.

Aims

Using Medicare claims databases, we aimed to determine rates of PSA testing in the context of screening recommendations during 1999–2015 for US men age ≥65, stratified by age group and census regions, after excluding claims relating to all prostate‐related conditions.

Methods and Results

Medicare claims databases encompassed 9.71–11.12 million men for the years under study. PSA testing rate was the proportion of men with ≥1 test(s) per 12 months of continuous enrollment. Men diagnosed with any prostate‐related condition were excluded. Annual percent change (APC) in PSA test use was estimated using joinpoint regression analysis. In 1999–2015, annual testing rate was 10.1%–23.1%, age ≥85; 16.6%–31.0%, age 80–84; 23.8%–35.8%, age 75–79; 28.3%–36.9%, age 70–74; and 26.4%–33.6%, age 65–69. From 1999 to 2015, PSA testing rate decreased 40.7%, 29.9%, 13.9%, and 2.9%, respectively, for men age ≥85, 80–84, 75–79, and 70–74. For men age 65–69, test use increased by 0.3%. Significant APC trends were: APC1999–2002 = +8.1%, P = .029 and APC2008–2015 = −9.0%, P < .001 for men age ≥85; APC2008–2015 = −7.1%, P = .001 for men age 80–84; APC2001–2015 = −2.5%, P < .001 for men age 75–79; APC2008–2015 = −3.3%, P = .007 for men age 70–74; and APC2010–2015 = −5.2%, P = .014 for men age 65–69.

Coclusion

Although decreased from 1999 to 2015, PSA testing rates remained high for men age ≥70. Further research could help understand why PSA testing continues inconsistent with recommendations.
Assessment of cough in head and neck cancer patients at risk for dysphagia—An overview
Authors: Mootassim‐Billah Sofiana , Van Nuffelen Gwen , Schoentgen Jean , De Bodt Marc , Dragan Tatiana , Digonnet Antoine , Roper Nicolas , Van Gestel Dirk
Published: May 2021

Background

This literature review explores the terminology, the neurophysiology, and the assessment of cough in general, in the framework of dysphagia and regarding head and neck cancer patients at risk for dysphagia. In the dysphagic population, cough is currently assessed perceptually during a clinical swallowing evaluation or aerodynamically.

Recent findings

Recent findings have shown intra and inter‐rater disagreements regarding perceptual scoring of cough. Also, aerodynamic measurements are impractical in a routine bedside assessment. Coughing, however, is considered to be a clinically relevant sign of aspiration and dysphagia in head and cancer patients treated with concurrent chemoradiotherapy.

Conclusion

This article surveys the literature regarding the established cough assessment and stresses the need to implement innovative methods for assessing cough in head and neck cancer patients treated with concurrent chemoradiotherapy at risk for dysphagia.
Can the predictive value of multiparametric MRI for prostate cancer be improved by a liquid biopsy with SelectMDx?
Authors: Rahnama'i Mohammad Sajjad , Bach Christian , Schulze‐Hagen Maximilian , Kuhl Christiane K , Vögeli Thomas Alexander
Published: May 2021

Background

SelectMDx is a urinary biomarker test for determining prostate cancer risk.

Aim

In a group of patients with a biopsy proven prostate cancer (PCa) who had undergone a multi parametric Magnetic Resonance Imaging (mpMRI) and urinary biomarker test with SelectMDx, we studied the additive value of SelectMDx to mpMRI and correlated that to the radical prostatectomy histology.

Methods and results

Thirty‐nine consecutive patients with a positive prostate biopsy were included in the study. They all had mpMRI and SelectMDx and underwent a radical prostatectomy. Overall, the mpMRI showed a PIRADS ≤3 lesion in seven cases out of the 39 patients. Significant lesions (PIRADS ≥4) were found in 32 cases (82%), that is, in 17 cases a PIRADS 5 lesion and in 15 cases a PIRADS 4 lesion. The mpMRI missed significant PCa in seven cases (18%) who had a PIRADS ≤3 lesion but had a significant PCa on final histology after RP. In our study, the positive predictive values of mpMRI were 97% and that of the SelectMDx was 100%.

Conclusion

In this real‐life selected group of consecutive patients with a confirmed positive PCa biopsy and available mpMRI, the liquid biopsy test with SelectMDx, did not provide an additional information about the PCa clinical significance. The addition of SelectMDx was only found valuable in those patients who had a very high‐risk PCa (ie, GS ≥8) who had a positive SelectMDx test outcome despite of a negative mpMRI outcome.
Immune checkpoint inhibitors in Wilms' tumor and Neuroblastoma: What now?
Authors: Valind Anders , Gisselsson David
Published: May 2021

Background

Therapeutic activation of tumor‐infiltrating lymphocytes using monoclonal antibodies targeting PD1 or PD‐L1 (immune checkpoint inhibitors—ICIs) has revolutionized treatment of specific solid tumors in adult cancer patients, and much hope has been placed on a similar effect in relapsed or refractory solid pediatric tumors. Recent clinical trials have disappointingly shown an almost nonexistent response rate, while case reports have demonstrated that some pediatric patients do achieve durable responses when treated with this type of drug.

Aim

To elucidate this paradox, we mapped the landscape of expressed neoantigens as well as the levels of immune cell infiltration in the two most common extracranial solid pediatric tumors: Wilms tumor and neuroblastoma using state‐of‐the‐art in silico analysis of a large cohort of patients with these tumors.

Methods

By integration of whole exome sequencing and RNA‐sequencing, we mapped the landscape of neoantigens in the TARGET cohorts for these diagnoses and correlated these findings with known genetic prognostic markers.

Results

Our analysis shows that these tumors typically have much lower levels of expressed neoantigens than commonly seen in adult cancers, but we also identify subgroups with significantly higher levels of neoantigens. For neuroblastomas, the cases with higher levels of neoantigens were confined to the group without MYCN‐amplification and for Wilms tumor restricted to the TP53‐mutated cases. Furthermore, we demonstrate that neuroblastomas have an unexpectedly high level of CD8+ tumor‐infiltrating lymphocytes, even when compared to adult tumor types where ICI is an approved treatment.

Conclusion

These results could be important to consider when designing future clinical trials of ICI treatment in pediatric patients with relapsed or refractory solid tumors.
Parvovirus B19‐associated graft failure after allogeneic hematopoietic stem cell transplantation
Authors: Rattani Nabila , Matheny Christina , Eckrich Michael J. , Madden Lisa M. , Quigg Troy C.
Published: May 2021

Background

Parvovirus B19 (PVB19) infection has been implicated in allograft failure or dysfunction in solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (allo‐HSCT), but the literature is limited.

Case

Two pediatric patients were diagnosed with PVB19 infection around the time of allo‐HSCT graft failure. Both cases were secondary graft failure and required second allo‐HSCT.

Conclusion

There are many risk factors and potential confounders in determining the exact etiology of graft failure after allo‐HSCT. These two cases highlight the importance of including PVB19 in the diagnostic evaluation for graft failure. PVB19 infection may be an important risk factor for allo‐HSCT graft failure.
Evaluation of the Effects of Repeat‐Dose Dabrafenib on the Single‐Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate)
Authors: Nebot Noelia , Won Christina S. , Moreno Victor , Muñoz‐Couselo Eva , Lee Dung‐Yang , Gasal Eduard , Bouillaud Emmanuel
Published: May 2021

Dabrafenib is an oral BRAF kinase inhibitor approved for the treatment of various BRAF V600 mutation–positive solid tumors. In vitro observations suggesting cytochrome P450 (CYP) 3A induction and organic anion transporting polypeptide (OATP) inhibition prompted us to evaluate the effect of dabrafenib 150 mg twice daily on the pharmacokinetics of midazolam 3 mg (CYP3A substrate) and rosuvastatin 10 mg (OATP1B1/1B3 substrate) in a clinical phase 1, open‐label, fixed‐sequence study in patients with BRAF V600 mutation–positive tumors. Repeat dabrafenib dosing resulted in a 2.56‐fold increase in rosuvastatin maximum observed concentration (Cmax), an earlier time to Cmax, but only a 7% increase in area under the concentration‐time curve from time 0 (predose) extrapolated to infinite time. Midazolam Cmax and AUC extrapolated to infinite time decreased by 47% and 65%, respectively, with little effect on time to Cmax. No new safety findings were reported. Exposure of drugs that are CYP3A4 substrates is likely to decrease when coadministered with dabrafenib. Concentrations of medicinal products that are sensitive OATP1B1/1B3 substrates may increase during the absorption phase.
When Can We Trust Real‐World Data To Evaluate New Medical Treatments?
Authors: Simon Gregory E. , Bindman Andrew B. , Dreyer Nancy A. , Platt Richard , Watanabe Jonathan H. , Horberg Michael , Hernandez Adrian , Califf Robert M.
Published: May 2021

Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real‐world evidence (RWE) in the evaluation of new treatments or products. RWE studies often rely on real‐world data (RWD), including data extracted from healthcare records or data captured by mobile phones or other consumer devices. Global assessments of RWD sources are not helpful in assessing whether any specific RWD element is fit for any specific purpose. Instead, evidence generators and evidence consumers should clearly identify the specific health state or clinical phenomenon of interest and then consider each step between that clinical phenomenon and its representation in a research database. We propose specific questions regarding potential error or bias affecting each of those steps: Would a person experiencing this clinical phenomenon present for care in this setting or interact with this recording device? Would this clinical phenomenon be accurately recognized or assessed? How might the recording environment or tools affect accurate and consistent recording of this clinical phenomenon? Can data elements from different sources be harmonized, both technically (same format) and semantically (same meaning)? Can the original data elements be consistently reduced to a useful clinical phenotype? Addressing these questions requires a range of clinical, organizational, and technical expertise. Transparency regarding each step in the creation of RWD is essential if evidence consumers are to rely on RWE studies.
Rational Design and Effective Control of Gold‐Based Bimetallic Electrocatalyst for Boosting CO2 Reduction Reaction: A First‐Principles Study
Authors: Guo Chen , Zhang Tian , Lu Xiaoqing , Wu Chi‐Man Lawrence
Published: May 2021

Electrochemical CO2 reduction reaction (CO2RR) is an effective strategy converting CO2 to value‐added products. Au is regarded as an efficient catalyst for electrochemical reduction of CO2 to CO, and the introduction of Pd can tune CO2RR properties due to its strong affinity to CO. Herein, Au−Pd bimetallic electrocatalysts with different metal ratio were firstly investigated on CO2RR mechanism by using density functional theory. The Au monolayer over Pd substrate and single Pd atom on Au(111) were found to show better CO2RR selectivity against hydrogen evolution reaction (HER). Based on this, various single‐atom catalysts on Au(111) and core–shell models with top Au monolayer were designed to study their CO2RR performance. The results indicated that Pt, Cu, and Rh substrates below Au monolayer could enhance the activity and selectivity for CO production compared to pure Au, in which the limiting potential reduced from −0.74 to −0.63, −0.69, and −0.71 V, respectively. The single Pd embedded on Au(111) could adjust the adsorption strength, which provided an effective site to receive and further reduce CO to CH3OH and CH4 at a low limiting potential of −0.61 V, and also avoided catalyst poisoning due to the over‐strengthened CO adsorption caused by high Pd proportion on the surface. In addition, the adsorption energy of COOH was observed as a better CO2RR reactivity descriptor than the common CO adsorption when establishing scaling relationship, which could avoid the fitting error caused by intermediate physisorption of CO.
4‐phenylbutyric acid promotes hepatocellular carcinoma via initiating cancer stem cells through activation of PPAR‐α
Authors: Chen Shu‐Zhen , Ling Yan , Yu Le‐Xing , Song Yu‐Ting , Chen Xiao‐Fei , Cao Qi‐Qi , Yu Han , Chen Can , Tang Jiao‐Jiao , Fan Zhe‐Cai , Miao Yu‐Shan , Dong Ya‐Ping , Tao Jun‐Yan , Monga Satdarshan P.S. , Wen Wen , Wang Hong‐Yang
Published: May 2021

Background and aims

4‐phenylbutyric acid (4‐PBA) is a low molecular weight fatty acid that is used in clinical practice to treat inherited urea cycle disorders. In previous reports, it acted as a chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown.

Methods

4‐PBA was administered alone or in combination with diethylnitrosamine to investigate its long‐term effect on liver tumorigenesis. The role of 4‐PBA in oncogene‐induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co‐expressed with hMet and β‐catenin point mutation (S45Y) was also observed. RNA‐seq and PCR array were used to screen the pathways and genes involved. In vitro and in vivo studies were conducted to explore the effect of 4‐PBA on liver and validate the underlying mechanism.

Results

4‐PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b‐Fzd5 mediating β‐catenin signaling. Peroxisome proliferator‐activated receptors (PPAR)‐α induced by 4‐PBA was responsible for the activation of β‐catenin signaling. Thus, intervention of PPAR‐α reversed 4‐PBA‐induced initiation of LCSCs and HCC development in vivo. Further study revealed that 4‐PBA could not only upregulate the expression of PPAR‐α transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR‐α expression predicted poor prognosis in HCC patients.

Conclusions

4‐PBA could upregulate PPAR‐α to initiate LCSCs by activating β‐catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor‐promoting effect of 4‐PBA under HCC‐inducing environment.
Deubiquitinase USP35 modulates ferroptosis in lung cancer via targeting ferroportin
Authors: Tang Zheng , Jiang Wanli , Mao Ming , Zhao Jinping , Chen Jiakuan , Cheng Nitao
Published: May 2021

Background

Ferroptosis is essential to regulate tumor growth and serves as a promising therapeutic target to lung cancer. Ubiquitin‐specific protease 35 (USP35) belongs to the deubiquitinases family that is associated with cell proliferation and mitosis. In this research, we aim to elucidate the potential role and molecular basis of USP35 in lung cancer.

Methods

Lung cancer cells were infected with lentiviral vectors to silence or overexpress USP35. Cell viability, colony formation, lipid reactive oxygen species production, intracellular iron metabolism, and other ferroptotic markers were detected. The role of USP35 on ferroptosis and tumor progression were also tested in mouse tumor xenograft models in vivo.

Results

USP35 was abundant in human lung cancer tissues and cell lines. USP35 knockdown promoted ferroptosis, and inhibited cell growth, colony formation, and tumor progression in lung cancer cells. USP35 overexpression did not affect tumorigenesis and ferroptosis under basal conditions, but reduced erastin/RSL3‐triggered iron disturbance and ferroptosis, thereby facilitating lung cancer cell growth and tumor progression. Further studies determined that USP35 directly interacted with ferroportin (FPN) and functioned as a deubiquitinase to maintain its protein stability. More importantly, we observed that USP35 knockdown sensitized lung cancer cells to cisplatin and paclitaxel chemotherapy.

Conclusion

USP35 modulates ferroptosis in lung cancer via targeting FPN, and it is a promising therapeutic target to lung cancer.
FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression
Authors: Miao Lei , Zhuo Zhenjian , Tang Jue , Huang Xiaomei , Liu Jiabin , Wang Hai‐Yun , Xia Huimin , He Jing
Published: May 2021

Neuroblastoma (NB) is the most common and deadliest pediatric solid tumor. Targeting and reactivating tumor‐associated macrophages (TAMs) is necessary for reversing immune suppressive state and stimulating immune defense to exert tumoricidal function. However, studies on the function and regulation of TAMs in NB progression are still limited. Fatty acid binding protein 4 (FABP4) in TAMs was correlated with advanced clinical stages and unfavorable histology of NB. FABP4‐mediated macrophages increased migration, invasion, and tumor growth of NB cells. Mechanically, FABP4 could directly bind to ATPB to accelerate ATPB ubiquitination in macrophages. The consequently decreased ATP levels could deactivate NF‐κB/RelA‐IL1α pathway, which subsequently results in macrophages reprogrammed to an anti‐inflammatory phenotype. We also demonstrated that FABP4‐enhanced migration and invasion were significantly suppressed by IL1α blocking antibody. Furthermore, circulating FABP4 was also associated with the clinical stages of NB. Our findings suggest that FABP4‐mediated macrophages may promote proliferation and migration phenotypes in NB cells through deactivating NF‐κB‐IL1α pathway by ubiquitinating ATPB. This study reveals the pathologic and biologic role of FABP4‐mediated macrophages in NB development and exhibits a novel application of targeting FABP4 in macrophages for NB treatment.
Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies
Authors: Slater Cody , Wang Qi
Published: May 2021

Alzheimer's disease (AD) poses a significant global health concern over the next several decades. Multiple hypotheses have been put forth that attempt to explain the underlying pathophysiology of AD. Many of these are briefly reviewed here, but to‐date no disease‐altering therapy has been achieved. Despite this, recent work expanding on the role of noradrenergic system dysfunction in both the pathogenesis and symptomatic exacerbation of AD has shown promise. The role norepinephrine (NE) plays in AD remains complicated but pre‐tangle tau has consistently been shown to arise in the locus coeruleus (LC) of patients with AD decades before symptom onset. The current research reviewed here indicates NE can facilitate neuroprotective and memory‐enhancing effects through β adrenergic receptors, while α2Aadrenergic receptors may exacerbate amyloid toxicity through a contribution to tau hyperphosphorylation. AD appears to involve a disruption in the balance between these two receptors and their various subtypes. There is also a poorly characterized interplay between the noradrenergic and cholinergic systems. LC deterioration leads to maladaptation in the remaining LC‐NE system and subsequently inhibits cholinergic neuron function, eventually leading to the classic cholinergic disruption seen in AD. Understanding AD as a dysfunctional noradrenergic system, provides new avenues for the use of advanced neural stimulation techniques to both study and therapeutically target the earliest stages of neuropathology. Direct LC stimulation and non‐invasive vagus nerve stimulation (VNS) have both demonstrated potential use as AD therapeutics. Significant work remains, though, to better understand the role of the noradrenergic system in AD and how electroceuticals can provide disease‐altering treatments.
Positive regulation of PFKFB3 by PIM2 promotes glycolysis and paclitaxel resistance in breast cancer
Authors: Lu Chao , Qiao Pengyun , Sun Yonghong , Ren Chune , Yu Zhenhai
Published: May 2021

Background

Breast cancer (BC) is one of the most common female malignancies in the world. Chemotherapeutic resistance is the major cause of BC therapy failure, leading to tumor recurrence and metastasis. Studies have illustrated the close relationship between glycolysis and BC progression and drug resistance. The key glycolysis regulator, PFKFB3 makes a difference during BC progression and drug resistance. However, the mechanism remains to be unknown.

Methods

Mass spectrometry analyses were used to found that PIM2 was a potential new binding protein of PFKFB3. Co‐immunoprecipitated and western blot were used to verify the interaction between PIM2 and PFKFB3 in BC and the molecular mechanism by which PIM2 phosphorylates PFKFB3 in regulating the protein function. PFKFB3 mutant forms were used to demonstrate the need for PFKFB3 in BC drug resistance.

Results

We identified that PIM2 is a new binding protein of PFKFB3. We used biochemical methods to determine that PIM2 can directly bind and change the phosphorylation of PFKFB3 at Ser478 to enhance PFKFB3 protein stability through the ubiquitin‐proteasome pathway. Importantly, phosphorylation of PFKFB3 at Ser478 promoted glycolysis, BC cell growth, and paclitaxel resistance together with PIM2 in vitro and in vivo.

Conclusion

Our study demonstrates that PIM2 mediates PFKFB3 phosphorylation thus regulates glycolysis and paclitaxel resistance to promote tumor progression in BC and provides preclinical evidence for targeting PFKFB3 as a new strategy in BC treatment to battle paclitaxel resistance.
Copy number and transcriptome alterations associated with metastatic lesion response to treatment in colorectal cancer
Authors: Gambaro Karen , Marques Maud , McNamara Suzan , Couetoux du Tertre Mathilde , Diaz Zuanel , Hoffert Cyrla , Srivastava Archana , Hébert Steven , Samson Benoit , Lespérance Bernard , Ko Yoo‐Joung , Dalfen Richard , St‐Hilaire Eve , Sideris Lucas , Couture Felix , Burkes Ronald , Harb Mohammed , Camlioglu Errol , Gologan Adrian , Pelsser Vincent , Constantin André , Greenwood Celia M.T. , Tejpar Sabine , Kavan Petr , Kleinman Claudia L. , Batist Gerald
Published: May 2021

Background

Therapeutic resistance is the main cause of death in metastatic colorectal cancer. To investigate genomic plasticity, most specifically of metastatic lesions, associated with response to first‐line systemic therapy, we collected longitudinal liver metastatic samples and characterized the copy number aberration (CNA) landscape and its effect on the transcriptome.

Methods

Liver metastatic biopsies were collected prior to treatment (pre, n = 97) and when clinical imaging demonstrated therapeutic resistance (post, n = 43). CNAs were inferred from whole exome sequencing and were correlated with both the status of the lesion and overall patient progression‐free survival (PFS). We used RNA sequencing data from the same sample set to validate aberrations as well as independent datasets to prioritize candidate genes.

Results

We identified a significantly increased frequency gain of a unique CN, in liver metastatic lesions after first‐line treatment, on chr18p11.32 harboring 10 genes, including TYMS, which has not been reported in primary tumors (GISTIC method and test of equal proportions, FDR‐adjusted p = 0.0023). CNA lesion profiles exhibiting different treatment responses were compared and we detected focal genomic divergences in post‐treatment resistant lesions but not in responder lesions (two‐tailed Fisher's Exact test, unadjusted p ≤ 0.005). The importance of examining metastatic lesions is highlighted by the fact that 15 out of 18 independently validated CNA regions found to be associated with PFS in this study were only identified in the metastatic lesions and not in the primary tumors.

Conclusion

This investigation of genomic‐phenotype associations in a large colorectal cancer liver metastases cohort identified novel molecular features associated with treatment response, supporting the clinical importance of collecting metastatic samples in a defined clinical setting.
Loss of m6A demethylase ALKBH5 promotes post‐ischemic angiogenesis via post‐transcriptional stabilization of WNT5A
Authors: Zhao Yongchao , Hu Jingjing , Sun Xiaolei , Yang Kun , Yang Lebing , Kong Lingqiu , Zhang Beijian , Li Fuhai , Li Chaofu , Shi Bei , Hu Kai , Sun Aijun , Ge Junbo
Published: May 2021

Background

Post‐ischemic angiogenesis is critical for blood flow recovery and ischemic tissue repair. N6‐methyladenosine (m6A) plays essential roles in numerous biological processes. However, the impact and connected mechanism of m6A on post‐ischemic angiogenesis are not fully understood.

Methods

AlkB homolog 5 (ALKBH5) was screened out among several methyltransferases and demethylases involved in dynamic m6A regulation. Cardiac microvascular endothelial cells (CMECs) angiogenesis and WNT family member 5A (WNT5A) stability were analyzed upon ALKBH5 overexpression with adenovirus or knockdown with small interfering RNAs in vitro. The blood flow recovery, capillary, and small artery densities were evaluated in adeno‐associated virus (AAV)‐ALKBH5 overexpression or ALKBH5 knockout (KO) mice in a hind‐limb ischemia model. The same experiments were conducted to explore the translational value of transient silencing of ALKBH5 with adenovirus.

Results

ALKBH5 was significantly upregulated in hypoxic CMECs and led to a global decrease of m6A level. ALKBH5 overexpression further reduced m6A level in normoxic and hypoxic CMECs, impaired proliferation, migration, and tube formation only in hypoxic CMECs. Conversely, ALKBH5 knockdown preserved m6A levels and promoted angiogenic phenotypes in hypoxic but not in normoxic CMECs. Mechanistically, ALKBH5 regulated WNT5A expression through post‐transcriptional mRNA modulation in an m6A‐dependent manner, which decreased its stability and subsequently impeded angiogenesis in hypoxic CMECs. Furthermore, ALKBH5 overexpression hindered blood flow recovery and reduced CD31 and alpha‐smooth muscle actin expression in hind‐limb ischemia mice. As expected, ALKBH5‐KO mice exhibited improved blood flow recovery, increased capillary, and small artery densities after hind‐limb ischemia, and similar beneficial effects were observed in mice with transient adenoviral ALKBH5 gene silencing.

Conclusion

We demonstrate that ALKBH5 is a negative regulator of post‐ischemic angiogenesis via post‐transcriptional modulation and destabilization of WNT5A mRNA in an m6A‐dependent manner. Targeting ALKBH5 may be a potential therapeutic option for ischemic diseases, including peripheral artery disease.
CSF metabolites associate with CSF tau and improve prediction of Alzheimer's disease status
Authors: Dong Ruocheng , Darst Burcu F. , Deming Yuetiva , Ma Yue , Lu Qiongshi , Zetterberg Henrik , Blennow Kaj , Carlsson Cynthia M. , Johnson Sterling C. , Asthana Sanjay , Engelman Corinne D.
Published: May 2021

Introduction

Cerebrospinal fluid (CSF) total tau (t‐tau) and phosphorylated tau (p‐tau) are biomarkers of Alzheimer's disease (AD), yet much is unknown about AD‐associated changes in tau metabolism and tau tangle etiology.

Methods

We assessed the variation of t‐tau and p‐tau explained by 38 previously identified CSF metabolites using linear regression models in middle‐age controls from the Wisconsin Alzheimer's Disease Research Center, and predicted AD/mild cognitive impairment (MCI) versus an independent set of older controls using metabolites selected by the least absolute shrinkage and selection operator (LASSO).

Results

The 38 CSF metabolites explained 70.3% and 75.7% of the variance in t‐tau and p‐tau, respectively. Of these, seven LASSO‐selected metabolites improved the prediction ability of AD/MCI versus older controls (area under the curve score increased from 0.92 to 0.97 and 0.78 to 0.93) compared to the base model.

Discussion

These tau‐correlated CSF metabolites increase AD/MCI prediction accuracy and may provide insight into tau tangle etiology.
Cerebrospinal fluid biomarker panel for synaptic dysfunction in Alzheimer's disease
Authors: Nilsson Johanna , Gobom Johan , Sjödin Simon , Brinkmalm Gunnar , Ashton Nicholas J. , Svensson Johan , Johansson Per , Portelius Erik , Zetterberg Henrik , Blennow Kaj , Brinkmalm Ann
Published: May 2021

Introduction

Synaptic dysfunction and degeneration is one of the earliest events in Alzheimer's disease (AD) and the best correlate of cognitive decline. Thus, identification and validation of biomarkers reflecting synaptic degeneration to be used as prognostic biomarkers are greatly needed.

Method

Solid‐phase extraction and parallel reaction monitoring mass spectrometry were used to quantify 17 synaptic proteins in CSF, in two cross‐sectional studies including AD (n = 52) and controls (n = 37).

Results

Increased concentrations of beta‐synuclein, gamma‐synuclein, neurogranin, phosphatidylethanolamine‐binding protein 1, and 14‐3‐3 proteins were observed in AD patients compared to controls, while neuronal pentraxin‐2 and neuronal pentraxin receptor were decreased.

Discussion

We have established a method with a novel panel of synaptic proteins as biomarkers of synaptic dysfunction. The results indicate that several of the proteins included in the panel may serve as synaptic biomarkers for AD.
Comparing CSF amyloid‐beta biomarker ratios for two automated immunoassays, Elecsys and Lumipulse, with amyloid PET status
Authors: Willemse Eline A. J. , Tijms Betty M. , van Berckel Bart N. M. , Le Bastard Nathalie , van der Flier Wiesje M. , Scheltens Philip , Teunissen Charlotte E.
Published: May 2021

Introduction

We evaluated for two novel automated biomarker assays how cerebrospinal fluid (CSF) amyloid beta (Aβ)1– 42‐ratios improved the concordance with amyloid positron emission tomography (PET) positivity compared to Aβ1– 42 alone.

Methods

We selected 288 individuals from the Amsterdam Dementia Cohort across the Alzheimer's disease clinical spectrum when they had both CSF and amyloid PET visual read available, regardless of diagnosis. CSF Aβ1– 42, phosphorylated tau (p‐tau), and total tau (t‐tau) were measured with Elecsys and Lumipulse assays, and Aβ1–40 with Lumipulse. CSF cut‐points were defined using receiver operating characteristic (ROC) for amyloid PET positivity.

Results

For both Elecsys and Lumipulse the p‐tau/Aβ1– 42, Aβ1– 42/Aβ1– 40, and t‐tau/Aβ1– 42 ratios showed similarly good concordance with amyloid PET (Elecsys: 93,90,90%; Lumipulse: 94,92,90%) and were higher than Aβ1– 42 alone (Elecsys 85%; Lumipulse 84%).

Discussion

Biomarker ratios p‐tau/Aβ1– 42, Aβ1– 42/Aβ1– 40, t‐tau/Aβ1– 42 on two automated platforms show similar optimal concordance with amyloid PET in a memory clinic cohort.
The influence of microbial mats on travertine precipitation in active hydrothermal systems (Central Italy)
Authors: Della Porta Giovanna , Hoppert Michael , Hallmann Christine , Schneider Dominik , Reitner Joachim
Published: May 2021

The study of hydrothermal travertines contributes to the understanding of the interaction between physico‐chemical processes and microbial mats in carbonate precipitation. Three active travertine sites were investigated in Central Italy to characterise the types of carbonate precipitates and the associated microbial mats at varying physico‐chemical parameters. Carbonate precipitated fabrics at the decimetre to millimetre‐scale and microbial mat composition vary with decreasing water temperature: (a) at relatively higher temperature (55–44°C) calcite and aragonite crystals precipitate on microbial mats of Chloroflexi and sulphur‐oxidizing microbes forming filamentous streamer fabrics with sparse cyanobacteria, (b) at intermediate temperature (44–40°C), rafts, coated gas bubbles and dendrites are associated with Spirulina cyanobacteria and other filamentous and rod‐shaped cyanobacteria, (c) low temperature (34–33°C) laminated crusts and oncoids forming in a terraced slope system are associated with diverse Oscillatoriales and Nostocales filamentous cyanobacteria, Spirulina and diatoms. At the microscale, carbonate precipitates are similar in the three sites consisting of prismatic calcite crystals organised in radial rosettes or fibrous aragonite spherulites (40–300 µm in diameter), overlying or embedded in Extracellular Polymeric Substances. Clotted peloidal micrite dominates at temperatures <40°C, also encrusting filamentous microbes. Carbonates are associated with gypsum crystals; extracellular polymeric substances are enriched in silicon, aluminium, magnesium, calcium, phosphorous and sulphur; authigenic aluminium‐silicates form aggregates on Extracellular Polymeric Substances. This study confirms that microbial communities in hydrothermal settings vary as a function of water temperature. Carbonate precipitates at the microscale are similar in the three settings, despite different microbial communities, suggesting that travertine precipitation, driven by carbon dioxide degassing, is influenced by biofilm extracellular polymeric substances acting as a substrate for crystal nucleation (Extracellular Polymeric Substances‐mediated mineralization) and affecting the resultant fabric types, independently from specific microbial community composition and metabolism.
Understanding evolutionary and ecological dynamics using a continuum limit
Authors: Czuppon Peter , Traulsen Arne
Published: May 2021

Continuum limits in the form of stochastic differential equations are typically used in theoretical population genetics to account for genetic drift or more generally, inherent randomness of the model. In evolutionary game theory and theoretical ecology, however, this method is used less frequently to study demographic stochasticity. Here, we review the use of continuum limits in ecology and evolution. Starting with an individual‐based model, we derive a large population size limit, a (stochastic) differential equation which is called continuum limit. By example of the Wright–Fisher diffusion, we outline how to compute the stationary distribution, the fixation probability of a certain type, and the mean extinction time using the continuum limit. In the context of the logistic growth equation, we approximate the quasi‐stationary distribution in a finite population.
Adaptive population structure shifts in invasive parasitic mites, Varroa destructor
Authors: Moro Arrigo , Blacquière Tjeerd , Dahle Bjørn , Dietemann Vincent , Le Conte Yves , Locke Barbara , Neumann Peter , Beaurepaire Alexis
Published: May 2021

Comparative studies of genetic diversity and population structure can shed light on the ecological and evolutionary factors governing host–parasite interactions. Even though invasive parasites are considered of major biological importance, little is known about their adaptative potential when infesting the new hosts. Here, the genetic diversification of Varroa destructor, a novel parasite of Apis mellifera originating from Asia, was investigated using population genetics to determine how the genetic structure of the parasite changed in distinct European populations of its new host. To do so, mites infesting two categories of hosts in four European regions were compared: (a) adapted hosts surviving through means of natural selection, thereby expected to impose strong selective pressure on the mites, and (b) treated host populations, surviving mite infestations because acaricides are applied, therefore characterized by a relaxed selection imposed by the host on the mites. Significant genetic divergence was found across regions, partially reflecting the invasion pattern of V. destructor throughout Europe and indicating local adaptation of the mite to the host populations. Additionally, varying degrees of genotypic changes were found between mites from adapted and treated colonies. Altogether, these results indicate that V. destructor managed to overcome the genetic bottlenecks following its introduction in Europe and that host‐mediated selection fostered changes in the genetic structure of this mite at diverse geographic scales. These findings highlight the potential of parasites to adapt to their local host populations and confirm that adaptations developed within coevolutionary dynamics are a major determinant of population genetic changes.
Understanding the impact of correlation within pair‐bonds on Cormack–Jolly–Seber models
Authors: Draghici Alexandru M. , Challenger Wendell O. , Bonner Simon J.
Published: May 2021

The Cormack–Jolly–Seber (CJS) model and its extensions have been widely applied to the study of animal survival rates in open populations. The model assumes that individuals within the population of interest have independent fates. It is, however, highly unlikely that a pair of animals which have formed a long‐term pairing have dissociated fates.

We examine a model extension which allows animals who have formed a pair‐bond to have correlated survival and recapture fates. Using the proposed extension to generate data, we conduct a simulation study exploring the impact that correlated fate data has on inference from the CJS model. We compute Monte Carlo estimates for the bias, range, and standard errors of the parameters of the CJS model for data with varying degrees of survival correlation between mates. Furthermore, we study the likelihood ratio test of sex effects within the CJS model by simulating densities of the deviance. Finally, we estimate the variance inflation factor for CJS models that incorporate sex‐specific heterogeneity.

Our study shows that correlated fates between mated animals may result in underestimated standard errors for parsimonious models, significantly deflated likelihood ratio test statistics, and underestimated values of for models taking sex‐specific effects into account.

Underestimated standard errors can result in lowered coverage of confidence intervals. Moreover, deflated test statistics will provide overly conservative test results. Finally, underestimated variance inflation factors can lead researchers to make incorrect conclusions about the level of extra‐binomial variation present in their data.
Head and mandible shapes are highly integrated yet represent two distinct modules within and among worker subcastes of the ant genus Pheidole
Authors: Casadei‐Ferreira Alexandre , Friedman Nicholas R. , Economo Evan P. , Pie Marcio R. , Feitosa Rodrigo M.
Published: May 2021

Ants use their mandibles for a wide variety of tasks related to substrate manipulation, brood transport, food processing, and colony defense. Due to constraints involved in colony upkeep, ants evolved a remarkable diversity of mandibular forms, often related to specific roles such as specialized hunting and seed milling. Considering these varied functional demands, we focused on understanding how the mandible and head shape vary within and between Pheidole subcastes. Using x‐ray microtomography and 3D geometric morphometrics, we tested whether these structures are integrated and modular, and how ecological predictors influenced these features. Our results showed that mandible and head shape of majors and minor workers tend to vary from robust to slender, with some more complex changes related to the mandibular base. Additionally, we found that head and mandible shapes are characterized by a high degree of integration, but with little correlation with feeding and nesting habits. Our results suggest that a combination of structural (allometric) constraints and the behavioral flexibility conferred by subcaste dimorphism might largely buffer selective pressures that would otherwise lead to a fine‐tuning between ecological conditions and morphological adaptation.
Rivers, not refugia, drove diversification in arboreal, sub‐Saharan African snakes
Authors: Allen Kaitlin E. , Greenbaum Eli , Hime Paul M. , Tapondjou N. Walter P. , Sterkhova Viktoria V. , Kusamba Chifundera , Rödel Mark‐Oliver , Penner Johannes , Peterson A. Townsend , Brown Rafe M.
Published: May 2021

The relative roles of rivers versus refugia in shaping the high levels of species diversity in tropical rainforests have been widely debated for decades. Only recently has it become possible to take an integrative approach to test predictions derived from these hypotheses using genomic sequencing and paleo‐species distribution modeling. Herein, we tested the predictions of the classic river, refuge, and river‐refuge hypotheses on diversification in the arboreal sub‐Saharan African snake genus Toxicodryas. We used dated phylogeographic inferences, population clustering analyses, demographic model selection, and paleo‐distribution modeling to conduct a phylogenomic and historical demographic analysis of this genus. Our results revealed significant population genetic structure within both Toxicodryas species, corresponding geographically to river barriers and divergence times from the mid‐Miocene to Pliocene. Our demographic analyses supported the interpretation that rivers are indications of strong barriers to gene flow among populations since their divergence. Additionally, we found no support for a major contraction of suitable habitat during the last glacial maximum, allowing us to reject both the refuge and river‐refuge hypotheses in favor of the river‐barrier hypothesis. Based on conservative interpretations of our species delimitation analyses with the Sanger and ddRAD data sets, two new cryptic species are identified from east‐central Africa. This study highlights the complexity of diversification dynamics in the African tropics and the advantages of integrative approaches to studying speciation in tropical regions.