bluuebunny/crossref_metadata_2025 huggingface dataset:
A Prosthetic and Surgical Approach for Full-Arch Rehabilitation in Atrophic Maxilla Previously Affected by Peri-Implantitis
Authors: Pavanelli Angélica Letícia Reis , de Avila Erica Dorigatti , Barros-Filho Luiz Antônio Borelli , Mollo Junior Francisco de Assis , Cirelli Joni Augusto , Borelli Barros Luiz Antônio , de Molon Rafael Scaf
Published: April 2021

Rehabilitation of atrophic maxilla with dental implants is still a challenge in clinical practice especially in cases of alveolar bone resorption due to peri-implantitis and pneumatization of the maxillary sinuses. Several surgical approaches have been employed to reconstruct the lost tissues allowing the proper tridimensional position of the implants. In this context, the aim of this case report is to describe a surgical and prosthetic approach to fully rehabilitate the atrophic maxilla with dental implants. The patient presented with unsatisfactory functional and esthetical implant-supported prosthesis with some of the implants already lost by peri-implantitis. The remaining three implants were also affected by peri-implantitis. Reversal prosthetic planning was performed, and a provisional prosthesis was fabricated and anchored in two short implants. Sinus floor augmentation procedure and onlay bone graft were then accomplished. After a healing period of 8 months, digital-guided surgery approach was performed to place the implants. Finally, a definitive prosthesis was installed. One-year follow-up has revealed stabilization of the bone tissue level, successful osseointegration, and a pleasant esthetic and functional result. A proper diagnosis and careful planning play an important role to enhance precision and to achieve patient esthetic and functional outcomes.
Suicide Behavior and Its Predictors in Patients with Schizophrenia in Ethiopia
Authors: Ayalew Mohammed , Defar Semira , Reta Yared
Published: April 2021

Background. People with schizophrenia (PWS) are at greater risk of suicide. However, suicide behaviors that occur in PWS are often overlooked, inadequately characterized, and not consistently integrated into treatment. Despite this burden and consequences in Ethiopia, there is a dearth of studies concerning suicide behavior in PWS. Therefore, this study is aimed at assessing the magnitude of suicide behavior and its predictors among PWS in Ethiopia. Methods. An institution based cross‐sectional study was employed. Data were collected using the structured interviewer‐administered questionnaire from a sample of 300 PWS at Amanuel Mental Specialized Hospital (AMSH). The revised version of Suicide Behavior Questionnaire (SBQ‐R) was used to assess suicide behavior in PWS. The data was collected from March 1 to 30, 2019. Binary logistic regression was performed to identify independent predictors of suicidal behavior at 95% confidence level. Statistical significance was declared at p value <0.05. Result. A total of 300 patients with schizophrenia participated in the study. More than two‐thirds of 203 (67.7%) of the participants were males, and 116 (38.7%) participants were between the ages of 28 and 37 years. We found that the prevalence of suicide behavior among PWS was 30.3%. Being unemployed (AOR = 3.65, CI = 1.32, 10.05), family history of suicide (AOR = 3.16, CI = 1.38, 7.23), substance use (AOR = 2.51, CI = 1.13, 5.59), current positive psychotic symptoms (hallucination (AOR = 6.39, CI = 2.86, 14.29), and delusion (AOR = 4.15, CI = 1.95, 14.29) and presence of comorbid depression (AOR = 4.81, CI = 1.98, 11.68) were independent significant predictors with suicidal behavior in PWS. Conclusion. The prevalence of suicidal behavior among PWS was found to be high. Hence, designing strategies for early screening and intervention is the most critical prevention strategy of suicide in PWS.
Optimal Three‐Dimensional Sensor Placement for Cable‐Stayed Bridge Based on Dynamic Adjustment of Attenuation Factor Gravitational Search Algorithm
Authors: Gao Bo , Bai Zhihui , Song Yubo
Published: April 2021

Structural health monitoring (SHM) is essential when detecting damage in large and complex structures in order to provide a comprehensive assessment of the structural health state. Optimal sensor placement (OSP) is critical in the structural health monitoring system, which aims to use a limited number of sensors to obtain high‐quality structural health diagnosis data. However, the current research mainly focuses on OSP for structures, without considering the values contributed by different modes to the bridge structure. In this article, an optimal sensor placement method based on initial sensor layout, using the dynamic adjustment of attenuation factor gravitational search algorithm (DGSA), is proposed. The effective modal mass participation ratio is introduced to ensure the validity of the initial data of optimal sensor placement. In view of the insufficient developmental ability of the gravitational search algorithm, the attenuation factor α adjusted dynamically aids the global search in the early iteration and the local fine search in the late iteration. The double coding method is used to apply the DGSA algorithm to OSP; taking cable‐stayed bridges as an example, the feasibility of the algorithm is verified. The results show that the improved algorithm has a good optimization ability and can accurately and efficiently determine the optimal placement of sensors.
Targeting Nanostrategies for Imaging of Atherosclerosis
Authors: Costagliola di Polidoro Angela , Grassia Agnese , De Sarno Francesca , Bevilacqua Paolo , Mollo Valentina , Romano Eugenia , Di Taranto Maria Donata , Fortunato Giuliana , Bracale Umberto Marcello , Tramontano Liberatore , Diomaiuti Tommaso Claudio , Torino Enza
Published: April 2021

Despite the progress in cardiovascular research, atherosclerosis still represents the main cause of death worldwide. Clinically, the diagnosis of Atherosclerotic Cardiovascular Disease (ASCVD) relies on imaging methodologies including X-ray angiography and computed tomography (CT), which however still fails in the identification of patients at high risk of plaque rupture, the main cause of severe clinical events as stroke and heart attack. Magnetic resonance imaging, which is characterized by very high spatial resolution, could provide a better characterization of atherosclerotic plaque (AP) anatomy and composition, aiding in the identification of “vulnerable” plaques. In this context, hydrogel matrices, which have been demonstrated able to boost relaxometric properties of Gd-based contrast agents (CAs) by the effect of Hydrodenticity, represent a valuable tool towards the precision imaging of ASCVD improving the performance of this class of CAs while reducing systemic toxicity. In particular, hydrogel nanoparticles encapsulating Gd-DTPA can further contribute to providing CA-specific accumulation in the AP by nanoparticle surface decoration triggering an active targeting of the AP with the overall effect of allowing an earlier and more accurate diagnosis. In this work, we tested crosslinked Hyaluronic Acid Nanoparticles (cHANPs) in the complex environment of human atherosclerotic plaque. In addition, the surface of cHANPs was decorated with the antibody anti-CD36 (Ab36-cHANPs) for the active targeting of AP-associated macrophages. Results demonstrate that the Hydrodenticity of cHANPs and Ab36-cHANPs is preserved in this complex system and, preliminarily, that interaction of these probes with the AP is present.
Reliability Analysis of Expansive Soil Slope Stability Based on the Three-Broken Line Model
Authors: Li Wenwei , Wang Baotian , Zuo Jinyu , Zhou Bingsheng , Zhang Haixia
Published: April 2021

Based on the characteristics of an expansive soil slope, the slip mass can be simplified to a simpler model with three-broken line rigid bodies. A solution was formulated to calculate the safety factors of the slope, and the results are similar to those based on the strength reduction method. However, similar to conventional methods to analyze the stability of slopes, the deterministic method to obtain the safety factors only calculates the safety factor using deterministic values without considering the randomness of soil parameters, which leads to unstable results. To improve the rationality of the calculated results, this paper aims to construct a reliability analysis method based on the simplified three-broken line model of a landslide. The reliability is calculated with the response surface method in a spreadsheet with efficiency and convenience. The designed program considers the changes in the strength of the shallow soil and the depth of the strongly weathered layer for different stages of the wetting-drying cycles and solves for the probability of failure of the sliding surface at the interface between the strong and weak weathered layers. Considering an expansive soil slope as an example, the reliability of the slope was analyzed based on laboratory test data and the proposed formula. The results show that multiple wetting-drying cycles significantly increase the probability of failure of an expansive soil slope and that the slope typically becomes unstable after six wetting-drying cycles. Slope cutting helps alleviate the adverse effects of wetting-drying cycles.
Study of Proton, Deuteron, and Triton at 54.4 GeV
Authors: Waqas M. , Peng G. X.
Published: April 2021

Transverse momentum spectra of proton, deuteron, and triton in gold-gold (Au-Au) collisions at 54.4 GeV are analyzed in different centrality bins by the blast wave model with Tsallis statistics. The model results are approximately in agreement with the experimental data measured by STAR Collaboration in special transverse momentum ranges. We extracted the kinetic freeze-out temperature, transverse flow velocity, and freeze-out volume from the transverse momentum spectra of the particles. It is observed that the kinetic freeze-out temperature is increasing from the central to peripheral collisions. However, the transverse flow velocity and freeze-out volume decrease from the central to peripheral collisions. The present work reveals the mass dependent kinetic freeze-out scenario and volume differential freeze-out scenario in collisions at STAR Collaboration. In addition, parameter

q

characterizes the degree of nonequilibrium of the produced system, and it increases from the central to peripheral collisions and increases with mass .
Potential Health Risks of Macro‐ and Microelements in Commercial Medicinal Plants Used to Treatment of Diabetes
Authors: de Souza Igor D. , Melo Elaine S. P. , Nascimento Valdir Aragão , Pereira Hugo S. , Silva Kassia R. N. , Espindola Paulo R. , Tschinkel Paula F. S. , Ramos Eliza M. , Reis Francisco J. M. , Ramos Iara B. , Paula Fernanda G. , Oliveira Karla R. W. , Lima Cleberson D. , Nunes Ângela A. , do Nascimento Valter Aragão
Published: April 2021

Information on the content of medicinal plants used in the treatment of diabetes is scarce in the literature. The objectives of this study were to determine the levels of macroelements and microelements in three different medicinal plant species including the dry samples and teas from Bauhinia forficata, Eleusine Indica, and Orthosiphon stamineus and assess the human health risks of ingestion of the tea. The content of the dry samples and teas was obtained using the technique of inductively coupled plasma optical emission spectrometry (ICP OES) after microwave digestion procedure. The hazard quotient (HQ) method was used to access the human health risks posed by heavy metal through tea consumption. The results revealed the presence of K, Mg, Na, P, Al, Fe, Zn, Mn, Cu, Ni, and Se in dry samples and plant teas. The dry plants have high concentration of K and P. All dry plants contain Mg, Na, Al, Fe, Mn, Ni, Zn, and Cu above the limit permissible level set by the World Health Organization (WHO). All the hazard index (HI) values in plant teas were found to be within safe limits for human consumption (HI < 1). The plants may have possible action benefits when used in popular medicine. However, the ingestion through capsules prepared by enclosing a plant powder or teas can be harmful to the health of diabetics. The prescription of this plant for the treatment of diabetes should be treated with caution.
Diagnosis and Prognosis of Retroperitoneal Liposarcoma: A Single Asian Center Cohort of 57 Cases
Authors: Xiao Jianchun , Liu Jianghao , Chen Minting , Liu Wei , He Xiaodong
Published: April 2021

Background. Liposarcoma is a soft tissue malignancy, commonly observed in the extremities. However, retroperitoneal liposarcoma is seldom reported and its diagnosis is frequently neglected. This study aims to present the clinical characteristics, diagnosis, and prognosis of five liposarcoma subtypes and report our experience of patient treatment. Methods. We conducted a single-center noninterventional retrospective study of 57 retroperitoneal liposarcoma patients admitted to Peking Union Medical College Hospital (PUMCH, Beijing, China) between July 2011 and December 2019. We collected and analyzed their demographic, clinical, imaging, histological, therapeutic, and prognostic data over a mean 4.5-year follow-up period. Results. Twenty-five (44%) patients were asymptomatic prior to diagnosis, with abdominal distension as the chief complaint in 18 (32%) patients and abdominal pain observed in 16 (28%) patients. Masses were evaluated by computed tomography (n = 48, 84%) or ultrasound (n = 25, 44%). Laparotomy (n = 52, 91%) was the dominant therapeutic modality rather than laparoscopy (n = 5, 9%). All patients were treated with R0 resection except two patients who underwent R2 resection. We conducted regular follow-ups every six months after surgery for a mean duration of 4.5 years. Recurrence was experienced by 14 (25%) patients and a further 9 (16%) died during follow-up. Conclusions. Abdominal distension and pain are chief complaints with liposarcoma. As the extremities are the main liposarcomas locations, the diagnosis of retroperitoneal liposarcoma is usually neglected. Since half of the patients are asymptomatic, timely diagnosis and treatment are highly dependent on regular ultrasound and computed tomography imaging. R0 resection is the key to retroperitoneal liposarcoma treatment. In comparison, patients who underwent R2 resection, which is considered a palliative treatment, had bad prognoses. Large, symptomatic dedifferentiated, and pleomorphic liposarcomas are more likely to have poor prognoses, while the prognosis for well-differentiated or myxoid liposarcoma is relatively good.
Experimental Studies on Cracking and Local Strain Behaviors of Rock-Like Materials with a Single Hole before and after Reinforcement under Biaxial Compression
Authors: Liao Jian , Zhao Yanlin , Tang Liming , Liu Qiang
Published: April 2021

In deep underground engineering, circular roadways are widely used; many rock engineering problems can usually be simplified as mechanical analysis of rock structures with holes. To reveal the influence of intrahole reinforcement on the mechanical properties of rock with a single hole, this paper takes the single-hole rock-like material specimens with different reinforcement conditions as the research object. The RYL600 rock shear rheometer was used to conduct biaxial compression tests and, combined with HD industrial cameras and high-precision strain gauges, to study the effects of different reinforcement thicknesses and different lateral pressure on the mechanical properties of single-hole rock-like materials during the total stress and strain process. The thickness of the reinforced aluminum alloy pipe in the whole test is divided into four types: 0, 1, 1.5, and 2 mm. Under different reinforcement conditions, it is divided into 4 series of 0, 0.5, 1, and 1.5 MPa according to the different lateral pressure. Research shows the following: (1) Under the same lateral pressure, as the reinforcement thickness of the aluminum alloy tube increases, the reinforcement effect of the aluminum alloy tube on the specimen increases, and the strength of the reinforced specimen is increased by 1.42%~33.04% compared with the strength of the unreinforced specimen; under the same reinforced thickness of the aluminum tube, the peak strength of the specimen increases with the increase of lateral pressure, and the peak strength of the specimen with lateral pressure is 3.34%~50.26% higher than that of the specimen without lateral pressure. (2) Increasing the lateral pressure can significantly reduce the primary tensile cracks of the specimen. As the reinforcement thickness increases, the primary tensile cracks and remote cracks of the specimen are significantly reduced, and the failure surface of the specimen gradually tends to the middle of the sample. (3) The failure modes of specimens with holes can be divided into five types: single bevel type I, single bevel type II, single bevel type III, bevel T type, and single part shear type. All of these five failure modes are shear cracks that develop into fracture surfaces, while remote cracks and primary tensile cracks do not develop into fracture surfaces.
In Vitro Antiplasmodial, Heme Polymerization, and Cytotoxicity of Hydroxyxanthone Derivatives
Authors: Zakiah Mistika , Syarif Rul Afiyah , Mustofa Mustofa , Jumina Jumina , Fatmasari Nela , Sholikhah Eti Nurwening
Published: April 2021

The previous study showed that xanthone had antiplasmodial activity. Xanthone, with additional hydroxyl groups, was synthesized to increase its antiplasmodial activity. One of the strategies to evaluate a compound that can be developed into an antimalarial drug is by testing its mechanism in inhibiting heme polymerization. In acidic condition, hematin can be polymerized to β-hematin in vitro, which is analog with hemozoin in Plasmodium. This study was conducted to evaluate the antiplasmodial activity of hydroxyxanthone derivative compounds on two strains of Plasmodium falciparum 3D-7 and FCR-3, to assess inhibition of heme polymerization activity and determine the selectivity of hydroxyxanthone derivative compounds. The antiplasmodial activity of each compound was tested on Plasmodium falciparum 3D-7 and FCR-3 with 72 hours incubation period, triplicated in three replications with the microscopic method. The compound that showed the best antiplasmodial activity underwent flow cytometry assay. Heme polymerization inhibition test was performed using the in vitro heme polymerization inhibition activity (HPIA) assay. The antiplasmodial activity and heme polymerization inhibition activity were expressed as the 50% inhibitory concentration (IC50). In vitro cytotoxicity was tested using the MTT assay method on Vero cell lines to determine its selectivity index. The results showed that among 5-hydroxyxanthone derivative compounds, the 1,6,8-trihydroxyxanthone had the best in vitro antiplasmodial activity on both 3D-7 and FCR-3 Plasmodium falciparum strains with IC50 values of 6.10 ± 2.01 and 6.76 ± 2.38 μM, respectively. The 1,6,8-trihydroxyxanthone showed inhibition activity of heme polymerization with IC50 value of 2.854 mM and showed the high selectivity with selectivity index of 502.2–556.54. In conclusion, among 5-hydroxyxanthone derivatives tested, the 1,6,8-trihydroxyxantone showed the best antiplasmodial activity and has heme polymerization inhibition activity and high selectivity.
Beyond Stamp Collecting: Evolutionary and Functional Genomics Advance Our Understanding of Cancer Biology
Authors: Lachance Joseph
Published: April 2021

In this issue of Cancer Research, Emami and colleagues leveraged genetic data from over 200,000 men of European descent to implicate rare alleles that are associated with prostate cancer. However, this study went beyond a simple description of statistical associations between genetic variants and cancer risk. Polygenic risk scores were applied to large cohorts from Kaiser Permanente and the UK Biobank, demonstrating the clinical utility of genetic predictors of disease risk. Furthermore, by placing their results in an evolutionary framework and integrating genetic information with functional data, the authors of this major study were able to bridge the gap between genome-wide association studies and the biological mechanisms underlying prostate cancer risk.

See related article by Emami et al., 1695
A Prospective Investigation of Circulating Metabolome Identifies Potential Biomarkers for Gastric Cancer Risk
Authors: Shu Xiang , Cai Hui , Lan Qing , Cai Qiuyin , Ji Bu-Tian , Zheng Wei , Shu Xiao-Ou
Published: April 2021

Background:

Metabolomics is widely used to identify potential novel biomarkers for cancer risk. No investigation, however, has been conducted to prospectively evaluate the role of perturbation of metabolome in gastric cancer development.

Methods:

250 incident cases diagnosed with primary gastric cancer were selected from the Shanghai Women’s Health and the Shanghai Men’s Health Study, and each was individually matched to one control by incidence density sampling. An untargeted global profiling platform was used to measure approximately 1,000 metabolites in prediagnostic plasma. Conditional logistic regression was utilized to generate ORs and P values.

Results:

Eighteen metabolites were associated with gastric cancer risk at P < 0.01. Among them, 11 metabolites were lysophospholipids or lipids of other classes; for example, 1-(1-enyl-palmitoyl)-GPE (P-16:0) (OR = 1.56; P = 1.89 × 10–4). Levels of methylmalonate, a suggested biomarker of vitamin B12 deficiency, was correlated with increased gastric cancer risk (OR = 1.42; P = 0.004). Inverse associations were found for three biomarkers for coffee/tea consumption (3-hydroxypyridine sulfate, quinate and N-(2-furoyl) glycine), although the associations were only significant when comparing cases that were diagnosed within 5 years after the blood collection to matched controls. Most of the identified associations were more profound in women and never smokers than their male or ever smoking counterparts and some with notable significant interactions.

Conclusions:

Our study identified multiple potential risk biomarkers for gastric cancer independent of Helicobacter pylori infection and other major risk factors.

Impact:

New risk-assessment tools to identify high-risk population could be developed to improve prevention of gastric cancer.

See related commentary by Drew et al., p. 1601
Female Immunity Protects from Cutaneous Squamous Cell Carcinoma
Authors: Budden Timothy , Gaudy-Marqueste Caroline , Craig Sarah , Hu Yuan , Earnshaw Charles H. , Gurung Shilpa , Ra Amelle , Akhras Victoria , Shenjere Patrick , Green Ruth , Jamieson Lynne , Lear John , Motta Luisa , Caulín Carlos , Oudit Deemesh , Furney Simon J. , Virós Amaya
Published: April 2021

Purpose:

Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation.

Experimental Design:

We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing.

Results:

We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation–damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women.

Conclusions:

This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.
Phase I Study of MEDI3726: A Prostate-Specific Membrane Antigen-Targeted Antibody–Drug Conjugate, in Patients with mCRPC after Failure of Abiraterone or Enzalutamide
Authors: de Bono Johann S. , Fleming Mark T. , Wang Judy S. , Cathomas Richard , Miralles Manuel Selvi , Bothos John , Hinrichs Mary Jane , Zhang Qu , He Peng , Williams Marna , Rosenbaum Anton I. , Liang Meina , Vashisht Kapil , Cho Song , Martinez Pablo , Petrylak Daniel P.
Published: April 2021

Purpose:

MEDI3726 is an antibody–drug conjugate targeting the prostate-specific membrane antigen and carrying a pyrrolobenzodiazepine warhead. This phase I study evaluated MEDI3726 monotherapy in patients with metastatic castration-resistant prostate cancer after disease progression on abiraterone and/or enzalutamide and taxane-based chemotherapy.

Patients and Methods:

MEDI3726 was administered at 0.015–0.3 mg/kg intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary objective was to assess safety, dose-limiting toxicities (DLT), and MTD/maximum administered dose (MAD). Secondary objectives included assessment of antitumor activity, pharmacokinetics, and immunogenicity. The main efficacy endpoint was composite response, defined as confirmed response by RECIST v1.1, and/or PSA decrease of ≥50% after ≥12 weeks, and/or decrease from ≥5 to <5 circulating tumor cells/7.5 mL blood.

Results:

Between February 1, 2017 and November 13, 2019, 33 patients received MEDI3726. By the data cutoff (January 17, 2020), treatment-related adverse events (TRAE) occurred in 30 patients (90.9%), primarily skin toxicities and effusions. Grade 3/4 TRAEs occurred in 15 patients (45.5%). Eleven patients (33.3%) discontinued because of TRAEs. There were no treatment-related deaths. One patient receiving 0.3 mg/kg had a DLT of grade 3 thrombocytopenia. The MTD was not identified; the MAD was 0.3 mg/kg. The composite response rate was 4/33 (12.1%). MEDI3726 had nonlinear pharmacokinetics with a short half-life (0.3–1.8 days). The prevalence of antidrug antibodies was 3/32 (9.4%), and the incidence was 13/32 (40.6%).

Conclusions:

Following dose escalation, no MTD was identified. Clinical responses occurred at higher doses, but were not durable as patients had to discontinue treatment due to TRAEs.
Next-Generation Sequencing of 487 Esophageal Adenocarcinomas Reveals Independently Prognostic Genomic Driver Alterations and Pathways
Authors: Sihag Smita , Nussenzweig Samuel C. , Walch Henry S. , Hsu Meier , Tan Kay See , Sanchez-Vega Francisco , Chatila Walid K. , De La Torre Sergio A. , Patel Assem , Janjigian Yelena Y. , Maron Steven , Ku Geoffrey Y. , Tang Laura H. , Hechtman Jaclyn , Shah Pari M. , Wu Abraham J. , Jones David R. , Molena Daniela , Solit David B. , Schultz Nikolaus , Berger Michael F.
Published: April 2021

Purpose:

To delineate recurrent oncogenic driver alterations and dysregulated pathways in esophageal adenocarcinoma and to assess their prognostic value.

Experimental Design:

We analyzed a large cohort of patients with lower esophageal and junctional adenocarcinoma, prospectively sequenced by MSK-IMPACT with high-quality clinical annotation. Patients were subdivided according to treatment intent, curative versus palliative, which closely mirrored clinical staging. Genomic features, alterations, and pathways were examined for association with overall survival using Cox proportional hazard models, adjusted for relevant clinicopathologic factors knowable at the time of diagnosis.

Results:

Analysis of 487 patients revealed 16 oncogenic driver alterations, mostly amplifications, present in ≥5% of patients. Patients in the palliative-intent cohort, compared with those in the curative-intent cohort, were more likely to have metastatic disease, ERBB2 amplifications, Cell-cycle and RTK–RAS pathway alterations, as well as a higher fraction of genome altered and rate of whole-genome doubling. In multivariable analyses, CDKN2A alterations, SMAD4 alterations, KRAS amplifications, Cell-cycle and TGFβ pathways, and overall number of oncogenic drivers were independently associated with worse overall survival. ERBB2 amplification was associated with improved survival, presumably due to trastuzumab therapy.

Conclusions:

Our study suggests that higher levels of genomic instability are associated with more advanced disease in esophageal adenocarcinoma. Furthermore, CDKN2A, KRAS, and SMAD4 represent prognostic biomarkers, given their strong association with poor survival.
Biallelic Mutations in DNAJB11are Associated with Prenatal Polycystic Kidney Disease in a Turkish Family
Authors: Ateş Esra Arslan , Turkyilmaz Ayberk , Delil Kenan , Alavanda Ceren , Söylemez Mehmet Ali , Geçkinli Bilgen Bilge , Ata Pinar , Arman Ahmet
Published: April 2021

Polycystic kidney disease (PKD) is a life-threatening condition resulting in end-stage renal disease. Two major forms of PKD are defined according to the inheritance pattern. Autosomal dominant PKD (ADPKD) is characterized by renal cysts, where nearly half of the patients suffers from renal failure in the 7th decade of life. Autosomal recessive PKD (ARPKD) is a rarer and more severe form presenting in childhood. Whole-exome sequencing (WES) analyses was performed to investigate molecular causes of the disease in the fetus. In this study, we present 2 fetuses prenatally diagnosed with PKD in a consanguineous family. WES analysis of the second fetus revealed a homozygous variant (c.740+1G>A) in DNAJB11 which is related to ADPKD. This study reveals that DNAJB11 biallelic mutations may cause an antenatal severe form of ARPKD and contributes to understanding the DNAJB11-related ADPKD phenotype. The possibility of ARPKD due to biallelic mutations in ADPKD genes should be considered in genetic counseling.
Real-World Therapeutic Outcomes of S-1 Adjuvant Chemotherapy for pStage II/III Gastric Cancer in the Elderly
Authors: Kunisaki Chikara , Sato Sho , Tsuchiya Nobuhiro , Kubo Hirokazu , Watanabe Jun , Sato Tsutomu , Takeda Kazuhisa , Tamura Yuko , Kasahara Kohei , Kosaka Takashi , Akiyama Hirotoshi , Endo Itaru
Published: April 2021

Background: The predictive factors for discontinuation of S-1 administration and prognostic factors in elderly patients with pStage II/III gastric cancer receiving S-1 adjuvant chemotherapy remain unclear. Methods: Between January 2004 and December 2016, 80 elderly gastric cancer patients (≥70 years) undergoing curative D2 gastrectomy were enrolled in this study. Predictive factors for completion of S-1 administration over 1 year, adverse events due to S-1 administration, and prognostic factors for overall survival (OS) and relapse-free survival (RFS) were evaluated. Results: Twenty-eight patients (35%) completed 8 courses of S-1. The median relative dose intensity was 82.1% (IQR 31.1–100%). The incidence rates of hematological and nonhematological adverse events were acceptable. Distal gastrectomy was an independent predictive factor for completion of S-1 administration (odds ratio [OR] 0.364; 95% confidence interval [CI] 0.141–0.939; p = 0.037). Higher postoperative neutrophil count/lymphocyte count (N/L) ratio and more advanced stage adversely influenced OS. Multivariate analysis revealed that a higher postoperative N/L ratio and more advanced stage adversely affected RFS. Conclusion: To complete adjuvant S-1 administration to elderly patients with pStage II/III gastric cancer, total gastrectomy should be avoided if possible. A new regimen for elderly gastric cancer patients with higher postoperative N/L ratios and more advanced stage should be established.
Chitin, Chitin Oligosaccharide, and Chitin Disaccharide Metabolism of Escherichia coli Revisited: Reassignment of the Roles of ChiA, ChbR, ChbF, and ChbG
Authors: Walter Axel , Friz Simon , Mayer Christoph
Published: April 2021

Escherichia coli is unable to grow on polymeric and oligomeric chitin, but grows on chitin disaccharide (GlcNAc-GlcNAc; N,N′-diacetylchitobiose) and chitin trisaccharide (GlcNAc-GlcNAc-GlcNAc; N,N′,N′′-triacetylchitotriose) via expression of the chb operon (chbBCARFG). The phosphotransferase system (PTS) transporter ChbBCA facilitates transport of both saccharides across the inner membrane and their concomitant phosphorylation at the non-reducing end, intracellularly yielding GlcNAc 6-phosphate-GlcNAc (GlcNAc6P-GlcNAc) and GlcNAc6P-GlcNAc-GlcNAc, respectively. We revisited the intracellular catabolism of the PTS products, thereby correcting the reported functions of the 6-phospho-glycosidase ChbF, the monodeacetylase ChbG, and the transcriptional regulator ChbR. Intracellular accumulation of glucosamine 6P-GlcNAc (GlcN6P-GlcNAc) and GlcN6P-GlcNAc-GlcNAc in a chbF mutant unraveled a role for ChbG as a monodeacetylase that removes the N-acetyl group at the non-reducing end. Consequently, GlcN6P- but not GlcNAc6P-containing saccharides likely function as coactivators of ChbR. Furthermore, ChbF removed the GlcN6P from the non-reducing terminus of the former saccharides, thereby degrading the inducers of the chb operon and facilitating growth on the saccharides. Consequently, ChbF was unable to hydrolyze GlcNAc6P-residues from the non-reducing end, contrary to previous assumptions but in agreement with structural modeling data and with the unusual catalytic mechanism of the family 4 of glycosidases, to which ChbF belongs. We also refuted the assumption that ChiA is a bifunctional endochitinase/lysozyme ChiA, and show that it is unable to degrade peptidoglycans but acts as a bona fide chitinase in vitro and in vivo, enabling growth of E. coli on chitin oligosaccharides when ectopically expressed. Overall, this study revises our understanding of the chitin, chitin oligosaccharide, and chitin disaccharide metabolism of E. coli.
Postoperative and Long-Term Endocrinologic Complications of Craniopharyngioma
Authors: Bereket Abdullah
Published: April 2021

Background: Craniopharyngioma (CP), despite being a malformational tumor of low histological grade, causes considerable morbidity and mortality mostly due to hypothalamo-pituitary dysfunction that is created by tumor itself or its treatment. Summary: Fluid-electrolyte disturbances which range from dehydration to fluid overload and from hypernatremia to hyponatremia are frequently encountered during the acute postoperative period and should be carefully managed to avoid permanent neurological sequelae. Hypopituitarism, increased cardiovascular risk, hypothalamic damage, hypothalamic obesity, visual and neurological deficits, and impaired bone health and cognitive function are the morbidities affecting the well-being of these patients in the long term. Key Messages: Timely and optimal treatment of early postoperative and long-term complications of CP is crucial for preserving quality of life of these patients.
High Cardiovascular Risk in Older Men With Severe Peripheral Artery Calcification on High-Resolution Peripheral QCT Scans
Authors: Szulc Pawel , Planckaert Catherine , Foesser Dominique , Patsch Janina , Chapurlat Roland
Published: April 2021

Objective:

Arterial calcification is associated with high cardiovascular risk. Our aim was to assess the utility of peripheral arterial calcification (PAC) in distal forearm and distal leg for the prediction of acute coronary syndrome (ACS) and major adverse cardiovascular event in older men.

Approach and Results:

In 815 home-dwelling older men, PAC was assessed on the scans of distal forearm and leg obtained by high-resolution peripheral quantitative computed tomography. PAC score (0–12) was calculated on the basis of the number and severity in small peripheral arteries. The information on ACS and major adverse cardiovascular event was collected prospectively for 8 years. PAC severity increased with age and body mass index (
P
<0.001). Median PAC score was higher in men with ischemic heart disease or pharmacologically treated diabetes (
P
<0.001). After adjustment for confounders, the risk of ACS was higher in men with severe PAC (6+) versus men with lower PAC (0–5; hazard ratio, 3.86 [95% CI, 1.65–9.02],
P
<0.005). After adjustment for confounders, the risk of major adverse cardiovascular event was higher in men with severe PAC (6+) versus men with lower PAC (hazard ratio, 2.58 [95% CI, 1.41–4.72],
P
<0.005). In men who did not have cardiovascular risk factors, severe PAC was associated with higher risk of ACS, for example, in men who did not self-report ischemic heart disease (hazard ratio, 6.62 [95% CI, 2.16–20.23],
P
<0.001).

Conclusions:

Severe PAC is associated with higher risk of ACS and major adverse cardiovascular event in older home-dwelling men, also in men without known ischemic heart disease. Incidentally found severe PAC can be a serious warning indicating high cardiovascular risk.
Hypertension, a Moving Target in COVID-19
Authors: Savoia Carmine , Volpe Massimo , Kreutz Reinhold
Published: April 2021

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associates with a considerable high rate of mortality and represents currently the most important concern in global health. The risk of more severe clinical manifestation of COVID-19 is higher in males and steeply raised with age but also increased by the presence of chronic comorbidities. Among the latter, early reports suggested that arterial hypertension associates with higher susceptibility to SARS-CoV-2 infection, more severe course and increased COVID-19–related deaths. Furthermore, experimental studies suggested that key pathophysiological hypertension mechanisms, such as activation of the renin-angiotensin system (RAS), may play a role in COVID-19. In fact, ACE2 (angiotensin-converting-enzyme 2) is the pivotal receptor for SARS-CoV-2 to enter host cells and provides thus a link between COVID-19 and RAS. It was thus anticipated that drugs modulating the RAS including an upregulation of ACE2 may increase the risk for infection with SARS-CoV-2 and poorer outcomes in COVID-19. Since the use of RAS-blockers, ACE inhibitors or angiotensin receptor blockers, represents the backbone of recommended antihypertensive therapy and intense debate about their use in the COVID-19 pandemic has developed. Currently, a direct role of hypertension, independent of age and other comorbidities, as a risk factor for the SARS-COV-2 infection and COVID-19 outcome, particularly death, has not been established. Similarly, both current experimental and clinical studies do not support an unfavorable effect of RAS-blockers or other classes of first line blood pressure lowering drugs in COVID-19. Here, we review available data on the role of hypertension and its management on COVID-19. Conversely, some aspects as to how the COVID-19 affects hypertension management and impacts on future developments are also briefly discussed. COVID-19 has and continues to proof the critical importance of hypertension research to address questions that are important for global health.
Arterial Stiffness and Cardiovascular Risk in Hypertension
Authors: Boutouyrie Pierre , Chowienczyk Phil , Humphrey Jay D. , Mitchell Gary F.
Published: April 2021

Arterial stiffness, a leading marker of risk in hypertension, can be measured at material or structural levels, with the latter combining effects of the geometry and composition of the wall, including intramural organization. Numerous studies have shown that structural stiffness predicts outcomes in models that adjust for conventional risk factors. Elastic arteries, nearer to the heart, are most sensitive to effects of blood pressure and age, major determinants of stiffness. Stiffness is usually considered as an index of vascular aging, wherein individuals excessively affected by risk factor exposure represent early vascular aging, whereas those resistant to risk factors represent supernormal vascular aging. Stiffness affects the function of the brain and kidneys by increasing pulsatile loads within their microvascular beds, and the heart by increasing left ventricular systolic load; excessive pressure pulsatility also decreases diastolic pressure, necessary for coronary perfusion. Stiffness promotes inward remodeling of small arteries, which increases resistance, blood pressure, and in turn, central artery stiffness, thus creating an insidious feedback loop. Chronic antihypertensive treatments can reduce stiffness beyond passive reductions due to decreased blood pressure. Preventive drugs, such as lipid-lowering drugs and antidiabetic drugs, have additional effects on stiffness, independent of pressure. Newer anti-inflammatory drugs also have blood pressure independent effects. Reduction of stiffness is expected to confer benefit beyond the lowering of pressure, although this hypothesis is not yet proven. We summarize different steps for making arterial stiffness measurement a keystone in hypertension management and cardiovascular prevention as a whole.
Oxidative Stress and Hypertension
Authors: Griendling Kathy K. , Camargo Livia L. , Rios Francisco J. , Alves-Lopes Rhéure , Montezano Augusto C. , Touyz Rhian M.
Published: April 2021

A link between oxidative stress and hypertension has been firmly established in multiple animal models of hypertension but remains elusive in humans. While initial studies focused on inactivation of nitric oxide by superoxide, our understanding of relevant reactive oxygen species (superoxide, hydrogen peroxide, and peroxynitrite) and how they modify complex signaling pathways to promote hypertension has expanded significantly. In this review, we summarize recent advances in delineating the primary and secondary sources of reactive oxygen species (nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, endoplasmic reticulum, and mitochondria), the posttranslational oxidative modifications they induce on protein targets important for redox signaling, their interplay with endogenous antioxidant systems, and the role of inflammasome activation and endoplasmic reticular stress in the development of hypertension. We highlight how oxidative stress in different organ systems contributes to hypertension, describe new animal models that have clarified the importance of specific proteins, and discuss clinical studies that shed light on how these processes and pathways are altered in human hypertension. Finally, we focus on the promise of redox proteomics and systems biology to help us fully understand the relationship between ROS and hypertension and their potential for designing and evaluating novel antihypertensive therapies.
Pathophysiology of Hypertension
Authors: Harrison David G. , Coffman Thomas M. , Wilcox Christopher S.
Published: April 2021

Dr Irvine Page proposed the Mosaic Theory of Hypertension in the 1940s advocating that hypertension is the result of many factors that interact to raise blood pressure and cause end-organ damage. Over the years, Dr Page modified his paradigm, and new concepts regarding oxidative stress, inflammation, genetics, sodium homeostasis, and the microbiome have arisen that allow further refinements of the Mosaic Theory. A constant feature of this approach to understanding hypertension is that the various nodes are interdependent and that these almost certainly vary between experimental models and between individuals with hypertension. This review discusses these new concepts and provides an introduction to other reviews in this compendium of
Circulation Research
.
Rosenzweig on Human Redemption: Neither Nothing nor Everything, but Only Something
Authors: Wolfson Elliot R.
Published: April 2021

Despite Franz Rosenzweig’s unequivocal condemnation of Gershom Scholem, his own view of the world and the possibility of human redemption therein is in some respect very close to the nihilistic sensibility and its gnostic underpinning. Although Rosenzweig obviously did not consider himself either a nihilist or a gnostic, the latter term can well be applied even to Rosenzweig’s mature speculation in The Star of Redemption and other writings from the 1920s. In spite of his initial rejection of negative theology in the Star, the swerve of Rosenzweig’s path winds its way to an apophasis of the apophasis, a turn that is encapsulated in the astounding statement, “That God is nothing becomes just as much a figurative sentence as the other one, that he is truth.”
Jurisdictional Challenges and Institutional Novelties – Procedural Developments in Law of the Sea Dispute Settlement in 2020
Authors: Lando Massimo , Oral Nilüfer
Published: April 2021

In 2020, law of the sea tribunals rendered one decision on jurisdiction and decided one case on the merits. First, the arbitral tribunal in the Azov Sea and Kerch Strait dispute dismissed the jurisdictional objections raised by the Russian Federation and thus will proceed to hear the merits of Ukraine’s claims. Second, the arbitral tribunal in the Enrica Lexie Incident case found, after upholding its jurisdiction in relation to the dispute before it, that the Italian marines who had shot an Indian fisherman in India’s Exclusive Economic Zone were entitled to immunity under international law and that Italy had breached certain provisions of the United Nations Convention on the Law of the Sea (UNCLOS). These two arbitral awards have confirmed and developed certain trends in the jurisprudence of law of the sea tribunals. In addition, a novelty in 2020 was the conclusion of a Model Agreement between Singapore and the International Tribunal for the Law of the Sea (ITLOS), for the latter to be able to discharge its judicial business in Singapore. Last, the Meeting of the States Parties to UNCLOS elected five new members of ITLOS and re-elected two.
Zebrus pallaoroi sp. nov.: a new species of goby (Actinopterygii: Gobiidae) from the Mediterranean Sea with a dna-based phylogenetic analysis of the Gobius-lineage
Authors: Kovačić Marcelo , Šanda Radek , Čekovská Katarína , Soukupová Tereza , Vukić Jasna
Published: April 2021

The gobies (Gobiidae) are the most diverse fish family in the Mediterranean Sea. Nevertheless, knowledge on their diversity, taxonomy, and phylogenetic relationships is still inadequate. The phylogenetic analyses reveal two genetically highly distinct clades among specimens identified as Zebrus zebrus. A new species, Zebrus pallaoroi sp. nov., is described based on an integrative approach. The neotype of Zebrus zebrus is designated. Genetic data confirm a pronounced level of divergence between Z. pallaoroi and Z. zebrus, with the mean genetic distance on cytochrome b being 18.1% and 1.07% on rhodopsin. Phylogenetic relationships within the Gobius-lineage were estimated on both markers. Morphologically, Z. pallaoroi is distinguished from the only congener Z. zebrus by having a snout longer than its eye, posterior nostril about 4/5–9/10 of the anterior nostril, eye diameter 4.3−4.7 in head length, ventrolateral head ridges transversally connected on the anterior side by a short transversal ridge, anterior membrane midline depth about 2/3 of the spinous ray, head canal pore α diameter about half of the distance between pore ρ and ρ1, suborbital sensory papillae row 5i going downwards to or near the level of row d, the distance between row 5i and row d absent or much smaller than the length of row 5i, and the body with ten to eleven vertical dark brown bands. Zebrus pallaoroi was recorded from the southern Adriatic, northern Ionian, and northern and western Aegean Seas, and is a cryptobenthic fish from very shallow waters.