bluuebunny/crossref_metadata_2025 huggingface dataset:
Frailty in older patients undergoing emergency colorectal surgery: USA National Surgical Quality Improvement Program analysis
Authors: Simon H L , Paula T , Luz M M , Nemeth S K , Moug S J , Keller D S
Published: July 2020

Background

Frailty is associated with advancing age and may result in adverse postoperative outcomes. A suspected growing elderly population needing emergency colorectal surgery stimulated this study of the prevalence and impact of frailty.

Methods

Elderly patients (defined as aged at least 65 years by Medicare and the United States Census Bureau) who underwent emergency colorectal resection between 2012 and 2016 were identified from the American College of Surgeons National Surgical Quality Improvement Program population database. The five-item modified frailty index (mFI-5) score was calculated, and patients stratified into groups 0, 1 or 2 +. Main outcome measures were the prevalence of frailty, and its impact on 30-day postoperative morbidity, mortality, reoperation, duration of hospital stay (LOS), discharge destination and readmission.

Results

A total of 10 025 patients were identified with a median age 75 years, of whom 41·8 per cent were men. The majority (87·7 per cent) had an ASA fitness grade of III or greater and 3129 (31·2 per cent) were frail (mFI-5 group 2+). Major morbidity occurred in one-third of patients and the postoperative mortality rate was 15·9 per cent. Some 52·0 per cent of patients had a prolonged hospital stay and 11·0 per cent were readmitted. Although most patients (88·0 per cent) lived independently before surgery, only 45·4 per cent were discharged home directly. Frailty (mFI-5 2+) predicted mortality, overall and major morbidity, reoperation, prolonged LOS, discharge to an institution and readmission, but frailty was independent of sex.

Conclusion

Frailty is associated with morbidity, mortality and loss of independence in elderly patients needing emergency colorectal surgery.
Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis
Authors: Yamada S , Fujii T , Yamamoto T , Takami H , Yoshioka I , Yamaki S , Sonohara F , Shibuya K , Motoi F , Hirano S , Murakami Y , Inoue H , Hayashi M , Murotani K , Kitayama J , Ishikawa H , Kodera Y , Sekimoto M , Satoi S
Published: July 2020

Background

Intraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.

Methods

The frequencies of dose-limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom-relieving effects, safety and overall survival.

Results

The recommended doses of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0–22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1-year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3–4 haematological toxicities developed in 35 of 46 patients, whereas non-haematological adverse events occurred in seven patients.

Conclusion

Adding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability.
Alibi believability: Corroborative evidence and contextual factors
Authors: Allison Meredith , Jung Sandy , Benjamin Amanda C.
Published: July 2020

A disbelief in alibis is one contributor to wrongful convictions. One reason that triers‐of‐fact may disbelieve alibis is that they lack evidence to corroborate the whereabouts of the suspect at the time of the crime. Contextual factors, such as when the alibi was disclosed and what was the nature of the crime, can also affect alibi believability. This paper outlines two studies where mock jurors evaluated an investigation and trial description online and rated alibi believability, defendant character trait ratings, and verdicts. Both studies examined the impact of corroborative alibi evidence and the timing of the alibi disclosure. In addition, Study 1 included the type of crime and Study 2 included the number of alibi corroborators as additional independent variables. We hypothesized that alibis would be viewed more positively when they were disclosed earlier rather than later, were corroborated by strong physical evidence and multiple corroborators, and involved less violent offenses. As hypothesized, in both studies, alibis with strong physical evidence were thought to be more believable than those with no physical evidence but the number of corroborators and type of crime did not affect any dependent measures. Delayed timing had some negative effects on views of the defendant's character. Corroborative physical evidence affected alibi believability consistently, and contextual factors mattered less. Both implications and suggestions for future research are further discussed.
The Effect of TIGAR Knockdown on Apoptotic and Epithelial‐Mesenchymal Markers Expression in Doxorubicin‐Resistant Non‐Small Cell Lung Cancer A549 Cell Lines
Authors: Agca Can Ali , Kırıcı Mahinur , Nedzvetsky Victor S. , Gundogdu Ramazan , Tykhomyrov Artem A.
Published: July 2020

Resistance to chemotherapeutic drugs is a critical problem in cancer therapy, but the underlying mechanism has not been fully elucidated. TP53‐induced glycolysis regulatory phosphatase (TIGAR), an important glycolysis and apoptosis regulator, plays a crucial role in cancer cell survival by protecting cells against oxidative stress‐induced apoptosis. In the present study, we investigated whether TIGAR is involved in epithelial‐mesenchymal transition (EMT) in doxorubicin (DOX)‐resistant human non‐small cell lung cancer (NSCLC), A549/DOX cells. We found that the expression of TIGAR was significantly higher in A549/DOX cells than in the parent A549 cell lines. siRNA‐mediated TIGAR knockdown reduced migration, viability and colony survival of doxorubicin‐resistant lung cancer cells. Also, TIGAR knockdown decreased pro‐survival protein Bcl‐2 and increased pro‐apoptotic Bax and cleaved poly (ADP‐ribose) polymerase (PARP). Moreover, TIGAR depletion significantly up‐regulated both caspase‐3 and caspase‐9 expression. Furthermore, TIGAR depletion up‐regulated the expression of E‐cadherin and down‐regulated the expression of vimentin. These results indicate that TIGAR knockdown may inhibit EMT in doxorubicin (DOX)‐resistant human NSCLC and may represent a therapeutic target for a non‐small lung cancer cells chemoresistance.
Mitral isthmus block is associated with favorable outcomes after reablation for long‐standing persistent atrial fibrillation
Authors: Wang Xin‐hua , Kong Ling‐cong , Li Zheng , Nie Peng , Pu Jun
Published: July 2020

Background

Mitral isthmus (MI) ablation was limited due to technical challenges in the index ablation for long‐standing persistent atrial fibrillation (LPeAF). The role of adjunctive MI ablation was controversial.

Hypothesis

MI block could be achieved in most patients undergoing repeat LPeAF ablation and was associated with favorable clinical outcomes.

Methods

Of 87 consecutively patients undergoing reablation for recurrent atrial tachyarrhythmias (ATa), 41 patients with residual MI conduction but without pulmonary vein reconnection or left atrial roof conduction were enrolled to treat recurrent atrial flutter (AFL) (n = 20) and AF (n = 21). After AFL ablation and AF cardioversion, MI conduction gaps (CGs) were mapped and closed.

Results

MI line was successfully blocked in 37 (90.2%) of 41 patients after closing 1.4 ± 0.5 CGs (31 endocardial CGs and 16 epicardial ones) in the initial MI lines. CGs were more often located at the endocardial sites close to the lateral ridge between left atrial appendage and left‐sided PVs, midportion of MI and at the epicardial breakthroughs within coronary sinus. At the end of 16.0 ± 1.9 months' follow‐up, 31 (83.8%) of 37 patients with MI block and 1 of 4 patients without MI block were free of further recurrence of ATa off anti‐arrhythmic drugs. MI block was positively associated with ATa‐free survival by Cox's regression analysis (hazard ratio [HR]: 0.012, 95% confidence interval [CI]: 0.000‐0.456, P = .02).

Conclusions

MI block could be achieved in the majority of patients during repeat ablation for LPeAF. MI block was associated with favorable clinical outcomes after LPeAF reablation.
Roots in Unique Land Lead to Life‐Long Career of Discovery
Authors: Rackley Denice
Published: July 2020

Deep roots in his home town, a closed door, thirst for knowledge, and an inquisitive spirit enabled CCA Bruce Palmer to work his way up in an agronomy company only to remain on the ground floor.
Lignin Source and Structural Characterization
Authors: Sun Run‐Cang
Published: July 2020

Lignin is a primary component of lignocellulosic biomass and an underutilized feedstock in the growing pulping and biofuel industries. Currently, over 50 million tons of industrial lignin are produced annually from pulping and bioethanol processes in the world. Around 95 % of industrial lignin is burned as fuel in heat and power plants due to its complicated, destructive, and condensed structures hindering direct industrial utilization, while the remaining 5 % of lignin is used for potential applications, such as additives, binders, dispersants, and surfactants, through modification. Meanwhile, different biorefinery processes also produce a considerable amount of lignin with various structural features and properties. The development of technologies for its structural characterization is currently desirable for lignin valorization, which will improve the techno‐economics of applications of lignins in industries.
Optimal approximation of asymmetric type fractional‐order bandpass Butterworth filter using decomposition technique
Authors: Mahata Shibendu , Kar Rajib , Mandal Durbadal
Published: July 2020

In this letter, the optimal rational approximation of fractional‐order bandpass Butterworth filter (FOBBF) is presented. The transfer function of the FOBBF is decomposed into a multiplication of first‐order and second‐order terms. As a result, the design stability conditions can be easily satisfied using only the variable boundary constraints. The proposed technique generalizes the symmetric fractional‐order roll‐off characteristic as only a special case of the asymmetric one. Several examples are presented to validate the modeling efficacy.
An FPGA‐based switching photovoltaic‐connected inverter topology for leakage current suppression in grid‐connected utilizations
Authors: Ghaderi Davood
Published: July 2020

This study presents a symmetrical photovoltaic (PV)‐connected inverter topology for eliminating the common‐state leakage current in grid‐connected inverters. A new inverter topology is introduced that minimizes the leakage current, increases efficiency, and is economically viable because it consists of six power switches and two power diodes that, compared with similar ones, consist of the same element numbers. In this inverter, power losses are lower than popular topologies such as H5, H6, and HERIC, and the voltage stresses of the switches are reduced. These features are due to the unique composition of the inverter branches and the location of the switches and diodes and the formation of a suitable freewheeling path for the current. The freewheeling path separates the alternating current (AC) side from the direct current side in the converter and cuts off the PV array leakage current to the AC grid. This will improve network reliability indices and maintain conservation standards. Finally, the content of this method is validated by comparing the proposed inverter with the existing conventional topologies. A prototype has been implemented for the performance analysis of the proposed inverter and results presented.
Development and characterisation of NKp44‐based chimeric antigen receptors that confer T cells with NK cell‐like specificity
Authors: Kasahara Yasushi , Shin Chansu , Kubo Nobuhiro , Mihara Keichiro , Iwabuchi Haruko , Takachi Takayuki , Imamura Masaru , Saitoh Akihiko , Imai Chihaya
Published: July 2020

Objectives

One of the reasons as to why chimeric antigen receptors (CAR)‐T cell therapy for malignancies other than CD19‐ or BCMA‐positive tumors has yet to produce remarkable progress is the paucity of targetable antigens. NKp44 is only expressed by activated natural killer cells and detects a variety of transformed cells, while it reportedly does not react with normal tissues. The aim of this study is to develop CAR‐T cell that can target multiple types of tumor cells.

Methods

We created a series of novel CAR constructs in first‐generation (1G) and second‐generation (2G) CAR format with the extracellular immunoglobulin‐like domain of NKp44 (NKp44‐CAR).

Results

Transduction of the best 1G construct into human primary T cells led to specific cytotoxic effects and cytokine secretion upon encountering multiple types of neoplastic cells including AML, T‐ALL and childhood solid tumors. Replacement of the extracellular hinge domain of NKp44 with that of CD8α resulted in diminished CAR function. The 1G NKp44‐CAR‐T cells exhibited significantly better tumor control in long‐term co‐culture assays compared with activated NK cells, as well as with NK cells transduced with identical NKp44‐CAR. T cells transduced with the best 2G‐CAR construct with 4‐1BB co‐stimulatory domain proliferated at significantly higher levels upon single antigen exposure and showed significantly better tumor control compared with the 1G‐CAR and 2G‐CAR with CD28 co‐stimulatory domain.

Conclusions

NKp44‐based CAR endows T cells with NK cell‐like anti‐tumor specificity. The CAR gene created in this study will be useful for the development of novel gene‐modified T‐cell immunotherapy.
Novel pathogenic mutations identified in the first Chinese pedigree of complete C6 deficiency
Authors: Li Philip H , Wong William WY , Leung Evelyn NY , Lau Chak‐sing , Au Elaine
Published: July 2020

Objectives

Complete C6 deficiency (C6Q0) is a rare primary immunodeficiency leading to increased susceptibility to recurrent Neisseria infections. Patients with C6Q0 have mostly been reported in individuals of African ancestry previously, but never in Chinese. We identify the first Chinese patients with C6Q0 through family screening of an index case presenting with recurrent Neisseria meningitis with septicaemia and performed extensive clinical, serological and genetic investigations.

Methods

Two variants in C6 were identified by next‐generation sequencing and confirmed by Sanger sequencing in an index case of C6Q0. Immunological investigations, complement haemolytic assays (CH50/AH50), C6 gene sequencing and quantification of serum C6 levels were performed for all available members of his nonconsanguineous family.

Results

Three C6Q0 patients were identified with near‐absent C6 levels, absent CH50/AH50 activity and compound heterozygous for two nonsense mutations in the C6 gene: NM_000065.4:c.1786C>T (p.Arg596Ter) and NM_000065.4:c.1816C>T (p.Arg606Ter). Neither mutations have been reported to be pathogenic previously. Two other family members who were heterozygous for either p.Arg596Ter or and p.Arg606Ter had intermediate C6 levels but preserved CH50/AH50 activity. These two loss‐of‐function mutations showed a strong genotype–phenotype correlation in C6 levels.

Conclusions

We report on two compound heterozygous mutations in C6, p.Arg596Ter and p.Arg606Ter inherited in three patients of the first recorded Chinese pedigree of C6Q0. Neither mutations had been reported to be pathogenic previously. We demonstrate that heterozygous family members with subtotal C6 levels had preserved complement haemolytic function and demonstrate a threshold effect of C6 protein level.
Observation of 1D−1S forbidden optical emission of atomic oxygen in atmospheric‐pressure N2/O2 plasma jet
Authors: Sasaki Koichi , Nishiyama Shusuke , Shirai Naoki
Published: July 2020

We observed green optical emission from an atmospheric‐pressure N2/O2 plasma jet. The green optical emission was composed of a line emission at λ = 557.71 ± 0.03 nm and a broadband component at 530 ≤ λ ≤ 560 nm. The line emission was assigned to the 1D−1S forbidden transition of atomic oxygen, whereas the broadband emission was due to the formation of O(1S)N2 excimer. We measured the absolute densities of O(1S) and O(1S)N2 using a spectrograph with the absolute sensitivity calibration, and we discussed the kinetics in the green plasma jet on the basis of the absolute O(1S) and O(1S)N2 densities. According to the rate coefficients and the transition probabilities reported in literature, the present experimental results are explained if the densities of and O(3P) are 9 × 1013 and 3 × 1013cm−3, respectively.
Hybrid genetic and shuffled frog‐leaping algorithm for neural network structure optimization and learning model to predict free spectrum in cognitive radio
Authors: Supraja P. , Babu S. , Gayathri V.M. , Divya G.
Published: July 2020

Cognitive radio, which is called an intelligent radio, will dynamically access the available spectrum. This mechanism will bring revolt in wireless communication, which lightens the spectrum utilization problem. Machine learning plays a vital role in every technology. Here, in cognitive radio, it helps train the model to predict the free spectrum. The cognitive clients utilize range‐detecting procedures to detect the groups previously transmitting on them to stay away from impact with the authorized clients that prompts deferral and moderates more vitality. To decrease postponement and vitality utilization and to foresee the future use of channels, range expectation procedures are utilized. Spectrum prediction is used to anticipate the future channel status in light of gathered chronicled information; here, to take care of the issue, the neural system‐based spectrum prediction utilizes a backpropagation training model that has been proposed. To enhance the structure of the neural system and to decrease the forceful weight auxiliary pattern, genetic algorithm (GA) along with the hybrid combination of shuffled frog‐leaping algorithm (SFLA) is proposed. Here, GA has been utilized to abstain from catching nearby ideal solutions. The selection, crossover, and mutation functions were performed to build the haphazardness, which stretches out the populace unite to the set that contains the global ideal solution. SFLA has been proposed for structure improvement; the paired structure has been recommended to demonstrate the memes with the motivation behind building up a subaccumulation with lesser measurements than that of the original group where recognizing affectability and precision would be versatile with that of the primary status. Simulation results show the GA‐SFLA‐based hybrid algorithm that is used has increased the results of getting the best weights by improving the system; additionally, the proposed conspire results show high forecast accuracy.
Interface Effect of Ru‐MoS2 Nanoflowers on Lignin Substrate for Enhanced Hydrogen Evolution Activity
Authors: Xu Yeqing , Jiang Xingxing , Shao Gonglei , Xiang Haiyan , Si Sisi , Li Xing , Hu Travis Shihao , Hong Guo , Dong Shengyi , Li Huimin , Feng Yexin , Liu Song
Published: July 2020

The catalytic performance of Molybdenum disulfide (MoS2) has been still far from that of Pt‐based catalysts for inadequate active sites and sluggish electron transfer kinetics. Through engineering the interface between MoS2‐based materials and supported substrates, hybrid Ru‐doped MoS2 on carbonized lignin (CL) is designed and prepared as efficient catalyst for hydrogen evolution reaction (HER). The CL substrate not only facilitates the growth of MoS2 nanoflowers, but also promotes the electron transfer. Ru doping increases active sites greatly for HER. The hybrid catalyst achieves a low onset overpotential of 25 mV and a low Tafel slope of 46 mV dec−1. The favorable HER activity ascribes to the interfacial interaction between MoS2 and CL. Density functional theory calculations further confirm the improved HER performance with doped Ru atoms. This study presents a prototype application to design electrocatalysts with enhanced carrier mobility and high‐density active sites based on interface effect.
Clinical and genetic characteristics of patients with Doose syndrome
Authors: Hinokuma Nodoka , Nakashima Mitsuko , Asai Hideyuki , Nakamura Kazuyuki , Akaboshi Shinjiro , Fukuoka Masataka , Togawa Masami , Oana Shingo , Ohno Koyo , Kasai Mariko , Ogawa Chikako , Yamamoto Kazuna , Okumiya Kiyohito , Chong Pin Fee , Kira Ryutaro , Uchino Shumpei , Fukuyama Tetsuhiro , Shinagawa Tomoe , Miyata Yohane , Abe Yuichi , Hojo Akira , Kobayashi Kozue , Maegaki Yoshihiro , Ishikawa Nobutsune , Ikeda Hiroko , Amamoto Masano , Mizuguchi Takeshi , Iwama Kazuhiro , Itai Toshiyuki , Miyatake Satoko , Saitsu Hirotomo , Matsumoto Naomichi , Kato Mitsuhiro
Published: July 2020

Objective

To elucidate the genetic background and genotype‐phenotype correlations for epilepsy with myoclonic‐atonic seizures, also known as myoclonic‐astatic epilepsy (MAE) or Doose syndrome.

Methods

We collected clinical information and blood samples from 29 patients with MAE. We performed whole‐exome sequencing for all except one MAE case in whom custom capture sequencing identified a variant.

Results

We newly identified four variants: SLC6A1 and HNRNPU missense variants and microdeletions at 2q24.2 involving SCN1A and Xp22.31 involving STS. Febrile seizures preceded epileptic or afebrile seizures in four patients, of which two patients had gene variants. Myoclonic‐atonic seizures occurred at onset in four patients, of which two had variants, and during the course of disease in three patients. Variants were more commonly identified in patients with a developmental delay or intellectual disability (DD/ID), but genetic status was not associated with the severity of DD/ID. Attention‐deficit/hyperactivity disorder and autistic spectrum disorder were less frequently observed in patients with variants than in those with unknown etiology.

Significance

MAE patients had genetic heterogeneity, and HNRNPU and STS emerged as possible candidate causative genes. Febrile seizures prior to epileptic seizures and myoclonic‐atonic seizure at onset indicate a genetic predisposition to MAE. Comorbid conditions were not related to genetic predisposition to MAE.
Prelacrimal approach vs conventional surgery for inverted papilloma in the maxillary sinus
Authors: Nakayama Tsuguhisa , Tsunemi Yasuhiro , Kuboki Akihito , Asaka Daiya , Okushi Tetsushi , Tsukidate Toshiharu , Otori Nobuyoshi , Kojima Hiromi , Haruna Shin‐ichi
Published: July 2020

Background

The prelacrimal approach, termed endoscopic modified medial maxillectomy (EMMM), has recently been applied for treatment of inverted papilloma (IP) in the maxillary sinus. EMMM provides wider access to the maxillary sinus while preserving the inferior turbinate and nasolacrimal duct.

Methods

We reviewed patients with IP in the maxillary sinus to compare the surgical results obtained by conventional surgery (ie, endoscopic maxillary sinus antrostomy or in combination with the Caldwell‐Luc approach) with those obtained by EMMM.

Results

All patients had a T3 on the Krouse staging system, and the average follow‐up time was 46.0 months. Of the 18 patients in the conventional group, recurrence was seen in 3 patients (16.6%). No recurrence was seen in the 27 patients who showed preservation of the inferior turbinate and nasolacrimal duct, and no complications occurred in the EMMM group.

Conclusions

EMMM is an effective surgical approach that reduces recurrence with fewer complications.
Drugging “undruggable” genes for cancer treatment: Are we making progress?
Authors: Duffy Michael J. , Crown John
Published: July 2020

RAS, TP53 (p53) and MYC are among the most frequently altered driver genes in cancer. Thus, RAS is the most frequently mutated oncogene, MYC the most frequently amplified gene and TP53 the most frequently mutated tumor suppressor gene and overall the most frequently mutated gene in cancer. Theoretically, therefore, these genes are highly attractive targets for cancer treatment. However, as the protein products of each of these genes lack an accessible hydrophobic pocket into which low molecular weight compounds might bind with high affinity, they have proved difficult to target and have traditionally been referred to as “undruggable.” Despite this branding, several low molecular weight compounds targeting each of these proteins have recently been reported to have anticancer activity in preclinical models. Indeed, several drugs inhibiting mutant KRAS, MYC overexpression or reactivating mutant p53 have undergone or are currently undergoing clinical trials. For targeting mutant KRAS and reactivating mutant p53, trials have progressed to a Phase III stage, that is, the mutant‐p53 reactivating drug, APR‐246 is currently being investigated in patients with myelodysplastic syndrome (MDS) and the RAS inhibitor, rigosertib is also undergoing evaluation in patients with MDS. Although there appears to be no directly acting MYC inhibitor currently being tested in a clinical trial, an anti‐MYC compound, known as OmoMYC has been extensively validated in multiple preclinical models and is being developed for clinical evaluation. Based on current evidence, the traditional perception of RAS, p53 and MYC as being “undruggable” would appear to be coming to an end.
Vulvar intraepithelial neoplasia: Incidence and long‐term risk of vulvar squamous cell carcinoma
Authors: Thuijs Nikki B. , van Beurden Marc , Bruggink Annette H. , Steenbergen Renske D. M. , Berkhof Johannes , Bleeker Maaike C. G.
Published: July 2020

The risk of vulvar squamous cell carcinoma (VSCC) in patients with high‐grade vulvar intraepithelial neoplasia (VIN) is considered lower in high‐grade squamous intraepithelial lesion (HSIL) compared to differentiated VIN (dVIN), but studies are limited. Our study investigated both the incidence of high‐grade VIN and the cumulative incidence of VSCC in patients with HSIL and dVIN separately. A database of women diagnosed with high‐grade VIN between 1991 and 2011 was constructed with data from the Dutch Pathology Registry (PALGA). The European standardized incidence rate (ESR) and VSCC risk were calculated, stratified for HSIL and dVIN. The effects of type of VIN (HSIL vs dVIN), age and lichen sclerosis (LS) were estimated by Cox regression. In total, 1148 patients were diagnosed with high‐grade VIN between 1991 and 2011. Between 1991‐1995 and 2006‐2011, the ESR of HSIL increased from 2.39 (per 100 000 woman‐years) to 3.26 and the ESR of dVIN increased from 0.02 to 0.08. The 10‐year cumulative VSCC risk was 10.3%; 9.7% for HSIL and 50.0% for dVIN (log rank P < .001). Type of VIN, age and presence of LS were independent risk factors for progression to VSCC, with hazard ratios of 3.0 (95% confidence interval [CI] 1.3‐7.1), 2.3 (95% CI 1.5‐3.4) and 3.1 (95% CI 1.8‐5.3), respectively. The incidence of high‐grade VIN is rising. Because of the high cancer risk in patients with dVIN, better identification and timely recognition are urgently needed.
Survival impact of adjuvant chemotherapy in patients with stage IIA colon cancer: Analysis of the National Cancer Database
Authors: Achilli Pietro , Crippa Jacopo , Grass Fabian , Mathis Kellie L. , D'Angelo Anne‐Lise D. , Abd El Aziz Mohamed A. , Day Courtney N. , Harmsen William S. , Larson David W.
Published: July 2020

Utility of adjuvant chemotherapy for stage II cancer remains a matter of debate. Clinical guidelines suggest adjuvant chemotherapy for stage II tumors with high‐risk features, in particular T4 tumors. However, limited consensus exists regarding the importance of other high‐risk features (lymphovascular or perineural invasion, microsatellite instability). Our study aimed to investigate the impact of adjuvant chemotherapy for stage IIA (T3N0) colon cancer patients. Patients who underwent colectomy for stage IIA colon adenocarcinoma (2010‐2015) were identified in the National Cancer Database (NCDB) and divided in two groups based on receipt of adjuvant chemotherapy vs observation. Inverse probability of treatment weighting (IPTW)‐adjusted Kaplan‐Meier and Cox proportional hazards regression analyses were performed to compare overall survival between the two groups. Subgroup analysis of patients with specific high‐risk features LVI, PNI and MSI was performed. Among 46 688 surgical patients with stage IIA colon adenocarcinoma 5937 (12.7%) received adjuvant chemotherapy, while 40 751 (87.3%) were observed. Five‐year IPTW‐adjusted survival was higher in the adjuvant chemotherapy group (79.7% [95% CI 79.1, 80.2]) compared to the observation group (70.3% [95% CI 69.7, 70.9]). Patients with high‐risk pathological features showed an estimated 5‐year survival benefit of 11.3% (78.2% [95% CI 77.4, 79.1] vs 66.9% [95% CI 65.9, 67.8]) when treated with adjuvant chemotherapy. This NCDB analysis revealed a survival benefit for patients with stage IIA colon adenocarcinoma and high‐risk features that were treated with adjuvant chemotherapy.
Testicular seminoma with a progressing pulmonary nodule and mediastinal lymphadenopathy without retroperitoneal metastasis
Authors: Sano Yuta , Fujiwara Motohiro , Yuasa Takeshi , Komai Yoshinobu , Yamamoto Tatsuya , Kohno Atsushi , Nakao Masayuki , Inamura Kentaro , Yonese Junji
Published: July 2020

Introduction

Testicular germ cell cancer has a relatively good prognosis even if visceral and/or lymph node metastases are present thanks to chemotherapy. Yet chemotherapy can lead to various adverse events. Therefore, it is crucial to distinguish whether a suspected metastatic disease is metastasis or not.

Case presentation

A 33‐year‐old male visited our hospital to receive subsequent therapy for suspected recurrent seminoma with a progressing pulmonary nodule and mediastinal lymphadenopathy after orchiectomy. The pathological diagnosis of needle aspiration and resected specimen of the several lesions was consistent with epithelioid cell granuloma without caseous necrosis. Based on these findings, the lung and mediastinal lymph node lesions were diagnosed as sarcoidosis.

Conclusion

In cases where the simultaneous occurrence of other benign or malignant diseases is suspected, pathological confirmation is necessary for appropriate decision‐making.
Possible abscopal effect after discontinuation of nivolumab in metastatic renal cell carcinoma
Authors: Nakajima Nobuyuki , Kano Tatsuo , Oda Kazuya , Uchida Takato , Otaki Tatsuya , Nagao Kentaro , Shimizu Yuki , Kawakami Masayoshi , Kim Hakushi , Nitta Masahiro , Hasegawa Masanori , Kawamura Yoshiaki , Miyajima Akira
Published: July 2020

Introduction

Renal cell carcinoma has been considered radioresistant. Recently, several studies have reported the efficacy of combination therapy using radiotherapy and immune checkpoint inhibitors.

Case presentation

In 1999, a 56‐year‐old woman underwent left nephrectomy (clear cell carcinoma, pT1bN0M0). Seventeen years postoperatively, recurrence in the left lung hilum was observed. Despite administration of three molecular target drugs, all treatments were terminated due to adverse events. Nivolumab was initiated in December 2016. In August 2017, subcutaneous and lung metastases were observed. Moreover in January 2018, right renal metastasis was noted. After 22 cycles of nivolumab treatment, metastasis in the iliac bone was observed, and the patient was subjected to conventional palliative external beam radiation therapy. Five months after radiotherapy, there was significant reduction in multiple metastases. Here, we reported the case presenting with possible abscopal effect.

Conclusion

Radiotherapy combined with immune checkpoint inhibitors may induce systemic effects against metastatic renal carcinoma.
Optical coherence tomography angiography for mapping cerebral microvasculature based on normalized differentiation analysis
Authors: Zhu Jiang , Liu Jianting , Zhu Lianqing , Wang Chongyang , Fan Fan , Yang Qiang , Zhang Fan
Published: July 2020

Optical coherence tomography angiography (OCTA) is a label‐free, noninvasive biomedical imaging modality for mapping microvascular networks and quantifying blood flow velocities in vivo. Simple computation and fast processing are critical for the OCTA in some applications. Herein, we report on a normalized differentiation method for mapping cerebral microvasculature with the advantages of simple analysis and high image quality, benefitting from computation of differentiation and characteristics of normalization. Normalized differentiation values are validated to have a nearly linear relationship with flow velocities in a range using a flow phantom. The measurements in a rat cerebral cortex show that the OCTA based on the normalized differentiation analysis can generate microvascular images with high quality and monitor spatiotemporal dynamics of blood flow with simple computation and fast processing before and after localized ischemia induced by arterial occlusion.
Poly(butyl methacrylate)‐grafted alginate/Fe3O4 nanocomposite: Synthesis and its application for removal of dyes
Authors: Alzahrani Eman , Abo‐Dief Hala M. , Algethami Faouzia
Published: July 2020

This study involved the utilization of a free radical‐graft copolymerization reaction for the development of a novel adsorbent, namely, poly(butyl methacrylate)‐grafted alginate/Fe3O4 nanocomposite (PBMA‐gft‐Alg/Fe3O4). Transmission electron microscopy, scanning electron microscopy, energy‐dispersive X‐ray analysis, X‐ray diffraction patterns analysis, and Fourier transform infrared spectroscopy (FT‐IR) were carried out for the characterization of Fe3O4 NPs and PBMA‐gft‐Alg/Fe3O4 nanocomposites. The capability of nanocomposites and nanoparticles to adsorb dyes such as MG and MB, resulting in their removal from aqueous media, was evaluated under different conditions such as pH, temperature, contact time, and dose of adsorbent. Optimum parameters for adsorption of dyes were found to be pH of 10, 50°C, contact time of 180 min, and 0.2 g of adsorbent. Efficiency of the PBMA‐gft‐Alg/Fe3O4 nanocomposite was found to be significantly greater than that of Fe3O4 NPs for eliminating the desired dye. Langmuir, Freundlich, Sips, and Temkin models were used for testing the experimental data. Freundlich model was the one that best described the adsorption.
Genes with evidence of positive selection as potentially related to coloniality and the evolution of morphological features among the lophophorates and entoprocts
Authors: Santagata Scott
Published: July 2020

Evolutionary mechanisms that underlie the origins of coloniality among organisms are diverse. Some animal colonies may be comprised strictly of clonal individuals formed from asexual budding or comprised of a chimera of clonal and sexually produced individuals that fuse secondarily. This investigation focuses on select members of the lophophorates and entoprocts whose evolutionary relationships remain enigmatic even in the age of genomics. Using transcriptomic data sets, two coloniality‐based hypotheses are tested in a phylogenetic context to find candidate genes showing evidence of positive selection and potentially convergent molecular signatures among solitary species and taxa‐forming colonies from aggregate groups or clonal budding. Approximately 22% of the 387 orthogroups tested showed evidence of positive selection in at least one of the three branch‐site tests (CODEML, BUSTED, and aBSREL). Only 12 genes could be reliably associated with a developmental function related to traits linked with coloniality, neuroanatomy, or ciliary fields. Genes testing for both positive selection and convergent molecular characters include orthologues of Radial spoke head, Elongation translation initiation factors, SEC13, and Immediate early response gene5. Maximum likelihood analyses included here resulted in tree topologies typical of other phylogenetic investigations based on wider genomic information. Further genomic and experimental evidence will be needed to resolve whether a solitary ancestor with multiciliated cells that formed aggregate groups gave rise to colonial forms in bryozoans (and perhaps the entoprocts) or that the morphological differences exhibited by phoronids and brachiopods represent trait modifications from a colonial ancestor.
Frizzled3 expression and colony development in hydractiniid hydrozoans
Authors: Sanders Steven M. , Travert Matthew K. , Cartwright Paulyn
Published: July 2020

Hydractiniid hydrozoan colonies are comprised of individual polyps connected by tube‐like stolons or a sheet‐like mat. Mat and stolons function to integrate the colony through continuous epithelia and shared gastrovascular cavity. Although mechanisms of hydrozoan polyp development have been well studied, little is known about the signaling processes governing the patterning of colonies. Here we investigate the Wnt receptor family Frizzled. Phylogenetic analysis reveals that hydrozoans possess four Frizzled orthologs. We find that one of these genes, Frizzled3, shows a spatially restricted expression pattern in colony‐specific tissue in two hydractiniid hydrozoans, Hydractinia symbiolongicarpus and Podocoryna carnea, in a manner that corresponds to their distinct colony forms (stolonal mat in Hydractinia and free stolons in Podocoryna). Interestingly, Frizzled3 was lost in the genome of Hydra, which is a solitary polyp and thus lacks colony‐specific tissue. Current evidence suggests that the Wnt signaling pathway plays a key role in the evolution of colony diversity and colony loss in Hydrozoa.
Cellular dynamics of double fertilization and early embryogenesis in flowering plants
Authors: Shin Ji Min , Yuan Ling , Ohme‐Takagi Masaru , Kawashima Tomokazu
Published: July 2020

Flowering plants (angiosperms) perform a unique double fertilization in which two sperm cells fuse with two female gamete cells in the embryo sac to develop a seed. Furthermore, during land plant evolution, the mode of sexual reproduction has been modified dramatically from motile sperm in the early‐diverging land plants, such as mosses and ferns as well as some gymnosperms (Ginkgo and cycads) to nonmotile sperm that are delivered to female gametes by the pollen tube in flowering plants. Recent studies have revealed the cellular dynamics and molecular mechanisms for the complex series of double fertilization processes and elucidated differences and similarities between animals and plants. Here, together with a brief comparison with animals, we review the current understanding of flowering plant zygote dynamics, covering from gamete nuclear migration, karyogamy, and polyspermy block, to zygotic genome activation as well as asymmetrical division of the zygote. Further analyses of the detailed molecular and cellular mechanisms of flowering plant fertilization should shed light on the evolution of the unique sexual reproduction of flowering plants.
Delays in repeat HIV viral load testing for those with elevated viral loads: a national perspective from South Africa
Authors: Fox Matthew P , Brennan Alana T , Nattey Cornelius , MacLeod William B , Harlow Alyssa , Mlisana Koleka , Maskew Mhairi , Carmona Sergio , Bor Jacob
Published: July 2020

Introduction

In South Africa, HIV patients with an elevated viral load (VL) should receive repeat VL testing after adherence counselling. We set out to use a national HIV Cohort to describe time to repeat viral load testing across South Africa and identify predictors of time to repeat testing.

Methods

We conducted a cohort study of prospectively collected laboratory data. HIV treatment guidelines have changed over time in South Africa, but call for repeat VL testing within six months if 400 to 1000 copies/mL and two to three months if >1000 copies/mL. We included patients with suppressed viral loads (indicating they are on ART) and a first elevated VL (>400 copies/mL) between April 2004 and December 2014. Follow‐up began at first elevated VL and continued until repeat testing, loss to follow‐up or December 2016. We calculated adjusted hazard ratios (aHR) using Cox proportional hazard models.

Results

Of 371,648 patients with a VL > 400, 83.9% (311,790) had a repeat VL, in a median (IQR) of 7.0 (4.1 to 12.2) months. Of those with a first viral load 400 to 1000 copies/mL, 56.4% had a repeat VL within guideline recommended six months (defined as up to nine months), whereas among those >1000 copies/mL only 47.7% had a repeat viral load within guideline recommended two to three months (defined as up to six months). We found a small increase in repeat testing associated with higher VL value (aHR 1.11; 95% CI: 1.10 to 1.12 comparing >1000 vs 400 to 1000 copies/mL) and very low CD4 counts at first elevated VL (aHR 1.16; 95% CI: 1.13 to 1.19 comparing CD4 < 50 vs <500 cells/mm3). We also found strong variation in time to repeat VL testing by province.

Conclusions

Median time to repeat viral load testing for those with an elevated viral load was longer than guidelines recommend. Future work should identify whether delays are due to patient or provider factors.
p67phox-derived self-assembled peptides prevent Nox2 NADPH oxidase activation by an auto-inhibitory mechanism
Authors: Bechor Edna , Zahavi Anat , Berdichevsky Yevgeny , Pick Edgar
Published: July 2020

Activation of the Nox2-dependent NADPH oxidase is the result of a conformational change in Nox2 induced by interaction with the cytosolic component p67phox. In preliminary work we identified a cluster of overlapping 15-mer synthetic peptides, corresponding to p67phox residues 259-279, which inhibited oxidase activity in an in vitro, cell-free assay, but the results did not point to a competitive mechanism. We recently identified an auto-inhibitory intramolecular bond in p67phox, one extremity of which was located within the 259-279 sequence, and we hypothesized that inhibition by exogenous peptides might mimic intrinsic auto-inhibition. In this study, we found that: (i) progressive N- and C-terminal truncation of inhibitory p67phox peptides, corresponding to residues 259-273 and 265-279, revealed that inhibitory ability correlated with the presence of residues 265NIVFVL270, exposed at either the N- or C-termini of the peptides; (ii) inhibition of oxidase activity was associated exclusively with self-assembled peptides, which pelleted upon centrifugation at 12,000 ×g; (iii) self-assembled p67phox peptides inhibited oxidase activity by specific binding of p67phox and the ensuing depletion of this component, essential for interaction with Nox2; and (iv) peptides subjected to scrambling or reversing the order of residues in NIVFVL retained the propensity for self-assembly, oxidase inhibitory ability, and specific binding of p67phox, indicating that the dominant parameter was the hydrophobic character of five of the six residues. This appears to be the first description of inhibition of oxidase activity by self-assembled peptides derived from an oxidase component, acting by an auto-inhibitory mechanism.
Modulation of neutrophil extracellular traps release by Klebsiella pneumoniae
Authors: Birnberg-Weiss Federico , Castillo Luis A , Pittaluga Jose R , Martire-Greco Daiana , Gómez Sonia A , Landoni Verónica I , Fernández Gabriela C
Published: July 2020

One of the main bactericidal mechanisms of polymorphonuclear neutrophils (PMN) is the release of neutrophil extracellular traps (NETs), which capture and destroy pathogens. Klebsiella pneumoniae (Kpn) producer of carbapenemase (KPC) and belonging to the sequence type 258 (ST258), is a hyper epidemic clone that causes a large number of infections worldwide associated with high persistence and mortality. It is necessary to investigate the interaction of Kpn KPC with the immune system to improve prevention and treatment of infections mediated by this bacterium. Based on the hypothesis that Kpn is able to subvert PMN-mediated death, the aim was to assess whether Kpn KPC ST258 could modulate the bactericidal response of PMN, focusing on NETs formation, compared to another opportunistic pathogen, as Escherichia coli (Eco). The results showed that the release of NETs was absent when PMN were challenged with Kpn KPC, while Eco was a strong inducer of NETosis. Moreover, Kpn KPC was able to inhibit NETosis induced by Eco. The inhibition of Kpn KPC-mediated NETs formation still occurred in spite of exogenous addition of hydrogen peroxide (H2O2), did not involve bacterial-released soluble factors or cell wall components, and was dependent on bacterial viability. Moreover, when degranulation was investigated, we found that Kpn KPC affected only the mobilization of primary granules, which harbor the proteins with more potent bactericidal properties and those related to NETosis. In conclusion, Kpn KPC ST258 effectively managed to evade the PMN response by inhibiting the release of NETs, and primary granule mobilization.
Neuronal gamma oscillations and activity‐dependent potassium transients remain regular after depletion of microglia in postnatal cortex tissue
Authors: Lewen Andrea , Ta Thuy‐Truc , Cesetti Tiziana , Hollnagel Jan‐Oliver , Papageorgiou Ismini E. , Chausse Bruno , Kann Oliver
Published: July 2020

Microglial cells (resident macrophages) feature rapid activation in CNS disease and can acquire multiple phenotypes exerting neuroprotection or neurotoxicity. The functional impact of surveying (“resting”) microglia on neural excitability and neurotransmission in physiology is widely unknown, however. We addressed this issue in male rat hippocampal slice cultures (in situ) by pharmacological microglial ablation within days and by characterizing neuronal gamma‐band oscillations (30–70 Hz) that are highly sensitive to neuromodulators and disturbances in ion and energy regulation. Gamma oscillations support action potential timing and synaptic plasticity, associate with higher brain functions like perception and memory, and require precise communication between excitatory pyramidal cells and inhibitory (GABAergic) interneurons. The slice cultures featured well‐preserved hippocampal cytoarchitecture and parvalbumin‐positive interneuron networks, microglia with ramified morphology, and low basal levels of IL‐6, TNF‐α, and nitric oxide (NO). Stimulation of slice cultures with the pro‐inflammatory cytokine IFN‐γ or bacterial LPS serving as positive controls for microglial reactivity induced MHC‐II expression and increased cytokine and NO release. Chronic exposure of slice cultures to liposome‐encapsulated clodronate reduced the microglial cell population by about 96%, whereas neuronal structures, astrocyte GFAP expression, and basal levels of cytokines and NO were unchanged. Notably, the properties of gamma oscillations reflecting frequency, number and synchronization of synapse activity were regular after microglial depletion. Also, electrical stimulus‐induced transients of the extracellular potassium concentration ([K+]o) reflecting cellular K+ efflux, clearance and buffering were unchanged. This suggests that nonreactive microglia are dispensable for neuronal homeostasis and neuromodulation underlying network signaling and rhythm generation in cortical tissue.