bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide binding of SEPALLATA3 and AGAMOUS complexes determined by sequential DNA-affinity purification sequencing
Authors: Lai Xuelei , Stigliani Arnaud , Lucas Jérémy , Hugouvieux Véronique , Parcy François , Zubieta Chloe
Published: August 2020

The MADS transcription factors (TF), SEPALLATA3 (SEP3) and AGAMOUS (AG) are required for floral organ identity and floral meristem determinacy. While dimerization is obligatory for DNA binding, SEP3 and SEP3–AG also form tetrameric complexes. How homo and hetero-dimerization and tetramerization of MADS TFs affect genome-wide DNA-binding and gene regulation is not known. Using sequential DNA affinity purification sequencing (seq-DAP-seq), we determined genome-wide binding of SEP3 homomeric and SEP3–AG heteromeric complexes, including SEP3Δtet-AG, a complex with a SEP3 splice variant, SEP3Δtet, which is largely dimeric and SEP3–AG tetramer. SEP3 and SEP3–AG share numerous bound regions, however each complex bound unique sites, demonstrating that protein identity plays a role in DNA-binding. SEP3–AG and SEP3Δtet-AG share a similar genome-wide binding pattern; however the tetrameric form could access new sites and demonstrated a global increase in DNA-binding affinity. Tetramerization exhibited significant cooperative binding with preferential distances between two sites, allowing efficient binding to regions that are poorly recognized by dimeric SEP3Δtet-AG. By intersecting seq-DAP-seq with ChIP-seq and expression data, we identified unique target genes bound either in SEP3–AG seq-DAP-seq or in SEP3/AG ChIP-seq. Seq-DAP-seq is a versatile genome-wide technique and complements in vivo methods to identify putative direct regulatory targets.
Histone chaperone FACT represses retrotransposon MERVL and MERVL-derived cryptic promoters
Authors: Chen Fuquan , Zhang Weiyu , Xie Dan , Gao Tingting , Dong Zhiqiang , Lu Xinyi
Published: August 2020

Endogenous retroviruses (ERVs) were usually silenced by various histone modifications on histone H3 variants and respective histone chaperones in embryonic stem cells (ESCs). However, it is still unknown whether chaperones of other histones could repress ERVs. Here, we show that H2A/H2B histone chaperone FACT plays a critical role in silencing ERVs and ERV-derived cryptic promoters in ESCs. Loss of FACT component Ssrp1 activated MERVL whereas the re-introduction of Ssrp1 rescued the phenotype. Additionally, Ssrp1 interacted with MERVL and suppressed cryptic transcription of MERVL-fused genes. Remarkably, Ssrp1 interacted with and recruited H2B deubiquitinase Usp7 to Ssrp1 target genes. Suppression of Usp7 caused similar phenotypes as loss of Ssrp1. Furthermore, Usp7 acted by deubiquitinating H2Bub and thereby repressed the expression of MERVL-fused genes. Taken together, our study uncovers a unique mechanism by which FACT complex silences ERVs and ERV-derived cryptic promoters in ESCs.
The Role of Prophylactic Intraventricular Antibiotics in Reducing the Incidence of Infection and Revision Surgery in Pediatric Patients Undergoing Shunt Placement
Authors: Lakomkin Nikita , Hadjipanayis Constantinos G
Published: August 2020

BACKGROUND

Ventriculoperitoneal shunt placement remains the primary treatment modality for children with hydrocephalus. However, morbidity and revision surgery secondary to infection remains high, even while using antibiotic-impregnated shunts.

OBJECTIVE

To determine whether intraoperative injection of antibiotics is independently associated with reduced rates of infection and revision surgery in children undergoing shunt placement.

METHODS

This is an analysis of a prospectively collected, multicenter, shunt-specific neurosurgical registry consisting of data from over 100 hospitals collected between 2016 and 2017. All patients under 18 yr of age undergoing first-time shunt placement for the definitive treatment of hydrocephalus were included. The primary exposure of interest was injection of intraventricular antibiotics into the shunt catheter following shunt placement and prior to closure. The use of additional surgical adjuncts, such as antibiotic-impregnated shunts, stereotactic guidance, and endoscopy was collected. The primary outcome metric was the need for additional intervention because of an infection.

RESULTS

A total of 2007 pediatric patients undergoing shunt placement for hydrocephalus were identified. Postoperatively, 97 (4.8%) patients had additional intervention. In a multivariable regression model controlling for patient characteristics, etiology of hydrocephalus, prior temporizing measures, and placement of an antibiotic-impregnated shunt, injection of intraventricular antibiotics was associated with a significant reduction in postoperative infections (odds ratio = 0.29, 95% CI: 0.04-0.89, P = .038). Of those receiving intraventricular antibiotics, only 2 (0.38%) went on to undergo re-intervention due to infection.

CONCLUSION

These data suggest that for this select group of patients, use of intraventricular antibiotics was associated with decreased rates of re-intervention secondary to infection.
Prepontine Shunting for Pseudotumor Cerebri in Previously Failed Shunt Patients: A 5-Year Analysis
Authors: White Ian , Tuohy Megan , Turner Michael , Lee Albert
Published: August 2020

BACKGROUND

Shunting procedures have a high failure rate when used to treat pseudotumor cerebri (PTC) patients who have failed medical therapy. This failure is believed to be attributable to the collapsibility of the ventricular system when exposed to increased differential pressure gradients in the cerebral spinal fluid compartments caused by ventriculoperitoneal shunts (VPS).

OBJECTIVE

To investigate whether prepontine/interpeduncular cistern shunting may be a reasonable alternative to VPS intervention in PTC patients with history of shunt failure. There have been no large series of cisternal-peritoneal shunt (CPS) patients in the PTC population.

METHODS

A retrospective review of 49 patients with placement of CPS for PTC with 2 failed prior shunting procedures was performed. Shunt survivability was based on shunt patency and resolution of ophthalmologic symptoms and cranial nerve deficits. All patients were followed for a minimum of 3 yr with serial ophthalmologic and neurosurgical evaluations.

RESULTS

At 3 yr, 44 of the 49 (88.9%) patients had working CPS. Three patients in this group had infections requiring complete shunt removal. Excluding infections, 44 of 46 (95.5%) shunts were functional at 3 yr. There were 3 small, asymptomatic hemorrhages that did not increase patient length of stay, and there were no catastrophic hemorrhages or strokes. There were also no abdominal complications related to shunt placement.

CONCLUSION

CPS is a viable alternative to VPS in PTC patients who have failed traditional shunting methods to give these patients a persistent benefit of a working shunt. The procedure provides this solution with low operative and perioperative morbidity.
Clinical and molecular characterization of a multi-institutional cohort of pediatric spinal cord low-grade gliomas
Authors: Grob Sydney T , Nobre Liana , Campbell Kristen R , Davies Kurtis D , Ryall Scott , Aisner Dara L , Hoffman Lindsey , Zahedi Shadi , Morin Andrew , Crespo Michele , Nellan Anandani , Green Adam L , Foreman Nicholas , Vibhakar Rajeev , Hankinson Todd C , Handler Michael H , Hawkins Cynthia , Tabori Uri , Kleinschmidt-DeMasters B K , Mulcahy Levy Jean M
Published: August 2020

Background

The mitogen-activated protein kinases/extracelluar signal-regulated kinases pathway is involved in cell growth and proliferation, and mutations in BRAF have made it an oncogene of interest in pediatric cancer. Previous studies found that BRAF mutations as well as KIAA1549–BRAF fusions are common in intracranial low-grade gliomas (LGGs). Fewer studies have tested for the presence of these genetic changes in spinal LGGs. The aim of this study was to better understand the prevalence of BRAF and other genetic aberrations in spinal LGG.

Methods

We retrospectively analyzed 46 spinal gliomas from patients aged 1–25 years from Children’s Hospital Colorado (CHCO) and The Hospital for Sick Children (SickKids). CHCO utilized a 67-gene panel that assessed BRAF and additionally screened for other possible genetic abnormalities of interest. At SickKids, BRAFV600E was assessed by droplet digital polymerase chain reaction and immunohistochemistry. BRAF fusions were detected by fluorescence in situ hybridization, reverse transcription polymerase chain reaction, or NanoString platform. Data were correlated with clinical information.

Results

Of 31 samples with complete fusion analysis, 13 (42%) harbored KIAA1549–BRAF. All 13 (100%) patients with confirmed KIAA1549–BRAF survived the entirety of the study period (median [interquartile range] follow-up time: 47 months [27–85 months]) and 15 (83.3%) fusion-negative patients survived (follow-up time: 37.5 months [19.8–69.5 months]). Other mutations of interest were also identified in this patient cohort including BRAFV600E, PTPN11, H3F3A, TP53, FGFR1, and CDKN2A deletion.

Conclusion

KIAA1549–BRAF was seen in higher frequency than BRAFV600E or other genetic aberrations in pediatric spinal LGGs and experienced lower death rates compared to KIAA1549–BRAF negative patients, although this was not statistically significant.
Remdesivir Treatment for Severe COVID-19 in Third-Trimester Pregnancy: Case Report and Management Discussion
Authors: Maldarelli Grace A , Savage Megan , Mazur Shawn , Oxford-Horrey Corrina , Salvatore Mirella , Marks Kristen M
Published: August 2020

We report a case of COVID-19 in third-trimester pregnancy, who required support in an intensive care unit and received remdesivir. After discharge, she had an uncomplicated vaginal delivery at term. COVID-19 in pregnancy may be managed without emergent delivery; a multispecialty team is critical in caring for these patients.
Impact of new consent procedures on uptake of the schools-based human papillomavirus (HPV) vaccination programme
Authors: Fisher Harriet , Hickman Matthew , Ferrie Joanne , Evans Karen , Bell Michael , Yates Julie , Roderick Marion , Reynolds Rosy , MacLeod John , Audrey Suzanne
Published: August 2020

Background

Local policy change initiating new consent procedures was introduced during 2017–2018 for the human papillomavirus (HPV) vaccination programme year in two local authorities in the south–west of England. This study aims to assess impact on uptake and inequalities.

Methods

Publicly available aggregate and individual-level routine data were retrieved for the programme years 2015–2016 to 2018–2019. Statistical analyses were undertaken to show: (i) change in uptake in intervention local authorities in comparison to matched local authorities and (ii) change in uptake overall, and by local authority, school type, ethnicity and deprivation.

Results

Aggregate data showed uptake in Local Authority One increased from 76.3% to 82.5% in the post-intervention period (risk difference: 6.2% P = 0.17), with a difference-in-differences effect of 11.5% (P = 0.03). There was no evidence for a difference-in-differences effect in Local Authority Two (P = 0.76). Individual-level data showed overall uptake increased post-intervention (risk difference: +1.1%, P = 0.05), and for young women attending school in Local Authority One (risk difference: 2.3%, P < 0.01). No strong evidence for change by school category, ethnic group and deprivation was found.

Conclusion

Implementation of new consent procedures can improve and overcome trends for decreasing uptake among matched local authorities. However, no evidence for reduction in inequalities was found.

Implications and discussion

The new consent procedures increased uptake in one of the intervention sites and appeared to overcome trends for decreasing uptake in matched sites. There are issues in relation to the quality of data which require addressing.
Evaluation of an oral joint supplement on gait kinematics and biomarkers of cartilage metabolism and inflammation in mature riding horses
Authors: Much Mattea L , Leatherwood Jessica L , Martinez Rafael E , Silvers Brittany L , Basta Casey F , Gray Lydia F , Bradbery Amanda N
Published: August 2020

Twenty stock-type horses (589 ± 126 kg BW; 13 ± 8 yr) were used in a completely randomized design for 28-d to evaluate the impact of a joint supplement on gait kinematics, inflammation, and cartilage metabolism. Horses were stratified by age, sex, body weight (BW), and initial lameness scores and were randomly assigned to one of two dietary treatments consisting of either a 100-g placebo top-dressed daily to 0.6% BW (as-fed) commercial concentrate (CON; n = 10; SafeChoice Original, Cargill, Inc.), or an oral joint supplement (SmartPak Equine LLC) containing glucosamine, chondroitin sulfate, hyaluronic acid, methylsulfonylmethane, turmeric, resveratrol, collagen, silica, and boron (TRT; n = 10). Horses were group-housed with ad libitum access to coastal bermudagrass hay (Cynodon dactylon) and allowed to graze pasture 2 h/d. Horses were exercised progressively 4 d/wk at 45 min each. On days 13 and 27, blood was harvested followed by a 19.3-km exercise stressor on concrete. Horses traveled at the walk, with no more than 15 min at the trot. Every 14 d, BW and BCS were recorded, and blood was collected for plasma prostaglandin E2 (PGE2), serum collagenase cleavage neopeptide (C2C), carboxypropeptide of type II collagen (CPII), and chondroitin sulfate 846 epitope (CS846) analysis. Kinematic gait analysis was performed every 14 d (Kinovea v.0.8.15) to determine stride length (SL) and range of motion (ROM) of the knee and hock at the walk and trot. Data were analyzed using PROC MIXED of SAS. All horses increased BW and BCS over time (P ≤ 0.01). Hock ROM increased in TRT horses (P ≤ 0.02) at the walk and tended to increase at the trot compared to CON (P = 0.09). At the walk, SL and knee ROM increased over time, independent of dietary treatment (P ≤ 0.01); no time effect was observed at the trot (P > 0.15). Regardless of treatment, C2C and CPII increased over time (P ≤ 0.05) and no effect was observed for CS846 or PGE2 (P > 0.12). In response to the exercise stressor, CPII and PGE2 decreased (P ≤ 0.05) from day 13 to 14, and CS846 and PGE2 tended to decrease (P ≤ 0.10) from day 27 to 28, independent of dietary treatment. In conclusion, hock ROM at the walk and trot was most sensitive to dietary treatment. Supplementation did not alter biomarker concentration of collagen metabolites or systemic inflammation in the 28-d period, but a future study utilizing arthrocentesis may be warranted to specifically evaluate intra-articular response to dietary treatment.
Towards sensor-based calving detection in the rangelands: a systematic review of credible behavioral and physiological indicators
Authors: Chang Anita Z , Swain David L , Trotter Mark G
Published: August 2020

Calving is a critical point in both a cow and calf’s life, when both become more susceptible to disease and risk of death. Ideally, this period is carefully monitored. In extensive grazing systems, however, it is often not economically or physically possible for producers to continuously monitor animals, and thus, calving frequently goes undetected. The development of sensor systems, particularly in these environments, could provide significant benefits to the industry by increasing the quantity and quality of individual animal monitoring. In the time surrounding calving, cows undergo a series of behavioral and physiological changes, which can potentially be detected using sensing technologies. Before developing a sensor-based approach, it is worthwhile considering these behavioral and physiological changes, such that the appropriate technologies can be designed and developed. A systematic literature review was conducted to identify changes in the dam’s behavioral and physiological states in response to a calving event. Articles (n = 104) consisting of 111 independent experiments were assessed following an intensive search of electronic databases. Commonly reported indicators of parturition (n = 38) were identified, and temporal trend graphs were generated for 13 of these changes. The results compare trends in behavioral and physiological changes across a variety of animal-related factors and identifies several reliable indicators of parturition for detection with sensors, namely calf grooming behavior, changes in rumination duration, and lying bouts. This synthesis of literature suggests that variability exists between individuals and thus, combining several calving indicators may result in a more broadly applicable and accurate detection of parturition.
Saccharin Provides Protection and Activates Defense Mechanisms in Wheat Against the Hemibiotrophic PathogenZymoseptoria tritici
Authors: Mejri Samara , Magnin-Robert Maryline , Randoux Beatrice , Ghinet Alina , Halama Patrice , Siah Ali , Reignault Philippe
Published: August 2020

Plant resistance inducers are among the most promising alternatives to develop sustainable crop protection. Here, we examined the ability of saccharin, a metabolite derived from probenazole, to protect wheat against Zymoseptoria tritici, the most frequently occurring and damaging foliar pathogen on this crop. The experiments were performed in the greenhouse by treating seedlings of the wheat cultivar ‘Alixan’ with 15 mM of saccharin 2 days before challenge inoculation with the Z. tritici pathogenic strain T02596. Foliar application of saccharin resulted in 77% lower disease severity than in nontreated control plants. In vitro and in planta assays showed that saccharin did not exhibit any direct antifungal effect on spore germination or hyphal growth. Molecular investigations from 2 to 7 days posttreatment (dpt) revealed that saccharin treatment upregulates the expression of genes encoding for lipoxygenase (LOX) at all sampled time points and pathogenesis-related protein 1 (PR1) at 7 dpt, in both noninfectious and infectious contexts, as well as peroxidase (POX2) in noninfectious conditions. However, saccharin did not induce significant change in the expression of PAL gene encoding for phenylalanine ammonia-lyase. Our findings report for the first time the potential of saccharin to confer protection in wheat against Z. tritici through an elicitation and priming of LOX and PR gene-related defense pathways. Additional investigations would provide a better deciphering of defense mechanisms activated by this molecule in wheat against Z. tritici.
The use of single-pill combinations as first-line treatment for hypertension: translating guidelines into clinical practice
Authors: Campana Erika , Cunha Vitória , Glaveckaite Sigita , Gruev Ivan , Lamirault Guillaume , Lehmann Elke , Masi Stefano , Mfeukeu Kuate Liliane , Mishshenko Larysa , Ona Deborah I.D. , Oo Min Zaw , Tautu Oana G.F. , Vachulova Anna , Vintila Ana-Maria , Wolf Jacek , Zvartau Nadezhda , Narkiewicz Krzysztof , Laurent Stephane
Published: August 2020

The 2008 European Society of Cardiology/European Society of Hypertension guidelines recommend the first-line prescription of two antihypertensive drugs in single-pill combinations (SPCs), also known as fixed-dose combinations, for the treatment of most patients with hypertension. This recommendation is based on a large amount of data, which shows that first-line treatment with SPCs supports reaching blood pressure targets rapidly and reducing cardiovascular outcome risk while keeping the therapeutic strategies as simple as possible and fostering adherence and persistence. As this approach constitutes a big shift from the stepped-care approaches that have been dominant for many years, practicing physicians have expressed concerns about using SPCs as first-line agents. In this review, we will discuss the barriers to the uptake of this recommendation. We will also offer suggestions to reduce the impact of these barriers and address specific concerns that have been raised.
Using Environmental Modification and Teacher Mediation to Increase Literacy Behaviors in Inclusive Preschool Settings
Authors: Deris Aaron R. , DiCarlo Cynthia F. , Wagner Dana , Krick Oborn Kellie
Published: August 2020

It is considered a recommended practice to integrate literacy concepts into child-initiated choice center time long before formal reading instruction begins. The purpose of this study was to determine whether environmental modification and a teacher-mediated literacy intervention would increase child engagement of literacy behaviors during free choice time in the classroom. Data were collected on the literacy behaviors of 9 children across 3 inclusive preschool classrooms in a suburban public school system. A multiple baseline design was used to determine the effects of an environmental modification using the Early Language and Literacy Classroom Observation and a teacher-mediated intervention on children's literacy behaviors. Results included an average increase of 43 percentage points (range = 39–45 percentage points) in observed literacy behaviors in each of the 3 classrooms. Individual children in each classroom demonstrated an increase in literacy behaviors from baseline to intervention. These results are consistent with previous research, which indicated that the modification of the environment and teacher mediation increase literacy behaviors.
Prism adaptation treatment for upper-limb complex regional pain syndrome: a double-blind randomized controlled trial
Authors: Halicka Monika , Vittersø Axel D. , McCullough Hayley , Goebel Andreas , Heelas Leila , Proulx Michael J. , Bultitude Janet H.
Published: August 2020

Initial evidence suggested that people with complex regional pain syndrome (CRPS) have reduced attention to the affected side of their body and the surrounding space, which might be related to pain and other clinical symptoms. Three previous unblinded, uncontrolled studies showed pain relief after treatment with prism adaptation, an intervention that has been used to counter lateralised attention bias in brain-lesioned patients. To provide a robust test of its effectiveness for CRPS, we conducted a double-blind randomized controlled trial of prism adaptation for unilateral upper-limb CRPS-I. Forty-nine eligible adults with CRPS were randomized to undergo 2 weeks of twice-daily home-based prism adaptation treatment (n = 23) or sham treatment (n = 26). Outcomes were assessed in person 4 weeks before and immediately before treatment, and immediately after and 4 weeks after treatment. Long-term postal follow-ups were conducted 3 and 6 months after treatment. We examined the effects of prism adaptation vs sham treatment on current pain intensity and the CRPS symptom severity score (primary outcomes), as well as sensory, motor, and autonomic functions, self-reported psychological functioning, and experimentally tested neuropsychological functions (secondary outcomes). We found no evidence that primary or secondary outcomes differed between the prism adaptation and sham treatment groups when tested at either time point after treatment. Overall, CRPS severity significantly decreased over time for both groups, but we found no benefits of prism adaptation beyond sham treatment. Our findings do not support the efficacy of prism adaptation treatment for relieving upper-limb CRPS-I. This trial was prospectively registered (ISRCTN46828292).
Use of recombinant activated factor VII for uncontrolled bleeding in a haematology/oncology paediatric ICU cohort
Authors: Shayeb Akram Mesleh , Li Chen , Kang Guolian , Reiss Ulrike M. , Elbahlawan Lama
Published: August 2020

Bleeding among critically ill paediatric haematology/oncology (CIPHO) patients leads to significant morbidity and mortality. Recombinant activated factor VII (rFVIIa) has shown some benefits in previous reported off-label use when conventional therapies have failed. However, data in CIPHO are lacking. We retrospectively studied (2006–2014) the efficacy and outcomes in CIPHO patients younger than 21 years who received at least one rFVIIa dose for bleeding in the ICU. Of 39 patients, the majority had leukaemia (59%), bone marrow transplantation (77%) and a life-threatening bleed (80%) with most common site being pulmonary haemorrhage (44%). Most needed invasive mechanical ventilation (87%) or vasopressor support (59%). After rFVIIa administration, 56% had cessation or decreased bleeding. Packed red blood cell transfusion requirements decreased significantly 48–72 h after rFVIIa administration. Lower baseline prothrombin time and more rFVIIa doses were related to bleeding control. A favourable response was associated with higher survival (55% in responders versus 18% in nonresponders, P = 0.019). Overall, bleeding-related mortality was 37.5%, highest in pulmonary haemorrhage. Two patients had thromboembolic events. Use of rFVIIa for CIPHO patients appears to be well tolerated with low adverse events. Despite half of the patients having a favourable response of cessation or decrease in bleeding after rFVIIa administration, mortality was high. These findings highlight the need for prospective studies to evaluate interventions to improve outcomes in this population.
Long-term opioid therapy for chronic noncancer pain: second update of the German guidelines
Authors: Petzke Frank , Bock Frietjof , Hüppe Michael , Nothacker Monika , Norda Heike , Radbruch Lukas , Schiltenwolf Marcus , Schuler Matthias , Tölle Thomas , Viniol Anika , Häuser Winfried
Published: August 2020

Introduction:

The opioid epidemic in North America challenges national guidelines worldwide to define the importance of opioids for the management of chronic noncancer pain (CNCP).

Methods:

The second update of the German guidelines on long-term opioid therapy for CNCP was developed by 26 scientific associations and 2 patient self-help organizations. A systematic literature search in CENTRAL, Medline, and Scopus (to May 2019) was performed. Meta-analyses of randomized controlled trials and open-label extension studies with opioids for CNCP were conducted. Levels of evidence were assigned according to the Oxford Centre for Evidence-Based Medicine classification system. The formulation and strength of recommendations were established by multistep formalized procedures to reach a consensus according to German Association of the Medical Scientific Societies regulations. The guidelines underwent external review by 4 experts and public commentary.

Results:

Opioids are one drug-based treatment option for short- (4–12 weeks), intermediate- (13–26 weeks), and long-term (>26 weeks) therapy of chronic pain in osteoarthritis, diabetic polyneuropathy, postherpetic neuralgia, and low back pain. Contraindications are primary headaches, functional somatic syndromes, and mental disorders with the (cardinal) symptom of pain. For specified other clinical pain conditions, short- and long-term therapy with opioids should be evaluated on an individual basis. Long-term therapy with opioids is associated with relevant risks.

Conclusion:

Responsible application of opioids requires consideration of possible indications and contraindications, as well as regular assessment of clinical response and adverse effects. Neither uncritical opioid prescription nor general rejection of opioids is justified in patients with CNCP.
Liver Resection for Early Hepatocellular Carcinoma
Authors: Gelli Maximiliano , Sebagh Mylène , Porcher Raphaël , Romanelli Elena , Vibert Eric , Sa Cunha Antonio , Castaing Denis , Rosmorduc Olivier , Samuel Didier , Adam René , Cherqui Daniel
Published: August 2020

Background and Aims:

LR and LT are the standard curative options for early HCC. LT provides best long-term survival but is limited by organ shortage. LR, readily available, is hampered by high recurrence rates. Salvage liver transplantation is an efficient treatment of recurrences within criteria. The aim of the study was to identify preoperative predictors of non transplantable recurrence (NTR) to improve patient selection for upfront LR or LT at initial diagnosis.

Study Design:

Consecutive LR for transplantable HCC between 2000 and 2015 were studied. A prediction model for NTR based on preoperative variables was developed using sub-distribution hazard ratio after multiple imputation and internal validation by bootstrapping. Model performance was evaluated by the concordance index after correction for optimism.

Results:

A total of 148 patients were included. Five-year overall survival and recurrence free survival were 73.6% and 29.3%, respectively (median follow-up 45.8 months). Recurrence rate was 54.8%. NTR rate was 38.2%. Preoperative model for NTR identified >1 nodule [sub-distribution hazard ratio 2.35 95% confidence interval (CI) 1.35–4.09], AFP >100 ng/mL (2.14 95% CI 1.17–3.93), and F4 fibrosis (1.93 95% CI 1.03–3.62). The apparent concordance index of the model was 0.664 after correction for optimism. In the presence of 0, 1, and ≥2 factors, NTR rates were 2.6%, 22.7%, and 40.9%, respectively. The number of prognostic factors was significantly associated with the pattern of recurrence (P = 0.001) and 5-year recurrence free survival (P < 0.001).

Conclusions:

Cirrhosis, >1 nodule, and AFP >100 ng/mL were identified as preoperative predictors of NTR. In the presence of 2 factors or more upfront transplantation should be probably preferred to resection in regard of organ availability. Other patients are good candidates for LR and salvage liver transplantation should be encouraged in eligible patients with recurrence.
Neoadjuvant Chemoradiotherapy Using Cisplatin and 5-Fluorouracil (PF) Versus Carboplatin and Paclitaxel (CROSS Regimen) for Esophageal Squamous Cell Carcinoma (ESCC)
Authors: Wong Ian Y. H. , Lam K. O. , Zhang Rui Qi , Chan Wendy W. L. , Wong Claudia L. Y. , Chan Fion S. Y. , Kwong Dora L. W. , Law Simon Y. K.
Published: August 2020

Objective:

This study compared the efficacy of PF-based and CROSS-based neoadjuvant chemoradiotherapy for ESCC.

Background:

PF-based regimen has been a standard regimen for ESCC, but it has been replaced by the CROSS regimen in the past few years, despite no prospective head-to-head comparative study has been performed.

Methods:

This is a single center retrospective study. Records of all ESCC patients who have received neoadjuvant PF with 40 Gy radiotherapy in 20 daily fractions (PFRT Group) or CROSS with 41.4 Gy radiotherapy in 23 daily fractions (CROSS Group) during the period 2002 to 2019 were retrieved. Propensity score matching (1:1) was performed to minimize baseline differences. The primary and secondary endpoints were overall survival and clinicopathological response. Subgroup analysis (“CROSS Eligibility”) was performed based on tumor length, cT-stage, cM-stage, age, and performance status.

Results:

One hundred (out of 109) patients (CROSS group) and propensity score matched 100 (out of 210) patients (PFRT group) were included. Esophagectomy rates in CROSS and PFRT group were 69% and 76%, respectively (P = 0.268). R0 resection rates were 85.5% and 81.6% (P = 0.525) and the pathological complete remission rates were 24.6% and 35.5% (P = 0.154). By intention-to-treat, the median survival was 16.7 and 32.7 months (P = 0.083). For “CROSS Eligible subgroup,” the median survival of the CROSS and PFRT group was 21.6 versus 44.9 months (P = 0.093).

Conclusions:

There is no statistically difference in survival or clinicopathological outcome between both groups, but the trend favors PFRT. Prospective head-to-head comparison and novel strategies to improve the outcomes in resectable ESCC are warranted.
First Long-term Oncologic Results of the ALPPS Procedure in a Large Cohort of Patients With Colorectal Liver Metastases
Authors: Petrowsky Henrik , Linecker Michael , Raptis Dimitri A. , Kuemmerli Christoph , Fritsch Ralph , Kirimker Onur E. , Balci Deniz , Ratti Francesca , Aldrighetti Luca , Voskanyan Sergey , Tomassini Federico , Troisi Roberto I. , Bednarsch Jan , Lurje Georg , Fard-Aghaie Mohammad-Hossein , Reese Tim , Oldhafer Karl J. , Ghamarnejad Omid , Mehrabi Arianeb , Abraham Mauro E. Tun , Truant Stéphanie , Pruvot Francois-René , Hoti Emir , Kambakamba Patryk , Capobianco Ivan , Nadalin Silvio , Fernandes Eduardo S. M. , Kron Philipp , Lodge Peter , Olthof Pim B. , van Gulik Thomas , Castro-Benitez Carlos , Adam René , Machado Marcel Autran , Teutsch Martin , Li Jun , Scherer Marcus N. , Schlitt Hans J. , Ardiles Victoria , de Santibañes Eduardo , Brusadin Roberto , Lopez-Lopez Victor , Robles-Campos Ricardo , Malagó Massimo , Hernandez-Alejandro Roberto , Clavien Pierre-Alain
Published: August 2020

Objectives:

To analyze long-term oncological outcome along with prognostic risk factors in a large cohort of patients with colorectal liver metastases (CRLM) undergoing ALPPS.

Background:

ALPPS is a two-stage hepatectomy variant that increases resection rates and R0 resection rates in patients with primarily unresectable CRLM as evidenced in a recent randomized controlled trial. Long-term oncologic results, however, are lacking.

Methods:

Cases in- and outside the International ALPPS Registry were collected and completed by direct contacts to ALPPS centers to secure a comprehensive cohort. Overall, cancer-specific (CSS), and recurrence-free (RFS) survivals were analyzed along with independent risk factors using Cox-regression analysis.

Results:

The cohort included 510 patients from 22 ALPPS centers over a 10-year period. Ninety-day mortality was 4.9% and median overall survival, CSS, and RFS were 39, 42, and 15 months, respectively. The median follow-up time was 38 months (95% confidence interval 32–43 months). Multivariate analysis identified tumor-characteristics (primary T4, right colon), biological features (K/N-RAS status), and response to chemotherapy (Response Evaluation Criteria in Solid Tumors) as independent predictors of CSS. Traditional factors such as size of metastases, uni versus bilobar involvement, and liver-first approach were not predictive. When hepatic recurrences after ALPPS was amenable to surgical/ablative treatment, median CSS was significantly superior compared to chemotherapy alone (56 vs 30 months, P < 0.001).

Conclusions:

This large cohort provides the first evidence that patients with primarily unresectable CRLM treated by ALPPS have not only low perioperative mortality, but achieve appealing long-term oncologic outcome especially those with favorable tumor biology and good response to chemotherapy.
Choices of Therapeutic Strategies for Colorectal Liver Metastases Among Expert Liver Surgeons
Authors: Ignatavicius Povilas , Oberkofler Christian E. , Chapman William C. , DeMatteo Ronald P. , Clary Bryan M. , D’Angelica Michael I. , Tanabe Kenneth K. , Hong Johnny C. , Aloia Thomas A. , Pawlik Timothy M. , Hernandez-Alejandro Roberto , Shah Shimul A. , Vauthey Jean-Nicolas , Torzilli Guido , Lang Hauke , Line Pål-Dag , Soubrane Olivier , Pinto-Marques Hugo , Robles-Campos Ricardo , Boudjema Karim , Lodge Peter , Adam René , Toso Christian , Serrablo Alejandro , Aldrighetti Luca , DeOliveira Michelle L. , Dutkowski Philipp , Petrowsky Henrik , Linecker Michael , Reiner Cäcilia S. , Braun Julia , Alikhanov Ruslan , Barauskas Giedrius , Chan Albert C. Y. , Dong Jiahong , Kokudo Norihiro , Yamamoto Masakazu , Kang Koo Jeong , Fong Yuman , Rela Mohamed , De Aretxabala Xabier , De Santibañes Eduardo , Mercado Miguel Ángel , Andriani Oscar C. , Torres Orlando Jorge M. , Pinna Antonio D. , Clavien Pierre-Alain
Published: August 2020

Objective:

To test the degree of agreement in selecting therapeutic options for patients suffering from colorectal liver metastasis (CRLM) among surgical experts around the globe.

Summary/Background:

Only few areas in medicine have seen so many novel therapeutic options over the past decades as for liver tumors. Significant variations may therefore exist regarding the choices of treatment, even among experts, which may confuse both the medical community and patients.

Methods:

Ten cases of CRLM with different levels of complexity were presented to 43 expert liver surgeons from 23 countries and 4 continents. Experts were defined as experienced surgeons with academic contributions to the field of liver tumors. Experts provided information on their medical education and current practice in liver surgery and transplantation. Using an online platform, they chose their strategy in treating each case from defined multiple choices with added comments. Inter-rater agreement among experts and cases was calculated using free-marginal multirater kappa methodology. A similar, but adjusted survey was presented to 60 general surgeons from Asia, Europe, and North America to test their attitude in treating or referring complex patients to expert centers.

Results:

Thirty-eight (88%) experts completed the evaluation. Most of them are in leading positions (92%) with a median clinical experience of 25 years. Agreement on therapeutic strategies among them was none to minimal in more than half of the cases with kappa varying from 0.00 to 0.39. Many general surgeons may not refer the complex cases to expert centers, including in Europe, where they also engage in complex liver surgeries.

Conclusions:

Considerable inconsistencies of decision-making exist among expert surgeons when choosing a therapeutic strategy for CRLM. This might confuse both patients and referring physicians and indicate that an international high-level consensus statements and widely accepted guidelines are needed.
Spinal cord injury can be relieved by the polysaccharides of Tricholoma matsutake by promoting axon regeneration and reducing neuroinflammation
Authors: Liu Jun , Yang Feng , Cheng Maofeng , Zhang Yan
Published: August 2020

Background

With an increase in the number of spinal cord injuries (SCIs) in China, severe dysfunction of the limb below the injured segment is prominent. Among the studies centered on the factors inducing SCIs, inflammatory response has a dramatic input on the pathogenesis of SCIs.

Objectives

This study aimed to investigate the effects of Tricholoma matsutake polysaccharides (TMP) on function recovery following SCIs.

Methods

The cell viability, neurite growth, NF-kappa B, TNFα and IL-6 production from hydrogen peroxide-treated PC12 cells were analyzed. In-vivo, a total of 36 male C57 mice were divided into sham group, SCI group and TMP group (100 mg/kg). The protective effects of TMP were evaluated by Basso mouse scale (BMS) scores, HE staining, immunofluorescence and Western blotting.

Results

TMP promoted neurite growth and inhibited TNFα, IL-6 and NF-kappa B signaling in a concentration-dependent manner in vitro. Moreover, compared with the SCI group, the BMS scores and nerve regeneration showed a significant increase, while NF-kappa B signaling, TNFα and IL-6 production significantly decreased after TMP treatment.

Conclusion

TMP has a protective effect against SCIs in vitro and in vivo, which may be a potential strategy for future application in clinical practice.
Increased expression of Fragile X mental retardation protein in malformative lesions of patients with focal cortical dysplasia
Authors: Reynolds Conner D. , Nolan Suzanne O. , Smith Gregory D. , Jefferson Taylor S. , Hodges Samantha L. , Brewster Amy L. , Lugo Joaquin N.
Published: August 2020

Objective

Focal cortical dysplasia (FCD) accounts for nearly half of all cases of medically refractory epilepsy in the pediatric and adult patient populations. This neurological disorder stems from localized malformations in cortical brain tissue due to impaired neuronal proliferation, differentiation, and migration patterns. Recent studies in animal models have highlighted the potential role of the Fragile X mental retardation protein (FMRP) levels in FCD. The purpose of this study was to investigate the status of FMRP activation in cortical brain tissues surgically resected from patients with FCD. In parallel, this study also investigated protein levels within the PI3K/AKT/mTOR and canonical Wnt signaling pathways.

Methods

Pathologic tissue from malformative lesions of FCD patients with medically refractory epilepsy was compared to relatively normal control non-epileptic tissue from patients with intracranial neoplasms. A series of western blotting assays were performed to assess key proteins in the PI3K/AKT/mTOR, canonical Wnt signaling pathways, and FMRP.

Results

There was suppression of S235/236-phosphorylated S6, GSK3α, and GSK3β protein levels in samples derived from FCD patients, compared to non-epileptic controls. FCD samples also had significantly greater levels of total and S499-phosphorylated FMRP.

Conclusion

These findings support our hypothesis that malformative lesions associated with FCD are characterized by high levels of FMRP activation along with dysregulation of both PI3K/AKT/mTOR and canonical Wnt signaling. These novel clinical findings extend previous work in animal models, further suggesting a potential unforeseen role of GSK3α and GSK3β in the pathophysiology of FCD and refractory epilepsy.
Microtubules enter centre stage for morphogenesis
Authors: Röper Katja
Published: August 2020

Cell shape changes are key to observable changes at the tissue level during morphogenesis and organ formation. The major driver of cell shape changes in turn is the actin cytoskeleton, both in the form of protrusive linear or branched dynamic networks and in the form of contractile actomyosin. Over the last 20 years, actomyosin has emerged as the major cytoskeletal system that deforms cells in epithelial sheets during morphogenesis. By contrast, the second major cytoskeletal system, microtubules, have so far mostly been assumed to serve ‘house-keeping' functions, such as directed transport or cell division, during morphogenetic events. Here, I will reflect on a subset of studies over the last 10 years that have clearly shown a major direct role for the microtubule cytoskeleton in epithelial morphogenesis, suggesting that our focus will need to be widened to give more attention and credit to this cytoskeletal system in playing an active morphogenetic role.

This article is part of a discussion meeting issue ‘Contemporary morphogenesis'.
Epithelial–mesenchymal plasticity: emerging parallels between tissue morphogenesis and cancer metastasis
Authors: Plygawko Andrew T. , Kan Shohei , Campbell Kyra
Published: August 2020

Many cells possess epithelial–mesenchymal plasticity (EMP), which allows them to shift reversibly between adherent, static and more detached, migratory states. These changes in cell behaviour are driven by the programmes of epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET), both of which play vital roles during normal development and tissue homeostasis. However, the aberrant activation of these processes can also drive distinct stages of cancer progression, including tumour invasiveness, cell dissemination and metastatic colonization and outgrowth. This review examines emerging common themes underlying EMP during tissue morphogenesis and malignant progression, such as the context dependence of EMT transcription factors, a central role for partial EMTs and the nonlinear relationship between EMT and MET.

This article is part of a discussion meeting issue ‘Contemporary morphogenesis'.
Brassinosteroids Promote Parenchyma Cell and Secondary Xylem Development in Sugar Beet (Beta vulgaris L.) Root
Authors: Wang Wei , Sun Yaqing , Li Guolong , Zhang Shaoying
Published: August 2020

Increasing crop yield has always been an important goal in agriculture. Brassinosteroids (BRs) are growth-promoting steroid hormones with vital roles in many root developmental processes. Sugar beet (Beta vulgaris L.) is a root crop with a tertiary root structure. The differentiation of vascular bundles and division of cambial cells increases root diameter. However, little is known about how BRs regulate the transverse growth of beetroot. Therefore, sugar beet with eight leaves was grown in medium containing epibrassinolide or brassinazole, an inhibitor of brassinosteroid biosynthesis. BRs increased the spacing between the cambial rings by increasing the size of parenchyma cells between the rings and ultimately increasing root diameter. BRs also promoted secondary xylem differentiation. These findings indicate that brassinosteroids function in transverse development in beetroot.
Botanical Medicines with Activity against Stationary PhaseBartonella henselae
Authors: Ma Xiao , Leone Jacob , Schweig Sunjya , Zhang Ying
Published: August 2020

Bartonella henselaeis a Gram-negative, facultative intracellular bacterium which is the causative agent of cat scratch disease. In humans, infections withB. henselaecan result in acute or chronic systemic infections with various clinical symptoms including local skin lesions, malaise, aches, chills, lymphadenopathy, endocarditis, or meningoencephalitis. The current treatment forBartonellainfections with antibiotics such as doxycycline and rifampin is not always effective presumably due to bacterial persistence. There have been various anecdotal reports of herbal extracts used for treating patients with persistentBartonellainfections but their activity onB. henselaeis unknown. To test the potential antimicrobial activity of botanical or herbal medicines and develop better therapies for persistentBartonellainfections, in this study, we screened an herbal product collection against stationary phaseB. henselae in vitrousing SYBR Green I/ propidium iodide (PI) viability assay. These herbal medicines were selected by the fact that they are commonly used to treat Lyme and co-infections by patients and herbalists, and as a follow-up to our recent study where these herbs were tested againstB. burgdorferi. We identified five herbal product extracts that had high activity against stationary phaseB. henselaeat 0.5% (v/v), includingCryptolepis sanguinolenta,Juglans nigra,Polygonum cuspidatum,Scutellaria baicalensis, andScutellaria barbata. Among them,Cryptolepis sanguinolenta,Juglans nigra, andPolygonum cuspidatumcould eradicate all stationary phaseB. henselaecells within 7 days at 0.25% (v/v) in drug exposure time-kill assay, whereasScutellaria baicalensisandScutellaria barbatashowed relatively poor activity. The minimum inhibitory concentration (MIC) determination of these top hits indicated they were not only active against stationary phase non-growingB. henselaebut also had good activity against log phase growingB. henselae. Our findings may help to develop more effective treatments for persistentBartonellainfections.
Genome assembly of a Mesoamerica-derivedPhaseolus lunatuscultivar enables the identification and comparative genomic analysis of a complex resistance locus
Authors: Wisser Randall J. , Oppenheim Sara J. , Ernest Emmalea G. , Mhora Terence T. , Scanlan Colin , Dumas Michael D. , Gregory Nancy F. , Evans Thomas A. , Donofrio Nicole M.
Published: August 2020

Lima bean,Phaseolus lunatus, is closely related to common bean and is high in fiber and protein, with a low glycemic index. Lima bean is widely grown in the state of Delaware, where late summer and early fall weather are conducive to pod production. The same weather conditions also promote diseases such as pod rot and downy mildew, the latter of which has caused previous epidemics. A better understanding of the genes underlying resistance to this and other pathogens is needed to keep this industry thriving in the region. Our current study sought to sequence, assemble and annotate a commercially available cultivar called Bridgeton, which could then serve as a reference genome, a basis of comparison to otherPhaseolustaxa and a resource for identification of potential resistance genes. Combined efforts of sequencing, linkage and comparative mapping analysis resulted in a 625 Mb genome assembly, as well as a better understanding of a locus underlying resistance to the current downy mildew race in the field.