bluuebunny/crossref_metadata_2025_split huggingface dataset:
Birinapant selectively enhances immunotoxin‐mediated killing of cancer cells conditional on the IAP protein levels within target cells
Authors: Antignani Antonella , Bilotta Maria Teresa , Roth Jacob S. , Urban Daniel J. , Shen Min , Hall Matthew D. , FitzGerald David 
Published: November 2023

AbstractImmunotoxins (ITs) target cancer cells via antibody binding to surface antigens followed by internalization and toxin‐mediated inhibition of protein synthesis. The fate of cells responding to IT treatment depends on the amount and stability of specific pro‐apoptotic and pro‐survival proteins. When treated with a pseudomonas exotoxin‐based immunotoxin (HB21PE40), the triple‐negative breast cancer (TNBC) cell line MDA‐MB‐468 displayed a notable resistance to toxin‐mediated killing compared to the epidermoid carcinoma cell line, A431, despite succumbing to the same level of protein synthesis inhibition. In a combination screen of ~1912 clinically relevant and mechanistically annotated compounds, we identified several agents that greatly enhanced IT‐mediated killing of MDA‐MB‐468 cells while exhibiting only a modest enhancement for A431 cells. Of interest, two Smac mimetics, birinapant and SM164, exhibited this kind of differential enhancement. To investigate the basis for this, we probed cells for the presence of inhibitor of apoptosis (IAP) proteins and monitored their stability after the addition of immunotoxin. We found that high levels of IAPs inhibited immunotoxin‐mediated cell death. Further, TNFα levels were not relevant for the combination's efficacy. In tumor xenograft studies, combinations of immunotoxin and birinapant caused complete regressions in MDA‐MB‐468tumor‐bearing mice but not in mice with A431 tumors. We propose that IAPs constitute a barrier to immunotoxin efficacy which can be overcome with combination treatments that include Smac mimetics.
Extracorporeal Membrane Oxygenation Without Invasive Ventilation for Respiratory Failure in Adults: A Systematic Review*
Authors: Belletti Alessandro , Sofia Rosaria , Cicero Perla , Nardelli Pasquale , Franco Annalisa , Calabrò Maria Grazia , Fominskiy Evgeny V. , Triulzi Margherita , Landoni Giovanni , Scandroglio Anna Mara , Zangrillo Alberto 
Published: November 2023

OBJECTIVES:
Extracorporeal membrane oxygenation (ECMO) is an advanced treatment for acute severe respiratory failure. Patients on ECMO are frequently maintained sedated and immobilized until weaning from ECMO, first, and then from mechanical ventilation. Avoidance of sedation and invasive ventilation during ECMO may have potential advantages. We performed a systematic literature review to assess efficacy and safety of awake ECMO without invasive ventilation in patients with respiratory failure.

DATA SOURCES:
PubMed, Web of Science, and Scopus were searched for studies reporting outcome of awake ECMO for adult patients with respiratory failure.

STUDY SELECTION:
We included all studies reporting outcome of awake ECMO in patients with respiratory failure. Studies on ECMO for cardiovascular failure, cardiac arrest, or perioperative support and studies on pediatric patients were excluded. Two investigators independently screened and selected studies for inclusion.

DATA EXTRACTION:
Two investigators abstracted data on study characteristics, rate of awake ECMO failure, and mortality. Primary outcome was rate of awake ECMO failure (need for intubation). Pooled estimates with corresponding 95% CIs were calculated. Subgroup analyses by setting were performed.

DATA SYNTHESIS:
A total of 57 studies (28 case reports) included data from 467 awake ECMO patients. The subgroup of patients with acute respiratory distress syndrome showed a pooled estimate for awake ECMO failure of 39.3% (95% CI, 24.0–54.7%), while in patients bridged to lung transplantation, pooled estimate was 23.4% (95% CI, 13.3–33.5%). Longest follow-up mortality was 121 of 439 (pooled estimate, 28%; 95% CI, 22.3–33.6%). Mortality in patients who failed awake ECMO strategy was 43 of 74 (pooled estimate, 57.2%; 95% CI, 40.2–74.3%). Two cases of cannula self-removal were reported.

CONCLUSIONS:
Awake ECMO is feasible in selected patients, although the effect on outcome remains to be demonstrated. Mortality is almost 60% in patients who failed awake ECMO strategy.
Risk Factors Associated With Development of Multiple-Organ Dysfunction Syndrome After Pediatric Drowning
Authors: Southard-Goebel Colton , Pike Francis , Rowan Courtney M. , Cater Daniel T. 
Published: November 2023

Objective
This study aimed to describe a single-center experience of pediatric drowning and to investigate risk factors associated with the development of pediatric multiple-organ dysfunction syndrome (MODS) after drowning events.

Methods
A single-center retrospective case-control study was performed at a tertiary children's hospital examining patients aged 1 month to 25 years who were admitted to the pediatric intensive care unit after a drowning event. The study period was June 2016 to June 2021. Patients who developed MODS at day 1 of intensive care admission were compared with those who did not.

Results
A total of 48 patients with a median age of 2.3 years were included. Twenty-nine (60%) had MODS at 24 hours. Those with MODS at 24 hours were more likely to require cardiopulmonary resuscitation (CPR), required longer duration of CPR, and had longer submersion times; otherwise, there were no differences in baseline characteristics. Those who developed MODS at 24 hours had longer lengths of stays, longer lengths of mechanical ventilation, and higher mortality. Multiple admission parameters were evaluated based on MODS-free survival at 24 hours. On univariable analysis, patients without MODS-free survival at 24 hours had higher rates of CPR, higher blood glucose on admission, higher illness severity scores, higher lactates, and lower Glasgow Coma Scale scores. A multivariable model was constructed using risk factors at presentation that were significant on univariable analysis; blood glucose greater than 200 mg/dL was associated with decreased odds of MODS-free survival at 24 hours after controlling for CPR administration of greater than 5 minutes and body temperature.

Conclusions
Development of MODS in pediatric drowning is associated with worse patient outcomes. Hyperglycemia was identified as a potentially modifiable risk factor for the development of MODS at 24 hours and could serve as a useful prognostic parameter in this unique patient population.
Use of Antipseudomonal Antibiotics is not Associated with Lower Rates of Postoperative Drainage Procedures or More Favorable Culture Profiles in Children with Complicated Appendicitis
Authors: Cramm Shannon L. , Graham Dionne A. , Feng Christina , Allukian Myron , Blakely Martin L. , Chandler Nicole M. , Cowles Robert A. , Kunisaki Shaun M. , Lipskar Aaron M. , Russell Robert T. , Santore Matthew T. , Campbell Brendan T. , Commander Sarah J. , DeFazio Jennifer R. , Dukleska Katerina , Echols Justice C. , Esparaz Joseph R. , Gerall Claire , Griggs Cornelia L. , Hanna David N. , He Katherine , Keane Olivia A. , McLean Sean E. , Pace Elizabeth , Scholz Stefan , Sferra Shelby R. , Tracy Elisabeth T. , Zhang Lucy , Rangel Shawn J. ,   On behalf of the Eastern Pediatric Surgery Network
Published: November 2023

Objective:
To compare rates of postoperative drainage and culture profiles in children with complicated appendicitis treated with the two most common antibiotic regimens with and without antipseudomonal activity (piperacillin-tazobactam [PT] and ceftriaxone with metronidazole [CM]).

Summary of Background Data:
Variation in use of antipseudomonal antibiotics has been driven by a paucity of multicenter data reporting clinically relevant, culture-based outcomes.

Methods:
Retrospective cohort study of patients with complicated appendicitis (7/2015-6/2020) using NSQIP-Pediatric data from 15 hospitals participating in a regional research consortium. Operative report details, antibiotic utilization, and culture data were obtained through supplemental chart review. Rates of 30-day postoperative drainage and organism-specific culture positivity were compared between groups using mixed effects regression to adjust for clustering after propensity matching on measures of disease severity.

Results:
1002 children met criteria for matching (58.9% received CM and 41.1% received PT). In the matched sample of 778 patients, children treated with PT had similar rates of drainage overall (PT: 11.8%, CM: 12.1%; OR 1.44 [OR:0.71-2.94]) and higher rates of drainage associated with growth of any organism (PT: 7.7%, CM: 4.6%; OR 2.41 [95%CI:1.08-5.39]) and Escherichia coli (PT: 4.6%, CM: 1.8%; OR 3.42 [95%CI:1.07-10.92]) compared to treatment with CM. Rates were similar between groups for drainage associated with multiple organisms (PT: 2.6%, CM: 1.5%; OR 3.81 [95%CI:0.96-15.08]) and Pseudomonas (PT: 1.0%, CM: 1.3%; OR 3.42 [95%CI:0.55-21.28]).

Conclusions and Relevance:
Use of antipseudomonal antibiotics is not associated with lower rates of postoperative drainage procedures or more favorable culture profiles in children with complicated appendicitis.
Minimally Invasive Pilonidal Sinus Treatment: EPSIT Versus PEBAI Method
Authors: Gulcu Baris , Ozturk Ersin 
Published: November 2023

Purpose:
We aimed to compare endoscopic pilonidal sinus treatment (EPSIT) and pit/sinus punch needle excision, brushing, ablation and irrigation (PEBAI) method that was performed with principles similar to EPSIT but without fistuloscope and vision in the treatment of pilonidal sinus disease (PSD).

Methods:
Patients who underwent EPSIT and PEBAI methods for PSD in a single center between January 2020 and October 2021 were retrospectively analyzed. The primary endpoint was healing, the secondary endpoints were operative time, pain, wound closure, quality of life, cosmetic results, and cost.

Results:
One hundred 4 patients who underwent EPSIT and 184 patients who underwent PEBAI were included in the study. Age (P=0.871), sex (P=0.669), BMI (P=0.176), number of pits (P=0.99) were similar in both groups. The operative time for PEBAI [20 min (18 to 32)] was shorter than EPSIT [32 min (24 to 44)] (P<0.0000, u value=3096, z-score=-9.459). Postoperative first (P=0.147) and 14th day(P=0.382) pain scores, postoperative analgesic requirements (P=0.609), time to return to daily activities (P=0.747), time to return to work (P=0.345), and wound complications (P=0.816) were similar, whereas the wound closure time was earlier after EPSIT [32 d (24 to 41)] than after PEBAI [37 d (26 to 58)] (P<0.00001, u value=5344, z-score=6.22141). The median follow-up was 24 (12 to 34) months. Complete wound healing (P=0.382), recurrence rate (P=0.533), quality of life at first month and (Wound evaluation scale score at first year (P=0.252) were similar in both groups. However, the cost of PEBAI [54.8 € (50.13 to 64.96)] was significantly lower than cost of EPSIT [147.36 € (132.53 to 169.60)] (P<0.00001, u value=0, z-score=7.210).

Conclusions:
PEBAI method is a cheaper alternative to EPSIT with similar surgical principles and clinical outcomes.
Clamp-crushing Pancreatic Transection in Minimally Invasive Distal Pancreatectomy
Authors: Sakamoto Katsunori , Ogawa Kohei , Tamura Kei , Honjo Masahiko , Hikida Takahiro , Iwata Miku , Ito Chihiro , Sakamoto Akimasa , Shine Mikiya , Nishi Yusuke , Uraoka Mio , Nagaoka Tomoyuki , Funamizu Naotake , Takada Yasutsugu 
Published: November 2023

Background:
Minimally invasive distal pancreatectomy has become a widely accepted procedure for tumors located in the pancreatic body or tail. However, pancreatic transection by linear stapler is generally avoided for pancreatic body tumors located above the portal vein because the surgical margin width is narrowed after taking into account the cutting allowance for insertion of the stapling device. Herein, we report a parenchymal clamp-crushing procedure that provides a sufficient surgical margin in pancreatic transection.

Methods:
Two patients with suspected early pancreatic cancer underwent pancreatic transection using the clamp-crushing procedure. The planned pancreatic transection line was set just to the left of the gastroduodenal artery in both cases. Robotic and laparoscopic distal pancreatectomy were performed in 1 patient each. Patients were positioned supine with split legs. Parenchymal transection was performed with crushing by VIO 3 (ERBE Elektromedizin) operated in softCOAG Bipolar mode with Effect 2/modulation 50. After crushing, remnant tissue was cut in autoCUT Bipolar mode operated by VIO 3 with Effect 2/modulation 50, or cut after secured by clipping.

Results:
The surgical duration was 253 and 212 minutes, and estimated blood loss was 0 and 50 mL in the 2 patients, and both were discharged with uneventful courses. Pathologic examination confirmed a negative surgical margin in both patients.

Conclusion:
Clamp-crushing pancreatic transection for distal pancreatectomy might be a suitable treatment option for achieving sufficient surgical margin in pancreatic body tumors located close to the portal vein.
Exploring the Therapeutic Potential of Cannabis Constituents in Parkinson’s Disease: Insights from Molecular Docking Studies
Authors: Aziz Moawaz , Rehman Hafsa , Iqbal Azhar , Nawaz Allah , Hussain Momina , Siddique Tehmina , Sehgal Sheikh Arslan Ashraf , Sajid Muhammad 
Published: November 2023

AbstractCannabis, often known as marihuana, marijuana, hashish, and hash, belongs to the genus Cannabis sativa L. This plant has excellent potential for the treatment of several brain disorders. Phytochemical compounds in this plant act as antioxidants, preserving synaptic plasticity and preventing neuronal degeneration. The neurodegenerative condition Parkinson’s has emerged as one of the most significant health concerns of the twenty-first century. A detailed in silico molecular docking study was carried out to assess the neuroprotective effects of cannabis compounds against four potential targets of PD, including monoamine oxidase B (MAO-B), catechol-O-methyltransferase (COMT), alpha-synuclein (ASN), and Adenosine A2A receptor (A2A). Physicochemical properties, drug-likeness, toxicity, and ADMET profiles were also investigated. In this docking study, the cannabis compound cannabicyclol showed a superior docking score of −10.8 kcal/mol with the MAO-B protein. Based on these results, cannabicyclol and the target protein MAO-B were used to perform MD simulations to analyze their stability at 100 ns. Furthermore, it is crucial to carry out in vitro and in vivo investigations to enhance the potency of cannabis components and understand the processes underlying the suppression of Parkinson’s disease-related enzymes.Abstract Figure
Breastfeeding enhances intestinal gluconeogenesis in infants
Authors: Ni Duan , Tan Jian , Macia Laurence , Nanan Ralph 
Published: November 2023

AbstractObjectivesBreastfeeding confers metabolic benefits to the infants, including reducing risks for metabolic syndromes such as obesity and diabetes later in life, but the underlying mechanisms is not yet fully understood. Hence, we aim to investigate the impacts of breastfeeding on the metabolic organs of infants.MethodsPrevious literatures directly studying the influences of breastfeeding on offspring’s metabolic organs were comprehensively reviewed. A microarray dataset of intestinal gene expression comparing infants fed on breastmilk versus formula milk was reanalyzed.ResultsReanalysis of microarray data showed that breastfeeding significantly enhanced gluconeogenesis in infants’ intestine. This resembled observations in other mammalian species where breastfeeding also promoted gluconeogenesis.ConclusionsBreastfeeding enhances intestinal gluconeogenesis in infants, which may underlie its metabolic advantages through finetuning the metabolic homeostasis. Such effect seems to be conserved across species, hinting its biological significance.
Similar metabolic pathways are affected in both Congenital Myasthenic Syndrome-22 and Prader-Willi Syndrome
Authors: Bhalla Kritika , Rosier Karen , Monnens Yenthe , Meulemans Sandra , Vervoort Ellen , Thorrez Lieven , Agostinis Patrizia , Meier Daniel T. , Rochtus Anne , Resnick James L , Creemers John W.M. 
Published: November 2023

AbstractLoss of prolyl endopeptidase-like (PREPL) encoding a serine hydrolase with (thio)esterase activity leads to the recessive metabolic disorder Congenital Myasthenic Syndrome-22 (CMS22). It is characterized by severe neonatal hypotonia, feeding problems, growth retardation, and hyperphagia leading to rapid weight gain later in childhood. The phenotypic similarities with Prader-Willi syndrome (PWS) are striking, suggesting that similar pathways are affected. The aim of this study was to identify changes in the hypothalamic-pituitary axis in mouse models for both disorders and to examine mitochondrial function in skin fibroblasts of patients and knockout cell lines. We have demonstrated thatPreplis downregulated in the brains of neonatal PWS-IC-p/+mmice. In addition, the hypothalamic-pituitary axis is similarly affected in bothPrepl-/-and PWS-IC-p/+mmice resulting in defective orexigenic signaling and growth retardation. Furthermore, we demonstrated that mitochondrial function is altered inPREPLknockout HEK293T cells and can be rescued with the supplementation of coenzyme Q10. Finally, PREPL-deficient and PWS patient skin fibroblasts display defective mitochondrial bioenergetics. The mitochondrial dysfunction in PWS fibroblasts can be rescued by overexpression of PREPL. In conclusion, we provide the first molecular links between CMS22 and PWS, raising the possibility that PREPL substrates might become therapeutic targets for treating both disorders.Graphical Abstract
Genetic Diversity and Structural Complexity of the Killer-Cell Immunoglobulin-Like Receptor Gene Complex: A Comprehensive Analysis Using Human Pangenome Assemblies
Authors: Hung Tsung-Kai , Liu Wan-Chi , Lai Sheng-Kai , Chuang Hui-Wen , Lee Yi-Che , Lin Hong-Ye , Hsu Chia-Lang , Chen Chien-Yu , Yang Ya-Chien , Hsu Jacob Shujui , Chen Pei-Lung 
Published: November 2023

AbstractThe killer-cell immunoglobulin-like receptor (KIR) gene complex, a highly polymorphic region of the human genome that encodes proteins involved in immune responses, poses strong challenges in genotyping due to its remarkable genetic diversity and structural intricacy. Accurate analysis of KIR alleles, including their structural variations, is crucial for understanding their roles in various immune responses. Leveraging the high-quality genome assemblies from the Human Pangenome Reference Consortium (HPRC), we present a novel bioinformatic tool, the Structural KIR annoTator (SKIRT), to investigate gene diversity and facilitate precise KIR allele analysis. We applied SKIRT on 47 HPRC-phased assemblies and identified a recurrent novelKIR2DS4/3DL1fusion gene in the paternal haplotype of HG02630 and maternal haplotype of NA19240. Additionally, SKIRT accurately identifies eight structural variants and 17 novel nonsynonymous alleles, all of which were independently validated using short-read data or quantitative polymerase chain reaction. Our study has discovered a total of 570 novel alleles, among which eight haplotypes harbor at least one KIR gene duplication, six haplotypes have lost at least one framework gene, and 75 out of 94 haplotypes (79.8%) carry at least five novel alleles, thus confirming KIR genetic diversity. These findings are pivotal in providing insights into KIR gene diversity and serve as a solid foundation for understanding the functional consequences of KIR structural variations. High-resolution genome assemblies offer unprecedented opportunities to explore polymorphic regions that are challenging to investigate using short-read sequencing methods. The SKIRT pipeline emerges as a highly efficient tool, enabling the comprehensive detection of the complete spectrum of KIR alleles within human genome assemblies.
TranSiGen: Deep representation learning of chemical-induced transcriptional profile
Authors: Tong Xiaochu , Qu Ning , Kong Xiangtai , Ni Shengkun , Wang Kun , Zhang Lehan , Wen Yiming , Zhang Sulin , Li Xutong , Zheng Mingyue 
Published: November 2023

AbstractWith the advancement of high-throughput RNA sequencing technologies, the use of chemical-induced transcriptional profiling has greatly increased in biomedical research. However, the usefulness of transcriptomics data is limited by inherent random noise and technical artefacts that may cause systematical biases. These limitations make it challenging to identify the true signal of perturbation and extract knowledge from the data. In this study, we propose a deep generative model called Transcriptional Signatures Generator (TranSiGen), which aims to denoise and reconstruct transcriptional profiles through self-supervised representation learning.TranSiGen uses cell basal gene expression and compound molecular structure representation to infer the chemical-induced transcriptional profile. Results demonstrate the effectiveness of TranSiGen in learning and predicting differential expression genes. The representation derived from TranSiGen can also serve as an alternative phenotype information, with applications in ligand-based virtual screening, drug response prediction, and phenotype-based drug repurposing. We envisage that integrating TranSiGen into the drug discovery and mechanism research pipeline will promote the development of biomedicine.
The genetic architecture of the load linked to dominant and recessive self-incompatibility alleles inArabidopsis halleriandA. lyrata
Authors: Le Veve Audrey , Genete Mathieu , Lepers-Blassiau Christelle , Ponitzki Chloé , Poux Céline , Vekemans Xavier , Durand Eleonore , Castric Vincent 
Published: November 2023

AbstractThe long-term balancing selection acting on mating-types or sex determining genes is expected to lead to the accumulation of deleterious mutations in the tightly linked chromosomal segments that are locally “sheltered” from purifying selection. However, the factors determining the extent of this accumulation are poorly understood. Here, we took advantage of variations in the intensity of balancing selection along a dominance hierarchy formed by alleles at the sporophytic self-incompatibility system of the Brassicaceae to compare the pace at which linked deleterious mutations accumulate among them. We first experimentally measured the phenotypic manifestation of the linked load at three different levels of the dominance hierarchy. We then sequenced and phased polymorphisms in the chromosomal regions linked to 126 distinct copies ofS-alleles in two populations ofArabidopsis halleriand three populations ofA. lyrata. We find that linkage to theS-locus locally distorts phylogenies over about 10-30kb along the chromosome. The more intense balancing selection on dominantS-alleles results in greater fixation of linked deleterious mutations, while recessiveS-alleles accumulate more linked deleterious mutations that are segregating. Hence, the structure rather than the overall magnitude of the linked genetic load differs between dominant and recessiveS-alleles. Our results have consequences for the long-term evolution of newS-alleles, the evolution of dominance modifiers between them, and raise the question of why the non-recombining regions of some sex and mating type chromosomes expand over evolutionary times while others, such as that theS-locus of the Brassicaceae, remain restricted to small chromosomal regions.