bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of genetic markers of resistance to macrolide class antibiotics in
Mannheimia haemolytica
isolates from a Saskatchewan feedlot
Authors: Deschner Darien , Voordouw Maarten J. , Fernando Champika , Campbell John , Waldner Cheryl L. , Hill Janet E.
Published: June 2024

Mannheimia haemolytica
is a major contributor to bovine respiratory disease (BRD), which causes substantial economic losses to the beef industry, and there is an urgent need for rapid and accurate diagnostic tests to provide evidence for treatment decisions and support antimicrobial stewardship. Diagnostic sequencing can provide information about antimicrobial resistance genes in
M. haemolytica
more rapidly than conventional diagnostics. Realizing the full potential of diagnostic sequencing requires a comprehensive understanding of the genetic markers of antimicrobial resistance. We identified genetic markers of resistance in
M. haemolytica
to macrolide class antibiotics commonly used for control of BRD. Genome sequences were determined for 99
M. haemolytica
isolates with six different susceptibility phenotypes collected over 2 years from a feedlot in Saskatchewan, Canada. Known macrolide resistance genes
estT
,
msr
(E), and
mph
(E) were identified in most resistant isolates within predicted integrative and conjugative elements (ICEs). ICE sequences lacking antibiotic resistance genes were detected in 10 of 47 susceptible isolates. No resistance-associated polymorphisms were detected in ribosomal RNA genes, although previously unreported mutations in the L22 and L23 ribosomal proteins were identified in 12 and 27 resistant isolates, respectively. Pangenome analysis led to the identification of 79 genes associated with resistance to gamithromycin, of which 95% (75 of 79) had no functional annotation. Most of the observed phenotypic resistance was explained by previously identified antibiotic resistance genes, although resistance to the macrolides gamithromycin and tulathromycin was not explained in 39 of 47 isolates, demonstrating the need for continued surveillance for novel determinants of macrolide resistance.

IMPORTANCE

Bovine respiratory disease is the costliest disease of beef cattle in North America and the most common reason for injectable antibiotic use in beef cattle. Metagenomic sequencing offers the potential to make economically significant reductions in turnaround time for diagnostic information for evidence-based selection of antibiotics for use in the feedlot. The success of diagnostic sequencing depends on a comprehensive catalog of antimicrobial resistance genes and other genome features associated with reduced susceptibility. We analyzed the genome sequences of isolates of
Mannheimia haemolytica
, a major bovine respiratory disease pathogen, and identified both previously known and novel genes associated with reduced susceptibility to macrolide class antimicrobials. These findings reinforce the need for ongoing surveillance for markers of antimicrobial resistance to support improved diagnostics and antimicrobial stewardship.
Investigating the importance of selected surface-exposed loops in HpuB for hemoglobin binding and utilization by
Neisseria gonorrhoeae
Authors: Awate Olivia A. , Ng Dixon , Stoudenmire Julie L. , Moraes Trevor F. , Cornelissen Cynthia N.
Published: June 2024

Neisseria gonorrhoeae
is the etiological agent of the sexually transmitted infection gonorrhea. The pathogen is a global health challenge since no protective immunity results from infection, and far fewer treatment options are available with increasing antimicrobial resistance. With no efficacious vaccines, researchers are exploring new targets for vaccine development and innovative therapeutics. The outer membrane TonB-dependent transporters (TdTs) produced by
N. gonorrhoeae
are considered promising vaccine antigens as they are highly conserved and play crucial roles in overcoming nutritional immunity. One of these TdTs is part of the hemoglobin transport system comprised of HpuA and HpuB. This system allows
N. gonorrhoeae
to acquire iron from hemoglobin (hHb). In the current study, mutations in the
hpuB
gene were generated to better understand the structure–function relationships in HpuB. This study is one of the first to demonstrate that
N. gonorrhoeae
can bind to and utilize hemoglobin produced by animals other than humans. This study also determined that when HpuA is absent, mutations targeting extracellular loop 7 of HpuB led to defective hHb binding and utilization. However, when the lipoprotein HpuA is present, these loop 7 mutants recovered their ability to bind hHb, although the growth phenotype remained significantly impaired. Interestingly, loop 7 contains putative heme-binding motifs and a hypothetical α-helical region, both of which may be important for the use of hHb. Taken together, these results highlight the importance of loop 7 in the functionality of HpuB in binding hHb and extracting and internalizing iron.
CRISPR-Cas9 high-throughput screening to study drug resistance in
Leishmania infantum
Authors: Queffeulou Marine , Leprohon Philippe , Fernandez-Prada Christopher , Ouellette Marc , Mejía-Jaramillo Ana María
Published: June 2024

Parasites of the genus
Leishmania
pose a global health threat with limited treatment options. New drugs are urgently needed, and genomic screens have the potential to accelerate target discovery, mode of action, and resistance mechanisms against these new drugs. We describe here our effort in developing a genome-wide CRISPR-Cas9 screen in
Leishmania
, an organism lacking a functional nonhomologous end joining system that must rely on microhomology-mediated end joining, single-strand annealing, or homologous recombination for repairing Cas9-induced double-stranded DNA breaks. A new vector for cloning and expressing single guide RNAs (sgRNAs) was designed and proven to be effective in a small pilot project while enriching specific sgRNAs during drug selection. We then developed a whole-genome library of 49,754 sgRNAs, targeting all the genes of
Leishmania infantum
. This library was transfected in
L. infantum
expressing Cas9, and these cells were selected for resistance to two antileishmanials, miltefosine and amphotericin B. The sgRNAs the most enriched in the miltefosine screen targeted the miltefosine transporter gene, but sgRNAs targeting genes coding for a RING-variant protein and a transmembrane protein were also enriched. The sgRNAs the most enriched by amphotericin B targeted the sterol 24 C methyltransferase genes and a hypothetical gene. Through gene disruption experiments, we proved that loss of function of these genes was associated with resistance. This study describes the feasibility of carrying out whole-genome CRISPR-Cas9 screens in
Leishmania
provided that a strong selective pressure is applied. Such a screen can be used for accelerating the development of urgently needed antileishmanial drugs.

IMPORTANCE

Leishmaniasis, a global health threat, lacks adequate treatment options and drug resistance exacerbates the challenge. This study introduces a CRISPR-Cas9 screening approach in
Leishmania infantum
, unraveling mechanisms of drug resistance at a genome-wide scale. Our screen was applied against two main antileishmanial drugs, and guides were enriched upon drug selection. These guides targeted known and new targets, hence validating the use of this screen against
Leishmania
. This strategy provides a powerful tool to expedite drug discovery as well as potential therapeutic targets against this neglected tropical disease.
Candida parapsilosis
candidemia in children admitted to a tertiary hospital in Turkey: clinical features and antifungal susceptibility
Authors: Çetin Fatma Tuğba , Çay Ümmühan , Polat Murat , Kılınç Fatma , Ünal Asena , Tapaç Nisa Nur , Gündeşlioğlu Özlem Özgür , Alabaz Derya , Bilen Sevcan , Kibar Filiz , Totik Nazlı
Published: June 2024

In recent years, the incidence and drug resistance of
Candida parapsilosis
have increased. Our study aimed to determine the antifungal sensitivity of
C. parapsilosis
and the clinical and demographic characteristics of children with candidemia. Two hundred pediatric patients with
C. parapsilosis
candidemia were included in the study between 1 January 2010 and 1 August 2023. Clinical samples were evaluated on a BACTEC-FX-40 automatic blood culture device (Becton Dickinson, USA). Yeast isolates were identified to the species level via identification cards (YST) using the VITEK 2 Compact (bioMeriéux, France) system. Antifungal susceptibility was performed using antifungal cell cards (AST-YST01). Approval for the study was received from the “University Faculty of Medicine” Hospital Clinical Research Ethics Committee. Non-catheter candidemia was detected in 127 (63.5%) patients, and catheter-related candidemia was detected in 73 (36.5%) patients. It was observed that the patients’ history of malignancy, mechanical ventilation, urinary catheter, nasogastric tube, and intensive care unit stay was associated with
C. parapsilosis
mortality. The mortality rate from candidemia was 9.5%. The most frequently preferred antifungal agents were amphotericin B and fluconazole. The fluconazole drug resistance rate was found to be 6%, and the amphotericin B drug resistance rate was 4%. Because
C. parapsilosis
candidemia mortality rates can be high depending on risk factors and clinical characteristics, it is important to initiate appropriate and timely antifungal therapy. We think that our study can provide important information about the clinical profiles, distributions, susceptibility profiles, and control of antifungal resistance of
C. parapsilosis
isolates.

IMPORTANCE

It has been observed that the frequency and antifungal resistance of
Candida parapsilosis
have increased recently. In our study, we aimed to determine the antifungal sensitivity of
C. parapsilosis
and the clinical and demographic characteristics of children with candidemia. It was observed that the patients’ history of malignancy, mechanical ventilation, urinary catheter, nasogastric tube, and intensive care stay was associated with
C. parapsilosis
mortality. The mortality rate from candidemia was 9.5%. The most frequently preferred antifungal agents were amphotericin B and fluconazole. The fluconazole drug resistance rate was found to be 6%, and the amphotericin B drug resistance rate was 4%. Because
C. parapsilosis
candidemia mortality rates can be high depending on risk factors and clinical characteristics, it is important to initiate appropriate and timely antifungal therapy.
Association between neutrophil-to-eosinophil ratio and efficacy outcomes with avelumab plus axitinib or sunitinib in patients with advanced renal cell carcinoma: post hoc analyses from the JAVELIN Renal 101 trial
Authors: Tucker Matthew , Chen Yu-Wei , Voss Martin H , McGregor Bradley A , Bilen Mehmet A , Grimm Marc-Oliver , Nathan Paul , Kollmannsberger Christian , Tomita Yoshihiko , Huang Bo , Amezquita Robert , Mariani Mariangela , di Pietro Alessandra , Rini Brian
Published: June 2024

Objective

We report post hoc analyses of efficacy with first-line avelumab plus axitinib or sunitinib according to baseline neutrophil-to-eosinophil ratio (NER) in patients with advanced renal cell carcinoma (aRCC) from the JAVELIN Renal 101 phase 3 trial.

Methods and analysis

Progression-free survival (PFS), overall survival (OS) and objective response per baseline NER were analysed in the overall population and in patients with programmed death ligand 1 (PD-L1+) tumours. Multivariable Cox regression analyses to assess the effect of NER after adjustment for other baseline variables were conducted.

Results

In NER <median versus ≥median subgroups of the avelumab plus axitinib arm, HRs for PFS and OS were 0.81 (95% CI 0.630 to 1.035) and 0.67 (95% CI 0.481 to 0.940), and objective response rates (ORRs) were 63.9% vs 55.2%, respectively. The HR for PFS in the PD-L1+ subgroup was 0.72 (95% CI 0.520 to 0.986). Comparing NER-defined subgroups in the sunitinib arm, HRs for PFS and OS were 0.93 (95% CI 0.728 to 1.181) and 0.57 (95% CI 0.424 to 0.779), and ORRs were 32.8% versus 30.8%, respectively. Within NER subgroups, analyses of PFS, OS and ORR favoured avelumab plus axitinib versus sunitinib treatment. Interaction tests that assessed the association between treatment and NER yielded conflicting results when NER was assessed as a dichotomised variable (median cut-off) or continuous variable.

Conclusion

Hypothesis-generating analyses suggest that baseline NER may be prognostic for longer OS irrespective of treatment. Analyses of the association between NER level and treatment outcomes with avelumab plus axitinib versus sunitinib were inconclusive.

Trial registration number

NCT02684006.
Assessing the treatment effect of cranberry type A proanthocyanidins on vulvovaginal candidiasis: a randomised controlled clinical interventional study
Authors: Wei Dongmei , Chen Yaoming , Chen Yueyue , Cui Tao , Niu Xiaoyu
Published: June 2024

Objective

This study aimed to evaluate the efficacy and safety of cranberry extracts: A-type proanthocyanidins (A-PACs) in the treatment and prevention of vulvovaginal candidiasis (VVC).

Method

An open, randomised, parallel-design study was conducted. A cohort of 300 eligible patients with VVC was recruited from the hospital. All participants were randomly divided into three groups according to a computer-generated randomisation list. Patients in group 1 were treated with standard antifungal therapy (oral single-dose fluconazole 150 mg and vaginal miconazole suppository 400 mg at bedtime for 3 days); patients in group 2 received oral A-PACs 16 mL two times per day for 6 days based on the treatment regimen of group 1; patients in group 3 were given oral A-PACs 16 mL two times per day for 6 days and vaginal miconazole suppository 400 mg at bedtime for 3 days. Patients who were clinically cured at the seventh day of follow-up in group 2 received maintenance therapy by oral A-PACs for 12 weeks.

Result

At the seventh day of follow-up, the vaginal mycological results of all patients in group 2 who initially tested positive for pseudohyphae exhibited negative results. The negative conversion rates of fungal spores and blastospores in group 2 were superior to those in both group 1 and group 3. The symptoms of patients in group 2 ameliorated conspicuously compared with those in group 1 (p<0.05). The clinical cure rate of VVC in both group 2 and group 3 was not inferior to group 1. Cox regression analysis showed maintenance therapy was not significantly associated with short-term recurrence (HR 0.44 (0.11, 1.67); p=0.23) but could significantly diminish the risk of long-term recurrence (HR 0.57 (0.33, 0.99); p<0.05).

Conclusion

This study revealed that A-PACs in cranberry juice combined with azole antibiotics can be used as a novel therapeutic option for the treatment and prevention of long-term recurrence of VVC.

Trial registration number

ChiCTR2300076392.
Practical guide to building machine learning-based clinical prediction models using imbalanced datasets
Authors: Luu Jacklyn , Borisenko Evgenia , Przekop Valerie , Patil Advait , Forrester Joseph D , Choi Jeff
Published: June 2024

Clinical prediction models often aim to predict rare, high-risk events, but building such models requires robust understanding of imbalance datasets and their unique study design considerations. This practical guide highlights foundational prediction model principles for surgeon-data scientists and readers who encounter clinical prediction models, from feature engineering and algorithm selection strategies to model evaluation and design techniques specific to imbalanced datasets. We walk through a clinical example using readable code to highlight important considerations and common pitfalls in developing machine learning-based prediction models. We hope this practical guide facilitates developing and critically appraising robust clinical prediction models for the surgical community.
Finite-temperature equations of state of compact stars with hyperons: three-dimensional tables
Authors: Tsiopelas Stefanos , Sedrakian Armen , Oertel Micaela
Published: June 2024

We construct tables of finite temperature equation of state (EoS) of hypernuclear matter in the range of densities, temperatures, and electron fractions that are needed for numerical simulations of supernovas, proto-neutron stars, and binary neutron star mergers and cast them in the format of CompOSE database. The tables are extracted from a model that is based on covariant density functional (CDF) theory that includes the full $$J^P=1/2^+$$

J
P

=
1
/

2
+

baryon octet in a manner that is consistent with the current astrophysical and nuclear constraints. We employ a parameterization with three different values of the slope of the symmetry energy $$L_\textrm{sym}=30$$

L
sym

=
30

, 50 and 70 MeV and fixed skewness $$Q_\textrm{sat}= 400$$

Q
sat

=
400

MeV for above saturation matter. A model for the EoS of inhomogeneous matter is matched at sub-saturation density to the high-density hypernuclear EoS. We discuss the generic features of the resulting EoS and the composition of matter as a function of density, temperature, and electron fraction. The nuclear characteristics and strangeness fraction of these models are compared to the alternatives from the literature. The integral properties of static and rapidly rotating compact stars in the limit of zero temperature are discussed and confronted with the multimessenger astrophysical constraints.
Impact of In element on the melting point and properties of Pb-56Bi-In eutectic alloy
Authors: Luo Fang , Huang Feihong , Hu Jinxin , Yang Youdong
Published: June 2024

Based on advanced first-principle calculations driven by density functional theory, our study used fusion casting techniques to incorporate minute quantities of In into the conventional Pb-56Bi eutectic alloy. Detailed examination identified the critical parameters of the prepared materials, including melting point, phase formation and microstructure. The initial Pb56Bi alloy had a melting point of 125°C, while the inclusion of In yielded Pb-56Bi-XIn (X represents the percentage of In element) and decreased the melting temperature to 85.7°C–119.7°C.
Self-Collaboration Code Generation via ChatGPT
Authors: Dong Yihong , Jiang Xue , Jin Zhi , Li Ge
Published: June 2024

Although large language models (LLMs) have demonstrated remarkable code-generation ability, they still struggle with complex tasks. In real-world software development, humans usually tackle complex tasks through collaborative teamwork, a strategy that significantly controls development complexity and enhances software quality. Inspired by this, we present a self-collaboration framework for code generation employing LLMs, exemplified by ChatGPT. Specifically, through role instructions, (1) Multiple LLM agents act as distinct “experts,” each responsible for a specific subtask within a complex task; (2) Specify the way to collaborate and interact, so that different roles form a virtual team to facilitate each other’s work, ultimately the virtual team addresses code generation tasks collaboratively without the need for human intervention. To effectively organize and manage this virtual team, we incorporate software-development methodology into the framework. Thus, we assemble an elementary team consisting of three LLM roles (i.e., analyst, coder, and tester) responsible for software development’s analysis, coding, and testing stages. We conduct comprehensive experiments on various code-generation benchmarks. Experimental results indicate that self-collaboration code generation relatively improves 29.9–47.1% Pass@1 compared to the base LLM agent. Moreover, we showcase that self-collaboration could potentially enable LLMs to efficiently handle complex repository-level tasks that are not readily solved by the single LLM agent.
Benchmarking Instance-Centric Counterfactual Algorithms for XAI: From White Box to Black Box
Authors: Moreira Catarina , Chou Yu-Liang , Hsieh Chihcheng , Ouyang Chun , Pereira João , Jorge Joaquim
Published: June 2024

This study investigates the impact of machine learning models on the generation of counterfactual explanations by conducting a benchmark evaluation over three different types of models: a decision tree (fully transparent, interpretable, white-box model), a random forest (semi-interpretable, grey-box model), and a neural network (fully opaque, black-box model). We tested the counterfactual generation process using four algorithms (DiCE, WatcherCF, prototype, and GrowingSpheresCF) in the literature in 25 different datasets. Our findings indicate that: (1) Different machine learning models have little impact on the generation of counterfactual explanations; (2) Counterfactual algorithms based uniquely on proximity loss functions are not actionable and will not provide meaningful explanations; (3) One cannot have meaningful evaluation results without guaranteeing plausibility in the counterfactual generation. Algorithms that do not consider plausibility in their internal mechanisms will lead to biased and unreliable conclusions if evaluated with the current state-of-the-art metrics; (4) A counterfactual inspection analysis is strongly recommended to ensure a robust examination of counterfactual explanations and the potential identification of biases.
Performance Losses and Current-Driven Recovery from Cation Contaminants in PEM Water Electrolysis
Authors: Padgett Elliot , Adesso Anthony , Yu Haoran , Wrubel Jacob , Bender Guido , Pivovar Bryan , Alia Shaun M.
Published: June 2024

Water contaminants are a common cause of failure for polymer electrolyte membrane (PEM) electrolyzers in the field as well as a confounding factor in research on cell performance and durability. In this study, we investigated the performance impacts of feed water containing representative tap water cations at concentrations ranging from 0.5–500 μM, with conductivities spanning from ASTM Type II to tap-water levels. We present multiple diagnostic signatures to help identify the presence of contaminants in PEM electrolysis cells. Through analysis of polarization curves and impedance spectroscopy to understand the origins of performance losses, we found that a switch from the acidic to alkaline hydrogen evolution mechanism is a key factor in contaminated cell behavior. Finally, we demonstrated that this mechanism switching can be harnessed to remove cation contaminants and recover cell performance without the use of an acid wash. We demonstrated near-complete recovery of cells contaminated with sodium and calcium, and partial recovery of a cell contaminated with iron, which was further investigated by post-mortem microscopy. The improved understanding of contaminant impacts from this work can inform development of strategies to mitigate or recover performance losses as well as improve the consistency and rigor of electrolysis research.
Dexterous manipulation: differential sensitivity of manipulation and grasp forces to task requirements
Authors: Noll William P. , Wu Yen-Hsun , Santello Marco
Published: June 2024

Successful dexterous object manipulation requires simultaneous prevention of object slip and object pose control. How these two task goals are attained can be investigated by decomposing digit forces into grasp and manipulation forces, respectively. We found that these forces were characterized by differential sensitivity to changes in object properties (mass and torque). This finding suggests the involvement of distinct sensorimotor mechanisms that, combined, simultaneously ensure grasp stability and dexterous control of object pose.
Onion skin is not a universal firing pattern for spinal motoneurons: simulation study
Authors: Mousa Mohamed H. , Wages Nathan P. , Elbasiouny Sherif M.
Published: June 2024

The literature reports two contrasting schemes, namely the onion skin and the afterhyperpolarization (AHP) regarding the relationship between motor units (MUs) firing rates and recruitment order. Previous studies have examined these schemes phenomenologically, imposing one scheme on the firing-recruitment relationship. Here, we used a high-fidelity computational model that prioritizes biological fidelity and heterogeneity to investigate motoneuron firing schemes without bias toward either scheme. Our objective findings offer an explanation for the longstanding dichotomy on MU firing patterns.
Digenic Origin of Difference of Sex Development in a Patient Harbouring DHX37 and MAMLD1 Variants
Authors: Margiotti Katia , Libotte Francesco , Fabiani Marco , Mesoraca Alvaro , Giorlandino Claudio
Published: June 2024

Background. The diagnostic process for identifying variations in sex development (DSD) remains challenging due to the limited availability of evidence pertaining to the association between phenotype and genotype. DSD incidence is reported as 2 in 10,000 births, and the etiology has been attributed to genetic causes. Case Presentation. The present study investigated genetic causes implicated in a case of a 15‐year‐old 46, XY patient, raised as a girl. Genetic analysis by clinical exome sequencing (CES) showed a digenic inheritance due to two known pathogenic mutations in the DHX37 gene and the MAMLD1 gene, while we excluded variants with pathogenic significance in 209 DSD‐related genes. Conclusions. Based on our literature review, this is the first case with the combined presence of pathogenic mutations in the MAMLD1 gene and DHX37 gene in a patient with gonadal dysgenesis.
A Pediatric Case of Fusobacterium necrophorum Mastoiditis and Meningitis Case Report in a Healthy Child and Review of the Literature
Authors: Feenstra Elizabeth , Van Roest Aalt , Boes Juul , Spiritus Tom , Kenis Sandra , Duval Els L. I. M. , Vanden Bossche Stephanie , Vanden Driessche Koen , Jorens Philippe G.
Published: June 2024

In infants and children, bacterial meningitis caused by anaerobic bacteria is rare. However, a serious infection with the anaerobe Fusobacterium necrophorum can occur in previously healthy children with a peak incidence in preschool children and in adolescents. As the clinical presentation can be very similar to meningitis caused by aerobic bacteria, one should consider Fusobacterium necrophorum as the causative agent when preceded by or associated with otitis media with purulent otorrhea or mastoiditis, in combination with minimal or no improvement on empiric antibiotic treatment. As this pathogen can be difficult to culture, anaerobic cultures should be obtained. Prompt treatment with a third‐generation cephalosporin and metronidazole should be initiated once suspected or confirmed. Surgical source control is often necessary, but even with adequate and prompt treatment, the morbidity and mortality in children with a Fusobacterium necrophorum meningitis remains high. In this report, we describe a case of Fusobacterium necrophorum meningitis in a previously healthy child and review the available literature.
A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors
Authors: Takaki Emiri O. , Kiyono Kunihiko , Obuchi Yutaka , Yamauchi Takeshi , Watanabe Takashi , Matsumoto Hideki , Karimine Miho , Kuniyoshi Yuki , Nishikori Shingo , Yokoyama Fumiharu , Nishimori Hikaru , Nabeshima Hiroshi , Nakamura Kazuhide
Published: June 2024

Purpose:

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor with KIT or PDGFRA driver mutations, is typically treated with tyrosine kinase inhibitors (TKI). However, resistance to TKIs due to secondary mutations is a common challenge in advanced GISTs. In addition, there are currently no effective therapies for several other molecular subtypes, such as succinate dehydrogenase–deficient GISTs. Therefore, novel therapeutic strategies are needed.

Experimental Design:

To address this need, we tested the efficacy of a novel non-TKI compound, OPB-171775, using patient-derived xenograft models of GISTs. In parallel, we sought to elucidate the mechanism of action of the compound.

Results:

Our study revealed that OPB-171775 exhibited significant efficacy against GISTs regardless of their KIT mutation status by inducing complex formation between phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12), which are highly expressed in GISTs, leading to SLFN12 RNase-mediated cell death. Furthermore, we identified the activation of general control non-derepressible 2 and its downstream response as an effector pathway of SLFN12 in mediating anticancer activity and revealed potential pharmacodynamic markers.

Conclusions:

These findings suggest that OPB-171775, with its significant efficacy, could potentially serve as a novel and effective treatment option for advanced GISTs, particularly those resistant to TKIs.
Table S8 from Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data
Authors: Darmofal Madison , Suman Shalabh , Atwal Gurnit , Toomey Michael , Chen Jie-Fu , Chang Jason C. , Vakiani Efsevia , Varghese Anna M. , Balakrishnan Rema Anoop , Syed Aijazuddin , Schultz Nikolaus , Berger Michael F. , Morris Quaid
Published: June 2024

Metrics for GDD-ENS performance across output confidence thresholds
Table S6 from Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data
Authors: Darmofal Madison , Suman Shalabh , Atwal Gurnit , Toomey Michael , Chen Jie-Fu , Chang Jason C. , Vakiani Efsevia , Varghese Anna M. , Balakrishnan Rema Anoop , Syed Aijazuddin , Schultz Nikolaus , Berger Michael F. , Morris Quaid
Published: June 2024

Accuracy across all individual MLP models that form GDD-ENS. FC = Fully Connected, ECE = Estimated Calibration Error
Table S4 from Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data
Authors: Darmofal Madison , Suman Shalabh , Atwal Gurnit , Toomey Michael , Chen Jie-Fu , Chang Jason C. , Vakiani Efsevia , Varghese Anna M. , Balakrishnan Rema Anoop , Syed Aijazuddin , Schultz Nikolaus , Berger Michael F. , Morris Quaid
Published: June 2024

Stepwise accuracy of various models generated during model development, including direct comparison of GDD-RF to GDD-ENS. Acc. = Accuracy, Conf. = Confidence, Macro Prec: Class-Averaged Precision, % Excluded: proportion of high-content, solid tumor training data that is not represented by the model training types. RF: Random Forest. GDD-RF Feature Set, training set and testing set = samples and features used in original GDD-RF model. GDD-ENS feature and training set = updated samples and features used in final GDD-ENS model. GDD-ENS-22 test set: GDD-ENS test set but limited to the 22 original types before expansion. GDD-RF-EXT test set = extended independent test set used in GDD-RF training. GDD-ENS-38 = Final GDD-ENS test set.
Table S13 from Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data
Authors: Darmofal Madison , Suman Shalabh , Atwal Gurnit , Toomey Michael , Chen Jie-Fu , Chang Jason C. , Vakiani Efsevia , Varghese Anna M. , Balakrishnan Rema Anoop , Syed Aijazuddin , Schultz Nikolaus , Berger Michael F. , Morris Quaid
Published: June 2024

Cancer Type Organ System Mapping
Figure S8: Organ Shapley Value Distributions from Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data
Authors: Darmofal Madison , Suman Shalabh , Atwal Gurnit , Toomey Michael , Chen Jie-Fu , Chang Jason C. , Vakiani Efsevia , Varghese Anna M. , Balakrishnan Rema Anoop , Syed Aijazuddin , Schultz Nikolaus , Berger Michael F. , Morris Quaid
Published: June 2024

Shapley values aggregated across 10 major organ systems, as described in Supp. Table S13. First column represents broad feature category importance across all correct, in-distribution predictions. Second and third columns represent top features for all correct and incorrect predictions, respectively, regardless of in-distribution or out of distribution status. Number of predictions within each category shown in bottom right of each figure.
Figure S3: Confusion Matrix Across All Confidence Predictions from Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data
Authors: Darmofal Madison , Suman Shalabh , Atwal Gurnit , Toomey Michael , Chen Jie-Fu , Chang Jason C. , Vakiani Efsevia , Varghese Anna M. , Balakrishnan Rema Anoop , Syed Aijazuddin , Schultz Nikolaus , Berger Michael F. , Morris Quaid
Published: June 2024

Overall heatmap of top prediction across all confidence values. Heatmap is row-normalized and sorted by overall precision. Off-target values represent proportion of the predicted type, row type that is of the true type along the columns. NSCLC, Non-Small Cell Lung Cancer; GIST, Gastrointestinal Stromal Tumor; SQC, Squamous Cell Carcinoma; SCLC, Small Cell Lung Cancer; PNET, Pancreatic Neuroendocrine Tumor; Lu-NET, Lung Neuroendocrine Tumor; GI-NET, Gastro-intestinal Neuroendocrine Tumor; Carc., Carcinoma; MPNST, Malignant Peripheral Nerve Sheath Tumor.
Figure S2: GDD-ENS Precision Recall Curves from Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data
Authors: Darmofal Madison , Suman Shalabh , Atwal Gurnit , Toomey Michael , Chen Jie-Fu , Chang Jason C. , Vakiani Efsevia , Varghese Anna M. , Balakrishnan Rema Anoop , Syed Aijazuddin , Schultz Nikolaus , Berger Michael F. , Morris Quaid
Published: June 2024

Precision Recall curves for GDD-ENS test set performance across all individual cancer types (grey) and the average of all outputs (black).
Figure S11: Heatmap of Labels Mapped for Adaptable Prior Distributions from Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data
Authors: Darmofal Madison , Suman Shalabh , Atwal Gurnit , Toomey Michael , Chen Jie-Fu , Chang Jason C. , Vakiani Efsevia , Varghese Anna M. , Balakrishnan Rema Anoop , Syed Aijazuddin , Schultz Nikolaus , Berger Michael F. , Morris Quaid
Published: June 2024

Proportion of all in-distribution discovery cohort samples that are either primary or metastatic (top), or have broad histological annotations (middle, top) per cancer type. Underlying distributions of metastatic site (middle) and histology (bottom) for all in-distribution discovery cohort samples across 19 metastatic sites and 2 histological subtypes. Heatmaps are row normalized, rounding of values means some results do not sum to 100.
Figure S10: KRAS Shapley Values across typesSupplementary Data from Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data
Authors: Darmofal Madison , Suman Shalabh , Atwal Gurnit , Toomey Michael , Chen Jie-Fu , Chang Jason C. , Vakiani Efsevia , Varghese Anna M. , Balakrishnan Rema Anoop , Syed Aijazuddin , Schultz Nikolaus , Berger Michael F. , Morris Quaid
Published: June 2024

Normalized absolute Shapley value scores for all KRAS-related features across cancer types with KRAS implicated within the top ten most predictive features per type. KRAS indicate presence of any broad alteration that affects KRAS within a sample, while KRAS hotspot indicates any hotspot alteration, and KRAS Amp reflects a KRAS amplification. All other rows represent features for specific KRAS hotspots. Importance of each specific hotspot differs across cancer types.
FIGURE 1 from Mechanistic Characterization of Cancer-associated Fibroblast Depletion via an Antibody–Drug Conjugate Targeting Fibroblast Activation Protein
Authors: Gallant Joseph P. , Hintz Hallie M. , Gunaratne Gihan S. , Breneman Matthew T. , Recchia Emma E. , West Jayden L. , Ott Kendahl L. , Heninger Erika , Jackson Abigail E. , Luo Natalie Y. , Rosenkrans Zachary T. , Hernandez Reinier , Zhao Shuang G. , Lang Joshua M. , Meimetis Labros , Kosoff David , LeBeau Aaron M.
Published: June 2024

HuB12 internalizes into FAP-expressing cells. A, Confocal microscopy images of hPrCSC-44 cells (top) or PC3 cells (bottom) after incubation with Alexa Fluor-647 (AF647)-labeled huB12 (50 nmol/L) for 1 hour. Single-channel images of huB12-AF647 localization, fluorescein-dextran labeled endosomes, and CellBrite Orange-labeled plasma membrane are shown. Composite images depicting whole-cell and enlarged regions of interest are shown as colored fluorescence overlays. B, Quantification of the organellar distribution of huB12-AF647, assessed using MCC with either fluorescein dextran (endosome marker) or CellBrite Orange (membrane marker). Values represent average ± SD of n ≥ 6 images, *, P <0.05 using two-tailed Student’s t-test. C, Representative images of CWR-R1FAP or parental CWR-R1 cells after 16 hours incubation with the indicated antibody (40 nmol/L). A panel of phase-contrast images overlaid with an outline of individual cells (yellow) and pHrodoRed fluorescence (red) is shown. D, Time course of pHrodoRed fluorescence intensity in CWR-R1FAP cells incubated with the indicated concentration of huB12-pHrodoRed, data shown from a representative experiment. Dose–response curves of peak pHrodoRed fluorescence values in CWR-R1 (gray) or CWR-R1FAP (red) cells after 24 hours incubation with increasing concentrations of huB12-pHrodoRed (E) or isotyped control IgG-pHrodoRed (F). Values represent average ± SEM from n = 3 replicates.
Kidney Amyloidosis: Updates on Pathogenesis and Therapeutic Frontiers
Authors: Cervantes C. Elena , Atta Mohamed G.
Published: June 2024

Background: Amyloidosis includes a diverse group of rare diseases characterized by the misfolding of native or mutant proteins, leading to extracellular accumulation in various organs. While 42 proteins have been identified to date, their distribution differs between systemic and localized forms. Summary: Mass spectrometry analysis of tissue samples in the USA shows immunoglobulin light chain (AL) amyloidosis as the most prevalent systemic type, followed by transthyretin (ATTR). Heart and kidney involvements are common. Although there are 14 recognized types of kidney-related amyloidosis, clinicopathologic studies in the USA have identified 11 types, with AL amyloidosis being the most prevalent cause of kidney involvement. Key Messages: This review focuses on AL, AA, and ATTR amyloidosis due to their common systemic presentations. Recent US-based clinicopathologic studies challenge conventional beliefs that toxicity is primarily driven by amyloid deposition and highlight the role of the complement pathway. Diagnostic methods, particularly mass spectrometry, are crucial for accurate typing. Treatment strategies vary depending on the underlying type, with AL amyloidosis primarily targeting plasma cell clones, AA amyloidosis addressing underlying inflammation with systemic therapies, and ATTR amyloidosis focusing on ATTR stabilization or gene silencing.
Anticoagulants Are a Risk Factor for Delayed Bleeding after Colorectal Endoscopic Submucosal Dissection: A HASID Multicenter Study
Authors: Kim Seong-Jung , Lee Jun , Song Hyo-Yeop , Seo Geom Seog , Jin Byung Chul , Kim Sang-Wook , Kim Dong Hyun , Kim Hyun-Soo , Oh Hyung-Hoon , Myung Dae-Seong , Joo Young-Eun ,   on behalf of the Honam Association for the Study of Intestinal Disease (HASID)
Published: June 2024

Introduction: Delayed bleeding is an important adverse event following colorectal endoscopic submucosal dissection (ESD). However, whether anticoagulants are risk factors for delayed bleeding after colorectal ESD remains debatable. Methods: We retrospectively analyzed 1,708 patients who underwent colorectal ESDs between January 2015 and December 2020 at five academic medical centers in South Korea. We aimed to identify the risk factors for delayed bleeding in patients after colorectal ESD and, in particular, to evaluate the effect of anticoagulants. Results: Delayed bleeding occurred in 40 of 1,708 patients (2.3%). The risk factors for delayed bleeding were antithrombotic agents (odds ratio [OR], 6.155; 95% confidence interval [CI], 3.201–11.825; p < 0.001), antiplatelet agents (OR, 4.609; 95% CI, 2.200–9.658; p < 0.001), anticoagulants (OR, 8.286; 95% CI, 2.934–23.402; p < 0.001), and tumor location in the rectum (OR, 2.055; 95% CI, 1.085–3.897; p = 0.027). In the analysis that excluded patients taking antiplatelet agents, the delayed bleeding rate was higher in patients taking anticoagulants (1.6% no antithrombotic agents vs. 12.5% taking anticoagulants, p < 0.001). There was no difference in the delayed bleeding rate (4.2% direct oral anticoagulants vs. 25.0% warfarin, p = 0.138) or clinical outcomes according to the type of anticoagulant used. Conclusions: Anticoagulants use was a risk factor for delayed bleeding after colorectal ESD, and there was no difference in the risk of delayed bleeding based on the type of anticoagulant used. Colorectal ESD in patients receiving anticoagulants requires careful observation and management for delayed bleeding.
Memorial PET: depoimentos de integrantes do programa
Authors: Humanidades em Diálogo Comissão Editorial
Published: June 2024

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De Ariel a Caliban: identidade latino-americana em José Enrique Rodó e Roberto Fernández Retamar
Authors: Meucci Isabella
Published: June 2024

A utilização dos personagens de A Tempestade como símbolos da identidade latino-americana tornou-se parte da história do pensamento político e social do subcontinente. Nesse artigo, foram analisadas duas obras centrais para apropriação dessas figuras da peça de Shakespeare do início do século XVII: Ariel (1900), do publicista uruguaio José Enrique Rodó e Caliban (1971), do escritor cubano Roberto Fernández Retamar. Embora profundamente ligadas a seus contextos de escrita, ambas as contribuições ultrapassaram seu tempo e tornaram-se centrais para o debate sobre a construção de uma identidade latino-americana. Para compreender como se deu esse processo, examinou-se a empreitada de Rodó e posteriormente a de Retamar, buscando indicar suas divergências e similaridades. A partir disso, observou-se como a concepção dessa identidade latino-americana foi entendida primeiramente como uma síntese do espiritualismo com o utilitarismo a ser levada adiante pela juventude guiada pelos intelectuais, e posteriormente como irreconciliável oposição entre opressor e oprimido, diante da qual essa intelectualidade deveria se posicionar.
Antiphospholipid antibodies in patients with antiphospholipid syndrome
Authors: Dodig Slavica , Čepelak Ivana
Published: June 2024

Graphical abstract
Highlights
• Antiphospholipid syndrome is a rare systemic autoimmune disease characterized by recurrent pregnancy morbidity or thrombosis in combination with the persistent presence of antiphospholipid antibodies in plasma/serum
• Specialists in laboratory medicine should take responsibility for the entire analytical process, so that possible interferences are minimized, and physicians obtain reliable results of the patient’s laboratory findings in a timely manner
• Due to possible problems in performing tests on aPLs for a more reliable (optimal) interpretation of laboratory findings, a close cooperation between laboratory specialists and clinical specialists is needed
Antiphospholipid syndrome (APS) is a rare systemic autoimmune disease characterized by recurrent pregnancy morbidity or thrombosis in combination with the persistent presence of antiphospholipid antibodies (aPLs) in plasma/serum. Antiphospholipid antibodies are a heterogeneous, overlapping group of autoantibodies, of which anti-β2-glycoprotein I (aβ2GPI), anticardiolipin (aCL) antibodies and antibodies that prolong plasma clotting time in tests in vitro known as lupus anticoagulant (LAC) are included in the laboratory criteria for the diagnosis of APS. The presence of LAC antibodies in plasma is indirectly determined by measuring the length of coagulation in two tests - activated partial thromboplastin time (aPTT) and diluted Russell’s viper venom time (dRVVT). The concentration of aβ2GPI and aCL (immunglobulin G (IgG) and immunoglobulin M (IgM) isotypes) in serum is directly determined by solid-phase immunoassays, either by enzyme-linked immunosorbent assay (ELISA), fluoroimmunoassay (FIA), immunochemiluminescence (CLIA) or multiplex flow immunoassay (MFIA). For patient safety, it is extremely important to control all three phases of laboratory testing, i.e. preanalytical, analytical and postanalytical phase. Specialists in laboratory medicine must be aware of interferences in all three phases of laboratory testing, in order to minimize these interferences. The aim of this review was to show the current pathophysiological aspects of APS, the importance of determining aPLs-a in plasma/serum, with an emphasis on possible interferences that should be taken into account when interpreting laboratory findings.
Animals, Atrocity, and Trivialization
Authors: Müller Nico Dario
Published: June 2024

Many philosophers have said that atrocities are being committed against animals, particularly in industrialized rearing and slaughter. But they have made little of this powerful description. This paper argues that atrocities call for a different response than minor wrongs or evils, including that one should not trivialize them. The paper offers a new framework for understanding the trivialization of atrocities against animals and discusses the moral difficulties that trivialization raises, in part because it is not always easy to avoid. It concludes discussing how animal advocates can avoid and challenge trivialization.
The Propagation, Evolution, and Rotation in Linear Storms (PERiLS) Project
Authors: Kosiba Karen A. , Lyza Anthony W. , Trapp Robert J. , Rasmussen Erik N. , Parker Matthew , Biggerstaff Michael I. , Nesbitt Stephen W. , Weiss Christopher C. , Wurman Joshua , Knupp Kevin R. , Coffer Brice , Chmielewski Vanna C. , Dawson Daniel T. , Bruning Eric , Bell Tyler M. , Coniglio Michael C. , Murphy Todd A. , French Michael , Blind-Doskocil Leanne , Reinhart Anthony E. , Wolff Edward , Schneider Morgan E. , Silcott Miranda , Smith Elizabeth , Aikins Joshua , Wagner Melissa , Robinson Paul , Wilczak James M. , White Trevor , Diedrichsen Madeline R. , Bodine David , Kumjian Matthew R. , Waugh Sean M. , Alford A. Addison , Elmore Kim , Kollias Pavlos , Turner David D.
Published: June 2024

Quasi-linear convective systems (QLCSs) are responsible for approximately a quarter of all tornado events in the United States, but no field campaigns have focused specifically on collecting data to understand QLCS tornadogenesis. The Propagation, Evolution, and Rotation in Linear Storms (PERiLS) project was the first observational study of tornadoes associated with QLCSs ever undertaken. Participants were drawn from more than 10 universities, laboratories, and institutes, with over 100 students participating in field activities. The PERiLS field phases spanned 2 years, late winters and early springs of 2022 and 2023, to increase the probability of intercepting significant tornadic QLCS events in a range of large-scale and local environments. The field phases of PERiLS collected data in nine tornadic and nontornadic QLCSs with unprecedented detail and diversity of measurements. The design and execution of the PERiLS field phase and preliminary data and ongoing analyses are shown.