bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of distinct impacts of CovS inactivation on the transcriptome of acapsular group A streptococci
Authors: DebRoy Sruti , Shropshire William C. , Vega Luis , Tran Chau , Horstmann Nicola , Mukherjee Piyali , Selvaraj-Anand Selvalakshmi , Tran Truc T. , Bremer Jordan , Gohel Marc , Arias Cesar A. , Flores Anthony R. , Shelburne Samuel A.
Published: June 2023

Group A streptococcal (GAS) strains causing severe, invasive infections often have mutations in the control of virulence two-component regulatory system (CovRS) which represses capsule production, and high-level capsule production is considered critical to the GAS hypervirulent phenotype. Additionally, based on studies in
emm1
GAS, hyperencapsulation is thought to limit transmission of CovRS-mutated strains by reducing GAS adherence to mucosal surfaces. It has recently been identified that about 30% of invasive GAS strains lacks capsule, but there are limited data regarding the impact of CovS inactivation in such acapsular strains. Using publicly available complete genomes (
n
= 2,455) of invasive GAS strains, we identified similar rates of CovRS inactivation and limited evidence for transmission of CovRS-mutated isolates for both encapsulated and acapsular
emm
types. Relative to encapsulated GAS, CovS transcriptomes of the prevalent acapsular
emm
types
emm28
,
emm87
, and
emm89
revealed unique impacts such as increased transcript levels of genes in the
emm
/mga region along with decreased transcript levels of pilus operon-encoding genes and the streptokinase-encoding gene
ska
. CovS inactivation in
emm87
and
emm89
strains, but not
emm28
, increased GAS survival in human blood. Moreover, CovS inactivation in acapsular GAS reduced adherence to host epithelial cells. These data suggest that the hypervirulence induced by CovS inactivation in acapsular GAS follows distinct pathways from the better studied encapsulated strains and that factors other than hyperencapsulation may account for the lack of transmission of CovRS-mutated strains.

IMPORTANCE

Devastating infections due to group A streptococci (GAS) tend to occur sporadically and are often caused by strains that contain mutations in the control of virulence regulatory system (CovRS). In well-studied
emm1
GAS, the increased production of capsule induced by CovRS mutation is considered key to both hypervirulence and limited transmissibility by interfering with proteins that mediate attachment to eukaryotic cells. Herein, we show that the rates of covRS mutations and genetic clustering of CovRS-mutated isolates are independent of capsule status. Moreover, we found that CovS inactivation in multiple acapsular GAS
emm
types results in dramatically altered transcript levels of a diverse array of cell-surface protein-encoding genes and a unique transcriptome relative to encapsulated GAS. These data provide new insights into how a major human pathogen achieves hypervirulence and indicate that factors other than hyperencapsulation likely account for the sporadic nature of the severe GAS disease.
Recurrent Campylobacter jejuni Infections with
In Vivo
Selection of Resistance to Macrolides and Carbapenems: Molecular Characterization of Resistance Determinants
Authors: Nunes Alexandra , Oleastro Mónica , Alves Frederico , Liassine Nadia , Lowe David M. , Benejat Lucie , Ducounau Astrid , Jehanne Quentin , Borges Vítor , Gomes João Paulo , Godbole Gauri , Philippe Lehours
Published: June 2023

Carbapenem susceptibility patterns suggest drug impermeability, related to either insertion and/or single nucleotide polymorphism (SNP) within
por
A. Similar molecular events occurring in two independent cases support the association of these mechanisms with carbapenem resistance in
Campylobacter
spp.
Genomic Insights into Global
bla
CTX-M-55
-Positive Escherichia coli Epidemiology and Transmission Characteristics
Authors: Yang Jin-Tao , Zhang Li-Juan , Lu Yang , Zhang Rong-Min , Jiang Hong-Xia
Published: June 2023

CTX-M-55 was first discovered in Thailand in 2004, and today, this enzyme is the most common CTX-M subtype in
E. coli
of animal origin in China. Thus,
bla
CTX-M-55
-positive
E. coli
getting widely spread is a growing public health problem.
Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in
ERG2
as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr
Authors: Asadzadeh Mohammad , Alfouzan Wadha , Parker Josie E. , Meis Jacques F. , Kelly Steven L. , Joseph Leena , Ahmad Suhail
Published: June 2023

Some yeast species exhibit intrinsic resistance or rapidly acquire resistance to azole antifungals. Despite >50 years of clinical use, resistance to amphotericin B (AMB) among yeast species has been extremely rarely reported until recently.
Weak Localization of Light in a Magneto-active Medium
Authors: Gorodnichev E. E. , Rogozkin D. B.
Published: June 2023

The interference contribution to the optical conductance (total transmittance) of a sample of a disordered Faraday medium is calculated. The suppression of wave interference in a magnetic field is shown to be due to helicity-flip scattering events. The magnetic field does not destroy the interference of waves with a given helicity, but suppresses it if the helicity changes along different parts of the wave trajectory. This leads to a decrease in the interference contribution to the conductance with increasing the magnetic field. A similar phenomenon, negative magnetoresistance, is known as a consequence of weak localization of electrons in metals with impurities. It is found that, as the magnetic field increases, the change in the interference correction to the optical conductance tends to a certain limiting value, which depends on the ratio of the transport mean free path to the helicity-flip scattering mean free path. We also discuss the possibility of controlling the transition to the regime of strong “Anderson” localization in the quasi-one-dimensional case by means of the field.
Development of a Reproducible and Scalable Method for the Synthesis of Biologically Active Pyrazolo[1,5-a]pyrimidine Derivatives
Authors: Novikova D. S. , Darwish F. , Grigoreva T. A. , Tribulovich V. G.
Published: June 2023

A reproducible and scalable method has been developed for the synthesis of a series of 3,6-substituted pyrazolo[1,5-a]pyrimidines, which are the basis for the rational design of selective inhibitors of AMP-activated protein kinase. Regarding the formation of new types of the carbon skeleton, the applicability of the Suzuki–Miyaura cross-coupling using the Buchwald ligands to form C–C bond in the sterically hindered position 6 of 5,7-dimethyl-substituted pyrazolo[1,5-a]pyrimidine has been shown.
Simple Access to Isoxazole-Containing Heterocyclic Hybrids: Isoxazole/Oxazole and Isoxazole/Pyridine
Authors: Taishev A. E. , Galenko E. E. , Novikov M. S. , Khlebnikov A. F.
Published: June 2023

The synthesis of substituted isoxazole–oxazole hybrids by the noncatalytic reaction of methyl 2-diazo-2-(alkyl/aryl/hetarylisoxazol-5-yl)acetates with alkyl and aryl cyanides has been reported. According to DFT calculations, the reaction proceeds through the intermediate formation of a nitrile ylide and its subsequent cyclization at the carbonyl oxygen. The reaction of acrylonitrile with methyl 2-diazo-2-(isoxazol-5-yl)acetate proceeds quite differently and leads to a mixture of the cis and trans isomers of cyclopropanes, which, according to DFT calculations, are formed by the cycloaddition of a diazo-derived carbene to the C=C bond of acrylonitrile. The hetero-Diels–Alder reaction of the 5-alkoxyoxazole moiety of isoxazole–oxazole hybrids makes it possible to obtain isoxazole–pyridine hybrids, albeit in low yield.
Novel usage of everolimus-eluting coronary stent for intracranial atherosclerotic disease: a technical report and case series
Authors: Coulibaly Nangorgo Jean Oumar , Ernst Griffin L , Shallwani Hussain , Hawkins Beau , Baber Usman , Shakir Hakeem J
Published: June 2023

Objectives

This report describes the use of an Everolimus-eluting stent (Xience Skypoint stent) for the treatment of medically-refractory ICAD.

Design

Retrospective, case-series

Setting

In-hospital patients

Participants

All patients in this report had a history of stroke secondary to ICAD. All patients failed aggressive medical treatments and had recurrence of symptoms despite anticoagulation or dual-antiplatelet therapy plus a statin. Diagnostic angiogram in each case showed severe vessel stenosis, therefore patients were recommended for intracranial artery stenting.

Main outcome measures

Technical feasibility of deploying Xience Skypoint stent for treatmet of ICAD.

Results

The Xience Skypoint stent was safely and effectively deployed in the vertebral artery (x1) and the internal carotid artery (x2) using trans-ulnar (x1), trans-radial (x1), and trans-femoral (x1) approaches without the use of an intermediate catheter.

Conclusion

Second-generation EES such as Xience Skypoint may be utilized for treatment of medically-refractory ICAD. This technical report serves as a proof of concept for further studies analysing long-term safety and efficacy of such stents for treatment of ICAD.
NF-kappa-B essential modulator (NEMO) gene polymorphism in an adult woman with systemic lupus erythematosus and recurrent non-tuberculous mycobacterial disseminated infections
Authors: Thomas Konstantinos , Tsioulos Georgios , Kotsogianni Christina , Banos Agellos , Niemela Julie E. , Cheng Aristine , DiMaggio Tom , Holland Steven , Rosenzweig Sergio D. , Tziolos Nikolaos , Papadopoulos Antonios , Lionakis Michail S. , Boumpas Dimitrios T.
Published: June 2023

Infections are among the most serious complications in patients with systemic lupus erythematosus (SLE), with bacterial and viral infections being the most common. Non-tuberculous mycobacterial (NTM) infections are quite rare and are typically seen in older patients with SLE with longstanding disease duration treated with corticosteroids. Here, we describe a 39-year-old woman with SLE and an unusual pattern of recurrent NTM disseminated infections. After excluding the presence of autoantibodies against interferon-γ, whole exome sequencing revealed a homozygous polymorphism in the NF-kappa-B essential modulator (NEMO) gene. Primary immunodeficiencies should be included in the differential diagnosis of patients with recurrent opportunistic infections, even in those with iatrogenic immunosuppression.
Assessment of family-derived metabolic traits for the conservation of an ancient fish
Authors: Deslauriers David , Yoon Gwangseok R. , McClellan Kari J. , Klassen Cheryl N. , Anderson W. Gary
Published: June 2023

Physiological and behavioral traits of aquatic organisms are often highly dependent on environmental conditions, but genetic (family) effects often contribute to phenotypic variation. In this study, a series of physiological indices were used to assess the variability that exists among progeny of lake sturgeon ( Acipenser fulvescens Rafinesque, 1817) produced from eight different families. We designed a controlled experiment aimed to evaluate metabolic performance of age-0 lake sturgeon where growth, energy density, survival, metabolic rate, volitional swimming performance, and critical thermal maxima were quantified for fish reared under the same environmental conditions. We found a strong family effect for most metrics that were quantified and primarily influenced by the female. Furthermore, poor growth and survival within families were strongly correlated to low energy density levels and depressed routine metabolic rates at the yolk sac stage. Lastly, the quantification of energy density at the onset of exogenous feeding appeared to be an excellent predictor of future growth and survival. Our results suggest that the choice of female for production of progeny in conservation hatcheries will have significant impacts on the success of stock enhancement as a conservation strategy for lake sturgeon.
The data on the boundary at order $$\alpha '$$
Authors: Garousi Mohammad R.
Published: June 2023

The least action principle indicates that for the open spacetime manifolds, there are data on the boundary. Recently, it has been proposed that the data for the effective actions at order $$\alpha '$$

α
′

are the values of the massless fields and their first derivatives. These data should be respected by the T-duality transformations at order $$\alpha '$$

α
′

. Moreover, the T-duality transformations should not change the unit vector to the boundary which in turns implies that the base space metric should be also invariant. Assuming such restricted T-duality transformations, we show that the transformation of the circular reduction of the parity-odd part of the effective action of the heterotic string theory at order $$\alpha '$$

α
′

under the Buscher rules is cancelled by some total derivative terms and by some restricted T-duality transformations at order $$\alpha '$$

α
′

. Using the Stokes’ theorem, we then show that the boundary terms in the base space corresponding to the total derivative terms are exactly cancelled by transformation of the circular reduction of the Gibbons–Hawking boundary term under the above restricted T-duality transformations. These calculations confirm the above proposal for the data on the boundary for the effective actions at order $$\alpha '$$

α
′

.
Probiotic Fermentation of Herbal Medicine: Progress, Challenges, and Opportunities
Authors: Yang Hao-Yu , Han Lin , Lin Yi-Qun , Li Tao , Wei Yu , Zhao Lin-Hua , Tong Xiao-Lin
Published: June 2023

Fermentation is a processing method used in traditional Chinese medicine (TCM). However, traditional fermentation methods suffer from poor production control. In contrast, probiotic fermented herbal medicine (PFHM) offers advantages such as the use of pure strains, a controllable process, and the ability to produce a variety of active enzymes during fermentation. As a result, PFHM has become a research hotspot. This review focuses on the progress, challenges, and opportunities in the research of PFHM. The use of probiotic enzymes during fermentation alters the active ingredients of TCM, resulting in positive pharmacological effects such as increased active ingredients, reduced toxicity, new pharmacological effects, and the reuse of herbal residues. PFHM has the potential to transfer the metabolic transformation of the effective components of TCM by intestinal flora outside the body during production and preparation, which has a broad application prospect. However, due to the complexity of the chemical composition of TCM, the mechanism of PFHM requires further investigation. Finally, we discuss the prospects of industrializing PFHM, which is essential for promoting the innovation and modernization of TCM.
Effects of ohmic and activation energy on the physical characteristics of MHD flow and variable heat transfer to a different fluids
Authors: Naik Lal Sing , Prakasha D. G. , Sudharani M. V. V. N. L. , Kumar K. Ganesh
Published: June 2023

This study examines different fluid flow through an elaborated plate. In the modeling of the physical phenomena under investigation, the impacts of viscous dissipation, activation energy and chemical reaction are considered. Also, the heat transport phenomena are explained by the variable thermal conductivity theory. By using the right transformations, the flow-generating PDEs are converted into nonlinear ordinary differential equations. The parameters’ impacts on the velocity, temperature and mass fields are analyzed in detail. The modeled problem is graphically handled in MATLAB using the numerical technique (BVP4c). Graphical representations of the important factors affecting temperature and velocity fields are illustrated through graphs. The findings disclose that the effectiveness of the velocity field is determined by the changing values of the magnetic parameter. The Prandtl values are decreased, the temperature profile becomes more pronounced.
Investigation on the Distinct Catalytic Origin of Nickel-Iron Sulfides/Selenides Oxygen Evolution Electrocatalyst
Authors: Wang Hongyu , Zhao Ximeng , Luo Yuhong , Wang Yanji , Liu Guihua , Li Jingde
Published: June 2023

Nickel-iron based electrocatalysts are efficient oxygen evolution reaction (OER) catalysts and their oxidative transition is widely reported in alkaline water splitting. However, the distinct catalytic origin governing their different catalytic performance is still unclear. Herein, NiFe chalcogenides, NixFe1−xSe and NixFe1−xS, are prepared, and their distinct OER performance and activity origin are comparatively investigated. NixFe1−xSe is found exhibits excellent OER electrocatalytic activity in 1 M KOH with an overpotential of 165 mV at 10 mA cm−2, outperforms that of NixFe1−xS (197 mV). Meanwhile, excellent stability performance is also achieved by NixFe1−xSe in anion exchange membrane water electrolyzer under high current density condition. Experimental analysis reveals that the high intrinsic activity of NixFe1−xSe is originated from the in-situ generated Se-doped γ-NiOOH species, whereas NixFe1−xS is converted into NiO/α-FeOOH during OER. Theoretical calculations show that, compared with NiO/α-FeOOH, Se/γ-NiOOH exhibits a higher degree of electron localization conducive to the stability of the Se/γ-NiOOH electronic structure, faster electron transfer, and favorable adsorption of reaction intermediates. The latter can effectively promote the transformation of *O into *OOH rate-controlling step, thereby exhibiting improved OER performance. These results provide new insights on the distinct catalytic origin of high efficiency NiFe-based OER electrocatalysts.
Teachers’ Emotions: Validation of the Teacher Emotions Scales in Albanian
Authors: Musliu Arian , Frenzel Anne C.
Published: June 2023

The topic of teacher emotions has gained increasing research attention over the past years. Initial predominantly qualitative inquiry methods have been complemented by quantitative ones, and different instruments to measure teacher emotions have been developed. These instruments mainly stem from Western, educated, industrialized, rich, and democratic (WEIRD) countries, and yet it is still unknown if these instruments are of universal cultural functionality. The current study aimed to validate the Teacher Emotions Scale (TES) in the low-to-middle income, Southeastern European country of Kosovo. Findings from N = 258 teachers in Kosovo provide evidence that TES-Albanian operates equivalently in terms of factor structure as the original German version of TES and the English version. Supporting the external validity of the scale, we found consistent low-to-medium relationships between the three emotions measured with the TES (enjoyment, anger, and anxiety) with other teachers’ experiential and behavioral constructs such as positive and negative affect, job satisfaction, burnout, self-efficacy, and the teacher–student relationship. Overall, we conclude that TES can effectively be translated into different languages to measure teacher emotions also in non-WEIRD cultural contexts.
A Comprehensive Insight into the Effect of Berberine on Nonalcoholic Fatty Liver Disease (NAFLD): A Systematic Review
Authors: Karimi Arash , Vajdi Mahdi , Sanaie Sarvin , Akhlaghi Shiva , Negari Aida , Dashti Farzaneh , Sefidmooye Azar Pouria
Published: June 2023

Hepatic dysfunction is primarily caused by nonalcoholic fatty liver disease (NAFLD). Recently, berberine (BBR) has attracted researchers’ interest with its hepatic protective property. A systematic review was conducted to evaluate the effects of BBR and its mechanisms of action in the management of NAFLD and its complications. The guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements were applied to perform the study. Embase, Web of Science, Google Scholar, Science Direct, PubMed, ProQuest, and Scopus databases were searched up until March 2023. According to the inclusion criteria, finally, 65 studies were entered into the study. The evidence provided in the study revealed that BBR could regulate the development of NAFLD via several mechanisms of action namely lowering body weight, modulating lipid and glucose metabolism, and reducing inflammation and oxidative stress (OS). The current systematic review demonstrated the beneficial effects of BBR on NAFLD and its associated metabolic disorders including dyslipidemia, obesity, and insulin resistance through regulating lipid metabolism, facilitating β-oxidation of fatty acids, and mitigating the accumulation of triglycerides in hepatocytes. These beneficial effects make BBR a potential therapeutic approach and an efficient agent in the management of NAFLD and its related risk factors. There is an insufficient number of clinical trials addressing the effects of BBR in humans, so conducting more human research in the future is recommended.
Supplementary Table S5 from Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis
Authors: Goldman Omer , Adler Lital N. , Hajaj Emma , Croese Tommaso , Darzi Naama , Galai Sivan , Tishler Hila , Ariav Yarden , Lavie Dor , Fellus-Alyagor Liat , Oren Roni , Kuznetsov Yuri , David Eyal , Jaschek Rami , Stossel Chani , Singer Oded , Malitsky Sergey , Barak Renana , Seger Rony , Erez Neta , Amit Ido , Tanay Amos , Saada Ann , Golan Talia , Rubinek Tamar , Sang Lee Joo , Ben-Shachar Shay , Wolf Ido , Erez Ayelet
Published: June 2023

Supplementary Table S5 lists the antibodies used for CyTOF
Supplementary Table S9 from C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3-Mutant Leukemia
Authors: Sabatier Marie , Birsen Rudy , Lauture Laura , Mouche Sarah , Angelino Paolo , Dehairs Jonas , Goupille Léa , Boussaid Ismael , Heiblig Maël , Boet Emeline , Sahal Ambrine , Saland Estelle , Santos Juliana C. , Armengol Marc , Fernández-Serrano Miranda , Farge Thomas , Cognet Guillaume , Simonetta Federico , Pignon Corentin , Graffeuil Antoine , Mazzotti Céline , Avet-Loiseau Hervé , Delos Océane , Bertrand-Michel Justine , Chedru Amélie , Dembitz Vilma , Gallipoli Paolo , Anstee Natasha S. , Loo Sun , Wei Andrew H. , Carroll Martin , Goubard Armelle , Castellano Rémy , Collette Yves , Vergez François , Mansat-De Mas Véronique , Bertoli Sarah , Tavitian Suzanne , Picard Muriel , Récher Christian , Bourges-Abella Nathalie , Granat Fanny , Kosmider Olivier , Sujobert Pierre , Colsch Benoit , Joffre Carine , Stuani Lucille , Swinnen Johannes V. , Guillou Hervé , Roué Gael , Hakim Nawad , Dejean Anne S. , Tsantoulis Petros , Larrue Clément , Bouscary Didier , Tamburini Jerome , Sarry Jean-Emmanuel
Published: June 2023

Table S9: CEBPA_UP signature
Supplementary Table S8 from C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3-Mutant Leukemia
Authors: Sabatier Marie , Birsen Rudy , Lauture Laura , Mouche Sarah , Angelino Paolo , Dehairs Jonas , Goupille Léa , Boussaid Ismael , Heiblig Maël , Boet Emeline , Sahal Ambrine , Saland Estelle , Santos Juliana C. , Armengol Marc , Fernández-Serrano Miranda , Farge Thomas , Cognet Guillaume , Simonetta Federico , Pignon Corentin , Graffeuil Antoine , Mazzotti Céline , Avet-Loiseau Hervé , Delos Océane , Bertrand-Michel Justine , Chedru Amélie , Dembitz Vilma , Gallipoli Paolo , Anstee Natasha S. , Loo Sun , Wei Andrew H. , Carroll Martin , Goubard Armelle , Castellano Rémy , Collette Yves , Vergez François , Mansat-De Mas Véronique , Bertoli Sarah , Tavitian Suzanne , Picard Muriel , Récher Christian , Bourges-Abella Nathalie , Granat Fanny , Kosmider Olivier , Sujobert Pierre , Colsch Benoit , Joffre Carine , Stuani Lucille , Swinnen Johannes V. , Guillou Hervé , Roué Gael , Hakim Nawad , Dejean Anne S. , Tsantoulis Petros , Larrue Clément , Bouscary Didier , Tamburini Jerome , Sarry Jean-Emmanuel
Published: June 2023

Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Supplementary Table S6 from C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3-Mutant Leukemia
Authors: Sabatier Marie , Birsen Rudy , Lauture Laura , Mouche Sarah , Angelino Paolo , Dehairs Jonas , Goupille Léa , Boussaid Ismael , Heiblig Maël , Boet Emeline , Sahal Ambrine , Saland Estelle , Santos Juliana C. , Armengol Marc , Fernández-Serrano Miranda , Farge Thomas , Cognet Guillaume , Simonetta Federico , Pignon Corentin , Graffeuil Antoine , Mazzotti Céline , Avet-Loiseau Hervé , Delos Océane , Bertrand-Michel Justine , Chedru Amélie , Dembitz Vilma , Gallipoli Paolo , Anstee Natasha S. , Loo Sun , Wei Andrew H. , Carroll Martin , Goubard Armelle , Castellano Rémy , Collette Yves , Vergez François , Mansat-De Mas Véronique , Bertoli Sarah , Tavitian Suzanne , Picard Muriel , Récher Christian , Bourges-Abella Nathalie , Granat Fanny , Kosmider Olivier , Sujobert Pierre , Colsch Benoit , Joffre Carine , Stuani Lucille , Swinnen Johannes V. , Guillou Hervé , Roué Gael , Hakim Nawad , Dejean Anne S. , Tsantoulis Petros , Larrue Clément , Bouscary Didier , Tamburini Jerome , Sarry Jean-Emmanuel
Published: June 2023

Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Supplementary Figure S5 from Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis
Authors: Goldman Omer , Adler Lital N. , Hajaj Emma , Croese Tommaso , Darzi Naama , Galai Sivan , Tishler Hila , Ariav Yarden , Lavie Dor , Fellus-Alyagor Liat , Oren Roni , Kuznetsov Yuri , David Eyal , Jaschek Rami , Stossel Chani , Singer Oded , Malitsky Sergey , Barak Renana , Seger Rony , Erez Neta , Amit Ido , Tanay Amos , Saada Ann , Golan Talia , Rubinek Tamar , Sang Lee Joo , Ben-Shachar Shay , Wolf Ido , Erez Ayelet
Published: June 2023

Supplementary Figure S5 demonstrate the significance of our liver score in predicting outcomes of BC and PDAC patients
Supplementary Figure S3 from Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis
Authors: Goldman Omer , Adler Lital N. , Hajaj Emma , Croese Tommaso , Darzi Naama , Galai Sivan , Tishler Hila , Ariav Yarden , Lavie Dor , Fellus-Alyagor Liat , Oren Roni , Kuznetsov Yuri , David Eyal , Jaschek Rami , Stossel Chani , Singer Oded , Malitsky Sergey , Barak Renana , Seger Rony , Erez Neta , Amit Ido , Tanay Amos , Saada Ann , Golan Talia , Rubinek Tamar , Sang Lee Joo , Ben-Shachar Shay , Wolf Ido , Erez Ayelet
Published: June 2023

Supplementary Figure S3 shows that targeting the IL-6-pSTAT-HNF4a pathway preserves liver metabolism and restricts BC growth
Supplementary Figure S1 from Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis
Authors: Goldman Omer , Adler Lital N. , Hajaj Emma , Croese Tommaso , Darzi Naama , Galai Sivan , Tishler Hila , Ariav Yarden , Lavie Dor , Fellus-Alyagor Liat , Oren Roni , Kuznetsov Yuri , David Eyal , Jaschek Rami , Stossel Chani , Singer Oded , Malitsky Sergey , Barak Renana , Seger Rony , Erez Neta , Amit Ido , Tanay Amos , Saada Ann , Golan Talia , Rubinek Tamar , Sang Lee Joo , Ben-Shachar Shay , Wolf Ido , Erez Ayelet
Published: June 2023

Supplementary Figure S1 demonstrates global metabolic changes in liver metabolism during early BC carcinogenesis
Supplementary Table S3 from Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hürthle Cell Carcinoma of the Thyroid
Authors: Frank Anderson R. , Li Vicky , Shelton Spencer D. , Kim Jiwoong , Stott Gordon M. , Neckers Leonard M. , Xie Yang , Williams Noelle S. , Mishra Prashant , McFadden David G.
Published: June 2023

Supplementary Table S3 shows the results of our genome-wide and targeted CRISPR-Cas9 screens.
Supplementary Figure S1-S6 from Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hürthle Cell Carcinoma of the Thyroid
Authors: Frank Anderson R. , Li Vicky , Shelton Spencer D. , Kim Jiwoong , Stott Gordon M. , Neckers Leonard M. , Xie Yang , Williams Noelle S. , Mishra Prashant , McFadden David G.
Published: June 2023

Supplementary Figure S1 shows validation of key genetic features in NCI-237 and metabolic characterization of thyroid cancer cell lines. Supplementary Figure S2 shows growth curves and depletion/enrichment plots for pooled CRISPR-Cas9 screens. Supplementary Figure S3 shows validation of complex I impairment conferring sensitivity to LDH inhibition. Supplementary Figure S4 shows metabolic profiling of LDH inhibition in NCI-237 cells. Supplementary Figure S5 shows the validation of NADH-oxidizing enzymes and that NAD+ regeneration rescues LDH inhibition. Supplementary Figure S6 shows that LDH inhibition impairs NCI-237-R PDX proliferation.
Supplementary Table 6 from A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities
Authors: McNicholas Michael , De Cola Antonella , Bashardanesh Zahedeh , Foss Amelia , Lloyd Cameron B. , Hébert Steven , Faury Damien , Andrade Augusto Faria , Jabado Nada , Kleinman Claudia L. , Pathania Manav
Published: June 2023

ssGEA signatures derived from snRNA-seq data.
Data from Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis
Authors: Goldman Omer , Adler Lital N. , Hajaj Emma , Croese Tommaso , Darzi Naama , Galai Sivan , Tishler Hila , Ariav Yarden , Lavie Dor , Fellus-Alyagor Liat , Oren Roni , Kuznetsov Yuri , David Eyal , Jaschek Rami , Stossel Chani , Singer Oded , Malitsky Sergey , Barak Renana , Seger Rony , Erez Neta , Amit Ido , Tanay Amos , Saada Ann , Golan Talia , Rubinek Tamar , Sang Lee Joo , Ben-Shachar Shay , Wolf Ido , Erez Ayelet
Published: June 2023

Abstract
Multiple studies have identified metabolic changes within the tumor and its microenvironment during carcinogenesis. Yet, the mechanisms by which tumors affect the host metabolism are unclear. We find that systemic inflammation induced by cancer leads to liver infiltration of myeloid cells at early extrahepatic carcinogenesis. The infiltrating immune cells via IL6–pSTAT3 immune–hepatocyte cross-talk cause the depletion of a master metabolic regulator, HNF4α, consequently leading to systemic metabolic changes that promote breast and pancreatic cancer proliferation and a worse outcome. Preserving HNF4α levels maintains liver metabolism and restricts carcinogenesis. Standard liver biochemical tests can identify early metabolic changes and predict patients’ outcomes and weight loss. Thus, the tumor induces early metabolic changes in its macroenvironment with diagnostic and potentially therapeutic implications for the host.
Significance:
Cancer growth requires a permanent nutrient supply starting from early disease stages. We find that the tumor extends its effect to the host's liver to obtain nutrients and rewires the systemic and tissue-specific metabolism early during carcinogenesis. Preserving liver metabolism restricts tumor growth and improves cancer outcomes.
Data from C/EBPa confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress-induced ferroptosis in FLT3-mutant leukemia
Authors: Sabatier Marie , Birsen Rudy , Lauture Laura , Mouche Sarah , Angelino Paolo , Dehairs Jonas , Goupille Lea , Boussaid Ismael , Heiblig Mael , Boet Emeline , Sahal Ambrine , Saland Estelle , Santos Juliana C. , Armengol Marc , Fernandez-Serrano Miranda , Farge Thomas , Cognet Guillaume , Simonetta Federico , Pignon Corentin , Graffeuil Antoine , Mazzotti Celine , Avet-Loiseau Herve , Delos Oceane , Bertrand-Michel Justine , Chedru Amelie , Dembitz Vilma , Gallipoli Paolo , Anstee Natasha S. , Loo Sun , Wei Andrew H. , Carroll Martin , Goubard Armelle , Castellano Remy , Collette Yves , Vergez Francois , Mansat-De Mas Veronique , Bertoli Sarah , Tavitian Suzanne , Picard Muriel , Recher Christian , Bourges-Abella Nathalie , Granat Fanny , Kosmider Olivier , Sujobert Pierre , Colsch Benoit , Joffre Carine , Stuani Lucille , Swinnen Johannes V. , Guillou Herve , Roue Gael , Hakim Nawad , Dejean Anne S. , Tsantoulis Petros , Larrue Clement , Bouscary Didier , Tamburini Jerome , Sarry Jean-Emmanuel
Published: June 2023

Abstract
While transcription factor C/AAT-enhancer binding protein a (C/EBPa) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPa and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPa regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPa inactivation decreased mono-unsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPa function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application
Data from C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3-Mutant Leukemia
Authors: Sabatier Marie , Birsen Rudy , Lauture Laura , Mouche Sarah , Angelino Paolo , Dehairs Jonas , Goupille Léa , Boussaid Ismael , Heiblig Maël , Boet Emeline , Sahal Ambrine , Saland Estelle , Santos Juliana C. , Armengol Marc , Fernández-Serrano Miranda , Farge Thomas , Cognet Guillaume , Simonetta Federico , Pignon Corentin , Graffeuil Antoine , Mazzotti Céline , Avet-Loiseau Hervé , Delos Océane , Bertrand-Michel Justine , Chedru Amélie , Dembitz Vilma , Gallipoli Paolo , Anstee Natasha S. , Loo Sun , Wei Andrew H. , Carroll Martin , Goubard Armelle , Castellano Rémy , Collette Yves , Vergez François , Mansat-De Mas Véronique , Bertoli Sarah , Tavitian Suzanne , Picard Muriel , Récher Christian , Bourges-Abella Nathalie , Granat Fanny , Kosmider Olivier , Sujobert Pierre , Colsch Benoit , Joffre Carine , Stuani Lucille , Swinnen Johannes V. , Guillou Hervé , Roué Gael , Hakim Nawad , Dejean Anne S. , Tsantoulis Petros , Larrue Clément , Bouscary Didier , Tamburini Jerome , Sarry Jean-Emmanuel
Published: June 2023

Abstract
Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.
Significance:
FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML.
Table S4 from Immunological characterization and T-cell receptor repertoires of expanded tumor-infiltrating lymphocytes in renal cell carcinoma patients
Authors: Lee Moon Hee , Theodoropoulos Jason , Huuhtanen Jani , Bhattacharya Dipabarna , Järvinen Petrus , Tornberg Sara , Nísen Harry , Mirtti Tuomas , Uski Ilona , Kumari Anita , Peltonen Karita , Draghi Arianna , Donia Marco , Kreutzman Anna , Mustjoki Satu
Published: June 2023

Supplementary Table S4 shows the publicly validated RCC-associated motifs, together with their antigen-specificities with TCRGP, and motifs found in the REP TILs using GLIPH2.
Supplementary Table 1 from NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Authors: Cecchini Michael , Walther Zenta , Wei Wei , Hafez Navid , Pilat Mary Jo , Boerner Scott A. , Durecki Diane E. , Eder Joseph P. , Schalper Kurt A. , Chen Alice P. , LoRusso Patricia
Published: June 2023

Molecular results and outcomes for each patient.
Supplementary Methods 1 from NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Authors: Cecchini Michael , Walther Zenta , Wei Wei , Hafez Navid , Pilat Mary Jo , Boerner Scott A. , Durecki Diane E. , Eder Joseph P. , Schalper Kurt A. , Chen Alice P. , LoRusso Patricia
Published: June 2023

The clinical trial protocol for NCI 7977.
Table S1 from Immunological characterization and T-cell receptor repertoires of expanded tumor-infiltrating lymphocytes in renal cell carcinoma patients
Authors: Lee Moon Hee , Theodoropoulos Jason , Huuhtanen Jani , Bhattacharya Dipabarna , Järvinen Petrus , Tornberg Sara , Nísen Harry , Mirtti Tuomas , Uski Ilona , Kumari Anita , Peltonen Karita , Draghi Arianna , Donia Marco , Kreutzman Anna , Mustjoki Satu
Published: June 2023

Supplementary Table S1 shows the RCC patient data including clinical parameters and status
Figure S8 from Immunological characterization and T-cell receptor repertoires of expanded tumor-infiltrating lymphocytes in renal cell carcinoma patients
Authors: Lee Moon Hee , Theodoropoulos Jason , Huuhtanen Jani , Bhattacharya Dipabarna , Järvinen Petrus , Tornberg Sara , Nísen Harry , Mirtti Tuomas , Uski Ilona , Kumari Anita , Peltonen Karita , Draghi Arianna , Donia Marco , Kreutzman Anna , Mustjoki Satu
Published: June 2023

Figure S8 shows the analyses of the different clonotype sizes and tracking their abundancies found in the bulk TCRb-seq data.
Supplementary Figure 1 from NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Authors: Cecchini Michael , Walther Zenta , Wei Wei , Hafez Navid , Pilat Mary Jo , Boerner Scott A. , Durecki Diane E. , Eder Joseph P. , Schalper Kurt A. , Chen Alice P. , LoRusso Patricia
Published: June 2023

Trial profile for enrolled patients.
Figure S14 from Immunological characterization and T-cell receptor repertoires of expanded tumor-infiltrating lymphocytes in renal cell carcinoma patients
Authors: Lee Moon Hee , Theodoropoulos Jason , Huuhtanen Jani , Bhattacharya Dipabarna , Järvinen Petrus , Tornberg Sara , Nísen Harry , Mirtti Tuomas , Uski Ilona , Kumari Anita , Peltonen Karita , Draghi Arianna , Donia Marco , Kreutzman Anna , Mustjoki Satu
Published: June 2023

Figure S14 shows the clonalities, expression scores and size of clonotypes represented in the T-cell UMAP clusters.
Figure S1 from Immunological characterization and T-cell receptor repertoires of expanded tumor-infiltrating lymphocytes in renal cell carcinoma patients
Authors: Lee Moon Hee , Theodoropoulos Jason , Huuhtanen Jani , Bhattacharya Dipabarna , Järvinen Petrus , Tornberg Sara , Nísen Harry , Mirtti Tuomas , Uski Ilona , Kumari Anita , Peltonen Karita , Draghi Arianna , Donia Marco , Kreutzman Anna , Mustjoki Satu
Published: June 2023

Figure S1 shows a schematic of the TIL expansion protocol.
Data from NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Authors: Cecchini Michael , Walther Zenta , Wei Wei , Hafez Navid , Pilat Mary Jo , Boerner Scott A. , Durecki Diane E. , Eder Joseph P. , Schalper Kurt A. , Chen Alice P. , LoRusso Patricia
Published: June 2023

Purpose:
Veliparib is a PARP inhibitor (PARPi) with activity in BRCA 1/2/PALB2-deficient tumors. Preclinical observations reveal topoisomerase inhibitors like irinotecan are synergistic with PARPi irrespective of homologous recombination deficiency (HRD), potentially expanding the role for PARPi.
Experimental Design:
NCI 7977 was a multicohort phase I clinical trial evaluating the safety and efficacy of multiple dose schedules of veliparib with irinotecan for solid tumors. In the intermittent veliparib cohort, escalating doses of veliparib were given twice daily at dose level (DL) 1 (50 mg) and DL 2 (100 mg) days 1–4 and 8–11 with irinotecan 100 mg/m2 days 3 and 10 in 21-day cycles.
Results:
Fifteen patients enrolled, 8 of 15 (53%) received ≥4 prior systemic treatments. At DL1, 1 of 6 patients experienced a dose-limiting toxicity (DLT) of diarrhea. At DL2, 9 patients were treated, with 3 unevaluable for DLT, and 2 of 6 evaluable patients experienced a DLT of grade 3 neutropenia. Irinotecan 100 mg/m2 and veliparib 50 mg twice daily was the MTD. No objective responses were observed, although 4 patients had progression-free survival >6 months.
Conclusions:
The MTD of intermittent veliparib is 50 mg twice daily days 1–4 and 8–11 with weekly irinotecan 100 mg/m2 days 3 and 10 every 21 days. Multiple patients experienced prolonged stable disease irrespective of HRD and prior irinotecan. However, due to the toxicities with higher dose intermittent veliparib and irinotecan, this schedule was determined too toxic for further development and the arm was closed prematurely.
Significance:
The combination of intermittent veliparib with weekly irinotecan was deemed too toxic for further development. Future PARPi combinations should focus on agents with nonoverlapping toxicities to improve tolerability. The treatment combination showed limited efficacy with prolonged stable disease observed in multiple heavily pretreated patients, but no objective responses were seen.
Real-World Use of AKI Biomarkers: A Quality Improvement Project Using Urinary Tissue Inhibitor Metalloprotease-2 and Insulin-Like Growth Factor Binding Protein 7 ([TIMP-2]*[IGFBP7])
Authors: La Ashley M. , Gunning Samantha , Trevino Sharon A. , Kunczt Alissa , Forni Lui G. , Swamy Varsha , Zarbock Alexander , Groboske Sarah , Leung Edward K.Y. , Yeo Kiang-Teck J. , Koyner Jay L.
Published: June 2023

Introduction: Novel urinary biomarkers, including tissue inhibitor metalloprotease-2 and insulin-like growth factor binding protein 7 ([TIMP-2]*[IGFBP7]), have been developed to identify patients at risk for acute kidney injury (AKI). We investigated the “real-world” clinical utility of [TIMP-2]*[IGFBP7] in preventing AKI. Methods: We performed a before and after single-center quality improvement study of intensive care unit (ICU) patients at risk for severe (KDIGO stage 2 or 3) AKI. In the prospective cohort, ICU providers were allowed to order [TIMP-2]*[IGFBP7] for patients at their discretion, then offered AKI practice recommendations based on the results. Outcomes were compared to a historical cohort in which biomarker values were not reported to clinical teams. Results: There was no difference in 7-day progression to severe AKI between the prospective (n = 116) and historical cohorts (n = 63) when [TIMP-2]*[IGFBP7] ≥0.3 (24 [28%] versus 8 [21%], p = 0.38) despite more stage 1 AKI at time of biomarker measurement in the prospective cohort (58 [67%] versus 9 [23%], p < 0.001). In the prospective cohort, patients with higher [TIMP-2]*[IGFBP7] values were more likely to receive a nephrology consult. Early consultation (within 24 h of biomarker measurement, n = 20) had a nonsignificant trend toward net negative volume balance (−1,787 mL [6,716 mL] versus + 4,974 mL [15,540 mL]) and more diuretic use (19 [95%] versus 8 [80%]) and was associated with less severe AKI (9 [45%] versus 10 [100%], p = 0.004) and inpatient dialysis (2 [10%] versus 7 [70%], p = 0.002) compared to delayed consultation (n = 10). Conclusions: Despite the prospective cohort having more preexisting stage 1 AKI, there were equal rates of progression to severe AKI in the prospective and historical cohorts. In the setting of [TIMP-2]*[IGFBP7] reporting, there were more nephrology consults in response to elevated biomarker levels. Early nephrology consultation resulted in improved volume balance and favorable outcomes compared to delayed consultation.
The Role of Pyroptosis in the Pathogenesis of Kidney Diseases
Authors: Zhou Zhuanli , Li Qin
Published: June 2023

Background: Recently, in addition to apoptosis and necrosis, several other forms of cell death have been discovered, such as necroptosis, autophagy, pyroptosis, and ferroptosis. These cell death modalities play diverse roles in kidney diseases. Pyroptosis is a newly described type of proinflammatory programmed necrosis. Further exploring pyroptosis is helpful to slow the progression of kidney diseases and reduce their complications. Summary: Pyroptosis is mainly mediated by the cleavage of gasdermin D (GSDMD) along with downstream inflammasome activation. Activated caspase-1 induces the release of cytokines by cleaving GSDMD. Inflammation is a major pathogenic mechanism for kidney diseases. Increasing evidence corroborated that pyroptosis was closely related to the progression of renal diseases, including acute kidney injury, renal fibrosis, diabetic nephropathy, and kidney cancer. In this paper, we reviewed the role and the therapeutic treatment of pyroptosis in renal diseases. Key Messages: The better understanding of the progress and new intervention approaches of pyroptosis in kidney diseases may pave the way for new therapeutic opportunities in clinical practice.
Curative Polyendocrine Therapy in a 21-year-Old Patient with Endometrial Carcinoma: Case Report and Review of the Literature
Authors: Schäffler Henning , Dimpfl Moritz , Schochter Fabienne , Janni Wolfgang , de Gregorio Nikolaus
Published: June 2023

Introduction: As the numbers of young patients diagnosed with early-stage endometrial carcinoma continue to rise, the question regarding fertility-preserving therapeutic options will increasingly gain significance in the future. Case Presentation: Here, we present the case of a 21-year-old patient diagnosed with symptomatic atypical endometrial hyperplasia. After 4 months of treatment with medroxyprogesterone acetate, a follow-up dilatation and curettage revealed early-stage, well-differentiated endometrioid endometrial carcinoma. Despite national guidelines recommending hysterectomy, the nulliparous patient expressed a desire to preserve her fertility. Subsequently, she underwent polyendocrine therapy with letrozole, everolimus, metformin, and Zoladex. Forty-three months after diagnosis, the patient successfully gave birth to a healthy child, and there have been no indications of recurrence thus far. Discussion: This case suggests that triple endocrine therapy may be an option for selected patients with early endometrial cancer and a desire for fertility-sparing therapy.