bluuebunny/crossref_metadata_2025 huggingface dataset:
Verification of acoustic streaming measurement accuracy via particle image velocimetry considering the interrogation window aspect ratio
Authors: Yanai Hiroki , Kuzuu Kazuto , Hasegawa Shinya
Published: April 2024

This study measured Rayleigh and Schlichting streaming velocities via particle image velocimetry (PIV) in a standing wave field. Emphasis was placed on balancing high measurement accuracy with high spatial resolution in the boundary layer region. We aimed to achieve high resolution and enhanced measurement accuracy, typically a trade-off, by significantly increasing the aspect ratio of the interrogation window in the flow direction during PIV post-processing. The experiment operated under conditions with a duct axis streaming velocity of approximately 8.3×10−3 m/s in the measurement area. Increasing the aspect ratio from 1 to 21 reduced the standard deviation across the entire radial direction, which served as the accuracy index, from 8.05×10−3 m/s to 5.23×10−4 m/s (94% reduction). Additionally, the method's validity was confirmed through synthetic images with particles of known velocity. This verification demonstrated a decrease in the standard deviation comparable to the experimental images (97% reduction), aligning the analyzed velocity's radial distribution with the known streaming velocity distribution.
The Ca
2+
-dependent phosphatase calcineurin dephosphorylates TBK1 to suppress antiviral innate immunity
Authors: Qu Yang , Wang Siyuan , Jiang Hui , Wang Qingyi , Liao Ying , Qiu Xusheng , Tan Lei , Song Cuiping , Ding Chan , Sun Yingjie , Yang Zengqi
Published: April 2024

Tumor necrosis factor receptor-associated factor family member-associated NF-κB activator-binding kinase 1 (TBK1) plays a key role in the induction of the type 1 interferon (IFN-I) response, which is an important component of innate antiviral defense. Viruses target calcium (Ca
2+
) signaling networks, which participate in the regulation of the viral life cycle, as well as mediate the host antiviral response. Although many studies have focused on the role of Ca
2+
signaling in the regulation of IFN-I, the relationship between Ca
2+
and TBK1 in different infection models requires further elucidation. Here, we examined the effects of the Newcastle disease virus (NDV)-induced increase in intracellular Ca
2+
levels on the suppression of host antiviral responses. We demonstrated that intracellular Ca
2+
increased significantly during NDV infection, leading to impaired IFN-I production and antiviral immunity through the activation of calcineurin (CaN). Depletion of Ca²
+
was found to lead to a significant increase in virus-induced IFN-I production resulting in the inhibition of viral replication. Mechanistically, the accumulation of Ca
2+
in response to viral infection increases the phosphatase activity of CaN, which in turn dephosphorylates and inactivates TBK1 in a Ca
2+
-dependent manner. Furthermore, the inhibition of CaN on viral replication was counteracted in
TBK1
knockout cells. Together, our data demonstrate that NDV hijacks Ca
2+
signaling networks to negatively regulate innate immunity via the CaN-TBK1 signaling axis. Thus, our findings not only identify the mechanism by which viruses exploit Ca
2+
signaling to evade the host antiviral response but also, more importantly, highlight the potential role of Ca
2+
homeostasis in the viral innate immune response.

IMPORTANCE

Viral infections disrupt intracellular Ca
2+
homeostasis, which affects the regulation of various host processes to create conditions that are conducive for their own proliferation, including the host immune response. The mechanism by which viruses trigger TBK1 activation and IFN-I induction through viral pathogen-associated molecular patterns has been well defined. However, the effects of virus-mediated Ca
2+
imbalance on the IFN-I pathway requires further elucidation, especially with respect to TBK1 activation. Herein, we report that NDV infection causes an increase in intracellular free Ca
2+
that leads to activation of the serine/threonine phosphatase CaN, which subsequently dephosphorylates TBK1 and negatively regulates IFN-I production. Furthermore, depletion of Ca
2+
or inhibition of CaN activity exerts antiviral effects by promoting the production of IFN-I and inhibiting viral replication. Thus, our results reveal the potential role of Ca
2+
in the innate immune response to viruses and provide a theoretical reference for the treatment of viral infectious diseases.
Regulation of ubiquitination and antiviral activity of Cactin by deubiquitinase Usp14 in
Drosophila
Authors: Rong Qiqi , Xi Zhichong , Guo Dongyang , Xu Wen , Zhang Liqin , Wu Qingfa
Published: April 2024

Cactin, a highly conserved protein, plays a crucial role in various physiological processes in eukaryotes, including innate immunity. Recently, the function of Cactin in the innate immunity of
Drosophila
has been explored, revealing that Cactin regulates a non-canonical signaling pathway associated with the Toll and Imd pathways
via
the Cactin-Deaf1 axis. In addition, Cactin exhibits specific antiviral activity against the
Drosophila
C virus (DCV) in
Drosophila
, with an unknown mechanism. During DCV infection, it has been confirmed that the protein level and antiviral activity of Cactin are regulated by ubiquitination. However, the precise ubiquitination and deubiquitination mechanisms of Cactin in
Drosophila
remain unexplored. In this study, we identified ubiquitin-specific protease 14 (Usp14) as a major deubiquitinase for Cactin through comprehensive deubiquitinase screening. Our results demonstrate that Usp14 interacts with the C_Cactus domain of Cactin
via
its USP domain. Usp14 efficiently removes K48- and K63-linked polyubiquitin chains from Cactin, thereby preventing its degradation through the ubiquitin-proteasome pathway. Usp14 significantly inhibits DCV replication in
Drosophila
cells by stabilizing Cactin. Moreover, Usp14-deficient fruit flies exhibit increased susceptibility to DCV infection compared to wild-type flies. Collectively, our findings reveal the regulation of ubiquitination and antiviral activity of Cactin by the deubiquitinase Usp14, providing valuable insights into the modulation of Cactin-mediated antiviral activity in
Drosophila
.

IMPORTANCE

Viral infections pose a severe threat to human health, marked by high pathogenicity and mortality rates. Innate antiviral pathways, such as Toll, Imd, and JAK-STAT, are generally conserved across insects and mammals. Recently, the multi-functionality of Cactin in innate immunity has been identified in
Drosophila
. In addition to regulating a non-canonical signaling pathway through the Cactin-Deaf1 axis, Cactin exhibits specialized antiviral activity against the
Drosophila
C virus (DCV) with an unknown mechanism. A previous study emphasized the significance of the Cactin level, regulated by the ubiquitin-proteasome pathway, in modulating antiviral signaling. However, the regulatory mechanisms governing Cactin remain unexplored. In this study, we demonstrate that Usp14 stabilizes Cactin by preventing its ubiquitination and subsequent degradation. Furthermore, Usp14 plays a crucial role in regulating the antiviral function mediated by Cactin. Therefore, our findings elucidate the regulatory mechanism of Cactin in
Drosophila
, offering a potential target for the prevention and treatment of viral infections.
Ascitic microbiota alteration is associated with portal vein tumor thrombosis occurrence and prognosis in hepatocellular carcinoma
Authors: Guo Yingyun , Tian Shan , Zhan Na , Liu Chuan , Li Jiao , Hu Jiaming , Qiu Meiqi , Huang Binglu , Dong Weiguo
Published: April 2024

Portal vein tumor thrombosis (PVTT) frequently leads to malignant ascites (MA) in individuals with hepatocellular carcinoma (HCC), remaining a bottleneck in the treatment. This study aimed to explore the differences in microbes in paired groups and provide novel insights into PVTT and MA-related treatments. Formalin-fixed paraffin embedding ascite samples were collected from MA secondary to HCC and benign ascites (BA) secondary to liver cirrhosis (LC). Ascitic microbiota profiles were determined in the HCC and LC groups by 16S rRNA sequencing. Prognostic risk factors were screened using survival analysis. The correlation between the significantly different microbial signatures in the groups with PVTT (WVT) and non-PVTT (NVT) and clinical characteristics was explored. The expression of different immune cells was determined by labeling four markers in the MA tissue chips using multiplex immunohistochemistry. A total of 240 patients (196 with HCC with MA and 44 with LC with BA) were included in this study. Microbial profiles differed between the HCC and LC groups. PVTT and Barcelona Clinic Liver Cancer stage were shown to be prognostic risk factors. Significant differences in the alpha and beta diversities were observed between the WVT and NVT groups.
Gammaproteobacteria
and
Acinetobacter
were the most abundant in the HCC MA. Differences in microbial signatures between the WVT and NVT groups were correlated with the level of C-reactive protein and apolipoprotein A1. This study revealed the microbial differences in the tumor microenvironment of MA secondary to HCC and BA secondary to LC.

IMPORTANCE

First, we explored the alteration of the ascites ecosystem through the microbiota in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Second, this is the first clinical study to investigate the differences between patients with HCC with and without portal vein tumor thrombosis via 16S rRNA sequencing. These results revealed a decreased microbial diversity and metabolic dysregulation in individuals with HCC and portal vein tumor thrombosis.
Gammaproteobacteria
and
Acinetobacter
were the most abundant in the HCC malignant ascitic fluid. Our study provides a new perspective on treating malignant ascites secondary to HCC.
Characterization of the transcriptionally active form of dephosphorylated DctD complexed with dephospho-IIA
Glc
Authors: Kang Sebin , Jang Bo-Ram , Lee Kyu-Ho
Published: April 2024

Bacterial enhancer-binding proteins (bEBPs) acquire a transcriptionally active state via phosphorylation. However, transcriptional activation by the dephosphorylated form of bEBP has been observed in DctD, which belongs to Group I bEBP. The formation of a complex between dephosphorylated DctD (d-DctD) and dephosphorylated IIA
Glc
(d-IIA
Glc
) is a prerequisite for the transcriptional activity of d-DctD. In the present study, characteristics of the transcriptionally active complex composed of d-IIA
Glc
and phosphorylation-deficient DctD (DctD
D57Q
) of
Vibrio vulnificus
were investigated in its multimeric conformation and DNA-binding ability. DctD
D57Q
formed a homodimer that could not bind to the DNA. In contrast, when DctD
D57Q
formed a complex with d-IIA
Glc
in a 1:1 molar ratio, it produced two conformations: dimer and dodecamer of the complex. Only the dodecameric complex exhibited ATP-hydrolyzing activity and DNA-binding affinity. For successful DNA-binding and transcriptional activation by the dodecameric d-IIA
Glc
/DctD
D57Q
complex, extended upstream activator sequences were required, which encompass the nucleotide sequences homologous to the known DctD-binding site and additional nucleotides downstream. This is the first report to demonstrate the molecular characteristics of a dephosphorylated bEBP complexed with another protein to form a transcriptionally active dodecameric complex, which has an affinity for a specific DNA-binding sequence.

IMPORTANCE

Response regulators belonging to the bacterial two-component regulatory system activate the transcription initiation of their regulons when they are phosphorylated by cognate sensor kinases and oligomerized to the appropriate multimeric states. Recently, it has been shown that a dephosphorylated response regulator, DctD, could activate transcription in a phosphorylation-independent manner in
Vibrio vulnificus
. The dephosphorylated DctD activated transcription as efficiently as phosphorylated DctD when it formed a complex with dephosphorylated form of IIA
Glc
, a component of the glucose-phosphotransferase system. Functional mimicry of this complex with the typical form of transcriptionally active phosphorylated DctD led us to study the molecular characteristics of this heterodimeric complex. Through systematic analyses, it was surprisingly determined that a multimer constituted with 12 complexes gained the ability to hydrolyze ATP and recognize specific upstream activator sequences containing a typical inverted-repeat sequence flanked by distinct nucleotides.
Catabolism of germinant amino acids is required to prevent premature spore germination in
Bacillus subtilis
Authors: Kasu Iqra R. , Reyes-Matte Octavio , Bonive-Boscan Alejandro , Derman Alan I. , Lopez-Garrido Javier
Published: April 2024

Spores of
Bacillus subtilis
germinate in response to specific germinant molecules that are recognized by receptors in the spore envelope. Germinants signal to the dormant spore that the environment can support vegetative growth, so many germinants, such as alanine and valine, are also essential metabolites. As such, they are also required to build the spore. Here we show that these germinants cause premature germination if they are still present at the latter stages of spore formation and beyond, but that
B. subtilis
metabolism is configured to prevent this: alanine and valine are catabolized and cleared from wild-type cultures even when alternative carbon and nitrogen sources are present. Alanine and valine accumulate in the spent media of mutants that are unable to catabolize these amino acids, and premature germination is pervasive. Premature germination does not occur if the germinant receptor that responds to alanine and valine is eliminated, or if wild-type strains that are able to catabolize and clear alanine and valine are also present in coculture. Our findings demonstrate that spore-forming bacteria must fine-tune the concentration of any metabolite that can also function as a germinant to a level that is high enough to allow for spore development to proceed, but not so high as to promote premature germination. These results indicate that germinant selection and metabolism are tightly linked, and suggest that germinant receptors evolve in tandem with the catabolic priorities of the spore-forming bacterium.

IMPORTANCE

Many bacterial species produce dormant cells called endospores, which are not killed by antibiotics or common disinfection practices. Endospores pose critical challenges in the food industry, where endospore contaminations cause food spoilage, and in hospitals, where infections by pathogenic endospore formers threaten the life of millions every year. Endospores lose their resistance properties and can be killed easily when they germinate and exit dormancy. We have discovered that the enzymes that break down the amino acids alanine and valine are critical for the production of stable endospores. If these enzymes are absent, endospores germinate as they are formed or shortly thereafter in response to alanine, which can initiate the germination of many different species' endospores, or to valine. By blocking the activity of alanine dehydrogenase, the enzyme that breaks down alanine and is not present in mammals, it may be possible to inactivate endospores by triggering premature and unproductive germination.
Draft genome sequence of the deep-subsurface
Ciceribacter
sp. strain T2.26MG-112.2, a second Rhizobiaceae isolated from the Iberian Pyrite Belt at 492.6 mbs
Authors: Martínez José M. , García R. , Leandro T. , Amils R.
Published: April 2024

T2.26MG-112.2 is a
Ciceribacter
strain that has been isolated from the deep subsurface of the Iberian Pyrite Belt. We report its draft genome consisting of a chromosome of ≈4.9 Mb and a plasmid of 357 kb. The annotation reveals 4,824 coding sequences, 48 tRNA genes, and 1 rRNA operon.
Oxytetracycline hyper-production through targeted genome reduction of
Streptomyces rimosus
Authors: Pšeničnik Alen , Slemc Lucija , Avbelj Martina , Tome Miha , Šala Martin , Herron Paul , Shmatkov Maksym , Petek Marko , Baebler Špela , Mrak Peter , Hranueli Daslav , Starčević Antonio , Hunter Iain S. , Petković Hrvoje
Published: April 2024

Most biosynthetic gene clusters (BGC) encoding the synthesis of important microbial secondary metabolites, such as antibiotics, are either silent or poorly expressed; therefore, to ensure a strong pipeline of novel antibiotics, there is a need to develop rapid and efficient strain development approaches. This study uses comparative genome analysis to instruct rational strain improvement, using
Streptomyces rimosus
, the producer of the important antibiotic oxytetracycline (OTC) as a model system. Sequencing of the genomes of two industrial strains M4018 and R6-500, developed independently from a common ancestor, identified large DNA rearrangements located at the chromosome end. We evaluated the effect of these genome deletions on the parental
S. rimosus
Type Strain (ATCC 10970) genome where introduction of a 145 kb deletion close to the OTC BGC in the Type Strain resulted in massive OTC overproduction, achieving titers that were equivalent to M4018 and R6-500. Transcriptome data supported the hypothesis that the reason for such an increase in OTC biosynthesis was due to enhanced transcription of the OTC BGC and not due to enhanced substrate supply. We also observed changes in the expression of other cryptic BGCs; some metabolites, undetectable in ATCC 10970, were now produced at high titers. This study demonstrated for the first time that the main force behind BGC overexpression is genome rearrangement. This new approach demonstrates great potential to activate cryptic gene clusters of yet unexplored natural products of medical and industrial value.

IMPORTANCE

There is a critical need to develop novel antibiotics to combat antimicrobial resistance.
Streptomyces
species are very rich source of antibiotics, typically encoding 20–60 biosynthetic gene clusters (BGCs). However, under laboratory conditions, most are either silent or poorly expressed so that their products are only detectable at nanogram quantities, which hampers drug development efforts. To address this subject, we used comparative genome analysis of industrial
Streptomyces rimosus
strains producing high titers of a broad spectrum antibiotic oxytetracycline (OTC), developed during decades of industrial strain improvement. Interestingly, large-scale chromosomal deletions were observed. Based on this information, we carried out targeted genome deletions in the native strain
S. rimosus
ATCC 10970, and we show that a targeted deletion in the vicinity of the OTC BGC significantly induced expression of the OTC BGC, as well as some other silent BGCs, thus suggesting that this approach may be a useful way to identify new natural products.
Pilot study exploring the presence of leadership curricula in undergraduate medical education
Authors: Korndorffer Melanie , Dewsnap Michael A , Barry Erin S , Grunberg Neil , Musick David W , Quinn Joann Farrell
Published: April 2024

Introduction

The physician’s role in the healthcare delivery system extends beyond patient care to include numerous critical leadership roles in healthcare. In addition to treating patients, physicians manage multidisciplinary teams and influence policies to optimise public health. Yet, leadership education is not currently emphasised as part of undergraduate medical education. The purpose of this pilot study was to survey US allopathic medical schools about their current leadership curricula for medical students, including aspects that promote or inhibit effective curricular implementation.

Methods

A survey was developed and administered to representatives at US allopathic medical schools regarding the presence and nature of leadership curricula for medical students currently in place, as well as barriers to effective implementation.

Results

A total of 41 of 144 medical schools (28%) responded to the survey. Of the schools that responded, 25 schools reported the presence of a leadership curriculum. Primary competencies and goals were similar among these institutions, but the structure of the curriculum and how it is being implemented varied. The study did not identify consistent methods of assessing student leadership competencies. Themes of improved communication and integration within the curriculum emerged as actions promoting successful implementation. Financial restraints and buy-in among stakeholder groups (eg, faculty, staff and students) were mentioned most frequently as barriers to the effective implementation of leadership curricula.

Conclusions

Although leadership education within undergraduate medical education is emphasised by a variety of groups, including the Association of American Medical Colleges, medical schools do not appear to universally address this topic. The Liaison Committee on Medical Education, the primary accrediting body for medical schools, does not currently require leadership education as a core topic for accreditation. To provide effective education on leadership to medical students, administrative bodies could improve their support for this topic by considering the factors identified that both hinder and promote implementation.
Identifying functional multi-host shuttle plasmids to advance synthetic biology applications in Mesorhizobium and Bradyrhizobium
Authors: Meaney Jordyn S. , Panchal Aakanx K. , Wilcox Aiden J. , diCenzo George C. , Karas Bogumil J.
Published: April 2024

Ammonia availability has a crucial role in agriculture as it ensures healthy plant growth and increased crop yields. Since diazotrophs are the only organisms capable of reducing dinitrogen to ammonia, they have great ecological importance and potential to mitigate the environmental and economic costs of synthetic fertilizer use. Rhizobia are especially valuable being that they can engage in nitrogen-fixing symbiotic relationships with legumes, and they demonstrate great diversity and plasticity in genomic and phenotypic traits. However, few rhizobial species have sufficient genetic tractability for synthetic biology applications. This study established a basic genetic toolbox with antibiotic resistance markers, multi-host shuttle plasmids and a streamlined protocol for biparental conjugation with Mesorhizobium and Bradyrhizobium species. We identified two repABC origins of replication from Sinorhizobium meliloti (pSymB) and Rhizobium etli (p42d) that were stable across all three strains of interest. Furthermore, the NZP2235 genome was sequenced and phylogenetic analysis determined its reclassification to Mesorhizobium huakuii. These tools will enable the use of plasmid-based strategies for more advanced genetic engineering projects and ultimately contribute towards the development of more sustainable agriculture practices by means of novel nitrogen-fixing organelles, elite bioinoculants, or symbiotic association with nonlegumes.
Transforming Automatically BPMN Models to Smart Contracts with Nested Trade Transactions (TABS+)
Authors: Liu Christian , Bodorik Peter , Jutla Dawn
Published: April 2024

Development of blockchain smart contracts is more difficult than mainstream software development, because the underlying blockchain infrastructure poses additional complexity. To ease the developer's task of writing smart contract, we use Business Process Model and Notation (BPMN) modeling to describe application requirements for trade of goods and services and then transform automatically the BPMN model into the methods of a smart contract. In our previous research, we described our approach and a tool to
Transform Automatically BPMN models into Smart contracts
(TABS). In this article, we describe how the TABS approach is augmented with the support for a BPMN trade transaction that is a collaboration by several actors. Our approach analyzes the BPMN model to determine which patterns in the BPMN model are suitable for use as trade transactions and show those patterns to the developer who decides which ones should be deployed as trade transactions. We describe how our approach automatically transforms the BPMN model into a smart contract that provides a transaction mechanism to enforce the transactional properties of the nested transactions. Our approach greatly reduces the developer's task as synchronization of collaborative activities is provided by our approach, so that the developer needs to code only isolated tasks with well-defined inputs and outputs. We also overview the TABS+ tool we built as a proof of concept to show that our approach is feasible, and we provide estimates on the cost of supporting the nested trade transactions.
Corrosion of Old Overhead Lines: Insights into Aluminum-Steel Galvanic Couple Using Electrochemical Techniques
Authors: Ramírez Rico Divino Salvador , Heurtault Stéphane , Said Julien , Xie Yuelin , Turmine Mireille , Vivier Vincent
Published: April 2024

In order to explain the corrosion inside 20th century power lines, the galvanic corrosion of steel and aluminum from 1949 was examined. In this investigation, 0.1 M Na2SO4 + 1 mM NaCl was used as moderately corrosive medium. Various electrochemical methods were applied to determine the corrosion potential and the different reactions involved in the corrosion process. The thickness of the oxide layer that regulates the corrosion of aluminum was obtained from impedance measurements and it was shown that the diffusion of oxygen through a porous oxide layer is the governing stage for the reaction occurring at the steel electrode. Finally, the corrosion of steel regulates the corrosion of both metals when they are in electrical contact.
Pennington Corner: Onward, Upward!
Authors: Jannuzzi Christopher J.
Published: April 2024

Welcome to the first Interface edition of the new year!
Investigation of the Efficiency of Roll Profiles and Technological Schemes of Deformation of Asymmetric Rolling in Relief Rolls of C11000 Copper Alloy by FEM Simulation
Authors: Panin Evgeniy , Esbolat Aibol , Arbuz Alexandr , Kuis Dmitry , Naizabekov Abdrakhman , Lezhnev Sergey , Yerzhanov Almas , Krupenkin Ivan , Tolkushkin Andrey , Kawalek Anna , Tsyba Pavel
Published: April 2024

In this paper, finite element simulation of asymmetric rolling in relief rolls of C11000 copper alloy in order to analyze the effectiveness of possible roll profiles and technological schemes of deformation was performed. The scientific innovation of this work lies in determining the patterns of development of stress-strain state parameters for various configurations of rolls, as well as determining the effectiveness of metal processing using various technological schemes. It was found that the use of trapezoidal relief makes it possible to increase the level of metal processing by almost 5 times compared with the use of radial relief. Comparison of technological schemes of deformation showed that deformation with 180° workpiece turning between passes significantly reduces the influence of the asymmetry factor. Deformation without changing the workpiece position between the passes has the opposite effect, and such a scheme significantly increases the influence of the asymmetry factor. Deformation with a transverse workpiece shift for the relief period between passes has the effect of a “golden mean.” The conducted laboratory experiment for lead billet showed that the shape change of lead billet during computer simulation has a high level of convergence with real conditions. At each stage of deformation, the difference in the geometric parameters of the workpiece between the model and the experiment did not exceed 3-5%. When deforming a copper billet, the maximum difference level was 8%, which is the result of the low rigidity of the rolling cage with smooth rolls.
A Fatal Case of Legionella bozemanii Pneumonia in an Immunocompetent Patient
Authors: Siddiqui Atif Saleem
Published: April 2024

Legionella bozemanii pneumonia is a rare form of Legionnaires’ disease caused by the bacterium Legionella bozemanii. It is well known to cause pneumonia in immunocompromised patients and has rarely been reported in immunocompetent hosts. We describe a case of a 59-year-old immunocompetent female presented with pneumonia, acute respiratory failure, acute respiratory distress, and septic shock, who was treated with azithromycin, goal-directed resuscitation, and extracorporeal membrane oxygenation (ECMO) but did not survive. Clinicians should have high suspicion of rare legionella pathogens as causative agents for pneumonia.
Immune-Related Peripheral Neuropathy Associated with Immune Checkpoint Inhibitors: Case Report and Review of Literature
Authors: Bonilla Carlos Eduardo , Ávila Vaneza
Published: April 2024

Immune checkpoint inhibitors (ICIs) are a group of drugs that have improved outcomes for patients with various cancers. Generally considered safe and well tolerated, these drugs are occasionally linked to immune-mediated or immune-related adverse events. Among these, autoimmune neurological events are rare, displaying varying incidence rates across different studies. Peripheral neuropathy, although one of the more common neurological immune-related events, is at times underestimated. This case report highlights an adult patient diagnosed with metastatic intrahepatic cholangiocarcinoma. Initially, the patient underwent chemoimmunotherapy with gemcitabine, cisplatin, and durvalumab for eight cycles, achieving partial response without significant toxicity. Following this, the patient continued with maintenance monotherapy with durvalumab every 28 days. After completing six cycles of maintenance therapy, the patient suddenly experienced paresthesia and hypoesthesia in four limbs, accompanied by apraxia in the hands that was more pronounced on the right side. Additionally, the patient reported neuropathic pain in the right arm and encountered limitations in certain instrumental activities of daily living. Diagnostic studies, including laboratory and electrophysiological studies, combined with the clinical presentation, identified immune-related peripheral polyneuropathy. Durvalumab was suspended and prednisolone therapy was initiated, resulting in a rapid resolution of all neuropathic symptoms. In addition to the clinical case, this article reviews the literature on immunotherapy-associated peripheral neuropathy.
Studies Related to the Involvement of EsA in Improving Intestinal Inflammation in Acute Pancreatitis via the NF-κB Pathway
Authors: Pan CuiPing , Zhang ChunXiang , Li YiJie , Cao Jie , Liang ShiWei , Fang HaiCheng , Liu Ying
Published: April 2024

Background. Acute pancreatitis (AP) is a clinically frequent acute abdominal condition, which refers to an inflammatory response syndrome of edema, bleeding, and even necrosis caused by abnormal activation of the pancreas’s own digestive enzymes. Intestinal damage can occur early in the course of AP and is manifested by impaired intestinal mucosal barrier function, and inflammatory reactions of the intestinal mucosa, among other factors. It can cause translocation of intestinal bacteria and endotoxins, further aggravating the condition of AP. Therefore, actively protecting the intestinal mucosal barrier, controlling the progression of intestinal inflammation, and improving intestinal dynamics in the early stages of AP play an important role in enhancing the prognosis of AP. Methods. The viability and apoptosis of RAW264.7 cells treated with Esculentoside A (EsA) and/or lipopolysaccharide were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry, respectively. The expression of apoptosis-related proteins and NF-κB signaling pathway-related proteins were detected by western blot (WB). An enzyme-linked immunosorbent assay was used to measure TNF-α and IL-6 secretion. Results. In vitro experiments demonstrated that EsA not only promoted the apoptosis of inflammatory cells but also reduced the secretion of TNF-α and IL-6 in a dose-dependent manner. Additionally, it inhibited the activation of the NF-κB signaling pathway by decreasing the expression of phosphorylated-p65(p-p65) and elevating the expression of IκBα. Similarly, in vivo experiments using a rat AP model showed that EsA inhibited the expression of p-p65 elevating the expression of IκBα in the intestinal tissues of the rat AP model and promoting the apoptosis of inflammatory cells in the intestinal mucosa in vivo experiments, while improving the pathological outcome of the pancreatic and intestinal tissues. Conclusion. Our results suggest that EsA can reduce intestinal inflammation in the rat AP model and that EsA may be a candidate for treating intestinal inflammation in AP and further arresting AP progression.
Supplementary Figure S1 from TAS0313 plus Pembrolizumab for Post-Chemotherapy Immune Checkpoint Inhibitor—Naïve Locally Advanced or Metastatic Urothelial Carcinoma
Authors: Nishiyama Hiroyuki , Yonese Junji , Kawahara Takashi , Matsumoto Ryuji , Miyake Hideaki , Matsubara Nobuaki , Uemura Hiroji , Eto Masatoshi , Azuma Haruhito , Obara Wataru , Terai Akito , Fukasawa Satoshi , Suekane Shigetaka
Published: April 2024

Figure S1
Supplementary Figure S7 from XTX301, a Tumor-Activated Interleukin-12 Has the Potential to Widen the Therapeutic Index of IL12 Treatment for Solid Tumors as Evidenced by Preclinical Studies
Authors: Patel Ekta , Malkova Natalia V. , Crowe David , Pederzoli-Ribeil Magali , Fantini Damiano , Fanny Manoussa , Madala Hanumantha Rao , Jenkins Kurt A. , Yerov Oleg , Greene Justin , Guzman Wilson , O'Toole Caitlin , Taylor Jacob , O'Donnell Rebekah K. , Johnson Parker , Lanter Bernard B. , Ames Brian , Chen Jia , Vu Sallyann , Wu Hsin-Jung , Cantin Susan , McLaughlin Megan , Hsiao Yu-Shan S. , Tomar Dheeraj S. , Rozenfeld Raphael , Thiruneelakantapillai Lakshmanan , O'Hagan Ronan C. , Nicholson Benjamin , O'Neil Jennifer , Bialucha Carl Uli
Published: April 2024

Supplemental Figure S7: XTX301 caused transient and reversible changes to LFTs and other safety parameters in NHP in a repeat dose GLP toxicology study. Male and female NHPs (N=3/sex; 2/sex for recovery animals) were administered XTX301 by intravenous infusion once weekly for a total of four doses, followed by a four-week recovery period. Changes in (a) aspartate aminotransferase, (b) alanine aminotransferase, (c) total lymphocytes, (d) albumin, and (e) IFN- were fully reversible in the main study and recovery animals. All values are shown as mean ± SD. The reference ranges, indicated by the grey-shaded area, were derived from the study facility’s historical control values.
Supplementary Figure S5 from XTX301, a Tumor-Activated Interleukin-12 Has the Potential to Widen the Therapeutic Index of IL12 Treatment for Solid Tumors as Evidenced by Preclinical Studies
Authors: Patel Ekta , Malkova Natalia V. , Crowe David , Pederzoli-Ribeil Magali , Fantini Damiano , Fanny Manoussa , Madala Hanumantha Rao , Jenkins Kurt A. , Yerov Oleg , Greene Justin , Guzman Wilson , O'Toole Caitlin , Taylor Jacob , O'Donnell Rebekah K. , Johnson Parker , Lanter Bernard B. , Ames Brian , Chen Jia , Vu Sallyann , Wu Hsin-Jung , Cantin Susan , McLaughlin Megan , Hsiao Yu-Shan S. , Tomar Dheeraj S. , Rozenfeld Raphael , Thiruneelakantapillai Lakshmanan , O'Hagan Ronan C. , Nicholson Benjamin , O'Neil Jennifer , Bialucha Carl Uli
Published: April 2024

Supplemental Figure S5: IFN- production in plasma: MC38 tumor-bearing mice were treated with the indicated doses of mXT301 or unmasked control. Plasma IFN- concentration was measured by MSD assay at indicated time points. The data represent mean ± SEM, N = 3 to 5 mice per group, and IFN- level was assessed by a two-way ANOVA with Bonferroni’s post-hoc pairwise comparison test compared to vehicle (PBS) treated animals (*p < 0.05, **p < 0.005, ****p < 0.0001)
Supplementary Table 4 from Elimusertib has Antitumor Activity in Preclinical Patient-Derived Pediatric Solid Tumor Models
Authors: Pusch Fabian F. , Dorado García Heathcliff , Xu Robin , Gürgen Dennis , Bei Yi , Brückner Lotte , Röefzaad Claudia , von Stebut Jennifer , Bardinet Victor , Chamorro Gonzalez Rocío , Eggert Angelika , Schulte Johannes H. , Hundsdörfer Patrick , Seifert Georg , Haase Kerstin , Schäfer Beat W. , Wachtel Marco , Kühl Anja A. , Ortiz Michael V. , Wengner Antje M. , Scheer Monika , Henssen Anton G.
Published: April 2024

Supplementary Table 4 lists the quantifications of IHC markers in RMS PDX.
Table S1 from Multiomic-Based Molecular Landscape of FaDu Xenograft Tumors in Mice after a Combinatorial Treatment with Radiation and an HSP90 Inhibitor Identifies Adaptation-Induced Targets of Resistance and Therapeutic Intervention
Authors: Bylicky Michelle A. , Shankavaram Uma , Aryankalayil Molykutty J. , Chopra Sunita , Naz Sarwat , Sowers Anastasia L. , Choudhuri Rajani , Calvert Valerie , Petricoin Emanuel F. , Eke Iris , Mitchell James B. , Coleman C. Norman
Published: April 2024

Supplementary Table of phosphoproteomic data
Supplementary Table 3 from Elimusertib has Antitumor Activity in Preclinical Patient-Derived Pediatric Solid Tumor Models
Authors: Pusch Fabian F. , Dorado García Heathcliff , Xu Robin , Gürgen Dennis , Bei Yi , Brückner Lotte , Röefzaad Claudia , von Stebut Jennifer , Bardinet Victor , Chamorro Gonzalez Rocío , Eggert Angelika , Schulte Johannes H. , Hundsdörfer Patrick , Seifert Georg , Haase Kerstin , Schäfer Beat W. , Wachtel Marco , Kühl Anja A. , Ortiz Michael V. , Wengner Antje M. , Scheer Monika , Henssen Anton G.
Published: April 2024

Supplementary Table 3 shows statistics for all tumor volume curves.
Supplementary Table 1 from Elimusertib has Antitumor Activity in Preclinical Patient-Derived Pediatric Solid Tumor Models
Authors: Pusch Fabian F. , Dorado García Heathcliff , Xu Robin , Gürgen Dennis , Bei Yi , Brückner Lotte , Röefzaad Claudia , von Stebut Jennifer , Bardinet Victor , Chamorro Gonzalez Rocío , Eggert Angelika , Schulte Johannes H. , Hundsdörfer Patrick , Seifert Georg , Haase Kerstin , Schäfer Beat W. , Wachtel Marco , Kühl Anja A. , Ortiz Michael V. , Wengner Antje M. , Scheer Monika , Henssen Anton G.
Published: April 2024

Supplementary Table 1 shows AUC and IC50 values for all pediatric cancer cell lines tested.
Figure S4 from Multiomic-Based Molecular Landscape of FaDu Xenograft Tumors in Mice after a Combinatorial Treatment with Radiation and an HSP90 Inhibitor Identifies Adaptation-Induced Targets of Resistance and Therapeutic Intervention
Authors: Bylicky Michelle A. , Shankavaram Uma , Aryankalayil Molykutty J. , Chopra Sunita , Naz Sarwat , Sowers Anastasia L. , Choudhuri Rajani , Calvert Valerie , Petricoin Emanuel F. , Eke Iris , Mitchell James B. , Coleman C. Norman
Published: April 2024

Supplemental Figure S4: Heat Shock protein gene expression was significantly modified by treatment over time. Statistical difference (2-fold change, p < 0.01) indicated with (*). No radiation samples showed statistically significant changes compared to time-matched Untreated tumors, though there was a trend towards significant downregulation for HSPB11 and HSP90AA1 in Rad Week 2 samples compared to UT_Wk2. HSPA1A was significantly upregulated in Drug+Rad Week 1 and Week 2 samples compared to respective UT_Wk1 and 2 samples. HSPA1B was also upregulated in Drug and Drug+Rad at Week 1 and Week 2 compared to respective UT_Wk1 and UT_Wk2. HSP90AA1 was only significantly downregulated at Drug Week 2. For HSPB11 only Drug+Rad Week 1 and Week 2 were significantly downregulated. HSPA14 showed significant downregulation at Drug and Drug+Rad Week 1 and Drug Week 2 compared to respective controls.
Supplementary Figure 7 from Elimusertib has Antitumor Activity in Preclinical Patient-Derived Pediatric Solid Tumor Models
Authors: Pusch Fabian F. , Dorado García Heathcliff , Xu Robin , Gürgen Dennis , Bei Yi , Brückner Lotte , Röefzaad Claudia , von Stebut Jennifer , Bardinet Victor , Chamorro Gonzalez Rocío , Eggert Angelika , Schulte Johannes H. , Hundsdörfer Patrick , Seifert Georg , Haase Kerstin , Schäfer Beat W. , Wachtel Marco , Kühl Anja A. , Ortiz Michael V. , Wengner Antje M. , Scheer Monika , Henssen Anton G.
Published: April 2024

Supplementary Figure 7 depicts the overall survival of each pediatric cancer entity under elimusertib treatment.
Supplementary Table S4 from Combination Therapy with EGFR Tyrosine Kinase Inhibitors and TEAD Inhibitor Increases Tumor Suppression Effects in EGFR Mutation–positive Lung Cancer
Authors: Ogimoto Tatsuya , Ozasa Hiroaki , Tsuji Takahiro , Funazo Tomoko , Yamazoe Masatoshi , Hashimoto Kentaro , Yoshida Hiroshi , Hosoya Kazutaka , Ajimizu Hitomi , Nomizo Takashi , Yoshida Hironori , Hamaji Masatsugu , Menju Toshi , Yoshizawa Akihiko , Date Hiroshi , Hirai Toyohiro
Published: April 2024

Supplementary Table S4 shows siRNA oligonucleotides.
Supplementary Table S2 from Combination Therapy with EGFR Tyrosine Kinase Inhibitors and TEAD Inhibitor Increases Tumor Suppression Effects in EGFR Mutation–positive Lung Cancer
Authors: Ogimoto Tatsuya , Ozasa Hiroaki , Tsuji Takahiro , Funazo Tomoko , Yamazoe Masatoshi , Hashimoto Kentaro , Yoshida Hiroshi , Hosoya Kazutaka , Ajimizu Hitomi , Nomizo Takashi , Yoshida Hironori , Hamaji Masatsugu , Menju Toshi , Yoshizawa Akihiko , Date Hiroshi , Hirai Toyohiro
Published: April 2024

Supplementary Table S2 shows antibodies used for immunofluorescence staining.
Supplementary Table S1 from Combination Therapy with EGFR Tyrosine Kinase Inhibitors and TEAD Inhibitor Increases Tumor Suppression Effects in EGFR Mutation–positive Lung Cancer
Authors: Ogimoto Tatsuya , Ozasa Hiroaki , Tsuji Takahiro , Funazo Tomoko , Yamazoe Masatoshi , Hashimoto Kentaro , Yoshida Hiroshi , Hosoya Kazutaka , Ajimizu Hitomi , Nomizo Takashi , Yoshida Hironori , Hamaji Masatsugu , Menju Toshi , Yoshizawa Akihiko , Date Hiroshi , Hirai Toyohiro
Published: April 2024

Supplementary Table S1 shows antibodies used for immunoblotting.
Supplementary Figure S4 from Combination Therapy with EGFR Tyrosine Kinase Inhibitors and TEAD Inhibitor Increases Tumor Suppression Effects in EGFR Mutation–positive Lung Cancer
Authors: Ogimoto Tatsuya , Ozasa Hiroaki , Tsuji Takahiro , Funazo Tomoko , Yamazoe Masatoshi , Hashimoto Kentaro , Yoshida Hiroshi , Hosoya Kazutaka , Ajimizu Hitomi , Nomizo Takashi , Yoshida Hironori , Hamaji Masatsugu , Menju Toshi , Yoshizawa Akihiko , Date Hiroshi , Hirai Toyohiro
Published: April 2024

Supplementary Figure S4 shows cell viability assays of KTOR27 cells treated with afatinib and verteporfin.
Supplementary Figure S1 from Combination Therapy with EGFR Tyrosine Kinase Inhibitors and TEAD Inhibitor Increases Tumor Suppression Effects in EGFR Mutation–positive Lung Cancer
Authors: Ogimoto Tatsuya , Ozasa Hiroaki , Tsuji Takahiro , Funazo Tomoko , Yamazoe Masatoshi , Hashimoto Kentaro , Yoshida Hiroshi , Hosoya Kazutaka , Ajimizu Hitomi , Nomizo Takashi , Yoshida Hironori , Hamaji Masatsugu , Menju Toshi , Yoshizawa Akihiko , Date Hiroshi , Hirai Toyohiro
Published: April 2024

Supplementary Figure S1 shows the cell viability signal with or without the freezing and thawing procedure.
Supplementary Data from ADCT-602, a Novel PBD Dimer–containing Antibody–Drug Conjugate for Treating CD22-positive Hematologic Malignancies
Authors: Zammarchi Francesca , Havenith Karin E. , Sachini Nikoleta , Janghra Narinder , Chivers Simon , Idusogie Esohe , Gaudio Eugenio , Tarantelli Chiara , Bertelli Francois , Santos Kathleen , Tyrer Peter , Corbett Simon , Spriano Filippo , Golino Gaetanina , Cascione Luciano , Bertoni Francesco , Hartley John A. , van Berkel Patrick H.
Published: April 2024

Supplementary File. Supervised analyses in B-cell lymphoma cell lines using Illumina HT-12 microarray data
This file contains all data, as well as lists of transcripts upregulated (logFC+) or downregulated (logFC−) in the resistant cell lines, gene sets significantly enriched in the 2 groups of cell lines, and IRAK1 expression levels from Illumina microarray.
Supplementary Methods from Oncogenic Cells of Renal Embryonic Lineage Sensitive to the Small-Molecule Inhibitor QC6352 Display Depletion of KDM4 Levels and Disruption of Ribosome Biogenesis
Authors: Pichavaram Prahalathan , Jablonowski Carolyn M. , Fang Jie , Fleming Andrew M. , Gil Hyea Jin , Boghossian Andrew S. , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Morton Christopher L. , Zambetti Gerard P. , Davidoff Andrew M. , Yang Jun , Murphy Andrew J.
Published: April 2024

Supplementary methods for qRT-PCR, ChIP-PCR for KDM4A occupancy at rDNA locus, and Click-iT assay for metabolic labeling of newly synthesized proteins.
Figure S5 from ADCT-602, a Novel PBD Dimer–containing Antibody–Drug Conjugate for Treating CD22-positive Hematologic Malignancies
Authors: Zammarchi Francesca , Havenith Karin E. , Sachini Nikoleta , Janghra Narinder , Chivers Simon , Idusogie Esohe , Gaudio Eugenio , Tarantelli Chiara , Bertelli Francois , Santos Kathleen , Tyrer Peter , Corbett Simon , Spriano Filippo , Golino Gaetanina , Cascione Luciano , Bertoni Francesco , Hartley John A. , van Berkel Patrick H.
Published: April 2024

Supplementary Fig. S5. Kaplan–Meier survival analysis in (A) Ramos and (B) WSU-DLCL2 xenograft models. Kaplan–Meier survival plots showing percentage animal survival (A) over 60 days in Ramos xenograft; and (B) over 59 days in WSU-DLCL2 cancer xenograft. QD once daily.
Supplementary Figure 4 from Oncogenic Cells of Renal Embryonic Lineage Sensitive to the Small-Molecule Inhibitor QC6352 Display Depletion of KDM4 Levels and Disruption of Ribosome Biogenesis
Authors: Pichavaram Prahalathan , Jablonowski Carolyn M. , Fang Jie , Fleming Andrew M. , Gil Hyea Jin , Boghossian Andrew S. , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Morton Christopher L. , Zambetti Gerard P. , Davidoff Andrew M. , Yang Jun , Murphy Andrew J.
Published: April 2024

Dose-dependent decrease in ribosomal protein expression in response to QC6352 treatment in WiT49 and HEK293. Treatment of WiT49 and HEK293 cells with the above concentrations of QC6352 for 72 hours resulted in a dose-dependent decrease in KDM4A-C and the ribosomal proteins RPS6, RPS3, RPL7a, RPL26, and RPS27a by western blot. In addition, a dose dependent decrease in P70 S6Kinase, which phosphorylates the ribosomal protein RPS6 to initiate protein translation, was observed.
Figure S1 from ADCT-602, a Novel PBD Dimer–containing Antibody–Drug Conjugate for Treating CD22-positive Hematologic Malignancies
Authors: Zammarchi Francesca , Havenith Karin E. , Sachini Nikoleta , Janghra Narinder , Chivers Simon , Idusogie Esohe , Gaudio Eugenio , Tarantelli Chiara , Bertelli Francois , Santos Kathleen , Tyrer Peter , Corbett Simon , Spriano Filippo , Golino Gaetanina , Cascione Luciano , Bertoni Francesco , Hartley John A. , van Berkel Patrick H.
Published: April 2024

Supplementary Fig. S1. Structure and characterization of ADCT-602. (A) Full-length amino acid sequence of light and heavy chains of hLL2-C220, with the mutations C219S in the light chain and C225V and C228V in the heavy chain indicated in bold. (B) Structure of ADCT-602 with the PBD dimer payload tesirine (SG3249) conjugated at C219 of hLL2-CC20 (C220 according to the EU numbering system) in the heavy chain. (C) ADCT-602 characterized by size exclusion chromatography and by (D) reduced reversed-phase chromatography. L indicates elution of the light chain, whereas H0 and H1 indicate elution of the unconjugated H-chain or H-chain conjugated to SG3249, respectively. (E) RP-HPLC analysis of the reduced tryptic digest of 2 batches of ADCT-602 (red and black traces). Ala alanine; PABC poly(A)-binding protein C-terminal; PBD pyrrolobenzodiazepine; Val valine.
Table S2 from Glucocorticoid Receptor (GR) Activation Is Associated with Increased cAMP/PKA Signaling in Castration-Resistant Prostate Cancer
Authors: Bennett Lynda , Jaiswal Praveen Kumar , Harkless Ryan V. , Long Tiha M. , Gao Ning , Vandenburg Brianna , Selman Phillip , Durdana Ishrat , Lastra Ricardo R. , Vander Griend Donald , Adelaiye-Ogala Remi , Szmulewitz Russell Z. , Conzen Suzanne D.
Published: April 2024

IPA-derived activation Z-scores in CWR-22Rv1 cells