bluuebunny/crossref_metadata_2025 huggingface dataset:
The nucleoid protein HU positively regulates the expression of type VI secretion systems in
Enterobacter cloacae
Authors: Hernández-Martínez Gabriela , Ares Miguel A. , Rosales-Reyes Roberto , Soria-Bustos Jorge , Yañez-Santos Jorge Antonio , Cedillo María L. , Girón Jorge A. , Martínez-Laguna Ygnacio , Leng Fenfei , Ibarra J. Antonio , De la Cruz Miguel A.
Published: April 2024

Enterobacter cloacae
is an emerging pathogen isolated in healthcare-associated infections. A major virulence factor of this bacterium is the type VI secretion system (T6SS). The genome of
E. cloacae
harbors two T6SS gene clusters (T6SS-1 and T6SS-2), and the functional characterization of both systems showed that these two T6SSs are not expressed under the same conditions. Here, we report that the major histone-like protein HU positively regulates the expression of both T6SSs and, therefore, the function that each T6SS exerts in
E. cloacae
. Single deletions of the genes encoding the HU subunits (
hupA
and
hupB
) decreased mRNA levels of both T6SS. In contrast, the
hupA hupB
double mutant dramatically affected the T6SS expression, diminishing its transcription. The direct binding of HU to the promoter regions of T6SS-1 and T6SS-2 was confirmed by electrophoretic mobility shift assay. In addition, single and double mutations in the
hup
genes affected the ability of inter-bacterial killing, biofilm formation, adherence to epithelial cells, and intestinal colonization, but these phenotypes were restored when such mutants were
trans
-complemented. Our data broaden our understanding of the regulation of HU-mediated T6SS in these pathogenic bacteria.

IMPORTANCE

T6SS is a nanomachine that functions as a weapon of bacterial destruction crucial for successful colonization in a specific niche.
Enterobacter cloacae
expresses two T6SSs required for bacterial competition, adherence, biofilm formation, and intestinal colonization. Expression of T6SS genes in pathogenic bacteria is controlled by multiple regulatory systems, including two-component systems, global regulators, and nucleoid proteins. Here, we reported that the HU nucleoid protein directly activates both T6SSs in
E. cloacae
, affecting the T6SS-related phenotypes. Our data describe HU as a new regulator involved in the transcriptional regulation of T6SS and its impact on
E. cloacae
pathogenesis.
Neoarchean and Paleoproterozoic magmatism in the Longjiang area, NE China: Implications for the recycling history of supracrustal components in the eastern Central Asian Orogenic Belt
Authors: Sun Chenyang , Xu Wenliang , Zhao Guochun , Zhang Xiaoming , Li Yu , Tang Jie
Published: April 2024

Substantial Phanerozoic crustal growth and reworking in the eastern Central Asian Orogenic Belt has partly obscured the Precambrian geological record. Accurate identification of such Precambrian magmatism and its petrogenesis is paramount to unveiling the early crustal evolution of the eastern Central Asian Orogenic Belt. Two outcrops of Neoarchean and Paleoproterozoic magmatism in the Longjiang area of NE China, eastern Central Asian Orogenic Belt, were recently discovered. The Kaoquantun outcrop consists of monzogranites that yield a zircon 207Pb/206Pb age of 2568 ± 8 Ma and are similar to peraluminous A1-type granites. They were derived from the partial melting of a hybrid crustal source comprising newly accreted Mesoarchean crust and abundant supracrustal metapelites in a post-collisional extensional setting. Such metapelites were initially part of the upper crust but were buried in the middle–lower crust due to crustal thickening prior to ca. 2.6 Ga. In the Zhanbeitun outcrop, basaltic andesites overlie monzogranites, and both have been intruded by syenogranites. The monzogranites and syenogranites yield zircon 207Pb/206Pb ages of 1881 ± 10 Ma and 1843 ± 3 Ma, respectively, whereas the basaltic andesites are inferred to have formed at 1.88–1.84 Ga. The 1.88 Ga monzogranites have relatively enriched zircon Hf-O isotopic compositions and were derived from a hybrid melt of mafic rocks in the lower crust and ancient metabasalts that had undergone low-temperature alteration at supracrustal depths. The 1.88–1.84 Ga basaltic andesites are Nb-rich and were generated by the partial melting of a mantle wedge that was metasomatized by subduction-derived fluids, recycled sediments, and slab-derived melts. The 1.84 Ga syenogranites are peraluminous and K-rich, and record a profound mixing and assimilation process involving melts derived from supracrustal sediments and the lower crust. Three stages of Paleoproterozoic magmatism emerged from subduction-related crustal thickening, slab breakoff, and collision, respectively. The zircon Hf isotopic data further indicate that the eastern Central Asian Orogenic Belt underwent at least one stage of proto-crustal growth at ca. 3.0 Ga, followed by multiple phases of crustal reworking during the Neoarchean and Paleoproterozoic, with dominant involvement of supracrustal components.
Gastrointestinal effects of caffeine in preterm infants: a systematic review and Bayesian meta-analysis
Authors: Gama Beatriz , von Hafe Madalena , Vieira Rafael , Soares Henrique , Azevedo Inês , Rocha Gustavo
Published: April 2024

Objective

Caffeine is widely used in preterm infants to prevent or treat apnoea of prematurity. Adverse gastrointestinal effects of caffeine have not been thoroughly researched in preterm infants. With this systematic review and meta-analysis, we aim to summarise the results of trials on the gastrointestinal effects of caffeine in preterm infants.

Design

We searched MEDLINE, Web of Science, Scopus and ClinicalTrials.gov up to 21 April 2023. We included randomised controlled trials assessing caffeine versus placebo in preterm neonates and reporting gastrointestinal side effects. Risk of bias was assessed using the Cochrane Risk of Bias tool. A Bayesian meta-analysis was performed to estimate the pooled OR of gastrointestinal side effects.

Results

Nine trials involving 2746 preterm infants were analysed. Seven trials assessing necrotising enterocolitis and four trials assessing feeding intolerance in our meta-analysis found no differences between caffeine and placebo (OR=1.007 (95% credible interval 0.021, 5.462), I2=97.4%, and OR=1.266 (95% credible interval 0.064, 28.326), I2=84.8%, respectively). Four trials assessed the outcomes spontaneous intestinal perforation, constipation, gastrointestinal disorder (composite outcome: gastro-oesophageal regurgitation or dilated bowel loops), age at oral feeding and cholestasis syndrome and found no differences between groups. One trial assessed the outcomes gastro-oesophageal symptoms and duration of tube feeding and found that caffeine was associated with a reduced burden of gastro-oesophageal reflux symptoms at 2 weeks (p<0.05), but not at term.

Conclusions

According to this systematic review and meta-analysis, the use of caffeine at usual doses in preterm infants does not seem to be associated with significant gastrointestinal adverse effects.
Rare presentation of solitary fibrous tumour in the floor of the mouth
Authors: Sagar Milind , Sunar Diwash , Konkimalla Abhilash , Das Sumanta
Published: April 2024

A male in his 20s, a tobacco chewer, presented to the outpatient department with a history of painless, slowly progressive swelling in the floor of the mouth. After a thorough history and clinical examination, MRI was done and the tumour was completely excised. Histopathological examination revealed the mass to be a solitary fibrous tumour, confirmed with immunohistochemical markers. On subsequent follow-ups, the patient was found to be asymptomatic with no clinical signs of recurrence.
Towards comprehensive clinical trials for new tuberculosis drug regimens: policy recommendations from a stakeholder analysis
Authors: Villa Simone , de Colombani Pierpaolo , Dall’Olio Lucia , Gargioni Giuliano , Raviglione Mario
Published: April 2024

Background

Research and development (R&D) of new drugs and regimens against tuberculosis (TB) is evolving to meet new challenges and face limited investments in the sector. To effectively improve and fill existing gaps, researchers and trialists should engage a broad spectrum of stakeholders. With this study, we aim to map the interests in TB R&D raised by the main stakeholders in the TB field.

Methods

We conducted semistructured, short interviews to gather insight and viewpoints on innovation on TB drugs and regimens R&D of policy-makers, national TB programme officers, donors, funders, non-governmental organisations and research institutions.

A composite measure of the relevance of topics that emerged was computed by implementing different models considering the importance for researchers and the urgency to implement those changes during the trial, the number of citations each topic received, and the maximum value of the influence of stakeholders who had raised the topic.

Results

50 stakeholders, out of 56 identified, were interviewed and almost half were policy-makers and governmental institutions. Several stakeholders highlighted the importance of disseminating information about clinical trials’ methodology and emerging preliminary results, followed by the need to pursue early discussion around access and pricing of safe and effective TB innovations, although different categories of stakeholders prioritised different topics. Using different methods for ranking topics, the results remained almost unchanged. Notably, post-trial operational research ranked higher in models with higher weight for the parameter considering the number of citations.

Conclusion

Researchers and research consortia embarking on phase 2 and 3 clinical trials should consider a broad set of elements when planning and designing trials’ protocols, all aiming at lowering the price and improving access to emerging TB innovations, besides meeting regulatory criteria. This can only be achieved by consulting and engaging relevant stakeholders in the discussion.
Can hospitalists improve COVID-19 vaccination rates?
Authors: Yu Nina , Punatar Nisha , Shaikh Ulfat , Agrawal Garima
Published: April 2024

Three years after the start of the SARS-CoV-2 virus (COVID-19) pandemic, its effects continue to affect society and COVID-19 vaccination campaigns continue to be a topic of controversy and inconsistent practice. After experiencing spikes in COVID-19 cases, our University of California Davis Health Division of Hospital Medicine sought to understand the reasons underlying the low COVID-19 vaccination rates in our county and find approaches to improve the number of vaccinations among adults admitted to the inpatient setting. This quality improvement project aimed to increase COVID-19 primary and booster vaccine efforts through a multi-pronged approach of increased collaboration with specialised staff and optimisation of use of our electronic health record system.

Our key interventions focused on developing a visual reminder of COVID-19 vaccine status using the functionality of our electronic medical record (EMR), standardising documentation of COVID-19 vaccine status and enhancing team-based vaccination discussions through team huddles and partnering with inpatient care coordinators. While our grassroots approach enhanced COVID-19 vaccination rates in the inpatient setting and had additional benefits such as increased collaboration among teams, system-level efforts often made a greater impact at our healthcare centre. For other institutions interested in increasing COVID-19 vaccination rates, our top three recommendations include integrating vaccination into pre-existing workflows, optimising EMR functionality and increasing vaccine accessibility in the inpatient setting.
Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials
Authors: Roller Andreas , Davydov Iakov I , Schwalie Petra C , Serrano-Serrano Martha L , Heller Astrid , Staedler Nicolas , Ferreira Cláudia S , Dietmann Gabriele , Klaman Irina , Valdeolivas Alberto , Korski Konstanty , Cannarile Michael A
Published: April 2024

Background

The immune status of a patient’s tumor microenvironment (TME) may guide therapeutic interventions with cancer immunotherapy and help identify potential resistance mechanisms. Currently, patients’ immune status is mostly classified based on CD8+tumor-infiltrating lymphocytes. An unmet need exists for comparable and reliable precision immunophenotyping tools that would facilitate clinical treatment-relevant decision-making and the understanding of how to overcome resistance mechanisms.

Methods

We systematically analyzed the CD8 immunophenotype of 2023 patients from 14 phase I–III clinical trials using immunohistochemistry (IHC) and additionally profiled gene expression by RNA-sequencing (RNA-seq). CD8 immunophenotypes were classified by pathologists into CD8-desert, CD8-excluded or CD8-inflamed tumors using CD8 IHC staining in epithelial and stromal areas of the tumor. Using regularized logistic regression, we developed an RNA-seq-based classifier as a surrogate to the IHC-based spatial classification of CD8+tumor-infiltrating lymphocytes in the TME.

Results

The CD8 immunophenotype and associated gene expression patterns varied across indications as well as across primary and metastatic lesions. Melanoma and kidney cancers were among the strongest inflamed indications, while CD8-desert phenotypes were most abundant in liver metastases across all tumor types. A good correspondence between the transcriptome and the IHC-based evaluation enabled us to develop a 92-gene classifier that accurately predicted the IHC-based CD8 immunophenotype in primary and metastatic samples (area under the curve inflamed=0.846; excluded=0.712; desert=0.855). The newly developed classifier was prognostic in The Cancer Genome Atlas (TCGA) data and predictive in lung cancer: patients with predicted CD8-inflamed tumors showed prolonged overall survival (OS) versus patients with CD8-desert tumors (HR 0.88; 95% CI 0.80 to 0.97) across TCGA, and longer OS on immune checkpoint inhibitor administration (phase III OAK study) in non-small-cell lung cancer (HR 0.75; 95% CI 0.58 to 0.97).

Conclusions

We provide a new precision immunophenotyping tool based on gene expression that reflects the spatial infiltration patterns of CD8+ lymphocytes in tumors. The classifier enables multiplex analyses and is easy to apply for retrospective, reverse translation approaches as well as for prospective patient enrichment to optimize the response to cancer immunotherapy.
Resistance training and cardiometabolic risk in women with metabolically healthy and unhealthy obesity
Authors: Tremblay Eve-Julie , Peyrel Paul , Karelis Antony D. , Rabasa-Lhoret Rémi , Tchernof André , Joanisse Denis R. , Mauriège Pascale
Published: April 2024

Despite some reported benefits, there is a low quality of evidence for resistance training (RT) improving metabolic health of individuals with overweight or obesity. We evaluated the impact of RT on body composition, cardiorespiratory fitness (CRF) and physical performance, lipid–lipoprotein profile, inflammation, and glucose–insulin homeostasis in 51 postmenopausal women versus 29 controls matched for age, obesity, and physical activity. Exercised women were further subdivided for comparison of RT effects into those presenting metabolically healthy obesity (MHO) and those with metabolically unhealthy obesity (MUHO) classified according to Karelis and Rabasa-Lhoret or an approach based on adipose tissue secretory dysfunction using the plasma adiponectin(A)/leptin (L) ratio. Participants followed a 4-month weekly RT program targeting major muscle groups (3 × 10 repetitions at 80% one repetition maximum (1-RM)). Percent fat marginally decreased and lean body mass increased (0.01 <  p < 0.05) while CRF and muscular strength improved in all women, after RT (effect size (ES): 0.11–1.21 (trivial to large effects), p ˂ 0.01). Fasting plasma triacylglycerol and high-density lipoprotein-cholesterol levels slightly increased and decreased, respectively, in participants with MHO using the A/L ratio approach (ES: −0.47 to 1.07 (small to large effects), p ˂ 0.05). Circulating interleukin-6 soluble receptor decreased in both groups and soluble tumor necrosis factor receptor-1/soluble tumor necrosis factor receptor-2 in women with MUHO only, irrespective of definition (ES: −0.42 to −0.84 (small to large effects), p ˂ 0.05). Glucose–insulin homeostasis was unchanged regardless of group or definition. RT improved physical performance and body composition but had a lesser impact on cardiometabolic risk in women with obesity, irrespective of their metabolic phenotype.
Photon scattering by an electric field in noncommutative spacetime
Authors: D’Ascanio Daniela , Pisani Pablo , Wainstein Haimovichi Ulises
Published: April 2024

As is known, the existence of a small noncommutativity between coordinates would generate nonlocal self-interactions in the electromagnetic theory. To explore some consequences of this effect on the propagation of photons we consider Moyal space half-filled with a static and homogeneous electric field and analyze electromagnetic fluctuations on top of this step-like background. Both the localization of photons and the possibility of photon production by strong electric fields are addressed. Several aspects of the Klein paradox in this setup are discussed as well.
Branching problem for tensoring two Verma modules and its application to differential symmetry breaking operators
Authors: Murakami Reiji
Published: April 2024

Kobayashi–Pevzner discovered in [Differential symmetry breaking operators: II. Rankin–Cohen operators for symmetric pairs, Selecta Math. (N.S.) 22(2) (2016) 847–911, MR 3477337] that the failure of the multiplicity-one property in the fusion rule of Verma modules of [Formula: see text] occurs exactly when the Rankin–Cohen brackets vanish, and classified all the corresponding parameters. In this paper, we provide yet another characterization for these parameters, and give a precise description of indecomposable components of the tensor product. Furthermore, we discuss when the tensor products of two Verma modules are isomorphic to each other for semisimple Lie algebras [Formula: see text].
BOX DIMENSION OF FRACTAL INTERPOLATION SURFACES WITH VERTICAL SCALING FUNCTION
Authors: JIANG LAI
Published: April 2024

In this paper, we first present a simple lemma which allows us to estimate the box dimension of graphs of given functions by the associated oscillation sums and oscillation vectors. Then we define vertical scaling matrices of generalized affine fractal interpolation surfaces (FISs). By using these matrices, we establish relationships between oscillation vectors of different levels, which enables us to obtain the box dimension of generalized affine FISs under certain constraints.
Mapping exploration targets through multifractal modelling of soil geochemical data in the Xiaohongshilazi Pb–Zn–(Ag) ore district, Jilin Province, NE China
Authors: Ma Huchao , Wang Da , Bai Feng , Zhang Xiaoxuan , Wang Gaotian , Dong Saina , Wang Guilong
Published: April 2024

The Xiaohongshilazi Pb–Zn–(Ag) ore district, located in the Jizhong–Yanbian Metallogenic Belt in NE China, presents challenges in identifying geochemical anomalies and prospecting minerals due to thick covers, complex geological evolution and mining activities. To overcome these obstacles, we adopted an innovative approach that combines multifractal theory with concentration-area (C-A) modelling and local singularity analysis (LSA) to characterize the geochemical signature. Initially, factor analysis of log-transformed data was used to identify ore-forming factors, which were then modelled using C-A and LSA. Subsequently, modelling results were compared to conventional maps generated using inverse distance weighted (IDW) interpolation. Additionally, the C-A model was employed to establish thresholds for singularity indices generated by LSA for target mapping. The results revealed a close relationship between Factor 1 (F1) and mineralization. The C-A model of F1 failed to detect weak anomalies compared to the IDW-interpolated map, while LSA not only identified weak anomalies but also enhanced the detection of reliable anomalies. Three prospecting targets (PT-01, PT-02 and PT-03) were identified. Validation of PT-01 using new drillholes and existing mineralization confirms the effectiveness of targets and the accuracy of the model. Our approach provides a robust alternative for prospecting at ore districts encountering similar challenges.
Q-SupCon: Quantum-Enhanced Supervised Contrastive Learning Architecture within the Representation Learning Framework
Authors: Kottahachchi Kankanamge Don Asitha , Khalil Ibrahim
Published: April 2024

In the evolving landscape of data privacy regulations, the challenge of providing extensive data for robust deep classification models arises. The accuracy of these models relies on the amount of training data, due to the multitude of parameters that require tuning. Unfortunately, obtaining such ample data proves challenging, particularly in domains like medical applications, where there is a pressing need for robust models for early disease detection but a shortage of labeled data. Nevertheless, the classical supervised contrastive learning models, have shown the potential to address this challenge up to a certain limit, by utilizing deep encoder models. However, recent advancements in quantum machine learning enable the extraction of meaningful representations from extremely limited and simple data. Thus, replacing classical counterparts in classical or hybrid quantum-classical supervised contrastive models enhances feature learning capability with minimal data. Therefore, this work proposes the Q-SupCon model, a fully quantum-powered supervised contrastive learning model comprising a quantum data augmentation circuit, quantum encoder, quantum projection head, and quantum variational classifier, enabling efficient image classification with minimal labeled data. Furthermore, the novel model attains 80%, 60%, and 80% test accuracy on MNIST, KMNIST, and FMNIST datasets, marking a significant advancement in addressing the data scarcity challenge.
Structural Chirality and Electronic Chirality in Quantum Materials
Authors: Yan Binghai
Published: April 2024

In chemistry and biochemistry, chirality represents the structural asymmetry characterized by nonsuperimposable mirror images for a material such as DNA. In physics, however, chirality commonly refers to the spin–momentum locking of a particle or quasiparticle in the momentum space. While seemingly disconnected, structural chirality in molecules and crystals can drive electronic chirality through orbital–momentum locking; that is, chirality can be transferred from the atomic geometry to electronic orbitals. Electronic chirality provides an insightful understanding of chirality-induced spin selectivity, in which electrons exhibit salient spin polarization after going through a chiral material, and electrical magnetochiral anisotropy, which is characterized by diode-like transport. It further gives rise to new phenomena, such as anomalous circularly polarized light emission, in which the light handedness relies on the emission direction. These chirality-driven effects will generate broad impacts for fundamental science and technology applications in spintronics, optoelectronics, and biochemistry.
Automation and Augmentation: Artificial Intelligence, Robots, and Work
Authors: Lei Ya-Wen , Kim Rachel
Published: April 2024

This article reviews the literature that examines the potential, limitations, and consequences of robots and artificial intelligence (AI) in automation and augmentation across various disciplines. It presents key observations and suggestions from the literature review. Firstly, displacement effects from task automation continue to persist. However, one should not assume an unequivocally increasing efficacy of technology in automation or augmentation, especially given the declining productivity growth in high-income countries and some large emerging economies in recent decades. Jobs less likely to be negatively impacted are those that require diverse tasks, physical dexterity, tacit knowledge, or flexibility, or are protected by professional or trade associations. Despite countervailing effects, without policy intervention, automation and augmentation could widen inequality between social groups, labor and capital, and firms. Secondly, AI's promise in task automation and labor augmentation is mixed. AI tools can cause harm, and dissatisfaction and disengagement often arise from their opaqueness, errors, disregard for critical contexts, lack of tacit knowledge, and lack of domain expertise, as well as their demand for extra labor time and resources. The inadequate autonomy to override AI-based assessments further frustrates users who have to use these AI tools at work. Finally, the article calls for sociological research to specify conditions and mechanisms that ameliorate adverse consequences and enhance labor augmentation by embedding the study of automation and augmentation in concrete social and political contexts at multiple levels.
Ubiquitin-driven G protein-coupled receptor inflammatory signaling at the endosome
Authors: Cheng Norton , Pimentel Julio M. , Trejo JoAnn
Published: April 2024

G protein-coupled receptors (GPCRs) are ubiquitously expressed cell surface receptors that mediate numerous physiological responses and are highly druggable. Upon activation, GPCRs rapidly couple to heterotrimeric G proteins and are then phosphorylated and internalized from the cell surface. Recent studies indicate that GPCRs not only localize at the plasma membrane but also exist in intracellular compartments where they are competent to signal. Intracellular signaling by GPCRs is best described to occur at endosomes. Several studies have elegantly documented endosomal GPCR-G protein and GPCR-β-arrestin signaling. Besides phosphorylation, GPCRs are also posttranslationally modified with ubiquitin. GPCR ubiquitination has been studied mainly in the context of receptor endosomal-lysosomal trafficking. However, new studies indicate that ubiquitination of endogenous GPCRs expressed in endothelial cells initiates the assembly of an intracellular p38 mitogen-activated kinase signaling complex that promotes inflammatory responses from endosomes. In this mini-review, we discuss emerging discoveries that provide critical insights into the function of ubiquitination in regulating GPCR inflammatory signaling at endosomes.
Effect of the mitochondrial transaminase (GOT2) on membrane potential-sensitive respiration in mitochondria of differentiated C2C12 muscle cells
Authors: Som Ritu , Fink Brian D. , Yu Liping , Sivitz William I.
Published: April 2024

Impairment of the mitochondrial transaminase, GOT2, reduces complex II (succinate dehydrogenase, SDH)-energized respiration in C2C12 myocytes. This occurs only at low inner membrane potential and is consistent with inhibition of SDH. Incidentally, we observed that C2C12 mitochondria compared with muscle tissue mitochondria differ in sensitivity of complex II respiration to ADP and in the expression of glutamate dehydrogenase.
A Bispecific Antibody That Targets the Membrane-Proximal Region of Mesothelin and Retains High Anticancer Activity in the Presence of Shed Mesothelin
Authors: Chakraborty Anirban , Onda Masanori , O’Shea Tara , Wei Junxia , Liu Xiufen , Bera Tapan K. , Pastan Ira
Published: April 2024

Mesothelin (MSLN) is a cell-surface protein that is expressed in many cancers, which makes it a popular target for Ab-based cancer therapy. However, MSLN is shed from cancer cells at high levels via proteases that cleave at its membrane-proximal C-terminal region. Shed MSLN accumulates in patients’ fluids and tumors and can block Ab-based MSLN-targeting drugs from killing cancer cells. A previously established mAb, 15B6, binds MSLN at its protease-sensitive C-terminal region and does not bind shed MSLN. Moreover, 15B6 variable fragment (Fv)–derived chimeric antigen receptor T cells are not inhibited by shed MSLN and kill tumors in mice more effectively than mAb SS1 Fv-derived chimeric antigen receptor T cells, which bind an epitope retained in shed MSLN. In this study, we have established 15B6 Fv-derived MSLN × CD3 bispecific antibodies (BsAb) that target MSLN-expressing cancers. We identified our lead candidate BsAb 5 after screening multiple 15B6-derived BsAb formats in vitro for cytotoxic activity. BsAb 5 activates T cells to kill various cancer cell lines in a MSLN-specific manner. MSLN 296-591 His, a recombinant protein mimicking shed MSLN, does not inhibit 15B6-derived BsAb 5 but completely inhibits humanized SS1-derived BsAb 7. Furthermore, BsAb 5 inhibits and delays tumor growth and is not inhibited by MSLN 296-585 His in mice. Our findings indicate that by targeting the protease-sensitive region of MSLN, BsAb 5 has high MSLN-specific anticancer activity that is not inhibited by shed MSLN. BsAb 5 may be a promising immunotherapy candidate for MSLN-expressing cancers.
A Selective FGFR1/2 PROTAC Degrader with Antitumor Activity
Authors: Kong Ying , Zhao Xinyue , Wang Zhaofu , Yuan Siqi , Chen Sheng , Lou Shidi , Ma Shichao , Li Yunfeng , Wang Xinghao , Ge Yangfeng , Li Guobin , Yang Hongbing , Zhao Mengxi , Li Dandan , Zhang Hailong , Tan Wenfu , Wang Juan
Published: April 2024

The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.
Antitumor Activity of a Novel LAIR1 Antagonist in Combination with Anti-PD1 to Treat Collagen-Rich Solid Tumors
Authors: Rodriguez Bertha L. , Huang Jiawei , Gibson Laura , Fradette Jared J. , Chen Hung-I.H. , Koyano Kikuye , Cortez Czrina , Li Betty , Ho Carmence , Ashique Amir M. , Lin Vicky Y. , Crawley Suzanne , Roda Julie M. , Chen Peirong , Fan Bin , Kim Jeong , Sissons James , Sitrin Jonathan , Kaplan Daniel D. , Gibbons Don L. , Rivera Lee B.
Published: April 2024

We recently reported that resistance to PD-1 blockade in a refractory lung cancer–derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). Thus, we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. In this study, we report that LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist mAb, elicits myeloid inflammation and allogeneic T-cell responses by binding to LAIR1 and blocking collagen engagement. Furthermore, a mouse-reactive NGM438 surrogate antibody sensitized refractory KP mouse lung tumors to anti-PD-1 therapy and resulted in increased intratumoral CD8+ T-cell content and inflammatory gene expression. These data place LAIR1 at the intersection of stroma and suppressive myeloid cells and support the notion that blockade of the LAIR1/collagen axis can potentially address resistance to checkpoint inhibitor therapy in the clinic.
Kinesin Facilitates Phenotypic Targeting of Therapeutic Resistance in Advanced Prostate Cancer
Authors: Archer Maddison , Begemann Diane , Gonzalez-Kozlova Edgar , Nepali Prerna R. , Labanca Estefania , Shepherd Peter , Dogra Navneet , Navone Nora , Kyprianou Natasha
Published: April 2024

Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes in patients with metastatic castration–resistant prostate cancer. Previous work showed that dynamic interconversions between epithelial–mesenchymal transition to mesenchymal–epithelial transition defines the phenotypic landscape of prostate tumors, as a potential driver of the emergence of therapeutic resistance. In this study, we use in vitro and in vivo preclinical MDA PCa patient-derived xenograft models of resistant human prostate cancer to determine molecular mechanisms of cross-resistance between antiandrogen therapy and taxane chemotherapy, underlying the therapeutically resistant phenotype. Transcriptomic profiling revealed that resistant and sensitive prostate cancer C4-2B cells have a unique differential gene signature response to cabazitaxel. Gene pathway analysis showed that sensitive cells exhibit an increase in DNA damage, while resistant cells express genes associated with protein regulation in response to cabazitaxel. The patient-derived xenograft model specimens are from patients who have metastatic lethal castration–resistant prostate cancer, treated with androgen deprivation therapy, antiandrogens, and chemotherapy including second-line taxane chemotherapy, cabazitaxel. Immunohistochemistry revealed high expression of E-cadherin and low expression of vimentin resulting in redifferentiation toward an epithelial phenotype. Furthermore, the mitotic kinesin-related protein involved in microtubule binding and the SLCO1B3 transporter (implicated in cabazitaxel intracellular transport) are associated with resistance in these prostate tumors. Combinational targeting of kinesins (ispinesib) with cabazitaxel was more effective than single monotherapies in inducing cell death in resistant prostate tumors.

Implications: Our findings are of translational significance in identifying kinesin as a novel target of cross-resistance toward enhancing therapeutic vulnerability and improved clinical outcomes in patients with advanced prostate cancer.
TABLE 5 from Disparities in Access to Liver Transplant Referral and Evaluation among Patients with Hepatocellular Carcinoma in Georgia
Authors: Ross-Driscoll Katherine , Ayuk-Arrey Arrey-Takor , Lynch Raymond , McCullough Lauren E. , Roccaro Giorgio , Nephew Lauren , Hundley Jonathan , Rubin Raymond A. , Patzer Rachel
Published: April 2024

Multivariable adjusted probability of transplant referral, evaluation initiation, and evaluation completion among patients with early-stage HCC in Georgia, accounting for non-transplant cancer treatment and death as competing risks
TABLE 2 from Disparities in Access to Liver Transplant Referral and Evaluation among Patients with Hepatocellular Carcinoma in Georgia
Authors: Ross-Driscoll Katherine , Ayuk-Arrey Arrey-Takor , Lynch Raymond , McCullough Lauren E. , Roccaro Giorgio , Nephew Lauren , Hundley Jonathan , Rubin Raymond A. , Patzer Rachel
Published: April 2024

Associations between early-stage HCC patient characteristics and liver transplant referral in Georgia (n = 1,379)
Choroidal Thickness in Healthy Eyes Measured by Widefield Optical Coherence Tomography
Authors: Eslava Blanca , Bryan Sofia , Puertas Mariluz , Ruiz-Medrano Jorge , Ruiz-Moreno José M.
Published: April 2024

Introduction: The choroid and its role in posterior segment pathology have become an increasing subject of study. The objective of the present study was to analyze choroidal thickness (CT) in healthy eyes by widefield (WF) optical coherence tomography (OCT) up to the periphery and to compare the reliability of manual versus automatic measurement. Methods: Cross-sectional and noninterventional study conducted on 191 healthy eyes of 101 patients. All patients were scanned by using WF-OCT (Xephilio WF-OCT S1; Canon Corp, Tokyo, Japan). CT was measured in 2,000 μm intervals automatically using the built-in software and manually by two masked observers. All analyses were performed using the IBM-PSSS statistical software program (IBM-SPSS, v. 28.0.0.0, Chicago, IL, USA). Results: CT was measured in 100% of the sample. The mean age of the study cohort was 39.05 ± 19.06 years old. Mean subfoveal CT measured automatically was 343.67 ± 84.18 μm and manually was 336.55 ± 75.57 μm. The thickest point was located 2,000 μm from the fovea in the superior sector in 62.83% of the subjects. According to age distribution, mean CT became significantly thinner from 40 years of age. When comparing automatic and manually measuring, the intraclass correlation coefficient was excellent (p < 0.01) in all quadrants. Moreover, manual measurement interobserver agreement was excellent in all quadrants (p < 0.01). Conclusion: The automatic system is valid and serves as the basis of choroid measurement. In more than 50% of the healthy subjects, superior CT is thicker than subfoveolar CT and mean CT became significantly thinner from 40 years of age.
Modified Ileal Conduit for Pelvic Lipomatosis: Technique Description and Outcome
Authors: Xia Mancheng , Meng Chang , Zhang Peng , Tan Xiaohui , Chen Yuke , Fan Jian , Li Zhihua , Wang Bing , Zhu Hongjian , Yang Kunlin , Zhou Liqun , Feng Ninghan , Zhang Kai , Li Xuesong
Published: April 2024

Introduction: The aim of this study was to present the surgical technique and clinical outcomes of modified ileal conduit for pelvic lipomatosis (PL). Methods: From 2020 to 2022, we prospectively enrolled 9 patients with PL undergoing modified ileal conduit. The patient characteristics, perioperative variables, and follow-up outcomes as well as the description of surgical technique were reported. Results: All 9 patients successfully completed the operation. Two patients had perioperative complications of Clavien-Dindo grade I. The mean operation time and bleeding volumes were 253 ± 51.4 min and 238.9 ± 196.9 mL, with a mean postoperative follow-up time of 13.0 ± 5.6 months. The postoperative 3-month and 1-year creatinine values were significantly decreased versus the preoperative (p = 0.006 and p = 0.024). The postoperative 3-month and 1-year estimated glomerular filtration rate values were significantly increased compared with those before operation (p = 0.0002 and p = 0.018). The separation value of left renal pelvis collection system after operation was significantly reduced compared with preoperative evaluation (p = 0.023 at 3 months and p = 0.042 at 1 year) and so was the right side (p = 0.019 and p = 0.023). Conclusion: Modified ileal conduit is safe and feasible for PL. A large sample cohort with long-term follow-up is needed to evaluate the clinical outcomes of PL.
Molecular Analysis of Parthenogenetic Chimerism in a 46,XX/46,XY Patient with Idiopathic Oligoasthenoteratozoospermia
Authors: He Yunjie , Yan Yuying , Lv Yuanyuan , Zeng Jian
Published: April 2024

Introduction: Parthenogenetic chimera is an extremely rare condition in human. Very few patients with parthenogenetic chimerism with XX/XY cells have been identified. Case Presentation: We report the clinical findings and molecular analysis of chimerism with a 46,XX/46,XY karyotype in a patient presenting idiopathic oligoasthenoteratozoospermia (OAT). To clarify the mechanism of chimera formation, short tandem repeat analysis using 21 loci was carried out. Quantitation of alleles in D6S1043, D12S391, fibrinogen alpha chain, and amelogenin revealed double paternal and one maternal genetic contribution to the patient, which is consistent with a parthenogenetic chimerism. The likely mechanism of chimerism formation was also discussed, followed by a literature review. Conclusion: This is the first documented case of parthenogenetic chimerism in an adult male with XX/XY cells presenting OAT. Improved cell sampling and more sensitive and specific detection methods are necessary to identify more patients with XX/XY chimerism for systematic studies on this condition in the future.
Feature Importance Analysis and Machine Learning for Alzheimer’s Disease Early Detection: Feature Fusion of the Hippocampus, Entorhinal Cortex, and Standardized Uptake Value Ratio
Authors: Hassouneh Aya , Bazuin Bradley , Danna-dos-Santos Alessander , Acar Ilgin , Abdel-Qader Ikhlas ,   The Alzheimer’s Disease Neuroimaging Initiative
Published: April 2024

Introduction: Alzheimer’s disease (AD) is a progressive neurological disorder characterized by mild memory loss and ranks as a leading cause of mortality in the USA, accounting for approximately 120,000 deaths per year. It is also the primary form of dementia. Early detection is critical for timely intervention as the neurodegenerative process often starts 15–20 years before cognitive symptoms manifest. This study focuses on determining feature importance in AD classification using fused texture features from 3D magnetic resonance imaging hippocampal and entorhinal cortex and standardized uptake value ratio (SUVR) derived from positron emission tomography (PET) images. Methods: To achieve this objective, we employed four distinct classifiers (Linear Support Vector Classification, Linear Discriminant Analysis, Logistic Regression, and Logistic Regression Classifier with Stochastic Gradient Descent Learning). These classifiers were used to derive both average and top-ranked importance scores for each feature based on their outputs. Our framework is designed to distinguish between two classes, AD-negative (or mild cognitive impairment stable [MCIs]) and AD-positive (or MCI conversion [MCIc]), using a probabilistic neural network classifier and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Results: The findings from the feature importance highlight the crucial role of the GLCM texture features extracted from the hippocampus and entorhinal cortex, demonstrating their superior performance compared to the volume and SUVR. GLCM texture AD classification achieved approximately 90% sensitivity in identifying MCIc cases while maintaining low false positives (below 30%) when fused with other features. Moreover, the receiver operating characteristic curves validate the GLCMs’ superior performance in distinguishing between MCIs and MCIc. Additionally, fusing different types of features improved classification performance compared to relying solely on any single feature category. Conclusion: Our study emphasizes the pivotal role of GLCM texture features in early Alzheimer’s detection.
Efficacy and Challenges: Minimally Invasive Procedures for Trigeminal Neuralgia Treatment in Multiple Sclerosis – A Systematic Review and Meta-Analysis
Authors: SohrabiAsl Masoud , Shirani Mohammad , Jahanbakhshi Amin , Iranmehr Arad
Published: April 2024

Introduction: Trigeminal neuralgia (TGN) poses a therapeutic challenge, particularly within the context of multiple sclerosis (MS). This study aimed to conduct a comprehensive meta-analysis and systematic review of four less-invasive treatment modalities for TGN in MS patients, namely, gamma knife radiosurgery (GKRS), glycerol rhizotomy (GR), balloon compression (BC), and radiofrequency ablation (RFA). Methods: Single-armed meta-analyses were employed to assess the overall efficacy of each treatment, while double-armed analyses compared the efficacy between different treatment options in double-armed studies. Outcome evaluations included acute pain relief (within 1 month post-procedure), recurrence rates throughout 18 months of follow-up, and reported complication rates. Results: The meta-analysis revealed diverse outcomes for each intervention. GKRS demonstrated favorable outcomes, achieving a 77% success rate in alleviating pain among a pooled cohort of 863 patients, reinforcing its status as a viable therapeutic option. Additionally, GR, BC, and RFA exhibited efficacy, with success rates of 77%, 71%, and 80%, respectively, based on outcomes observed in 611, 385, and 203 patients. Double-armed analyses highlighted distinctions between the treatments, providing nuanced insights for clinical decision-making. Conclusion: This meta-analysis provides a comprehensive overview of less-invasive treatments for TGN in MS patients. GKRS emerges as a leading option with comparable efficacy and fewer complications. However, the study underscores the nuanced efficacy and considerations associated with GR, BC, and RFA. The findings offer valuable insights for clinicians navigating treatment choices in this challenging patient population, considering acute pain relief, recurrence rates, and complication profiles.
Development of a New Scoring System in Higher Animals for Testing Cognitive Function in the Newborn Period: Effect of Prenatal Hypoxia-Ischemia
Authors: Shi Zhongjie , Sharif Nadiya , Luo Kehuan , Tan Sidhartha
Published: April 2024

Introduction: Enhanced models for assessing cognitive function in the neonatal period are imperative in higher animals. Postnatal motor deficits, characteristic of cerebral palsy, emerge in newborn kits within our prenatal rabbit model of hypoxia-ischemia (HI). In humans, prenatal HI leads to intellectual disability and cerebral palsy. In a study examining cognitive function in newborn rabbits, we explored several questions. Is there a distinction between conditioned and unconditioned kits? Can the kits discern the human face or the laboratory coat? Do motorically normal kits, born after prenatal HI, exhibit cognitive deficits? Methods: The conditioning protocol was randomly assigned to kits from each litter. For conditioning, the same human, wearing a laboratory coat, fed the rabbit kits for 9 days before the cognitive test. The 6-arm radial maze was chosen for its simplicity and ease of use. Normally appearing kits, born after uterine ischemia at 79% or 92% term in New Zealand White rabbits, were compared to naïve kits. On postpartum day 22/23 or 29/30, the 6-arm maze helped determine if the kits recognized the original feeder from bystander (test 1) or the laboratory coat on bystander (test 2). The use of masks of feeder/bystander (test 3) assessed confounding cues. A weighted score was devised to address variability in entry to maze arms, time, and repeated-trial learning. Results: In conditioned kits, both naïve and HI kits exhibited a significant preference for the face of the feeder but not the laboratory coat. Cognitive deficits were minimal in normal-appearing HI kits. Conclusion: The weighted score was amenable to statistical manipulation.