bluuebunny/crossref_metadata_2025_split huggingface dataset:
Irgm proteins attenuate inflammatory disease in mouse models of genital
Chlamydia
infection
Authors: Dockterman Jacob , Reitano Jeffrey R. , Everitt Jeffrey I. , Wallace Graham D. , Hendrix Meghan , Taylor Gregory A. , Coers Jörn 
Published: March 2024

ABSTRACT

Chlamydiae
are obligate intracellular bacterial pathogens that may cause genital pathology via induction of destructive host immune responses. Human-adapted
Chlamydia trachomatis
causes inflammatory disease in human hosts but is easily cleared in mice, and mouse-adapted
Chlamydia muridarum
establishes a productive and pathogenic infection in murine hosts. While numerous anti-chlamydial host resistance factors have been discovered in mice and humans alike, little is known about host factors promoting host fitness independent of host resistance. Here, we show that interferon-inducible immunity-related GTPase M (Irgm) proteins function as such host factors ameliorating infection-associated sequalae in the murine female genital tract, thus characterizing Irgm proteins as mediators of disease tolerance. Specifically, we demonstrate that mice deficient for all three murine Irgm paralogs (pan-
Irgm
−/−
) are defective for cell-autonomous immunity to
C. trachomatis
, which correlates with an early and transient increase in bacterial burden and sustained hyperinflammation
in vivo
. In contrast, upon infection of pan-
Irgm
−/−
mice with
C. muridarum
, bacterial burden is unaffected, yet genital inflammation and scarring pathology are nonetheless increased, demonstrating that Irgm proteins can promote host fitness without altering bacterial burden. Additionally, pan-
Irgm
−/−
mice display increased granulomatous inflammation in genital
Chlamydia
infection, implicating Irgm proteins in the regulation of granuloma formation and maintenance. These findings demonstrate that Irgm proteins regulate pathogenic immune responses to
Chlamydia
infection
in vivo
, establishing an effective infection model to examine the immunoregulatory functions and mechanisms of Irgm proteins.

IMPORTANCE
In response to genital Chlamydia infection, the immune system mounts a proinflammatory response to resist the pathogen, yet inflammation must be tightly controlled to avoid collateral damage and scarring to host genital tissue. Variation in the human IRGM gene is associated with susceptibility to autoinflammatory diseases but its role in ameliorating inflammatory diseases caused by infections is poorly defined. Here, we use mice deficient for all three murine Irgm paralogs to demonstrate that Irgm proteins not only provide host resistance to Chlamydia infections but also limit associated inflammation in the female genital tract. In particular, we find that murine Irgm expression prevents granulomatous inflammation, which parallels inflammatory diseases associated with variants in human IRGM. Our findings therefore establish genital Chlamydia infection as a useful model to study the roles for Irgm proteins in both promoting protective immunity and limiting pathogenic inflammation.
Differentiation of keratinocytes or exposure to type 2 cytokines diminishes
S. aureus
internalization
Authors: Morgenstern Alexis R. , Peterson Liam F. , Arnold Kimberly A. , Brewer Matthew G. 
Published: March 2024

ABSTRACT

Staphylococcus aureus
is a leading cause of skin and soft tissue infections. Colonization by this bacterium is increased in individuals with chronic cutaneous diseases such as atopic dermatitis, psoriasis, and bullous pemphigoid. The greater abundance of
S. aureus
on the skin of subjects with atopic dermatitis in particular has been linked to recurrent cutaneous infections. The primary cell type of the epidermal layer of the skin is the keratinocyte, and it is thought that
S. aureus
internalized in keratinocytes associates with an increased incidence of skin infections. This study addresses whether keratinocyte differentiation and/or inflammation, two important characteristics altered in cutaneous diseases, influence bacterial internalization. To do this,
S. aureus
internalization was measured in immortalized and primary keratinocytes that were differentiated using high Ca
2+
-containing media and/or exposed to cytokines characteristic of atopic dermatitis (IL-4 and IL-13) or psoriasis (IL-17A and IL-22) skin. Our results indicate that
S. aureus
internalization is uniquely decreased upon keratinocyte differentiation, since this was not observed with another skin-resident bacterium,
S. epidermidis
. Additionally, treatment with IL-4 + IL-13 diminished bacterial internalization. We interpret this decrease as a mechanism of keratinocyte-based bacterial killing since a similar number of bacterial genomes were detected in cytokine-treated cells, but less viable internalized
S. aureus
was recovered. Finally, of the receptors reported for
S. aureus
binding/internalizing into keratinocytes, expression of the α
5
component of the α
5
β
1
integrin was in greatest accordance with the number of internalized bacteria in the context of keratinocyte differentiation.

IMPORTANCE

Individuals with chronic cutaneous diseases demonstrate heightened susceptibility for severe and recurrent infections from
Staphylococcus aureus
. What drives this altered susceptibility remains poorly understood. Previous publications have detected
S. aureus
as deep as the dermal layer of skin in subjects with atopic dermatitis, suggesting that the cutaneous environment of this disease enables deeper bacterial infiltration than occurs in healthy individuals. This observation indicates that
S. aureus
has greater opportunity to interact with multiple skin cell types in individuals with chronic inflammatory skin diseases. Identifying the characteristics of the skin that influence bacterial internalization, a common method to establish reservoirs and evade the immune response, is critical for our understanding of
S. aureus
pathogenesis. The significance of this research is the novel identification of epidermal characteristics that influence
S. aureus
internalization. With this knowledge, methods can be developed to identify patient populations at greater risk for cutaneous infections.
Incidence and predictors of restenosis following successful recanalization of non-acute internal carotid artery occlusion in 252 cases
Authors: Lu Guangdong , Wang Junqing , Wang Tao , Xu Xinjuan , Li Xin , Sun Xinyi , Wang Zhengyu , Luo Jichang , Ma Yan , Yang Bin , Gao Peng , Wang Yabing , Chen Yanfei , Liu Sheng , Jiao Liqun 
Published: March 2024

BackgroundData concerning restenosis following successful recanalization of non-acute internal carotid artery occlusion (ICAO) are scarce. This study was conducted to identify the incidence and predictors of restenosis following successful recanalization of non-acute ICAO.MethodsWe reviewed the incidence of restenosis (defined as >70% restenosis or reocclusion) among 252 consecutive patients with successful recanalization of non-acute ICAO. Baseline, imaging, and surgery-related characteristics were analyzed to assess their association with restenosis. A scoring system was developed to identify high-risk patients for restenosis.ResultsDuring a median follow-up of 12.6 months, restenosis occurred in 56 patients (22.2%), including 39 with reocclusion and 17 with >70% restenosis. The cumulative restenosis rate was 18.0% at 12 months and 24.1% at 24 months. The incidence of stroke was higher in patients with restenosis (25.0% vs 1.5%, P<0.01). Multivariate analysis showed occlusion length (5–10 cm vs <5 cm (hazard ratio (HR) 3.15, 95% confidence interval (95% CI) 1.07 to 9.29); ≥ 10 cm vs <5 cm (HR 5.01, 95% CI 1.73 to 14.49)), residual stenosis ≥30% (HR 3.08, 95% CI 1.79 to 5.30), and internal carotid artery (ICA) wall collapse (HR 1.96, 95% CI 1.12 to 3.44) as independent predictors of restenosis. Point scores proportional to model coefficients were assigned, with scores ranging from 0 to 6. Patients scoring 3–6 had a 4.00 times higher chance of developing restenosis (95% CI 2.35 to 6.79) compared with those scoring 0–2.ConclusionsNearly one in five patients experienced restenosis following successful recanalization of non-acute ICAO. Occlusion length, residual stenosis ≥30%, and ICA wall collapse were independently associated with restenosis.
Optimizing resources: financial evaluation of flow diverters versus stent assisted coiling in large and giant cerebral aneurysm management in Brazil public health system
Authors: Machado Elias Antônio Tanus , Batista Savio , Braga Fausto de Oliveira , Alves Filho Cesar Augusto Ferreira , Almeida Filho Jose Alberto , Lopes Plínio Gabriel , Cartobei Carlos Leandro , Oliveira Leonardo de Barros , Pereira Paulo José da Mata , Niemeyer Filho Paulo 
Published: March 2024

BackgroundCerebral aneurysms, especially large and giant aneurysms, pose challenges in neurointerventional surgery. Treatment choices involve clinical presentation, aneurysm details, and global resource variations. Neurointerventional methods, while innovative, may be cost restrictive in certain regions. In public healthcare, cost is crucial, notably in countries like Brazil. This study examines the device specific cost estimation of flow diverters (FD) and traditional stent assisted coiling (SAC) for large and giant cerebral aneurysms, providing insights into optimizing neurosurgical interventions within the Brazilian public health system’s unique challenges.MethodsA comprehensive retrospective analysis was conducted at our medical center of cases of large and giant aneurysms treated between 2013 and 2023. Determination of the estimated number of coils for aneurysms previously treated with FDs at our center was made, with the cost of each case, and the difference between both treatments was calculated.ResultsWe investigated the profiles of 77 patients: 40 had large aneurysms (51.9%) and 37 had giant aneurysms (48.1%). Large aneurysms had a mean cost difference of US$274 (standard deviation (SD) $2071), underscoring the device specific cost estimation of FDs over SAC in their treatment. For giant aneurysms, the mean cost difference increased to $6396 (SD $2694), indicating FDs as the more economically sound choice.ConclusionOur study indicated that, for the treatment of giant aneurysms and some large aneurysms, the FD intervention was more economical than SAC.
Circuit-based neuromodulation enhances delayed recall in amnestic mild cognitive impairment
Authors: Ma Jie , Wu Jia-Jia , Xing Xiang-Xin , Xue Xin , Xiang Yun-Ting , Zhen Xiao-Min , Li Jian-Hua , Lu Juan-Juan , Zhang Jun-Peng , Zheng Mou-Xiong , Hua Xu-Yun , Xu Jian-Guang 
Published: March 2024

BackgroundThis study aimed to investigate the efficacy of circuits-based paired associative stimulation (PAS) in adults with amnestic mild cognitive impairment (aMCI).MethodsWe conducted a parallel-group, randomised, controlled clinical trial. Initially, a cohort of healthy subjects was recruited to establish the cortical-hippocampal circuits by tracking white matter fibre connections using diffusion tensor imaging. Subsequently, patients diagnosed with aMCI, matched for age and education, were randomly allocated in a 1:1 ratio to undergo a 2-week intervention, either circuit-based PAS or sham PAS. Additionally, we explored the relationship between changes in cognitive performance and the functional connectivity (FC) of cortical-hippocampal circuits.ResultsFCs between hippocampus and precuneus and between hippocampus and superior frontal gyrus (orbital part) were most closely associated with the Auditory Verbal Learning Test (AVLT)_N5 score in 42 aMCI patients, thus designated as target circuits. The AVLT_N5 score improved from 2.43 (1.43) to 5.29 (1.98) in the circuit-based PAS group, compared with 2.52 (1.44) to 3.86 (2.39) in the sham PAS group (p=0.003; Cohen’s d=0.97). A significant decrease was noted in FC between the left hippocampus and left precuneus in the circuit-based PAS group from baseline to postintervention (p=0.013). Using a generalised linear model, significant group×FC interaction effects for the improvements in AVLT_N5 scores were found within the circuit-based PAS group (B=3.4, p=0.017).ConclusionsCircuit-based PAS effectively enhances long-term delayed recall in adults diagnosed with aMCI, which includes individuals aged 50–80 years. This enhancement is potentially linked to the decreased functional connectivity between the left hippocampus and left precuneus.Trial registration numberChiCTR2100053315; Chinese Clinical Trial Registry.
Juçara (Euterpe edulis Martius) improves time-to-exhaustion cycling performance and increased reduced glutathione: a randomized, placebo-controlled, crossover, and triple-blind study
Authors: Copetti Cândice Laís Knöner , Diefenthaeler Fernando , Lanferdini Fábio Juner , Dambrós Betina Fernanda , Marques Bruna Soares , da Silva Edson Luiz , Vieira Francilene Gracieli Kunradi , Willems Mark Elisabeth Theodorus , Pietro Patricia Faria Di 
Published: March 2024

To examine the effects of 7-days juçara powder (JP) intake on oxidative stress biomarkers and endurance and sprint cycling performances. In a randomized, placebo-controlled, crossover, and triple-blind study, 20 male trained cyclists were assigned to intake 10 g of JP (240 mg anthocyanins) or placebo (PLA) for 7 days and performed a cycling time-to-exhaustion (TTE). A 5 s cycling sprint was performed before and after the cycling TTE. Blood oxidative stress biomarkers and lactate concentration where evaluated 1 h before (T-1), immediately after (T0), and 1 h after (T1) the cycling TTE. The mean duration time for the cycling TTE was 8.4 ± 6.0% (63 ± 17 s) longer in the JP condition (JP: 751 ± 283 s) compared to PLA (688 ± 266 s) ( P < 0.019). Two-way repeated measures Analysis of variance showed an increase in the JP condition for reduced glutathione (GSH) ( P = 0.049) at T0 ( P = 0.039) and T1 ( P = 0.029) compared to PLA with a moderate effect size at T0 ( d = 0.61) and T1 ( d = 0.57). Blood lactate levels increased over time in both conditions ( P ≤ 0.001). No differences were observed for the post-TTE sprint fatigue index, total phenols, protein carbonyls, and glutathione peroxidase activity. Seven-day intake of JP improved cycling endurance performance and increased GSH levels but had no effect on lactate and cycling sprint-induced fatigue.
Oncogenic KRAS Induces Arginine Auxotrophy and Confers a Therapeutic Vulnerability to SLC7A1 Inhibition in Non–Small Cell Lung Cancer
Authors: Gai Xiameng , Liu Yingluo , Lan Xiaojing , Chen Luoyi , Yuan Tao , Xu Jun , Li Yize , Zheng Ying , Yan Yiyang , Yang Liya , Fu Yixian , Tang Shuai , Cao Siyuwei , Dai Xiaoyang , Zhu Hong , Geng Meiyu , Ding Jian , Pu Congying , Huang Min 
Published: March 2024

Abstract

The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation of the underlying mechanism by which oncogenic signaling mediates urea cycle reprogramming could help identify targetable metabolic vulnerabilities. In this study, we discovered that oncogenic activation of KRAS in non–small cell lung cancer (NSCLC) silenced the expression of argininosuccinate synthase 1 (ASS1), a urea cycle enzyme that catalyzes the production of arginine from aspartate and citrulline, and thereby diverted the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication. Specifically, KRAS signaling facilitated a hypoacetylated state in the promoter region of the ASS1 gene in a histone deacetylase 3–dependent manner, which in turn impeded the recruitment of c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cells impaired the biosynthesis of arginine and rendered a dependency on the arginine transmembrane transporter SLC7A1 to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models inhibited KRAS-driven NSCLC growth. Together, these findings uncover the role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability for treating KRAS-mutant NSCLC.

Significance:
ASS1 deficiency is induced by mutant KRAS in NSCLC to facilitate DNA synthesis and creates a dependency on SLC7A1, revealing dietary arginine restriction and SLC7A1 inhibition as potential therapeutic strategies.
ATG-101 Is a Tetravalent PD-L1×4-1BB Bispecific Antibody That Stimulates Antitumor Immunity through PD-L1 Blockade and PD-L1–Directed 4-1BB Activation
Authors: Yuwen Hui , Wang Huajing , Li Tengteng , Ren Yijing , Zhang Yun-kai , Chen Peng , Sun Ao , Bian Gang , Li Bohua , Flowers David , Presler Marc , Subramanian Kalyanasundaram , Xue Jia , Wang Jingjing , Lynch Kevin , Mei Jay , He Xiaowen , Shan Bo , Hou Bing 
Published: March 2024

Abstract

Immune checkpoint inhibitors (ICI) have transformed cancer treatment. However, only a minority of patients achieve a profound response. Many patients are innately resistant while others acquire resistance to ICIs. Furthermore, hepatotoxicity and suboptimal efficacy have hampered the clinical development of agonists of 4-1BB, a promising immune-stimulating target. To effectively target 4-1BB and treat diseases resistant to ICIs, we engineered ATG-101, a tetravalent "2+2″ PD-L1×4-1BB bispecific antibody. ATG-101 bound PD-L1 and 4-1BB concurrently, with a greater affinity for PD-L1, and potently activated 4-1BB+ T cells when cross-linked with PD-L1–positive cells. ATG-101 activated exhausted T cells upon PD-L1 binding, indicating a possible role in reversing T-cell dysfunction. ATG-101 displayed potent antitumor activity in numerous in vivo tumor models, including those resistant or refractory to ICIs. ATG-101 greatly increased the proliferation of CD8+ T cells, the infiltration of effector memory T cells, and the ratio of CD8+ T/regulatory T cells in the tumor microenvironment (TME), rendering an immunologically “cold” tumor “hot.” Comprehensive characterization of the TME after ATG-101 treatment using single-cell RNA sequencing further revealed an altered immune landscape that reflected increased antitumor immunity. ATG-101 was well tolerated and did not induce hepatotoxicity in non-human primates. According to computational semimechanistic pharmacology modeling, 4-1BB/ATG-101/PD-L1 trimer formation and PD-L1 receptor occupancy were both maximized at around 2 mg/kg of ATG-101, providing guidance regarding the optimal biological dose for clinical trials. In summary, by localizing to PD-L1–rich microenvironments and activating 4-1BB+ immune cells in a PD-L1 cross-linking–dependent manner, ATG-101 safely inhibits growth of ICI resistant and refractory tumors.

Significance:
The tetravalent PD-L1×4-1BB bispecific antibody ATG-101 activates 4-1BB+ T cells in a PD-L1 cross-linking–dependent manner, minimizing the hepatotoxicity of existing 4-1BB agonists and suppressing growth of ICI-resistant tumors.
See related commentary by Ha et al., p. 1546
Oncogenic Cell Tagging and Single-Cell Transcriptomics Reveal Cell Type–Specific and Time-Resolved Responses to Vhl Inactivation in the Kidney
Authors: Kurlekar Samvid , Lima Joanna D.C.C. , Li Ran , Lombardi Olivia , Masson Norma , Barros Ayslan B. , Pontecorvi Virginia , Mole David R. , Pugh Christopher W. , Adam Julie , Ratcliffe Peter J. 
Published: March 2024

Abstract

Defining the initial events in oncogenesis and the cellular responses they entrain, even in advance of morphologic abnormality, is a fundamental challenge in understanding cancer initiation. As a paradigm to address this, we longitudinally studied the changes induced by loss of the tumor suppressor gene von Hippel Lindau (VHL), which ultimately drives clear cell renal cell carcinoma. Vhl inactivation was directly coupled to expression of a tdTomato reporter within a single allele, allowing accurate visualization of affected cells in their native context and retrieval from the kidney for single-cell RNA sequencing. This strategy uncovered cell type–specific responses to Vhl inactivation, defined a proximal tubular cell class with oncogenic potential, and revealed longer term adaptive changes in the renal epithelium and the interstitium. Oncogenic cell tagging also revealed markedly heterogeneous cellular effects including time-limited proliferation and elimination of specific cell types. Overall, this study reports an experimental strategy for understanding oncogenic processes in which cells bearing genetic alterations can be generated in their native context, marked, and analyzed over time. The observed effects of loss of Vhl in kidney cells provide insights into VHL tumor suppressor action and development of renal cell carcinoma.

Significance:
Single-cell analysis of heterogeneous and dynamic responses to Vhl inactivation in the kidney suggests that early events shape the cell type specificity of oncogenesis, providing a focus for mechanistic understanding and therapeutic targeting.
Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer
Authors: Harrold Emily , Keane Fergus , Walch Henry , Chou Joanne F. , Sinopoli Jenna , Palladino Silvia , Al-Rawi Duaa H. , Chadalavada Kalyani , Manca Paolo , Chalasani Sree , Yang Jessica , Cercek Andrea , Shia Jinru , Capanu Marinela , Bakhoum Samuel F. , Schultz Nikolaus , Chatila Walid K. , Yaeger Rona 
Published: March 2024

Abstract

Purpose:
Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance.

Experimental Design:
We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT).

Results:
All patients stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. &lt;3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases.

Conclusions:
Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.