bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A015: A synergistic combination of a novel mTORC1-activator with proteasome inhibitor confers a remission in acute myeloid leukemia
Authors: Pattanayak Shakti Prasad , Sunita Priyashree , Hajihassani Omid , Fisher-Wellman Kelsey , Wald David , Eriksson Leif A , Tirosh Boaz
Published: October 2024

Despite the well-characterized oncogenic properties of mTORC1, in the presence of chemotherapy or other stress conditions, the suppression of mTORC1 promotes survival and bestows tumors with drug resistance. While highly potent inhibitors of mTORC1 were developed, small molecules that activate mTORC1 directly are lacking. The best way to activate mTORC1 is by suppressing its negative regulator, the tuberous sclerosis complex, which comprises TSC1, TSC2, and TBC1D7. We discovered that, deleting TSC2 upsurged the sensitivity of multiple myeloma cells to proteasome inhibitors (PI s). To replicate this pharmacologically, we designed in silico docking and additional chemical modifications to create AcTor, a potential first-of-its-kind TSC2 inhibitor. When AcTor was used in combination with the proteasome inhibitor ixazomib (IXZ), we identified a significant boost in cytotoxic activity in multiple myeloma cells. The combination had an even stronger effect in various acute myeloid leukemia (AML) cell lines. AcTor and IXZ together led to a rapid loss of mitochondrial activity in AML cells, specifically affecting complex IV of the electron transport chain and generating ROS. In animal models, AcTor alone accelerated AML growth, which aligns with mTORC1 activation. However, when combined with IXZ for three weeks, the growth of AML was inhibited, and the leukemic cells underwent apoptosis. This effect was perceived in both peripheral blast cells and the leukemic stem cells in the bone marrow, which are particularly challenging to eliminate. In a relapse model of AML, the AcTor/IXZ treatment sustained to be effective even after the tumor reoccurred. We suggest that treatment courses with AcTor and IXZ could offer a lasting anti-AML benefit, both before and after relapse.

Citation Format: Shakti Prasad Pattanayak, Priyashree Sunita, Omid Hajihassani, Kelsey Fisher-Wellman, David Wald, Leif A Eriksson, Boaz Tirosh. A synergistic combination of a novel mTORC1-activator with proteasome inhibitor confers a remission in acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A015.
Abstract A026: Lysosomal ion gradients are key determinants of T cell metabolism and function
Authors: Jenkins Chelsea , Briones Jessica , Eil Robert MD
Published: October 2024

We discovered that high extracellular potassium (↑[K+]e) within tumors limits T cell effector function and exhaustion. Moreover, the existing model of K+ transport in T cells could not account for our results. Specifically, ↑[K+]e constrained T cell activation and exhaustion independent of its impact upon membrane potential (Vm) or Ca2+ influx. Rather, ↑[K+]e controlled T cell state by elevating intracellular K+ ([K+]i), limiting Akt-mTOR signaling and inducing a state of autophagy despite exogenous nutrient sufficiency (Eil Nature 2016 & Science 2019). Thus, T cell ion transport is relevant to antitumor function but poorly understood. To apply ionic reprogramming as a means to advance cancer immunotherapy, we performed an in vivo CRISPR Cas9 screen targeting ion transporters we found to be expressed across T cell state. We transduced spCas9 OT-I TCR transgenic CD8+ T cells with retroviral particles encoding a custom pool of sgRNAs targeting ion transporters expressed in CD8 T cells (133 ion transporters with 6 sgRNAs per target) that we then transferred to B16 (murine melanoma)-OVA bearing mice. Our analyses identified numerous transmembrane and organellar ion transporters not previously recognized to have a role in T cell behavior as critical regulators of T cell function. Those transporters whose genetic disruption impacted T cell persistence in tumors converged on maintenance cytoplasmic K+ concentration and organellar transporters of Na+, H+, and K+. The importance of cytoplasmic K+ was apparent in the impact of Atp1a1 disruption (α subunit of the Na+/K+ ATPase), resulting in a severe defect of persistence in both primary tumor and lymphoid sites. The provision of exogenous K+ restored intracellular levels in Atp1a1-deficient T cells and prevented the accumulation of toxic metabolites (ROS; Collier & Eil, Cancer Immunol Res 2023). Conversely, enhanced Na+/ K+ ATPase expression and ↑[K+]e increased the in vivo persistence of CD8 T cells in vivo. The impact of numerous additional sgRNAs from our screen highlighted the previously unrecognized importance of endolysosomal transporters of Na+, H+, and K+ in T cell function within tumors. Moreover, ongoing proteomic analysis of CD8+ T cells in ↑[K+]e also highlights the relationship between endolysosome metabolism balance. These findings encourage a reconsideration of cytoplasmic and endolysosomal ion gradients in cellular metabolism to inform novel therapeutic strategies targeting T cell ion transport in tumors. Additional translational relevant questions include the impact of K+ gradients within tumors upon the function of other types of immune cells.

Citation Format: Chelsea Jenkins, Jessica Briones, Robert MD Eil. Lysosomal ion gradients are key determinants of T cell metabolism and function [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A026.
Abstract A032: KRAS mutations have distinct effects on the tumor immune microenvironment in pancreatic cancer
Authors: Wenger Andrew , Baron Tal , Vega-Perez Adrian , Sisso Whitney , Zafra Maria Paz , Dow Lukas , Siolas Despina
Published: October 2024

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with abysmal survival rates. The highly immunosuppressive microenvironment of PDAC poses a major barrier to effective therapy. KRAS mutations are near-ubiquitous in PDAC, and studies indicate clinical outcomes vary depending on the specific KRAS genotype. Given that tumor genotype can shape the immune cell composition of tumors, we examined the immune cell composition of pancreatic tumors with specific KRAS mutations, focusing on KRASG12D mutations (representing 40% of PDAC cases which have the worst prognosis) and KRASG12R mutations (which make up 20% of PDAC cases and have a better prognosis). Orthotopically implanted Kras G12R/+ ;Trp53 KO mouse pancreatic tumors have a distinct immune profile in comparison to Kras G12D/+ ;Trp53 KO tumors, characterized by an influx of intratumoral CD3+ T cells and mature dendritic cells. Selective depletion of CD4+ T cells induces a rapid progression in KRASG12R, but not KRASG12D mouse tumors. RNA sequencing of KRASG12R tumor cells revealed enrichment of Type I interferon (IFN) pathways accompanied by related chemokines, CXCL9 and CXCL10 in comparison to KRASG12D tumors. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in inflammatory pathways in KRASG12R tumors. Collectively, these data link the KRASG12R mutation to an immunogenic role that is distinct from KRASG12D tumors.

Citation Format: Andrew Wenger, Tal Baron, Adrian Vega-Perez, Whitney Sisso, Maria Paz Zafra, Lukas Dow, Despina Siolas. KRAS mutations have distinct effects on the tumor immune microenvironment in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A032.
Abstract B015: Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma
Authors: Krishnan Shanmugarajan , Lee Somin , Amoozgar Zohreh , Subudhi Sonu , Kumar Ashwin S. , Posada Jessica , Lindeman Neal , Lei Pinji , Duquette Mark , Huang Peigen , Andersson Patrik , Datta Meenal , Munn Lance L. , Fukumura Dai , Jain Rakesh K.
Published: October 2024

Immune checkpoint blockers, including anti-PD-1 (αPD1), have failed in multiple phase III clinical trials in glioblastoma (GBM), a malignant brain tumor with a median survival of <2 years with current treatments. Wnt signaling plays a crucial role in multiple developmental processes and contributes to limited treatment outcomes of several malignancies, including GBM. Wnt signaling aids GBM progression by maintaining stemness, promoting epithelial-mesenchymal transition, and inducing chemoresistance. Preclinical evidence indicates that Wnt signaling may contribute to αPD1 resistance in extracranial tumors. However, its pertinence in the failure of αPD1 in GBM is unknown. In our study, we identified Wnt7b, upregulated in GBM patients, is a determinant of resistance to αPD1 therapy in a clinically relevant GBM murine model with abundant GSCs. Increased levels of Wnt7b and β-catenin correlated with resistance to αPD1 therapy. We hypothesized that Wnt inhibition could potentiate αPD1 therapy by reprogramming the immunosuppressive tumor microenvironment (TME) to an immune-stimulatory state. We orthotopically implanted a stem-rich syngeneic mouse GBM cell line, GSC005, into immunocompetent mice, then tracked tumor growth and analyzed tumor and immune cell subpopulations using Western blot, qPCR, and immunohistochemistry and flow cytometry. Combining a porcupine inhibitor (WNT974) with αPD1 therapy enhanced anti-tumor immune responses and extended the median survival of mice with orthotopic GBM from 25 to 59 days, with 25% cured. Furthermore, this combination reprogrammed the TME, increasing antigen-presenting DC3-like dendritic cells and reducing granulocytic myeloid-derived suppressor cells (gMDSCs). Moreover, it increased the Ki67+CD8/Ki67+Treg (regulatory T cell) ratio, shifting the CD8 balance towards an anti-tumor immune response. Interestingly, resistance to the combination therapy was associated with an increase in monocytic MDSCs (mMDSCs). Our preclinical findings provide compelling data and rationale to test WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling.

Citation Format: Shanmugarajan Krishnan, Somin Lee, Zohreh Amoozgar, Sonu Subudhi, Ashwin S. Kumar, Jessica Posada, Neal Lindeman, Pinji Lei, Mark Duquette, Peigen Huang, Patrik Andersson, Meenal Datta, Lance L. Munn, Dai Fukumura, Rakesh K. Jain. Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B015.
Abstract B024: Causal Association between Wnt/β-catenin Gene expression with Cervical Cancer Risk: Two Sample Mendelian Randomization (MR)
Authors: Jee Yongho , Ju Woong
Published: October 2024

Background: Increasing evidence indicates that Wnt/β-catenin signaling, one of the best-characterized cancer drivers, promotes cancer progression by regulating the tumor-immune cycle. This study aims to test this hypothesis using Mendelian Randomization (MR), which can infer causality free from confounding factors. Methods: We utilized the Icelandic deCODE Genetics dataset (deCODE), published by Ferkingstad et al. (2021), which analyzes genetic variations, plasma proteins, and diseases in a cohort of 35,559 Icelandic individuals. Additionally, we used the Biobank Japan (BBJ) dataset, a large-scale biobank comprising genetic and biomarker information from approximately 200,000 Japanese individuals. Genetic variations related to the protein quantitative trait loci (pQTL) for Wnt/β-catenin genes (specifically WNT10A) were identified in the deCODE dataset. Corresponding SNPs associated with cervical cancer risk were identified in the BBJ dataset. We examined the pQTL-related single nucleotide polymorphisms (SNPs) of Wnt/β-catenin genes. Two-sample MR was performed to infer causality between Wnt/β-catenin pQTL expression levels and cervical cancer risk using the SNPs identified in the BBJ biobank. Results Before removing outliers, the analysis included 9 SNPs related to the pQTL expression of WNT10A. Using inverse variance weighting, the odds ratio (OR) was calculated as 1.19 (0.71-2.00, 95% confidence interval, p-value: 0.5044), indicating no statistically significant causality. After removing duplicated SNPs and conducting Linkage Disequilibrium (LD) clumping, 7 SNPs were included in the final analysis. The effect of WNT10A on cervical cancer was recalculated using inverse variance weighting, yielding an OR of 1.21 (0.79-1.84, 95% confidence interval, p-value: 0.3767), still indicating no statistically significant causality. Conclusions This study highlights the application of MR, which is robust against confounding variables, to explore the causal association between Wnt/β-catenin pQTL expression and cervical cancer risk. While our results do not support a significant causal relationship, the use of MR provides valuable insights and has public health implications for discovering new drug targets or biomarkers for prevention or treatment.

Citation Format: Yongho Jee, Woong Ju. Causal Association between Wnt/β-catenin Gene expression with Cervical Cancer Risk: Two Sample Mendelian Randomization (MR) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B024.
Abstract B039: Elucidating the tumor-driven mechanisms of resistance to immunotherapies in pancreatic cancer through in vivo CRISPR/Cas9 knockout screening
Authors: Froese Julia , Whittaker Charlie , Leclerc Paul , Langenbucher Adam , Hellinger Riley , Goulet Daniel , Hemann Michael T.
Published: October 2024

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death by 2030. PDAC lacks effective treatment options and innovative strategies for therapeutic intervention are urgently needed. Chimeric Antigen Receptor (CAR)-T cell therapy has shown remarkable success in treating hematologic malignancies, yet achieving efficacy in solid tumors remains a significant challenge. Early results from clinical trials show limited efficacy of CAR T-cell therapy in PDAC. To uncover tumor-intrinsic mechanisms of resistance to CAR T-cell therapy in vivo, we performed iterative CRISPR/Cas9-based pooled screens in a fully immunocompetent, orthotopic model of PDAC. We identified a variety of genes influencing CAR T-cell treatment efficacy. In particular, loss of genes involved in redox biology and oxidative stress sensitized PDAC tumors to CAR T-cell therapy in vivo. Additionally, single-cell RNA sequencing of PDAC tumors subjected to CAR T-cell therapy unveiled a distinct subset of tumor cells resilient to the treatment, characterized by changes in oxidative stress. Our findings indicate a potential avenue for therapeutic synergy by targeting pathways involved in oxidative stress to increase the efficacy of CAR T cell therapy in PDAC.

Citation Format: Julia Froese, Charlie Whittaker, Paul Leclerc, Adam Langenbucher, Riley Hellinger, Daniel Goulet, Michael T. Hemann. Elucidating the tumor-driven mechanisms of resistance to immunotherapies in pancreatic cancer through in vivo CRISPR/Cas9 knockout screening [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B039.
Abstract B052: Recombinant Listeria-Monocytogenes Vaccine Induces Anti-tumor Immune Response in Inflammatory Cell Death Machinery-Deficient Mice
Authors: Olagunju Abolaji S , Victor Sardinha Andrew Diniz , Amarante-Mendes Gustavo P.
Published: October 2024

Recombinant Listeria monocytogenes (LM)-based cancer vaccines show an optimistic immunotherapeutic approach for treating cancer. Employing LM's unique capacity to stimulate strong and targeted anticancer immune responses and activation of in vivo antigen-specific CD8+ T cells. LM has been shown to trigger inflammatory and/or immunogenic cell death processes, including necroptosis and pyroptosis, to modulate immunological responses positively. Nevertheless, the consequence of the deficiency of the host inflammatory cell death machinery on the efficacy of LM to induce an effective anti-tumor immune response remains unresolved. Therefore, we projected that a deficiency in regulatory or effector molecules involved in necroptosis or pyroptosis would interfere with the host response to LM and the consequent stimulation of CD8+ T cell-mediated immunity. To test our hypothesis, wild-type (WT), caspase-1/11-/-, gsdmd-/-, ripk3-/-, and mlkl-/-C57Bl/6 mice were vaccinated with recombinant L. monocytogenes carrying the ovalbumin gene (LM.OVA) intravenously. An in vivo cytotoxicity assay was carried out to assess the efficiency of target cell elimination by OVA-specific CD8+ T lymphocytes. In addition, the in vivo growth of B16F0 and B16F0.OVA melanoma cell lines were measured in control and vaccinated mice. Our findings showed that Caspase-1/11 and GSDMD help control LM-OVA infection, but a single deficiency of either of the molecules did not affect the LM-OVA-induced antigen-specific anti-tumor response.

Citation Format: Abolaji S Olagunju, Andrew Diniz Victor Sardinha, Gustavo P. Amarante-Mendes. Recombinant Listeria-Monocytogenes Vaccine Induces Anti-tumor Immune Response in Inflammatory Cell Death Machinery-Deficient Mice [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B052.
Stratum Corneum Hydration Measurements with a Bluetooth Wireless Probe: A Real-Life Study at Home Compared to Measurements under Laboratory Conditions
Authors: Fluhr Joachim W. , Voisard Agnès , Nikolaeva Dessyslava G. , Herzog Leonie , Wiora Georg , Gayer Jeremias , Lehmann Nicolas J. , Darlenski Razvigor
Published: October 2024

Introduction: Non-invasive measurement of the stratum corneum hydration (SCH) with capacitance-based instrumentation is established in dermatological and cosmetic studies. We wanted to test the reliability of non-invasive self-measurements for SCH performed under real-life conditions by volunteers with a Bluetooth-based (wireless) probe Corneometer® (CM 825i) transmitting the data via a smartphone application to a central server. Probes and smartphones communicated using Bluetooth Low Energy. Data from the smartphone were securely transferred to a remote server in a different country with TLS encryption using HTTPS protocols. CM 825i values were correlated with the established CM 825 under laboratory conditions. The primary endpoint was the correlation of the two probes. Secondary endpoints were the coefficient of variation (CV) and delta values (before and after treatment). Methods: Eighteen healthy volunteers (f: 8; m: 10) participated in the prospective observational study. The real-world home use of the wireless CM 825i was performed before and after treatments with base cream DAC for 7 days. Results: Both instruments showed a significant and relevant correlation (p < 0.0001; Spearman coefficient of r = 0.8647). CM 825i and CM 825 differentiate significantly between normal and high SCH. Both devices showed comparable robustness in repeated measurements with a CV between 5.6% and 9.2%. Conclusion: We could show a significant correlation between both devices and a comparable differentiation between low and high SCH and comparable CVs. The real-life use demonstrated adequate acquiring and transmitting of in vivo data to a smartphone and subsequently transmitting to the secure server with low numbers of missed transmissions (<0.2%) and missed measurements (<5%).
Targeting Lipid Metabolism in Obese Asthma: Perspectives and Therapeutic Opportunities
Authors: Wang Shanshan , Zhao Jianping , Xie Jungang
Published: October 2024

Background: Obese asthma represents a unique phenotype of asthma characterized by severe symptoms, poor medication controls, increased frequency of exacerbations, and an overall diminished quality of life. Numerous factors, including the complex interactions between environment, mechanical processes, inflammatory responses, and metabolites disturbance, contribute to the onset of obese asthma. Summary: Notably, multiple metabolomics studies in the last several years have revealed the significant abnormalities in lipid metabolism among obese asthmatic patients. Several bioactive lipid messengers participate in the development of obese asthma has also been observed. Here, we present and discuss the latest advances regarding how bioactive lipid molecules contribute to the pathogenic process and mechanisms underlying obese asthma. The key roles of potentially significant effector cells and the pathways by which they respond to diverse lipid metabolites are also described. We finally summarize current lipid-related therapeutic options for the treatment of obese asthma and discuss their application prospects. Key Messages: This review underscores the impacts of abnormal lipid metabolism in the etiopathogenesis of obese asthma and asks for further investigation to elucidate the intricate correlations among lipids, obesity, and asthma.
A New Case with Weaver Syndrome: Delineating Natural Course and Growth Pattern, Further Clarifying Clinical Phenotype
Authors: Ünsal Yağmur , Yıldırım Nalan , Buluş Ayşe Derya , Kılıç Esra
Published: October 2024

Introduction: Weaver syndrome, rare syndromic cause of tall stature, presents with overgrowth, accelerated skeletal maturation, dysmorphic features, and camptodactly. Despite expanding knowledge and widespread use of genetic tests, differential diagnosis of tall statue may be challenging, complicating follow-up. Here we describe a patient with a variant in EZH2, underlining presenting features and natural course. Case Presentation: Twenty-month-old girl consulted for tall stature was born at term (birthweight: 2,600 g [−0.8 SDS], birth length: 54 cm [2.4 SDS]) as the third child of non-consanguineous parents. Without any other complaints, she was 15.2 kg (2.5 SDS) and her height was 95 cm (3.1 SDS). She was proportionately tall compared to her parents (target height: 156 cm [−1.1 SDS]). Endocrine evaluation did not reveal pathology, growth traced parallel to 97th percentile of growth curve. Karyotype analysis and fibrillin gene analysis were normal. As she had mild intellectual disability and minor dysmorphic features (broad forehead, mild hypertelorism, long philtrum, thin upper lip and a prominent chin dimple, bilateral camptodactyly), whole exome analysis including copy number variant changes that revealed a heterozygous variant on EZH2 was performed when she was 14 years old. Weaver syndrome was diagnosed. Conclusion: Tall stature, height SDS exceeding target height SDS, tall stature at birth, normal growth rate, minor dysmorphic features, and mild intellectual disability should prompt syndromic etiology of tall stature. Further genetic analysis should be implemented. Diagnosis of rare syndromes is crucial for defining prognosis, organ involvement, and natural course, avoiding unnecessary endocrine investigations.
Inference-Based Cognitive Behavioral Therapy versus Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder: A Multisite Randomized Controlled Non-Inferiority Trial
Authors: Wolf Nadja , van Oppen Patricia , Hoogendoorn Adriaan W. , van den Heuvel Odile A. , van Megen Harold J.G.M. , Broekhuizen Aniek , Kampman Mirjam , Cath Daniëlle C. , Schruers Koen R.J. , van Es Saskia M. , Opdam Tamara , van Balkom Anton J.L.M. , Visser Henny A.D.
Published: October 2024

Introduction: Although cognitive behavioral therapy (CBT) effectively treats obsessive-compulsive disorder (OCD), many patients refuse CBT or drop out prematurely, partly because of anxiety regarding exposure and response prevention (ERP) exercises. Inference-based cognitive behavioral therapy (I-CBT) focuses on correcting distorted inferential thinking patterns, enhancing reality-based reasoning, and addressing obsessional doubt by targeting underlying dysfunctional reasoning, without incorporating an ERP component. We hypothesized that I-CBT would be non-inferior to CBT. Additionally, we hypothesized that I-CBT would be more tolerable than CBT. Methods: 197 participants were randomly assigned to 20 sessions CBT or I-CBT and assessed at baseline, posttreatment, and 6 and 12 months’ follow-up. The primary outcome was OCD symptom severity measured using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS; non-inferiority margin: 2 points). The secondary outcome, treatment tolerability, was assessed using the Treatment Acceptability/Adherence Scale (TAAS). A linear mixed-effects model was used to assess the non-inferiority of the primary outcome and superiority of secondary outcomes. Results: Statistically significant within-group improvements in the primary and secondary outcomes were observed in both treatments. No statistically significant between-group differences in Y-BOCS were found at any assessment point, but the confidence intervals exceeded the non-inferiority threshold, making the results inconclusive. The estimated mean posttreatment TAAS score was significantly higher in the I-CBT group than in the CBT group. Conclusion: While both CBT and I-CBT are effective for OCD, whether I-CBT is non-inferior to CBT in terms of OCD symptom severity remains inconclusive. Nevertheless, I-CBT offers better tolerability and warrants consideration as an alternative treatment for OCD.
Propafenone-Induced Cholestatic Liver Injury: When Diagnosis Does Not Skip a Beat
Authors: Ferreira Ana Isabel , Macedo Silva Vítor , Arieira Cátia , Xavier Sofia , Magalhães Joana , Cotter José
Published: October 2024

Introduction: Propafenone is a widely used class Ic antiarrhythmic drug that is mainly metabolised by the liver. Hepatotoxicity associated with propafenone is rare, with only a few clinical cases reported in the literature. Case Presentation: We presented a case of propafenone-related hepatotoxicity, with cholestatic liver injury and development of jaundice and pruritus within 3 to 4 weeks of treatment initiation. Three months after discontinuation, the patient was asymptomatic, and all liver tests normalised. Conclusion: With this clinical case, we aimed to emphasise the importance of the medication history and the exclusion of other possible causes of altered liver enzymes.
Intraocular Pressure Fluctuation as Assessed by Water Drinking Test following iStent Inject Implantation in Open-Angle Glaucoma Patients
Authors: Khoo Phong Yue , Lam Chenshen , Tang Seng Fai , Perera Shamira , Cheng Teck Chee , Md Din Norshamsiah
Published: October 2024

Introduction: This study investigated the intraocular pressure (IOP) fluctuation as assessed by the water drinking test (WDT) in open-angle glaucoma (OAG) patients after combined cataract surgery with iStent implantation. Methods: This was a prospective non-randomized comparative study. Eyes with OAG and cataracts that were planned for either combined phacoemulsification and iStent implantation (iStent+CS) or phacoemulsification alone (CS) were recruited. The iStent inject (Model G2-M-IS) or iStent injectW (Model G2-W) trabecular micro-bypass stent (Glaukos Corporation, San Clemente, CA, USA) was implanted in the iStent+CS group. WDT was performed before and 3 months after surgery. WDT-IOP parameters including peak IOP, IOP fluctuation, and area under the curve (AUC) were compared between the two groups. Results: There were 20 eyes in the iStent+CS group and 16 eyes in the CS group. Both groups had similar pre-operative baseline IOP (15.6 ± 3.7 mm Hg vs. 15.8 ± 1.8 mm Hg in the iStent+CS and CS group, respectively, p = 0.883). The iStent+CS group experienced greater numerical reduction in peak IOP (2.6 ± 1.9 mm Hg vs. 1.9 ± 2.4 mm Hg; p = 0.355), IOP fluctuation (1.7 ± 2.2 mm Hg vs. 0.8 ± 2.5 mm Hg; p = 0.289), and AUC (54.8 ± 103.6 mm Hg × minute vs. 25.3 ± 79.0 mm Hg × minute; p = 0.355) than the CS group. There was more reduction in the number of anti-glaucoma medications in the iStent+CS group (1.4 ± 1.2) than the CS group (0.3 ± 0.9; p = 0.005). Conclusion: Both combined phacoemulsification with iStent inject implantation and phacoemulsification alone reduced peak IOP, IOP fluctuation, and AUC, and none of these parameters showed statistically significant difference. Greater reduction in anti-glaucoma medications was seen in the combined group.
Thalamus of Reptiles and Mammals: Some Significant Differences
Authors: Pritz Michael B.
Published: October 2024

Background: Most studies comparing forebrain organization between reptiles and mammals have focused on similarities. Equally important are the differences between their brains. While differences have been addressed infrequently, this approach can highlight the evolution of brains in relation to their respective environments. Summary: This review focuses on three key differences between the dorsal and ventral thalamus of reptiles and mammals. One is the organization of thalamo-telencephalic interconnections. Reptiles have at least three circuits that transmit information between the dorsal thalamus and telencephalon, whereas mammals have just one. A second is the number and distribution of local circuit neurons in the dorsal thalamus. Most reptilian dorsal thalamic nuclei lack local circuit neurons, whereas these same nuclei in mammals contain varying numbers. The third is the organization of the thalamic reticular nucleus. In crocodiles, at least, the neurons in the thalamic reticular nucleus are heterogeneous with two separate nuclei each being associated with a different circuit. In mammals, the neurons in the thalamic reticular nucleus, which is a single structure, are homogeneous. Key Messages: Transcriptomics and development are suggested to be the most likely approaches to explain these differences between reptiles and mammals. Transcriptomics can reveal which neuron types are “new” or “old” and whether neurons and their respective circuits have been re-purposed to be used differently. Examination of the development and connections of the dorsal and ventral thalamus will determine whether their formation is similar or different from what has been described for mammals.
TCIC-SC-RNet: A Hybrid Model for TC Intensity Estimation Based on Transfer Learning
Authors: Zhang Chang-Jiang , Wang Yu , Ma Lei-Ming , Lu Xiao-Qin
Published: October 2024

Tropical cyclone (TC) monitoring relies heavily on remotely sensed observations as they generally form and move through remote oceanic areas. This is an important part of monitoring the TC current intensity. In this study, a hybrid model (TCIC-SC-RNet) based on transfer learning, consisting of a cascade of classification, secondary correction classification, and regression modules, is proposed to estimate the intensity of TCs in the northwest Pacific basin. We used 1023 TCs (1979, 1981–2019), totaling 23 629 infrared satellite images, to train and test the TCIC-SC-RNet model. First, an improved Swin Transformer network is used to divide TCs into three categories according to intensity levels. Then, the primary classification result combines with direct intensity estimation results of the RegNet model input into the secondary correction classification module to classify further TCs, so as to reduce the misclassification errors and improve the model effect. Finally, the corrected TC intensity classification results are sent to the corresponding RegNet regression network to output the estimated TC intensity. The results show that the total root-mean-square error (RMSE) and mean absolute error (MAE) of our model were 7.47 and 5.60 kt (1 kt ≈ 0.51 m s−1), respectively, compared with the TC best track, which is competitive among current TC intensity estimation models.
Prostate cancer cell-derived exosomes ZNF667-AS1 reduces TGFBR1 mRNA stability to inhibit Treg expansion and DTX resistance by binding to U2AF1
Authors: Shi Zhenfeng , Pu Wenjing , Li Min , Aihemaitijiang Mierzhayiti , Li Shuo , Zhang Xiaoan , Liu Bide , Sun Min , Li Jiuzhi , Li Zhiwei
Published: October 2024

Background

Docetaxel (DTX) resistance attenuates anti-tumor effects of DTX on prostate cancer (mCRPC) and drug resistance was related to Treg expansion in tumors. ZNF667-AS1 played a suppressing role in various tumors and tumor-derived exosomes carry lncRNAs to participate in tumor progression. Here, the effects of ZNF667-AS1 on malignant characteristics and DTX resistance in PC and the effect and its underlying molecular mechanism of tumor-derived exosomes carrying ZNF667-AS1 on Treg expansion were investigated.

Methods

The identification of exosomes were determined using TEM, NTA and western blot. The abundance of genes and proteins were evaluated using IHC, RT-qPCR, western blot and FISH. Malignant phenotypes of PC cells were evaluated by means of Edu, scratch test, transwell, CCK-8 and flow cytometry. The percentage of CD4+CD25+Foxp3+ Tregs was detected using flow cytometry. The location of ZNF667-AS1 was detected using nuclear-cytoplasmic fractionation. The co-location of ZNF667-AS1 and U2AF1 protein was detected using IF-FISH assay. The interactions among ZNF667-AS1, TGFBR1 and U2AF1 were verified using RNA pull-down, RIP and dual luciferase activity.

Results

ZNF667-AS1 expression in PC samples was lowered, which was negatively relative to poor prognosis and DTX resistance. ZNF667-AS1 overexpression inhibited malignant phenotypes of PC cells, tumor growth and DTX resistance. Besides, DTX resistant cell-derived exosomes expressed lower ZNF667-AS1 expression. Exosomes carrying exogenously high ZNF667-AS1 expression derived PC cells or serum of mice suppressed Treg expansion. On the mechanism, ZNF667-AS1 interacted with U2AF1 to destabilize TGFBR1 mRNA and reduce TGFBR1 expression in CD4+T cells.

Conclusion

ZNF667-AS1 suppressed cell growth of PC cells, tumor growth of mice and DTX resistance to PC cells and exogenously high ZNF667-AS1 expression in tumor-derived exosomes destabilized TGFBR1 mRNA and reduce TGFBR1 expression through interacting with U2AF1, thus resulting in attenuated Treg expansion, which was related to DTX resistance.
Application of the estimand framework for an emulated trial using reference based multiple imputation to investigate informative censoring
Authors: Atkinson A. , Zwahlen M. , De Wit S. , Furrer H. , Carpenter J. R.
Published: October 2024

Background

The ICH E9 (R1) addendum on Estimands and Sensitivity analysis in Clinical trials proposes a framework for the design and analysis of clinical trials aimed at improving clarity around the definition of the targeted treatment effect (the estimand) of a study.

Methods

We adopt the estimand framework in the context of a study using “trial emulation” to estimate the risk of pneumocystis pneumonia, an opportunistic disease contracted by people living with HIV and AIDS having a weakened immune system, when considering two antibiotic treatment regimes for stopping antibiotic prophylaxis treatment against this disease. A “while on treatment” strategy has been implemented for post-randomisation (intercurrent) events. We then perform a sensitivity analysis using reference based multiple imputation to model a scenario in which patients lost to follow-up stop taking prophylaxis.

Results

The primary analysis indicated a protective effect for the new regime which used viral suppression as prophylaxis stopping criteria (hazard ratio (HR) 0.78, 95% confidence interval [0.69, 0.89], p < 0.001). For the sensitivity analysis, when we apply the “jump to off prophylaxis” approach, the hazard ratio is almost the same compared to that from the primary analysis (HR 0.80 [0.69, 0.95], p = 0.009). The sensitivity analysis confirmed that the new regime exhibits a clear improvement over the existing guidelines for PcP prophylaxis when those lost to follow-up “jump to off prophylaxis”.

Conclusions

Our application using reference based multiple imputation demonstrates the method’s flexibility and simplicity for sensitivity analyses in the context of the estimand framework for (emulated) trials.
An investigation of the impact of ‘Living with COVID’ on workplace COVID-19 transmission risk, response and resilience - lessons learnt and future challenges
Authors: Lewis Catherine , Johnson Sheena , Mann Claire , Ubido Janet , Farrell Bernadine , Coleman Anna , van Tongeren Martie
Published: October 2024

Background

Previous research has highlighted links between occupation and risk of COVID-19 transmission and suggests that occupational risk is influenced by covariates including socio-economic status, and deprivation. This study examined the perspectives of local authority teams of how changes in policy and advice, as set out in the UK government report ‘Living with COVID,’ affected COVID-19 transmission risk, response and resilience in workplace settings in Greater Manchester, an area that was disproportionately affected by the pandemic.

Methods

The project, which took place between August and November 2022, undertook a mixed methods approach to incorporate wide-ranging reflections of changes following the publication of ‘Living with COVID’. Quantitative data was collected from local employers (n = 149) and employees (n = 397) using online surveys, and qualitative interview data was collected from Greater Manchester local authority teams (n = 19).

Results

The research highlighted the inequitable impact of the pandemic on those already experiencing health inequalities, including people on more precarious employment contracts or those who were unable to work from home during the pandemic.

The study found that the facilitators that helped local authorities to support employers to manage transmission included clear, detailed and timely national and local guidance, good communication, partnership working, funding, and timely access to data. Barriers to supporting employers included contradictory or confusing national guidance, structural inequalities, lack of funding, and delayed access to data. Interview participants reported that they were now utilising lessons learnt during the pandemic, along with the that partnerships developed, in order to tackle wider health issues and to prepare for future pandemics or health crises.

Conclusion

The findings of the study, which concur with previously published research conducted as part of the PROTECT project, highlight the importance of active reflection on the lessons learned during the course of the pandemic. The study draws on PH and EH teams’ perspectives of managing COVID-19 transmission, in an area that was disproportionately affected by the pandemic, in order to add to our understanding of the best ways to ensure preparedness for future pandemics or health crises at a national level.
Impact of a large-scale fruit and vegetable irrigation scheme on the micro-epidemiology of malaria in southwest Ethiopia
Authors: Getachew Tewodros , Zeynudin Ahmed , Degefa Teshome , Lee Ming-Chieh , Yewhalaw Delenasaw
Published: October 2024

Background

Malaria continues to represent an important public health problem in Ethiopia. The expansion of irrigated agricultural development projects turns out to be a major impediment to long-lasting and sustainable malaria prevention and control efforts in the country. The aim of this study was to determine the micro-epidemiology of malaria and associated risk factors in and around Gojeb Horizon Irrigation Plantation in southwest Ethiopia.

Methods

A community-based comparative cross-sectional study was conducted from May to June 2018 in Gimbo District, southwest Ethiopia. A total of 186 households (94 from irrigated village and 92 from non-irrigated village) were randomly selected from among the communities living around the Gojeb Horizon plantation. In total, 718 individuals (368 from irrigated village and 350 from non-irrigated village) were recruited from the selected households. A finger-prick blood sample was obtained from each participant. Socio-demographic data from the households and individual study participants were collected using a semi-structured questionnaire. Multivariate regression was used to assess factors associated with micro-epidemiology of malaria. P-value < 0.05 was considered statistically significant.

Results

The prevalence of malaria in irrigated and non-irrigated villages was 8.2% and 3.4%, respectively. Plasmodium falciparum, Plasmodium vivax and mixed infections accounted for 57.1%, 38.1%, and 4.8% of the cases, respectively. Individuals living in the irrigated villages were 2.53 (95% CI: 1.23–5.20) times at higher risk of Plasmodium infection as compared to those living in the non-irrigated village. Age (AOR = 1.03, 95% CI: 1.01–1.06) and non-use of long-lasting insecticidal net (AOR = 2.72, 95% CI: 1.03–7.22) were co-predictors of malaria infection in the area.

Conclusion

This study revealed that communities living in irrigation village were at a higher risk of Plasmodium infection than those living in non-irrigated village, which necessitates the development of tailored interventions that are both targeted and customized.
Bullying and oral health in Egyptian adolescents: the moderating role of sense of coherence and resistance to peer influence
Authors: Elwan Amira H. , Samaha Abdelwahab , Abdelaziz Wafaa E.
Published: October 2024

Background

Bullying is the intentional, repeated and prolonged aggressive behavior towards victim(s) who feel powerless to defend themselves. It could influence adolescents’ mental health. Some adolescents possess coping skills which enable them to overcome such adversities. The present study assessed the association between bullying, sense of coherence (SOC), resistance to peer influence (RPI) and oral health in Egyptian adolescents.

Materials and methods

A cross-sectional survey that included 12–16 year old adolescents attending 6 schools in Damanhour, Egypt was conducted from March to December 2023. Data were collected through clinical examination and self-administered questionnaires. Clinical examination assessed dental caries (DMFT), oral hygiene (plaque index) and gingival condition (gingival index). Toothbrushing frequency and sugar consumption were assessed by (World Health Organization-child form), bullying (Revised Olweus Bully Victim Questionnaire), SOC (Sense of Coherence Scale-Short Form) and RPI (Resistance to Peer Influence Questionnaire). The independent variables were bullying, SOC and RPI. The dependent variables were untreated caries, gingival inflammation and toothbrushing frequency. Multivariable multilevel regression assessed the relationship between the independent and dependent variables after adjusting for potential confounders. Adjusted regression coefficients (B), adjusted odds ratios (AOR) and 95% confidence intervals (CI) were calculated. Effect modifications by SOC and RPI were evaluated.

Results

The response rate was 95.25% (N = 602), mean (SD) age was 14.01 (1.15). Half of the students (49.83%) were girls. About 42% had untreated caries, only 15.78% brushed their teeth twice daily and the mean (SD) gingival index was 1.57 (0.40). About 25% were victims, (9.30%) bullies and (18.60%) bully-victims. Victims showed significantly lower odds of twice daily toothbrushing (AOR = 0.52, p = 0.04). Bullies and bully-victims showed non-significantly higher odds of untreated caries (AOR = 1.42, p = 0.25), (AOR = 1.21, p = 0.42), respectively. Bullying was not associated with gingival inflammation. Higher SOC and RPI mitigated the impact of bullying on untreated caries and toothbrushing frequency.

Conclusion

Bullying was associated with higher odds of untreated caries and lower odds of twice daily toothbrushing in Egyptian adolescents. Higher SOC and RPI alleviated this relationship, highlighting the importance of individual coping strategies to oral health.
Experimental peri-implantitis induces neuroinflammation: An exploratory study in rats
Authors: Cafferata Emilio A. , Ramanauskaite Ausra , Cuypers Astrid , Obreja Karina , Dohle Eva , Ghanaati Shahram , Schwarz Frank
Published: October 2024

Purpose

Cumulating evidence supports the close association between periodontal diseases, neuroinflammation and neurodegenerative pathologies, except for peri-implantitis (PI). Thus, this study explored the association between experimental PI and neuropathological changes in the rat brain.

Materials and methods

After bilateral first molars extraction, experimental PI was induced at titanium implants placed in the maxillae by lipopolysaccharide injections and ligature placement. Following 28-weeks of disease progression, the maxillae and brains were retrieved from 6 rats. Healthy brains from 3 rats were used as control. Brains were analyzed by immunohistochemistry to detect signs of neuroinflammation (interleukin (IL)-6 and tumor necrosis factor (TNF)-α)), microglial activation (IBA-1) and astrogliosis (GFAP). To explore signs of neurodegeneration, hematoxylin/eosin and Nissl stainings were used. Also, four different antibodies against amyloid beta (Aβ 1–42) were tested.

Results

Chronic PI lesions showed peri-implant bone resorption accompanied by large inflammatory infiltrates. IL-6+ and TNF-α+ cells were found within the CA1 and Dentate Gyrus regions of the hippocampus of the PI-affected group, while almost no immune-positivity was detected in the control (p < 0.05). Detection of activated GFAP+ microglia and IBA-1+ astrocytes surface were significantly higher at the CA areas, and cerebral cortex of the PI-affected group, in comparison with control (p < 0.05). Shrunk neurons with pyknotic nuclei were inconsistently found among the PI-affected group, and these were almost not detected in control. No positive Aβ reactivity was detected in any of the samples.

Conclusion

Chronic experimental PI lesions led to an increased detection of IL-6 and TNF-α, GFAP+ microgliosis and IBA-1+ astrocytosis, and in some cases, neurodegeneration, in the rat brain.