bluuebunny/crossref_metadata_2025 huggingface dataset:
Utility of surveillance data for planning for dengue elimination in Yogyakarta, Indonesia: a scenario-tree modelling approach
Authors: Bannister-Tyrrell Melanie , Hillman Alison , Indriani Citra , Ahmad Riris Andono , Utarini Adi , Simmons Cameron P , Anders Katherine L , Sergeant Evan
Published: November 2023

Introduction

Field trials and modelling studies suggest that elimination of dengue transmission may be possible through widespread release ofAedes aegyptimosquitoes infected with the insect bacteriumWolbachia pipientis(wMel strain), in conjunction with routine dengue control activities. This study aimed to develop a modelling framework to guide planning for the potential elimination of locally acquired dengue in Yogyakarta, a city of almost 400 000 people in Java, Indonesia.

Methods

A scenario-tree modelling approach was used to estimate the sensitivity of the dengue surveillance system (including routine hospital-based reporting and primary-care-based enhanced surveillance), and time required to demonstrate elimination of locally acquired dengue in Yogyakarta city, assuming the detected incidence of dengue decreases to zero in the future. Age and gender were included as risk factors for dengue, and detection nodes included the probability of seeking care, probability of sample collection and testing, diagnostic test sensitivity and probability of case notification. Parameter distributions were derived from health system data or estimated by expert opinion. Alternative simulations were defined based on changes to key parameter values, separately and in combination.

Results

For the default simulation, median surveillance system sensitivity was 0.131 (95% PI 0.111 to 0.152) per month. Median confidence in dengue elimination reached 80% after a minimum of 13 months of zero detected dengue cases and 90% confidence after 25 months, across different scenarios. The alternative simulations investigated produced relatively small changes in median system sensitivity and time to elimination.

Conclusion

This study suggests that with a combination of hospital-based surveillance and enhanced clinic-based surveillance for dengue, an acceptable level of confidence (80% probability) in the elimination of locally acquired dengue can be reached within 2 years. Increasing the surveillance system sensitivity could shorten the time to first ascertainment of elimination of dengue and increase the level of confidence in elimination.
CD8+chimeric antigen receptor T cells manufactured in absence of CD4+cells exhibit hypofunctional phenotype
Authors: Lee Sang Yun , Lee Dong Hoon , Sun Wei , Cervantes-Contreras Francisco , Basom Ryan S , Wu Feinan , Liu Si , Rai Richa , Mirzaei Hamid R , O’Steen Shyril , Green Damian J , Shadman Mazyar , Till Brian G
Published: November 2023

Background

Cell culture conditions during manufacturing can impact the clinical efficacy of chimeric antigen receptor (CAR) T cell products. Production methods have not been standardized because the optimal approach remains unknown. Separate CD4+and CD8+cultures offer a potential advantage but complicate manufacturing and may affect cell expansion and function. In a phase 1/2 clinical trial, we observed poor expansion of separate CD8+cell cultures and hypothesized that coculture of CD4+cells and CD8+cells at a defined ratio at culture initiation would enhance CD8+cell expansion and simplify manufacturing.

Methods

We generated CAR T cells either as separate CD4+and CD8+cells, or as combined cultures mixed in defined CD4:CD8 ratios at culture initiation. We assessed CAR T cell expansion, phenotype, function, gene expression, and in vivo activity of CAR T cells and compared these between separately expanded or mixed CAR T cell cultures.

Results

We found that the coculture of CD8+CAR T cells with CD4+cells markedly improves CD8+cell expansion, and further discovered that CD8+cells cultured in isolation exhibit a hypofunctional phenotype and transcriptional signature compared with those in mixed cultures with CD4+cells. Cocultured CAR T cells also confer superior antitumor activity in vivo compared with separately expanded cells. The positive impact of CD4+cells on CD8+cells was mediated through both cytokines and direct cell contact, including CD40L-CD40 and CD70-CD27 interactions.

Conclusions

Our data indicate that CD4+cell help during cell culture maintains robust CD8+CAR T cell function, with implications for clinical cell manufacturing.
Non-invasive CT imaging biomarker to predict immunotherapy response in gastric cancer: a multicenter study
Authors: Huang Weicai , Xiong Wenjun , Tang Lei , Chen Chuanli , Yuan Qingyu , Zhang Cheng , Zhou Kangneng , Sun Zepang , Zhang Taojun , Han Zhen , Feng Hao , Liang Xiaokun , Zhong Yonghong , Deng Haijun , Yu Lequan , Xu Yikai , Wang Wei , Shen Lin , Li Guoxin , Jiang Yuming
Published: November 2023

Background

Despite remarkable benefits have been provided by immune checkpoint inhibitors in gastric cancer (GC), predictions of treatment response and prognosis remain unsatisfactory, making identifying biomarkers desirable. The aim of this study was to develop and validate a CT imaging biomarker to predict the immunotherapy response in patients with GC and investigate the associated immune infiltration patterns.

Methods

This retrospective study included 294 GC patients who received anti-PD-1/PD-L1 immunotherapy from three independent medical centers between January 2017 and April 2022. A radiomics score (RS) was developed from the intratumoral and peritumoral features on pretreatment CT images to predict immunotherapy-related progression-free survival (irPFS). The performance of the RS was evaluated by the area under the time-dependent receiver operating characteristic curve (AUC). Multivariable Cox regression analysis was performed to construct predictive nomogram of irPFS. The C-index was used to determine the performance of the nomogram. Bulk RNA sequencing of tumors from 42 patients in The Cancer Genome Atlas was used to investigate the RS-associated immune infiltration patterns.

Results

Overall, 89 of 294 patients (median age, 57 years (IQR 48–66 years); 171 males) had an objective response to immunotherapy. The RS included 13 CT features that yielded AUCs of 12-month irPFS of 0.787, 0.810 and 0.785 in the training, internal validation, and external validation 1 cohorts, respectively, and an AUC of 24-month irPFS of 0.805 in the external validation 2 cohort. Patients with low RS had longer irPFS in each cohort (p<0.05). Multivariable Cox regression analyses showed RS is an independent prognostic factor of irPFS. The nomogram that integrated the RS and clinical characteristics showed improved performance in predicting irPFS, with C-index of 0.687–0.778 in the training and validation cohorts. The CT imaging biomarker was associated with M1 macrophage infiltration.

Conclusion

The findings of this prognostic study suggest that the non-invasive CT imaging biomarker can effectively predict immunotherapy outcomes in patients with GC and is associated with innate immune signaling, which can serve as a potential tool for individual treatment decisions.
Vessel wall MRI characteristics associated with intraprocedural stent thrombosis during angioplasty for intracranial atherosclerotic stenosis
Authors: Ma Xiaotong , Yan Peng , Ju Jiachen , Yang Zhengyu , Wang Wenjuan , Wang Qiuting , Liu Xiaohui , Xia Zhangyong , Sun Qinjian
Published: November 2023

Background

Few studies have so far explored plaque characteristics on high-resolution magnetic resonance vessel wall imaging (HR-VWI) associated with intraprocedural stent thrombosis (IPST) during angioplasty for intracranial atherosclerotic stenosis (ICAS). We aimed to investigate the plaque features on HR-VWI associated with IPST during stenting for ICAS.

Methods

This study recruited 77 patients with ICAS who underwent intracranial stenting using the Gateway-Wingspan system, and were performed with enhanced pre- and post-contrast T1-weighted HR-VWI on a 3.0T MRI scanner before angioplasty. During stenting for ICAS, eight patients (male: 100%, age mean ± standard deviation (SD): 58.7±2.47) developed IPST within 30 minutes after stenting. To ensure comparability, 16 patients who had undergone intracranial stenting but did not develop IPST were matched as controls for this study. Univariable and binary logistic models were used to explore the plaque characteristics on HR-VWI associated with IPST.

Results

Patients who developed IPST had less plaque diffusion (37.50% vs 81.25%, p=0.036), a more severe degree of area stenosis (median 96.30% vs 81.65%, p<0.01), and a higher plaque enhancement index (median 37.99 vs 13.12, p<0.01) compared with those who did not. After multivariate adjustment, IPST was independently associated with a more severe degree of area stenosis (adjusted odds ratio (OR) 1.20, 95% confidence interval (CI) 1.01–1.43, p=0.044) and a higher plaque enhancement index (adjusted OR 1.17, 95% CI 1.01 to 1.36, p=0.036).

Conclusion

Intraprocedural stent thrombosis during intracranial angioplasty for patients with ICAS may be independently associated with a higher plaque enhancement index and a more severe degree of area stenosis on HR-VWI.
Real-Time Spatial-Temporal Depth Separable CNN for Multi-Functional Crowd Analysis in Videos
Authors: Tripathy Santosh Kumar , Shanmugam Poonkuntran
Published: November 2023

Crowd behavior prediction (CBP) and crowd counting (CC) are the essential functions of vision-based crowd analysis (CA), which play a crucial role in controlling crowd disasters. The CA using different models for the CBP and the CC will increase computational overheads and have synchronization issues. The state-of-the-art approaches utilized deep convolutional architectures to exploit spatial-temporal features to accomplish the objective, but such models suffer from computational complexities during convolution operations. Thus, to sort out the issues as mentioned earlier, this paper develops a single deep model which performs two functionalities of CA: CBP and CC. The proposed model uses multilayers of depth-wise separable CNN (DSCNN) to extract fine-grained spatial-temporal features from the scene. The DSCNN can minimize the number of matrix multiplications during convolution operation compared to traditional CNN. Further, the existing datasets are available to accomplish the single functionality of CA. In contrast, the proposed model needs a dual-tasking CA dataset which should provide the ground-truth labels for CBP and CC. Thus, a dual functionality CA dataset is prepared using a benchmark crowd behavior dataset, i.e. MED. Around 41[Formula: see text]000 frames have been manually annotated to obtain ground-truth crowd count values. This paper also demonstrates an experiment on the proposed multi-functional dataset and outperforms the state-of-the-art methods regarding several performance metrics. In addition, the proposed model processes each test frame at 3.40 milliseconds, and thus is easily applicable in real-time.
How Do Remittance Inflows Cause the Dutch Disease in the Financial Sector? The Role of Financial Risk and Human Capital
Authors: Khan Zeeshan , Faraz Raza Syed Muhammad , Dong Kangyin , Haouas Ilham
Published: November 2023

This research examines whether the remittance (REM) inflows cause Dutch disease and how it affects financial development (FD). The sample consists of the top global REM recipients, namely China, Egypt, India, Mexico and the Philippines, based on the latest World Bank data from 1990 to 2019. This study employs three econometric models to evaluate the REM inflows’ impact on FD. Using the cross-sectionally augmented autoregressive distributed lag (CS-ARDL) estimation technique, we reveal that the REM inflows have impeded FD and have triggered Dutch disease issues in the financial sectors. Furthermore, the estimation found a positive effect of economic growth, globalization, human capital and financial risks on FD across all models, both in the short and long runs. In addition, the interplay among the REM, human capital, and financial risks also facilitates FD. The study suggests that robust resource flows and price adjustment processes tackle the hazard of deteriorating FD and emphasize the Dutch disease’s effects on the top REM recipients.
Cloning for the Twenty-First Century and Its Place in Endangered Species Conservation
Authors: Cowl Veronica B. , Comizzoli Pierre , Appeltant Ruth , Bolton Rhiannon L. , Browne Robert K. , Holt William V. , Penfold Linda M. , Swegen Aleona , Walker Susan L. , Williams Suzannah A.
Published: November 2023

Cloning as it relates to the animal kingdom generally refers to the production of genetically identical individuals. Because cloning is increasingly the subject of renewed attention as a tool for rescuing endangered or extinct species, it seems timely to dissect the role of the numerous reproductive techniques encompassed by this term in animal species conservation. Although cloning is typically associated with somatic cell nuclear transfer, the recent advent of additional techniques that allow genome replication without genetic recombination demands that the use of induced pluripotent stem cells to generate gametes or embryos, as well as older methods such as embryo splitting, all be included in this discussion. Additionally, the phenomenon of natural cloning (e.g., a subset of fish, birds, invertebrates, and reptilian species that reproduce via parthenogenesis) must also be pointed out. Beyond the biology of these techniques are practical considerations and the ethics of using cloning and associated procedures in endangered or extinct species. All of these must be examined in concert to determine whether cloning has a place in species conservation. Therefore, we synthesize progress in cloning and associated techniques and dissect the practical and ethical aspects of these methods as they pertain to endangered species conservation.
Emerging Technologies in Cardiac Pacing
Authors: Vajapey Ramya , Chung Mina K.
Published: November 2023

Cardiac pacing to treat bradyarrhythmias has evolved in recent decades. Recognition that a substantial proportion of pacemaker-dependent patients can develop heart failure due to electrical and mechanical dyssynchrony from traditional right ventricular apical pacing has led to development of more physiologic pacing methods that better mimic normal cardiac conduction and provide synchronized ventricular contraction. Conventional biventricular pacing has been shown to benefit patients with heart failure and conduction system disease but can be limited by scarring and fibrosis. His bundle pacing and left bundle branch area pacing are novel techniques that can provide more physiologic ventricular activation as an alternative to conventional or biventricular pacing. Leadless pacing has emerged as another alternative pacing technique to overcome limitations in conventional transvenous pacemaker systems. Our objective is to review the evolution of cardiac pacing and explore these new advances in pacing strategies.
Spontaneous Bladder Rupture in a Catatonic Schizophrenia Patient
Authors: Miyakoshi Megumi , Arai Takayuki , Kurose Shin , Kaji Masataka , Nakane Jun , Onaya Mitsumoto , Koreki Akihiro
Published: November 2023

Catatonia is a psychiatric emergency in schizophrenia that often leads to excessive activation of the sympathetic nervous system. Urinary retention in catatonia is often underestimated but has potentially detrimental consequences. Herein, we present the case of a woman in her 40s with schizophrenia treated for catatonia during a relapse. When treated as an inpatient, the patient suddenly complained of severe abdominal pain. Computed tomography revealed a spontaneous rupture of the posterior wall of the bladder, requiring emergency repair surgery in the urology department. The patient was readmitted to our hospital following surgery and ultimately discharged 1 month later. Bladder rupture is life-threatening, and delayed diagnosis and treatment can be fatal. This case report serves as a warning that psychiatrists should not overlook urinary retention in patients with catatonia and should consider bladder rupture in the differential diagnosis when these patients have abdominal pain.
Antibacterial and Immunoregulatory Effects of Metformin against Helicobacter pylori Infection in Rat Model
Authors: Valadbeigi Hassan , Khoshnood Saeed , Negahdari Babak , Abdullah Mohd Azmuddin , Haddadi Mohammad Hossein
Published: November 2023

Introduction. Helicobacter pylori (H. pylori) induces gastritis by stimulating Th17 cells and related cytokines. The aim of our study was to investigate the synergistic effect of metformin with amoxicillin as an antibiotic in inhibiting H. pylori and modulating the immune response in a rat model. Methods. Forty‐five male Sprague‐Dawley rats were divided into seven groups and infected with H. pylori. Over the course of 14 days, all animals were treated with metformin and amoxicillin alone and in combination. The antibacterial activity of metformin was evaluated by growth curves and colony counts. The immunoregulatory effect on Treg/Th17 balance was assessed by flow cytometry, and the cytokine profile of IL‐17A, IL‐1β, IL‐6, IL‐8, TGF‐β, and IL‐10 was determined by ELISA. The effect of metformin on gene expression of cagA and IL‐8 was investigated by RT‐PCR. Pathological changes were assessed by hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining. Results. Metformin showed weak antibacterial activity against clinically isolated H. pylori. However, the combination of metformin and amoxicillin (AMX) showed strong synergistic antibacterial activity (ΣFIC = 0.24). Compared with AMX, metformin reduced inflammation and tissue damage but resulted in increased bacterial growth. During metformin administration, both TGF‐β levels and Treg cells increased dramatically (P = 0.002). In synergy with AMX, metformin decreased the effective dose of antibiotic to eradicate H. pylori. Conclusions. The combination of metformin with potential antibiotics such as AMX had a positive effect on the relief of H. pylori‐related inflammation by inducing Treg cells while successfully eliminating H. pylori.
Topoisomerase 1 Inhibition in MYC-Driven Cancer Promotes Aberrant R-Loop Accumulation to Induce Synthetic Lethality
Authors: Lin Peter , Lourenco Corey , Cruickshank Jennifer , Palomero Luis , van Leeuwen Jenna E. , Tong Amy H. Y. , Chan Katherine , El Ghamrasni Samah , Pujana Miquel Angel , Cescon David W. , Moffat Jason , Penn Linda Z.
Published: November 2023

MYC is a central regulator of gene transcription and is frequently dysregulated in human cancers. As targeting MYC directly is challenging, an alternative strategy is to identify specific proteins or processes required for MYC to function as a potent cancer driver that can be targeted to result in synthetic lethality. To identify potential targets in MYC-driven cancers, we performed a genome-wide CRISPR knockout screen using an isogenic pair of breast cancer cell lines in which MYC dysregulation is the switch from benign to transformed tumor growth. Proteins that regulate R-loops were identified as a potential class of synthetic lethal targets. Dysregulated MYC elevated global transcription and coincident R-loop accumulation. Topoisomerase 1 (TOP1), a regulator of R-loops by DNA topology, was validated to be a vulnerability in cells with high MYC activity. Genetic knockdown of TOP1 in MYC-transformed cells resulted in reduced colony formation compared with control cells, demonstrating synthetic lethality. Overexpression of RNaseH1, a riboendonuclease that specifically degrades R-loops, rescued the reduction in clonogenicity induced by TOP1 deficiency, demonstrating that this vulnerability is driven by aberrant R-loop accumulation. Genetic and pharmacologic TOP1 inhibition selectively reduced the fitness of MYC-transformed tumors in vivo. Finally, drug response to TOP1 inhibitors (i.e., topotecan) significantly correlated with MYC levels and activity across panels of breast cancer cell lines and patient-derived organoids. Together, these results highlight TOP1 as a promising target for MYC-driven cancers.

Significance:

CRISPR screening reveals topoisomerase 1 as an immediately actionable vulnerability in cancers harboring MYC as a driver oncoprotein that can be targeted with clinically approved inhibitors.
Supplementary Table S6 from Exogenous Sequences in Tumors and Immune Cells (Exotic): A Tool for Estimating the Microbe Abundances in Tumor RNA-seq Data
Authors: Hoyd Rebecca , Wheeler Caroline E. , Liu YunZhou , Jagjit Singh Malvenderjit S. , Muniak Mitchell , Jin Ning , Denko Nicholas C. , Carbone David P. , Mo Xiaokui , Spakowicz Daniel J.
Published: November 2023

Pathways enriched in the genes linked to microbes with the highest degree centrality.
Supplementary Table S5 from Exogenous Sequences in Tumors and Immune Cells (Exotic): A Tool for Estimating the Microbe Abundances in Tumor RNA-seq Data
Authors: Hoyd Rebecca , Wheeler Caroline E. , Liu YunZhou , Jagjit Singh Malvenderjit S. , Muniak Mitchell , Jin Ning , Denko Nicholas C. , Carbone David P. , Mo Xiaokui , Spakowicz Daniel J.
Published: November 2023

Ranked list of microbes by betweenness centrality in a gene-microbe network controlling for cancer type (on GitHub as spakowiczlab/exotic-manuscript/analyses/tables/S4_network_microbe_betweeenness-centrality.csv)
Supplementary Table S3 from Exogenous Sequences in Tumors and Immune Cells (Exotic): A Tool for Estimating the Microbe Abundances in Tumor RNA-seq Data
Authors: Hoyd Rebecca , Wheeler Caroline E. , Liu YunZhou , Jagjit Singh Malvenderjit S. , Muniak Mitchell , Jin Ning , Denko Nicholas C. , Carbone David P. , Mo Xiaokui , Spakowicz Daniel J.
Published: November 2023

Ranked list of microbes by degree centrality in a gene-microbe network controlling for cancer type (on GitHub as spakowiczlab/exotic-manuscript/analyses/tables/S3_network_microbe_degree-centrality.csv).
Supplementary Table S1 from Exogenous Sequences in Tumors and Immune Cells (Exotic): A Tool for Estimating the Microbe Abundances in Tumor RNA-seq Data
Authors: Hoyd Rebecca , Wheeler Caroline E. , Liu YunZhou , Jagjit Singh Malvenderjit S. , Muniak Mitchell , Jin Ning , Denko Nicholas C. , Carbone David P. , Mo Xiaokui , Spakowicz Daniel J.
Published: November 2023

Individual results for the associations of microbe prevalence with survival (on GitHub as spakowiczlab/exotic-manuscript/analyses/data).
Supplemental Figure S1 from Exogenous Sequences in Tumors and Immune Cells (Exotic): A Tool for Estimating the Microbe Abundances in Tumor RNA-seq Data
Authors: Hoyd Rebecca , Wheeler Caroline E. , Liu YunZhou , Jagjit Singh Malvenderjit S. , Muniak Mitchell , Jin Ning , Denko Nicholas C. , Carbone David P. , Mo Xiaokui , Spakowicz Daniel J.
Published: November 2023

Example survival analysis using multiple stratification thresholds. The p-values for the separations between survival curves at each quantile are shown, colored by the direction of association (hazard ratio greater or less than 1).
FIGURE 3 from Exogenous Sequences in Tumors and Immune Cells (Exotic): A Tool for Estimating the Microbe Abundances in Tumor RNA-seq Data
Authors: Hoyd Rebecca , Wheeler Caroline E. , Liu YunZhou , Jagjit Singh Malvenderjit S. , Muniak Mitchell , Jin Ning , Denko Nicholas C. , Carbone David P. , Mo Xiaokui , Spakowicz Daniel J.
Published: November 2023

Network-based exploration of microbe–gene interactions. A, Summary of the correlations between all microbes and all genes, selecting only the correlations significant in both datasets and where the effect direction agrees. B, Consistent correlations are further filtered for the 5% most extreme values and then used to build a network for which the number of edges per node follows a power-law distribution. C, The top taxa by degree centrality are shown, which include those with precedence for affecting cancer outcomes (Bifidobacterium), as well as microbes that have only been described in the gut (Alistipes). Each microbe shows a distinct pattern of gene relationships (colored lines), suggesting a variety of interaction types. D, Examples of pathway enrichment analyses of the genes interacting with microbes include Alistipes finegoldii, Bifidobacterium bifidum, and a strain of Pseudomonas.
FIGURE 1 from Exogenous Sequences in Tumors and Immune Cells (Exotic): A Tool for Estimating the Microbe Abundances in Tumor RNA-seq Data
Authors: Hoyd Rebecca , Wheeler Caroline E. , Liu YunZhou , Jagjit Singh Malvenderjit S. , Muniak Mitchell , Jin Ning , Denko Nicholas C. , Carbone David P. , Mo Xiaokui , Spakowicz Daniel J.
Published: November 2023

Summary and validation of the {exotic} tool. A, Schematic of the {exotic} tool, showing the process of aligning raw RNA-seq FASTQs to databases for human and microbial identification, followed by filtering to remove contaminants. Filtering steps include the removal of samples with a high percentage of exogenous reads and samples from small batches that prevent contaminant checks, as well as reads that align to microbes found to be contaminants by statistical or literature review–based filtering. The remaining samples’ microbe counts are normalized by VOOM-SNM. B, The loss of reads at each step of the {exotic} tool. C, Normalization removes batch effects from the sequencing center (all ORIEN samples were sequenced at TCC, and all TCGA at UNC) and preservation method from decontaminated counts. D, Microbe-level filtering removes taxa that align with input RNA concentration and are consistently found in negative controls. Microbes with strong literature precedence as commensals are returned. E, Comparison of the prevalence of Fusobacterium found by {exotic} compared with literature values captured by non–RNA-seq–based approaches, with a much higher prevalence appearing in colorectal samples compared with all cancer types. F, A comparison of the prevalence of various taxa to those reported by Poore and colleagues (9) for TCGA dataset finds mostly lower prevalences of bacteria and viruses but includes the identification of fungi (Malassezia). G, The abundance of microbes found in a 16S-based validation dataset compared with the RNA-seq–based approach. H, Comparison of the distances between microbes identified by 16S and RNA-seq for samples from the same patient and tumor (Paired = TRUE, Tumor) and adjacent normal tissue (Paired = TRUE, Normal) versus samples from different patients (Paired = FALSE).
Data from Exogenous Sequences in Tumors and Immune Cells (Exotic): A Tool for Estimating the Microbe Abundances in Tumor RNA-seq Data
Authors: Hoyd Rebecca , Wheeler Caroline E. , Liu YunZhou , Jagjit Singh Malvenderjit S. , Muniak Mitchell , Jin Ning , Denko Nicholas C. , Carbone David P. , Mo Xiaokui , Spakowicz Daniel J.
Published: November 2023

Abstract
The microbiome affects cancer, from carcinogenesis to response to treatments. New evidence suggests that microbes are also present in many tumors, though the scope of how they affect tumor biology and clinical outcomes is in its early stages. A broad survey of tumor microbiome samples across several independent datasets is needed to identify robust correlations for follow-up testing. We created a tool called {exotic} for “exogenous sequences in tumors and immune cells” to carefully identify the tumor microbiome within RNA sequencing (RNA-seq) datasets. We applied it to samples collected through the Oncology Research Information Exchange Network (ORIEN) and The Cancer Genome Atlas. We showed how the processing removes contaminants and batch effects to yield microbe abundances consistent with non–high-throughput sequencing–based approaches and DNA-amplicon–based measurements of a subset of the same tumors. We sought to establish clinical relevance by correlating the microbe abundances with various clinical and tumor measurements, such as age and tumor hypoxia. This process leveraged the two datasets and raised up only the concordant (significant and in the same direction) associations. We observed associations with survival and clinical variables that are cancer specific and relatively few associations with immune composition. Finally, we explored potential mechanisms by which microbes and tumors may interact using a network-based approach. Alistipes, a common gut commensal, showed the highest network degree centrality and was associated with genes related to metabolism and inflammation. The {exotic} tool can support the discovery of microbes in tumors in a way that leverages the many existing and growing RNA-seq datasets.
Significance:
The intrinsic tumor microbiome holds great potential for its ability to predict various aspects of cancer biology and as a target for rational manipulation. Here, we describe a tool to quantify microbes from within tumor RNA-seq and apply it to two independent datasets. We show new associations with clinical variables that justify biomarker uses and more experimentation into the mechanisms by which tumor microbiomes affect cancer outcomes.
Iridoid Glycoside Cornuside Alleviates the Symptom of Gestational Diabetes Mellitus by Suppressing Inflammation and Regulating Beta Cell Function
Authors: Cui Xiaorong , Yu Yani , Yu Jia , Xu Kun , Sun Xin
Published: November 2023

Objective: Gestational diabetes mellitus (GDM) is a frequently occurring complication during pregnancy and has adverse effects on both mother and offspring. β-Cell dysfunction and inflammation play important roles in GDM pathogenesis. Cornuside (CNS) is an iridoid glycoside that exhibits anti-inflammation activities. In the present study, we explored the effects of CNS on β-cell and GDM. Design: MIN6 β-cell line cells were treated with varying concentrations of CNS. The content and secretion of insulin were measured. Methods: The expression of Pdx1, Rac1, Piezo, and NeuroD1 and cell proliferation in CNS-treated MIN6 cells were detected. CNS was administered to GDM mice, and the symptoms of GDM, expression of IL-6 and TNF-α, and activation of NF-κB in GDM mice were measured. Results: CNS promoted cell proliferation of MIN6 cells, enhanced insulin content and secretion, and expression of Pdx1, Rac1, Piezo, and NeuroD1 in MIN6 cells. CNS alleviated symptoms of GDM mice and decreased serum levels of IL-6 and TNF-α in GDM mice. CNS suppressed the expression of IL-6 and TNF-α, as well as the activation of NF-κB in the placenta of GDM mice. Conclusion: CNS ameliorates GDM symptoms by suppressing inflammation and enhancing β-cell functions.
Research Progress on the Role and Mechanism of GDF15 in Body Weight Regulation
Authors: Dong Xiao-Chen , Xu Dan-Yan
Published: November 2023

Background: Growth differentiation factor-15 (GDF15) is a member of the growth differentiation factor subfamily in the transforming growth factor beta superfamily. GDF15 has multiple functions and can regulate biological processes. High levels of GDF15 in the circulation can affect metabolic processes. Studies have shown that GDF15 is associated with changes in body weight. Summary: This review reviews the current knowledge on the relationship between GDF15 and body weight change, focusing on the role and mechanism of GDF15 in body weight regulation. GDF15 plays an important role in reducing food intake, improving insulin resistance, and breaking down fat, suggesting that GDF15 has an important regulatory effect on body weight. The mechanism by which GDF15 causes reduced food intake may be related to changes in food preference, delayed gastric emptying, and conditioned taste aversion. GDF15 can combat insulin resistance induced by inflammation or protect β cell from apoptosis. GDF15 probably promotes lipolysis through a brain-somatic tissue circuit. Several factors and related signaling pathways are also mentioned that can contribute to the effects of GDF15 on reducing weight. Key Message: GDF15 plays an important role in weight regulation and provides a new direction for the treatment of obesity. Its effects on resisting obesity are of great significance to inhibiting the progression of metabolic diseases. It is expected to become a new target for regulating body weight, improving obesity, and treating metabolic diseases such as diabetes.
Human Monocytes Exposed to SARS-CoV-2 Display Features of Innate Immune Memory Producing High Levels of CXCL10 upon Restimulation
Authors: Cvetkovic Jelena , Jacobi Ronald H.J. , Miranda-Bedate Alberto , Pham Nhung , Kutmon Martina , Groot James , van de Garde Martijn D.B. , Pinelli Elena
Published: November 2023

Introduction: A role for innate immune memory in protection during COVID-19 infection or vaccination has been recently reported. However, no study so far has shown whether the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can train innate immune cells. The aim of this study was to investigate whether this virus can induce trained immunity in human monocytes. Methods: Monocytes were exposed to inactivated SARS-CoV-2 (iSARS-CoV-2) for 24 h, followed by a resting period in the medium only and a secondary stimulation on day 6 after which the cytokine/chemokine and transcriptomic profiles were determined. Results: Compared to untrained cells, the iSARS-CoV-2-trained monocytes secreted significantly higher levels of IL-6, TNF-α, CXCL10, CXCL9, and CXCL11 upon restimulation. Transcriptome analysis of iSARS-CoV-2-trained monocytes revealed increased expression of several inflammatory genes. As epigenetic and metabolic modifications are hallmarks of trained immunity, we analyzed the expression of genes related to these processes. Findings indicate that indeed SARS-CoV-2-trained monocytes show changes in the expression of genes involved in metabolic pathways including the tricarboxylic acid cycle, amino acid metabolism, and the expression of several epigenetic regulator genes. Using epigenetic inhibitors that block histone methyl and acetyltransferases, we observed that the capacity of monocytes to be trained by iSARS-CoV-2 was abolished. Conclusion: Overall, our findings indicate that iSARS-CoV-2 can induce properties associated with trained immunity in human monocytes. These results contribute to the knowledge required for improving vaccination strategies to prevent infectious diseases.
Bempedoic Acid: How Will It Shape the Future Lipid-Lowering Landscape? Mode of Action, Evidence, and Clinical Use
Authors: Drexel Heinz , Mader Arthur
Published: November 2023

Background: Low-density lipoproteins are now proven to be causal for atherosclerosis. Pharmacological treatment focuses on an increase of low-density lipoprotein (LDL) receptors, particularly in the hepatocyte, which leads to uptake of LDL from blood, thereby reducing the burden to the arterial wall. This mechanism has first been proven by statins to be effective to reduce cardiovascular morbidity and mortality. The concept of “the lower, the better” was shown by high-intensity statins and new compounds like ezetimibe, PCSK9 antibodies, inclisiran, and ultimately bempedoic acid. Summary: Although first considered only a relatively weak LDL-C lowering drug, bempedoic acid proved to be very effective, for example, in statin-intolerant patients to reduce cardiovascular events in the CLEAR-Outcomes study. In the era of personalized medicine, it should not be forgotten that the individual response to a LDL-C lowering drug can vary considerably. Bempedoic acid has a favorable safety profile, particularly it does not induce muscle problems because its precursor is not metabolized to the active drug in the muscle, and it does not induce hyperglycemia. Bempedoic acid probably is best used in combination with ezetimibe, which leads to LDL-C reductions in the range of moderately intensive statins; in an oral triple combination with a high-intensity statin, LDL-C reductions in the range of two-thirds can be achieved. Key Messages: Bempedoic acid is a further weapon against the atherogenic effect of LDL cholesterol – in both primary and secondary prevention.
THE CHALLENGES AND OPPORTUNITIES OF SUSTAINABLE ENTREPRENEURSHIP IN THE DIGITAL AGE: HOW TO LEVERAGE TECHNOLOGY AND EFFICIENCY FOR SOCIAL AND ENVIRONMENTAL IMPACT
Authors: Ramadhan Hanifa Maulani , Prastya Bayu Andriansyah
Published: November 2023

In today's rapidly evolving digital landscape, a new breed of entrepreneurs is emerging with a dual mission for businesses to achieve success while also positively impacting society and the environment. This chapter explores how these visionary entrepreneurs are leveraging technology and efficiency to revolutionize supply chain management, resource optimization, waste management, and the integration of cutting-edge technologies to generate tangible social and environmental benefits. This chapter examines the dynamic world of supply chain management within the context of sustainable entrepreneurship in depth. It examines how entrepreneurs are leveraging digital tools to enhance supply chain transparency, traceability, and accountability. Through the use of real-world case studies, this chapter explores how businesses are employing cutting-edge technology to ensure the authenticity of sustainable sourcing, utilizing IoT devices to monitor supply chain conditions, and utilizing data analytics to make informed decisions that minimize environmental impact. In an era where global challenges are reshaping traditional business models, this chapter serves as a source of inspiration. It envisions a future in which technologically driven sustainability is not merely an option but a requirement. This book empowers entrepreneurs to create thriving businesses that contribute to a more equitable and eco-friendly world through the use of real-world examples and strategy.
Práticas linguístico-sociais de rappers brasileiros
Authors: Pecuch Gabriele , Pereira Hélcius Batista
Published: November 2023

O presente estudo toma por objeto as práticas linguístico-discursivas de rappers, a partir da concepção da terceira onda da sociolinguística, acerca das interações entre a linguagem e o social, descrita por trabalhos como Eckert (2005; 2006). Para tanto, analisamos transcrições de entrevistas de quatro sujeitos, concedidas ao programa “Manos e Minas”, focalizando os marcadores discursivos e as escolhas lexicais realizadas. Para melhor compreender como a linguagem é utilizada na construção das práticas sociais desse grupo de falantes, analisamos também as representações discursivas desses depoimentos e os contornos identitários realizados.
linguagem das narrativas e a representação da realidade
Authors: Netto Waldemar Ferreira
Published: November 2023

É comum considerar narrativas apenas como sequências lineares de sentenças, orais ou escritas, que descrevam eventos falsos, como, por exemplo, nas obras de ficção, ou verdadeiros, como nos testemunhos ou nos livros de história. Aqui se vai tomar a mesma narrativa, mas inserida de volta em seu contexto de enunciação. Uma narrativa se caracteriza como uma sequência contínua de eventos reais, da qual se extraem alguns para serem efetivamente codificados em sentenças. Os modelos de símbolos de Peirce e de Frege possibilitam que tais sequências sejam tratadas, respectivamente, como representâmen ou Sinn e os eventos, como interpretantes ou representações. A proposição de Bruner de que a enunciação decorre das disposições do interlocutor de atribuir intenções a esses representâmens e seus interpretantes exige do locutor que seus enunciados sejam atos linguísticos perlocucionais efetivos.
Sobrenomes não nascem em árvores
Authors: Módolo Marcelo , Cardoso Guilherme Aragão
Published: November 2023

O objetivo deste estudo é oferecer uma explicação linguística para o fenômeno dos sobrenomes de cristãos-novos, evidenciando que o vínculo é arbitrário e que os sobrenomes não projetam sentidos, semanticamente. A partir da seleção de documentos oficiais emitidos pela Igreja Católica que registraram transações financeiras entre católicos e judeus, entre os séculos XII e XV, e de registros inquisitoriais de denúncias contra os cristãos-novos no Brasil do século XVIII, foram analisados os processos de (re)construção e (re)categorização dos referentes nos textos, identificando marcas da (re)categorização incorporadas nos sobrenomes e o desaparecimento dessas em função da instabilidade discursivo-textual.
Improving Stroke Risk Factor Management Focusing on Health Disparities and Knowledge Gaps
Authors: Sur Nicole B. , Kozberg Mariel , Desvigne-Nickens Patrice , Silversides Candice , Bushnell Cheryl , Goldstein Larry B. , Saver Jeffrey , Broderick Joseph , Gokcal Elif , Merino Jose G. , Wadhwa Manish , Kamel Hooman , Elkind Mitchell S. V. , Ovbiagele Bruce , Neisen Karah B. , Ziegler Paul D. , Edip Gurol M. , Selim Magdy H , Reddy Harry , Savitz Sean I. , Morgan John R.
Published: November 2023

Stroke is a leading cause of death and disability in the United States and worldwide, necessitating comprehensive efforts to optimize stroke risk factor management. Health disparities in stroke incidence, prevalence, and risk factor management persist among various race/ethnic, geographic, and socioeconomic populations and negatively impact stroke outcomes. This review highlights existing literature and guidelines for stroke risk factor management, emphasizing health disparities among certain populations. Moreover, stroke risk factors for special groups, including the young, the very elderly, and pregnant/peripartum women are outlined. Strategies for stroke risk factor improvement at every level of the health care system are discussed, from the individual patient to providers, health care systems, and policymakers. Improving stroke risk factor management in the context of the social determinants of health, and with the goal of eliminating inequities and disparities in stroke prevention strategies, are critical steps to reducing the burden of stroke and equitably improving public health.
Atrial Fibrillation Detection and Load: Knowledge Gaps Related to Stroke Prevention
Authors: Smith Eric E. , Yaghi Shadi , Sposato Luciano A. , Fisher Marc , Broderick Joseph , Das Alvin S. , Elkind Mitchell S.V. , Goldstein Larry B. , Gurol M. Edip , Kamel Hooman , Morgan John R. , Ovbiagele Bruce , Savitz Sean , Selim Magdy , Wadhwa Manish
Published: November 2023

Atrial fibrillation is a major cause of ischemic stroke. Technological advances now support prolonged cardiac rhythm monitoring using either surface electrodes or insertable cardiac monitors. Four major randomized controlled trials show that prolonged cardiac monitoring detects subclinical paroxysmal atrial fibrillation in 9% to 16% of patients with ischemic stroke, including in patients with potential alternative causes such as large artery disease or small vessel occlusion; however, the optimal monitoring strategy, including the target patient population and the monitoring device (whether to use an event monitor, insertable cardiac monitor, or stepped approach) has not been well defined. Furthermore, the clinical significance of very short duration paroxysmal atrial fibrillation remains controversial. The relevance of the duration of monitoring, burden of device-detected atrial fibrillation, and its proximity to the acute ischemic stroke will require more research to define the most effective methods for stroke prevention in this patient population.
American Gun Violence & Mental Illness: Reducing Risk,
Restoring Health, Respecting Rights & Reviving
Communities
Authors: Swanson Jeffrey W. , Rosenberg Mark L.
Published: November 2023

Intentional injuries claimed nearly two hundred lives every day in the United States in 2020, about two-thirds of them suicides, each a story of irretrievable human loss. This essay addresses the complex intersection of injurious behavior with mental illness and access to firearms. It explores what more can be done to stop gun violence while respecting the rights of lawful gun owners, preserving the dignity of persons with mental illnesses, and promoting racial equity. Strategies to prevent firearm injury in the United States are uniquely conditioned by a constitutional right to bear arms, the cultural entrenchment and prevalence of private gun ownership, and strident political disagreement on regulatory solutions to stem gun violence. Broad implementation of a range of complementary policies is needed, including community-based programs to address the social and developmental determinants of violence, improved access to a continuum of mental health services, firearm restrictions based on behavioral indicators of risk (not mental illness, per se), licensing for firearm purchase or ownership, comprehensive background checks for firearm purchase, and supply-side approaches to interrupt illegal firearm markets.
Rethinking Psychiatry: Solutions for a Sociogenic
Crisis
Authors: Hansen Helena , Gutierrez Kevin J. , Garcia Saudi
Published: November 2023

This essay draws on Frantz Fanon's insights about the sociogenesis of psychiatric disorders, and on the insights of feminist standpoint theory, to sketch a map toward sociogenic mental health. We argue that psychiatry should move away from iatrogenesis (the harms of our current individual-level and pathologizing approach) toward sociogenesis of mental health through robust collaboration with social movements of oppressed people, and their collective healing approaches, ranging from harm reduction centers to community gardens. The essay ends with the outlines of a reinvented, community collaborative psychiatry that supports sociogenesis.
Disorders of Mood: The Experience of Those Who Have
Them
Authors: Jamison Kay Redfield
Published: November 2023

Mood disorders are common, painful, and closely tied to suicide and alcohol and substance use. They are also treatable. Mania and depression, a part of the human record for as long as it has been kept, were well-recognized and described by physicians of antiquity. Our knowledge of mood disorders has broadened and deepened in the many centuries since those early times, and crosses many scientific and clinical fields, including genetics, neuropharmacology, neuroimaging, psychopathology, and neuropsychology. We have as well a rich history of personal narratives of depression and bipolar disorder that gives a different but essential perspective; I present several of these accounts here.
Good Mental Health Care: What It Is, What It Is Not & What It
Could Be
Authors: Kleinman Arthur , Gardner Caleb
Published: November 2023

What makes for good mental health care? What are the barriers to good care and, when they can be overcome, what accounts for successful treatment? What does successful treatment and care, in fact, mean? Can they mean different things to different people? If so, how can we think about them in a practical way that is useful to patients, families, and clinicians? On the one hand, from work infields as various as neuroscience, clinical psychology, and anthropology, we are learning (and rediscovering) more and more about how the human mind works and the many ways that psychological suffering can be preempted and treated. On the other hand, in many ways, the mental health care system is either dysfunctional or working against what we know to be best for psychological and social flourishing-the disappearance, for example, of true “care” from medical and mental health care systems. In this essay, set against the background of diverse perspectives provided by the foregoing essays in this volume, we attempt to frame and address some of these basic questions, giving priority to practical, down-to-earth, lay, and professional considerations.