bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B018: Investigating vulnerabilities associated with chromosome arm aneuploidy in cancer
Authors: Zhakula-Kostadinova Nadja , Jain Sejal , Byron Laura , Meyerson Matthew L. , Taylor Alison M.
Published: June 2024

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR016) of the Conference Program/Proceedings.

Citation Format: Nadja Zhakula-Kostadinova, Sejal Jain, Laura Byron, Matthew L. Meyerson, Alison M. Taylor. Investigating vulnerabilities associated with chromosome arm aneuploidy in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B018.
Abstract B026: Screening non-small cell lung cancer patient-derived organoids with epigenetic probes reveals PRMT5 as an oncogenic target
Authors: Jafarova Khadija , Li Quan , Radulovich Nikolina , Liu Geoffrey , Tsao Ming S
Published: June 2024

Lung cancer is the leading cause of cancer-related mortality. Detection of drug actionable genetic alterations has made the standard systemic therapy to a more personalized one including targeted therapy and immune checkpoint blockade. Despite the initial response, majority of patients develop resistance to treatment. Therefore, understanding the mechanisms of resistance as well as discovering novel cancer targets is necessary. Resistance to therapies can be associated with an existing clone of tumor cells with genetic alteration, or the emergence of cells with epigenetic changes overcoming the treatment-induced stress. Therefore, investigating the epigenetic aberrations that occur in tumor cells may reveal novel targetable markers that can be of great clinical significance. Methods: Organoid models established from non-small cell lung cancer (NSCLC) patient surgical resections and pleural effusion were dissociated into single cells and plated in matrigel-coated 384-well plate. A panel of 32 NSCLC organoid models were treated with a library of 41 epigenetic probes (1uM) and a DMSO control over a period of 8 days. Cell titre glo assay was performed to measure cell survival. Results: Arginine methyl transferase protein 5 (PRMT5) inhibited the cell growth of large proportion of the NSCLC organoid models. LLY-283 showed the most significant effect, with 50% of all organoid models (16/32) treated with LLY283 showing ≥50% reduction in cell viability. Further testing with multiple concentrations of several PRMT5 inhibitors revealed models with differential responses to PRMT5 inhibition. To investigate the differential gene expression changes induced by PRMT5 inhibition, we performed RNA-sequencing on three PRMT5 inhibitor sensitive and three resistant organoid models. Ongoing analyses aim at identifying differentially expressed genes in sensitive and resistant models in response to PRMT5 inhibition, and pathway enrichment analysis to determine the differential mechanisms of response to PRMT5 inhibition. Conclusion: Epigenetic drug screening on a large cohort of NSCLC organoid models reveals PRMT5 as potential novel therapeutic target in NSCLC. Further correlative analysis with transcriptomic changes induced by the PRMT5 inhibitors may reveal biomarkers of response.

Citation Format: Khadija Jafarova, Quan Li, Nikolina Radulovich, Geoffrey Liu, Ming S Tsao. Screening non-small cell lung cancer patient-derived organoids with epigenetic probes reveals PRMT5 as an oncogenic target [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B026.
Abstract B029: Assessing gene expression and methylation of KMT2D and IGF2 genes in patients with non-small cell lung cancer
Authors: Matinahmadi Arash , Zayani Zoofa , Bidooki Seyed Hesamoddin , Tavakolpournegari Alireza
Published: June 2024

Background: Aberrant promoter methylation of CpG islands is an important mechanism for regulation of gene expression. Recent data suggest that epigenetic abnormalities may occur very early in lung carcinogenesis. Systemic methylation changes may be a diagnostic marker for tumor development or prognosis. In this study, the expression and methylation of KMT2D and IGF2 genes were investigated in the lung cancer tissue compared to the adjacent normal tissue. Methods: The status of methylation of KMT2D and IGF2 genes were investigated in 30 patients with NSCLC after genomic DNA extraction using bisulfite treatment and MS-HRM method and the expression of these genes were checked by Real-Time PCR method in same samples. Results: For KMT2D gene, the expression and methylation level increased in 46.6% and 6.67% (respectively) for tumor samples comparison with normal samples (P>0.05). Also, for IGF2 gene 50% tumor samples overexpressed and 50% tumor samples showed that reduced expression comparison with the normal samples (P>0.05). In addition, 96.66% of tumor tissues did not show any change in methylation level for IGF2 gene promoter (P>0.05). Conclusion: This study showed that expression and methylation level of KMT2D and IGF2 genes did not change in NSCLC tumor samples compared to normal samples. However, this study was designed as a pilot study, and further investigations are required to confirm our findings.

Citation Format: Arash Matinahmadi, Zoofa Zayani, Seyed Hesamoddin Bidooki, Alireza Tavakolpournegari. Assessing gene expression and methylation of KMT2D and IGF2 genes in patients with non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B029.
Abstract IA011: Towards mapping the landscape of cancer vulnerabilities
Authors: Vazquez Francisca
Published: June 2024

I will introduce the Cancer Dependency Map (DepMap) project. This project aims to build a resource to identify the landscape of cancer vulnerabilities by linking molecular alterations of tumors to gene dependencies or drug sensitivities. This resource is being used by scientists around the world and has made significant contributions to basic and translational cancer research. I will describe how we are building DepMap and the multiple components it requires. Additionally, I will discuss ongoing projects to expand DepMap, including screening next-generation models. I will also present how to identify potential therapeutic targets using DepMap data and the emerging types of targets. Lastly, I will highlight a recently identified synthetic lethal target in the ribosome rescue pathway in molecularly defined patient populations, demonstrating the power of DepMap in identifying such targets.

Citation Format: Francisca Vazquez. Towards mapping the landscape of cancer vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA011.
Abstract IA018: Vulnerabilities of TP53-mutated AML and therapeutic implications
Authors: Bhatt Shruti
Published: June 2024

Acute myeloid leukemia (AML) is a complex and genetically diverse with an overall survival rate of less than 32%. Despite the remarkable success of targeted therapy in mediating remission, the emergence of acquired resistance remains a major clinical challenge to overcome. The prevailing understanding of acquired resistance identifies successive genetic changes as the primary cause.TP53 mutations are found in 70-80% of acute myeloid leukemia (AML) patients with complex karyotypes and associated with resistance towards both conventional chemotherapy and newly approved venetoclax plus azacytidine (VEN/AZA) combination. By using CRISPR-Cas9-edited isogenic AML cells harboring, mutation (6 missense mutations) or deletion (KO) of TP53, we found that TP53 mutant/KO cells are less sensitive to etoposide or VEN-AZA induced apoptosis compared to WT without defect in G1 arrest. Surprisingly, we found that TP53-mutant and TP53-wild-type (WT) isogenic AML cells and primary tumors (n=40) had comparable mitochondrial outer membrane permeabilization (MOMP) at baseline, despite the key role of TP53 in transcriptionally activating proapoptotic regulators of MOMP (such as BAX, PUMA, and NOXA). Based on these findings, we hypothesize that the targets downstream of mitochondrial permeabilization drive resistance to HMA/VEN combinations in TP53 mutant disease. By leveraging unbiased bulk RNA-seq and proteomics, and whole genome CRISPR-cas9 screen we identified IAPs as functional vulnerability. Collectively we reveal novel chemoresistance mechanisms in TP53 mutant/KO downstream of MOMP and provide a targeting strategy to improve existing therapy by targeting non-transcriptional function of TP53 in overcoming therapy resistance.

Citation Format: Shruti Bhatt. Vulnerabilities of TP53-mutated AML and therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA018.
Abstract IA019: Identification of metabolic adaptation mechanisms that confer resistance to glutathione depletion in Ewing sarcoma
Authors: Sorensen Poul H. , Zhang Hai-Feng , Hughes Christopher , Delaidelli Alberto , Aparicio Samuel
Published: June 2024

Aggressive cancer cells must overcome diverse stress forms in the tumor microenvironment and circulation, such as oxidative stress, to survive and metastasize. One adaptive process to counter oxidative stress is to upregulate glutathione (GSH), a tripeptide consisting of glutamate, cysteine, and glycine, which is a powerful antioxidant in cells, including in tumor cells. A rate-liming step in GSH production is the availability of the amino acid, cysteine. Tumor cells can either import cystine, a dimer of cysteine, through the xCT antiporter system, for conversion to the reduced cysteine monomer, or in some tumor types, they can synthesize cysteine de novo from methionine and serine through the transsulfuration pathway. GSH is not only critical for redox homeostasis, but is taken up into mitochondria where is acts as a source of sulphur to generate iron-sulphur (Fe-S) clusters that are essential for many mitochondrial enzymes including electron transport complexes. We wished to determine if Ewing sarcoma cells could tolerate reduced levels of GSH, using either xCT genetic or pharmacologic inhibition, or by blocking downstream enzymes in the GSH synthesis pathway, including GCLC using buthionine sulfoximine (BSO), or glutaminase using CB-839. To our surprise, we were able to generate BSO and CB-839 resistant cells with vanishingly low levels of GSH. These cells somehow maintained not only redox homeostasis, but also showed functional mitochondrial respiration (oxidative phosphorylation). We then performed CRISPR dropout screens to identify how these cells might be surviving in the absence of GSH, and to tease out specific dependencies of these BSO and CB-839 resistant cells. These studies revealed unexpected dependencies, and opportunities for synthetic lethal interventions, as will be discussed.

Citation Format: Poul H. Sorensen, Hai-Feng Zhang, Christopher Hughes, Alberto Delaidelli, Samuel Aparicio. Identification of metabolic adaptation mechanisms that confer resistance to glutathione depletion in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA019.
Abstract IA022: Mechanisms of splicing dysregulation and dependency in cancer
Authors: Karlin Kristen
Published: June 2024

Dysregulated RNA splicing is a hallmark feature of cancer. Much like mutational signatures in tumors, RNA mis-splicing patterns are widely heterogeneous and segregate tumors into clades, suggesting there are distinct mechanisms underlying these splicing aberrations. However, the mechanisms driving such distinct RNA splicing dysregulation remain largely unknown. Herein, we discovered that copy-number variation of essential splicing factors is a pervasive cause of splicing dysregulation, and in some tumor contexts, confers deep dependencies on RNA-binding proteins (RBPs) that converge on these mechanisms. Using a systematic chemical biology approach, we delineate how splicing RBPs participate in distinct types of RNA quality control in cells, and when disrupted, produce surprisingly unique patterns of RNA mis-splicing. These RBP-specific mis-splicing patters are common in distinct cancer types. Notably, unbiased genome-wide analysis revealed that RBP-specific mis-splicing patterns found in tumors were significantly associated with copy number loss of a network of functionally linked splicing factors. These splicing factors often reside on tumor suppressor loci that are frequently deleted in breast and other cancers, suggesting that copy number loss of essential splicing RBPs is a collateral event with selected loss of tumor suppressors. Importantly, RBP-specific mis-splicing signatures also segregate tumor models that are dependent on the concordant RBP, suggesting that these tumors evolve defects in RBP function that predispose them to further perturbation. Together, our work suggests that deletions of tumor suppressor loci may drive collateral dysregulation of RNA splicing through partial loss of splicing RBPs and provokes the hypothesis that these mis-splicing signatures may predict actionable dependencies in the cancers that harbor them.

Citation Format: Kristen Karlin. Mechanisms of splicing dysregulation and dependency in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA022.
Abstract IA023: Targeting epigenetic complexes in leukemia
Authors: Grembecka Jolanta
Published: June 2024

Chromatin-associated multi-protein complexes, which often comprise proteins involved in epigenetic regulation, play an important role in various cancers, including leukemia. Thus, pharmacologic inhibition of proteins involved in these complexes can lead to new anti-cancer therapies. We have focused on therapeutic targeting of various chromatin-bound multi-protein complexes, including Mixed Lineage Leukemia 1 (MLL1) and Polycomb Repressive Complex 1 (PRC1) complexes, as a novel treatment for leukemia. These efforts led to the development of small molecule inhibitors targeting the menin-MLL1 interaction, which were translated to leukemia patients, demonstrating promising efficacy in Acute Myeloid Leukemia (AML) with NPM1 mutations or MLL1 translocations. However, clinical studies revealed resistance to the single agent menin inhibitor in a sub-set of AML patients, suggesting that combinatorial treatments or new generations of menin inhibitors might be required to overcome resistance. Our recent efforts to address resistance to menin inhibitors will be presented, including combinatorial studies with other targeted agents (e.g. kinases inhibitors), which resulted in synergistic effects. Furthermore, discovery of a new generation of menin inhibitors with promising activity against menin patient mutations will also be presented.

Citation Format: Jolanta Grembecka. Targeting epigenetic complexes in leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA023.
Table S1 from Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis
Authors: Rashidi Armin , Ebadi Maryam , Rehman Tauseef U. , Elhusseini Heba , Kazadi David , Halaweish Hossam , Khan Mohammad H. , Hoeschen Andrea , Cao Qing , Luo Xianghua , Kabage Amanda J. , Lopez Sharon , Ramamoorthy Sivapriya , Holtan Shernan G. , Weisdorf Daniel J. , Khoruts Alexander , Staley Christopher
Published: June 2024

UPLC-MS/MS metabolites in serum
TABLE 1 from Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis
Authors: Rashidi Armin , Ebadi Maryam , Rehman Tauseef U. , Elhusseini Heba , Kazadi David , Halaweish Hossam , Khan Mohammad H. , Hoeschen Andrea , Cao Qing , Luo Xianghua , Kabage Amanda J. , Lopez Sharon , Ramamoorthy Sivapriya , Holtan Shernan G. , Weisdorf Daniel J. , Khoruts Alexander , Staley Christopher
Published: June 2024

Baseline patient characteristics
FIGURE 5 from Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis
Authors: Rashidi Armin , Ebadi Maryam , Rehman Tauseef U. , Elhusseini Heba , Kazadi David , Halaweish Hossam , Khan Mohammad H. , Hoeschen Andrea , Cao Qing , Luo Xianghua , Kabage Amanda J. , Lopez Sharon , Ramamoorthy Sivapriya , Holtan Shernan G. , Weisdorf Daniel J. , Khoruts Alexander , Staley Christopher
Published: June 2024

Early post-FMT/placebo serum metabolomics and subsequent aGVHD. A, Logistic LASSO regression to find early posttreatment serum metabolomic predictors of grade II–IV aGVHD. The y axis has all the features evaluated in the model including metabolites and the GVHD prophylactic regimen. Stability (x axis) indicates the proportion of the 100 cross-validated runs in which a given feature remained a significant predictor of GVHD. Positive/negative values show metabolites positively/negatively associated with aGVHD. Other than one metabolite negatively associated with aGVHD, all features were insignificant and formed an almost straight line with 0 stability. B, Association between the novel metabolite in LASSO and grade II–IV aGVHD. C, sPLS-DA loading plot for significant contributors to the first latent component in classification of aGVHD status. Each variable's contribution is shown by a vector. Vectors pointing to the right versus left represent differentially abundant metabolites in early post-FMT/placebo samples not preceding versus preceding grade II–IV aGVHD, respectively. Longer vectors correspond to metabolites with more importance in group classification. D, Multi-omics correlation plot. Spearman correlation coefficients (color gradient) are shown for statistically significant (P < 0.05) correlations. The top five taxa in each cluster (along with the clusters as individual units) and the first 50 metabolites with the highest variance among samples (along with the novel metabolite) were used in this analysis. Each box in B shows the median (horizontal middle line) and interquartile range. Whisker lines indicate nonoutlier maximum and minimum values. A small jitter is included for better visualization. P value is from a Wilcoxon test. aGVHD: acute graft-versus-host disease.
FIGURE 4 from Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis
Authors: Rashidi Armin , Ebadi Maryam , Rehman Tauseef U. , Elhusseini Heba , Kazadi David , Halaweish Hossam , Khan Mohammad H. , Hoeschen Andrea , Cao Qing , Luo Xianghua , Kabage Amanda J. , Lopez Sharon , Ramamoorthy Sivapriya , Holtan Shernan G. , Weisdorf Daniel J. , Khoruts Alexander , Staley Christopher
Published: June 2024

Serum metabolomics before and after FMT versus placebo. A, Distribution of serum metabolites across different pathways. B, PCA using logarithmically transformed metabolite levels, centered and scaled. 50% ellipses are shown. C, sPLS-DA loading plot for significant contributors to the first latent component in treatment arm-based classification. Each variable's contribution is shown by a vector. Vectors pointing to the right versus left represent differentially abundant metabolites in baseline versus pre-FMT/placebo samples, respectively. Longer vectors correspond to metabolites with more importance in group classification. D, Serum metabolomic heatmap among baseline and pre-FMT/placebo samples using the best classifying metabolites from sPLS-DA. Each row is a sample, and each column is a metabolite. The blue-red gradient shows metabolite levels scaled column-wise. E, Same analysis as in D, but for early post-FMT and early post-placebo samples. Logarithmically transformed metabolite values, Euclidean distance, and the complete method for hierarchical clustering were used to generate the heat maps in D and E. FMT: fecal microbiota transplantation, PC: principal component.
FIGURE 2 from Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis
Authors: Rashidi Armin , Ebadi Maryam , Rehman Tauseef U. , Elhusseini Heba , Kazadi David , Halaweish Hossam , Khan Mohammad H. , Hoeschen Andrea , Cao Qing , Luo Xianghua , Kabage Amanda J. , Lopez Sharon , Ramamoorthy Sivapriya , Holtan Shernan G. , Weisdorf Daniel J. , Khoruts Alexander , Staley Christopher
Published: June 2024

Microbiota clusters and aGVHD risk. A, Principal coordinates analysis of early post-FMT/placebo gut microbiota using topic model-based cluster abundances, with groups defined according to treatment arm. B, Same analysis as in A, but with groups defined according to subsequent development of grade II–IV aGVHD or not. C, Comparison between early post-FMT versus early post-placebo samples in topic model-based cluster abundances. D, Same analysis as in C, but with groups defined based on the occurrence of subsequent grade II–IV aGVHD. Samples are early post-FMT/placebo. E, Principal coordinates analysis of pre-FMT/placebo gut microbiota using topic model-based cluster abundances, with groups defined according to GVHD prophylaxis. P values in A, B, and E are from an adonis test with 999 permutations, with percent variation explained by each axis is shown in parentheses. 95% ellipses are shown. P values in C are from a Wilcoxon test after Bonferroni correction. Comparisons in D were not statistically significant. In C and D, each box shows the median (horizontal middle line) and interquartile range. Whisker lines indicate nonoutlier maximum and minimum values. A small jitter is included for better visualization. aGVHD: acute graft-versus-host disease; FMT: fecal microbiota transplantation; PC: principal coordinate; PTCy: posttransplantation cyclophosphamide.
Evolução do uso abusivo de derivados de ópio
Authors: Pereira Mariana de Moura , Andrade Letycia de Paiva , Takitane Juliana
Published: June 2024

Opium is a substance extracted from a plant that belongs to the Papaveraceae family, known popularly as poppy. The name has Greek origin and its nomenclature varies according to provenance, being opiates for natural and some semi-synthetic substances and opioids for synthetic. They act as agonists of specific presynaptic or postsynaptic opioid receptors, located generally in the central nervous system and peripheral system. It is estimated that there are between 12 and 21 million opioid users worldwide and recently some European countries and the United States reached epidemiological levels of consumption. Usually opium derivatives are used as a drug of recreation or as medication for treatment of pain and may cause irreparable damage when used in excess. Thus, the administration, the dose and its frequency should be watched carefully, avoiding undesirable side effects. The aim of this paper is to present the complications arising from the use of these substances, as well as providing information and establish consumption parameters in Brazil and other countries. As it is a topic of concern for public health, it is necessary to encourage further clinical and epidemiological research.
Arithmetic in two languages: Localizing simple multiplication processing in the adult bilingual brain
Authors: Cerda Vanessa R. , Suárez-Pellicioni Macarena , Booth James R. , Wicha Nicole Y.
Published: June 2024

Verbally memorized multiplication tables are thought to create language-specific memories. Supporting this idea, bilinguals are typically faster and more accurate in the language in which they learned math (LA+) than in their other language (LA-). No study has yet revealed the underlying neurocognitive mechanisms explaining this effect, or the role of problem size in explaining the recruitment of different brain regions in LA+ and LA-. To fill this gap in the literature, 29 Spanish-English early bilingual adults, proficient in both languages, verified simple multiplication problems in each language while functional magnetic resonance imaging (fMRI) was acquired. More specifically, this study aimed to answer two questions: 1) Does LA+ recruit left superior and middle temporal gyri (STG/MTG) to a greater extent than LA-, reflecting more robust verbal representations of multiplication facts in LA+? In contrast, does LA- recruit the inferior frontal gyrus (IFG), reflecting more effortful retrieval, or the intraparietal sulcus (IPS), reflecting reliance on quantity processes? 2) Is there an interaction between language and problem size, where language differences are more pronounced for less practiced, large multiplication problems (e.g., 8 x 9) in comparison to more familiar, small problems (e.g., 2 x 3). Functional localizer tasks were used to identify hypothesis-driven regions of interest in verbal areas associated with verbal representations of arithmetic facts (left STG/MTG) and with the effortful retrieval of these facts (left IFG) and quantity areas engaged when calculation-based strategies are used (bilateral IPS). In planned analyses, no cluster reached significance for the direct comparison of languages (question 1) or for the interaction between language and problem size (question 2). An exploratory analysis found a main effect of problem size, where small problems recruited left STG/MTG and left IFG to a greater extent than large problems, suggesting greater verbal involvement for these problems in both languages. Additionally, large problems recruited right IPS to a greater extent than small problems, suggesting reliance on quantity processes. Our results suggest that proficient early bilingual adults engage similar brain regions in both languages, even for more difficult, large problems.
A new species of the fossil pufferfish genus †Archaeotetraodon (Tetraodontidae) from the Middle Miocene of the North Caucasus, Russia
Authors: BANNIKOV ALEXANDRE F. , TYLER JAMES C.
Published: June 2024

The fossil puffer fish genus †Archaeotetraodon Tyler & Bannikov, 1994 is unique among the Tetraodontidae in having the upright central spinule of the dermal scale plates bifid rather than singular and undivided. Six species of this genus have previously been described variously from the Oligocene and Miocene of Russia, Italy, Algeria, and Ukraine. Described herein is a seventh species of this genus, †Archaeotetraodon bemisae sp. nov., based upon two specimens from the Pshekha River, Krasnodar Region, North Caucasus, Russia. These Maikopian specimens are no less than 15 mya, in the basal-most Middle Miocene. The new species is distinguished from the other six species in the genus by the following combination of characters: thick, sturdy, and smooth bifid spinules; frontal width broad over the orbit; 18 vertebrae; slender ventral postcleithrum; a moderately long rayless pterygiophore; height/length ratio of the posteriormost abdominal centrum being 0.78–0.79; 10 dorsal-fin rays; 9 anal-fin rays; and 14 pectoral-fin rays.
PE/PPE mutations in the transmission of Mycobacterium tuberculosis in China revealed by whole genome sequencing
Authors: Fang Wei-wei , Kong Xiang-long , Yang Jie-yu , Tao Ning-ning , Li Ya-meng , Wang Ting-ting , Li Ying-Ying , Han Qi-lin , Zhang Yu-zhen , Hu Jin-jiang , Li Huai-chen , Liu Yao
Published: June 2024

Objective

This study aims to examine the impact of PE/PPE gene mutations on the transmission of Mycobacterium tuberculosis (M. tuberculosis) in China.

Methods

We collected the whole genome sequencing (WGS) data of 3202 M. tuberculosis isolates in China from 2007 to 2018 and investigated the clustering of strains from different lineages. To evaluate the potential role of PE/PPE gene mutations in the dissemination of the pathogen, we employed homoplastic analysis to detect homoplastic single nucleotide polymorphisms (SNPs) within these gene regions. Subsequently, logistic regression analysis was conducted to analyze the statistical association.

Results

Based on nationwide M. tuberculosis WGS data, it has been observed that the majority of the M. tuberculosis burden in China is caused by lineage 2 strains, followed by lineage 4. Lineage 2 exhibited a higher number of transmission clusters, totaling 446 clusters, of which 77 were cross-regional clusters. Conversely, there were only 52 transmission clusters in lineage 4, of which 9 were cross-regional clusters. In the analysis of lineage 2 isolates, regression results showed that 4 specific gene mutations, PE4 (position 190,394; c.46G > A), PE_PGRS10 (839,194; c.744 A > G), PE16 (1,607,005; c.620T > G) and PE_PGRS44 (2,921,883; c.333 C > A), were significantly associated with the transmission of M. tuberculosis. Mutations of PE_PGRS10 (839,334; c.884 A > G), PE_PGRS11 (847,613; c.1455G > C), PE_PGRS47 (3,054,724; c.811 A > G) and PPE66 (4,189,930; c.303G > C) exhibited significant associations with the cross-regional clusters. A total of 13 mutation positions showed a positive correlation with clustering size, indicating a positive association. For lineage 4 strains, no mutations were found to enhance transmission, but 2 mutation sites were identified as risk factors for cross-regional clusters. These included PE_PGRS4 (338,100; c.974 A > G) and PPE13 (976,897; c.1307 A > C).

Conclusion

Our results indicate that some PE/PPE gene mutations can increase the risk of M. tuberculosis transmission, which might provide a basis for controlling the spread of tuberculosis.
Genome-wide association analysis and transgenic characterization for amylose content regulating gene in tuber of Dioscorea zingiberensis
Authors: Sun Shixian , Guan Binbin , Xing Yue , Li Xiang , Liu Lanlan , Li Yanmei , Jia Lu , Ye Shili , Dossa Komivi , Zheng Li , Luan Yunpeng
Published: June 2024

Background

Amylose, a prebiotic found in yams is known to be beneficial for the gut microflora and is particularly advantageous for diabetic patients’ diet. However, the genetic machinery underlying amylose production remains elusive. A comprehensive characterization of the genetic basis of amylose content in yam tubers is a prerequisite for accelerating the genetic engineering of yams with respect to amylose content variation.

Results

To uncover the genetic variants underlying variation in amylose content, we evaluated amylose content in freshly harvested tubers from 150 accessions of Dioscorea zingibensis. With 30,000 high-quality single nucleotide polymorphisms (SNP), we performed a genome-wide association analysis (GWAS). The population structure analysis classified the D. zingiberensis accessions into three groups. A total of 115 significant loci were detected on four chromosomes. Of these, 112 significant SNPs (log10(p) = 5, q-value < 0.004) were clustered in a narrow window on the chromosome 6 (chr6). The peak SNP at the position 75,609,202 on chr6 could explain 63.15% of amylose variation in the population and fell into the first exon of the ADP-glucose pyrophosphorylase (AGPase) small subunit gene, causing a non-synonymous modification of the resulting protein sequence. Allele segregation analysis showed that accessions with the rare G allele had a higher amylose content than those harboring the common A allele. However, AGPase, a key enzyme precursor of amylose biosynthesis, was not expressed differentially between accessions with A and G alleles. Overexpression of the two variants of AGPase in Arabidopsis thaliana resulted in a significantly higher amylose content in lines transformed with the AGPase-G allele.

Conclusions

Overall, this study showed that a major genetic variant in AGPase probably enhances the enzyme activity leading to high amylose content in D. zingiberensis tuber. The results provide valuable insights for the development of amylose-enriched genotypes.
Efficacy and safety of intrathecal dexamethasone combined with isoniazid in the treatment of tuberculous meningitis: a meta-analysis
Authors: Gao Yan , Su Jinwen , Ma Yuxiang , Sun Yunliang , Cui Jiyong , Jin Xianhe , Li Yuxi , Chen Zhi
Published: June 2024

Background

The treatment regimen for tuberculous meningitis (TBM) remains unclear and requires optimization. There are some reports on successful adjunct intrathecal dexamethasone and isoniazid (IDI) treatment strategies for TBM, however, there is equivocal evidence on their efficacy and safety.

Methods

A comprehensive search of English and Chinese databases was conducted from inception to February 2024. A meta-analysis was performed on randomized controlled trials (RCTs) estimating the effects of adjunct IDI on conventional anti-TB (C anti-TB) treatments or C anti-TB alone. Efficacy, adverse reaction rate, cerebrospinal fluid (CSF) leukocytes, and CSF protein were used as primary outcome indicators. CSF glucose, CSF chlorides, CSF pressure, recovery time for laboratory indicators and recovery time for clinical symptoms were used as secondary outcome indicators.

Results

A total of 17 studies involving 1360 (IDI group vs. C anti-TB group: 392 vs. 372; higher-dose IDI group vs. lower-dose IDI group: 319 vs. 277) patients were included in our analysis. Efficacy was significantly higher (RR 1.3, 95% CI 1.2-1.4, P < 0.001) and adverse reaction rate was significantly lower in the IDI groups (RR 0.59, 95% CI 0.37-0.92, P = 0.021). Furthermore, CSF leukocytes (WMD - 29.33, 95% CI [- 40.64 to-18.02], P < 0.001) and CSF protein (WMD - 0.79, 95%CI [-0.96 to-0.61], P < 0.001) were significantly lower in the IDI groups. Recovery time indicators were all shorter in the IDI groups, fever (SMD - 2.45, 95% CI [-3.55 to-1.35], P < 0.001), coma (SMD-3.75, 95% CI [-4.33 to-3.17], P < 0.001), and headache (SMD  - 3.06, 95% CI [- 4.05 to-2.07], P < 0.001), respectively. Higher-dose IDI was more effective than lower-dose IDI (RR 1.23, 95% CI 1.14-1.33, P < 0.001), with no significant difference in adverse reaction rate between the two (RR 0.82, 95%CI 0.43–1.56, P = 0.544).

Conclusion

Adjunct IDI with C anti-TB can enhance therapeutic outcomes and reduce adverse reaction rate in adult TBM patients, with higher-dose IDI showing superior efficacy. These findings highlight the potential of IDI as an adjunctive therapy in TBM management. However, more high-quality RCTs from more regions should be conducted to support our results.

Trial registration

Retrospectively registered in PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023388860.
Women’s and maternity care providers’ perceptions of pain management during childbirth in hospitals in Southern Tanzania
Authors: Thorgaard-Rasmussen Katrine , Alvesson Helle Mölsted , Pembe Andrea B. , Mselle Lilian T. , Unkels Regine , Metta Emmy , Alwy Al-beity Fadhlun M.
Published: June 2024

Background

The majority of women experience pain during childbirth. Offering and supporting women to use different methods for coping with pain is an essential competency for maternity care providers globally. Research suggests a gap between what women desire for pain management and what is available and provided in many low-and middle-income settings. The study aimed to understand how pain management is perceived by those involved: women experiencing childbirth and maternity care providers.

Methods

Individual semi-structured interviews with women (n = 23), maternity care providers (n = 17) and focus group discussions (n = 4) with both providers and women were conducted in two hospitals in Southern Tanzania in 2021. Transcribed interviews were analysed using reflexive thematic analysis. Coding and analysis were supported by the software MAXQDA.

Results

Three main themes were generated from the data. The first, ‘pain management is multifaceted’, describes how some providers and women perceived pain management as entailing various methods to manage pain. Providers perceived themselves as having a role in utilization of pain management to varying degree. The second theme ‘pain management is primarily a woman’s task’ highlights a perception of pain management as unnecessary, which appeared to link with some providers’ perceptions of pain as natural and necessary for successful childbirth. Few women explicitly shared this perception. The third theme ‘practice of pain management can be improved’ illustrates how women and maternity care providers perceived current practices of pain management as suboptimal. According to providers, this is primarily due to contextual factors such as shortage of staff and poor ward infrastructure.

Conclusion

Women’s and maternity care providers’ perceptions ranged from perceiving pain management as involving a combination of physiological, psychological and social aspects to perceive it as related with limited to no pain relief and/or support. While some women and providers had similar perceptions about pain management, other women also reported a dissonance between what they experienced and what they would have preferred. Efforts should be made to increase women’s access to respectful pain management in Tanzania.
Development and validation of an inflammatory biomarkers model to predict gastric cancer prognosis: a multi-center cohort study in China
Authors: Zhang Shaobo , Xu Hongxia , Li Wei , Cui Jiuwei , Zhao Qingchuan , Guo Zengqing , Chen Junqiang , Yao Qinghua , Li Suyi , He Ying , Qiao Qiuge , Feng Yongdong , Shi Hanping , Song Chunhua
Published: June 2024

Background

Inflammatory factors have increasingly become a more cost-effective prognostic indicator for gastric cancer (GC). The goal of this study was to develop a prognostic score system for gastric cancer patients based on inflammatory indicators.

Methods

Patients’ baseline characteristics and anthropometric measures were used as predictors, and independently screened by multiple machine learning(ML) algorithms. We constructed risk scores to predict overall survival in the training cohort and tested risk scores in the validation. The predictors selected by the model were used in multivariate Cox regression analysis and developed a nomogram to predict the individual survival of GC patients.

Results

A 13-variable adaptive boost machine (ADA) model mainly comprising tumor stage and inflammation indices was selected in a wide variety of machine learning models. The ADA model performed well in predicting survival in the validation set (AUC = 0.751; 95% CI: 0.698, 0.803). Patients in the study were split into two sets – “high-risk” and “low-risk” based on 0.42, the cut-off value of the risk score. We plotted the survival curves using Kaplan-Meier analysis.

Conclusion

The proposed model performed well in predicting the prognosis of GC patients and could help clinicians apply management strategies for better prognostic outcomes for patients.
Prognostic marker VPS72 could promote the malignant progression of prostate cancer
Authors: Xu Xiaolong , Wang Wei , He Yi , Yao Yiqun , Yang Bo
Published: June 2024

Background

This paper attempted to clarify the role and mechanism of vacuolar protein sorting-associated protein 72 homolog (VPS72) in the progression of prostate cancer (PCa).

Methods

Clinical information and gene expression profiles of patients with prostate cancer were obtained from The Cancer Genome Atlas (TCGA). VPS72 expression in PCa and the potential mechanism by which VPS72 affects PCa progression was investigated. Next, we performed COX regression analysis to identify the independent prognostic factors of PCa, and constructed a nomogram. The sensitivity of chemotherapeutic medications was anticipated using “pRRophetic”. Subsequently, in vitro assays to validate the effect of VPS72 on PCa cell proliferation, migration and susceptibility to anti-androgen therapy.

Results

The expression of VPS72 was considerably higher in PCa tissues compared to normal tissues. Significant correlations were found between high VPS72 expression and a poor prognosis and adverse clinicopathological factors. The nomogram model constructed based on VPS72 expression has good predictive performance. According to GSEA, VPS72-related genes were enriched in the NF-kB pathways, cytokine-cytokine receptor interaction and chemokine signaling pathway in PCa. Although PCa with low VPS72 expression was more adaptable to chemotherapeutic medications, our in vitro experiment showed that VPS72 knockdown significantly decreased the PCa cell migration, proliferation, and resistance to anti-androgen therapy.

Conclusions

In summary our findings suggests that VPS72 could play a crucial role in the malignant progression of PCa, and its expression level can be employed as a possible biomarker of PCa prognosis.
Neurotrophic keratitis caused by lightning injury: a case report
Authors: Yi Sidou , Wang Guoping , Meng Xuan , Lu Xuejing
Published: June 2024

Background

This study aimed to report a case of neurotrophic keratitis caused by lightning.

Case presentation

A 38-year-old man was hit by lightning and suffered eye injury. He eventually developed neurotrophic keratitis.

Results

The patient’s injury history and burn site were analyzed, and it was judged that lightning directly damaged his cornea, eventually resulting in neurotrophic keratitis. Fortunately, the patient’s vision improved after treatment.

Conclusion

Lightning can cause eye damage, and the clinical manifestations are diverse. Lightning currents cause corneal nerve loss, resulting in neurotrophic keratitis. To maintain corneal integrity and prevent disease progression, early assessment and appropriate treatment are necessary.
Awareness of glaucoma among adult patients attending hawassa university comprehensive specialized hospital ophthalmic outpatient department, Sidama, Ethiopia, August 2022
Authors: Kebede Balcha Negese , Seid Seid Mohammed , Kefyalew Biruktayit
Published: June 2024

Background

Due to the asymptomatic nature of the disease and lack of awareness, most glaucoma patients present for eye examination late, after significant damage of optic nerve occur. Being aware of glaucoma is important for timely diagnosis of the disease and preventing blindness from it.

Objective

The aim of this study was to assess glaucoma awareness and associated factors among adult patients aged 35 and over attending the eye outpatient department.

Methods

Hospital based cross-sectional study was conducted on 284 adult patients aged 35 and over attending ophthalmic outpatient department from July to August 2022 using systematic random sampling. An interviewer-administered questionnaire was used to collect data. The data were checked for completeness, and then entered to SPSS version 22 software. Descriptive and binary logistic regression analyses were performed. Independent variables with p-value ≤ 0.05 in multivariate logistic regression were considered as statistically significant.

Results

About 284 study participants, of whom 57.75% were male, participated in this study with a response rate of 94.1%. The mean age of the study participants was 53.58 years. Only 39.09%(95% CI: 36.53–41.65) were aware of glaucoma. Age groups 46–50 [AOR; 1.83: 1.18, 2.56] and 51–64 [AOR; 3.21: 2.03, 4.39], having college education or above [AOR; 3.1: 2.20, 6.64], family member with glaucoma [AOR; 5.86:3.25, 8.0], income 6500 ETB [AOR; 2.9: 1.97, 5.00] and previous eye examination [AOR; 2.15: 1.46, 4.05] were factors significantly associated with awareness of glaucoma. The main sources of information were news media, family members with glaucoma and health workers.

Conclusion

More than half (60.91%) of adult ophthalmic patients attending HUCSH were unaware of glaucoma and need eye health education concerning glaucoma.
Using structural equation modeling to examine correlations between health-related physical fitness and cell health among Chinese college students
Authors: Zhu Jian , Yang Yi , Zhao Yanmin , Qin Guoyang , Su Xin
Published: June 2024

Introduction

College students’ physical fitness is likely to be directly related to their cells’ health. However, there is a lack of literature on whether the relationship between cell health and college students’ physical fitness is direct or indirect. This study used a structural equation modeling (SEM) approach to investigate the connection between cell health and college students’ physical fitness.

Methods

This cross-sectional study collected data from 838 volunteers (502 males and 336 females, average age of 18.74 ± 1.5 years) who were college students from the Shandong province of China in July 2023. Initially, we obtained anthropometric measurements and conducted physical fitness tests on the students. Then, we performed Pearson correlation analysis and principal component analysis to screen variables and explore potentially influencing factors. Finally, we examined associations between the variables and determined whether there were direct or indirect influences among factors using SEM.

Results

The results revealed a significant correlation between the cell health factor and the muscle strength factor (path coefficient = 0.97; p < 0.001) as well as the fat obesity factor (path coefficient = -0.52; p < 0.001). The cardiovascular factor exhibited a weak correlation with the cell health factor (path coefficient = 0.11; p < 0.01). Moreover, the cardiovascular factor acted as a mediating variable between the muscle strength factor and the cell health factor, with a positive correlation observed between the muscle strength factor and the cell health factor (path coefficient = 0.40; p < 0.001).

Conclusion

These findings suggest that cell health is indicative of muscle strength and cardiorespiratory fitness. Our findings demonstrate that assessing the cell health of college students can be a valuable method for evaluating their overall health.