Club-like cells in proliferative inflammatory atrophy of the prostate.

Club cells are a type of bronchiolar epithelial cell that serve a protective role in the lung and regenerate damaged lung epithelium. Single-cell RNA sequencing (scRNA-seq) of young adult human prostate and urethra identified cell populations in the prostatic urethra and collecting ducts similar in morphology and transcriptomic profile to lung club cells. We further identified club cell-like epithelial cells by scRNA-seq of prostate peripheral zone tissues. Here, we aimed to identify and spatially localize club cells in situ in the prostate, including in the peripheral zone. We performed chromogenic RNA in situ hybridization for five club cell markers (CP, LTF, MMP7, PIGR, SCGB1A1) in a series of (1) nondiseased organ donor prostate and (2) radical prostatectomy specimens from individuals with prostate cancer. We report that expression of club cell genes in the peripheral zone is associated with inflammation and limited to luminal epithelial cells classified as intermediate cells in proliferative inflammatory atrophy (PIA). Club-like cells were enriched in radical prostatectomy specimens compared to nondiseased prostates and associated with high-grade prostate cancer. We previously reported that luminal epithelial cells in PIA can rarely harbor oncogenic TMPRSS2:ERG (ERG+) gene fusions, and we now demonstrate that club cells are present in association with ERG+ PIA that is transitioning to early adenocarcinoma. Finally, prostate epithelial organoids derived from prostatectomy specimens demonstrate that club-like epithelial cells can be established in organoids and are sensitive to anti-androgen-directed treatment in vitro in terms of decreased androgen signaling gene expression signatures compared to basal or hillock cells. Overall, our study identifies a population of club-like cells in PIA and proposes that these cells play an analogous role to that of club cells in bronchiolar epithelium. Our results further suggest that inflammation drives lineage plasticity in the human prostate and that club cells in PIA may be prone to oncogenic transformation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Mn(II) Coordination Complex Loaded Hydrogel: Synthesis, Characterization, Fluorescence Properties, and Application in Treating Knee Arthritis.

Using a mixed-ligand approach, we successfully obtained two Mn(II)-based coordination compounds, namely [Mn2(L1)(TBIP)·H2O]n (1) and [Mn2(L2)(NPTA)·H2O]n (2) (where L1 and L2 are 1,4-bis(thiabenzimidazol-1-ylmethyl)benzene and 1,2-bis(thiabenzimidazol-1-ylmethyl)benzene, H2NPTA is 2-nitroterephthalic acid, and H2TBIP is 5-tert-butylisophthalic acid). Fluorescence performance testing of complexes 1 and 2 showed excellent green and blue fluorescence properties. Based on this, we further prepared HA/CMCS hydrogels using natural polysaccharides hyaluronic acid (HA) and carboxymethyl chitosan (CMCS) as raw materials and studied their internal structural characteristics using scanning electron microscopy. Using "Duhuo Jisheng Decoction" as a drug model, two metal gel scaffolds loaded with "Duhuo Jisheng Decoction" were prepared, and their potential for treating knee osteoarthritis was evaluated.

The association between leptin and diabetes: A meta-analysis.

PURPOSE: The study object was to determine the relationship between leptin and diabetes. METHODS: We searched for the literature on the relationship between leptin and diabetes from PubMed, EMBASE, Cochrane Library, and CNKI databases. We carried out the meta-analysis by calculating the Std. Mean Difference (SMD) and 95% confidence intervals (CIs) to study the relationship between leptin and diabetes. We performed the Chi-square-based Q test and I2 statistics to evaluate the potential heterogeneity, and the sensitivity analysis was performed to evaluate the stability of our results. Moreover, Begg's test was performed to evaluate the publication bias. RESULTS: There are 10 studies in this study for meta-analysis, which include 1879 patients (diabetic (n = 1024); and nondiabetic patients (n = 855)). The results indicated that the levels of serum leptin were significantly increased in patients with diabetes (SMD = 1.78, 95% CI [0.81, 2.76]), especially those with gestational diabetes mellitus compared with controls (SMD = 3.03, 95% CI [1.21, 4.86]). However, the results showed that there was no difference in serum leptin levels between type 2 diabetes and controls (SMD = 0.34, 95% CI [-1.06, 1.74]). CONCLUSIONS: Our analysis indicated that the levels of serum leptin were significantly elevated in patients with diabetes especially those with gestational diabetes mellitus compared with controls.

Transcriptomic profiling and genomic rearrangement landscape of Nigerian prostate cancer.

BACKGROUND: Men of African ancestry have disproportionately high incidence rates of prostate cancer (PCa) and have high mortality rates. While there is evidence for a higher genetic predisposition for incidence of PCa in men of African ancestry compared to men of European ancestry, there have been few transcriptomic studies on PCa in men of African ancestry in the African continent. OBJECTIVE: We performed transcriptomic profiling and fusion analysis on bulk RNA sequencing (RNA-seq) samples from 24 Nigerian PCa patients to investigate the transcriptomic and genomic rearrangement landscape of PCa in Nigerian men. DESIGN: Bulk RNA-seq was performed on 24 formalin-fixed paraffin-embeded (FFPE) prostatectomy specimens of Nigerian men. Transcriptomic analysis was performed on 11 high-quality samples. Arriba Fusion and STAR Fusion were used for fusion detection. RESULTS: 4/11 (36%) of the samples harbored an erythroblast transformation-specific (ETS) fusion event; 1/11 (9%) had a TMPRSS2-ERG fusion; 2/11 had a TMPRSS2-ETV5 fusion, and 1/11 had a SLC45A3-SKIL fusion. Hierarchical clustering of normalized and mean-centered gene expression showed clustering of fusion positive samples. Furthermore, we developed gene set signatures for Nigerian PCa based on fusion events. By projecting the cancer genome atlas prostate adenocarcinoma (TCGA-PRAD) bulk RNA-seq data set onto the transcriptional space defined by these signatures derived from Nigerian PCa patients, we identified a positive correlation between the Nigerian fusion signature and fusion positive samples in the TCGA-PRAD data set. CONCLUSIONS: Less frequent ETS fusion events other than TMPRSS2-ERG such as TMPRSS2-ETV5 and non-ETS fusion events such as SLC45A3-SKIL may be more common in PCa in Nigerian men. This study provides useful working transcriptomic signatures that characterize oncogenic states representative of specific gene fusion events in PCa from Nigerian men.

Heat stress promotes the conversion of putrescine to spermidine and plays an important role in regulating ganoderic acid biosynthesis in Ganoderma lucidum.

Heat stress (HS) is inescapable environmental stress that can induce the production of ganoderic acids (GAs) in Ganoderma lucidum. Our previous studies found that putrescine (Put) played an inhibitory role in GAs biosynthesis, which appeared to be inconsistent with the upregulated transcription of the Put biosynthetic gene GlOdc under HS. To uncover the mechanism underlying this phenomenon, two spermidine (Spd) biosynthetic genes, GlSpds1 and GlSpds2, were identified and upregulated under HS. Put and Spd increased by 94% and 160% under HS, respectively, suggesting that HS induces polyamine biosynthesis and promotes the conversion of Put to Spd. By using GlSpds knockdown mutants, it is confirmed that Spd played a stimulatory role in GAs biosynthesis. In GlOdc-kd mutants, Put decreased by 62-67%, Spd decreased by approximately 34%, and GAs increased by 15-22% but sharply increased by 75-89% after supplementation with Spd. In GlSpds-kd mutants, Put increased by 31-41%, Spd decreased by approximately 63%, and GAs decreased by 24-32% and were restored to slightly higher levels than a wild type after supplementation with Spd. This result suggested that Spd, rather than Put, is a crucial factor that leads to the accumulation of GAs under HS. Spd plays a more predominant and stimulative role than Put under HS, possibly because the absolute content of Spd is 10 times greater than that of Put. GABA and H2O2, two major catabolites of Spd, had little effect on GAs biosynthesis. This study provides new insight into the mechanism by which environmental stimuli regulate secondary metabolism via polyamines in fungi. KEY POINTS: • HS induces polyamine biosynthesis and promotes the conversion of Put to Spd in G. lucidum. • Put and Spd played the inhibitory and stimulatory roles in regulating GAs biosynthesis, respectively. • The stimulatory role of Spd was more predominant than the inhibitory role of Put in GAs biosynthesis.

First Report of Pseudopestalotiopsis theae Causing Leaf Spot of Date Palm (Phoenix dactylifera) in China.

Date palm (Phoenix dactylifera L.) is a popular landscape tree in Fujian province, in South China. In November 2018 and June 2019, a leaf spot disease was observed on date palm in Fuzhou city. A survey of date palm plants grown in four different locations revealed that the disease incidence was almost 20%. The spots were brown with a yellow margin, 1 to 20 mm in diameter, and oval to irregular. In later stages, the spots gradually expanded and coalesced, became dry and died. For isolation, small pieces (0.5 cm2) were cut from leaf spots obtained from seven trees and disinfested with 70% alcohol. Leaf pieces were then placed onto 2% potato dextrose agar (PDA) and incubated at 25±2°C for 3 to 4 days. One fungus was consistently isolated from fifteen leaves. Fungal colonies were white with undulating margins and a light cream on the reverse side. Black globose to oblate conidiomata were irregularly distributed throughout ten-day-old colonies. The conidiogenous cells were septate, colorless, smooth-walled, straight to slightly curved, ampulliform or subcylindrical, and 6.0 to 13.5 × 1.3 to 3.0 µm [(n=50); x̄ ± SD = 9.5 ± 2× 2 ± 0.5µm]. Conidia were fusiform and five-celled with constrictions at the septa, measuring 18.5 to 31.5 × 5.0 to 7.5 µm [(n=50); x̄ ± SD = 25.5 ± 2 × 6.5± 0.2µm]. The three median cells were light to dark brown and the two end cells were colorless. Apical cells had 2 to 4 appendages ranging from 10.2 to 22.5 µm long. Basal cells had one appendage ranging from 3.5 to 5.5 µm long. The internal transcribed spacer (ITS) region of the ribosomal DNA and translation elongation factor 1-alpha (TEF1-α) gene of fungus were amplified using primers ITS1/ITS4 and EF1728F/EF1986R, respectively. Amplified products (ITS: MN294700 and TEF1-α: MN970514) showed 99% sequence identity to Pestalotiopsis sp., and Pseudoestalotiopsis theae sequences in GenBank. A comparison of MRC12 sequences with the type culture sequences (ITS: JQ683727 and TEF1-a: JQ683743) also showed high similarity, where ITS sequences exhibited only a three-nucleotide difference at the start of the sequences. No differences, however, were found between the TEF1-α sequences. On the basis of morphology and molecular characteristics, the fungus was identified as Ps. theae (Sawada) Maharachch., K.D. Hyde & Crous Steyaert (Maharachchikumbura et al. 2014). To confirm pathogenicity, five disinfested leaves on three healthy five-year-old date palm plants in a nursery (average temperature 26°C), were punctured 3 to 5 times with a sterilized needle, and then 10 to 15 mL conidial suspension (105 conidia/mL in sterilized distilled water) was sprayed over punctured areas of the leaves. For the control treatment, punctured leaves were sprayed with sterilized distilled water. All inoculated leaves plus the control were covered with plastic bags. After 10 days, brown leaf spots similar in appearance to those observed in the field appeared on all wounded leaves, and Ps. theae was successfully re-isolated; the control leaves remained asymptomatic. Previously, Ps. theae was reported on oil palm (Elaeis guineensis Jacq.) from Sierra Leone and Thailand (Turner, 1971; Suwannarach et al. 2013). To our knowledge, this is the first report of Ps. theae on date palm in China. This report expands the host range Ps. theae to date palm and underscores the potential threat of an emerging leaf spot pathogen on Phoenix species. References Maharachchikumbura, K.D., et al. 2014. Stud. Mycol. 79: 121-186. Suwannarach, N., et al. 2013. J. Gen. Plant Pathol. 79: 277-279. Turner, P.D. 1971. Phytopathol. 14: 1-58.

Functional Interactions between Mammalian Respiratory Rhythmogenic and Premotor Circuitry.

UNLABELLED: Breathing in mammals depends on rhythms that originate from the preBötzinger complex (preBötC) of the ventral medulla and a network of brainstem and spinal premotor neurons. The rhythm-generating core of the preBötC, as well as some premotor circuits, consist of interneurons derived from Dbx1-expressing precursors (Dbx1 neurons), but the structure and function of these networks remain incompletely understood. We previously developed a cell-specific detection and laser ablation system to interrogate respiratory network structure and function in a slice model of breathing that retains the preBötC, the respiratory-related hypoglossal (XII) motor nucleus and XII premotor circuits. In spontaneously rhythmic slices, cumulative ablation of Dbx1 preBötC neurons decreased XII motor output by ∼50% after ∼15 cell deletions, and then decelerated and terminated rhythmic function altogether as the tally increased to ∼85 neurons. In contrast, cumulatively deleting Dbx1 XII premotor neurons decreased motor output monotonically but did not affect frequency nor stop XII output regardless of the ablation tally. Here, we couple an existing preBötC model with a premotor population in several topological configurations to investigate which one may replicate the laser ablation experiments best. If the XII premotor population is a "small-world" network (rich in local connections with sparse long-range connections among constituent premotor neurons) and connected with the preBötC such that the total number of incoming synapses remains fixed, then the in silico system successfully replicates the in vitro laser ablation experiments. This study proposes a feasible configuration for circuits consisting of Dbx1-derived interneurons that generate inspiratory rhythm and motor pattern. SIGNIFICANCE STATEMENT: To produce a breathing-related motor pattern, a brainstem core oscillator circuit projects to a population of premotor interneurons, but the assemblage of this network remains incompletely understood. Here we applied network modeling and numerical simulation to discover respiratory circuit configurations that successfully replicate photonic cell ablation experiments targeting either the core oscillator or premotor network, respectively. If premotor neurons are interconnected in a so-called "small-world" network with a fixed number of incoming synapses balanced between premotor and rhythmogenic neurons, then our simulations match their experimental benchmarks. These results provide a framework of experimentally testable predictions regarding the rudimentary structure and function of respiratory rhythm- and pattern-generating circuits in the brainstem of mammals.

All-Optical Control of Ultrafast Switching between the Hybridized Plasmonic Fields of Au Nanorod Dimer in fs-nm Scale with Dispersed Femtosecond Laser.

With the increasing demand for ultrafast communication and information processing in future optical chips, arbitrary manipulation of electromagnetic fields in the femtosecond-nanometer spatiotemporal scale has attracted great attention in integrated optics. Manipulation of the nanoscale light field in the real femtosecond temporal domain is challenging work. Here, we have demonstrated all-optical control of ultrafast switching between the hybridized plasmonic fields of a Au nanorod dimer in the fs-nm scale using a dispersed femtosecond laser and revealed the transformation process with ultrahigh spatiotemporal resolved technology via the combination of a pump-probe technique and photoemission electron microscopy (PEEM). The results show that we can actively and coherently control the transformation sequence and time (with the shortest temporal interval of around 15 fs) of the two hybridized modes in the Au nanorod dimer by tuning the dispersion of the laser pulse. The nanoscale light manipulation achieved by all-optical control may contribute to the design of high-speed miniaturized signal-processing systems.

RPL22 is a tumor suppressor in MSI-high cancers and a splicing regulator of MDM4.

Microsatellite instability-high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion and cell proliferation and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses the expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.

Conocybe Section Pilosellae in China: Reconciliation of Taxonomy and Phylogeny Reveals Seven New Species and a New Record.

Conocybe belongs to the Bolbitiaceae. The morphological classification and molecular phylogenetics of Conocybe section Pilosellae are not in agreement. In this study, based on the specimens from China, we investigated the sect. Pilosellae and identified 17 species, including 7 new species: Conocybe pilosa, with a densely hairy pileus and stipe; C. reniformis, with reniform spores; C. ceracea, with waxy dehydration of the lamellae; C. muscicola, growing on moss; C. sinobispora, with two-spored basidia; C. hydrophila, with a hygrophanous pileus; C. rufostipes, growing on dung with a brown stipe; and C. pseudocrispa, one new record for China. A key was compiled for the sect. Pilosellae in China. Here, the sect. Pilosellae, and new species and records from China are morphologically described and illustrated. Maximum likelihood and Bayesian analyses were performed using a combined nuc rDNA internal transcribed spacer region (ITS) and nuc 28S rDNA (nrLSU), and translation elongation factor 1-alpha (tef1-α) dataset to reconstruct the relationships of this section. We found that the sect. Pilosellae was the basal clade of Conocybe, and its evolutionary features may shed light on the characteristics of Conocybe. By integrating morphological classification and phylogenetic analysis, we explored the possible phylogenetic relationships among the species of the sect. Pilosellae in China.

Novel Autophagy-Related Blood Biomarkers Associated with Immune Cell Infiltration in Ankylosing Spondylitis.

Background: This study aims to identify new therapeutic targets and explore the molecular mechanism of ankylosing spondylitis (AS), a rheumatic immune disease that mainly affects the sacroiliac and spinal joints. Despite extensive research, the exact cause of AS is still unknown. The research team utilized a bioinformatics approach to achieve their objectives. Methods: The GSE73754 dataset was downloaded from GEO database. Autophagy-related genes (ARGs) were collected from the Human Autophagy-dedicated Database. The limma package was used to screen for differentially expressed genes (DEGs), which were then intersected with the autophagy-related genes (ARGs) to identify differentially expressed autophagy-related genes (DEARGs). Subsequently, the DEARGs associated with AS were subjected to GO-BP and KEGG enrichment analyses using the clusterProfiler package. Core genes were identified using the cytoHubba plug-in of Cytoscape and were validated by clinical blood samples. Additionally, the Cell algorithm was utilized to evaluate the proportion of immune cell infiltration. Results: A total of 29 DEARGs were identified, which were found to be mainly enriched in autophagy, apoptosis, and necroptosis through functional enrichment analysis. Two core genes, HSPA5 and SQSTM1, were confirmed to have diagnostic value in AS. Immune cell infiltration analysis revealed CD8+ T cells, CD8+ T effector memory (Tem), natural killer (NK) cells, T gamma delta (Tgd) cells, and T-helper 1 (Th1) cells as major participants in AS development. Furthermore, HSPA5 expression was significantly correlated with Th1 cells, CD8+ T cells, CD4+ memory cells, and macrophages. Conclusion: This study suggested that HSPA5 and SQSTM1 can serve as useful diagnostic biomarkers for AS. These findings lay the foundation for identifying crucial mRNAs in the whole blood of AS patients, which may aid in the development of novel markers for AS.

Single-nuclei characterization of pervasive transcriptional signatures across organs in response to COVID-19.

Background: Infection by coronavirus SARS-CoV2 is a severe and often deadly disease that has implications for the respiratory system and multiple organs across the human body. While the effects in the lung have been extensively studied, less is known about the impact COVID-19 has across other organs. Methods: Here, we contribute a single-nuclei RNA-sequencing atlas comprising six human organs across 20 autopsies where we analyzed the transcriptional changes due to COVID-19 in multiple cell types. The integration of data from multiple organs enabled the identification of systemic transcriptional changes. Results: Computational cross-organ analysis for endothelial cells and macrophages identified systemic transcriptional changes in these cell types in COVID-19 samples. In addition, analysis of gene modules showed enrichment of specific signaling pathways across multiple organs in COVID-19 autopsies. Conclusions: Altogether, the COVID Tissue Atlas enables the investigation of both cell type-specific and cross-organ transcriptional responses to COVID-19, providing insights into the molecular networks affected by the disease and highlighting novel potential targets for therapies and drug development. Funding: The Chan-Zuckerberg Initiative, The Chan-Zuckerberg Biohub.

Spermidine Synthase and Saccharopine Reductase Have Co-Expression Patterns Both in Basidiomycetes with Fusion Form and Ascomycetes with Separate Form.

Gene fusion is a process through which two or more distinct genes are fused into a single chimeric gene. Unlike most harmful fusion genes in cancer cells, in this study, we first found that spermidine synthetase- (SPDS, catalyst of spermidine biosynthesis) and saccharopine reductase- (SR, catalyst of the penultimate step of lysine biosynthesis) encoding genes form a natural chimeric gene, FfSpdsSr, in Flammulina filiformis. Through the cloning of full-length ORFs in different strains and the analysis of alternative splicing in developmental stages, FfSpdsSr has only one copy and unique transcript encoding chimeric SPDS-SR in F. filiformis. By an orthologous gene search of SpdsSr in more than 80 fungi, we found that the chimeric SpdsSr exists in basidiomycetes, while the two separate Spds and Sr independently exist in ascomycetes, chytridiomycetes, and oomycetes. Further, the transcript level of FfSpdsSr was investigated in different developmental stages and under some common environmental factors and stresses by RT-qPCR. The results showed that FfSpdsSr mainly up-regulated in the elongation stage and pileus development of F. filiformis, as well as under blue light, high temperature, H2O2, and MeJA treatments. Moreover, a total of 15 sets of RNA-Seq data, including 218 samples of Neurospora crassa, were downloaded from the GEO database and used to analyze the expression correlation of NcSpds and NcSr. The results showed that the separate NcSpds and NcSr shared highly similar co-expression patterns in the samples with different strains and different nutritional and environmental condition treatments. The chimeric SpdsSr in basidiomycetes and the co-expression pattern of the Spds and Sr in N. crassa indicate the special link of spermidine and lysine in fungi, which may play an important role in the growth and development of fruiting body and in response to the multiple environmental factors and abiotic stresses.

A comprehensive metabolomics analysis of Torreya grandis nuts with the effective de-astringent treatment during the postharvest ripening stage.

Astringency removal is important for the quality of Torreya grandis nut and occurs after harvest. Here, we evaluated the effect of NaHCO3 treatment on astringency removal and compared the differential metabolites of the seed coat and kernel using a UHPLC QQQ-MS-based metabolomics approach. The result revealed the nut astringency was primarily enriched in the seed coat with more soluble tannins. The NaHCO3 treatment greatly shortened the de-astringency process, as indicated by a faster conversion of soluble tannins to insoluble tannins and more acetaldehyde production. Besides, a total of 293 metabolites, including 92 phenolic acids and 37 flavonoids, were tentatively characterized in the seed coat. A further comparative analysis of the metabolomics indicated epigallocatechin, gallocatechin, catechin, procyanidin B1, B2, B3 and C1 to be the major metabolites influenced by the NaHCO3 treatment. This study provides new insights regarding the metabolite differences of Torreya grandis nuts processed with different de-astringent treatments.

RPL22 is a tumor suppressor in MSI-high cancers and a key splicing regulator of MDM4.

Microsatellite instability high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion, cell proliferation, and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.

Profiling the Somatic Mutational Landscape of Breast Tumors from Hispanic/Latina Women Reveals Conserved and Unique Characteristics.

Somatic mutational profiling is increasingly being used to identify potential targets for breast cancer. However, limited tumor-sequencing data from Hispanic/Latinas (H/L) are available to guide treatment. To address this gap, we performed whole-exome sequencing (WES) and RNA sequencing on 146 tumors and WES of matched germline DNA from 140 H/L women in California. Tumor intrinsic subtype, somatic mutations, copy-number alterations, and expression profiles of the tumors were characterized and compared with data from tumors of non-Hispanic White (White) women in The Cancer Genome Atlas (TCGA). Eight genes were significantly mutated in the H/L tumors including PIK3CA, TP53, GATA3, MAP3K1, CDH1, CBFB, PTEN, and RUNX1; the prevalence of mutations in these genes was similar to that observed in White women in TCGA. Four previously reported Catalogue of Somatic Mutations in Cancer (COSMIC) mutation signatures (1, 2, 3, 13) were found in the H/L dataset, along with signature 16 that has not been previously reported in other breast cancer datasets. Recurrent amplifications were observed in breast cancer drivers including MYC, FGFR1, CCND1, and ERBB2, as well as a recurrent amplification in 17q11.2 associated with high KIAA0100 gene expression that has been implicated in breast cancer aggressiveness. In conclusion, this study identified a higher prevalence of COSMIC signature 16 and a recurrent copy-number amplification affecting expression of KIAA0100 in breast tumors from H/L compared with White women. These results highlight the necessity of studying underrepresented populations. SIGNIFICANCE: Comprehensive characterization of genomic and transcriptomic alterations in breast tumors from Hispanic/Latina patients reveals distinct genetic alterations and signatures, demonstrating the importance of inclusive studies to ensure equitable care for patients. See related commentary by Schmit et al., p. 2443.

Elucidation of the Key Therapeutic Targets and Potential Mechanisms of Marmesine against Knee Osteoarthritis via Network Pharmacological Analysis and Molecular Docking.

Background: Marmesine, a major active ingredient isolated from Radix Angelicae biseratae (Duhuo), has been reported to have multiple pharmacological activities. However, its therapeutic effects against knee osteoarthritis (OA) remain poorly investigated. The present study is aimed at uncovering the core targets and signaling pathways of marmesine against osteoarthritis using a combined method of bioinformatics and network pharmacology. Methods: We utilized SwissTargetPrediction and PharmMapper to collect the potential targets of marmesine. OA-related differentially expressed genes (DEGs) were identified from GSE98918 dataset. Then, the intersection genes between DEGs and candidate genes of marmesine were subjected to protein-protein interaction (PPI) network construction and functional enrichment analysis. The core targets were verified using the molecular docking technology. Results: A total of 320 marmesine-related genes and 5649 DEGs and 60 ingredient-disease targets between them were identified. The results of functional enrichment analyses revealed that response to oxygen levels, neuroinflammatory response, PI3K-Akt signaling pathway, MAPK signaling pathway, FoxO signaling pathway, and osteoclast differentiation was identified as the potential mechanisms of marmesine against OA. EGFR, CASP3, MMP9, PPARG, and MAPK1 served as hub genes regulated by marmesine in the treatment of OA, and the molecular docking further verified the results. Conclusion: Marmesine exerts the therapeutic effects against OA through multitarget and multipathways, in which EGFR, CASP3, MMP9, PPARG, and MAPK1 might be hub genes. Our research indicated that the combination of bioinformatics and network pharmacology could serve as an effective approach for investigating the potential mechanisms of natural product.

Single-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids.

Pediatric hepatoblastoma is the most common primary liver cancer in infants and children. Studies of hepatoblastoma that focus exclusively on tumor cells demonstrate sparse somatic mutations and a common cell of origin, the hepatoblast, across patients. In contrast to the homogeneity these studies would suggest, hepatoblastoma tumors have a high degree of heterogeneity that can portend poor prognosis. In this study, we use single-cell transcriptomic techniques to analyze resected human pediatric hepatoblastoma specimens, and identify five hepatoblastoma tumor signatures that may account for the tumor heterogeneity observed in this disease. Notably, patient-derived hepatoblastoma spheroid cultures predict differential responses to treatment based on the transcriptomic signature of each tumor, suggesting a path forward for precision oncology for these tumors. In this work, we define hepatoblastoma tumor heterogeneity with single-cell resolution and demonstrate that patient-derived spheroids can be used to evaluate responses to chemotherapy.

The CIC-ERF co-deletion underlies fusion-independent activation of ETS family member, ETV1, to drive prostate cancer progression.

Human prostate cancer can result from chromosomal rearrangements that lead to aberrant ETS gene expression. The mechanisms that lead to fusion-independent ETS factor upregulation and prostate oncogenesis remain relatively unknown. Here, we show that two neighboring transcription factors, Capicua (CIC) and ETS2 repressor factor (ERF), which are co-deleted in human prostate tumors can drive prostate oncogenesis. Concurrent CIC and ERF loss commonly occur through focal genomic deletions at chromosome 19q13.2. Mechanistically, CIC and ERF co-bind the proximal regulatory element and mutually repress the ETS transcription factor, ETV1. Targeting ETV1 in CIC and ERF-deficient prostate cancer limits tumor growth. Thus, we have uncovered a fusion-independent mode of ETS transcriptional activation defined by concurrent loss of CIC and ERF.

Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states.

Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.