Molecular Features Research Articles

Diversity in the population of Fusarium oxysporum f. sp. ricini causing castor wilt disease in India

A major constraint on castor crop productivity is wilt disease caused by Fusarium oxysporum f. sp. ricini (For). In this study, morphological, pathogenic and molecular features of F. oxysporum f. sp. ricini isolates collected from different castor-growing agro-climatic zones of India were analyzed. Eighty-nine F. oxysporum f. sp. ricini isolates were obtained from wilt-infected root samples of castor plants from different states of India viz., Andhra Pradesh, Bihar, Gujarat, Haryana, Karnataka, Madhya Pradesh, Maharashtra, Odisha, Rajasthan, Telangana and Tamil Nadu. Morphology assessment in terms of variability in radial growth, size of micro and macroconidia and number of septa, grouped the isolates into 5 clusters in biplot analysis. A genotype-by-isolates bi-plot analysis ranked genotypes for pathogen susceptibility, with JI-35 being closest to the ideal and most susceptible, and DCS-9, and Kranthi being less susceptible. In contrast, 48–1 and JI-258 showed resistance, while Haritha and VP-1 exhibited intermediate susceptibility levels. K-means cluster analysis found 5 groups for pathogenic variability studies of isolates. The six isolates viz., For-12-5 (61.8 %), For-12-10 (50.5 %), For-13-47 (51.4 %), For-113 (86.1 %), For-13-33 (77.9 %) and For-53 (62.2 %) recorded as highly virulent isolates against wilt disease which showed >50 % average wilt incidence mean value across cultivars. Out of 40 ISSR primers tested, 11 primers gave polymorphic bands and analysis of genetic variability among 36 F. oxysporum f. sp. ricini isolates showed polymorphism with PIC, heterogygosity index, effective multiplex ratio, Marker index, and Shannon Diversity Index which ranged (in %) between 0.22 and 0.69, 0.19–0.44, 11.09–27.9, 6.14–8.98, and 0.78–3.04 respectively. The dendrogram analysis revealed 53 % similarity among the isolates studied and these isolates grouped broadly into 6 clusters. Variability among isolates was significant in morphological, pathogenic and molecular characters of F. oxysporum f. sp. ricini.

Temperature sensitivity of bat antibodies links metabolic state of bats with antigen-recognition diversity

The bat immune system features multiple unique properties such as dampened inflammatory responses and increased tissue protection, explaining their long lifespan and tolerance to viral infections. Here, we demonstrated that body temperature fluctuations corresponding to different physiological states in bats exert a large impact on their antibody repertoires. At elevated temperatures typical for flight, IgG from the bat species Myotis myotis and Nyctalus noctula show elevated antigen binding strength and diversity, recognizing both pathogen-derived antigens and autoantigens. The opposite is observed at temperatures reflecting inactive physiological states. IgG antibodies of human and other mammals, or antibodies of birds do not appear to behave in a similar way. Importantly, diversification of bat antibody specificities results in preferential recognition of damaged endothelial and epithelial cells, indicating an anti-inflammatory function. The temperature-sensitivity of bat antibodies is mediated by the variable regions of immunoglobulin molecules. Additionally, we uncover specific molecular features of bat IgG, such as low thermodynamic stability and implication of hydrophobic interactions in antigen binding as well as high prevalence of polyreactivity. Overall, our results extend the understanding of bat tolerance to disease and inflammation and highlight the link between metabolism and immunity.

Mucinous tubular and spindle renal cell carcinoma revealed by a trauma of the kidney: a case report

BackgroundMucinous tubular and spindle cell carcinoma is a rare renal tumor. It has been recognized as a distinct entity in the 2004 World Health Organization tumor classification. Since then, several dozen of these tumor have been reported with additional complementary morphologic characteristics, immunohistochemical profile, and molecular genetic features that have further clarified its clinicopathologic aspects.Case presentationWe report the case of a 52-year-old male African patient who was found to have a mucinous tubular and spindle renal cell carcinoma on a nephrectomy specimen for a severe kidney trauma.ConclusionsThis tumor has a histological spectrum ranging from low to high grade, which includes sarcomatoid differentiation that can confer the tumor an aggressive clinical course.

Complete pathological response to pembrolizumab in pretreated pancreatic acinar cell carcinoma

BackgroundTherapeutic approach used for pancreatic ductal adenocarcinoma is usually translated also for the rarer acinar counterpart, which shows a different mutational landscape nevertheless. While dMMR/MSI-H status is rare in the ductal histotype, it appears to be more prevalent in pancreatic acinar cell carcinoma (PACC).Case presentationWe report the case of a patient with locally advanced MSI-H PACC in whom the treatment with the anti-PD-1 pembrolizumab, administered as third line, made possible surgical resection, achieving even an exceptional pathological complete response.ConclusionsTreatment of PACC should be tailored based on the peculiar molecular features that distinguish PACC from ductal adenocarcinoma. Evaluation of potentially therapeutically targetable alterations should be mandatory in case of PACC diagnosis.

First Report of bacterial wilt disease of banana caused by Klebsiella variicola in Malaysia.

In Malaysia, bananas (Musa spp.) are the second most cultivated fruit and the fourth most cultivated fruit in terms of export revenue. In October 2018, about 5.0 out of 6.6 hectares of a banana plantation located in Teluk Intan, Malaysia, was impacted by an outbreak of banana disease. The onset of bacterial wilt symptoms is characterized by initial leaf wilting, followed by the subsequent withering of the entire plant during later stages, fruit stalk and fruit pulp discoloration, fruit rotting, and pseudostem necrosis. The diseased banana's symptomatic pseudostems and fruit pulps were surface-sterilised in 70% ethanol for 30 s, followed by 2% NaClO for 3 min, rinsed three times in sterilised water, and cut into small pieces approximately 5 mm2 in size. The tissues were macerated in a sterilised 0.85% NaCl solution for 5 min, and the resulting suspension was streaked onto nutrient agar, followed by incubation at 28°C for 2 days. After incubation, bacterial colonies with five unique morphological characteristics were observed. Two colonies of each unique morphological type were randomly chosen and subjected to preliminary bacterial identification by 16S rRNA gene sequencing. Based on BLASTn analysis, the five unique morphological types of bacteria were preliminarily identified as Enterobacter cloacae, Citrobacter farmeri, Klebsiella variicola, Kosakonia radicincitans, and Phytobacter ursingii. Previous reports identified K. variicola and K. radicincitans as banana pathogens, but Malaysia has yet to report the former. The amplified partial 16S rDNA sequences of both K. variicola isolates (designated as UTAR-BC1 and UTAR-BC2; GenBank accession numbers: PP531448 and PP531460, respectively), which were chosen to be the focus of this study, exhibited complete similarity to each other and were 100% identical (1426/1426 identity and 1420/1420 identity, respectively) to K. variicola (CP026013.1). To verify the identity of the bacterial isolate, three housekeeping genes, namely, infB(PP538994), rpoB (PP538995), and gyrB (PP538996) of UTAR-BC1, were amplified, sequenced, and subjected to multilocus phylogenetic analysis via the neighbour-joining method (1,000 bootstrap values). Phylogenetic analysis revealed that UTAR-BC1 belongs to the K. variicola clade. A pathogenicity assay of UTAR-BC1 was conducted on 4-month-old healthy banana plantlets (cv. Nangka) using the pseudostem injection method (Tripathi et al., 2008). First, UTAR-BC1 was grown overnight in nutrient broth and then adjusted to 108 CFU/ml in a sterile 10 mM MgCl2 solution. A total volume of 100 µL of the bacterial suspension was injected into the pseudostem of five healthy banana plantlets via a syringe with a needle. Control plants were mock-inoculated with a sterile 10 mM MgCl2 solution. The experiments were replicated thrice and inoculated plants were maintained at room temperature with natural sunlight and humidity, which resembled the field conditions. Two months after inoculation, all of the UTAR-BC1 inoculated spots of banana plantlets showed severe necrosis, while the banana leaves showed symptoms of wilted appearance, whereas the control plants remained symptomless. The reisolated pathogen from 90% of the symptomatic pseudostems and leaf blades shares the same morphological and molecular features as UTAR-BC1, thus fulfilling Koch's postulates. Previously, K. variicola has been reported to be a banana pathogen causing rhizome rot in India (Loganathan et al., 2021), plantain soft rot in Haiti (Fulton et al. 2020), and sheath rot and bulb rot in China (Sun et al., 2023; Jiang et al., 2024). To the best of our knowledge, this is the first report of bacterial wilt disease in bananas attributed to K. variicola in Malaysia. This finding will facilitate the surveillance of K. variicola as an emerging pathogen in banana plants in this region, thereby safeguarding the country's food security and promoting socio-economic growth.

Primary Meningeal Melanocytic Tumors of the Central Nervous System: A Review from the Ultra-Rare Brain Tumors Task Force of the European Network for Rare Cancers (EURACAN).

Primary meningeal melanocytic tumors are ultra-rare entities with distinct histological and molecular features compared with other melanocytic or pigmented lesions, such as brain and leptomeningeal metastases from metastatic melanoma. The European Network for Rare Cancers (EURACAN) Task Force on Ultra-Rare Brain Tumors (domain 10, subdomain 10) performed a literature review from January 1985 to December 2023 regarding the epidemiologic and clinical characteristics, histological and molecular features, radiological findings, and efficacy of local treatments (surgery and radiotherapy) and systemic treatments for these entities. Molecular analysis can detect specific mutations, including GNAQ, GNA11, SF3B1, EIF1AX, BAP1, that are typically found in circumscribed primary meningeal melanocytic tumors and not in other melanocytic lesions, whereas NRAS and BRAF mutations are typical for diffuse primary meningeal melanocytic tumors. The neuroimaging of the whole neuroaxis suggests a melanocytic nature of a lesion, depicts its circumscribed or diffuse nature, but cannot predict the tumor's aggressiveness. Gross-total resection is the first choice in the case of circumscribed meningeal melanocytoma and melanoma; conversely, meningeal biopsy may be reserved for patients with diffuse and multinodular leptomeningeal spread to achieve a definitive diagnosis. High-dose radiotherapy is rarely indicated in diffuse melanocytic tumors except as palliative treatment to alleviate symptoms. Last, a definitive advantage of a specific systemic treatment could not be concluded, as most of the data available derive from case reports or small cohorts. As primary meningeal melanocytic tumors are extremely rare, the correlations between the clinical characteristics, molecular profile, radiological findings at diagnosis and progression are weak, and poor evidence on the best therapeutic approach is available. There is a need to develop shared platforms and registries to capture more knowledge regarding these ultra-rare entities.

On the Boundary of Exploratory Genomics and Translation in Sequential Glioblastoma.

OMICS methods brought significant advancements to the understanding of tumor cell biology, which transformed the treatment and prognosis of several cancers. Clinical practice and outcomes, however, changed significantly less in the case of glioblastoma (GBM). In this study, we aimed to assess the utility of whole exome (WES) sequencing in the clinical setting. Ten pairs of formalin-fixed, paraffin-embedded (FFPE) GBM specimens were obtained at onset (GBM-P) and at recurrence (GBM-R). Histopathological and molecular features of all samples supported the diagnosis of GBM based on WHO CNS5. WES data were filtered, applying a strict and custom-made pipeline, and occurrence of oncogenic and likely oncogenic variants in GBM-P, GBM-R or both were identified by using the VarSeq program version 2.5.0 (Golden Helix, Inc.). Characteristics and recurrence of the variants were analyzed in our own cohort and were also compared to those available in the COSMIC database. The lists of oncogenic and likely oncogenic variants corresponded to those identified in other studies. The average number of these variants were 4 and 5 out of all detected 24 and 34 variants in GBM-P and GBM-R samples, respectively. On average, one shared oncogenic/likely oncogenic variant was found in the pairs. We assessed the identified variants' therapeutic significance, also taking into consideration the guidelines by the Association for Molecular Pathology (AMP). Our data support that a thorough WES analysis is suitable for identifying oncogenic and likely oncogenic variants in an individual clinical sample or a small cohort of FFPE glioma specimens, which concur with those of comprehensive research studies. Such analyses also allow us to monitor molecular dynamics of sequential GBM. In addition, careful evaluation of data according to the AMP guideline reveal that though therapeutic applicability of the variants is generally limited in the clinic, such information may be valuable in selected cases, and can support innovative preclinical and clinical trials.

The State of the Art of Artificial Intelligence Applications in Eosinophilic Esophagitis: A Systematic Review

Introduction: Artificial intelligence (AI) tools are increasingly being integrated into computer-aided diagnosis systems that can be applied to improve the recognition and clinical and molecular characterization of allergic diseases, including eosinophilic esophagitis (EoE). This review aims to systematically evaluate current applications of AI, machine learning (ML), and deep learning (DL) methods in EoE characterization and management. Methods: We conducted a systematic review using a registered protocol published in the International Prospective Register of Systematic Reviews (CRD42023451048). The risk of bias and applicability of eligible studies were assessed according to the prediction model study risk of bias assessment tool (PROBAST). We searched PubMed, Embase, and Web of Science to retrieve the articles. The literature review was performed in May 2023. We included original research articles (retrospective or prospective studies) published in English in peer-reviewed journals, studies whose participants were patients with EoE, and studies assessing the application of AI, ML, or DL models. Results: A total of 120 articles were found. After removing 68 duplicates, 52 articles were reviewed based on the title and abstract, and 34 were excluded. Eleven full texts were assessed for eligibility, met the inclusion criteria, and were analyzed for the systematic review. The AI models developed in three studies for identifying EoE based on endoscopic images showed high score performance with an accuracy that ranged from 0.92 to 0.97. Five studies developed AI models that histologically identified EoE with high accuracy (87% to 99%). We also found two studies where the AI model identified subgroups of patients according to their clinical and molecular features. Conclusions: AI technologies could promote more accurate evidence-based management of EoE by integrating the results of molecular signature, clinical, histology, and endoscopic features. However, the era of AI application in medicine is just beginning; therefore, further studies with model validation in the real-world environment are required.

Comprehensive Identification of the Chemical Substances in Effective Component Groups of Polygalae Radix Based on Targeted Tandem Mass Spectrometry Analysis Strategy

ABSTRACTPolygalae Radix is a commonly used traditional Chinese medicine with multiple pharmacological activities. Modern research have revealed that saponins, xanthones, and oligosaccharide esters are its effective component groups. However, up to date the chemical substances in these effective component groups are still unclear, which has become a fundamental scientific issue needing to be addressed. In our study, an analysis strategy based on targeted tandem mass spectrometry (MS/MS) analysis was proposed to comprehensively identify the chemical substances in effective component groups. First, the extract of the Polygalae Radix was detected by ultra‐performance liquid chromatography coupled with electrospray ionization–orbitrap mass spectrometry in a full MS scan mode to minimize the losses of signals; second, the precursor ions of all compounds were extracted from the obtained full MS scan data using Compound Discoverer software; third, the interested precursor ions were locked based on their molecular features and constructed in a precursor ion list; finally, each precursor ion in the list was subjected to targeted MS/MS analysis for structure characterization. Using our analysis strategy, a total of 565 components were successfully identified.

Molecular epidemiology and genomic features of Bordetella parapertussis in Shanghai, China, 2017-2022.

Pertussis is a highly contagious respiratory illness mainly caused by Bordetella pertussis (BP). Bordetella parapertussis (BPP) can induce symptoms compatible with pertussis, but has been underdiagnosed and underreported. The current pertussis vaccines offer low protection against BPP. Herein, we aim to reveal the epidemiology and genomic evolution of BPP in Shanghai, China. Children diagnosed with BPP infection from January 2017 to December 2022 in Shanghai, China were enrolled. We performed antimicrobial susceptibility testing (AST), multiple locus variable-number tandem repeat analysis (MLVA), and whole genome sequencing (WGS) analysis. A total of 260 international BPP genomes were chosen for comparison to investigate the genomic diversity and phylogenetic characteristics of Chinese strains within a global context. Sixty patients were diagnosed with BPP infection by culture, with the positive ratio of 3.5‰ (60/17337) for BPP in nasopharyngeal swap samples. The average age of patients was 4.5 ± 0.3 years. BPPs contained four MLVA types including MT6 (65.0%), MT4 (26.7%), untype-1 (6.7%) and MT5 (1.7%), and none of strains showed resistance to macrolides. All strains carried virulence genotype of ptxP37/ptxA13/ptxB3/ptxC3/ptxD3/ptxE3/fim2-2/fim3-10. MT4 and MT5 strains carried prn54, whereas MT6 and untype-1 BPPs expressed prn101. We identified two outbreaks after 2020 caused by MT4 and MT6 strains, each corresponding to distinct WGS-based phylogenetic lineages. The MT4-lineage is estimated to have originated around 1991 and has since spread globally, being introduced to China between 2005 and 2010. In contrast, the MT6-lineage was exclusively identified in China and is inferred to have originated around 2002. We revealed the genomic diversity of BPPs circulating in Shanghai, China, and reported the outbreaks of MT6 and MT4 BPPs after 2020. This is the first report on the emergence and regional outbreak of MT6 BPPs in the world, indicating that continuous surveillance on BPPs are thus required.

Weifuchun suppresses the malignancy of gastric cancer cells by targeting KPNA2 through miR-26a-5p-mediated destabilization and the deactivation of the MAPK signaling pathway

Ethnopharmacological relevanceWeifuchun (WFC) is a Traditional Chinese Medicine commonly used for treating atrophic gastritis and intestinal metaplasia. Till date, its antitumor effect on gastric cancer (GC) and the underlying mechanisms of the effect remains unelucidated. Aim of the studyWe aim to investigate if WFC can suppress the malignancy of stomach cancer cells and dissect the molecular basis and the associated molecular and cellular features. Materials and methodsStomach cancer cell lines and normal gastric epithelial cells were treated with WFC. CCK8 assay, caspase-3 activity assay, adhesion assay, microRNA database analysis, transfection, RT-PCR, Western Blotting, signaling pathway analysis, and in vivo GC model were employed to examine the changes in the features of the gastric cancer cells and the molecular mechanisms of the effect of WFC. ResultsHere we present data demonstrating that WFC suppresses the malignant cellular phenotypes of GC and this inhibitory effect is mediated by downregulating the expression of oncogenic KPNA2. Furthermore, WFC downregulates KPNA2 through miR-26a-5p-mediated gene silencing and the deactivated phosphorylation dynamics of mitogen-activated protein kinase (MAPK). The suppressive effect of WFC on stomach cancer cell behavior was further confirmed in animal model. ConclusionTherefore, WFC can exert inhibitory effect on the malignancy of GC cells by reducing the levels of KPNA2. Moreover, the miR-26a-5p rescue and the deactivation MAPK pathway induced by WFC result in the downregulation of KPNA2 expression. Thus, our findings suggest WFC as a potential treatment option against GC.

Prediction on Air-Nasal Mucus Partition Coefficients of Odor Compounds.

The air-nasal mucus partition coefficient is a crucial property among all of the interaction mechanisms between odor molecules and olfactory receptors, since this property contributes to our sense of smell. Due to the complexity of the mucus composition, in vivo determination of the air-mucus partition coefficient is a technical challenge. A predictable model of the air-mucus partition coefficient can provide valuable insights into the chemical properties that govern olfactory perception and can help design desired odorants. In this study, we propose a novel model based on the deep-layer neural network (DNN) algorithm to predict the air-mucus partition coefficients for a range of odor compounds. The molecular surface charge density (σ-profile) calculated from the COnductor like Screening MOdel for Real Solvents (COSMO-RS) thermodynamic package was adapted as descriptors of structural features of odor molecules. The results revealed that the air-mucus partition coefficients are highly correlated to the σ-profile of the studied compounds. The information obtained from the study provided interpretable results, which not only help in identifying the molecular features that contribute to the air-mucus partition coefficient of odorants but also aid in the design of compounds with the desired odor properties.

Multiomics analysis reveals the potential of LPCAT1-PC axis as a therapeutic target for human intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is a highly prevalent musculoskeletal disorder that is associated with considerable morbidity. However, there is currently no drug available that has a definitive therapeutic effect on IDD. In this study, we aimed to identify the molecular features and potential therapeutic targets of IDD through a comprehensive multiomics profiling approach. By integrating transcriptomics, proteomics, and ultrastructural analyses, we discovered dysfunctions in various organelles, including mitochondria, the endoplasmic reticulum, the Golgi apparatus, and lysosomes. Metabolomics analysis revealed a reduction in total phosphatidylcholine (PC) content in IDD. Through integration of multiple omics techniques with disease phenotypes, a pivotal pathway regulated by the lysophosphatidylcholine acyltransferase 1 (LPCAT1)-PC axis was identified. LPCAT1 exhibited low expression levels and exhibited a positive correlation with PC content in IDD. Suppression of LPCAT1 resulted in inhibition of PC synthesis in nucleus pulposus cells, leading to a notable increase in nucleus pulposus cell senescence and damage to cellular organelles. Consequently, PC exhibits potential as a therapeutic agent, as it facilitates the repair of the biomembrane system and alleviates senescence in nucleus pulposus cells via reversal of downregulation of the LPCAT1-PC axis.

The roles of tertiary lymphoid structures in genitourinary cancers: molecular mechanisms, therapeutic strategies, and clinical applications.

The presence of tertiary lymphoid structures (TLSs) associated with distinct treatment efficacy and clinical prognosis has been identified in various cancer types. However, the mechanistic roles and clinical implications of TLSs in genitourinary (GU) cancers remain incompletely explored. Despite their potential role as predictive markers described in numerous studies, it is essential to comprehensively evaluate the characteristics of TLSs, including drivers of formation, structural foundation, cellular compositions, maturation stages, molecular features, and specific functionality to maximize their positive impacts on tumor-specific immunity. The unique contributions of these structures to cancer progression and biology have fueled interest in these structures as mediators of antitumor immunity. Emerging data are trying to explore the effects of therapeutic interventions targeting TLSs. Therefore, a better understanding of the molecular and phenotypic heterogeneity of TLSs may facilitate the development of TLSs-targeting therapeutic strategies to obtain optimal clinical benefits for GU cancers in the setting of immunotherapy. In this review, the authors focus on the phenotypic and functional heterogeneity of TLSs in cancer progression, current therapeutic interventions targeting TLSs and the clinical implications and therapeutic potential of TLSs in GU cancers.

Molecular and diffusion features for identification of clinically significant prostate cancer in PI-RADS 3 lesions

BackgroundThe recommendation to perform biopsy of PIRADS 3 lesions has not been adopted with strength as compared to higher scored lesions on multiparametric MRI. This represents a challenging scenario and an unmet need for clinicians to apply a risk adapted approach in these cases. In the present study, we examined clinical and radiologic characteristics in men with PI-RADS 3 index lesions that can predict csPCa on mpMRI-target biopsy. MethodsRevision of a prospective database with patients who underwent targeted and systematic biopsies from 2015 to 2023 for PI-RADS 3 lesions identified on mpMRI. Baseline variables were collected, such as PSA density (PSAd), 4Kscore, prostate size, and the apparent diffusion coefficient (ADC) value of the lesion on mpMRI. Logistic regression, receiver operating characteristic (ROC) and decision curve analyses (DCA) assessing the association between clinic-radiologic factors and csPCa were performed. ResultsOverall, 230 patients were included in the study and the median age was 65 years. The median prostate size and PSA were 50 g and 6.26 ng/mL, respectively. 17.4% of patients had csPCa, while 27.5% had Gleason group 1. In univariable logistic analyses, we found that age, BMI, prostate size, PSAd, ADC, and 4Kscore were significant csPCa predictors (P < 0.05). PSAd showed the best prediction performance in terms of AUC (= 0.679). On multivariable analysis, PSAd and 4Kscore were associated with csPCa. The net benefit of PSAd combined with clinical features was superior to those of other parameters. Within patients with PSAd < 0.15, 4Kscore was a statistically significant predictor of csPCa (OR = 3.25, P = 0.032). ConclusionPSAd and 4Kscore are better predictors of csPCa in patients with PIRADS 3 lesions compared to ADC. The predictive role of 4Kscore is higher in patients with low PSAd. These results can assist practitioners in the risk stratification of patients with equivocal lesions to determine the need of biopsy.

Clinicopathological and molecular genetic features of confined placental mosaicism

Objective: To investigate the clinicopathological and genetic features of confined placental mosaicism (CPM) and its effect on fetal intrauterine growth. Methods: Fourteen CPM cases of Haidian Maternal and Children Health Hospital were collected from May 2018 to March 2022. Clinicopathological examination on placental specimens and molecular genetic analysis were performed. Results: The age of the parturient women ranged from 27 to 34 years, with an average age of (30.0±3.54) years. The gestational weeks ranged from 35+1 to 41+2 weeks. There were 4 premature births and 10 term births, among which 6 were female and 8 were male fetuses. Nine cases (9/14) had adverse pregnancy outcomes, including 7 cases of fetal growth restriction. The weight of CPM placenta decreased, with 6 cases below the 10th percentile of weight standards and 5 cases between the 10th and 25th percentile. All 14 CPM placental specimens showed morphological changes of perfusion dysfunction to varying degrees, with mainly placental-maternal vascular malperfusion followed by placental-fetal vascular malperfusion. The mosaic chromosomes in different CPM cases varied, with 16-trisomy/monosomy mosaicism being the most common followed by 7-trisomy and 21-trisomy/monosomy mosaicism. The mosaic proportion was unequal in different parts of the same CPM placenta, with the mosaic proportion of umbilical cord, fetal membranes, fetal surface, maternal surface, and edge ranging from 1% to 70%. Conclusions: The mosaic chromosomes in different CPM cases vary, and the mosaic proportion is unequal in different parts of the same CPM placenta. The pathological morphology is mainly manifested as perfusion dysfunction, which can lead to adverse pregnancy outcomes such as fetal growth restriction and preterm birth.

Uncovering molecular features driving lung adenocarcinoma heterogeneity in patients who formerly smoked

BackgroundAn increasing proportion of lung adenocarcinoma (LUAD) occurs in patients even after they have stopped smoking. Here, we aimed to determine whether tobacco smoking induced changes across LUADs from patients who formerly smoked correspond to different biological and clinical factors.MethodsRandom forest models (RFs) were trained utilizing a smoking associated signature developed from differentially expressed genes between LUAD patients who had never smoked (NS) or currently smoked (CS) from TCGA (n = 193) and BCCA (n = 69) cohorts. The RFs were subsequently applied to 299 and 131 formerly smoking patients from TCGA and MSKCC cohorts, respectively. FS were RF-classified as either CS-like or NS-like and associations with patient characteristics, biological features, and clinical outcomes were determined.ResultsWe elucidated a 123 gene signature that robustly classified NS and CS in both RNA-seq (AUC = 0.85) and microarray (AUC = 0.92) validation test sets. The RF classified 213 patients who had formerly smoked as CS-like and 86 as NS-like from the TCGA cohort. CS-like and NS-like status in formerly smoking patients correlated poorly with patient characteristics but had substantially different biological features including tumor mutational burden, number of mutations, mutagenic signatures and immune cell populations. NS-like formerly smoking patients had 17.5 months and 18.6 months longer overall survival than CS-like patients from the TCGA and MSKCC cohorts, respectively.ConclusionsPatients who had formerly smoked with LUAD harbor heterogeneous tumor biology. These patients can be divided by smoking induced gene expression to inform prognosis and underlying biological characteristics for treatment selection.

The Use of Hexokinase 2-Displacing Peptides as an Anti-Neoplastic Approach for Malignant Peripheral Nerve Sheath Tumors.

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.

Network-based integrative multi-omics approach reveals biosignatures specific to COVID-19 disease phases.

COVID-19 disease is characterized by a spectrum of disease phases (mild, moderate, and severe). Each disease phase is marked by changes in omics profiles with corresponding changes in the expression of features (biosignatures). However, integrative analysis of multiple omics data from different experiments across studies to investigate biosignatures at various disease phases is limited. Exploring an integrative multi-omics profile analysis through a network approach could be used to determine biosignatures associated with specific disease phases and enable the examination of the relationships between the biosignatures. To identify and characterize biosignatures underlying various COVID-19 disease phases in an integrative multi-omics data analysis. We leveraged a multi-omics network-based approach to integrate transcriptomics, metabolomics, proteomics, and lipidomics data. The World Health Organization Ordinal Scale WHO Ordinal Scale was used as a disease severity reference to harmonize COVID-19 patient metadata across two studies with independent data. A unified COVID-19 knowledge graph was constructed by assembling a disease-specific interactome from the literature and databases. Disease-state specific omics-graphs were constructed by integrating multi-omics data with the unified COVID-19 knowledge graph. We expanded on the network layers of multiXrank, a random walk with restart on multilayer network algorithm, to explore disease state omics-specific graphs and perform enrichment analysis. Network analysis revealed the biosignatures involved in inducing chemokines and inflammatory responses as hubs in the severe and moderate disease phases. We observed distinct biosignatures between severe and moderate disease phases as compared to mild-moderate and mild-severe disease phases. Mild COVID-19 cases were characterized by a unique biosignature comprising C-C Motif Chemokine Ligand 4 (CCL4), and Interferon Regulatory Factor 1 (IRF1). Hepatocyte Growth Factor (HGF), Matrix Metallopeptidase 12 (MMP12), Interleukin 10 (IL10), Nuclear Factor Kappa B Subunit 1 (NFKB1), and suberoylcarnitine form hubs in the omics network that characterizes the moderate disease state. The severe cases were marked by biosignatures such as Signal Transducer and Activator of Transcription 1 (STAT1), Superoxide Dismutase 2 (SOD2), HGF, taurine, lysophosphatidylcholine, diacylglycerol, triglycerides, and sphingomyelin that characterize the disease state. This study identified both biosignatures of different omics types enriched in disease-related pathways and their associated interactions (such as protein-protein, protein-transcript, protein-metabolite, transcript-metabolite, and lipid-lipid interactions) that are unique to mild, moderate, and severe COVID-19 disease states. These biosignatures include molecular features that underlie the observed clinical heterogeneity of COVID-19 and emphasize the need for disease-phase-specific treatment strategies. The approach implemented here can be used to find associations between transcripts, proteins, lipids, and metabolites in other diseases.

Combining Molecular and Traditional Prognostic Factors: A Holistic Approach to Breast Cancer Prognostication.

Breast cancer is a heterogeneous disease with various morphologies and molecular features, and it is the second leading cause of cancer death in women in developed countries. According to the literature, we currently lack both prognostic biomarkers and therapeutic targets. The most important prognostic factors are disease stage and Nottingham grade. We conducted a retrospective analysis involving 273 patients with BC who underwent neoadjuvant therapy before proceeding to curative surgical treatment between 1 January 2014 and 31 December 2023. Pathological procedures were conducted at the Department of Pathology, Emergency County Hospital of Targu Mureș, Romania. A statistical analysis was performed. Regarding the relationship between Nottingham grade and Ki67, grade I was associated with a Ki67 of less than 14. The relationship between tumor grade and luminal was similar (p = 0.0001): Grade I was associated with luminal A. Regarding TNM stage, it was statistically significantly correlated with TILs (p = 0.01) and RCB (p = 0.0001). Stages III and IV were associated with a high RCB and poor prognosis. Regarding the prognostic value, Nottingham grade 3 and TNM stages III and IV were correlated with low overall survival and disease-free survival, with poor prognosis, and, among the molecular variables, RCB played the most important prognostic role.