RESUMEN
Small cell carcinoma of the esophagus (SCCE) is a rare and highly malignant type of esophageal cancer with no standard treatment, facing challenges of resistance to conventional therapies. This study presents the cases of one extensive-stage and two limited-stage SCCE patients treated with chemoimmunotherapy. The two limited-stage patients underwent surgery post-treatment and experienced notable and enduring positive responses. This represents the first documented application of neoadjuvant chemoimmunotherapy in limited-stage SCCE patients. Additionally, comprehensive immunohistochemical analysis and whole exome sequencing were performed on the case patients. The findings revealed that infiltration of CD8+ T cells and PD-L1 expression in the SCCE tumor were key factors for favorable responses in SCCE patients receiving chemoimmunotherapy.
Asunto(s)
Carcinoma de Células Pequeñas , Neoplasias Esofágicas , Inmunoterapia , Terapia Neoadyuvante , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamiento farmacológico , Terapia Neoadyuvante/métodos , Carcinoma de Células Pequeñas/terapia , Carcinoma de Células Pequeñas/tratamiento farmacológico , Masculino , Inmunoterapia/métodos , Persona de Mediana Edad , Antígeno B7-H1/metabolismo , Resultado del Tratamiento , Anciano , Biomarcadores de Tumor , Linfocitos T CD8-positivos/inmunología , Femenino , Secuenciación del ExomaRESUMEN
Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) protein significantly improve survival in patients with advanced non-small-cell lung cancer (NSCLC), but its impact on early-stage ground-glass opacity (GGO) lesions remains unclear. This is a single-arm, phase II trial (NCT04026841) using Simon's optimal two-stage design, of which 4 doses of sintilimab (200 mg per 3 weeks) were administrated in 36 enrolled multiple primary lung cancer (MPLC) patients with persistent high-risk (Lung-RADS category 4 or had progressed within 6 months) GGOs. The primary endpoint was objective response rate (ORR). T/B/NK-cell subpopulations, TCR-seq, cytokines, exosomal RNA, and multiplexed immunohistochemistry (mIHC) were monitored and compared between responders and non-responders. Finally, two intent-to-treat (ITT) lesions (pure-GGO or GGO-predominant) showed responses (ORR: 5.6%, 2/36), and no patients had progressive disease (PD). No grade 3-5 TRAEs occurred. The total response rate considering two ITT lesions and three non-intent-to-treat (NITT) lesions (pure-solid or solid-predominant) was 13.9% (5/36). The proportion of CD8+ T cells, the ratio of CD8+/CD4+, and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time. Correspondingly, the mIHC analysis showed more CD8+ T cells infiltrated in responders. Besides, responders' cytokine concentrations of EGF and CTLA-4 increased during treatment. The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders. Collectively, PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns. Such effects were associated with specific T-cell re-distribution, EGF/CTLA-4 cytokine compensation, and regulation of metabolism pathways.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptor de Muerte Celular Programada 1/genética , Antígeno CTLA-4/uso terapéutico , Linfocitos T CD8-positivos , Factor de Crecimiento Epidérmico , Tomografía Computarizada por Rayos X , Pulmón/patología , Receptores de Antígenos de Linfocitos T , CitocinasRESUMEN
Next generation sequencing (NGS) is typically used to reveal tumor gene variation feature for targeted therapy of various types of human cancers, including non-small cell lung cancer (NSCLC). Here, we report the role and potential applicable value of combining DNA and RNA sequencing in gene variation detection in NSCLC. 386 NSCLC patients with stage II-IV were enrolled and detected using NGS sequencing of DNA and RNA panels that covered all well-documented target driver genes from the Chinese Society of Clinical Oncology (CSCO). The rate of epidermal growth factor receptor (EGFR) single nucleotide variation (SNV)/indel, mesenchymal-epithelial transition factor (MET) copy number variation (CNV) and anaplastic lymphoma kinase (ALK) fusion were 52.1%, 4.1% and 6.0% in the NSCLC cohort. The landscapes of SNV/indel, CNV and gene fusion in the cohort were depicted as well. Meanwhile, we assessed detection efficacy of DNA and RNA sequencing in gene fusion. Detected number and types of gene fusion using the RNA sequencing were better than those using the DNA sequencing. Gene fusion with intergenic region was only detected by DNA sequencing and MET exon 14 skipping (METΔex14) was more easily identified by RNA sequencing. Finally, we investigated clinical correlations of SNV/indel/CNV/fusion with clinicopathologic features in the NSCLC cohort. Taken together, RNA sequencing significantly complements deficiency of DNA sequencing for gene fusion, which cooperatively presents comprehensive and reliable gene variation features and facilitate the identification of potential drug targets for NSCLC patients.
RESUMEN
OBJECTIVE: To study the phenomenon, incidence and management of pathological migrating intramural hematoma in stenting for carotid artery dissection. METHODS: We consecutively enrolled CAD patients with stenting treatment over 10-year period, and retrospectively analyzed the pathological migrating intramural hematoma (PMIH) incidence of these CAD patients. Besides, we also explored the related factors with PMIH and provided an appropriate management strategy. RESULTS: A total of 67 CAD underwent stenting. PMIH occurred in 7 cases (10.4%). The median time from onset of symptoms to stenting was 5 days (3 to 11 days). There were 4 cases of PMIH in the proximal segment of stent and 3 cases of PMIH in the distal segment of stent. All the patients presented with new stenosis and no patient presented with dissecting aneurysm. Through proper management, none of the patients had occurred clinical complications. CONCLUSION: Pathological migrating intramural hematoma phenomenon exists in the stenting for carotid artery dissection, rescue angioplasty or stenting is needed for early treatment of moderate and severe stenosis due to migrating intramural hematoma on preventing further ischemic events.
Asunto(s)
Disección Aórtica , Enfermedades de las Arterias Carótidas , Estenosis Carotídea , Accidente Cerebrovascular , Humanos , Estenosis Carotídea/patología , Estudios de Cohortes , Constricción Patológica/etiología , Estudios Retrospectivos , Disección Aórtica/cirugía , Arterias Carótidas , Stents/efectos adversos , Hematoma/cirugía , Hematoma/etiología , Resultado del Tratamiento , Accidente Cerebrovascular/etiologíaRESUMEN
PURPOSE: Immune checkpoint inhibitors (ICI) have become the standard of care for patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer. However, biomarkers of response to ICI are still lacking. EXPERIMENTAL DESIGN: Forty-two patients with dMMR colorectal cancer treated with neoadjuvant PD-1 blockade were prospectively enrolled. To identify biomarkers of pathologic complete response (pCR) to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles based on next-generation sequencing, and immune cell density based on multiplex immunofluorescence (mIF) staining. An integrated analysis of single-cell RNA sequencing from our previous study and GSE178341, as well as mIF was performed to further explore the significance of the tumor microenvironment (TME) on pCR response. RESULTS: The tumor mutation burden of both tumor tissue and plasma blood samples was comparable between the pCR and non-pCR groups, while HLA-DQA1 and HLA-DQB1 were significantly overexpressed in the pCR group. Gene signature enrichment analysis showed that pathways including T-cell receptor pathway, antigen presentation pathway were significantly enriched in the pCR group. In addition, higher pre-existing CD8+ T-cell density was associated with pCR response (767.47 per.mm2 vs. 326.64 per.mm2, P = 0.013 Wilcoxon test). Further integrated analysis showed that CD8+ T cells with low PD-1 expression (PD-1lo CD8+ T cells) expressing high levels of TRGC2, CD160, and KLRB1 and low levels of proliferated and exhausted genes were significantly associated with pCR response. CONCLUSIONS: Immune-associated transcriptomic features, particularly CD8+ T cells were associated with pCR response to ICI in dMMR colorectal cancer. Heterogeneity of TME within dMMR colorectal cancer may help to discriminate patients with complete response to neoadjuvant ICI.
Asunto(s)
Neoplasias Encefálicas , Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Terapia Neoadyuvante , Reparación de la Incompatibilidad de ADN/genética , Respuesta Patológica Completa , Receptor de Muerte Celular Programada 1/genética , Biomarcadores , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Inestabilidad de Microsatélites , Inmunoterapia , Microambiente Tumoral/genéticaRESUMEN
A 27-year-old female patient suffered from recurrent episodes of dizziness, visual rotation, and intermittent right-hand numbness over one month. Symptoms persisted and were triggered by rotating the head to the right or left for more than 10 seconds. Neurological examination showed that the symptoms were most pronounced when the head was rotated over 45 degrees to the right. Dynamic digital subtraction angiography (dDSA) was performed to confirm the diagnosis. Leftward head rotation caused occlusion of the right vertebral artery(VA) . However, the symptoms were mild, owing to sufficient compensation by the right posterior communicating artery (PCA) . Rightward head rotation exceeding 45 degrees resulted in occlusion of the left VA. The resultant symptoms were pronounced due to inadequate compensation of the left PCA. CT angiographic reconstruction showed bilateral vertebral arteries with tortuous loops of vessels at the level of the C2 vertebrae . CT images showed no cleavage between the left VA and the anterior surface of the left C2 transverse foramen. Conservative treatment was recommended considering the patient's young age and limited severity of her symptoms. Bow Hunter's syndrome is a rare neurovascular disorder characterized by dynamic occlusion of the VAs during head rotation, leading to inadequate blood flow to the posterior cerebral circulation. Bow hunter syndrome, where bilateral dynamic occlusion occurs without a discernible dominant side of the VA, is uncommon. The medical community must acknowledge cervical vertigo as a distinct disorder. dDSA remains the gold standard for its diagnosis.
Asunto(s)
Mucopolisacaridosis II , Insuficiencia Vertebrobasilar , Humanos , Femenino , Adulto , Insuficiencia Vertebrobasilar/diagnóstico por imagen , Mucopolisacaridosis II/complicaciones , Angiografía de Substracción Digital/efectos adversos , Angiografía Cerebral , Arteria Vertebral/diagnóstico por imagen , Arteria Vertebral/cirugíaRESUMEN
Fungal infections present a growing global public health concern, necessitating the development of novel antifungal drugs. However, many potential antifungals, particularly the expelled potential active agents (EPAAs), are often underestimated owing to their limitations in cellular entry or expulsion by efflux pumps. Herein, we identified 68 EPAAs out of 2322 candidates with activity against a Candida albicans efflux pump-deficient strain and no inhibitory activity against the wild-type strain. Using a novel conjugation strategy involving benzamidine (BM) as a mitochondrion-targeting warhead, we successfully converted EPAAs into potent antifungals against various urgent-threat azole-resistantCandida strains. Among the obtained EPAA-BM conjugates, IS-2-BM (11) exhibited excellent antifungal activities and induced negligible drug resistance. Furthermore, IS-2-BM prevented biofilm formation, eradicated mature biofilms, and exhibited excellent therapeutic effects in a murine model of systemic candidiasis. These findings provide a promising strategy for increasing the possibilities of discovering more antifungals.
Asunto(s)
Candidiasis , Micosis , Animales , Ratones , Humanos , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Candidiasis/tratamiento farmacológico , Candidiasis/microbiología , Candida albicans , Micosis/tratamiento farmacológico , Biopelículas , Pruebas de Sensibilidad Microbiana , Farmacorresistencia FúngicaRESUMEN
Inducing paraptosis, a nonapoptotic form of cell death, has great therapeutic potential in cancer therapy, especially for drug-resistant tumors. However, the specific molecular target(s) that trigger paraptosis have not yet been deciphered yet. Herein, by using activity-based protein profiling, we identified the GDP-dissociation inhibitor beta (GDI2) as a manipulable target for inducing paraptosis and uncovered benzo[a]quinolizidine BQZ-485 as a potent inhibitor of GDI2 through the interaction with Tyr245. Comprehensive target validation revealed that BQZ-485 disrupts the intrinsic GDI2-Rab1A interaction, thereby abolishing vesicular transport from the endoplasmic reticulum (ER) to the Golgi apparatus and initiating subsequent paraptosis events including ER dilation and fusion, ER stress, the unfolded protein response, and cytoplasmic vacuolization. Based on the structure of BQZ-485, we created a small benzo[a]quinolizidine library by click chemistry and discovered more potent GDI2 inhibitors using a NanoLuc-based screening platform. Leveraging the engagement of BQZ-485 with GDI2, we developed a selective GDI2 degrader. The optimized inhibitor (+)-37 and degrader 21 described in this study exhibited excellent in vivo antitumor activity in two GDI2-overexpressing pancreatic xenograft models, including an AsPc-1 solid tumor model and a transplanted human PDAC tumor model. Altogether, our findings provide a promising strategy for targeting GDI2 for paraptosis in the treatment of pancreatic cancers, and these lead compounds could be further optimized to be effective chemotherapeutics.
RESUMEN
BACKGROUND: The cellular dynamics in the tumour microenvironment (TME) along with non-small cell lung cancer (NSCLC) progression remain unclear. METHODS: Multiplex immunofluorescence test detecting 10 immune-related markers on 553 primary tumour (PT) samples of NSCLC was conducted and spatial information in TME was assessed by the StarDist depth learning model. The single-cell transcriptomic atlas of PT (n = 4) and paired tumour-draining lymph nodes (TDLNs) (n = 5 for tumour-invaded, n = 3 for tumour-free) microenvironment was profiled. Various bioinformatics analyses based on Gene Expression Omnibus, TCGA and Array-Express databases were also used to validate the discoveries. RESULTS: Spatial distances of CD4+ T cells-CD38+ T cells, CD4+ T cells-neutrophils and CD38+ T cells-neutrophils prolonged and they were replaced by CD163+ macrophages in PT along with tumour progression. Neutrophils showed unique stage and location-dependent prognostic effects. A high abundance of stromal neutrophils improved disease-free survival in the early-stage, whereas high intratumoural neutrophil infiltrates predicted poor prognosis in the mid-to-late-stage. Significant molecular and functional reprogramming in PT and TDLN microenvironments was observed. Diverse interaction networks mediated by neutrophils were found between positive and negative TDLNs. Five phenotypically and functionally heterogeneous subtypes of tumour-associated neutrophil (TAN) were further identified by pseudotime analysis, including TAN-0 with antigen-presenting function, TAN-1 with strong expression of interferon (IFN)-stimulated genes, the pro-tumour TAN-2 subcluster, the classical subset (TAN-3) and the pro-inflammatory subtype (TAN-4). Loss of IFN-stimulated signature and growing angiogenesis activity were discovered along the transitional trajectory. Eventually, a robust six neutrophil differentiation relevant genes-based model was established, showing that low-risk patients had longer overall survival time and may respond better to immunotherapy. CONCLUSIONS: The cellular composition, spatial location, molecular and functional changes in PT and TDLN microenvironments along with NSCLC progression were deciphered, highlighting the immunoregulatory roles and evolutionary heterogeneity of TANs.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neutrófilos , Microambiente Tumoral , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neutrófilos/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Pronóstico , Conjuntos de Datos como Asunto , Algoritmos , Carcinoma de Pulmón de Células no Pequeñas/inmunologíaRESUMEN
Filamentation is an important virulence factor of the pathogenic fungus Candida albicans. The abolition of Candida albicans hyphal formation by disrupting sterol synthesis is an important concept for the development of antifungal drugs with high safety. Here, we conduct a high-throughput screen using a C. albicans strain expressing green fluorescent protein-labeled Dpp3 to identify anti-hypha agents by interfering with ergosterol synthesis. The antipyrine derivative H55 is characterized to have minimal cytotoxicity and potent inhibition of C. albicans hyphal formation in multiple cultural conditions. H55 monotherapy exhibits therapeutic efficacy in mouse models of azole-resistant candidiasis. H55 treatment increases the accumulation of zymosterol, the substrate of C-24 sterol methyltransferase (Erg6). The results of enzyme assays, photoaffinity labeling, molecular simulation, mutagenesis, and cellular thermal shift assays support H55 as an allosteric inhibitor of Erg6. Collectively, H55, an inhibitor of the fungal-specific enzyme Erg6, holds potential to treat C. albicans infections.
Asunto(s)
Candida albicans , Candidiasis , Animales , Ratones , Esteroles/uso terapéutico , Metiltransferasas , Candidiasis/tratamiento farmacológico , Antifúngicos/farmacología , Antifúngicos/uso terapéuticoRESUMEN
The application of numerous chemotherapeutic drugs has been limited due to poor solubility, adverse side effects, and even multidrug resistance in patients. Polymeric micelles with reversibly cross-linked structures provide a promising solution to these issues. Herein, we optimized and synthesized programable-released disulfide cross-linked micelle (PDCM) based on our previous well-defined dendrimers to deliver the antitumor drug betulinic acid (BA) and paclitaxel (PDCM@PTX) and evaluated the therapeutic efficacy of multidrug-resistant (MDR) simulative orthotopic intraperitoneal ovarian cancer mice models. Comprehensive results demonstrated that PDCM@PTX formed stable nanoparticles able to improve the pharmacokinetic profile and circulation time of PTX, allowing for increased tumor penetration. Furthermore, in the tumor microenvironment, the programable-switches (ester bonds and disulfide cross-linking) of PDCM@PTX were cleaved by the high concentration of glutathione (tumor microenvironment) and esterase (intracellular) present in the tumor, allowing for in situ release of PTX and BA, resulting in intensive therapeutic efficacy in MDR ovarian cancer.
Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Animales , Ratones , Sistemas de Liberación de Medicamentos/métodos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Paclitaxel/química , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Micelas , Disulfuros , Línea Celular Tumoral , Resistencia a Antineoplásicos , Microambiente TumoralRESUMEN
BACKGROUND: Conventional immunohistochemistry technologies were limited by the inability to simultaneously detect multiple markers and the lack of identifying spatial relationships among cells, hindering understanding of the biological processes in cancer immunology. METHODS: Tissue slices of primary tumours from 553 IAâ¼IIIB non-small cell lung cancer (NSCLC) cases were stained by multiplex immunofluorescence (mIF) assay for 10 markers, including CD4, CD38, CD20, FOXP3, CD66b, CD8, CD68, PD-L1, CD133 and CD163, evaluating the amounts of 26 phenotypes of cells in tumour nest and tumour stroma. StarDist depth learning model was utilised to determine the spatial location of cells based on mIF graphs. Single-cell RNA sequencing (scRNA-seq) on four primary NSCLC cases was conducted to investigate the putative cell interaction networks. RESULTS: Spatial proximity among CD20+ B cells, CD4+ T cells and CD38+ T cells (r2 = 0.41) was observed, whereas the distribution of regulatory T cells was associated with decreased infiltration levels of CD20+ B cells and CD38+ T cells (r2 = -0.45). Univariate Cox analyses identified closer proximity between CD8+ T cells predicted longer disease-free survival (DFS). In contrast, closer proximity between CD133+ cancer stem cells (CSCs), longer distances between CD4+ T cells and CD20+ B cells, CD4+ T cells and neutrophils, and CD20+ B cells and neutrophils were correlated with dismal DFS. Data from scRNA-seq further showed that spatially adjacent N1-like neutrophils could boost the proliferation and activation of T and B lymphocytes, whereas spatially neighbouring M2-like macrophages showed negative effects. An immune-related risk score (IRRS) system aggregating robust quantitative and spatial prognosticators showed that high-IRRS patients had significantly worse DFS than low-IRRS ones (HR 2.72, 95% CI 1.87-3.94, p < .001). CONCLUSIONS: We developed a framework to analyse the cell interaction networks in tumour microenvironment, revealing the spatial architecture and intricate interplays between immune and tumour cells.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Transcriptoma , Microambiente Tumoral/genética , Técnica del Anticuerpo FluorescenteRESUMEN
The homotypic fusion and vacuole protein sorting (HOPS) complex mediates membrane trafficking involved in endocytosis, autophagy, lysosome biogenesis, and phagocytosis. Defects in HOPS subunits are associated with various forms of cancer, but their potential as drug targets has rarely been examined. Here, we identified vacuolar protein sorting-associated protein 41 homolog (VPS41), a subunit of the HOPS complex, as a target of methyl 2,4-dihydroxy-3-(3-methyl-2-butenyl)-6-phenethylbenzoate (DMBP), a natural small molecule with preferable anticancer activity. DMBP induced methuosis and inhibited autophagic flux in cancer cells by inhibiting the function of VPS41, leading to the restrained fusion of late endosomes and autophagosomes with lysosomes. Moreover, DMBP effectively inhibited metastasis in a mouse metastatic melanoma model. Collectively, the current work revealed that targeting VPS41 would provide a valuable method of inhibiting cancer proliferation through methuosis.
Asunto(s)
Endosomas , Neoplasias , Ratones , Animales , Transporte de Proteínas , Endosomas/metabolismo , Autofagia , Endocitosis , Lisosomas/metabolismo , Neoplasias/metabolismo , Proteínas de Transporte Vesicular/metabolismoRESUMEN
Background: Chemotherapy has been the standard treatment for small-cell lung cancer (SCLC) for decades. Nonetheless, patients are usually responsive to initial chemotherapy but quickly suffer from relapse, resulting in a poor long-term outcome. Treating advances that greatly ameliorate survival outcomes are historically finite, and credible biomarkers for therapeutic evaluation are deficient. As the genetic biology emerges, investigating biomarkers to optimize individualized treatment for SCLC is necessary. Methods: Based on following inclusion criteria: (I) patients diagnosed as SCLC by pathology; (II) patients treated with first-line etoposide/cisplatin (EP) chemotherapy; (III) patients who received long-term follow-up and signed informed consent, a total of 24 SCLC patients receiving first-line standard chemotherapy were divided into progressive disease (PD) and partial response (PR) groups. They were regularly followed every 3 months with computed tomography (CT) scan until recurrences determined by CT scan results. Next-generation sequencing (NGS) with a panel of 1,406 cancer-related genes was conducted on the tumor tissue-derived DNA of patients to compare genetic variations, including deletions (indels), single nucleotide variations (SNVs), copy number variations (CNVs), and copy number instability (CNI) between the two groups. Results: For the clinical characteristics of enrolled SCLC patients, except for significant differences in sex, age, clinical stage, and limited or extensive stage, PD patients showed distinctly shorter overall survival than those with PR (6.5 vs. 14.0 months, respectively, P=0.007). Genetic variations analysis discovered several common genes with CNV mutations between the PR and PD groups, and increased epidermal growth factor receptor (EGFR) gene copy numbers gain was found in PR groups in comparing with PD patients (P=0.006). However, no significant differences in terms of SNVs, indels, genotypes associated with first-line chemotherapy, CNI of tumor tissue-derived DNA, and tumor mutational burden of tumor tissues were observed between two groups. Additionally, the relationship between EGFR gene mutation and clinicopathological features of SCLC indicated that EGFR gene mutation may be an independent indicator for SCLC patients. Conclusions: Increased EGFR gene CNVs may be an independent indicator influencing the survival time and PR in SCLC patients receiving standard first-line chemotherapy.
RESUMEN
The global emergence of antifungal resistance threatens the limited arsenal of available treatments and emphasizes the urgent need for alternative antifungal agents. Targeting fungal pathogenic functions is an appealing alternative therapeutic strategy. Here, we show that cystathionine ß-synthase (CBS), compared with cystathionine γ-lyase, is the major enzyme that synthesizes hydrogen sulfide in the pathogenic fungus Candida albicans. Deletion of CBS leads to deficiencies in resistance to oxidative stress, retarded cell growth, defective hyphal growth, and increased ß-glucan exposure, which, together, reduce the pathogenicity of C. albicans. By high-throughput screening, we identified protolichesterinic acid, a natural molecule obtained from a lichen, as an inhibitor of CBS that neutralizes the virulence of C. albicans and exhibits therapeutic efficacy in a murine candidiasis model. These findings support the application of CBS as a potential therapeutic target to fight fungal infections.
Asunto(s)
Cistationina betasintasa , Sulfuro de Hidrógeno , Ratones , Animales , Virulencia , Cistationina gamma-Liasa , Sulfuro de Hidrógeno/farmacología , Candida albicansRESUMEN
Nut fruits likely played a significant role before and during the origin of agriculture; however, relatively little research conducted on the morphological characteristics and statistical comparisons of nut fruit starch granule hinders the progress of paleodietary analysis of prehistorical society. For better species identification of starch granule remaining on tools discovered at archaeological sites, it is desirable to develop a more abundant morphology database of modern nut fruit starch granules as well as the establishment of relevant identification standards. Therefore, nuts from 40 species in four genera (Quercus, Lithocarpus, Castanea, and Castanopsis) of Fagaceae were collected from South China for statistical measurement and comparative analysis. Starch granules are highly accumulated in 34 species except for 6 species, whose shapes involve oval, subcircular, drop-shaped, rounded triangle, polygonal, spherical caps, and bell-shaped types, or a combination of several types, and the average length is between 10 and 20 µm. According to research on Quercus phylogeny relationships, it was found that the species in the same infragenious section produce similar morphological characteristics of starch granules. The result was applied in the identification of starch granules extracted from stone tools from the 20 to 10 ka cultural layer of Xiaodong Rockshelter, and some starch granules can be recognized to species level, revealing that nuts from Quercus and Lithocarpus were gathered and exploited by ancient people. This expansion of modern starch presentation and comparison of nuts helps to improve the accuracy of the identification of ancient starch and deepen the understanding of plant utilization of ancient humans.
RESUMEN
Phytoliths, as a newly developing plant proxy, have broad application prospects in paleoclimate and paleoethnobotany. However, the shortage of studies regarding tropical-subtropical plants and topsoil phytoliths interferes with the research progress on primitive humanity's utilization of plant resources and paleoclimate in the region. This research focuses on the subtropical mountainous region with a monsoon climate of low latitudes in Southwest China to conduct phytolith morphology analysis of living plants and phytolith/pollen assemblages of topsoil to reveal the indicative significance of vegetation and climate. A total of 111 species from 50 families, including 73 species from 33 tree/shrub families, 31 species from 12 herb families and 7 species from 5 fern families, were collected for morphological characteristics analysis, as well as 19 topsoil specimens for phytolith and pollen assemblage analysis. The results suggest that phytoliths are mainly deposited in situ, with assemblages of topsoil corresponding well with plant types in the quadrat and being able to exhibit constructive species in small regions. In comparison, pollen assemblages of topsoil dominantly respond to regional vegetation due to their long-distance transportation and widespread presence, in addition to their characteristics that correspond to the vegetation in the quadrat. The topsoil phytolith assemblages are mainly based on the elongate-bulliform flabellate-square/rectangle-broadleaf-types (including spheroid echinate), and the vegetation types indicate the subtropical climate. In addition, phytolith assemblages of Poaceae are dominated by collapsed saddle-bulliform flabellate square/rectangle-elongate-point, reflecting warm and humid conditions. The pollen assemblages mainly consist of Pinus, Betula, Alnus, deciduous Quercus, Euphorbiaceae, Rhamnaceae and Polygonum, reflecting tropical-subtropical plant communities and indicating warm and humid conditions. Overall, phytolith and pollen assemblages have unique characteristics and are thus explicitly representative of the low-latitude subtropical monsoon climate.