Exploring the impact of hydrogen sulfide on hematologic malignancies: A review.

Hydrogen sulfide (H2S) is one of the three most crucial gaseous messengers in the body. The discovery of H2S donors, coupled with its endogenous synthesis capability, has sparked hope for the treatment of hematologic malignancies. In the last decade, the investigation into the impact of H2S has expanded, particularly within the fields of cardiovascular function, inflammation, infection, and neuromodulation. Hematologic malignancies refer to a diverse group of cancers originating from abnormal proliferation and differentiation of blood-forming cells, including leukemia, lymphoma, and myeloma. In this review, we delve deeply into the complex interrelation between H2S and hematologic malignancies. In addition, we comprehensively elucidate the intricate molecular mechanisms by which both H2S and its donors intricately modulate the progression of tumor growth. Furthermore, we systematically examine their impact on pivotal aspects, encompassing the proliferation, invasion, and migration capacities of hematologic malignancies. Therefore, this review may contribute novel insights to our understanding of the prospective therapeutic significance of H2S and its donors within the realm of hematologic malignancies.

Mitochondria transcription and cancer.

Mitochondria are major organelles involved in several processes related to energy supply, metabolism, and cell proliferation. The mitochondria function is transcriptionally regulated by mitochondria DNA (mtDNA), which encodes the key proteins in the electron transport chain that is indispensable for oxidative phosphorylation (OXPHOS). Mitochondrial transcriptional abnormalities are closely related to a variety of human diseases, such as cardiovascular diseases, and diabetes. The mitochondria transcription is regulated by the mtDNA, mitochondrial RNA polymerase (POLRMT), two transcription factors (TFAM and TF2BM), one transcription elongation (TEFM), and one known transcription termination factor (mTERFs). Dysregulation of these factors directly leads to altered expression of mtDNA in tumor cells, resulting in cellular metabolic reprogramming and mitochondrial dysfunction. This dysregulation plays a role in modulating tumor progression. Therefore, understanding the role of mitochondrial transcription in cancer can have implications for cancer diagnosis, prognosis, and treatment. Targeting mitochondrial transcription or related pathways may provide potential therapeutic strategies for cancer treatment. Additionally, assessing mitochondrial transcriptional profiles or biomarkers in cancer cells or patient samples may offer diagnostic or prognostic information.

Metformin and buparlisib synergistically induce apoptosis of non-small lung cancer (NSCLC) cells via Akt/FoxO3a/Puma axis.

Non-small cell lung cancer (NSCLC) is a global health issue lacking effective treatments. Buparlisib is a pan-PI3K inhibitor that shows promising clinical results in treating NSCLC. However, chemoresistance is inevitable and hampers the application of buparlisib. Studies show that a combination of phytochemicals and chemotherapeutics enhances its effectiveness. Here, we evaluated the role of metformin, an agent with multiple pharmacological properties, in enhancing the anti-tumour activities of buparlisib against NSCLC cells. Our results showed that metformin and buparlisib synergistically inhibited cell viability, migration, and invasion of NSCLC cells. In addition, co-treatment of metformin and buparlisib also induced cell cycle arrest and cell death in NSCLC cells. Mechanistically, metformin and buparlisib repressed Mcl-1 and upregulated Puma in NSCLC cells in a p53-independent manner. Moreover, they inhibited the PI3K/Akt signalling pathway, leading to activation of the FoxO3a/Puma signalling in NSCLC cells. Our findings suggest that combined treatment of metformin and buparlisib might provide a promising strategy for treating NSCLC.

Differentiation of pulmonary solid nodules attached to the pleura detected by thin-section CT.

BACKGROUND: Pulmonary solid pleura-attached nodules (SPANs) are not very commonly detected and thus not well studied and understood. This study aimed to identify the clinical and CT characteristics for differentiating benign and malignant SPANs. RESULTS: From January 2017 to March 2023, a total of 295 patients with 300 SPANs (128 benign and 172 malignant) were retrospectively enrolled. Between benign and malignant SPANs, there were significant differences in patients' age, smoking history, clinical symptoms, CT features, nodule-pleura interface, adjacent pleural change, peripheral concomitant lesions, and lymph node enlargement. Multivariate analysis revealed that smoking history (odds ratio [OR], 2.016; 95% confidence interval [CI], 1.037-3.919; p = 0.039), abutting the mediastinal pleura (OR, 3.325; 95% CI, 1.235-8.949; p = 0.017), nodule diameter (> 15.6 mm) (OR, 2.266; 95% CI, 1.161-4.423; p = 0.016), lobulation (OR, 8.922; 95% CI, 4.567-17.431; p < 0.001), narrow basement to pleura (OR, 6.035; 95% CI, 2.847-12.795; p < 0.001), and simultaneous hilar and mediastinal lymph nodule enlargement (OR, 4.971; 95% CI, 1.526-16.198; p = 0.008) were independent predictors of malignant SPANs, and the area under the curve (AUC) of this model was 0.890 (sensitivity, 82.0%, specificity, 77.3%) (p < 0.001). CONCLUSION: In patients with a smoking history, SPANs abutting the mediastinal pleura, having larger size (> 15.6 mm in diameter), lobulation, narrow basement, or simultaneous hilar and mediastinal lymph nodule enlargement are more likely to be malignant. CRITICAL RELEVANCE STATEMENT: The benign and malignant SPANs have significant differences in clinical and CT features. Understanding the differences between benign and malignant SPANs is helpful for selecting the high-risk ones and avoiding unnecessary surgical resection. KEY POINTS: • The solid pleura-attached nodules (SPANs) are closely related to the pleura. • Relationship between nodule and pleura and pleural changes are important for differentiating SPANs. • Benign SPANs frequently have broad pleural thickening or embed in thickened pleura. • Smoking history and lesions abutting the mediastinal pleura are indicators of malignant SPANs. • Malignant SPANs usually have larger diameters, lobulation signs, narrow basements, and lymphadenopathy.

Permanent Shape Reconfiguration and Locally Reversible Actuation of a Carbon Nanotube/Ethylene Vinyl Acetate Copolymer Composite by Constructing a Dynamic Cross-Linked Network.

Given the rapid developments in modern devices, there is an urgent need for shape-memory polymer composites (SMPCs) in soft robots and other fields. However, it remains a challenge to endow SMPCs with both a reconfigurable permanent shape and a locally reversible shape transformation. Herein, a dynamic cross-linked network was facilely constructed in carbon nanotube/ethylene vinyl acetate copolymer (CNT/EVA) composites by designing the molecular structure of EVA. The CNT/EVA composite with 0.05 wt % CNT realized a steady-state temperature of ∼75 °C under 0.11 W/cm2 light intensity, which gave rise to remote actuation behavior. The dynamic cross-linked network along with a wide melting temperature offered opportunities for chemical and physical programming, thus realizing the achievement of the programmable three-dimensional (3D) structure and locally reversible actuation. Specifically, the CNT/EVA composite exhibited a superior permanent shape reconfiguration by activating the dynamic cross-linked network at 140 °C. The composite also showed a high reversible deformation rate of 11.1%. These features endowed the composites with the capability of transformation to 3D structure as well as locally reversible actuation performance. This work provides an attractive guideline for the future design of SMPCs with sophisticated structures and actuation capability.

Reticulation Sign on Thin-Section CT: Utility for Predicting Invasiveness of Pure Ground-Glass Nodules.

BACKGROUND. Pure ground-glass nodules (pGGNs) may represent a diverse range of histologic entities of varying aggressiveness. OBJECTIVE. The purpose of this study was to evaluate the use of the reticulation sign on thin-section CT images for predicting the invasiveness of pGGNs. METHODS. This retrospective study included 795 patients (mean age, 53.4 ± 11.1 [SD] years; 254 men, 541 women) with a total of 876 pGGNs on thin-section CT that underwent resection between January 2015 and April 2022. Two fellowship-trained thoracic radiologists independently reviewed unenhanced CT images to assess the pGGNs for a range of features, including diameter, attenuation, location, shape, air bronchogram, bubble lucency, vascular change, lobulation, spiculation, margins, pleural indentation, and the reticulation sign (defined as multiple small linear opacities resembling a mesh or a net); differences were resolved by consensus. The relationship between the reticulation sign and lesion invasiveness on pathologic assessment was evaluated. RESULTS. On pathologic assessment, the 876 pGGNs included 163 nonneoplastic and 713 neoplastic pGGNs (323 atypical adenomatous hyperplasias [AAHs] or adenocarcinomas in situ [AISs], 250 minimally invasive adenocarcinomas [MIAs], and 140 invasive adenocarcinomas [IACs]). Interobserver agreement for the reticulation sign, expressed as kappa, was 0.870. The reticulation sign was detected in 0.0% of nonneoplastic lesions, 0.0% of AAHs/AISs, 6.8% of MIAs, and 54.3% of IACs. The reticulation sign had sensitivity of 24.0% and specificity of 100.0% for a diagnosis of MIA or IAC and sensitivity of 54.3% and specificity of 97.7% for a diagnosis of IAC. In multivariable regression analyses including all of the assessed CT features, the reticulation sign was a significant independent predictor of IAC (OR, 3.64; p = .001) but was not a significant independent predictor of MIA or IAC. CONCLUSION. The reticulation sign, when observed in a pGGN on thin-section CT, has high specificity (albeit low sensitivity) for invasiveness and is an independent predictor of IAC. CLINICAL IMPACT. Those pGGNs that show the reticulation sign should be strongly suspected to represent IAC; this suspicion may guide risk assessments and follow-up recommendations.

Correlations Between Inflammatory Cell Infiltration and Relative Density and the Boundary Manifestation of Pulmonary Non-Neoplastic Ground Glass Nodules.

Purpose: To investigate the influence factors for the various boundary manifestations of pulmonary non-neoplastic ground glass nodules (GGNs) on computed tomography (CT). Materials and Methods: From January 2015 to March 2022, a total of 280 patients with 318 non-neoplastic GGNs were enrolled. The correlations between degree of inflammatory cell infiltration and relative density (ΔCT) and the boundary manifestations of lesions were evaluated, respectively. Results: Nongranulomatous nodules (283, 89.0%) with fibrous tissue proliferation and/or inflammatory cells as the predominant pathological findings were the most common non-neoplastic GGNs, followed by granulomatous nodules (28, 8.8%). Among nongranulomatous GGNs, cases with more and less/no inflammatory cells were 15 (10.9%) and 122 (89.1%) in 137 well-defined ones with smooth margin, 16 (24.6%) and 49 (75.4%) in 65 well-defined ones with coarse margin, 43 (91.5%) and 4 (8.5%) in 47 ill-defined ones with higher ΔCT (>151HU), and 4 (11.8%) and 30 (88.2%) in 34 ill-defined ones with lower ΔCT (< 151HU). The proportion of cases with more inflammatory cells in well-defined nodules was similar to that in ill-defined ones with lower ΔCT (P = 0.587) but significantly lower than that in ill-defined ones with higher ΔCT (P < 0.001). Among the granulomatous nodules, ill-defined cases with higher ΔCT (16, 57.1%) were the most common, and they (7/8, 87.5%) frequently had changes during short-term follow-up. Conclusion: Nongranulomatous nodules are the most common non-neoplastic GGNs, their diverse boundary manifestations closely correlate with degree of inflammatory cell infiltration and density difference.

A combined non-enhanced CT radiomics and clinical variable machine learning model for differentiating benign and malignant sub-centimeter pulmonary solid nodules.

BACKGROUND: Radiomics has been used to predict pulmonary nodule (PN) malignancy. However, most of the studies focused on pulmonary ground-glass nodules. The use of computed tomography (CT) radiomics in pulmonary solid nodules, particularly sub-centimeter solid nodules, is rare. PURPOSE: This study aims to develop a radiomics model based on non-enhanced CT images that can distinguish between benign and malignant sub-centimeter pulmonary solid nodules (SPSNs, <1 cm). METHODS: The clinical and CT data of 180 SPSNs confirmed by pathology were analyzed retrospectively. All SPSNs were divided into two groups: training set (n = 144) and testing set (n = 36). From non-enhanced chest CT images, over 1000 radiomics features were extracted. Radiomics feature selection was performed using the analysis of variance and principal component analysis. The selected radiomics features were fed into a support vector machine (SVM) to develop a radiomics model. The clinical and CT characteristics were used to develop a clinical model. Associating non-enhanced CT radiomics features with clinical factors were used to develop a combined model using SVM. The performance was evaluated using the area under the receiver-operating characteristic curve (AUC). RESULTS: The radiomics model performed well in distinguishing between benign and malignant SPSNs, with an AUC of 0.913 (95% confidence interval [CI], 0.862-0.954) in the training set and an AUC of 0.877 (95% CI, 0.817-0.924) in the testing set. The combined model outperformed the clinical and radiomics models with an AUC of 0.940 (95% CI, 0.906-0.969) in the training set and an AUC of 0.903 (95% CI, 0.857-0.944) in the testing set. CONCLUSIONS: Radiomics features based on non-enhanced CT images can be used to differentiate SPSNs. The combined model, which included radiomics and clinical factors, had the best discrimination power between benign and malignant SPSNs.

Quantitative evaluation of density variability in the lesion-lung boundary zone to differentiate pulmonary subsolid nodules.

Background: Transition of the CT values from nodule to peripheral normal lung is related to pathological changes and may be a potential indicator for differential diagnosis. This study investigated the significance of the standard deviation (SD) values in the lesion-lung boundary zone when differentiating between benign and neoplastic subsolid nodules (SSNs). Methods: From January 2012 to July 2021, a total of 229 neoplastic and 84 benign SSNs confirmed by pathological examination were retrospectively and nonconsecutively enrolled in this study. The diagnostic study was not registered with a clinical trial platform, and the study protocol was not published. Computed tomography (CT) values of the ground-glass component (CT1), adjacent normal lung tissue (CT2), and lesion-lung boundary zone (CT3) were measured consecutively. The SD of CT3 was recorded to assess density variability. The CT1, CT2, CT3, and SD values were compared between benign and neoplastic SSNs. Results: No significant differences in CT1 and CT2 were observed between benign and neoplastic SSNs (each P value >0.05). CT3 (-736.1±51.0 vs. -792.6±73.9; P<0.001) and its SD (135.6±29.6 vs. 83.6±20.6; P<0.001) in neoplastic SSNs were significantly higher than those in benign SSNs. Moreover, the SD increased with the invasiveness degree of neoplastic SSNs (r=0.657; P<0.001). The receiver operating characteristic (ROC) curve revealed that the area under the curve was 0.927 (95% CI: 0.896-0.959) when using the SD (cutoff value =106.98) as a factor to distinguish SSNs, which increased to 0.966 (95% CI: 0.934-0.985) when including nodules with a CT1 of ≥-715 Hounsfield units (HU) only (cutoff of SD 109.9, sensitivity 0.930, and specificity 0.914). Conclusions: The SD as an objective index is valuable for differentiating SSNs, especially for those with a CT1 of ≥-715 HU, which have a higher possibility of neoplasm if the SD is >109.9.

Exosomal circNFIX promotes angiogenesis in ovarian cancer via miR-518a-3p/TRIM44 axis.

Ovarian cancer (OC) is a gynecological cancer with high mortality. OC-derived exosomal circRNAs can regulate angiogenesis. This study aims to explore the role and mechanism of exosomal circRNA nuclear factor I X (CircNFIX) derived from OC cells in angiogenesis. Quantitative real-time polymerase chain reaction was employed to evaluate the levels of circNFIX, miR-518a-3p, and tripartite motif protein 44 (TRIM44) in OC and adjacent tissues. Exosomes from the ovarian surface epithelial cell (HOSEpiC) and OC cells (SKOV3 or OVCAR3) were isolated by differential centrifugation. Exosomes were cocultured with the human umbilical vein endothelial cells (HUVECs). The angiogenesis capacity was analyzed by Tube formation assay. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and Transwell assays were used to determine the cell viability and migration ability. The dual-luciferase report, RNA immunoprecipitation (RIP), and RNA pull-down assays were applied to validate the gene's interaction. CircNFIX and TRIM44 expression were higher and miR-518a-3p was lower in OC tissues than in the adjacent tissues. Upregulated circNFIX and TRIM44 were significantly correlated with the tumor size and International Federation of Gynecology and Obstetrics (FIGO) stage of OC patients. HUVECs treated OC-derived exosomes had higher proliferation, migration, and angiogenesis capacities than the control group. While OC-derived exosomal circNFIX silencing restrained HUVECs' proliferation, migration, and angiogenesis, compared with the OC-derived exosomes group. OC-derived exosomal circNFIX positively regulated TRIM44 expression by targeting miR-518a-3p in HUVECs. OC-derived exosomal circNFIX promoted angiogenesis by regulating the Janus-activated kinase/signal transducer and activator of transcription 1 (JAK/STAT1) pathway via miR-518a-3p/TRIM44 axis in HUVECs.

CircNFIX stimulates the proliferation, invasion, and stemness properties of ovarian cancer cells by enhancing SH3RF3 mRNA stability via binding LIN28B.

We aimed to study the regulatory roles and mechanism of circular nuclear factor IX (circNFIX) in cancer growth and stemness properties of ovarian cancer (OC). CircNFIX and SH3RF3 levels in OC tissues and cells were tested by quantitative real-time PCR. RNase R treatment quantified circNFIX RNA stability. Molecular interaction among circNFIX, LIN28B, and SH3RF3 was predicted by bioinformatics software and validated through RNA immunoprecipitation (RIP) assay. The gain- or loss-experiments of circNFIX on capabilities of metastasis and stemness in vitro were assessed using Cell Counting Kit-8, Transwell, western blot, and sphere-formation assays. CircNFIX and SH3RF3 were markedly elevated in OC tissues and OC cells. Knocking down circNFIX repressed the proliferation, migration, invasion, and stemness properties of A2780 and SKOV3 cells. The RIP assay verified the direct binding relationship between LIN28B, circNFIX, and SH3RF3. Additionally, overexpression of circNFIX elevated the SH3RF3 expression, while this effect was reversed by LIN28B silence. Rescue experiments demonstrated that the overexpression of SH3RF3 reversed the knockdown of circNFIX on OC cells' proliferation, metastasis, and stemness properties. CircNFIX improved the mRNA stability and translation of SH3RF3 via recruiting LIN28B, thus promoting the proliferation, invasion, and stemness properties of OC cells in vitro.

Crosstalk between exosomes and autophagy in spinal cord injury: fresh positive target for therapeutic application.

Spinal cord injury (SCI) is a very serious clinical traumatic illness with a very high disability rate. It not only causes serious functional disorders below the injured segment, but also causes unimaginable economic burden to social development. Exosomes are nano-sized cellular communication carriers that exist stably in almost all organisms and cell types. Because of their capacity to transport proteins, lipids, and nucleic acids, they affect various physiological and pathological functions of recipient cells and parental cells. Autophagy is a process that relies on the lysosomal pathway to degrade cytoplasmic proteins and organelles and involves a variety of pathophysiological processes. Exosomes and autophagy play critical roles in cellular homeostasis following spinal cord injury. Presently, the coordination mechanism of exosomes and autophagy has attracted much attention in the early efficacy of spinal cord injury. In this review, we discussed the interaction of autophagy and exosomes from the perspective of molecular mechanisms, which might provide novel insights for the early therapeutic application of spinal cord injury.

Differential diagnosis of benign and malignant patchy ground-glass opacity by thin-section computed tomography.

BACKGROUND: Previous studies confirmed that ground-glass nodules (GGNs) with certain CT manifestations had a higher probability of malignancy. However, differentiating patchy ground-glass opacities (GGOs) and GGNs has not been discussed solely. This study aimed to investigate the differences between the CT features of benign and malignant patchy GGOs to improve the differential diagnosis. METHODS: From January 2016 to September 2021, 226 patients with 247 patchy GGOs (103 benign and 144 malignant) confirmed by postoperative pathological examination or follow-up were retrospectively enrolled. Their clinical and CT data were reviewed, and their CT features were compared. A binary logistic regression analysis was performed to reveal the predictors of malignancy. RESULTS: Compared to patients with benign patchy GGOs, malignant cases were older (P <  0.001), had a lower incidence of malignant tumor history (P = 0.003), and more commonly occurred in females (P = 0.012). Based on CT images, there were significant differences in the location, distribution, density pattern, internal bronchial changes, and boundary between malignant and benign GGOs (P <  0.05). The binary logistic regression analysis revealed that the independent predictors of malignant GGOs were the following: patient age ≥ 58 years [odds ratio (OR), 2.175; 95% confidence interval (CI), 1.135-6.496; P = 0.025], locating in the upper lobe (OR, 5.481; 95%CI, 2.027-14.818; P = 0.001), distributing along the bronchovascular bundles (OR, 12.770; 95%CI, 4.062-40.145; P < 0.001), centrally distributed solid component (OR, 3.024; 95%CI, 1.124-8.133; P = 0.028), and well-defined boundary (OR, 5.094; 95%CI, 2.079-12.482; P < 0.001). CONCLUSIONS: In older patients (≥58 years), well-defined patchy GGOs with centric solid component, locating in the upper lobe, and distributing along the bronchovascular bundles should be highly suspected as malignancy.

PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation.

(1) Background: PTC124 (Ataluren) is an investigational drug for the treatment of nonsense mutation-mediated genetic diseases. With the exception of the TP53 tumor suppressor gene, there has been little research on cancers with nonsense mutation. By conducting a database search, we found that another two tumor suppressor genes, NOTCH1 and FAT1, have a high nonsense mutation rate in head and neck squamous cell carcinoma (HNSCC). PTC124 may re-express the functional NOTCH1 or FAT1 in nonsense mutation NOTCH1 or FAT1 in HSNCC (2) Methods: DOK (with NOTCH1 Y550X) or HO-1-u-1 (with FAT1 E378X) HNSCC cells were treated with PTC124, and the NOTCH1 or FAT1 expression, cell viability, and NOTCH1- or FAT1-related downstream gene profiles were assayed. (3) Results: PTC124 was able to induce NOTCH1 or FAT1 expression in DOK and HO-1-u-1 cells. PTC124 was able to upregulate NOTCH downstream genes HES5, AJUBA, and ADAM10 in DOK cells. PTC124 enhanced DDIT4, which is under the control of the FAT1-YAP1 pathway, in HO-1-u-1 cells. FLI-06 (a NOTCH signaling inhibitor) reversed PTC124-mediated cell growth inhibition in DOK cells. PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) Conclusions: PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation.

Sensitivity and specificity of computed tomography hypodense sign when differentiating pulmonary inflammatory and malignant mass-like lesions.

Background: Hypodense sign (HyS) reportedly is associated with pulmonary fungal infection, while it also common in many non-fungal lesions. This study aims to determine the significance of a HyS presented on contrast-enhanced computed tomography (CECT) when distinguishing pulmonary inflammatory from malignant mass-like lesions. Methods: From January 2013 to January 2021, we retrospectively evaluated the clinical and computed tomography (CT) data of patients with pathologically confirmed pulmonary inflammatory lesions (ILs) and malignant lesions (MLs). We analyzed and compared the CT features of the HyS in MLs and ILs, and then evaluated whether the HyS helped to differentiate MLs and ILs. Results: There were significant differences in age and tumor markers between patients with ILs and MLs (both P<0.05). Compared with that in MLs, the occurrence of the HyS in ILs was higher (62.81% vs. 28.81%; P<0.0001). In ILs, more HyS were single, round or oval, well-defined, and had lower enhancement (ΔCT). Logistic regression analysis revealed that an ill-defined boundary, peripheral fibrosis, presence of a well-defined HyS, and a ΔCT value of the HyS <9.5 Hounsfield units (HU) were independent indicators for predicting ILs. After including the HyS CT features, the area under the curve (AUC) of the model predicting ILs increased from 0.953 to 0.986 with a sensitivity of 96.03% and a specificity of 94.03% (P=0.0027). Conclusions: The HyS is more common in ILs than in MLs. A single, regular, and well-defined HyS with a ΔCT value of <9.5 HU on CECT is highly suggestive of ILs. Combining the HyS with other morphological features could improve the diagnosis accuracy of pulmonary mass-like lesions.

Rapid Identification of Polypeptide from Carbapenem-Resistant and Susceptible Escherichia coli via Orbitrap-MS and Pattern Recognition Analyses.

A rapid and accurate analytical method was established to identify CREC and CSEC. Orbitrap-MS was used to detect the polypeptide of CREC and CSEC strains, and MS data were analyzed by pattern recognition analyses such as hierarchical cluster analysis (HCA), principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA). HCA based on the farthest distance method could well distinguish the two types of E. coli, and the cophenetic correlation coefficient of the farthest distance method was 0.901. Comparing the results of PCA, PLS-DA, and OPLS-DA, OPLS-DA exhibited the highest accuracy in predicting the CREC and CSEC strains. A total of 26 compounds were identified, and six of the compounds were the highly significant difference between the two types of strains. MS combined with pattern recognition can achieve a more comprehensive and efficient statistical analysis of complex biological samples.

P63 and P73 Activation in Cancers with p53 Mutation.

The members of the p53 family comprise p53, p63, and p73, and full-length isoforms of the p53 family have a tumor suppressor function. However, p53, but not p63 or p73, has a high mutation rate in cancers causing it to lose its tumor suppressor function. The top and second-most prevalent p53 mutations are missense and nonsense mutations, respectively. In this review, we discuss possible drug therapies for nonsense mutation and a missense mutation in p53. p63 and p73 activators may be able to replace mutant p53 and act as anti-cancer drugs. Herein, these p63 and p73 activators are summarized and how to improve these activator responses, particularly focusing on p53 gain-of-function mutants, is discussed.

Acute recurrent cerebral infarction caused by moyamoya disease complicated with adenomyosis: A case report.

BACKGROUND: Moyamoya disease is essentially an ischemic cerebrovascular disease. Here, we describe a case of acute recurrent cerebral infarction caused by moyamoya disease with concurrent adenomyosis which, to our knowledge, is the first in the literature. A literature review is also presented. CASE SUMMARY: A 38-year-old female presented to the Research and Treatment Center of Moyamoya Disease in our hospital with "left limb weakness" as the main symptom. She was diagnosed with acute cerebral infarction and moyamoya disease through magnetic resonance imaging and digital subtraction angiography. Prior to this, she had experienced a prolonged menstrual period of one-month duration. This was investigated and adenomyosis was diagnosed. After passing the acute cerebral infarction phase, the patient underwent surgery for adenomyosis followed by combined cerebral revascularization. During the postoperative follow-up, improvements of the perfusion imaging stage and modified Rankin Scale were observed. A review of the literature showed only 16 reported cases of gynecological diseases complicated with stroke. The clinical characteristics, pathogenesis, therapeutic effects, and long-term prognosis of these cases have been studied and discussed. CONCLUSION: In patients with moyamoya disease, early management of gynecological-related bleeding disorders is essential to prevent the complications of cerebral events.

NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner.

The p53 family has the following three members: p53, p63 and p73. p53 is a tumor suppressor gene that frequently exhibits mutation in head and neck cancer. Most p53 mutants are loss-of-function (LoF) mutants, but some acquire some oncogenic function, such as gain of function (GoF). It is known that the aggregation of mutant p53 can induce p53 GoF. The p73 activators RETRA and NSC59984 have an anti-cancer effect in p53 mutation cells, but we found that p73 activators were not effective in all head and neck squamous cell carcinoma (HNSCC) cell lines, with different p53 mutants. A comparison of the gene expression profiles of several regulator(s) in mutant HNSCC cells with or without aggregation of p53 revealed that nicotinamide phosphoribosyltransferase (NAMPT) is a key regulator of mutant p53 aggregation. An NAMPT inhibitor, to reduce abnormal aggregation of mutant p53, used in combination with a p73 activator, was able to effectively repress growth in HNSCC cells with p53 GoF mutants. This study, therefore, suggests a potential combination therapy approach for HNSCC with a p53 GoF mutation.

Everolimus accelerates Erastin and RSL3-induced ferroptosis in renal cell carcinoma.

Renal cell carcinoma (RCC) is a common type of urological cancer and is often diagnosed at an advanced stage. Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is used as second-line therapy for sorafenib- or sunitinib-refractory metastatic RCC. However, the clinical benefits of Everolimus are often hampered by drug resistance. Ferroptosis is a novel form of regulated cell death that has recently been implicated in the development and therapeutic responses to different cancers. RSL3 ((1S,3R)-RSL3) and Erastin are two experimental compounds that can induce ferroptosis. In the present study, we evaluated the anti-tumor effects of Everolimus in combination with RSL3 or Erastin in RCC. Everolimus and RSL3/Erastin could synergistically inhibit the viability and induce ferroptosis in RCC cells. Mechanistically, the inhibition of the mTOR-4EBP1 axis was found to be essential for the synergistic effects of Everolimus and RSL3/Erastin. Moreover, the forced expression of GPX4 abrogated ferroptosis induced by the combined treatment of Everolimus and RSL3/Erastin. Taken together, these results demonstrated that Everolimus in combination with RSL3/Erastin is a promising therapeutic option for RCC treatment and it may also help to overcome the limitation in clinical applicability of Everolimus.