Search

Marasmiellus (Omphalotaceae, Agaricales) specimens collected in Thailand were investigated based on morphological characteristics and molecular phylogenetic analyses. In the present study, two species are introduced as new to science, namely Marasmiellus thailandicus and M. minutisporus. Phylogenetic analyses were carried out based on the internal transcribed spacer (nrITS) and nuclear ribosomal RNA large subunit (nrLSU) regions, and the results revealed that the two new taxa are distinct species within Marasmiellus. Another specimen was identified as M. scandens and is reported for the first time with morphology and molecular data from Thailand. Descriptions, illustrations, and phylogenetic results are provided. In addition, M. diaphanus and M. colocasiae are proposed as new combinations of Collybiopsis diaphana and Paramarasmius colocasiae, respectively, based on the phylogenetic evidence.

Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme per se was insufficient to cause cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic enzyme GAPDH, leading to a significant depletion of ATP and inhibition of cancer growth in vitro and in vivo. Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with immune checkpoint inhibitors would be a logical strategy to increase the therapeutic activity.

Abstract Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.

Abstract Background Lung adenocarcinoma (LUAD), the most common and lethal subtype of lung cancer, continues to be a major health concern worldwide. Despite advances in targeted and immune therapies, only a minority of patients derive substantial benefits. As a result, the urgent need for novel therapeutic strategies to improve lung cancer treatment outcomes remains undiminished. Methods In our study, we employed the TIMER database to scrutinize TNFSF11 expression across various cancer types. We further examined the differential expression of TNFSF11 in normal and tumor tissues utilizing the TCGA-LUAD dataset and tissue microarray, and probed the associations between TNFSF11 expression and clinicopathological parameters within the TCGA-LUAD dataset. We used the GSE31210 dataset for external validation. To identify genes strongly linked to TNFSF11, we engaged LinkedOmics and conducted a KEGG pathway enrichment analysis using the WEB-based Gene SeT AnaLysis Toolkit. Moreover, we investigated the function of TNFSF11 through gene knockdown or overexpression approaches and explore its function in tumor cells. The therapeutic impact of ferroptosis inducers in tumors overexpressing TNFSF11 were also investigated through in vivo and in vitro experiments. Through these extensive analyses, we shed light on the potential role of TNFSF11 in lung adenocarcinoma, underscoring potential therapeutic targets for this malignancy. Results This research uncovers the overexpression of TNFSF11 in LUAD patients and its inverse correlation with peroxisome-related enzymes. By utilizing gene knockdown or overexpression assays, we found that TNFSF11 was negatively associated with GPX4. Furthermore, cells with TNFSF11 overexpression were relatively more sensitive to the ferroptosis inducers. Conclusions Our research has provided valuable insights into the role of TNFSF11, revealing its negative regulation of GPX4, which could be influential in crafting therapeutic strategies. These findings set the stage for further exploration into the mechanisms underpinning the relationship between TNFSF11 and GPX4, potentially opening up new avenues for precision medicine in the treatment of LUAD.

Backgrounds: Y-box binding protein 1 (YBX1) is a DNA/RNA binding protein known to contribute to the progression of various malignancies, however, a comprehensive pan-cancer analysis to investigate YBX1 across a broad spectrum of cancer types has not yet been conducted. Methods: We utilized the TIMER database for a comprehensive pan-cancer analysis and assessed YBX-1 expression via the TCGA and GEO databases. The relationship between YBX-1 expression and tumor-infiltrating cells was examined using TIMER and the R programming language. To evaluate the prognostic value of YBX1, we performed Kaplan-Meier plots and Cox regression analyses. Through LinkedOmics, we identified genes significantly correlated with YBX-1. The WEB-based Gene SeT AnaLysis Toolkit was used for KEGG pathway enrichment analysis. Additionally, using shRNA-mediated knockdown, we explored the potential role of YBX1 in tumor cell biology. Results: Our study identifies pronounced overexpression of YBX-1 across multiple cancer types, correlating with adverse outcomes, notably in liver hepatocellular carcinoma (LIHC). A distinct association between elevated YBX-1 expression and heightened immune cell infiltration suggests YBX-1′s potential role in reshaping the tumor microenvironment. Intriguingly, our KEGG pathway analysis indicated a tight nexus between YBX-1 expression and lipid metabolism. Moreover, the suppression of YBX-1 via shRNA revealed diminished cellular proliferation and marked reductions in crucial molecules steering the fatty acid synthesis pathway, implicating YBX-1′s potential regulatory role in lipid metabolism within LIHC. Conclusions: YBX-1 serves as a favorable prognostic indicator in various cancers, particularly in liver hepatocellular carcinoma. Targeting YBX1 in HCC offers potential therapeutic strategies. This work paves the way for fresh insights into targeted therapeutic approaches for cancers, especially benefiting liver hepatocellular carcinoma patients.

The complex and diverse phenomenon of fungal bioluminescence has captured human curiosity. Nevertheless, in the field of studies, there are not many attempts made particularly to reveal the new species of these interesting fungi. This study comprehensively reviews the diversity, distribution, evolution, bioluminescence mechanisms, ecological roles, and potential applications of these fungi. Most importantly, we also present an updated list of the reported bioluminescent fungi (122) so far identified from five distinct evolutionary lineages worldwide—Armillaria, Eoscyphella, Lucentipes, Mycenoid, and Omphalotus—mainly in tropical and subtropical areas. Bioluminescent fungi are descended from the last common ancestor of the Mycenoid and the Marasmioid clades of Agaricales, which have been maintained for at least 160 million years of evolution. We underscore the potential for future research to understand the ecological role of bioluminescent fungi, inspiring hope and optimism for the future of this field.

Alcohol misuse is a significant health concern among gay, bisexual, same-gender-loving, and other men who have sex with men (MSM). Yet, little is known about the severity and predictors of alcohol misuse among self-reported young Black MSM. This study aimed to identify patterns of and factors associated with alcohol misuse in a sample of young Black MSM living in New York City. Baseline data from a randomized controlled trial aimed at improving the uptake of HIV testing among 250 MSM aged 18 to 29 were analyzed. Log-binominal regression analyses were conducted to assess the association of demographic and psychosocial factors with alcohol misuse in the past year and past 3 months among young Black MSM. Overall, 33.2% and 28.0% of young Black MSM in the study experienced alcohol misuse in the past year and past 3 months, respectively. In the adjusted model, factors positively associated with past-year alcohol misuse included marijuana use, a history of drug use, and having one-two or more than two male sex partners. Likewise, participants who used marijuana and those with one-two or more than two male partners were more likely to report past 3-month alcohol misuse. No significant association was found between positive screening for depressive symptoms, chemsex, internalized homophobia, and the likelihood of having alcohol misuse. The high prevalence of alcohol misuse underscores the importance of raising awareness of alcohol misuse and designing alcohol risk reduction programs that jointly address HIV risk among young Black MSM.

(1) Background: In vitro diagnostic (IVD) tests are the main means of obtaining diagnostic information for clinical purposes. The electrochemiluminescence immunoassay (ECLIA) has become an important in vitro diagnostic technique. It has unique advantages and broad market prospects due to its sensitivity, detection limit, detection range and reagent stability. At present, there is a need to develop and optimize electrochemiluminescence immunoassay subsystems to achieve high-throughput outputs and accurate detection of instruments to promote their clinical application. (2) Methods: On the basis of the demand for clinical testing instruments with high detection accuracy and speed, this study constructed an electrochemiluminescence immunoassay system by designing magnetic separation modules, introducing PMT and optimizing the system timing regulation capability. (3) Results: The magnetic separation modules can increase the detection accuracy, the PMT system increases the detection sensitivity and optimized system timing can achieve maximum test output. Furthermore, this system performs well in terms of its linearity, detection limit, signal-to-noise ratio, precision and accuracy. (4) Conclusions: The electrochemiluminescence immunoassay system is capable of high throughput with good sensitivity and accuracy, meeting the basic requirements of clinical applications for detection capacity and output throughput.

Phytopathogenic Ganoderma species pose a significant threat to global plant health, resulting in estimated annual economic losses exceeding USD (US Dollars) 68 billion in the agriculture and forestry sectors worldwide. To combat this pervasive menace effectively, a comprehensive understanding of the biology, ecology, and plant infection mechanisms of these pathogens is imperative. This comprehensive review critically examines various aspects of Ganoderma spp., including their intricate life cycle, their disease mechanisms, and the multifaceted environmental factors influencing their spread. Recent studies have quantified the economic impact of Ganoderma infections, revealing staggering yield losses ranging from 20% to 80% across various crops. In particular, oil palm plantations suffer devastating losses, with an estimated annual reduction in yield exceeding 50 million metric tons. Moreover, this review elucidates the dynamic interactions between Ganoderma and host plants, delineating the pathogen’s colonization strategies and its elicitation of intricate plant defense responses. This comprehensive analysis underscores the imperative for adopting an integrated approach to Ganoderma disease management. By synergistically harnessing cultural practices, biological control, and chemical treatments and by deploying resistant plant varieties, substantial strides can be made in mitigating Ganoderma infestations. Furthermore, a collaborative effort involving scientists, breeders, and growers is paramount in the development and implementation of sustainable strategies against this pernicious plant pathogen. Through rigorous scientific inquiry and evidence-based practices, we can strive towards safeguarding global plant health and mitigating the dire economic consequences inflicted by Ganoderma infections.

Mitochondria are promising drug target for cancer treatment. We previously demonstrated that a bi-gold compound BGC2a was more potent than the mono-gold drug auranofin in suppressing cancer cells due to increased gold atom number that led to higher drug accumulation in and thereby inhibition of mitochondria. To exploit the potential of this new strategy, we further designed and synthesized a series of bi-gold mitocans, the compounds targeting mitochondria. The results showed that most of the newly synthesized mitocans exhibited obviously lower IC50 than auranofin, an old drug that is repurposed in clinical trials for cancer treatment. The best mitocan C3P4 was nearly 2-fold more potent than BGC2a in human non-small cell lung cancer A549 cells and mantle cell lymphoma Jeko-1 cells, exhibiting substantial colony formation-suppressing and tumor-suppressing effects in A549 cells xenograft model. C3P4 induced apoptosis in a dose-dependent manner and arrested cell cycle at G0/G1 phase. The mechanistic study showed that C3P4 significantly increased the global reactive oxygen species and mitochondrial superoxide level, and reduced the mitochondrial membrane potential. C3P4 preferentially accumulated in mitochondria as measured by the gold content and substantially inhibited oxygen consumption rate and ATP production. These results further validated our hypothesis that targeting mitochondria would be promising to develop more potent anticancer agents. C3P4 may be further evaluated as a drug candidate for lung cancer treatment.

Abstract Differential diagnosis of pulmonary nodules detected by computed tomography (CT) remains a challenge in clinical practice. Here, we characterize the global metabolomes of 480 serum samples including healthy controls, benign pulmonary nodules, and stage I lung adenocarcinoma. The adenocarcinoma demonstrates a distinct metabolomic signature, whereas benign nodules and healthy controls share major similarities in metabolomic profiles. A panel of 27 metabolites is identified in the discovery cohort (n = 306) to distinguish between benign and malignant nodules. The discriminant model achieves an AUC of 0.915 and 0.945 in the internal validation (n = 104) and external validation cohort (n = 111), respectively. Pathway analysis reveals elevation in glycolytic metabolites associated with decreased tryptophan in serum of lung adenocarcinoma vs benign nodules and healthy controls, and demonstrates that uptake of tryptophan promotes glycolysis in lung cancer cells. Our study highlights the value of the serum metabolite biomarkers in risk assessment of pulmonary nodules detected by CT screening.

Background: Compared with adults of other age groups, young adults are more likely to have substance use disorders (SUDs) but less likely to receive treatment. Untreated SUDs can lead to lethal consequences, particularly deaths related to drug overdose. Objectives: This study aimed to examine trends and sociodemographic differences in the prevalence and treatment use of SUDs among US young adults aged 18 to 25 in the National Survey on Drug Use and Health 2011–2019. Methods: Bivariable logistic regression analyses were conducted to examine annual changes in the prevalence and treatment use of SUDs, and multivariable logistic regression was used to examine sociodemographic differences in SUD prevalence and treatment use in the pooled sample of young adults from 2011 to 2019. Results: From 2011 to 2019, the overall SUD prevalence increased significantly from 5.4% to 6.2%. Cannabis use disorder was the most common SUD annually. Groups with lower prevalence of SUDs included females, young adults aged 22–25, and Hispanic, Black, and Asian participants. Across the survey years, the prevalence of treatment use fluctuated insignificantly between 10.9% and 16.9% among young adults with SUDs, and most young adults received SUD treatment in self-help groups and residential and outpatient rehabilitation facilities. Compared to White participants, treatment use was lower in Hispanic, Black, Asian participants, as well as young adults of two or more races. Young adults covered by Medicaid/CHIP were more likely to use treatment. Conclusions: This study revealed an alarming level of unmet treatment need and significant disparities in treatment use among young adults with SUDs. To reduce barriers to treatment utilization, more coordinated efforts that leverage policy and structural changes alongside innovations to engage young adults with SUD care are needed.

How and when Earth acquired its major volatiles N-C-H-S remains unclear. Here the authors show that Earth may have acquired its major volatiles from both reduced and oxidized impactors before and during the Moon-forming giant impact.

Abstract Background The outbreak of SARS-CoV-2 continues to pose a serious threat to human health and social. The ongoing pandemic of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a serious threat to public health and economic stability worldwide. Given the urgency of the situation, researchers are attempting to repurpose existing drugs for treating COVID-19. Methods We first established an anti-coronavirus drug screening platform based on the Homogeneous Time Resolved Fluorescence (HTRF) technology and the interaction between the coronavirus spike protein and its host receptor ACE2. Two compound libraries of 2,864 molecules were screened with this platform. Selected candidate compounds were validated by SARS-CoV-2_S pseudotyped lentivirus and ACE2-overexpressing cell system. Molecular docking was used to analyze the interaction between S protein and compounds. Results We identified three potential anti-coronavirus compounds: tannic acid (TA), TS-1276 (anthraquinone), and TS-984 (9-Methoxycanthin-6-one). Our in vitro validation experiments indicated that TS-984 strongly inhibits the interaction of the coronavirus S protein and the human cell ACE2 receptor. Additionally, tannic acid showed moderate inhibitory effect on the interaction of S protein and ACE2. Conclusion This platform is a rapid, sensitive, specific, and high throughput system, and available for screening large compound libraries. TS-984 is a potent blocker of the interaction between the S-protein and ACE2, which might have the potential to be developed into an effective anti-coronavirus drug.

Water, in trace amounts, can greatly alter chemical and physical properties of mantle minerals and exert primary control on Earth’s dynamics. Quantifying how water is retained and distributed in Earth’s deep interior is essential to our understanding of Earth’s origin and evolution. While directly sampling Earth’s deep interior remains challenging, the experimental technique using laser-heated diamond anvil cell (LH-DAC) is likely the only method available to synthesize and recover analog specimens throughout Earth’s lower mantle conditions. The recovered samples, however, are typically of micron sizes and require high spatial resolution to analyze their water abundance. Here we use nano-scale secondary ion mass spectrometry (NanoSIMS) to characterize water content in bridgmanite, the most abundant mineral in Earth’s lower mantle. We have established two working standards of natural orthopyroxene that are likely suitable for calibrating water concentration in bridgmanite, i.e., A119(H2O) = 99 ± 13 μg/g (1SD) and A158(H2O) = 293 ± 23 μg/g (1SD). We find that matrix effect among orthopyroxene, olivine, and glass is less than 10%, while that between orthopyroxene and clinopyroxene can be up to 20%. Using our calibration, a bridgmanite synthesized by LH-DAC at 33 ± 1 GPa and 3,690 ± 120 K is measured to contain 1,099 ± 14 μg/g water, with partition coefficient of water between bridgmanite and silicate melt ∼0.025, providing the first measurement at such condition. Applying the unique analytical capability of NanoSIMS to minute samples recovered from LH-DAC opens a new window to probe water and other volatiles in Earth’s deep mantle.

Tumor cell migration induced by arsenite (iAsIII) is closely associated with cancer progression. However, transcriptomic and metabolic traits of migrative human cells exposed to iAsIII remain to be well characterized. Here, the combination of transcriptomics and metabolomics approaches were employed to construct interactive networks of functional genes and metabolites in human colorectal cancer (DLD-1) cells exposed to iAsIII. The number of DLD-1 cells passing through the Transwell membrane was at least 6 times greater in the iAsIII-treated groups than in controls. Following iAsIII treatment, the expression of ZEB1 and SLUG protein was significantly upregulated while the expression of CRB2 was downregulated (p

Abstract Background Isocitrate dehydrogenase-2 (IDH2) is a mitochondrial enzyme that catalyzes the metabolic conversion between isocitrate and alpha-ketoglutarate (α-KG) in the TCA cycle. IDH2 mutation is an oncogenic event in acute myeloid leukemia (AML) due to the generation of 2-hydroxyglutarate. However, the role of wild-type IDH2 in AML remains unknown, despite patients with it suffer worse clinical outcome than those harboring mutant type. Methods IDH2 expression in AML cell lines and patient samples was evaluated by RT-qPCR, western blotting and database analyses. The role of wild-type IDH2 in AML cell survival and proliferation was tested using genetic knockdown and pharmacological inhibition in AML cells and animal models. LC–MS, GC–MS, isotope metabolic tracing, and molecular analyses were performed to reveal the underlying mechanisms. Results We found that wild-type IDH2 was overexpressed in AML and played a major role in promoting leukemia cell survival and proliferation in vitro and in vivo. Metabolomic analyses revealed an active IDH2-mediated reductive TCA cycle that promoted the conversion of α-KG to isocitrate/citrate to facilitate glutamine utilization for lipid synthesis in AML cells. Suppression of wild-type IDH2 by shRNA resulted in elevated α-KG and decreased isocitrate/citrate, leading to reduced lipid synthesis, a significant decrease in c-Myc downregulated by α-KG, and an inhibition of AML viability and proliferation. Importantly, pharmacological inhibition of IDH2 showed significant therapeutic effect in mice inoculated with AML cells with wt-IDH2 and induced a downregulation of C-MYC in vivo. Conclusions Wt-IDH2 is an essential molecule for AML cell survival and proliferation by promoting conversion of α-KG to isocitrate for lipid synthesis and by upregulating c-Myc expression and could be a potential therapeutic target in AML.

Bacteria in nature are present in different lifestyles with distinct characteristics. Streptococcus mutans is the etiologic pathogen of dental caries and could easily gain access into the bloodstream after oral surgery and adopt a biofilm lifestyle, resulting in infective endocarditis. A growing amount of evidence have revealed that the large web-like structure composed of extracellular DNA and antimicrobial proteins released by neutrophils, named Neutrophil Extracellular Traps (NETs), play an active role in the defense against bacterial invasion. The present study demonstrated that NETs formation was discriminatively affected by S. mutans biofilm and its planktonic counterpart. The free-floating planktonic S. mutans exhibited an active NETs response, whereas the biofilm community exhibited a reverse negative NETs response. Besides, impaired biofilm killing correlated with the decrease in NETs production. Unlike planktonic cells, biofilm avoided the burst of reactive oxygen species (ROS) when co-culture with neutrophils, and the NADPH-oxidase pathway was partially involved. A mice infection model also supported the distinguishing response of neutrophils challenged by different lifestyles of S. mutans. In conclusion, different bacterial physiological states can affect the distinct response of the host–microbe interaction, thus contributing to the anti-pathogen immune response activation and immune surveillance survival.

Psoriasis can be provoked or exacerbated by environmental exposures such as certain microbiomes. The distinction between plaque psoriasis (PP) and guttate psoriasis (GP) in the skin or pharyngeal microbiota is not yet clear. High-throughput sequencing using Illumina MiSeq was used in this study to characterize skin and pharyngeal microbial composition in patients with PP [large PP (LPP, n = 62), small PP (SPP, n = 41)] and GP (n = 14). The alpha- and beta-diversity of skin microbiota LPP was similar to that of the SPP group, but different from the GP group. There were no differences in pharyngeal microbiota among the groups. According to linear discriminant analysis effect size (LEfSe) analysis, Staphylococcus, Stenotrophomonas, Enhydrobacter, Brevundimonas, and Allorhizobium–Neorhizobium–Pararhizobium–Rhizobium were the dominant genera of skin microbiota in PP. Diversity of skin microbiota correlated with Psoriasis Area and Severity Index (PASI). Moderate-to-severe psoriasis and mild psoriasis have different microbiota compositions. The skin microbiota may be related to the pharyngeal microbiota. Furthermore, two microbiota-based models could distinguish psoriasis subtypes with area under the receiver-operating characteristic curve (AUC-ROC) of 0.935 and 0.836, respectively. In conclusion, the skin microbiota in patients with LPP is similar to that in patients with SPP, but displays variations compared to that of GP, no differences are noted between subtypes in pharyngeal microbiota. Skin microbiota diversity correlated with PASI.

B‐cell non‐Hodgkin's lymphoma (NHL) is a class of heterogeneous diseases with variable clinical outcomes. Immunosuppression is particularly common in the subtypes of lymphoma with poor prognosis, but the underlying mechanism remains unclear. Using a RT‐PCR array analysis, we have identified that glycosyltransferase 1 domain‐containing 1 (GLT1D1), an enzyme that transfers glycosyl groups to proteins, is highly upregulated in the incurable subtype of B‐cell NHL and in early relapse diffuse large B‐cell lymphoma. Analysis of clinical specimens revealed that GLT1D1 expression was positively correlated with the level of glycosylated programmed cell death‐ligand 1 (PD‐L1) in B‐cell NHL and that high GLT1D1 expression was associated with poor prognosis. Mechanistically, we showed that GLT1D1 transferred N‐linked glycans to PD‐L1, thus promoting the immunosuppressive function of glycosylated PD‐L1. Downregulation of GLT1D1 resulted in a decrease of glycosylated PD‐L1 and enhanced cytotoxic T‐cell function against lymphoma cells. In vivo, overexpression of GLT1D1 promoted tumor growth by facilitating tumor immune escape through increased levels of PD‐L1. Our work has identified GLT1D1 as a predictive biomarker for B‐cell NHL. It has also shown that this enzyme enhances PD‐L1 stabilization via N‐glycosylation, thus promoting immunosuppression and tumor growth. As such, GLT1D1 might be a novel therapeutic target for the treatment of B‐NHL.

Mitochondrial isocitrate dehydrogenase 2 (IDH2) is an important metabolic enzyme in the tricarboxylic acid cycle (TCA) cycle. Our previous study showed that high expression of wild-type IDH2 promotes the proliferation of lung cancer cells. This study aims to test the potential of targeting IDH2 as a therapeutic strategy to inhibit lung cancer in vitro and in vivo. First, we analyzed the available data from the databases gene expression omnibus (GEO) database to evaluate the clinical relevance of IDH2 expression in affecting lung cancer patient survival. We then generated a stable IDH2-knockdown lung cancer cell line using a lentivirus-based method for in vitro and in vivo study. Cell growth, apoptosis, cell viability, and colony formation assays were conducted to test the sensitivity of lung cancer cells with different IDH2 expression status to cisplatin or radiation treatment in vitro. For mechanistic study, Cellular oxygen consumption and extracellular acidification rates were measured using a Seahorse metabolic analyzer, and reactive oxygen species (ROS) generation was analyzed using flow cytometry. An animal study using a xenograft tumor model was performed to further evaluate the in vivo therapeutic effect on tumor growth. We found that high IDH2 expression was associated with poor survival in lung cancer patients undergoing chemotherapy. Inhibition of IDH2 significantly enhanced the anticancer activity of cisplatin and also increased the effect of radiation against lung cancer cells. IDH2 was upregulated in cisplatin-resistant lung cancer cells, which could be sensitized by targeted inhibition of IDH2. Mechanistic study showed that abrogation of IDH2 caused only minimal changes in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in lung cancer cells, but induced a significant increase in ROS, which rendered the cancer cells more sensitive to cisplatin. Pretreatment of lung cancer cells with the ROS scavenger N-acetyl-cysteine could partially rescue cells from the cytotoxic effect of cisplatin and IDH2 inhibition. Importantly, abrogation of IDH2 significantly increased the sensitivity of lung cancer cells to cisplatin in vivo.

Internal tandem duplications (ITD) mutation within FMS-like tyrosine kinase 3 (FLT3), the most frequent mutation happens in almost 20% acute myeloid leukemia (AML) patients, always predicts a poor prognosis. As a small molecule tyrosine kinase inhibitor, sorafenib is clinically used for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and differentiated thyroid cancer (DTC), with its preclinical and clinical activity demonstrated in the treatment of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant AML. Even though it shows a rosy future in the AML treatment, the short response duration remains a vital problem that leads to treatment failure. Rapid onset of drug resistance is still a thorny problem that we cannot overlook. Although the mechanisms of drug resistance have been studied extensively in the past years, there is still no consensus on the exact reason for resistance and without effective therapeutic regimens established clinically. My previous work reported that sorafenib-resistant FLT3-ITD mutant AML cells displayed mitochondria dysfunction, which rendered cells depending on glycolysis for energy supply. In my present one, we further illustrated that losing the target protein FLT3 and the continuously activated PI3K/Akt signaling pathway may be the reason for drug resistance, with sustained activation of PI3K/AKT signaling responsible for the highly glycolytic activity and adenosine triphosphate (ATP) generation. PI3K inhibitor, LY294002, can block PI3K/AKT signaling, further inhibit glycolysis to disturb ATP production, and finally induce cell apoptosis. This finding would pave the way to remedy the FLT3-ITD mutant AML patients who failed with FLT3 targeted therapy.

Reactive oxygen species (ROS) homeostasis and mitochondrial metabolism are critical for the survival of cancer cells, including cancer stem cells (CSCs), which often cause drug resistance and cancer relapse. Auranofin is a mono-gold anti-rheumatic drug, and it has been repurposed as an anticancer agent working by the induction of both ROS increase and mitochondrial dysfunction. Hypothetically, increasing auranofin’s positive charges via incorporating more gold atoms to enhance its mitochondria-targeting capacity could enhance its anti-cancer efficacy. Hence, in this work, both mono-gold and bi-gold compounds were designed and evaluated to test our hypothesis. The results showed that bi-gold compounds generally suppressed cancer cells proliferation better than their mono-gold counterparts. The most potent compound, BGC2a, substantially inhibited the antioxidant enzyme TrxR and increased the cellular ROS. BGC2a induced cell apoptosis, which could not be reversed by the antioxidant agent vitamin C, implying that the ROS induced by TrxR inhibition might not be the decisive cause of cell death. As expected, a significant proportion of BGC2a accumulated within mitochondria, likely contributing to mitochondrial dysfunction, which was further confirmed by measuring oxygen consumption rate, mitochondrial membrane potential, and ATP production. Moreover, BGC2a inhibited colony formation and reduced stem-like side population (SP) cells of A549. Finally, the compound effectively suppressed the tumor growth of both A549 and PANC-1 xenografts. Our study showed that mitochondrial disturbance may be gold-based compounds’ major lethal factor in eradicating cancer cells, providing a new approach to developing potent gold-based anti-cancer drugs by increasing mitochondria-targeting capacity.

Objective: Mitochondrial aconitase (ACO2) is an essential enzyme that bridges the TCA cycle and lipid metabolism. However, its role in cancer development remains to be elucidated. The metabolic subtype of colorectal cancer (CRC) was recently established. We investigated ACO2's potential role in CRC progression through mediating metabolic alterations. Methods: We compared the mRNA and protein expression of ACO2 between paired CRC and non-tumor tissues from 353 patients. Correlations between ACO2 levels and clinicopathological features were examined. CRC cell lines with knockdown or overexpression of ACO2 were analyzed for cell proliferation and tumor growth. Metabolomics and stable isotope tracing analyses were used to study the metabolic alterations induced by loss of ACO2. Results: ACO2 decreased in >50% of CRC samples compared with matched non-tumor tissues. Decreased ACO2 levels correlated with advanced disease stage (P

Background Neutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1+) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1+ neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1+ neutrophils in hepatocellular carcinoma.Methods Neutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1+ neutrophil infiltration. Further in vivo assays were used for verification.Results Lenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1+ neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1+ neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1+ neutrophil and promoted the antitumor effect of lenvatinib.Conclusions PD-L1+ neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1+ neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.

Abstract Background Internal tandem duplications (ITD) within the juxtamembrane domain of FMS-like tyrosine kinase 3 (FLT3) represent a poor prognostic indicator in acute myeloid leukemia (AML). Therapeutic benefits of tyrosine kinase inhibitors, such as sorafenib, are limited due to the emergence of drug resistance. While investigations have been conducted to improve the understanding of the molecular mechanisms underlying the resistance to this FLT3 inhibitor, a profile of cell functioning at the metabolite level and crosstalk between metabolic pathways has yet to be created. This study aimed to elucidate the alteration of metabolomic profile of leukemia cells resistant to the FLT3 inhibitor. Methods We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations, namely the murine BaF3/ITD-R and the human MV4-11-R cell lines. We performed a global untargeted metabolomics and stable isotope-labeling mass spectrometry analysis to identify the metabolic alterations relevant to the therapeutic resistance. Results The resistant cells displayed fundamentally rewired metabolic profiles, characterized by a higher demand for glucose, accompanied by a reduction in glucose flux into the pentose phosphate pathway (PPP); and by an increase in oxidative stress, accompanied by an enhanced glutathione synthesis. We demonstrated that the highest scoring network of altered metabolites in resistant cells was related to nucleotide degradation. A stable isotope tracing experiment was performed and the results indicated a decrease in the quantity of glucose entering the PPP in resistant cells. Further experiment suggested that the inhibition of major enzymes in the PPP consist of glucose-6-phosphate dehydrogenase deficiency (G6PD) in the oxidative arm and transketolase (TKT) in the non-oxidative arm. In addition, we observed that chronic treatment with sorafenib resulted in an increased oxidative stress in FLT3/ITD-positive leukemia cells, which was accompanied by decreased cell proliferation and an enhanced antioxidant response. Conclusions Our data regarding comparative metabolomics characterized a distinct metabolic and redox adaptation that may contribute to sorafenib resistance in FLT3/ITD-mutated leukemia cells.

Background Dendritic cells (DCs) play a critical role in antitumor immunity, but the therapeutic efficacy of DC-mediated cancer vaccine remains low, partly due to unsustainable DC function in tumor antigen presentation. Thus, identifying drugs that could enhance DC-based antitumor immunity and uncovering the underlying mechanism may provide new therapeutic options for cancer immunotherapy.Methods In vitro antigen presentation assay was used for DC-modulating drug screening. The function of DC and T cells was measured by flow cytometry, ELISA, or qPCR. B16, MC38, CT26 tumor models and C57BL/6, Balb/c, nude, and Batf3−/− mice were used to analyze the in vivo therapy efficacy and impact on tumor immune microenvironment by clotrimazole treatment.Results By screening a group of small molecule inhibitors and the US Food and Drug Administration (FDA)-approved drugs, we identified that clotrimazole, an antifungal drug, could promote DC-mediated antigen presentation and enhance T cell response. Mechanistically, clotrimazole acted on hexokinase 2 to regulate lactate metabolic production and enhanced the lysosome pathway and Chop expression in DCs subsequently induced DC maturation and T cell activation. Importantly, in vivo clotrimazole administration induced intratumor immune infiltration and inhibited tumor growth depending on both DCs and CD8+ T cells and potentiated the antitumor efficacy of anti-PD1 antibody.Conclusions Our findings showed that clotrimazole could trigger DC activation via the lactate-lysosome axis to promote antigen cross-presentation and could be used as a potential combination therapy approach to improving the therapeutic efficacy of anti-PD1 immunotherapy.

Introduction: Mental disorders represent serious public health concerns in the U.S. Compared with Whites, racial/ethnic minority adolescents are more likely to be affected by mental disorders but less likely to use mental health services. This systematic review aimed to summarize factors related to mental health service use among minority adolescents in the U.S. as identified in previous research.Methodology: Following the PRISMA guideline, we systematically searched seven databases for peer reviewed articles related to barriers and facilitators of mental health service use among racial/ethnic minority adolescents.Results: Thirty-two quantitative studies met our inclusion criteria, among which 12 studies (37.5%) sampled mostly Blacks or African Americans, 6 studies (18.7%) focused primarily on Hispanics or Latin/a/x, including Mexican Americans and Puerto Ricans, and 4 studies (12.5%) were mostly Asian Americans (e.g., Chinese, Vietnamese). Based on the socio-ecological framework, 21 studies (65.6%) identified adolescent-related barriers and facilitators of mental health service use, including biological (e.g., age, gender), clinical (e.g., symptom severity), behavioral (e.g., drug/alcohol use), and psychological characteristics (e.g., internal asset) of minority youth. Ten studies (31.3%) identified parents-related factors that influenced minority adolescent mental health service use, including parental perceptions and beliefs, family and parenting issues, and demographic characteristics. Primary factors at the therapist level included ethnic match between patient and practitioner, relationship with healthcare practitioners, and patient-therapist co-endorsement of etiological beliefs. Fifteen studies (46.9%) identified factors influencing minority adolescent mental health service use at the contextual/structural level, including household income, insurance status, and family structure. Lastly, acculturation and school experiences were major factors at the social/cultural level that influence minority adolescent service use.Conclusion: More empirical studies are needed to understand the mechanism underlying minority adolescents' unmet mental health service needs. Culturally competent interventions are warranted to engage minority adolescents with mental disorders into treatment.

Children of immigrants are often considered to be at increased risk of mental health problems due to families' immigration-related stress and perceived discrimination and prejudice from the host country. However, many studies found them to have better developmental outcomes than children with native-born parents in the U.S. This study aims to unfold this paradoxical phenomenon using data from a population-based cohort of children born in large U.S. cities. Specifically, we investigated differences in mental health outcomes between children of immigrants and those with native-born parents, stratified by children's race-ethnicity. We also explored the mediating role of child maltreatment risk in the association of parental nativity status and race-ethnicity with children's mental health. Our findings supported the immigrant paradox, with better self-reported and parent-reported internalizing and externalizing outcomes in Hispanic and Black children of immigrants than their same race-ethnicity peers and White children of native-born. Such immigrant-native variations were partially explained by parents' physically and psychologically abusive behaviors. Hispanic and Black children with immigrant parents were less likely to be physically or psychologically abused than their peers of native-born at ages 4–5, which translated into mental health advantages of children of immigrants at age 9. Our findings shed light on future research to further clarify the mechanism underlying different parenting practices between same race-ethnicity immigrants and native-born families so that culturally responsive interventions can be developed to safeguard racial-ethnic minority children's mental health.

Machine learning is about finding patterns and making predictions from raw data. In this study, we aimed to achieve two goals by utilizing the modern logistic regression model as a statistical tool and classifier. First, we analyzed the associations between Major Depressive Episode with Severe Impairment (MDESI) in adolescents with a list of broadly defined sociodemographic characteristics. Using findings from the logistic model, the second and ultimate goal was to identify the potential MDESI cases using a logistic model as a classifier (i.e., a predictive mechanism). Data on adolescents aged 12–17 years who participated in the National Survey on Drug Use and Health (NSDUH), 2011–2017, were pooled and analyzed. The logistic regression model revealed that compared with males and adolescents aged 12-13, females and those in the age groups of 14-15 and 16-17 had higher risk of MDESI. Blacks and Asians had lower risk of MDESI than Whites. Living in single-parent household, having less authoritative parents, having negative school experiences further increased adolescents' risk of having MDESI. The predictive model successfully identified 66% of the MDESI cases (recall rate) and accurately identified 72% of the MDESI and MDESI-free cases (accuracy rate) in the training data set. The rates of both recall and accuracy remained about the same (66 and 72%) using the test data. Results from this study confirmed that the logistic model, when used as a classifier, can identify potential cases of MDESI in adolescents with acceptable recall and reasonable accuracy rates. The algorithmic identification of adolescents at risk for depression may improve prevention and intervention.

Alterations in ROS metabolism and redox signaling are often observed in cancer cells and play a significant role in tumor development and drug resistance. However, the mechanisms by which redox alterations impact cellular sensitivity to anticancer drugs remain elusive. Here we have identified the mitochondrial isoform of thioredoxin reductase 3 (mtTXNRD3), through RT-PCR microarray screen, as a key molecule that confers drug resistance to sorafenib and other clinical anticancer agents. High expression of mtTXNRD3 is detected in drug-resistant leukemia and hepatocellular carcinoma cells associated with significant metabolic alterations manifested by low mitochondrial respiration and high glycolysis. Mechanistically, high mtTXNRD3 activity keeps the mitochondrial thioredoxin2 (Trx2) in a reduced stage that in turn stabilizes several key survival molecules including HK2, Bcl-XL, Bcl-2, and MCL-1, leading to increased cell survival and drug resistance. Pharmacological inhibition of thioredoxin reductase by auranofin effectively overcomes such drug resistance in vitro and in vivo, suggesting that targeting this redox mechanism may be a feasible strategy to treat drug-resistant cancer.

This study aimed to investigate the protective effect of family functioning, social capital, and civic engagement on mental health in adolescents with adverse childhood experiences (ACEs). Parents of adolescents aged 12 to 17 years (N = 20,708) who participated in the 2015-2016 National Survey of Children’s Health were surveyed about their children’ ACEs (e.g., parental divorce, being a victim of violence, living with anyone who had substance abuse) and current mental health disorders, including depression, anxiety, and behavioral problems. Parents were further asked about their family functioning, perceived social capital, and adolescents’ civic engagement. Structural equation modeling was conducted to test the hypothesized pathways using Mplus 8.0.Based on parents’ report, about 55% of adolescents have experienced at least one kind of ACE. The final structural model proved an excellent fit to the data (CFI = 0.96, RMSEA = 0.009, WRMR = 1.12). A significantly positive relationship was found between adolescents’ ACEs and current mental disorders (β = 0.13, p

To examine mental health status, COVID-19 vaccine intention and barriers among college students in the U.S. Participants: Students (n = 337) registered at a large public university in 2021. Methods: Cross-sectional survey data were collected online and analyzed using independent samples t test, chi-square test, and one-way ANOVA. Results: Compared to male students, females reported greater anxiety (p < 0.05) and fear (p < 0.01). Hispanic participants reported increased anxiety level and the least positive pandemic coping strategies (both p < 0.05) across the ethnic groups. Black students were the racial group with the lowest trust in the safety and effectiveness of COVID-19 vaccine (p < 0.05). Vaccine intention was positively correlated with factors such as vaccine safety measures, and perceptions toward vaccination (both p < 0.001). Conclusions: These gender- and ethnicity- based mental health struggles should be addressed immediately for better health and vaccine promotion outcomes amid the COVID-19 pandemic.

A new variant of the full truckload vehicle routing problem is studied. In this problem there are more than one delivery points corresponding to the same pickup point, and one order is allowed to be served several times by the same vehicle or different vehicles. For the orders which cannot be assigned because of resource constraint, the logistics company outsources them to other logistics companies at a certain cost. To maximize its profits, logistics company decides which to be transported by private fleet and which to be outsourced. The mathematical model is constructed for the problem. Since the problem is NP-hard and it is difficult to solve the large-scale problems with an exact algorithm, a hybrid genetic algorithm is proposed. Computational results show the effectiveness of the hybrid genetic algorithm.

In our current work, acetyl chloride-mediated synthesis of phenethyl isothiocyanate (PEITC) derivatives proves to be convenient and provides the expected products at good to excellent yields. Biological evaluation and structure-activity relationship analysis found that the novel compound 7 showed the best anticancer activity against human cancer cell line Panc1 and HGC27 compared with PEITC. Compounds 6 and 7 induced more apoptosis in pancreatic cancer cells but less toxicity in non-cancer cells. Further biological study demonstrated that 7 substantially increased intracellular reactive oxygen species (ROS) and depleted glutathione (GSH), leading to an oxidative stress to kill cancer cell.