Lethal Threat Research Articles

Enhanced Antiglioma Effect by a Vitamin D3-Inserted Lipid Hybrid Neutrophil Membrane Biomimetic Multimodal Nanoplatform.

Glioblastoma, the most prevalent malignant brain tumor, is a lethal threat to human health, with aggressive and infiltrative growth characteristics that compromise the clinical treatment. Herein, we developed a vitamin D3-inserted lipid hybrid neutrophil membrane biomimetic multimodal nanoplatform (designated as NED@MnO2-DOX) through doxorubicin (DOX)-loaded manganese dioxide nanoparticles (MnO2) which were coated with a vitamin D3-inserted lipid hybrid neutrophil membrane. It was demonstrated that in addition to chemotherapy and chemo-dynamic therapy efficacy, NED@MnO2-DOX exhibited great power to activate and amplify immune responses related to the cGAS STING pathway, bolstering the secretion of type I interferon-β and proinflammatory cytokines, promoting the maturation of DC cells and infiltration of CD8+T cells into the glioma tissue, thereby reversing the immunosuppressive microenvironment of glioma from a "cold" tumor to a "hot" tumor. The biomimetic multimodal nanoplatform has potential as a multimodal strategy for glioma-targeted treatment, especially holding considerable promise for the development of innate immune therapy for glioma.

A prophage competition element protects Salmonella from lysis.

Most bacteria are polylysogens that carry multiple prophages integrated into the chromosome. These prophages confer advantages to their bacterial host, yetalso pose a lethal threat as they can reactivate and enter a lytic cycle. DNA damage of the bacterial host is a common trigger of prophage lytic cycles. Because DNA damage is frequently experienced by bacterial pathogens exposed to host immune defenses, prophage activation may be common during infection. Investigating the consequences of prophage induction in Salmonella, we discover a prophage competition element in the Gifsy-1 prophage that we name ribonuclease effector module with ATPase, inhibitor, and nuclease (RemAIN) because it blocks the lytic cycles and release of viral particles of co-resident prophages. Intramacrophage Salmonella persisters, a subpopulation that incurs DNA damage, experience prophage reactivation and subsequent RemAIN activation, which influences Salmonella persisters and macrophage response to infection. Our findings reveal a multi-layered host-pathogen arms race in which prophage-prophage competition influences bacterial persistence and the mammalian immune response.

Portable DNA extraction and loop-mediated isothermal amplification (LAMP) for the on-site detection of white spot syndrome virus (WSSV)

White spot disease (WSD) has been the most severe and lethal threat to the global shrimp industry for the past three decades. WSD caused by white spot syndrome virus (WSSV) can result in severe economic losses in shrimp culture. The disease can cause rapid and mass mortality of 90–100 % within 3–10 days. Currently, there are no effective treatment measures available for the control of WSD. Strict biosecurity, possible elimination, and early diagnosis can prevent the spread of the pathogen. Several advanced diagnostic methods have been standardised for the early and rapid detection of WSD. However, the field deployable diagnostic methods are limited. LAMP is a cost-effective, alternative nucleic acid amplification method that operates under isothermal conditions. In this study, a novel field-portable LAMP was developed for the diagnosis of WSSV. The WSSV amplification was optimized at an isothermal condition of 65 °C and a reaction time of 55 min. In this closed-tube amplification, the end results were easily visualized with the naked eye by observing the simple color change. This assay is highly sensitive and can detect up to 6 copies of WSSV plasmid DNA and 0.1 fg of WSSV genomic DNA. Additionally, this diagnostic method is highly specific and did not cross-react with other shrimp pathogens such as IHHNV, IMNV, EHP and Vibrio parahaemolyticus or host DNA of Penaeus vannamei, P. monodon, and P. indicus. Furthermore, a field-deployable DNA (FDD) extraction method has been standardised with a simple rotor and dry bath. This visual LAMP-coupled FDD extraction did not require any sophisticated equipment or technical expertise. Thus this robust LAMP assay can potentially be used for routine surveillance, point-of-care testing, early detection, and timely intervention of WSD.

Unforeseen green tide of floating tubular Ulva meridionalis, a lethal threat to oyster farming, along the west coast of Taiwan: tracking its origin and ecophysiological insights

Abstract Ulva green tides have adversely affected coastal ecosystems. In June 2023 in Changhua County, Taiwan, an unprecedented floating tubular Ulva bloom spanning about 30 km of coastline caused about 30 % reduction in oyster yield as reported by local farmers. Understanding its taxonomic and ecological basis is crucial for preemptive and remedial measures. Based on molecular (rbcL and tufA) and morphological evidence, U lva meridionalis was the cause of this green tide. Haplotype network analysis (based on ITS) suggests that this green tide originated from northern China via the China Coastal Current. Historical survey data indicate that U. meridionalis arrived in Taoyuan Algal Reef (about 150 km north of the bloom area) as far back as 2018. Our ecophysiological experiments revealed that U. meridionalis exhibited a rapid daily growth rate with biomass increment up to 13–21 % when subjected to local nutrient-rich waters under lower salinity and spring-like conditions. Although historical ecological and poultry/livestock data analyses showed no noticeable change in sea surface temperature and rainfall over the past decade, a gradual rise in agricultural nitrogen and phosphorus output was observed. This taxonomic and ecological background lays the groundwork for long-term ecological monitoring. Moreover, this study exemplifies the detrimental impact of an unforeseen Ulva bloom on oyster farming.

Insights into the antifungal mechanism of Bacillus subtilis cyclic lipopeptide iturin A mediated by potassium ion channel

Fungal infections pose severe and potentially lethal threats to plant, animal, and human health. Ergosterol has served as the primary target for developing antifungal medications. However, many antifungal drugs remain highly toxic to humans due to similarity in cell membrane composition between fungal and animal cells. Iturin A, lipopeptide produced by Bacillus subtilis, efficiently inhibit various fungi, but demonstrated safety in oral administration, indicating the existence of targets different from ergosterol. To pinpoint the exact antifungal target of iturin A, we used homologous recombination to knock out and overexpress erg3, a key gene in ergosterol synthesis. Saccharomyces cerevisiae and Aspergillus carbonarius were transformed using the LiAc/SS-DNNPEG and Agrobacterium-mediated transformation (AMT), respectively. Surprisingly, increasing ergosterol content did not augment antifungal activity. Furthermore, iturin A's antifungal activity against S. cerevisiae was reduced while it pre-incubation with voltage-gated potassium (Kv) channel inhibitor, indicating that Kv activation was responsible for cell death. Iturin A was found to activate the Kv protein, stimulating K+ efflux from cell. In vitro tests confirmed interaction between iturin A and Kv protein. This study highlights Kv as one of the precise targets of iturin A in its antifungal activity, offering a novel target for the development of antifungal medications.

Rabies Vaccine for Prophylaxis and Treatment of Rabies: A Narrative Review.

Rabies, a millennia-old viral infection transmitted through animal bites, poses a lethal threat to humans, with a historic fatality rate of 100% if left untreated. Louis Pasteur's introduction of the rabies vaccine in1885 marked a turning point in the battle against rabies, preventing numerous cases. The purpose of this paper is to review the historical development, current challenges, and future prospects of rabies vaccination and treatment, with emphasis on the importance of continued research and collaborative efforts in the quest to eradicate this deadly infection. Historical vaccine development progressed from inactivated to live-attenuated forms, with modern recombinant techniques showing promise. The preventive measures at present primarily involve vaccination, but challenges persist, such as differing safety profiles and immunogenicity among vaccine types.Pre-exposure prophylaxis with a three-dose vaccine series is crucial, especially in high-risk scenarios.Post-exposure prophylaxis combines human rabies immunoglobulin and inactivated rabies virus vaccine. The quest for the next generation of vaccines explores genetically modified and viral vector-based approaches; emerging treatments include gene therapy, virus-like particles, and monoclonal antibodies, offering hope for improved outcomes. Economic barriers to post-exposure prophylaxis, limited education, and awareness challenge rabies control. Cost-effective solutions and comprehensive awareness campaigns are vital for the successful eradication of rabies. More research and collaborative endeavors remain pivotal in the ongoing journey to eradicate rabies, one of the deadliest infectious diseases known to humans, if not met with prophylactic measures.

Emulation and evaluation of tumor cell combined chemotherapy in isotropic/anisotropic collagen fiber microenvironments.

The rapid emergence of anisotropic collagen fibers in the tissue microenvironment is a critical transition point in late-stage breast cancer. Specifically, the fiber orientation facilitates the likelihood of high-speed tumor cell invasion and metastasis, which pose lethal threats to patients. Thus, based on this transition point, one key issue is how to determine and evaluate efficient combination chemotherapy treatments in late-stage cancer. In this study, we designed a collagen microarray chip containing 241 high-throughput microchambers with embedded metastatic breast cancer cell MDA-MB-231-RFP. By utilizing collagen's unique structure and hydromechanical properties, the chip constructed three-dimensional isotropic and anisotropic collagen fiber structures to emulate the tumor cell microenvironment at early and late stages. We injected different chemotherapeutic drugs into its four channels and obtained composite biochemical concentration profiles. Our results demonstrate that anisotropic collagen fibers promote cell proliferation and migration more than isotropic collagen fibers, suggesting that the geometric arrangement of fibers plays an important role in regulating cell behavior. Moreover, the presence of anisotropic collagen fibers may be a potential factor leading to the poor efficacy of combined chemotherapy in late-stage breast cancer. We investigated the efficacy of various chemotherapy drugs using cell proliferation inhibitors paclitaxel and gemcitabine and tumor cell migration inhibitors 7rh and PP2. To ensure the validity of our findings, we followed a systematic approach that involved testing the inhibitory effects of these drugs. According to our results, the drug combinations' effectiveness could be ordered as follows: paclitaxel + gemcitabine > gemcitabine + 7rh > PP2 + paclitaxel > 7rh + PP2. This study shows that the biomimetic chip system not only facilitates the creation of a realistic in vitro model for examining the cell migration mechanism in late-stage breast cancer but also has the potential to function as an effective tool for future chemotherapy assessment and personalized medicine.

Abstract PO4-15-07: ESR1 mutations emerging during neoadjuvant endocrine therapy in postmenopausal ER+/HER2- early breast cancer patients: prevalence and prognostic impact

Abstract Background Neoadjuvant endocrine therapy (NET) is currently used in several clinical trials to select patients for chemotherapy de-escalation. However, exposure to NET may induce/select endocrine-resistant tumor cell clones harboring ESR1 mutations (ESR1mut), which are well known to confer poor prognosis and ET resistance to aromatase inhibitors in the metastatic setting. In this study, we sought to determine the frequency and prognostic significance of ESR1mut after NET in postmenopausal patients with HR+/HER2- early breast cancer. Materials and methods We conducted a retrospective study in postmenopausal patients with ER+/HER2-early breast cancer diagnosed between 2000 and 2012 and treated with NET for at least three months at Institut Curie Hospitals (Paris and Saint Cloud, France). Exclusion criteria were: stage IV breast cancer, no surgery of the primary tumor, neoadjuvant radiation therapy, chemotherapy or targeted therapies. DNA from post-NET surgical samples was extracted using the phenol-chloroform DNA isolation method. ESR1mut were detected with multiplex drop-off ddPCR assay previously used in the PADA-1 trial (targeting clustered hotspot mutations in exon 8 and 5, using a BioRad QX100 system and analyzed with QuantaSoft v.1.7.4 software). Associations between ESR1mut detection and patient outcomes, distant relapse-free interval (DRFI) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards models. Results N=143 patients treated with NET were eligible for this study, of whom N=136 had interpretable ESR1mut detection results. Median age at NET initiation was 75.4 (IQR 66.6-81.3) years. The median duration of NET was 6.6 months (IQR 5.8 – 7.6). Most patients were treated with aromatase inhibitors (n=107, 75.9%), while 24.1% (n=34) received tamoxifen. The median time between diagnosis and surgery was 7.6 (IQR 6.4 – 8.7) months. ESR1mut were detected in post-NET surgical samples in N=7 patients (5.2%). Baseline clinicopathological characteristics were not associated with post-NET ESR1mut detection status. The median follow-up for DRFI and OS was 11.0 (IQR 7.7 – 13.8) and 18.7 (IQR 13.3 – 18.7) years, respectively. The median DRFI was 6.7 (95%CI [4.9-NR]) vs 14.0 [10.7-NR] years in ESR1mut and ESR1wt patients, respectively (HR=1.9 [0.6-6.2], p=0.29). Similarly, median OS was numerically shorter in patients with post-NET ESR1mut (6.8 [3.7-NR] vs 9.8 [8.5-NR]; HR=2.0 [0.9-4.7], p=0.09). Conclusions Post-NET tumors are enriched in ESR1mut subclones, which represent a potentially lethal threat in the context of aromatase inhibitor-based adjuvant endocrine therapy. Although the limited sample size of our study did not allow reaching statistical significance, our results suggest, for the first time, worse survival outcomes for patients with a ESR1mut detected in post-NET primary tumors. The role of next-generation oral SERDs as neoadjuvant or adjuvant endocrine therapy to prevent ESR1mut-related relapses remains to be determined. Citation Format: José Luis Sandoval, Helene Salaun, Shufang Renault, Marcela Carausu, Aurore Rampanou, Caroline Hego, Matthieu Carton, Luc Cabel, Jean-Yves Pierga, Romain Geiss, Francois-Clement Bidard, Florence Lerebours. ESR1 mutations emerging during neoadjuvant endocrine therapy in postmenopausal ER+/HER2- early breast cancer patients: prevalence and prognostic impact [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-07.

Turning Threat to Therapy: A Nanozyme-Patch in Surgical Bed for Convenient Tumor Vaccination by Sustained In Situ Catalysis.

Complete surgical resection of tumor is difficult as the invasiveness of cancer, making the residual tumor a lethal threat to patients. The situation is deteriorated by the immune suppression state after surgery, which further nourishes tumor recurrence and metastasis. Immunotherapy is promising to combat tumor metastasis, but is limited by severe toxicity of traditional immunostimulants and complexity of multiple functional units. Here, it is reported that the simple "trans-surgical bed" delivery of Cu2- xSe nanozyme (CSN) by a microneedle-patch can turn the threat to therapy by efficient in situ vaccination. The biocompatible CSN exhibits both peroxidase and glutathione oxidase-like activities, efficiently exhausting glutathione, boosting free radical generation, and inducing immunogenic cell death. The once-for-all inserting of the patch on surgical bed facilitates sustained catalytic action, leading to drastic decrease of recurrence rate and complete suppression of tumor-rechallenge in cured mice. In vivo mechanism interrogation reveals elevated cytotoxic T cell infiltration, re-educated macrophages, increased dendritic cell maturation, and memory T cells formation. Importantly, preliminary metabolism and safety evaluation validated that the metal accumulation is marginable, and the important biochemical indexes are in normal range during therapy. This study has provided a simple, safe, and robust tumor vaccination approach for postsurgical metastasis control.

Silver Lining in the Dark Clouds: Radiological Resolution of Non-Functional Giant Pituitary Adenoma after Traumatic Spinal Cord Injury

Tumors of pituitary are considered relatively rare. Giant adenomas of this gland further add in rarity. Pituitary apoplexy (PA) is an unusual event, which may occur as a result of hemorrhage, necrosis and/or infarction within the tumor and/or adjacent gland parenchyma. The presentation of PA is highly variable. In some cases, it may be the initial presentation of tumor while at the other end of spectrum it can be asymptomatic. Whenever symptomatic, it represents medical emergency due to associated potentially lethal adrenal insufficiency and threat to permanent visual loss. Management begins with fluid resuscitation and empiric corticosteroid administration. It is followed by detailed endocrine assessment and needful supplementation. Neurosurgical decompression is indicated in a specific subset of patients. Head injury is an established factor in causation of PA, but there are only handful of cases where traumatic spinal cord injury had led to it. Cases of apoplexy culminating into resolution of adenoma are very sparse. Hereby authors report a case where non-functional giant pituitary adenoma (NFGPA) has radiologically evanished after spinal cord trauma. In this manuscript, authors also discuss the pathophysiology of apoplexy in pituitary adenomas, types of apoplexy as well as standard protocol recommended for follow-up of such cases.

Enhancing broad-band light and CO gas sensing with BDT/ZnO nanocomposites

Gas/light dual sensors based on benzodithiophene-based derivates (BDT)/zinc oxide (ZnO) nanocomposites are fabricated for the monitoring of hazardous light and the detection of toxic gases. The lethal threat posed by colorless and odorless carbon monoxide (CO) gas, as well as the potential dangers of ultraviolet-A (UV-A) and visible light, emphasize the need for sensitive and portable gas/light dual sensor. Organic BDT/inorganic ZnO hybrid materials have gained attention for their cost-effectiveness, and enhanced gas/light sensing performance. This study explores the incorporation of the organic material, BDT, onto the ZnO nanorods (NRs) to enhance the UV and visible light detection, and CO gas sensing capabilities. The results demonstrate that improved light absorption and gas detection are attributed to the broad absorption wavelength range of BDT and efficient charge transfer from BDT to ZnO NRs. The study introduces a novel approach for dual sensing applications, highlighting the promising future of BDT/ZnO nanocomposites in environmental monitoring and wearable devices.

De novo design of a protein binder against Staphylococcus enterotoxin B

Staphylococcus enterotoxin B (SEB) interacts with MHC-II molecules to overactivate immune cells and thereby to produce excessive pro-inflammatory cytokines. Disrupting the interactions between SEB and MHC-II helps eliminate the lethal threat posed by SEB. In this study, a de novo computational approach was used to design protein binders targeting SEB. The MHC-II binding domain of SEB was selected as the target, and the possible promising binding mode was broadly explored. The obtained original binder was folded into triple-helix bundles and contained 56 amino acids with molecular weight 5.9 kDa. The interface of SEB and the binder was highly hydrophobic. ProteinMPNN optimization further enlarged the hydrophobic region of the binder and improved the stability of the binder-SEB complex. In vitro study demonstrated that the optimized binder significantly inhibited the inflammatory response induced by SEB. Overall, our research demonstrated the applicability of this approach in de novo designing protein binders against SEB, and thereby providing potential therapeutics for SEB induced diseases.

Lethal threat in the use of glass doors at home: A case report

BackgroundVarious instruments, including glass fragments, can inflict sharp-force damage, resulting in injuries ranging from superficial wounds to life-threatening trauma. This case report explores the lethal consequences of a 78-year-old man accidentally sustaining a stabbed-incised wound after falling against an ordinary glass door, leading to fatal bleeding from the subclavian artery. Case Report:The man's fall caused a sharp-edged glass fragment to penetrate his neck, resulting in a fatal outcome despite resuscitation attempts. Autopsy Findings:The autopsy revealed a transected subclavian artery, additional injuries to the thorax. Notably, the type of glass used in construction played a crucial role in the severity of injuries, emphasizing the need for safety standards and awareness in architectural design. DiscussionThe discussion delves into the historical use of annealed glass in construction and the evolution of safety standards for architectural glazing materials. A comparison between annealed and tempered glass underscores the importance of the latter in preventing severe injuries. The prevalence of annealed glass in older constructions raises concerns, given its propensity to cause larger and more dangerous shards upon breakage. The report highlights cases of glass-related fatalities, emphasizing the unexpected dangers associated with glass-topped furniture. ConclusionsRecommendations include the adoption of safety glass in new constructions, particularly in residences with elderly occupants, and the installation of night lights to mitigate the risk of injuries from glass and other furniture. The report contributes to enhancing understanding in forensic pathology, emphasizing the evolving role of glass in fatal incidents.

Bioinspired PM2.5 filter: An AgNWs reinforced PAN/PVP composite membrane with the porous and multilayered network structure

Particulate matter (PM) pollution poses a lethal threat to human health. Fortunately, nature has evolved efficient strategies to construct unique structures that exhibit high PM2.5 purification efficiency, one such example is found in the aloe leaf. Here, inspired by the surface structure of aloe vera leaves, a PAN/PVP nanofiber composite membrane with the porous and multilayered network structure (P-N) was designed and fabricated for efficient air filtration via electrospinning combined with hot-pressing technique. Furthermore, the dynamic purification process of PM2.5 in the P-N was racked and studied through a combination of experimental and computational fluid dynamics methods. The results demonstrated that the flow path of PM2.5 is extended and the tortuosity of flow channel is increased by the P-N, leading to a significant improvement in the purification efficiency. Notably, the P-N/Ag-Nylon composite membrane, fabricated by introducing AgNWs into the P-N, not only capitalizes on the inertia and gravity but also leverages electrostatic interactions to further enhance its adsorption capacity for PM2.5. At a voltage of 9 V, it achieves a pressure drop of 35 Pa with an impressive filtration efficiency of 99.49%. This work is expected to provide new perspectives on the microstructural design of air filtration materials with high purification efficiency.

The Israel-Iran conflict: between Washington and Beijing

ABSTRACT Since its establishment in 1979, the Islamic Republic of Iran has been openly and vociferously committed to the destruction of the State of Israel. To thwart this genocidal goal – especially the lethal threat of Tehran’s dogged quest for nuclear weapons – Israel has heavily relied on the United States, its longstanding, foremost international ally. Over the past two decades, as its relations with China have greatly expanded, Israel has also sought to harness Beijing’s close and multifaceted ties with Tehran to the fight against a nuclear Iran – to no avail. With the burgeoning Israeli-Chinese relationship stirring recurrent frictions with Washington, especially due to the latter’s alarm over Beijing’s involvement in key infrastructure and hi-tech projects in Israel, Jerusalem has been forced to walk a tight rope between the two rival superpowers so as to maintain their maximum support without alienating either of them. This dilemma was resolved overnight after the invasion of southern Israel by the Iranian-backed Hamas terrorist organization (on 7 October 2023) and its massacre of some 1500 Israelis (fifteen times the 9/11 death toll in relative terms). With Beijing quickly siding with the Palestinians (and Iran), and President Biden throwing the US’ full support behind Israel, warning Tehran and its proxies off intervention and sending a large naval force to the eastern Mediterranean, it has transpired beyond shadow of a doubt who Israel’s real friend is and where its interests lie.

Synthesis of Nitrogen‐Doped Carbon Quantum Dot (N‐CQDs) for Cyanide Detection

AbstractSelective and sensitive detection of Cyanide (CN−) is critical essential due to it is one of the most lethal chemicals and threat to human health. In this study, nitrogen‐doped carbon quantum dots (N‐CQDs) were synthesized by one‐step hydrothermal method using 4‐aminosalicylic acid and tartaric acid as raw materials. The prepared N‐CQDs were spherical particles with good water solubility and uniform particle size distribution, the optimal excitation and emission wavelengths of N‐CQDs were 495 nm and 514 nm, respectively. Based on the selective fluorescence quenching effect between CN− and N‐CQDs, achieving accurate and rapid detection of CN−. Fluorescence quantum yield (PLQY) of N‐CQDs is 39 %, and the other competing anions showed little or no interference to CN−. For highly sensitivity detections of N‐CQDs under optimal conditions, the fluorescence quenching degree was linearly correlated with the CN− concentration in the range of 0–100 μM (R2=0.9929).

Treatment of Superbug Infection through a Membrane‐Disruption and Immune‐Regulation Cascade Effect Based on Supramolecular Peptide Hydrogels

AbstractInfections from antimicrobial resistant pathogens have been considered as lethal threats to human health if antibiotic treatments become ineffective. Antimicrobial peptides (AMPs) show broad‐spectrum antimicrobial activity against resistant strains via a membrane disruptive mechanism without developing further resistance and are promising candidates to combat resistant microbes. However, currently developed small molecular AMPs are limited by weak antimicrobial efficacy and potential cytotoxicity. Herein, an antimicrobial AMP hydrogel based on supramolecular self‐assembly is developed. The hydrogel shows strong antimicrobial activity and high potency against antimicrobial resistant microbes. It also possesses high cytocompatibility and immunoregulative activity. The synergistic effects lead to its significant healing of the skin abscess disease induced by the methicillin‐resistant Staphylococcus aureus infection. This study not only sheds light on the design strategies and immune‐related antimicrobial actions of supramolecular AMP hydrogels, but also advances the development of self‐assembly peptide platform to fight against antimicrobial resistant infections.

The anticancer mechanism of Terpenoid-based drug candi-dates: focus on tumor microenvironment.

Cancer is considered to be the most lethal threat to human life globally. Although, versatile strategies have been established in the field of surgery, chemotherapy, radiotherapy and im-munotherapy against cancer, discovery of new therapeutic drugs from natural products still un-derlays anticancer remedy due to their unique functional mechanisms and potential low side ef-fects. Terpenoids are among the most diversified and enormous natural products which have been proved promising in cancer treatment. Some terpenoids have been through multiple stages of clinical trials and some even approved as anticancer agent, but most of these studies empha-sized the direct effects on tumor cells while paying less attention to their systemic effects on tu-mor microenvironment (TME) Therefore, we recruited the patent drugs and investigated drug candidates of terpenoids in this review and summarized their general anti-tumor mechanisms among which the regulation on TME was highlighted. Finally, the prospect on the drug ability of terpenoids and their potential benefits in immunotherapy were discussed to illuminate fur-ther researches on these natural products. Keywords.

Teaching children to identify and avoid food allergens using behavioral skills training.

Allergic reactions to allergenic foods can pose a lethal threat to children with food allergies. Previous research has demonstrated the effectiveness of using behavioral skills training (BST) plus in situ training (IST) to teach safety responses to children. However, there has not been an evaluation of using BST to teach food safety to children with food allergies. Three elementary-school children of neurotypical development with food allergies participated. We evaluated the efficacy of BST with IST in teaching participants to identify and respond to allergenic foods by (a) asking to see the food packaging, (b) scanning the food label for the allergenic food, and (c) reporting the safety threat to an adult while not consuming the food. Trials without allergenic foods were also presented to ensure discriminated responding. All participants demonstrated the three correct safety responses after BST and responded differentially across allergenic and nonallergenic foods, with two participants requiring feedback (IST).

Forecasting the transit times of earth-directed halo CMEs using artificial neural network: A case study application with GCS forward-modeling technique

Mitigating the lethal threats caused by coronal mass ejections (CMEs) on human and space operations can be accomplished with a fast and accurate forecast of Earth-directed CME transit times. The current paper presents a robust Cascade Forward Neural Network (CFNN) framework to predict the transit times of Earth-directed halo CMEs using a total of 290 CME/Interplanetary coronal mass ejections (ICME) pairs of datasets for the past two and half decades (solar cycle; SC 23, 24, 25). It is the first time incorporating deprojected speeds into a machine learning framework to mitigate uncertainties due to projection effects during CME transit time prediction. The CFNN model forecasted the transit times of 87 Earth-directed CMEs and recorded a mean absolute error (MAE) of 7.3 h. In addition, 5 selected fast-moving (energetic) halo CME episodes during the deep phases (solar minima) of SC 25 were reconstructed using the Graduated Cylindrical Shell (GCS) forward-modeling technique. The events were predicted using the CFNN model (MAE = 4.5 h) in comparison with the Drag-Based model (DBM; MAE = 6.2 h) and Empirical Shock Arrival model (ESA; MAE = 13.5 h) to evaluate the robustness and the flexibility of the CFNN framework as well as the reliability of the CME 3D speed as a proxy for the space speed. The CFNN framework demonstrated satisfactory performance in contrast to previously used models by minimizing CME arrival time prediction errors due to projection effects. Hence, the study validated the efficiency of the GCS model for studying the 3D kinematics of CMEs and emphasized the essence of utilizing deprojected speeds in machine learning frameworks as better alternatives for fast, reliable, and accurate CME arrival (transit) time predictions.