Systematic Optimization of Universal Real-Time Hypersensitive Fast Detection Method for HBsAg in Serum Based on SERS.

Hepatitis B virus (HBV) is a major cause of liver cirrhosis and hepatocellular carcinoma, with HBV surface antigen (HBsAg) being a crucial marker in the clinical detection of HBV. Due to the significant harm and ease of transmission associated with HBV, HBsAg testing has become an essential part of preoperative assessments, particularly for emergency surgeries where healthcare professionals face exposure risks. Therefore, a timely and accurate detection method for HBsAg is urgently needed. In this study, a surface-enhanced Raman scattering (SERS) sensor with a sandwich structure was developed for HBsAg detection. Leveraging the ultrasensitive and rapid detection capabilities of SERS, this sensor enables quick detection results, significantly reducing waiting times. By systematically optimizing critical factors in the detection process, such as the composition and concentration of the incubation solution as well as the modification conditions and amount of probe particles, the sensitivity of the SERS immune assay system was improved. Ultimately, the sensor achieved a sensitivity of 0.00576 IU/mL within 12 min, surpassing the clinical requirement of 0.05 IU/mL by an order of magnitude. In clinical serum assay validation, the issue of false positives was effectively addressed by adding a blocker. The final sensor demonstrated 100% specificity and sensitivity at the threshold of 0.05 IU/mL. Therefore, this study not only designed an ultrasensitive SERS sensor for detecting HBsAg in actual clinical serum samples but also provided theoretical support for similar systems, filling the knowledge gap in existing literature.

Effects of postweaning cadmium exposure on socioemotional behaviors in adolescent male mice.

Exposure to cadmium (Cd), a toxic heavy metal classified as an environmental endocrine disruptor, can exert significant toxicity in both animals and humans. However, the potential effects of Cd exposure on socioemotional behaviors are still poorly understood, as are the underlying mechanisms. In the present study, employing a series of behavioral tests as well as 16 S rRNA sequencing analysis, we investigated the long-term effects of Cd exposure on socioemotional behaviors and their associated mechanisms in mice based on the brain-gut interaction theory. The results showed that postweaning exposure to Cd reduced the ability to resist depression, decreased social interaction, subtly altered sexual preference, and changed the composition of the gut microbiota in male mice during adolescence. These findings provided direct evidence for the deleterious effects of exposure to Cd in the postweaning period on socioemotional behaviors later in adolescence, and suggested that these effects of Cd exposure may be linked to changes in the gut microbiota.

Effects of exposing Japanese quail eggs to a low dose of gamma radiation and in ovo feeding by two sources of trace elements on embryonic development activities.

The present study investigated the influence of exposing quail eggs to low-dose gamma radiation (GR) and in ovo feeding with 2 sources of a mixture of trace elements (Zn, Fe, and Cu), including sulfate (TES) and loaded with montmorillonite (TEM), on embryonic development activities and prehatch quality. A total of 960 eggs on the seventh day of incubation were randomly divided into 6 groups (160 eggs/group) with 4 replicate of 40 eggs in each. A 3 × 2 factorial arrangement experiment was performed and included 3 sources in ovo feeding with a mixture of trace elements (Zn, Fe, and Cu), including 0 mg/egg, 50 mg TES/egg, and 50 mg TEM/egg with egg irradiation using 0 and 0.2 Gy from GR. Eggs injected with 50 mg TEM/egg and exposed to 0.2 Gy from GR (TEM/GR) was significantly (P ≤ 0.05 and 0.01) higher in hatchability, hatch body weight, and relative organ weight (liver, gizzard, proventriculus, heart, and intestine). The obtained results indicated significant (P ≤ 0.05) decreased in the serum concentration of malondialdehyde (MDA) in TEM/GR group. There was significant (P ≤ 0.05) increased of catalase (CAT) activity and the concentrations of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in TEM/GR group; however; total antioxidant capacity (T-AOC) was significant (P ≤ 0.05) increased in CT/GR group. Serum concentrations of immunoglobulin M (IgM) (P ≤ 0.05) and tumor necrosis factor-alpha (TNF-α) were increased in the TEM/CR group; the concentration of transforming growth factor beta (TGF-ß) significant (P ≤ 0.05) increased in the TEM/GR group; and interleukins (IL6 and IL10) showed no significant differences among the groups. Our results showed increase in thyroxine and myostatin concentrations with TES/CR and CT/GR of our study groups, respectively. The relative mRNA expression levels of the GH, IGF-1, and Fas cell surface death receptor (FAS) genes were significantly (P ≤ 0.05 and 0.01) upregulated in the liver tissue of the TEM/GR group compared with the other groups. In conclusion, TEM/GR was the best treatment for improving prehatch quality, increasing serum antioxidant enzyme activities, and promoting the expression of growth and immune genes in fertilized quail eggs.

BRMS1L confers anticancer activity in non-small cell lung cancer by transcriptionally inducing a redox imbalance in the GPX2-ROS pathway.

Low expression levels of breast cancer metastasis suppressor 1 like (BRMS1L) have been associated with the growth of cancer cells. However, the mechanisms underlying the role of BRMS1L as an antitumour transcription factor in the progression of NSCLC have not been explored. Herein, we reveal that BRMS1L plays a key role as a tumour suppressor in inhibiting NSCLC proliferation and metastasis. Mechanistically, BRMS1L overexpression results in the downregulation of glutathione peroxidase 2 (GPX2) expression and consequently causes abnormal glutathione metabolism and increased levels of reactive oxygen species (ROS) in cells, inducing oxidative stress injury and apoptosis. Furthermore, overexpression of GPX2 enhances the growth advantage and oxidative stress repair conferred by knockdown of BRMS1L. Importantly, we show that low expression of BRMS1L in NSCLC cells causes relatively high levels of antioxidant accumulation to maintain cell redox balance and renders cancer cells more sensitive to treatment with piperlongumine as an ROS inducer both in vitro and in vivo. These findings offer new insights into the role of BRMS1L as a transcriptional repressor in NSCLC and suggest that the BRMS1L expression level may be a potential biomarker for predicting the therapeutic response to small molecule ROS inducers, providing new ideas for targeted therapy.

Loop-mediated isothermal amplification linked a nanoparticles-based biosensor for detecting Epstein-Barr virus.

Epstein-Barr virus (EBV) is a ubiquitous gamma herpesvirus that maintains a lifelong latent association with B lymphocytes. Here, a rapid and reliable diagnosis platform for detecting EBV infection, employing loop-mediated isothermal amplification (LAMP) combined with a gold nanoparticles-based lateral flow biosensors (AuNPs-LFB) (termed LAMP Amplification Mediated AuNPs-LFB Detection, LAMAD), was developed in the current study. A set of specific LAMP primers targeting the Epstein-Barr nuclear antigen (EBNA) leader protein (EBNA-LP) gene was designed and synthesized. Subsequently, these templates extracted from various pathogens and whole blood samples were used to optimize and evaluate the EBV-LAMAD assay. As a result, the limit of detection (LoD) of the EBV-LAMAD assay was 45 copies/reaction. The EBV-LAMAD assay can detect all representative EBV pathogens used in the study, and of note, no cross-reactions were observed with other non-EBV organisms. Moreover, the whole workflow of the EBV-LAMAD assay can be completed within 70 min, including rapid EBV template preparation, EBV-LAMP amplification, and AuNPs-LFB-mediated detection. Taken together, the EBV-LAMAD assay targeting the EBNA-LP gene is a rapid, simplified, sensitive, reliable, and easy-to-use detection protocol that can be used as a competitive potential diagnostic/screening tool for EBV infection in clinical settings, especially in basic laboratories in resource-limited regions. KEY POINTS: • A novel, simplified, and easy-to-use AuNPs-LFB biosensor was designed and prepared. • LAMP combined with an AuNPs-LFB targeting the novel EBNA-LP gene was established. • EBV-LAMAD is a rapid, sensitive, and reliable detection protocol for EBV infection.

Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection.

Kaposi's sarcoma herpesvirus (KSHV) is a leading cause of malignancy in AIDS and current therapies are limited. Like all herpesviruses, KSHV infection can be latent or lytic. KSHV latency-associated nuclear antigen (LANA) is essential for viral genome persistence during latent infection. LANA also maintains latency by antagonizing expression and function of the KSHV lytic switch protein, RTA. Here, we find LANA null KSHV is not capable of lytic replication, indicating a requirement for LANA. While LANA promoted both lytic and latent gene expression in cells partially permissive for lytic infection, it repressed expression in non-permissive cells. Importantly, forced RTA expression in non-permissive cells led to induction of lytic infection and LANA switched to promote, rather than repress, most lytic viral gene expression. When basal viral gene expression levels were high, LANA promoted expression, but repressed expression at low basal levels unless RTA expression was forcibly induced. LANA's effects were broad, but virus gene specific, extending to an engineered, recombinant viral GFP under control of host EF1α promoter, but not to host EF1α. Together, these results demonstrate that, in addition to its essential role in genome maintenance, LANA broadly regulates viral gene expression, and is required for high levels of lytic gene expression during lytic infection. Strategies that target LANA are expected to abolish KSHV infection.

Lipocalin 2 (LCN2) confers acquired resistance to almonertinib in NSCLC through LCN2-MMP-9 signaling pathway.

Almonertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is highly selective for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC). However, the development of resistance inevitably occurs and poses a major obstacle to the clinical efficacy of almonertinib. Therefore, a clear understanding of the mechanism is of great significance to overcome drug resistance to almonertinib in the future. In this study, NCI-H1975 cell lines resistant to almonertinib (NCI-H1975 AR) were developed by concentration-increasing induction and were employed for clarification of underlying mechanisms of acquired resistance. Through RNA-seq analysis, the HIF-1 and TGF-ß signaling pathways were significantly enriched by gene set enrichment analysis. Lipocalin-2 (LCN2), as the core node in these two signaling pathways, were found to be positively correlated to almonertinib-resistance in NSCLC cells. The function of LCN2 in the drug resistance of almonertinib was investigated through knockdown and overexpression assays in vitro and in vivo. Moreover, matrix metalloproteinases-9 (MMP-9) was further identified as a critical downstream effector of LCN2 signaling, which is regulated via the LCN2-MMP-9 axis. Pharmacological inhibition of MMP-9 could overcome resistance to almonertinib, as evidenced in both in vitro and in vivo models. Our findings suggest that LCN2 was a crucial regulator for conferring almonertinib-resistance in NSCLC and demonstrate the potential utility of targeting the LCN2-MMP-9 axis for clinical treatment of almonertinib-resistant lung adenocarcinoma.

Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome.

To establish lifelong, latent infection, herpesviruses circularize their linear, double-stranded, DNA genomes through an unknown mechanism. Kaposi's sarcoma (KS) herpesvirus (KSHV), a gamma herpesvirus, is tightly linked with KS, primary effusion lymphoma, and multicentric Castleman's disease. KSHV persists in latently infected cells as a multi-copy, extrachromosomal episome. Here, we show the KSHV genome rapidly circularizes following infection, and viral protein expression is unnecessary for this process. The DNA damage response (DDR) kinases, ATM and DNA-PKcs, each exert roles, and absence of both severely compromises circularization and latency. These deficiencies were rescued by expression of ATM and DNA-PKcs, but not catalytically inactive mutants. In contrast, γH2AX did not function in KSHV circularization. The linear viral genomic ends resemble a DNA double strand break, and non-homologous DNA end joining (NHEJ) and homologous recombination (HR) reporters indicate both NHEJ and HR contribute to KSHV circularization. Last, we show, similar to KSHV, ATM and DNA-PKcs have roles in circularization of the alpha herpesvirus, herpes simplex virus-1 (HSV-1), while γH2AX does not. Therefore, the DDR mediates KSHV and HSV-1 circularization. This strategy may serve as a general herpesvirus mechanism to initiate latency, and its disruption may provide new opportunities for prevention of herpesvirus disease.

Continuous Monitoring of Buried Free Bone Flap Microcirculation Using a Near-Infrared Spectroscopy System.

SUMMARY: Postoperative evaluation of free flaps remains a challenging task. The current accepted standard for diagnosis of vascular compromise remains clinical observation. In recent years, near-infrared spectroscopy (NIRS) has been widely used as a noninvasive objective monitoring tool for postoperative evaluation of soft-tissue flaps. However, methods for monitoring bone flaps remain inadequate. In this study, NIRS was applied for the first time to monitor free buried bone flaps that were used for mandibular reconstruction. The penetrating property of NIRS was used to measure the tissue oxygenation index (TOI) of deep tissues, which reflected the microcirculatory status of the tissues. Changes in TOI values were monitored continuously in 59 cases of free bone flaps up to 72 hours after surgery. Five cases of vascular compromise were noted by clinical observation. Two fibula flaps were total failures, one of which showed a sharp decrease in TOI value to 45% in a short period of time; the other showed a continual gradual decrease to 55%. The observed sudden (<50%) and continuous (>10%) decreases in TOI values suggest that more attention should be paid to revision surgical procedures. The authors conclude that NIRS holds promise as an objective and valid method for clinical evaluation of buried bone flaps.

A GPU-based fast Monte Carlo code that supports proton transport in magnetic field for radiation therapy.

This paper presents the effort to extend a previously reported code ARCHER, a GPU-based Monte Carlo (MC) code for coupled photon and electron transport, into protons including the consideration of magnetic fields. The proton transport is modeled using a Class-II condensed-history algorithm with continuous slowing-down approximation. The model includes ionization, multiple scattering, energy straggling, elastic and inelastic nuclear interactions, as well as deflection due to the Lorentz force in magnetic fields. An additional direction change is added for protons at the end of each step in the presence of the magnetic field. Secondary charge particles, except for protons, are terminated depositing kinetic energies locally, whereas secondary neutral particles are ignored. Each proton is transported step by step until its energy drops to below 0.5 MeV or when the proton leaves the phantom. The code is implemented using the compute unified device architecture (CUDA) platform for optimized GPU thread-level parallelism and efficiency. The code is validated by comparing it against TOPAS. Comparisons of dose distributions between our code and TOPAS for several exposure scenarios, ranging from single square beams in water to patient plan with magnetic fields, show good agreement. The 3D-gamma pass rate with a 2 mm/2% criterion in the region with dose greater than 10% of the maximum dose is computed to be over 99% for all tested cases. Using a single NVIDIA TITAN V GPU card, the computational time of ARCHER is found to range from 0.82 to 4.54 seconds for 1 × 107 proton histories. Compared to a few hours running on TOPAS, this speed improvement is significant. This work presents, for the first time, the performance of a GPU-based MC code to simulate proton transportation magnetic fields, demonstrating the feasibility of accurate and efficient dose calculations in potential magnetic resonance imaging (MRI)-guided proton therapy.

Macrophages enhance cisplatin resistance in gastric cancer through the transfer of circTEX2.

Cisplatin-based chemotherapy is often used in advanced gastric cancer (GC) treatment, yet resistance to cisplatin may lead to treatment failure. Mechanisms underlying cisplatin resistance remain unclear. Recent evidence highlighted the role of macrophages in cancer chemoresistance. Macrophage-derived exosomes were shown to facilitate intercellular communication. Here, we investigated the cisplatin resistance mechanism based on macrophage-derived exosomes in gastric cancer. Cell growth and apoptosis detection experiments revealed that M2-polarized macrophages increased the resistance of GC cells to cisplatin. qRT-PCR, RNAase R assay, actinomycin D assay and cell nucleo-cytoplasmic separation experiments confirmed the existence of circTEX2 in macrophage cytoplasm, with a higher expression level in M2 macrophages than that in M1 macrophages. Further experiments showed that circTEX2 acted as microRNA sponges for miR-145 and regulated the expression of ATP Binding Cassette Subfamily C Member 1 (ABCC1). Inhibition of the circTEX2/miR-145/ABCC1 axis blocked the cisplatin resistance of gastric cancer induced by M2 macrophages, as evidenced by in vitro and in vivo experiments. In conclusion, our research suggests that the exosomal transfer of M2 macrophage-derived circTEX2 enhances cisplatin resistance in gastric cancer through miR-145/ABCC1. Additionally, communication between macrophages and cancer cells via exosomes may be a promising therapeutic target for the treatment of cisplatin-resistant gastric cancer.

Incidence and risk of fatal adverse events in cancer patients treated with HER2-targeted antibody-drug conjugates: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Antibody-drug conjugates (ADCs) that target human epidermal growth factor receptor 2 (HER2) are leading a new era of targeted cancer therapy. These drugs have also been associated with several fatal adverse events, such as pneumonia, interstitial lung disease, and infection. We performed a meta-analysis of randomized controlled trials (RCTs) to estimate the incidence and risk of fatal adverse events in cancer patients treated with HER2-targeted ADCs. METHODS: We performed a systematic search in Embase, PubMed, Web of Science, and Scopus databases from inception to February 1, 2022, and the last search was updated to July 1, 2023. The eligible studies for inclusion in our analysis were limited to RCTs of HER2-targeted ADCs that were approved by the US Food and Drug Administration and examined on cancer patients with available data on fatal adverse events. The protocol for this study was registered in PROSPERO (No. CRD42022331627). RESULTS: Fifteen studies (13 RCTs) involving 7,277 patients were finally included for meta-analysis. Of these patients, 4,246 received HER2-targeted ADCs and 3,481 received the control treatment. The data were combined using Bayesian hierarchical modeling, which allowed for the estimation of the mean incidence of fatal adverse events to be 0.78% (95% CrI: 0.28-1.37%, τ = 0.006) for the patients treated with HER2-targeted ADCs. The relative risk was 0.80 (95% CrI, 0.5-1.26, τ = 0.17) compared to control patients. Among 43 reported deaths caused by HER2-targeted ADCs, the most common fatal adverse event was respiratory toxicity, including pneumonia, pneumonitis, and interstitial lung disease. On subgroup analysis, no difference in the risk of fatal adverse events was found between different HER2-targeted ADCs or cancer types. CONCLUSION: Our findings suggest that the risk of fatal adverse events with HER2-targeted ADCs may be lower compared to standard control therapies in cancer patients, and there is no significant difference in risk observed between different HER2-targeted ADCs or cancer types. However, the most common fatal adverse event was respiratory toxicity, suggesting that cancer patients who use the above drugs should strengthen respiratory system monitoring and take preventive measures in some severe cases.

Peripheral neuropathy associated with monomethyl auristatin E-based antibody-drug conjugates.

Since the successful approval of gemtuzumab ozogamicin, antibody-drug conjugates (ADCs) have emerged as a pivotal category of targeted therapies for cancer. Among these ADCs, the use of monomethyl auristatin E (MMAE) as a payload is prevalent in the development of ADC drugs, which has significantly improved overall therapeutic efficacy against various malignancies. However, increasing clinical observations have raised concerns regarding the potential nervous system toxicity associated with MMAE-based ADCs. Specifically, a higher incidence of peripheral neuropathy has been reported in ADCs incorporating MMAE as payloads. Considering the increasing global use of MMAE-based ADCs, it is imperative to provide an inclusive overview of diagnostic and management strategies for this adverse event. In this review, we examine current information and what future research directions are required to better understand and manage this type of clinical challenge.

DNA Methylation-Based Testing in Peripheral Blood Mononuclear Cells Enables Accurate and Early Detection of Colorectal Cancer.

An effective blood-based method for the diagnosis of colorectal cancer has not yet been developed. Molecular alterations of immune cells occur early in tumorigenesis, providing the theoretical underpinning for early cancer diagnosis based on immune cell profiling. Therefore, we aimed to develop an effective detection method based on peripheral blood mononuclear cells (PBMC) to improve the diagnosis of colorectal cancer. Analysis of the genome-wide methylation landscape of PBMCs from patients with colorectal cancer and healthy controls by microarray, pyrosequencing, and targeted bisulfite sequencing revealed five DNA methylation markers for colorectal cancer diagnosis, especially early-stage colorectal cancer. A single-tube multiple methylation-specific quantitative PCR assay (multi-msqPCR) for simultaneous detection of five methylation markers was established, which allowed quantitative analysis of samples with as little as 0.1% PBMC DNA and had better discriminative performance than single-molecule detection. Then, a colorectal cancer diagnostic model (CDM) based on methylation markers and the multi-msqPCR method was constructed that achieved high accuracy for early-stage colorectal cancer (AUC = 0.91; sensitivity = 81.18%; specificity = 89.39%), which was improved compared with CEA (AUC = 0.79). The CDM also enabled a high degree of discrimination for advanced adenoma cases (AUC = 0.85; sensitivity = 63.04%). Follow-up data also demonstrated that the CDM could identify colorectal cancer potential up to 2 years before currently used diagnostic methods. In conclusion, the approach constructed in this study based on PBMC-derived DNA methylation markers and a multi-msqPCR method is a promising and easily implementable diagnostic method for early-stage colorectal cancer. SIGNIFICANCE: Development of a diagnostic model for early colorectal cancer based on epigenetic analysis of PBMCs supports the utility of altered DNA methylation in immune cells for cancer diagnosis.

A multiplex blood-based assay targeting DNA methylation in PBMCs enables early detection of breast cancer.

The immune system can monitor tumor development, and DNA methylation is involved in the body's immune response to tumors. In this work, we investigate whether DNA methylation alterations in peripheral blood mononuclear cells (PBMCs) could be used as markers for early detection of breast cancer (BC) from the perspective of tumor immune alterations. We identify four BC-specific methylation markers by combining Infinium 850 K BeadChips, pyrosequencing and targeted bisulfite sequencing. Based on the four methylation markers in PBMCs of BC, we develop an efficient and convenient multiplex methylation-specific quantitative PCR assay for the detection of BC and validate its diagnostic performance in a multicenter cohort. This assay was able to distinguish early-stage BC patients from normal controls, with an AUC of 0.940, sensitivity of 93.2%, and specificity of 90.4%. More importantly, this assay outperformed existing clinical diagnostic methods, especially in the detection of early-stage and minimal tumors.

CircSOD2 polarizes macrophages towards the M1 phenotype to alleviate cisplatin resistance in gastric cancer cells by targeting the miR-1296/STAT1 axis.

Cisplatin is the first-line drug for gastric cancer (GC). Cisplatin resistance is the most important cause of poor prognosis for GC. Increasing evidence has identified the important role of macrophage polarization in chemoresistance. CircRNAs are newly discovered non-coding RNAs, characterized by covalently closed loops with high stability. Previous studies have reported a significant difference between circRNA profiles expressed in classically activated M1 macrophages, and those expressed in alternatively activated M2 macrophages. However, the underlying mechanism behind the regulation of GC cisplatin resistance by macrophages remains unclear. In our study, we observed the aberrant high expression of circSOD2 in M1 macrophages derived from THP-1. These expression patterns were confirmed in macrophages from patients with GC. Detection of the M1 and M2 markers confirmed that overexpression of circSOD2 enhances M1 polarization. The viability of cisplatin-treated GC cells was significantly reduced in the presence of macrophages overexpressing circSOD2, and cisplatin-induced apoptosis increased dramatically. In vivo experiments showed that macrophages expressing circSOD2 enhanced the effect of cisplatin. Moreover, we demonstrated that circSOD2 acts as a microRNA sponge for miR-1296 and regulates the expression of its target gene STAT1 (signal transducer and activator of transcription 1). CircSOD2 exerts its function through the miR-1296/STAT1 axis. Inhibition of circSOD2/miR-1296/STAT1 may therefore reduce M1 polarization. Overexpression of circSOD2 promotes the polarization of M1 macrophages and enhances the effect of cisplatin in GC. CircSOD2 is a novel positive regulator of M1 macrophages and may serve as a potential target for GC chemotherapy.

Antitumor activity of aumolertinib, a third-generation EGFR tyrosine kinase inhibitor, in non-small-cell lung cancer harboring uncommon EGFR mutations.

Uncommon epidermal growth factor receptor (EGFR) mutations account for 10%-20% of all EGFR mutations in non-small-cell lung cancer (NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors (TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC. Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models (V769-D770insASV and L861Q mutations) and a patient-derived xenografts model (H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.

Macrophages drive KSHV B cell latency.

Kaposi's sarcoma herpesvirus (KSHV) establishes lifelong infection and persists in latently infected B cells. Paradoxically, in vitro B cell infection is inefficient, and cells rapidly die, suggesting the absence of necessary factor(s). KSHV epidemiology unexpectedly mirrors that of malaria and certain helminthic infections, while other herpesviruses are ubiquitous. Elevated circulating monocytes are common in these parasitic infections. Here, we show that KSHV infection of monocytes or M-CSF-differentiated (M2) macrophages is highly efficient. Proteomic analyses demonstrate that infection induces macrophage production of B cell chemoattractants and activating factor. We find that KSHV acts with monocytes or M2 macrophages to stimulate B cell survival, proliferation, and plasmablast differentiation. Further, macrophages drive infected plasma cell differentiation and long-term viral latency. In Kenya, where KSHV is endemic, we find elevated monocyte levels in children with malaria. These findings demonstrate a role for mononuclear phagocytes in KSHV B cell latency and suggest that mononuclear phagocyte abundance may underlie KSHV's geographic disparity.

Facial Reanimation After Peripheral Facial Nerve Paralysis: A Single-institution Surgical Experience.

Facial nerve trauma occasionally develops during oral and maxillofacial surgery. This study was aimed at enhancing the available knowledge on facial nerve reanimation correlated to surgery and proposing our surgical algorithm. We retrospectively analyzed medical records of patients who underwent facial reanimation surgery at our hospital. The inclusion criterion was surgery for facial reanimation from January 2004 to June 2021. We included 383 eligible patients who underwent facial reanimation surgery. Trauma or maxillofacial neoplasms were noted in 208 of 383 and 164 of 383 cases, respectively. In 238 of 383 cases, nerve branches were likely more vulnerable. Facial nerve anastomosis was performed in 256 patients. Sixty-eight patients received nerve grafts. In 22 patients, distal facial nerve transfer to the masseteric nerve, sublingual nerve, or contralateral facial nerve was performed. Twenty-five patients received static surgery; in most cases, the temporalis fascia flap (20/25) was used. The nerve function outcomes were HB grade I (n=17), Grade Ⅱ (n=108), Grade Ⅲ (n=118), Grade Ⅳ (n=94), and Grade V (n=46). The mean follow-up time was 4.88 ± 3.93 years. Facial paralysis caused by trauma ( P =0.000), branch injury ( P =0.000), and the primary reconstruction of facial nerve ( P =0.000) were predictive of favorable treatment outcomes. Although facial nerve injury caused by trauma was more likely, cases of interference in facial expression could be limited, and so did the injury to branches. Nerve anastomosis was prioritized if a tension-free suture was possible. Maintaining the integrity of the nerve and shortening the duration of mimetic muscular denervation were crucial.

Application of nanotechnology in breast cancer screening under obstetrics and gynecology through the use of CNN and ANFIS.

Breast cancer is the leading reason of death among women aged 35 to 54. Breast cancer diagnosis still presents significant challenges, and preventing the disease's most severe symptoms requires early detection. The role of nanotechnology in the tumor-treatment has recently attracted a lot of interest. In cancer therapies, nanotechnology plays a major role in the medication distribution process. Nanoparticles have the ability to target tumors. Nanoparticles are favorable and maybe preferable for usage in tumor detection and imaging due to their incredibly small size. Quantum dots, semiconductor crystals with increased labeling and imaging capabilities for cancer cells, are one of the particles that have received the most research attention. The design of the research is cross-sectional and descriptive. From April through September of 2020, data were gathered at the State Hospital. All pregnant women who came to the hospital throughout the first and second trimesters of the research's data collection were included in the study population. 100 pregnant women between the ages of 20 and 40 who had not yet had a mammogram comprised the research sample. 1100 digitized mammography images are included in the dataset, which was obtained from a hospital. Convolutional neural networks (CNN) were used to scan all images, and breast masses and mass comparisons were made using the malignant-benign categorization. The adaptive neuro-fuzzy inference system (ANFIS) then examined all of the data obtained by CNN in order to identify breast cancer early using inputs based on the nine different inputs. The precision of the mechanism used in this technique to determine the ideal radius value is significantly impacted by the radius value. Nine variables that define breast cancer indicators were utilized as inputs to the ANFIS classifier, which was then used to identify breast cancer. The parameters were given the necessary fuzzy functions, and the combined dataset was applied to train the method. Testing was initially performed by 30% of dataset that was later done with the real data obtained from the hospital. The accuracy of the results for 30% data was 84% (specificity =72.7%, sensitivity =86.7%) and the results for the real data was 89.8% (sensitivity =82.3%, specificity =75.9%), respectively.