Mosaicism-independent mechanisms contribute to Pcdh19-related epilepsy and repetitive behaviors in Xenopus.

Protocadherin19 (PCDH19)-related epilepsy syndrome is a rare disorder characterized by early-onset epilepsy, intellectual disability, and autistic behaviors. PCDH19 is located on the X chromosome and encodes a calcium-dependent single-pass transmembrane protein, which regulates cell-to-cell adhesion through homophilic binding. In human, 90% of heterozygous females, containing PCDH19 wild-type and mutant cells due to random X inactivation, are affected, whereas mutant males, containing only mutant cells, are typically not. The current view, the cellular interference, is that the altered interactions between wild-type and mutant cells during development, rather than loss of function itself, are responsible. However, studies using Pcdh19 knockout mice showed that the complete loss of function also causes autism-like behaviors both in males and females, suggesting that other functions of PCDH19 may also contribute to pathogenesis. To address whether mosaicism is required for PCDH19-related epilepsy, we generated Xenopus tropicalis tadpoles with complete or mosaic loss of function by injecting antisense morpholino oligonucleotides into the blastomeres of neural lineage at different stages of development. We found that either mosaic or complete knockdown results in seizure-like behaviors, which could be rescued by antiseizure medication, and repetitive behaviors. Our results suggest that the loss of PCDH19 function itself, in addition to cellular interference, may also contribute to PCDH19-related epilepsy.

An epidermal growth factor receptor-targeting immunotoxin based on IgG shows potent antitumor activity against head and neck cancer.

The epidermal growth factor receptor (EGFR) is an important target for cancer therapies. Many head and neck cancer (HNC) cells have been reported to overexpress EGFR; therefore, anti-EGFR therapies have been attempted in patients with HNC. However, its clinical efficacy is limited owing to the development of drug resistance. In this study, we developed an EGFR-targeting immunotoxin consisting of a clinically proven anti-EGFR IgG (cetuximab; CTX) and a toxin fragment (LR-LO10) derived from Pseudomonas exotoxin A (PE) using a novel site-specific conjugation technology (peptide-directed photo-crosslinking reaction), as an alternative option. The immunotoxin (CTX-LR-LO10) showed specific binding to EGFR and properties of a typical IgG, such as stability, interactions with receptors of immune cells, and pharmacokinetics, and inhibited protein synthesis via modification of elongation factor-2. Treatment of EGFR-positive HNC cells with the immunotoxin resulted in apoptotic cell death and the inhibition of cell migration and invasion. The efficacy of CTX-LR-LO10 was evaluated in xenograft mouse models, and the immunotoxin exhibited much stronger tumor suppression than CTX or LR-LO10. Transcriptome analyses revealed that the immunotoxins elicited immune responses and altered the expression of genes related to its mechanisms of action. These results support the notion that CTX-LR-LO10 may serve as a new therapeutic agent targeting EGFR-positive cancers.

A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs.

c-Myc (Myc) is an important transcriptional regulator in embryonic stem (ES) cells, somatic cell reprogramming, and cancer. Here, we identify a Myc-centered regulatory network in ES cells by combining protein-protein and protein-DNA interaction studies and show that Myc interacts with the NuA4 complex, a regulator of ES cell identity. In combination with regulatory network information, we define three ES cell modules (Core, Polycomb, and Myc) and show that the modules are functionally separable, illustrating that the overall ES cell transcription program is composed of distinct units. With these modules as an analytical tool, we have reassessed the hypothesis linking an ES cell signature with cancer or cancer stem cells. We find that the Myc module, independent of the Core module, is active in various cancers and predicts cancer outcome. The apparent similarity of cancer and ES cell signatures reflects, in large part, the pervasive nature of Myc regulatory networks.

Sirtuin 3 regulates astrocyte activation by reducing Notch1 signaling after status epilepticus.

Sirtuin3 (Sirt3) is a nicotinamide adenine dinucleotide enzyme that contributes to aging, cancer, and neurodegenerative diseases. Recent studies have reported that Sirt3 exerts anti-inflammatory effects in several neuropathophysiological disorders. As epilepsy is a common neurological disease, in the present study, we investigated the role of Sirt3 in astrocyte activation and inflammatory processes after epileptic seizures. We found the elevated expression of Sirt3 within reactive astrocytes as well as in the surrounding cells in the hippocampus of patients with temporal lobe epilepsy and a mouse model of pilocarpine-induced status epilepticus (SE). The upregulation of Sirt3 by treatment with adjudin, a potential Sirt3 activator, alleviated SE-induced astrocyte activation; whereas, Sirt3 deficiency exacerbated astrocyte activation in the hippocampus after SE. In addition, our results showed that Sirt3 upregulation attenuated the activation of Notch1 signaling, nuclear factor kappa B (NF-κB) activity, and the production of interleukin-1ß (IL1ß) in the hippocampus after SE. By contrast, Sirt3 deficiency enhanced the activity of Notch1/NF-κB signaling and the production of IL1ß. These findings suggest that Sirt3 regulates astrocyte activation by affecting the Notch1/NF-κB signaling pathway, which contributes to the inflammatory response after SE. Therefore, therapies targeting Sirt3 may be a worthy direction for limiting inflammatory responses following epileptic brain injury.

Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2.

NF-κB essential modulator (NEMO) is a key regulatory protein that functions during NF-κB- and interferon-mediated signaling in response to extracellular stimuli and pathogen infections. Tight regulation of NEMO is essential for host innate immune responses and for maintenance of homeostasis. Here, we report that the E3 ligase MARCH2 is a novel negative regulator of NEMO-mediated signaling upon bacterial or viral infection. MARCH2 interacted directly with NEMO during the late phase of infection and catalyzed K-48-linked ubiquitination of Lys326 on NEMO, which resulted in its degradation. Deletion of MARCH2 resulted in marked resistance to bacterial/viral infection, along with increased innate immune responses both in vitro and in vivo. In addition, MARCH2-/- mice were more susceptible to LPS challenge due to massive production of cytokines. Taken together, these findings provide new insight into the molecular regulation of NEMO and suggest an important role for MARCH2 in homeostatic control of innate immune responses.

Deciphering head and neck cancer microenvironment: Single-cell and spatial transcriptomics reveals human papillomavirus-associated differences.

Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), and the incidence of HPV- associated HNSCC is increasing. The role of tumor microenvironment in viral infection and metastasis needs to be explored further. We studied the molecular characteristics of primary tumors (PTs) and lymph node metastatic tumors (LNMTs) by stratifying them based on their HPV status. Eight samples for single-cell RNA profiling and six samples for spatial transcriptomics (ST), composed of matched primary tumors (PT) and lymph node metastases (LNMT), were collected from both HPV- negative (HPV- ) and HPV-positive (HPV+ ) patients. Using the 10x Genomics Visium platform, integrative analyses with single-cell RNA sequencing were performed. Intracellular and intercellular alterations were analyzed, and the findings were confirmed using experimental validation and publicly available data set. The HPV+ tissues were composed of a substantial amount of lymphoid cells regardless of the presence or absence of metastasis, whereas the HPV- tissue exhibited remarkable changes in the number of macrophages and plasma cells, particularly in the LNMT. From both single-cell RNA and ST data set, we discovered a central gene, pyruvate kinase muscle isoform 1/2 (PKM2), which is closely associated with the stemness of cancer stem cell-like populations in LNMT of HPV- tissue. The consistent expression was observed in HPV- HNSCC cell line and the knockdown of PKM2 weakened spheroid formation ability. Furthermore, we found an ectopic lymphoid structure morphology and clinical effects of the structure in ST slide of the HPV+ patients and verified their presence in tumor tissue using immunohistochemistry. Finally, the ephrin-A (EPHA2) pathway was detected as important signals in angiogenesis for HPV- patients from single-cell RNA and ST profiles, and knockdown of EPHA2 declined the cell migration. Our study described the distinct cellular composition and molecular alterations in primary and metastatic sites in HNSCC patients based on their HPV status. These results provide insights into HNSCC biology in the context of HPV infection and its potential clinical implications.

Liquid plasma promotes angiogenesis through upregulation of endothelial nitric oxide synthase-induced extracellular matrix metabolism: potential applications of liquid plasma for vascular injuries.

BACKGROUND: Applications of nonthermal plasma have expanded beyond the biomedical field to include antibacterial, anti-inflammatory, wound healing, and tissue regeneration. Plasma enhances epithelial cell repair; however, the potential damage to deep tissues and vascular structures remains under investigation. RESULT: This study assessed whether liquid plasma (LP) increased nitric oxide (NO) production in human umbilical vein endothelial cells by modulating endothelial NO synthase (eNOS) phosphorylation and potential signaling pathways. First, we developed a liquid plasma product and confirmed the angiogenic effect of LP using the Matrigel plug assay. We found that the NO content increased in plasma-treated water. NO in plasma-treated water promoted cell migration and angiogenesis in scratch and tube formation assays via vascular endothelial growth factor mRNA expression. In addition to endothelial cell proliferation and migration, LP influenced extracellular matrix metabolism and matrix metalloproteinase activity. These effects were abolished by treatment with NG-L-monomethyl arginine, a specific inhibitor of NO synthase. Furthermore, we investigated the signaling pathways mediating the phosphorylation and activation of eNOS in LP-treated cells and the role of LKB1-adenosine monophosphate-activated protein kinase in signaling. Downregulation of adenosine monophosphate-activated protein kinase by siRNA partially inhibited LP-induced eNOS phosphorylation, angiogenesis, and migration. CONCLUSION: The present study suggests that LP treatment may be a novel strategy for promoting angiogenesis in vascular damage. Video Abstract.

Fabrication and Evaluation of Ultrasound-Responsive Emulsion Loading Paclitaxel for Targeted Chemotherapy.

Chemotherapy is the most widely used cancer treatment, but it has several drawbacks such as adverse side effects and low bioavailability. To address these limitations, various drug delivery systems have been investigated, including liposomes, micelles, and emulsions. These drug delivery technologies have been improving the efficacy and safety of conventional chemotherapy. This study presents an emerging drug delivery technology for targeted chemotherapy using drug-loaded ultrasound-responsive emulsion (URE) as a drug carrier and ultrasound technology for external activation. URE was designed to be responsive to ultrasound energy and fabricated by using an emulsification technique. To investigate this technology, paclitaxel, as a model drug, was used and encapsulated into URE. The size distribution, morphology, and drug release behavior of paclitaxel-loaded URE (PTX-URE) were characterized, and the echogenicity of PTX-URE was assessed by using ultrasound imaging equipment. The cellular uptake and cytotoxicity of PTX-URE with ultrasound were evaluated in breast cancer cells (MDA-MB-231). Our in vitro results indicate that the combination of PTX-URE and ultrasound significantly enhanced cellular uptake by 10.6-fold and improved cytotoxicity by 24.1% compared to PTX alone. These findings suggest that the URE platform combined with ultrasound is a promising technology to improve the drug delivery efficiency for chemotherapy.

Photocatalytic Conversion of CO2 to Formate/CO by an (η6-para-Cymene)Ru(II) Half-Metallocene Catalyst: Influence of Additives and TiO2 Immobilization on the Catalytic Mechanism and Product Selectivity.

The catalytic efficacy of the monobipyridyl (η6-para-Cymene)Ru(II) half-metallocene, [(p-Cym)Ru(bpy)Cl]+ was evaluated in both mixed homogeneous (dye + catalyst) and heterogeneous hybrid systems (dye/TiO2/Catalyst) for photochemical CO2 reduction. A series of homogeneous photolysis experiments revealed that the (p-Cym)Ru(II) catalyst engages in two competitive routes for CO2 reduction (CO2 to formate conversion via RuII-hydride vs CO2 to CO conversion through a RuII-COOH intermediate). The conversion activity and product selectivity were notably impacted by the pKa value and the concentration of the proton source added. When a more acidic TEOA additive was introduced, the half-metallocene Ru(II) catalyst leaned toward producing formate through the RuII-H mechanism, with a formate selectivity of 86%. On the other hand, in homogeneous catalysis with TFE additive, the CO2-to-formate conversion through RuII-H was less effective, yielding a more efficient CO2-to-CO conversion with a selectivity of >80% (TONformate of 140 and TONCO of 626 over 48 h). The preference between the two pathways was elucidated through an electrochemical mechanistic study, monitoring the fate of the metal-hydride intermediate. Compared to the homogeneous system, the TiO2-heterogenized (p-Cym)Ru(II) catalyst demonstrated enhanced and enduring performance, attaining TONs of 1000 for CO2-to-CO and 665 for CO2-to-formate.

Feasibility of Noninvasive Assessment of Cardiac Output during Exercise in Healthy Adults by a Novel Elaboration on Systolic Time Intervals.

BACKGROUND: Although assessment of cardiovascular hemodynamics during exercise can provide clinical insights, it is challenging to acquire it in clinical settings. OBJECTIVES: Accordingly, this preliminary study was to determine whether a novel elaboration on systolic time interval measures (eSTICO) method of quantifying cardiac output and stroke volume was comparable to those obtained using a validated soluble gas (open circuit CO measure [OpCircCO]) method or calculation based on oxygen consumption (oxygen consumption-based CO [VO2CO]) during exercise. METHODS: For the present study, 14 healthy subjects (male: n = 12, female: n = 2) performed incremental exercise on a recumbent cycle ergometer. At rest and during exercise, cardiac output (CO) was obtained via the eSTICO method, while the OpenCircCO and VO2CO measures were obtained at the last minute of each workload. RESULTS: At peak, there was no difference between eSTICO and OpCircCO (12.39 ± 3.06 vs. 13.96 ± 2.47 L/min, p > 0.05), while there was a slight difference between eSTICO and VO2CO (12.39 ± 3.06 vs. 14.28 ± 2.55 L/min, p < 0.05). When we performed correlation analysis with all subjects and all measures of CO at all WL, between eSTICO and OpenCircCO, there was a good relationship (r = 0.707, p < 0.001) with a Bland and Altman agreement analysis demonstrating a -1.6 difference (95% LoA: -6.3-3.5). Between eSTICO and VO2CO, we observed an r = 0.865 (p < 0.001) and a Bland and Altman agreement analysis with a -1.2 difference (95% LoA: -4.8-2.4). CONCLUSION: A novel exploitation of cardiac hemodynamics using systolic timing intervals may allow a relatively good assessment of CO during exercise in healthy adults.

Factors associated with the development of exudation in treatment-naive eyes with nonexudative macular neovascularization.

PURPOSE: To identify the predictive factors for development of exudation in patients with treatment-naïve nonexudative macular neovascularization (MNV). METHODS: We retrospectively analyzed 61 treatment-naïve patients with nonexudative MNV who had not received treatment for nonexudative MNV before the exudation developed. Baseline characteristics and changes in MNV were evaluated using multivariate modeling to determine the potential risk factors for exudative conversion. RESULTS: Exudation development was identified in 31.1% (19/61 eyes) of the study eyes during the 46.2 ± 8.2-month mean follow-up period. The mean period of development of exudation from the baseline was 21.5 ± 6.7 months. Multivariate Cox regression analysis identified that older age (hazard ratio [HR] of 1.380, 95% confidence interval [CI] 1.129-1.688, P = 0.008), larger MNV area at baseline (HR of 1.715, CI 1.288-2.308; P = 0.006), increase of MNV area by doubling (HR of 4.992, CI 1.932-9.246; P = 0.002), and retinal pigment epithelium (RPE) elevation more than 100 µm (HR of 1.017, CI 1.006-1.233; P = 0.015) were associated with increased risk of the development of exudation. CONCLUSION: Older age, larger MNV area, increasing MNV area, and higher RPE elevation were associated with an increased risk of exudative conversion in patients with treatment-naïve nonexudative MNV. Identifying these risk factors may be helpful in establishing treatment strategies and monitoring patients.

CHARACTERISTICS PREDICTIVE OF FELLOW-EYE GEOGRAPHIC ATROPHY WITHOUT NEOVASCULARIZATION IN UNILATERAL TYPE 3 MACULAR NEOVASCULARIZATION.

PURPOSE: To evaluate the predictive characteristics of fellow-eye geographic atrophy (GA) without neovascularization in patients with unilateral Type 3 macular neovascularization. METHODS: This retrospective study included 84 patients who were diagnosed with unilateral Type 3 macular neovascularization. Patients who developed fellow-eye neovascularization and those exhibiting GA without neovascularization at the final follow-up were included in the neovascularization and GA groups, respectively. The patient demographics and baseline fellow-eye characteristics were compared between the two groups. RESULTS: The mean follow-up period was 40.5 ± 11.5 months after diagnosis. Patients included in the GA group (n = 28) were significantly older (mean 77.4 ± 5.2 years vs. 74.2 ± 5.8 years, P = 0.016), had significantly thinner subfoveal choroidal thickness (mean 109.4 ± 36.8 µ m vs. 173.1 ± 77.6 µ m, P < 0.001), and had a significantly higher incidence of baseline GA (39.3% vs. 16.1%, P = 0.019) than those included in the neovascularization group (n = 56). In the multivariate analysis, subfoveal choroidal thickness showed a close negative association with the risk of GA rather than neovascularization ( P = 0.004, ß = 0.982, 95% confidence interval = 0.970-0.994). CONCLUSION: In patients with unilateral Type 3 macular neovascularization, older age, the presence of GA, and a thin choroid in the fellow eye were found to be indicative of a higher probability of progression toward fellow-eye GA instead of neovascularization may be potential candidates for future complement inhibitor treatments targeting fellow-eye GA.

Brown Algae Dictyopteris divaricata Attenuates Adipogenesis by Modulating Adipocyte Differentiation and Promoting Lipolysis through Heme Oxygenase-1 Activation in 3T3-L1 Cells.

The present study aims to explore the probable anti-adipogenesis effect of Dictyopteris divaricata (D. divaricata) in 3T3-L1 preadipocytes by regulating heme oxygenase-1 (HO-1). The extract of D. divaricata retarded lipid accretion and decreased triglyceride (TG) content in 3T3-L1 adipocytes but increased free glycerol levels. Treatment with the extract inhibited lipogenesis by inhibiting protein expressions of fatty acid synthase (FAS) and lipoprotein lipase (LPL), whereas lipolysis increased by activating phosphorylation of hormone-sensitive lipase (p-HSL) and AMP-activated protein kinase (p-AMPK). The extract inhibited adipocyte differentiation of 3T3-L1 preadipocytes through down-regulating adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP1). This is attributed to the triggering of Wnt/ß-catenin signaling. In addition, this study found that treatment with the extract activated HO-1 expression. Pharmacological approaches revealed that treatment with Zinc Protoporphyrin (ZnPP), an HO-1 inhibitor, resulted in an increase in lipid accumulation and a decrease in free glycerol levels. Finally, three adipogenic transcription factors, such as PPARγ, C/EBPα, and SREBP1, restored their expression in the presence of ZnPP. Analysis of chemical constituents revealed that the extract of D. divaricata is rich in 1,4-benzenediol, 7-tetradecenal, fucosterol, and n-hexadecanoic acid, which are known to have multiple pharmacological properties.

Condition Monitoring of Railway Bridges Using Vehicle Pitch to Detect Scour.

This study proposes the new condition monitoring concept of using features in the measured rotation, or 'pitch' signal, of a crossing vehicle as an indicator of the presence of foundation scour in a bridge. The concept is explored through two-dimensional vehicle-bridge interaction modelling, with a reduction in stiffness under a pier used to represent the effects of scour. A train consisting of three 10-degree-of-freedom carriages cross the model on a profiled train track, each train varying slightly in terms of mass and velocity. An analysis of the pitch of the train carriages can clearly identify when scour is present. The concept is further tested in a scaled laboratory experiment consisting of a tractor-trailer crossing a four-span simply supported bridge on piers. The foundation support is represented by four springs under each pier, which can be replaced with springs of a reduced stiffness to mimic the effect of scour. The laboratory model also consistently shows a divergence in vehicle pitch between healthy and scoured bridge states.

Integrated Analysis of DNA Methylation and Gene Expression Profiles in a Rat Model of Osteoarthritis.

Osteoarthritis (OA) is common and affected by several factors, such as age, weight, sex, and genetics. The pathogenesis of OA remains unclear. Therefore, using a rat model of monosodium iodoacetate (MIA)-induced OA, we examined genomic-wide DNA methylation using methyl-seq and characterized the transcriptome using RNA-seq in the articular cartilage tissue from a negative control (NC) and MIA-induced rats. We identified 170 genes (100 hypomethylated and upregulated genes and 70 hypermethylated and downregulated genes) regulated by DNA methylation in OA. DNA methylation-regulated genes were enriched in functions related to focal adhesion, extracellular matrix (ECM)-receptor interaction and the PI3K-Akt and Hippo signaling pathways. Functions related to extracellular matrix organization, extracellular matrix proteoglycans, and collagen formation were involved in OA. A molecular and protein-protein network was constructed using methylated expression-correlated genes. Erk1/2 was a downstream target of OA-induced changes in DNA methylation and RNA expression. We found that the integrin subunit alpha 2 (ITGA2) gene is important in focal adhesion, alpha6-beta4 integrin signaling, and the inflammatory response pathway in OA. Overall, gene expression changes because DNA methylation influences OA pathogenesis. ITGA2, whose gene expression changes are regulated by DNA methylation during OA onset, is a candidate gene. Our findings provide insights into the epigenetic targets of OA processes in rats.

Eucommia ulmoides Leaves Alleviate Cognitive Dysfunction in Dextran Sulfate Sodium (DSS)-Induced Colitis Mice through Regulating JNK/TLR4 Signaling Pathway.

Ulcerative colitis (UC) is one of the inflammatory bowel diseases (IBD) that is characterized by systemic immune system activation. This study was performed to assess the alleviative effect of administering an aqueous extract of Eucommia ulmoides leaves (AEEL) on cognitive dysfunction in mice with dextran sulfate sodium (DSS)-induced colitis. The major bioactive compounds of AEEL were identified as a quinic acid derivative, caffeic acid-O-hexoside, and 3-O-caffeoylquinic acid using UPLC Q-TOF/MSE. AEEL administration alleviated colitis symptoms, which are bodyweight change and colon shortening. Moreover, AEEL administration protected intestinal barrier integrity by increasing the tight junction protein expression levels in colon tissues. Likewise, AEEL improved behavioral dysfunction in the Y-maze, passive avoidance, and Morris water maze tests. Additionally, AEEL improved short-chain fatty acid (SCFA) content in the feces of DSS-induced mice. In addition, AEEL improved damaged cholinergic systems in brain tissue and damaged mitochondrial and antioxidant functions in colon and brain tissues caused by DSS. Also, AEEL protected against DSS-induced cytotoxicity and inflammation in colon and brain tissues by c-Jun N-terminal kinase (JNK) and the toll-like receptor 4 (TLR4) signaling pathway. Therefore, these results suggest that AEEL is a natural material that alleviates DSS-induced cognitive dysfunction with the modulation of gut-brain interaction.

The effect of support surface on the prevention of pressure injury in acute care settings: A multi-center prospective observational study.

PURPOSE: This study aimed to analyze if a multi-foam core mattress with a laminated cover can reduce the incidence of pressure injuries, compared to an alternating air mattress overlay among critically ill patients in acute settings. DESIGN: Prospective observational study. PARTICIPANTS: and setting: Patients with a Braden scale score ≤16 on intensive care unit admission at five general hospitals in Korea were included in this study between February 2022 and March 2022. METHODS: One hundred and twenty patients in acute settings were enrolled and categorized into two groups: a multi-form core mattress with a laminated cover group (n = 60) and an alternating air mattress overlay group (n = 60). Data were collected for 7 days by wound care nurses. RESULTS: Pressure injury developed at a significantly lower rate in the multi-form core mattress with a laminated cover group (n = 4/60, 6.7 %) than in the alternating air mattress overlay group (n = 25/60, 25.0 %) (P = 0.011). Using a multi-foam core mattress with a laminated cover demonstrated a protective effect against pressure injuries (odds ratio 0.123, 95 % confidence interval 0.024-0.620, P = 0.011). CONCLUSIONS: A multi-foam core mattress with a laminated cover was significantly more effective than an alternating air mattress overlay in preventing pressure injury in critically ill patients.

[Pedunculated Giant Condyloma Acuminatum of the Scrotum].

The patient was a 71-year-old male whose chief complaint was a scrotum mass. The mass had gradually increased in size without any associated symptoms. The physical examination revealed a pedunculated, radish brown, and elastic soft tumor (4. 5×3. 5×3. 0 cm) in the right scrotum. Blood chemical analysis of HbA1c and squamous carcinoma antigen were 8. 3% and 38. 4 ng/ml (≦1. 5), respectively. This tumor was successfully treated with surgical resection. Histopathological examination showed condyloma acuminatum without malignant findings. Giant condyloma acuminatum commonly affects the genital and perianal areas. An immunocompromised state generally exists in the background of the patients.

USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity.

Lung squamous cell carcinoma (LUSC) is associated with high mortality and limited targeted therapies. USP13 is one of the most amplified genes in LUSC, yet its role in lung cancer is largely unknown. Here, we established a novel mouse model of LUSC by overexpressing USP13 on KrasG12D/+; Trp53flox/flox background (KPU). KPU-driven lung squamous tumors faithfully recapitulate key pathohistological, molecular features, and cellular pathways of human LUSC. We found that USP13 altered lineage-determining factors such as NKX2-1 and SOX2 in club cells of the airway and reinforced the fate of club cells to squamous carcinoma development. We showed a strong molecular association between USP13 and c-MYC, leading to the upregulation of squamous programs in murine and human lung cancer cells. Collectively, our data demonstrate that USP13 is a molecular driver of lineage plasticity in club cells and provide mechanistic insight that may have potential implications for the treatment of LUSC.

Evaluation of PSMA target diagnostic PET tracers for therapeutic monitoring of [177Lu]ludotadipep of prostate cancer: Screening of PSMA target efficiency and biodistribution using [18F]DCFPyL and [68Ga]PSMA-11.

We have compared the similarity of the in vivo distribution of the prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging agents [18F]DCFPyL, [68Ga]galdotadipep, and [68Ga]PSMA-11. This study is designed for a further selection of a PSMA-targeted PET imaging agent for the therapeutic evaluation of [177Lu]ludotadipep, our previously developed prostate-specific membrane antigen (PSMA)-targeted prostate cancer therapeutic radiopharmaceutical. In vitro cell uptake was performed to evaluate the affinity to PSMA using PSMA + PC3-PIP, and PSMA- PC3-flu was used for the study. MicroPET/CT 60 min dynamic imaging and biodistribution were performed at 1, 2, and 4 h after injection. Autoradiography and immunohistochemistry were performed to evaluate the PSMA + tumor target efficiency. In the microPET/CT image, [68Ga]PSMA-11 showed the highest uptake in the kidney among all three compounds. [18F]DCFPyL and [68Ga]PSMA-11 showed similar patterns of in vivo biodistribution and high tumor targeting efficiency, similar to those of[68Ga]galdotadipep. All three agents showed high uptake in tumor tissue on autoradiography, and PSMA expression was confirmed by immunohistochemistry. Thus, [18F]DCFPyL or [68Ga]PSMA-11 can be used as a PET imaging agent to monitor [177Lu]ludotadipep therapy in prostate cancer patients.