Single-Crystalline 3D Covalent Organic Frameworks with Exceptionally High Specific Surface Areas and Gas Storage Capacities.

Single-crystalline covalent organic frameworks (COFs) are highly desirable toward understanding their pore chemistry and functions. Herein, two 50-100 µm single-crystalline three-dimensional (3D) COFs, TAM-TFPB-COF and TAPB-TFS-COF, were prepared from the condensation of 4,4',4″,4‴-methanetetrayltetraaniline (TAM) with 3,3',5,5'-tetrakis(4-formylphenyl)bimesityl (TFPB) and 3,3',5,5'-tetrakis(4-aminophenyl)bimesityl (TAPB) with 4,4',4″,4‴-silanetetrayltetrabenzaldehyde (TFS), respectively, in 1,4-dioxane under the catalysis of acetic acid. Single-crystal 3D electron diffraction reveals the triply interpenetrated dia-b networks of TAM-TFPB-COF with atom resolution, while the isostructure of TAPB-TFS-COF was disclosed by synchrotron single-crystal X-ray diffraction and synchrotron powder X-ray diffraction with Le Bail refinements. The nitrogen sorption measurements at 77 K disclose the microporosity nature of both activated COFs with their exceptionally high Brunauer-Emmett-Teller surface areas of 3533 and 4107 m2 g-1, representing the thus far record high specific surface area among imine-bonded COFs. This enables the activated COFs to exhibit also the record high methane uptake capacities up to 28.9 wt % (570 cm3 g-1) at 25 °C and 200 bar among all COFs reported thus far. This work not only presents the structures of two single-crystalline COFs with exceptional microporosity but also provides an example of atom engineering to adjust permanent microporous structures for methane storage.

Pathological Intraplaque Hemorrhage as the Gold Standard to Assess the Efficacy of Ultrasound in Predicting Vulnerable Carotid Plaque Rupture.

OBJECTIVE: To assess the clinical utility of ultrasound in predicting the risk of carotid vulnerable plaque rupture using pathological intraplaque hemorrhage as the gold standard. METHODS: A total of 118 patients who underwent endarterectomy due to symptomatic carotid artery stenosis were enrolled. Conventional ultrasound assessed the plaque thickness, area stenosis rate, echo, and surface morphology. Neovascularization were assessed by contrast-enhanced ultrasound (CEUS) and tracing intraplaque nonenhanced areas. According to neovascularization grade (0-4), plaques were classified as low-, intermediate-, and high risk. Fresh intraplaque hemorrhage within the pathology was adopted as the gold standard for diagnosing plaque rupture risk. Thus, we divided patients into ruptured risk and nonruptured risk groups to assess the value of crucial factors for plaque rupture risk using ultrasound. RESULTS: Of the 118 patients, hypertension accounted for 71.2%, hyperlipidemia 68.6%, diabetes 52.5%, and statin history 64.4%. In the rupture risk group, diabetes, smoking, and stenosis rate were significantly higher than the nonrupture risk group (P < .001); plaque thickness ≥4 mm (P > .05); and mainly hypoechoic with irregular surface morphology (P < .001), nonenhanced areas in the plaques (P < .001), and neovascularization >grade 2 (P < .001). Compared with the low-risk group, plaque rupture risk was 7.219 times higher in the medium-risk group and 18.333 times higher in the high-risk group. The kappa value of the interobserver consistency of crucial ultrasound parameters was >0.75, and the intraclass correlation coefficient was 0.919 (P < .01). CONCLUSIONS: Both conventional ultrasound and CEUS have significant clinical importance in the prediction of rupture risk in vulnerable carotid plaques, thereby enabling stroke risk stratification and the assessment of plaque rupture risk.

The role of JMJD2A in immune evasion and malignant behavior of esophageal squamous cell carcinoma.

OBJECTIVE: This study aimed to investigate the role of JMJD2A in radiotherapy tolerance of esophageal squamous cell carcinoma (ESCC). METHODS: The levels of H3K9me3 modification were analyzed in anti-PD-1 therapy non-responder or responder patients, and the expression differences of H3K9me3-related modifying enzymes were assessed in TCGA-ESCC and ICGC cohorts. Subsequently, JMJD2A was knocked down in ESCC cells using CRISPR-Cas9 or lentivirus-mediated shRNA, and changes in malignant behavior of ESCC cells were observed. RNA-seq, ATAC-seq, and ChIP-seq analyses were then conducted to investigate the genes and downstream signaling pathways regulated by JMJD2A, and functional validation experiments were performed to analyze the role of downstream regulated genes and pathways in ESCC malignant behavior and immune evasion. RESULTS: JMJD2A was significantly overexpressed in ESCC and anti-PD-1 therapy non-responders. Knockdown or deletion of JMJD2A significantly promoted the malignant behavior and immune evasion of ESCC. JMJD2A facilitated the structural changes in chromatin and promoted the binding of SMARCA4 to super-enhancers, thereby inducing the expression of GPX4. This resulted in the inhibition of radiation-induced DNA damage and cell ferroptosis, ultimately promoting the malignant behavior and immune evasion of ESCC cells. CONCLUSION: JMJD2A plays an indispensable role in the malignant behavior and immune evasion of ESCC. It regulates the binding of SMARCA4 to super-enhancers and affects the chromatin's epigenetic landscape, thereby promoting the expression of GPX4 and attenuating iron-mediated cell death caused by radiotherapy. Consequently, it triggers the malignant behavior and immune evasion of ESCC cells.

Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression.

Alterations in the tumor microenvironment are closely associated with the metabolic phenotype of tumor cells. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth and metastasis. Existing studies have suggested that lactate produced by tumor cells can activate CAFs, yet the precise underlying mechanisms remain largely unexplored. In this study, we initially identified that lactate derived from lung cancer cells can promote nuclear translocation of NUSAP1, subsequently leading to the recruitment of the transcriptional complex JUNB-FRA1-FRA2 near the DESMIN promoter and facilitating DESMIN transcriptional activation, thereby promoting CAFs' activation. Moreover, DESMIN-positive CAFs, in turn, secrete IL-8, which recruits TAMs or promotes M2 polarization of macrophages, further contributing to the alterations in the tumor microenvironment and facilitating lung cancer progression. Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer.

From metabolism to malignancy: the multifaceted role of PGC1α in cancer.

PGC1α, a central player in mitochondrial biology, holds a complex role in the metabolic shifts seen in cancer cells. While its dysregulation is common across major cancers, its impact varies. In some cases, downregulation promotes aerobic glycolysis and progression, whereas in others, overexpression escalates respiration and aggression. PGC1α's interactions with distinct signaling pathways and transcription factors further diversify its roles, often in a tissue-specific manner. Understanding these multifaceted functions could unlock innovative therapeutic strategies. However, challenges exist in managing the metabolic adaptability of cancer cells and refining PGC1α-targeted approaches. This review aims to collate and present the current knowledge on the expression patterns, regulators, binding partners, and roles of PGC1α in diverse cancers. We examined PGC1α's tissue-specific functions and elucidated its dual nature as both a potential tumor suppressor and an oncogenic collaborator. In cancers where PGC1α is tumor-suppressive, reinstating its levels could halt cell proliferation and invasion, and make the cells more receptive to chemotherapy. In cancers where the opposite is true, halting PGC1α's upregulation can be beneficial as it promotes oxidative phosphorylation, allows cancer cells to adapt to stress, and promotes a more aggressive cancer phenotype. Thus, to target PGC1α effectively, understanding its nuanced role in each cancer subtype is indispensable. This can pave the way for significant strides in the field of oncology.

Engineering of Halide Methyltransferase BxHMT through Dynamic Cross-Correlation Network Analysis.

Halide methyltransferases (HMTs) provide an effective way to regenerate S-adenosyl methionine (SAM) from S-adenosyl homocysteine and reactive electrophiles, such as methyl iodide (MeI) and methyl toluene sulfonate (MeOTs). As compared with MeI, the cost-effective unnatural substrate MeOTs can be accessed directly from cheap and abundant alcohols, but shows only limited reactivity in SAM production. In this study, we developed a dynamic cross-correlation network analysis (DCCNA) strategy for quickly identifying hot spots influencing the catalytic efficiency of the enzyme, and applied it to the evolution of HMT from Paraburkholderia xenovorans. Finally, the optimal mutant, M4 (V55T/C125S/L127T/L129P), exhibited remarkable improvement, with a specific activity of 4.08 U/mg towards MeOTs, representing an 82-fold increase as compared to the wild-type (WT) enzyme. Notably, M4 also demonstrated a positive impact on the catalytic ability with other methyl donors. The structural mechanism behind the enhanced enzyme activity was uncovered by molecular dynamics simulations. Our work not only contributes a promising biocatalyst for the regeneration of SAM, but also offers a strategy for efficient enzyme engineering.

Exploring the causal relationship between antihypertensive drugs and glioblastoma by combining drug target Mendelian randomization study, eQTL colocalization, and single-cell RNA sequencing.

Recent reports indicate a potential oncogenic role of antihypertensive drugs in common cancers. However, it remains uncertain whether this phenomenon influences the risk of glioblastoma multiforme (GBM). This study aimed to assess the potential causal effects of blood pressure (BP) and antihypertensive drugs on GBM. Genome-wide association study (GWAS) summary statistics for systolic blood pressure (SBP), diastolic blood pressure (DBP), and GBM in Europeans were downloaded. To represent the effects of antihypertensive drugs, we utilized single nucleotide polymorphisms (SNPs) associated with SBP/DBP adjacent to the coding regions of different antihypertensive drugs as instrumental variables to model five antihypertensive drugs, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, ß-receptor blockers (BBs), and thiazide diuretics. Positive control studies were performed using GWAS data in chronic heart failure. The primary method for causality estimation was the inverse-variance-weighted method. Mendelian randomization analysis showed that BBs with the ß1-adrenergic receptor (ADRB1) as a therapeutic target could significantly reduce the risk of GBM by mediating DBP (OR = 0.431, 95% CI: 0.267-0.697, p < .001) and that they could also significantly reduce the risk of GBM by mediating SBP (OR = 0.595, 95% CI: 0.422-0.837, p = .003). Sensitivity analysis and colocalization analysis reinforced the robustness of these findings. Finally, the low expression of the ADRB1 gene in malignant gliomas was found by GBM data from TCGA and single-cell RNA sequencing, which most likely contributed to the poor prognosis of GBM patients. In summary, our study provides preliminary evidence of some causal relationship between ADRB1-targeted BBs and glioblastoma development. However, more studies are needed to validate these findings and further reveal the complex relationship between BP and GBM.

Erratum: Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma: Erratum.

[This corrects the article DOI: 10.7150/ijbs.54014.].

Green Synthesis of PtPdNiFeCu High-Entropy Alloy Nanoparticles for Glucose Detection.

High-entropy alloys have long been used as a new type of alloy material and have attracted widespread concern because of their excellent performance, including their stable microstructure and particular catalytic properties. To design a safer preparation method, we report a novel approach targeting green synthesis, using tea polyphenols to prepare PtPdNiFeCu high-entropy alloy nanoparticles for glucose detection. The fabricated sensors were characterized by transmission electron microscopy and electrochemical experiments. Physical characterization showed that the nanoparticle has better dispersibility, and the average particle size is 7.5 nm. The electrochemical results showed that Tp-PtPdNiFeCu HEA-NPs had a high sensitivity of 1.264 µA mM-1 cm-2, a low detection limit of 4.503 µM, and a wide detection range of 0 - 10 mM. In addition, the sensor has better stability and selectivity for glucose detection.

CD24 is a novel target of chimeric antigen receptor T cells for the treatment of triple negative breast cancer.

Triple negative breast cancer (TNBC) is a subtype of breast cancer with the highest degree of malignancy and the worst prognosis. The application of immunotherapy for TNBC is limited. This study was to verify the potential application of chimeric antigen receptor-T cells (CAR-T cells) targeting CD24 named as 24BBz in treatment of TNBC. 24BBz was constructed by lentivirus infection and then was co-culture with breast cancer cell lines to evaluate the activation, proliferation and cytotoxicity of engineered T cells. The anti-tumor activity of 24BBz was verified in the subcutaneous xenograft model of nude mice. We found that CD24 gene was significantly up-regulated in breast cancer (BRCA), especially in TNBC. 24BBz showed antigen-specific activation and dose-dependent cytotoxicity against CD24-positive BRCA tumor cells in vitro. Furthermore, 24BBz showed significant anti-tumor effect in CD24-positive TNBC xenografts and T cells infiltration in tumor tissues, while some T cells exhibited exhaustion. No pathological damage of major organs was found during the treatment. This study proved that CD24-specific CAR-T cells have potent anti-tumor activity and potential application value in treatment of TNBC.

TNFAIP2 confers cisplatin resistance in head and neck squamous cell carcinoma via KEAP1/NRF2 signaling.

BACKGROUND: Drug resistance limits the treatment effect of cisplatin-based chemotherapy in head and neck squamous cell carcinoma (HNSCC), and the underlying mechanism is not fully understood. The aim of this study was to explore the cause of cisplatin resistance in HNSCC. METHODS: We performed survival and gene set variation analyses based on HNSCC cohorts and identified the critical role of tumor necrosis factor alpha-induced protein 2 (TNFAIP2) in cisplatin-based chemotherapy resistance. Half-maximal inhibitory concentration (IC50) examination, colony formation assays and flow cytometry assays were conducted to examine the role of TNFAIP2 in vitro, while xenograft models in nude mice and 4-nitroquinoline N-oxide (4NQO)-induced HNSCC models in C57BL/6 mice were adopted to verify the effect of TNFAIP2 in vivo. Gene set enrichment analysis (GSEA) and coimmunoprecipitation coupled with mass spectrometry (Co-IP/MS) were performed to determine the mechanism by which TNFAIP2 promotes cisplatin resistance. RESULTS: High expression of TNFAIP2 is associated with a poor prognosis, cisplatin resistance, and low reactive oxygen species (ROS) levels in HNSCC. Specifically, it protects cancer cells from cisplatin-induced apoptosis by inhibiting ROS-mediated c-JUN N-terminal kinase (JNK) phosphorylation. Mechanistically, the DLG motif contained in TNFAIP2 competes with nuclear factor-erythroid 2-related factor 2 (NRF2) by directly binding to the Kelch domain of Kelch-like ECH-associated protein 1 (KEAP1), which prevents NRF2 from undergoing ubiquitin proteasome-mediated degradation. This results in the accumulation of NRF2 and confers cisplatin resistance. Positive correlations between TNFAIP2 protein levels and NRF2 as well as its downstream target genes were validated in HNSCC specimens. Moreover, the small interfering RNA (siRNA) targeting TNFAIP2 significantly enhanced the cisplatin treatment effect in a 4NQO-induced HNSCC mouse model. CONCLUSIONS: Our results reveal the antioxidant and cisplatin resistance-regulating roles of the TNFAIP2/KEAP1/NRF2/JNK axis in HNSCC, suggesting that TNFAIP2 might be a potential target in improving the cisplatin treatment effect, particularly for patients with cisplatin resistance.

PPDPF suppresses the development of hepatocellular carcinoma through TRIM21-mediated ubiquitination of RIPK1.

Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we report that PPDPF is significantly downregulated in HCC and the decreased PPDPF expression indicates poor prognosis. In the dimethylnitrosamine (DEN)-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promotes hepatocarcinogenesis, and reintroduction of PPDPF into liver-specific Ppdpf knockout (LKO) mice inhibits the accelerated HCC development. Mechanistic study shows that PPDPF regulates nuclear factor κB (NF-κB) signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzes K63-linked ubiquitination of RIPK1 at K140. In addition, liver-specific overexpression of PPDPF activates NF-κB signaling and attenuates apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-κB signaling and provides a potential therapeutic candidate for HCC.

Development and validation of a nomogram to predict occult cervical metastasis in early oral squamous cell carcinoma.

Background: Lack of adequate objectivity and universality, available models are still difficult to be applied to clinical practice in predicting occult cervical metastasis of early oral squamous cell carcinoma (OSCC). Taking abnormal metabolic state into consideration, the current model is helpful to distinguish those patients with or without occult cervical metastasis. Methods: This study retrospectively analyzed 330 OSCC patients initially diagnosed cT1-2N0M0 stage and received neck dissection from January 2020 to July 2022. The occult cervical metastasis was identified by pathological examination.. After screening independent risk factors using logistic regression, patients were divided into training and validation cohorts at the ratio of 2:1 randomly, and a novel diagnostic model was constructed. Performances of this model were evaluated by the area under the curve (AUC), calibrating curve, decision curve analysis (DCA) and clinical impact curve (CIC). Results: Of the 330 included patients {age mean [standard deviation (SD)], 61.24 (12.99) years; 202 (61.2%) males}, 49 (14.8%) had occult nodal metastasis. Five variables, including body mass index (BMI) [high odds ratio (OR): 1.132; 95% confidence interval (CI): 1.019-1.258, P=0.021], primary tumor site (tongue & floor of mouth (TF) OR: 3.756; 95% CI: 1.295-10.898, P=0.015), depth of invasion (DOI) (5-10 mm OR: 2.973; 95% CI: 1.266-6.981; P=0.012), pathological differentiation (Poor differentiation OR: 2.65; 95% CI: 1.341-5.239; P=0.005), and diabetes (OR: 3.123; 95% CI: 1.23-7.929; P=0.017) were screened to establish the predictive model. In training cohort (n=220), this model achieved an AUC of 0.814 and had a sensitivity of 78.1% and specificity of 70.2%. Calibration plots showed favorable consistency between the prediction of the model and actual observations (Hosmer-Lemeshow value >0.05). Decision curve analysis (DCA) and clinical impact curve (CIC) showed the model was clinically useful and had better discriminative ability under the threshold probability of 0.5. Above evaluations were verified in the validation cohort (n=110). Compared to previous reported models, the concordance index (C-index), net reclassification index (NRI), and integrated discrimination improvement (IDI) values were superior in both training and validation cohorts (P<0.05). Conclusions: This constructed model might have reference value for clinicians in making neck management decisions of early OSCC patients.

Nutlin-3 suppresses tumorigenesis and progression of oral squamous cell carcinoma and enhances chemosensitivity to cisplatin.

Oral squamous cell carcinoma (OSCC) is an epithelial malignant tumor with great challenges of tumor metastasis and drug resistance. Nutlin-3 is a MDM2 inhibitor that can potently activate tumor suppressor gene p53. However, the exact role of Nutlin-3 in OSCC has not been identified yet. SCC-9 cells were treated with 0, 2.5, 5, 10, 20 µM Nutlin3. MDM2 and p53 protein levels were assessed using western blot analysis. Then, CCK8 assay, clone formation assay, TUNEL staining, wound healing and transwell assays were conducted to analyze the influences of Nutlin3 on the proliferation, apoptosis, migration, and invasion in SCC-9 cells. Moreover, SCC-9 cells were co-treated with 0, 0.5, 1, 2.5, 5 µM cisplatin and Nutlin3 to determine the effect of Nutlin3 on cisplatin chemosensitivity in OSCC. As expected, Nutlin-3 inhibited MDM2 but restored p53 in OSCC in a concentration-dependent manner. Meanwhile, Nutlin-3 suppressed the proliferation, clone formation, migration, invasion and epithelial-mesenchymal transition of SCC-9 cells and both boosted the apoptosis. In addition, Nutlin-3 caused a reduced cell viability and an elevated cell apoptosis rate in cisplatin-treated SCC-9 cells, indicating that Nutlin-3 enhanced cisplatin chemosensitivity in OSCC cells. Taken together, Nutlin-3 may suppress tumorigenesis and progression of OSCC and enhance chemosensitivity to cisplatin in OSCC.

Resveratrol protects renal damages induced by periodontitis via preventing mitochondrial dysfunction in rats.

OBJECTIVES: Periodontitis is closely associated with kidney disease and reactive oxygen species (ROS) involvement. Mitochondria are the primary source of both endogenous ROS and renal energy. We investigated whether resveratrol (RSV) prevents renal injury and mitochondrial dysfunction in periodontitis rats. METHODS: Thirty male Wistar rats were divided into control, experimental periodontitis (Ep) and Ep-RSV groups. To induce periodontitis, a steel ligature was placed on the cervix of the bilateral first maxillary molars. RSV (50 mg/kg/day) to the Ep-RSV group and vehicle to the Ep and control groups were gavaged. After 8 weeks, alveolar bone loss, pocket depth, gingival blood index and tooth mobility were assessed. Oxidative stress parameters, mitochondrial structure, mitochondrial membrane potential (MMP), mitochondrial ROS, adenosine triphosphate (ATP), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) were analysed in renal. Renal function and histology were also evaluated. RESULTS: Compared with the control group, the Ep group showed renal structural destruction, elevated oxidative stress levels, mitochondrial structure destruction, MMP loss, mitochondrial ROS accumulation, ATP reduction, and decreased SIRT1 and PGC-1α levels. RSV prevented these destruction (p < 0.05). However, there was no significant impairment in renal function (p > 0.05). CONCLUSIONS: Periodontitis induces mitochondrial dysfunction in renal tissues. Resveratrol exerts a preventive effect on periodontitis-induced kidney injury by preventing mitochondrial dysfunction.

Preliminary Study on Human Adipose Stem Cells Promoting Skin Wound Healing through Notch Signaling Pathway.

BACKGROUND: Mesenchymal stem cells (MSCs) have been documented as possible candidates for wound healing treatment because their use could reinforce the regenerative capacity of many tissues. Human adipose stem cells (hADSCs) have the advantages of easy access, large quantity and easy operation. They can be fully applied in the treatment of skin wounds. OBJECTIVE: In this study, we aim to explore the roles and potential mechanisms of hADSCs in cutaneous wound healing. METHODS: hADSCs were obtained from human subcutaneous fat. Adipocytes and osteocytes differentiated from hADSCs were determined by staining with Oil Red O and alkaline phosphatase (ALP), respectively. We assessed the effects of hADSCs and hADSC conditional medium (CM) on wound healing in an injury model of mice. Then, we investigated the biological effects of hADSCs on human keratinocytes HaCAT cells in vitro. RESULTS: The results showed that hADSCs could be successfully differentiated into osteogenic and lipogenic cells. hADSCs and hADSCs-CM significantly promote skin wound healing in vivo. hADSCs significantly promoted HaCAT cell proliferation and migration by activating the Notch signaling pathway and activated the AKT signaling pathway by Rps6kb1 kinase in HaCAT cells. In addition, we found that hADSCs-mediated activation of Rps6kb1/AKT signaling was dependent on the Notch signaling pathway. CONCLUSION: We demonstrated that hADSCs can promote skin cell-HaCAT cell proliferation and migration via the Notch pathway, suggesting that hADSCs may provide an alternative therapeutic approach for the treatment of skin injury.

PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1.

The guanine nucleotide exchange factor (GEF) SOS1 catalyzes the exchange of GDP for GTP on RAS. However, regulation of the GEF activity remains elusive. Here, the authors report that PPDPF functions as an important regulator of SOS1. The expression of PPDPF is significantly increased in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and recurrence of PDAC patients. Overexpression of PPDPF promotes PDAC cell growth in vitro and in vivo, while PPDPF knockout exerts opposite effects. Pancreatic-specific deletion of PPDPF profoundly inhibits tumor development in KRASG12D -driven genetic mouse models of PDAC. PPDPF can bind GTP and transfer GTP to SOS1. Mutations of the GTP-binding sites severely impair the tumor-promoting effect of PPDPF. Consistently, mutations of the critical amino acids mediating SOS1-PPDPF interaction significantly impair the GEF activity of SOS1. Therefore, this study demonstrates a novel model of KRAS activation via PPDPF-SOS1 axis, and provides a promising therapeutic target for PDAC.

Intraoral versus transcervical approaches in mandibular reconstruction with free flaps: A retrospective study.

This study aims to investigate the clinical and functional differences between intraoral and transcervical approaches for segmental mandible resection and reconstruction with free flaps. Patients diagnosed as benign and low-grade mandibular malignant tumors without neck dissections were retrospectively reviewed and divided into intraoral and transcervical groups. Patients of intraoral group underwent intraoral mandibulectomy and vascular anastomosis was performed through a 2-cm submandibular incision, while traditional submandibular approach was used in transcervical group. Clinical characteristics of two groups were assessed including body mass index (BMI), defect types and number of fibular segments, as well as perioperative variables such as operation time, blood loss, drainage volume. The score of appearance, swallowing and speech using the University of Washington Quality of Life Questionnaire (UW-QOL) was recorded and analyzed 6-month postoperatively. A total of 14 patients in intraoral group and 21 patients in transcervical group was collected, respectively. In intraoral group, intraoperative blood loss and postoperative drainage volume were significantly reduced in comparison with transcervical group (p = 0.0146, p = 0.0017; respectively). The score of appearance was 87.50 ± 12.97 in intraoral group, which was significantly higher than 64.29 ± 12.68 in transcervical group (p < 0.0001). Similar results were found in patients of subtype Class II mandibular defect between two groups. However, patients of intraoral group had a significant increase in operative time and a comparable amount of intraoperative blood loss (p = 0.0472, p = 0.1434; respectively). Within the limitations of the study it seems that an intraoral approach combined with a 2-cm submandibular incision should be preferred over a transcervical approach for segmental mandibulectomy and free flap reconstruction whenever appropriate.

A Reactivity-Tunable Self-Immolative Design Enables Histone Deacetylase-Targeted Imaging and Prodrug Activation.

Histone deacetylase (HDAC)-targeted probes and prodrugs are crucial for cancer theranostics. We developed a self-immolative design that enables in vivo activatable near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging and prodrug release in response to HDAC. This design comprises a phenyl ester linker with tunable reactivity, facilitating efficient release of caged fluorophores/drugs upon deacetylation. We engineered a new fluorophore using a spirocyclic xanthene scaffold with ring-open property, affording NIRF/PA detection with high contrast. We showed that a nitro-substituted self-immolative linker allows sensitive NIRF/PA in vivo imaging of HDAC with minimal interference. A highly efficient prodrug system was further developed for targeted therapy in HDAC-overexpressed triple negative breast tumors in mice. Our study provides a valuable paradigm for HDAC-targeted NIRF/PA imaging and prodrug release in vivo, highlighting its potential for bioimaging and drug development.