HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

TRPV1+ sensory nerves suppress conjunctival inflammation via SST-SSTR5 signaling in murine allergic conjunctivitis.

Allergic conjunctivitis (AC), an allergen-induced ocular inflammatory disease, primarily involves mast cells (MCs) and eosinophils. The role of neuroimmune mechanisms in AC, however, remains to be elucidated. We investigated the effects of transient receptor potential vanilloid 1 (TRPV1)-positive sensory nerve ablation (using resiniferatoxin) and TRPV1 blockade (using Acetamide, N-[4-[[6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2-benzothiazolyl] (AMG-517)) on ovalbumin-induced conjunctival allergic inflammation in mice. The results showed an exacerbation of allergic inflammation as evidenced by increased inflammatory gene expression, MC degranulation, tumor necrosis factor-α production by MCs, eosinophil infiltration and activation, and C-C motif chemokine 11 (CCL11) (eotaxin-1) expression in fibroblasts. Subsequent findings demonstrated that TRPV1+ sensory nerves secrete somatostatin (SST), which binds to SST receptor 5 (SSTR5) on MCs and conjunctival fibroblasts. SST effectively inhibited tumor necrosis factor-α production in MCs and CCL11 expression in fibroblasts, thereby reducing eosinophil infiltration and alleviating AC symptoms, including eyelid swelling, lacrimation, conjunctival chemosis, and redness. These findings suggest that targeting TRPV1+ sensory nerve-mediated SST-SSTR5 signaling could be a promising therapeutic strategy for AC, offering insights into neuroimmune mechanisms and potential targeted treatments.

[Research Progress of Indocyanine Green Fluorescence Laparoscopic Technique in Clinical Application].

Indocyanine green (ICG) is the most commonly used near-infrared fluorescent (NIRF) dye in clinical practice, and its mediated near-infrared fluorescence imaging technology is gradually applied in clinical practice. It has shown great potential in invasive surgery (MIS) and is expected to become the standard technology for surgical diagnosis and treatment of diseases. The clinical application of ICG fluorescence laparoscopy is reviewed here.

Deep learning driven colorectal lesion detection in gastrointestinal endoscopic and pathological imaging.

Colorectal cancer has the second highest incidence of malignant tumors and is the fourth leading cause of cancer deaths in China. Early diagnosis and treatment of colorectal cancer will lead to an improvement in the 5-year survival rate, which will reduce medical costs. The current diagnostic methods for early colorectal cancer include excreta, blood, endoscopy, and computer-aided endoscopy. In this paper, research on image analysis and prediction of colorectal cancer lesions based on deep learning is reviewed with the goal of providing a reference for the early diagnosis of colorectal cancer lesions by combining computer technology, 3D modeling, 5G remote technology, endoscopic robot technology, and surgical navigation technology. The findings will supplement the research and provide insights to improve the cure rate and reduce the mortality of colorectal cancer.

Value of systemic PET/CT in the diagnosis and differential diagnosis of aplastic anemia.

The aim of the present study was to investigate the value of systemic [18F]fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) in the diagnosis and differential diagnosis of aplastic anemia (AA). Systemic PET/CT imaging results of 24 patients diagnosed with AA in The First Affiliated Hospital of Sun Yat-Sen University between May 2011 and August 2014 were retrospectively analyzed and compared with results from healthy individuals and patients with acute leukemia (AL) or myelodysplastic syndrome (MDS) in the same period to summarize the PET/CT characteristics of patients with AA. Systemic PET/CT manifestations of the 24 patients with AA were classified into three types: Normal bone marrow metabolism, hypometabolism and hypometabolism complicated by focal hyperproliferation. Focal hyperproliferation was frequently identified in the vertebral body, breast bones and iliac bones. Bone marrow maximum standardized uptake values (SUV) of AA were associated, to certain extents, with the degree of proliferation and the bone marrow T/B cell ratio. The overall bone marrow SUV of AA were lower compared with those of healthy individuals and AL or patients with MDS, indicating hypometabolism. Considering the T/B cell ratio, systemic PET/CT manifestations of patients with AA are able to predict treatment responses to certain degrees. Systemic PET/CT is highly valuable in the diagnosis and differential diagnosis of AA, and may also indicate treatment responses.

Gambogic Acid Induces Cell Apoptosis and Inhibits MAPK Pathway in PTEN-/-/p53-/- Prostate Cancer Cells In Vitro and Ex Vivo.

OBJECTIVE: To investigate the effect of gambogic acid (GA) on the growth and cell death of castrate resistant prostate cancer (PC) with phosphate and tension homology (PTEN) and p53 genes deleted in vitro and ex vivo, and elucidate the underlying possible molecular mechanisms. METHODS: PTEN-/-/p53-/- PC cells and Los Angeles prostate cancer-4 (LAPC-4) cells were treated with GA for 24 h and 48 h, then cell viability was determined by cell proliferation assay. PTEN-/-/p53-/- PC cells organoids number was calculated under GA treatment for 1 week. In addition, cell titer glo assay was performed to analyze 3 dimensional cell viability of patients derived xenografts (PDX) 170.2 organoids. Flow cytometry was used to detect apoptotic cells treated with GA. And confocal image was performed to detect the apoptotic mitochondrial morphological changes. Apoptotic cell death related protein levels were measured through Western blot (WB) in GA treated cells and organoids. The expression levels of mitogen-activated protein kinases (MAPKs) pathway related ribonucleic acid (RNAs) and proteins were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and WB, respectively. RESULTS: The treatment of GA significantly reduced cell viability of PTEN-/-/p53-/- PC cells and LAPC-4 in a time- and concentration-dependent manner. In organoids, GA showed strong inhibition towards organoids' numbers and diameters and continuously led to a complete organoids inhibition with GA 150 nmol/L. Ex vivo results validated that GA 1 µmol/L inhibited 44.6% PDX170.2 organoids growth. As for mechanism, flow cytometry detected continuously increased apoptotic portion under GA treatment from 1.98% to 11.78% (6 h) and 29.94% (8 h, P<0.05). In addition, mitochondrial fragmentation emerged in GA treated cells indicated the mitochondrial apoptotic pathway might be involved. Furthermore, WB detected caspases-3, -9 activation and light chain (LC)-3 conversion with GA treatment. WB revealed decreased activity of MAPK pathway and down-regulation of downstream c-fos oncogene RNA level was detected by RT-PCR before undergoing apoptosis (P<0.05). CONCLUSION: GA was a potent anti-tumor compound as for PTEN-/-/p53-/- PC, which contributed to cell apoptosis via inhibition of the MAPK pathway and c-fos.

Comprehensive treatment with Chinese medicine in patients with advanced non-small cell lung cancer: A multicenter, prospective, cohort study.

OBJECTIVE: To determine whether additional Chinese medicine (CM) could prolong survival and improve the quality of life (QOL) in patients with advanced non-small cell lung cancer (NSCLC) compared with Western medicine (WM) alone. METHODS: This was a multicenter, prospective cohort study. A total of 474 hospitalized patients with stage III-IV NSCLC were recruited and divided into 2 groups. Patients in the WM group received radiotherapy, chemotherapy, and optimal supportive therapy according to the National Comprehensive Cancer Network (NCCN) guidelines. In the integrative medicine (IM) group, individualized CM (Chinese patent medicines and injections) and WM were administered. The primary end point was overall survival, and the secondary end points were time to disease progression, adverse events, and QOL. Follow-up clinical examinations and chest radiography were performed every 2 months. RESULTS: The median survival was 16.60 months in the IM group and 13.13 months in the WM group (P<0.01). The incidences of loss of appetite, nausea, and vomiting in the IM group were significantly lower than those in the WM group (P<0.05). The QOL based on Functional Assessment of Cancer Therapy-Lung in the IM group was markedly higher than that in the WM group at the fourth course (P<0.05). CONCLUSIONS: Additional CM may prolong survival and improve the QOL patients with NSCLC. The adverse effects of radio- and chemotherapy may be attenuated as CM is used in combination with conventional treatments.