Perineural invasion (PNI) by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma (OSCC). Since Schwann cells (SCs) and fibroblasts maintain the physiological homeostasis of the peripheral nervous system, and we have focused on cancer-associated fibroblasts (CAFs) for decades, it's imperative to elucidate the impact of CAFs on SCs in PNI⁺ OSCCs. We describe a disease progression-driven shift of PNI^- towards PNI⁺ during the progression of early-stage OSCC (31%, n = 125) to late-stage OSCC (53%, n = 97), characterized by abundant CAFs and nerve demyelination. CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin in vitro, and this involved up-regulated ER stress and decreased MAPK signals. Moreover, CAFs also aggravated the paralysis of the hind limb and PNI in vivo. Unexpectedly, leukemia inhibitory factor (LIF) was exclusively expressed on CAFs and up-regulated in metastatic OSCC. The LIF inhibitor EC330 restored CAF-induced SC inactivation. Thus, OSCC-derived CAFs inactivate SCs to aggravate nerve injury and PNI development.
Schwann Cells/metabolism* ; Mouth Neoplasms/metabolism* ; Humans ; Cancer-Associated Fibroblasts/metabolism* ; Animals ; Carcinoma, Squamous Cell/metabolism* ; Neoplasm Invasiveness/pathology* ; Male ; Female ; Mice ; Cell Movement/physiology* ; Cell Proliferation/physiology* ; Cell Line, Tumor ; Leukemia Inhibitory Factor/metabolism* ; Middle Aged

Resistance to poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi) presents a considerable obstacle in the treatment of ovarian cancer. F-box and tryptophan-aspartic (WD) repeat domain containing 11 (FBXW11) modulates the ubiquitination of growth-and invasion-related factors in lung cancer, colorectal cancer, and osteosarcoma. The function of FBXW11 in PARPi therapy is still ambiguous. In this study, RNA sequencing (RNA-seq) showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi. FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer (HGSOC) tissues, and low levels of FBXW11 were associated with shorter overall survival (OS) and progression-free survival (PFS) in HGSOC patients. Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi, while knocking down FBXW11 made it less sensitive. The four-dimensional (4D) label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11 (S100A11) and promoted its degradation through ubiquitination. The increased degradation of S100A11 led to less efficient DNA damage repair, which in turn contributed to increased PARPi-induced DNA damage. The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models. In summary, our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S100A11-mediated DNA damage repair.

Objective To analyze the characteristics of time in range(TIR)and its relationship with oxidative stress(OS)and insulin resistance status(HOMA-IR)in patients with type 2 diabetes mellitus(T2DM)and sleep apnea-hypopnea syndrome(OSAHS).Methods According to apnea-hypopnea index(AHI),165 T2DM in patients were divided into simple T2DM group(AHI<5 times/h,n=43),T2DM combine OSAHS mild group(OSAHS-G,5≤AHI<15 times/h,n=51),T2DM combined OSAHS moderate group(OSAHS-M,15≤AHI≤30 times/h,n=40)and T2DM combine OSAHS severe group(OSAHS-S,AHI>30 times/h,n=31).TIR was calculated by dynamic blood glucose monitoring.Superoxide dismutase(SOD),glutathione peroxidase(GSH-Px)and other indexes were detected and analyzed.Results Compared with simple T2DM group,the levels of HOMA-IR,8-iso-PGF2a and Ox-LDL were higher in T2DM combined OSAHS-G,OSAHS-M or OSAHS-S group,while the levels of TIR,SOD and GSH-Px were lower(P<0.05).Pearson correlation analysis showed that TIR was positively correlated with the levels of SOD and GSH-Px(P<0.05 or P<0.01),and negatively correlated with the levels of 8-iso-PGF2a,Ox-LDL,HbA1c,HOMA-IR and the severity of OSAHS(P<0.01).Logistic regression analysis showed that TIR,SOD and GSH-Px were protective factors for severe OSAHS in T2DM patients,while 8-iso-PGE2a and Ox-LDL were the risk factors for severe OSAHS.Conclusions The glucose level fluctuates greatly in patients with T2DM and OSAHS.Insulin resistance and oxidative stress are factors that affect the normalization of TIR.

Objective:To analyze the influential factors of blurred vision after general anesthesia.Methods:The clinical data of 997 patients who underwent elective general anesthesia at The No. 1 People's Hospital of Pinghu from September 2022 to May 2023 were retrospectively analyzed. The data collected included age, sex, body mass index, American Society of Anesthesiologists classification, history of hypertension, history of diabetes, operation duration (specifically whether it exceeded 3 hours), surgical position (whether the patient was in the supine position), operating room temperature, use of penehyclidine hydrochloride, use of muscle relaxant antagonists, use of atropine, blood pressure (specifically whether it was ≥ 30% of the baseline value), fluid input, blood loss, and use of pneumoperitoneum. Collinearity diagnosis and univariate logistic regression analysis were conducted to select factors with statistical significance. Subsequently, multivariate logistic regression analysis was performed.Results:Univariate and multivariate logistic regression analyses showed that age > 65 years ( OR = 1.47, 95% CI: 1.01-2.15, P = 0.043), surgical position (non-supine position) ( OR = 1.54, 95% CI: 1.06-2.25, P = 0.025), operation time exceeding 3 hours ( OR = 1.76, 95% CI: 1.05-2.94, P = 0.031), and the use of penehyclidine hydrochloride ( OR = 4.91, 95% CI: 3.35-7.21, P < 0.001) were identified as factors contributing to postoperative blurred vision in patients undergoing general anesthesia. Conclusion:Factors contributing to postoperative blurred vision in patients undergoing general anesthesia include age > 65 years, the use of penehyclidine hydrochloride during surgery, operation time exceeding 3 hours, and non-supine surgical position. Clinically, it is essential to implement early and effective preoperative education, enhance intraoperative nursing quality, and optimize preoperative medication for general anesthesia to reduce the incidence of blurred vision after surgery.

Neoadjuvant therapy for locally advanced colorectal cancer has made great progress in the past 20 years, but there are still limitations such as side effects, organ dysfunction and unsatisfactory control of metastasis. In recent years, with the improvement of surgical techniques and further development of molecular research, how to further improve local control, reduce distant metastasis, and even avoid surgery according to clinical remission to achieve organ preservation, is the current demand and research goal. With the advancement of molecular research, colorectal cancer has different treatment strategies based on microsatellite status. For patients with microsatellite instability locally advanced colorectal cancer, immune checkpoint inhibitor therapy significantly increased the pathologic complete response rate, reduced the incidence of adverse events and improved organ function compared with conventional chemoradiotherapy. For patients with microsatellite stable locally advanced colon cancer, neoadjuvant therapy is still in the exploratory stage. The standard of care is surgery combined with perioperative chemotherapy. For microsatellite stable locally advanced rectal cancer, the complete response rate is improved by enhancing neoadjuvant therapy, which helps to preserve organs. On the other hand, selective radiotherapy preserves organ function and improves quality of life. This article reviews the neoadjuvant treatment strategies for locally advanced colorectal cancer based on organ-sparing strategies.

Neoadjuvant therapy for locally advanced colorectal cancer has made great progress in the past 20 years, but there are still limitations such as side effects, organ dysfunction and unsatisfactory control of metastasis. In recent years, with the improvement of surgical techniques and further development of molecular research, how to further improve local control, reduce distant metastasis, and even avoid surgery according to clinical remission to achieve organ preservation, is the current demand and research goal. With the advancement of molecular research, colorectal cancer has different treatment strategies based on microsatellite status. For patients with microsatellite instability locally advanced colorectal cancer, immune checkpoint inhibitor therapy significantly increased the pathologic complete response rate, reduced the incidence of adverse events and improved organ function compared with conventional chemoradiotherapy. For patients with microsatellite stable locally advanced colon cancer, neoadjuvant therapy is still in the exploratory stage. The standard of care is surgery combined with perioperative chemotherapy. For microsatellite stable locally advanced rectal cancer, the complete response rate is improved by enhancing neoadjuvant therapy, which helps to preserve organs. On the other hand, selective radiotherapy preserves organ function and improves quality of life. This article reviews the neoadjuvant treatment strategies for locally advanced colorectal cancer based on organ-sparing strategies.

Objective:To evaluate the diagnostic efficacy and practicality of the Jaundice color card (JCard) as a screening tool for neonatal jaundice.Methods:Following the standards for reporting of diagnostic accuracy studies (STARD) statement, a multicenter prospective study was conducted in 9 hospitals in China from October 2019 to September 2021. A total of 845 newborns who were admitted to the hospital or outpatient department for liver function testing due to their own diseases. The inclusion criteria were a gestational age of ≥35 weeks, a birth weight of ≥2 000 g, and an age of ≤28 days. The neonate′s parents used the JCard to measure jaundice at the neonate′s cheek. Within 2 hours of the JCard measurement, transcutaneous bilirubin (TcB) was measured with a JH20-1B device and total serum bilirubin (TSB) was detected. The Pearson′s correlation analysis, Bland-Altman plots and the receiver operating characteristic (ROC) curve were used for statistic analysis.Results:Out of the 854 newborns, 445 were male and 409 were female; 46 were born at 35-36 weeks of gestational age and 808 were born at ≥37 weeks of gestational age. Additionally, 432 cases were aged 0-3 days, 236 cases were aged 4-7 days, and 186 cases were aged 8-28 days. The TSB level was (227.4±89.6) μmol/L, with a range of 23.7-717.0 μmol/L. The JCard level was (221.4±77.0) μmol/L and the TcB level was (252.5±76.0) μmol/L. Both the JCard and TcB values showed good correlation ( r=0.77 and 0.80, respectively) and agreements (96.0% (820/854) and 95.2% (813/854) of samples fell within the 95% limits of agreement, respectively) with TSB. The JCard value of 12 had a sensitivity of 0.93 and specificity of 0.75 for identifying a TSB ≥205.2?μmol/L, and a sensitivity of 1.00 and specificity of 0.35 for identifying a TSB ≥342.0?μmol/L. The TcB value of 205.2?μmol/L had a sensitivity of 0.97 and specificity of 0.60 for identifying TSB levels of 205.2 μmol/L, and a sensitivity of 1.00 and specificity of 0.26 for identifying TSB levels of 342.0 μmol/L. The areas under the ROC curve (AUC) of JCard for identifying TSB levels of 153.9, 205.2, 256.5, and 342.0 μmol/L were 0.96, 0.92, 0.83, and 0.83, respectively. The AUC of TcB were 0.94, 0.91, 0.86, and 0.87, respectively. There were both no significant differences between the AUC of JCard and TcB in identifying TSB levels of 153.9 and 205.2 μmol/L (both P>0.05). However, the AUC of JCard were both lower than those of TcB in identifying TSB levels of 256.5 and 342.0 μmol/L (both P<0.05). Conclusions:JCard can be used to classify different levels of bilirubin, but its diagnostic efficacy decreases with increasing bilirubin levels. When TSB level are ≤205.2 μmol/L, its diagnostic efficacy is equivalent to that of the JH20-1B. To prevent the misdiagnosis of severe jaundice, it is recommended that parents use a low JCard score, such as 12, to identify severe hyperbilirubinemia (TSB ≥342.0 μmol/L).

Shaoyaotang is composed of Cptidis Rhizoma， Scutellariae Radix， Rhei Radix et Rhizoma， Paeoniae Radix Alba， Angelicae Sinensis Radix， Aucklandiae Radix， Arecae Semen， Cinnamomi Cortex and Glycyrrhizae Radix et Rhizoma， with the functions of clearing away heat， eliminating dampness， regulating Qi and activating blood. Thus， it is proposed as the main formula for the treatment of dampness-heat dysentery by later generations of doctors. In modern clinical application， in addition to original Shaoyaotang， its modified formulas are also used for the treatment of ulcerative colitis， and can be used in combination with other prescriptions （such as Tongxie Yaofang， Pulsatilla Soup， Shenling Baizhu San）， western medicine （such as mesalazine， sulfasalazine， Infliximab）， traditional Chinese medicine （TCM） acupuncture or moxibustion and other characteristic therapies. Clinical efficacy results indicate that Shaoyaotang and its modified formulas can significantly lower Mayo Endoscopic Score （MES）， Baron score， TCM syndrome score and other disease scores， and improve patients’ intestinal symptoms， with few side effects. Experimental pharmacological studies reveal that Shaoyaotang can inhibit tumor necrosis factor-α （TNF-α）， nuclear transcription factor-κB （NF-κB）， interleukin-1β （IL-1β） and other pro-inflammatory factors to up regulate the expression of anti-inflammatory factors such as interleukin-10 （IL-10）， thereby reducing the inflammatory response. The formula could also reduce apoptosis by regulating inflammatory signaling pathway and blocking the chain reaction， and repair abnormal immune barrier by balancing immune axis and regulating immune proteins. Additionally， it could adjust the balance of intestinal flora， promote intestinal epithelial cell regeneration and improve mucosal permeability， so as to restore the balance of intestinal environment and thus treat ulcerative colitis. Its monomers baicalin， paeoniflorin， and berberine have anti-inflammatory， antibacterial， metabolism-regulating and other effects. This paper systematically reviewed the clinical and basic research progress of Shaoyaotang in the treatment of ulcerative colitis.

ObjectiveTo investigate the role of cyclic adenosine monophosphate （cAMP）/protein kinase A （PKA）/cAMP-response element binding protein （CREB） signaling pathway in water metabolism and intestinal epithelial permeability in ulcerative colitis （UC） and the intervention mechanism of Shaoyaotang based on the theory of large intestine governing fluids. MethodSixty male SD rats were divided into blank group， model group， mesalazine group （0.42 g·kg^-1）， Shaoyaotang low-dose group （11.1 g·kg^-1）， Shaoyaotang medium-dose group （22.2 g·kg^-1） and Shaoyaotang high-dose group （44.4 g·kg^-1）， with 10 in each group. The UC rat model of internal retention of dampness-heat was established by compound factors. The blank group and the model group were given normal saline （ig）. The mesalazine group was given mesalazine （ig）， and Shaoyaotang low-， medium- and high-dose groups were administrated with corresponding doses of Shaoyaotang （ig）. The treatment lasted for 14 days. The diarrhea score and fecal moisture content of rats in each group were observed. The contents of diamine oxidase （DAO） and D-lactic acid in plasma were detected by enzyme-linked immunosorbent assay （ELISA）. The protein expressions of aquaporin （AQP）8， AQP4， ZO-1 and Occludin in colon tissues were detected by immunohistochemistry， while those of cAMP， PKA and CREB in colon tissues were determined by Western blot. ResultCompared with the normal group， the model group had elevated diarrhea score and fecal moisten content （P<0.01）， increased contents of DAO and D-lactic acid in plasma （P<0.01） and decreased protein expressions of ZO-1， Occludin， AQP8， AQP4， cAMP， PKA and CREB in colon （P<0.01）. Compared with the conditions in the model group， the contents of DAO and D-lactic acid in plasma in each administration groups were lower （P<0.01）， while the protein expressions of ZO-1， Occludin， AQP8， AQP4， cAMP， PKA and CREB in colon were higher （P<0.01）. ConclusionShaoyaotang alleviates the diarrhea in UC， probably through activating cAMP/PKA/CREB signaling pathway， up-regulating expressions of AQPs， enhancing tight junctions in intestinal epithelium and thus improving the water metabolism in colon and the intestinal mucosal permeability.

ObjectiveTo investigate the effect of Shaoyaotang on fecal metabolites in rats with ulcerative colitis （UC） induced by 2，4，6-trinitrobenzenesulfonic acid （TNBS） based on liquid chromatography-mass spectrometry （LC-MS）. MethodMale SPF SD rats were randomly divided into normal group， model group and Shaoyaotang group （11.1 g·kg^-1）. Except for normal group， UC rat model was induced by TNBS， and each group was given normal saline except Shaoyaotang group. All groups were treated for 7 days， and the general condition and disease activity index （DAI） were observed. Hematoxylin-eosin （HE） staining was used to observe the histopathological changes of colon， and the protein expressions of interleukin-8 （IL-8） and interleukin-22 （IL-22） in colon tissue were detected by immunohistochemistry （IHC）. Rat fecal samples were detected by LC-MS， and the data were analyzed by principal component analysis （PCA） and partial least squares discriminant analysis （PLS-DA）. Human Metabolome Database （HMDB） and Kyoto Encyclopedia of Genes and Genomes （KEGG） were searched to screen differential metabolites in combination with literature reference. Then， pathway enrichment analysis was conducted using Metabo Analyst 5.0. ResultShaoyaotang （ig） decreased the DAI of UC rats. Compared with the normal group， the model group had damaged colonic mucosa structure， submucosal inflammatory cell infiltration， increased protein expressions of IL-8 （P<0.01） and IL-22 （P<0.05） in colon tissue. Compared with the conditions in the model group， the colonic damage was alleviated in the Shaoyaotang group， and the protein expressions of IL-8 and IL-22 in colon tissue were decreased （P<0.01）. After screening， 15 differential metabolites were identified from the Shaoyaotang group， and the involved pathways mainly included biosynthesis of unsaturated fatty acids， linoleic acid metabolism， terpenoid backbone biosynthesis， porphyrin and chlorophyll metabolism， amino sugar and nucleotide sugar metabolism， pyrimidine metabolism and steroid hormone biosynthesis. ConclusionShaoyaotang has a therapeutic effect on UC， and its anti-inflammatory effect may be related to improving lipid metabolism and regulating the metabolism of cofactors and vitamins as well as the abnormal carbohydrate metabolism.