DDX18 Facilitates the Tumorigenesis of Lung Adenocarcinoma by Promoting Cell Cycle Progression through the Upregulation of CDK4.

Lung adenocarcinoma (LUAD) is the most prevalent and aggressive subtype of lung cancer, exhibiting a dismal prognosis with a five-year survival rate below 5%. DEAD-box RNA helicase 18 (DDX18, gene symbol DDX18), a crucial regulator of RNA metabolism, has been implicated in various cellular processes, including cell cycle control and tumorigenesis. However, its role in LUAD pathogenesis remains elusive. This study demonstrates the significant upregulation of DDX18 in LUAD tissues and its association with poor patient survival (from public databases). Functional in vivo and in vitro assays revealed that DDX18 knockdown potently suppresses LUAD progression. RNA sequencing and chromatin immunoprecipitation experiments identified cyclin-dependent kinase 4 (CDK4), a cell cycle regulator, as a direct transcriptional target of DDX18. Notably, DDX18 depletion induced G1 cell cycle arrest, while its overexpression promoted cell cycle progression even in normal lung cells. Interestingly, while the oncogenic protein c-Myc bound to the DDX18 promoter, it did not influence its expression. Collectively, these findings establish DDX18 as a potential oncogene in LUAD, functioning through the CDK4-mediated cell cycle pathway. DDX18 may represent a promising therapeutic target for LUAD intervention.

Myeloid Cell-Derived IL-1 Signaling Damps Neuregulin-1 from Fibroblasts to Suppress Colitis-Induced Early Repair of the Intestinal Epithelium.

Neuregulin-1 (Nrg1, gene symbol: Nrg1), a ligand of the ErbB receptor family, promotes intestinal epithelial cell proliferation and repair. However, the dynamics and accurate derivation of Nrg1 expression during colitis remain unclear. By analyzing the public single-cell RNA-sequencing datasets and employing a dextran sulfate sodium (DSS)-induced colitis model, we investigated the cell source of Nrg1 expression and its potential regulator in the process of epithelial healing. Nrg1 was majorly expressed in stem-like fibroblasts arising early in mouse colon after DSS administration, and Nrg1-Erbb3 signaling was identified as a potential mediator of interaction between stem-like fibroblasts and colonic epithelial cells. During the ongoing colitis phase, a significant infiltration of macrophages and neutrophils secreting IL-1ß emerged, accompanied by the rise in stem-like fibroblasts that co-expressed Nrg1 and IL-1 receptor 1. By stimulating intestinal or lung fibroblasts with IL-1ß in the context of inflammation, we observed a downregulation of Nrg1 expression. Patients with inflammatory bowel disease also exhibited an increase in NRG1+IL1R1+ fibroblasts and an interaction of NRG1-ERBB between IL1R1+ fibroblasts and colonic epithelial cells. This study reveals a novel potential mechanism for mucosal healing after inflammation-induced epithelial injury, in which inflammatory myeloid cell-derived IL-1ß suppresses the early regeneration of intestinal tissue by interfering with the secretion of reparative neuregulin-1 by stem-like fibroblasts.

The Synergistic Effect of Proanthocyanidin and HDAC Inhibitor Inhibit Breast Cancer Cell Growth and Promote Apoptosis.

Histone deacetylase inhibitor (HDACi) is a drug mainly used to treat hematological tumors and breast cancer, but its inhibitory effect on breast cancer falls short of expectations. Grape seed proanthocyanidin extract (GSPE) with abundant proanthocyanidins (PAs) has been explored for its inhibition of HDAC activity in vitro and in vivo. To enhance HDACi's effectiveness, we investigated the potential of PA to synergistically enhance HDACi chidamide (Chi), and determined the underlying mechanism. We evaluated the half-inhibitory concentration (IC50) of PA and Chi using the cell counting kit 8 (CCK8), and analyzed drugs' synergistic effect with fixed-ratio combination using the software Compusyn. Breast cancer cell's phenotypes, including short-term and long-term proliferation, migration, invasion, apoptosis, and reactive oxygen species (ROS) levels, were assessed via CCK8, clone-formation assay, wound-healing test, Transwell Matrigel invasion assay, and flow-cytometry. Protein-protein interaction analysis (PPI) and KEGG pathway analysis were used to determine the underlying mechanism of synergy. PA + Chi synergistically inhibited cell growth in T47D and MDA-MB-231 breast cancer cell lines. Short-term and long-term proliferation were significantly inhibited, while cell apoptosis was promoted. Ten signaling pathways were identified to account for the synergistic effect after RNA sequencing. Their synergism may be closely related to the steroid biosynthesis and extracellular matrix (ECM) receptor interaction pathways. PA + Chi can synergistically inhibit breast cancer cell growth and proliferation, and promote apoptosis. These effects may be related to steroid biosynthesis or the ECM receptor pathway.

Proanthocyanidins Should Be a Candidate in the Treatment of Cancer, Cardiovascular Diseases and Lipid Metabolic Disorder.

The conventional view of using medicines as routine treatment of an intractable disease is being challenged in the face of extensive and growing evidence that flavonoids in foods, especially proanthocyanidins (PAs), can participate in tackling fatal diseases like cancer, cardiovascular and lipid metabolic diseases, both as a precautionary measure or as a dietary treatment. Although medical treatment with medicines will remain necessary in some cases, at least in the short term, PAs' function as antioxidant, anti-inflammatory drugs, signal pathway regulators remain critical in many diseases. This review article demonstrates the physical and biological properties of PAs, summarizes the health benefits of PAs found by researchers previously, and shows the possibility and importance of being a dietary treatment substance.

miR­210­3p regulates cell growth and affects cisplatin sensitivity in human ovarian cancer cells via targeting E2F3.

The potential role of microRNA (miR)­210­3p in carcinogenesis and the cisplatin sensitivity of ovarian cancer were evaluated in the present study. The relative expression levels of miR­210­3p in cisplatin­sensitive SKOV­3 cells and cisplatin­resistant SKOV­3/DDP cells were determined using reverse transcription­quantitative polymerase chain reaction analysis. miR­210­3p mimics and inhibitors were transfected into SKOV­3/DDP cells. Cell Counting Kit­8, scratch and Transwell invasion assays and flow cytometry were conducted to evaluate the role of miR­210­3p in ovarian cancer cells. A luciferase reporter assay was used to verify the association between miR­210­3p and E2F transcription factor 3 (E2F3). Drug sensitivity was evaluated by treating the cells with cisplatin. The expression level of miR­210­3p was lower in SKOV­3/DDP cells than in SKOV­3 cells. Compared with the untransfected control, SKOV­3 cells transfected with miR­210­3p exhibited a significantly higher survival rate. The overexpression of miR­210­3p inhibited SKOV­3/DDP cell proliferation, migration and invasion, and promoted cell apoptosis. By contrast, the inhibition of miR­210­3p promoted cell migration and invasion. The luciferase reporter assay confirmed that E2F3 was a direct target gene of miR­210­3p. Cisplatin treatment resulted in a sharp decrease in the survival rate of SKOV­3/DDP cells transfected with the miR­210­3p mimics. The decrease in cell survival rate caused by the overexpression of miR­210­3p was rescued by the overexpression of E2F3 in SKOV­3/DDP cells. Taken together, these results suggest that miR­210­3p may act as a tumor suppressor in ovarian cancer cells and affect the sensitivity of cells to cisplatin by directly targeting E2F3. This indicates its potential use as a therapeutic target for improving drug resistance in ovarian cancer.

The anti-inflammatory and anti-nociceptive activities of Patrinia villosa and its mechanism on the proinflammatory cytokines of rats with pelvic inflammation.

This study explores the anti-inflammatory and anti-nociceptive activities of Patrinia villosa, a Chinese medicinal plant, and to explore its effects on the proinflammatory cytokines of the rats with pelvic inflammation model. The animals were randomly divided into Patrinia villosa group (PV group), dexamethasone group (DEX group), and model-control group (CON group) to perform an ear edema test, a carrageenin-induced paw edema test, a cotton pellet-induced granuloma formation test, and an acetic acid-induced writhing test. The model rats with pelvic inflammation were established, and the serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) in each group was detected with the Enzyme-Linked ImmunoSorbent Assay (ELISA). The results of the ear edema test, carrageenin-induced paw edema test, cotton pellet-induced granuloma formation test, and acetic acid-induced writhing test all showed that Patrinia villosa had strong anti-inflammatory and anti-nociceptive effects. In the experiment using model rats with pelvic inflammation, we found that the serum levels of IL-6, IL-8 and TNF-α in PV and DEX group were all significantly lower than those of the CON group, and the serum levels of IL-6 and IL-8 in PV group were significantly lower than those of the DEX group. Patrinia villosa, with its strong anti-inflammatory and anti-nociceptive activities, can be used to treat pelvic inflammation and to relieve the associated pain.

Effects of a Chinese medicinal plant Radix astragali on the ovariectomized female rats.

Perimenopausal syndrome occurs during the transition to menopause. Complementary and alternative medicine, especially Chinese medicinal plants, has manifested significant effects in alleviating perimenopausal symptoms. However, little research has been focused on the effects of Chinese medicinal plant on the immune function of the perimenopausal women. The present study aimed to explore the effects of Radix Astragali (RA) on the sex hormone levels and the interleukins of the ovariectomized female rats. 24 female Sprague-Dawley (SD) rats were randomly divided into model control group (MOD group), sham-operation group (SHAM group), RA group and estrogen group (EST group). After all the treatment ended, the serum levels of estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), interleukin-2 (IL-2), and interleukin-8 (IL-8) were measured using enzyme-linked immune-sorbent assay (ELISA) and the uterus was removed and weighed after blood exsanguinations immediately. In the MOD group, the serum levels of E2 were significantly lower, and the serum levels of FSH and LH were markedly higher than those of the RA group, EST group and SHAM group (P<0.05). In the RA group, the serum levels of E2 were significantly lower, and the serum levels of FSH were markedly higher than those of the SHAM group and EST group, respectively. In the MOD group, the serum levels of IL-2 and IL-8 were significantly lower than those of the RA group, EST group and SHAM group (P<0.05), and no marked differences existed among RA group, EST group and SHAM group in the serum levels of IL-2 and IL-8 (P>0.05). The uterine weight of the rats in the RA group, EST group and SHAM group were significantly higher than those of the rats in MOD group (P<0.05). There were no marked differences among the rats from RA group, EST group and SHAM group on the uterine weight (P>0.05). It is concluded that RA can significantly improve the immune functions of the ovariectomized female rats, although it cannot change the sex hormones levels as significantly as estrogen.

[Clinicopathologic study on 61 cases of uterine papillary serous carcinoma with or without adjuvant therapy].

OBJECTIVE: To study the clinicopathologic features of uterine papillary serous carcinoma (UPSC) and the roles of adjuvant therapy. METHODS: Sixty-one cases of UPSC with operation done and followed up for a period of 4 to 9 years were enrolled into the study. The histology of slides specimens were reviewed and immunohistochemical study was performed. The follow-up and survival data were analyzed. RESULTS: All of the 61 patients were post-menopausal, with a median age of 68 years. The clinical presentations included abnormal vaginal bleeding, abdominal symptoms and abnormal Pap smears. The median size of the tumors was 7.5 cm (range=1.2 to 14.8 cm). There were 27.9% cases in FIGO stage I (8.2% in stage IA, 14.8% in stage IB and 4.9% in stage IC), 9.8% in stage II, 32.8% in stage III and 29.5% in FIGO stage IV. The histologic features were similar to those of the ovarian counterpart, with tumor cells containing the high-grade nuclei and arranged in complex papillae. Psammoma bodies were identified in 24.6% of the cases. Immunohistochemical study showed that the tumor cells demonstrated diffuse and strong nuclear staining for p53 and Ki-67. They were negative for estrogen receptor and progesterone receptor. Fifteen of the 61 cases (24.6%) showed no evidence of myometrial invasion. However, ten of the 15 cases had extrauterine disease, with peritoneal (6/15) and nodal (9/15) involvement. Tumors with deep myometrial invasion, lymphovascular permeation and nodal metastasis were associated with worse prognosis by univariate analysis. Fifty-six patients received adjuvant therapy. The number of patients receiving adjuvant chemotherapy alone, adjuvant radiotherapy alone and combined adjuvant chemotherapy/radiotherapy were 42, 24 and 10, respectively. The median survivals of the chemotherapy group and non-chemotherapy group (with or without radiotherapy) were 66.4 months and 32.8 months, respectively. CONCLUSIONS: UPSC has distinctive clinical and pathologic features. The tumor stage, lymph node status, lymphovascular permeation and depth of myometrial invasion were important prognostic factors. Adjuvant chemotherapy for stage III/IV tumors or recurrent UPSC may have survival benefit.

[Therapeutic efficacy of augmentative plate fixation in long-bone hypertrophic nonunion subsequent to intramedullary nailing].

OBJECTIVE: To determine the therapeutic efficacy of augmentation plate fixation in nonunion of long-bone fracture after interlocking intramedullary nailing. METHODS: From April 1998 to April 2009, 14 patients with long-bone hypertrophic nonunion after intramedullary nail internal fixation were treated with augmentative plate. There were nine patients with nonunion of femur, three of humerus and two of tibia. After implanting the intramedullary nail in situ, an augmentative plate fixation was applied to the fracture site to counter the rotational instability. A general plate with at least two screws reaching the opposite cortical bone above and below the fracture was fixated to the lateral side of bone shaft. In all patients, the rotational instability of fracture site was verified intra-operatively in all cases. However, motion disappeared after plate augmentation. RESULTS: All patients achieved radiological solid union at an average of 8 months (range: 6 - 11). Hardware was removed in six cases at 6-11 months post-operation. No infection, hardware loosening or rupture was found. CONCLUSION: The augmentative plate fixation can be applied at the fracture site to prevent the rotational instability. Augmentation plate fixation is indicated for femoral and tibial nonunion of proximal or distal metaphyseal-diaphyseal junctional areas, primary comminuted fracture and humeral nonunion after intramedullary nailing.

Total laparoscopic hysterectomy after liver transplantation.

BACKGROUND: The number of females who undergo liver transplantation is growing and sometimes gynecologic operations are needed to control gynecologic diseases after liver transplantation. METHOD: Total laparoscopic hysterectomy was performed in 2 patients who had undergone liver transplantation, one for adenomyosis and the other for hysteromyoma. RESULTS: It was safe to create a pneumoperitoneum through the umbilical skinfold even though mild adhesion in the pelvic cavity occurred in one patient. The operative times were 95 and 90 minutes, with blood loss of about 100 and 60 ml, respectively. Oral intake, flatus passage, and ambulation recovered within a day, after the operation. No significant changes in liver function were observed except complication of diarrhea caused by Candida albicans in one patient. CONCLUSIONS: The result of the two patients suggest that total laparoscopic hysterectomy is a safe and effective surgical approach for patients who have undergone liver transplantation.

[Augmentative plate fixation for the treatment of femoral hypertrophic nonunions subsequent to intramedullary nailing fixation].

OBJECTIVE: To investigate the effect of augmentative plate fixation to increase stability in the treatment of femoral shaft nonunions subsequent to intramedullary fixation. METHODS: Nine patients with femoral nonunions after intramedullary nail internal fixation were treated with augmentative plate internal fixation from April 1998 to Jane 2008, included 8 males and 1 female, with an average age of 32 years old ranging from 21 to 54 years. One case was upper 1/3 femoral fractures, 5 cases were middle 1/3 femoral fractures, 3 cases were lower 1/3 femoral fractures. The interspace of bone nonunion was more than 5 mm in 6 cases, of them, iliac bone grafting were applied in 4 cases, artificial bone combined with iliac bone grafting were applied in 2 cases; The interspace of bone nonunion was less than 5 mm in other 3 cases,artificial bone grafting was applied in 1 case, fitting bone callus were applied in 2 cases. All patients got protected weight loading preventing the main screw break. RESULTS: All patients achieved radiological solid union at an average of 8 months (ranged 6 to 11 months ). The fixation was removed during 6 to 11 months after operation in 5 cases. Donor site pain of iliac occurrenced on 4 cases,3 cases relieved 1 month later and 1 case relieved 3 months later. No infection, fixation loosening or breaking was observed. CONCLUSION: The augmentative plate fixation can be applied at the fracture site to prevent the rotational instability. The technique is simple and does not require any special instrument, which facilitates an early weight bearing and gives a quick recovery from nonunion.

[Value of imaging in the preoperative diagnosis of pygopagus conjoined twins].

OBJECTIVE: To explore the value of imaging in the preoperative evaluation of pygopagus conjoined twins (PCT), and analyze the significance of imaging for separation surgery plan and prognosis. METHODS: Imaging data of a case with PCT, including ultrasound, X-ray, CT, MRI were collected from the case with PCTs treated in our hospital. The features of the images were analyzed for identification of the conjoined region, size, and structures and for judgement of other organ malformation and general body state. RESULTS: The conjoined region located at the lumbosacral spine of which anteroposterior diameter was 7.9 cm, and 6.0 cm for cranial-caudal diameter. Spina bifida were found below L3 in bilateral twins. There were no bone structures but cartilage fusion in spine and pelvis. The neural structure such as spinal cord and cauda equina, lower GI tract and anus, and urinary tract were separated. The dural sac were fused. There were cryptorchidism in one twin, patent ductus arteriosus in both twins. The intraoperative finding matched with imaging results. Crossing V-shaped skin flap was used to cover the wound surface. The dura of conjoined twins were sutured. Successful separation of the PCT was achieved. There were no complications of infection, cerebrospinal fluid leakage and neurological deficit. The healing of the skin flap was good. With 6 months follow-up, the growth and neurological function were normal. CONCLUSIONS: Imaging methods were selected according to the type of conjoined twins and the clinical symptoms and signs. The radiologic investigation can reveal the structure and size of conjunction area. Imaging investigation has important significance for the prediction of difficulty in surgery, selection of surgical procedures, and evaluation of prognosis.

[An experimental study on percutaneous autologous bone marrow mesenchymal stem cell grafting for bone defect].

OBJECTIVES: To investigate in vive osteogenic potential in size-critical bone defect after percutaneous autologous grafting of culture-expanded rabbit autologous BMSCs, osteo-induced BMSCs and combination of both. METHODS: BMSCs were cultured and then induced with osteogenic supplement (OS) medium. BMSCs with and without OS induction were collected and percutaneously autologously injected respectively into the 15 mm bone defect of 20 experimental rabbit model. The grafts were BMSCs, osteo-induced BMSCs, BMSCs and osteo-induced BMSCs, BMP combined with fibrin sealant, and 0.9% NaCl solution. Osteogenesis at the defect areas were observed by regular radiography, histology and biomechanics. RESULTS: The group transplanted with BMSCs + osteo-induced BMSCs achieved complete bone healing with medullary cavity united, which showed the largest quantity of new bone measured by X-ray analysis, and also their maximal load were better than those in other groups. CONCLUSION: The bone-forming ability of rabbit osteo-induced BMSCs combined with BMSCs in bone defect is superior to those of BMSCs and osteo-induced BMSCs.

[Expression of receptor-binding cancer antigen expressed on SiSo cells in endometrial carcinoma and the correlation thereof with the expression of estrogen receptor subtypes].

OBJECTIVE: To investigate the expression of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) and estrogen receptor subtypes in normal, hyperplastic, and carcinomatous endometrium and to explore their possible roles in carcinogenesis and progression of endometrial carcinoma. METHODS: Immunohistochemistry and semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) were applied to detect the protein and mRNA expression of RCAS1, estrogen receptor (ER) alpha and ERbeta in 20 specimens of normal endometrium, 24 specimens of hyperplastic endometrium, and 50 specimens of carcinomatous endometrium. Western blotting was used to detect the RCAS1 protein expression. RESULTS: Normal endometrium and simple and complex hyperplastic endometrium showed a P pattern of RCAS1 expression; carcinomatous endometrium showed the D pattern; and the atypical hyperplastic endometrium showed both, 30% (6/20) of which showed D pattern. The high level RCAS1 protein expression rates of the normal, simple and complex hyperplasia, atypical hyperplasia, and endometrial carcinoma were 0% (0/20), 9.1% (2/22), 45.0% (9/20), and 68.0% (34/50) respectively with a significant difference between any 2 groups (all P < 0.05). The high level expression of RCAS1 was detected more frequently in the carcinomatous endometrium with deep myometrial invasion, vascular invasion, and positive of ERalpha (all P < 0.05). The Western blotting and RT-PCR results were correlated with the immunohistochemistry results. The RCAS1 mRNA level was positively correlated with the ERalphamRNA level (P < 0.01), but not correlated with the ERbetamRNA level (P > 0.05). CONCLUSION: The expression and distribution of RCAS1 may be involved in the malignant transformation of endometrium, and RCAS1 coexpression with ERalpha may be associated with the development and metastasis of endometrial carcinoma.

[Progress in electrophysiologic and clinical examination for dorsal spinal cord injury].

Electrophysiologic examination of dorsal spinal cord injury (DSCI) is focused on transcranial magnetic stimulation induced motor evoked potentials. It were recorded at thenar muscles, exector spinae muscle, intercostals muscle, and internal oblique muscles. In complete spinal cord injury, the exector musle motor evoked potentials may occur although clinically that muscle shows no recovery. The ipsilateral exector and internal oblique muscles may be distributed by non-cross fibers in cerebrospinal tract. The progress in clinical sensory examination includes cutaneous electrical perceptional sensory threshold and quantitative sensory test. The former is more sensitive than two-points discrepentive test. Quantitative sensory test includes light touch threshold, vibration perceptual threshold, thermal threshold, pain, and cutaneous axon flare respone. It has been used in DSCI patients above and below the injury level. The thermal threshold elevates above the injury level in complete and incomplete DSCI patients.