Deep learning-based facial analysis for predicting difficult videolaryngoscopy: a feasibility study.

While videolaryngoscopy has resulted in better overall success rates of tracheal intubation, airway assessment is still an important prerequisite for safe airway management. This study aimed to create an artificial intelligence model to identify difficult videolaryngoscopy using a neural network. Baseline characteristics, medical history, bedside examination and seven facial images were included as predictor variables. ResNet-18 was introduced to recognise images and extract features. Different machine learning algorithms were utilised to develop predictive models. A videolaryngoscopy view of Cormack-Lehane grade of 1 or 2 was classified as 'non-difficult', while grade 3 or 4 was classified as 'difficult'. A total of 5849 patients were included, of whom 5335 had non-difficult and 514 had difficult videolaryngoscopy. The facial model (only including facial images) using the Light Gradient Boosting Machine algorithm showed the highest area under the curve (95%CI) of 0.779 (0.733-0.825) with a sensitivity (95%CI) of 0.757 (0.650-0.845) and specificity (95%CI) of 0.721 (0.626-0.794) in the test set. Compared with bedside examination and multivariate scores (El-Ganzouri and Wilson), the facial model had significantly higher predictive performance (p < 0.001). Artificial intelligence-based facial analysis is a feasible technique for predicting difficulty during videolaryngoscopy, and the model developed using neural networks has higher predictive performance than traditional methods.

First-in-human, phase I study of AK109, an anti-VEGFR2 antibody in patients with advanced or metastatic solid tumors.

BACKGROUND: Vascular endothelial growth factor receptor 2 (VEGFR2) plays a key role in antiangiogenesis which has been an essential strategy for cancer treatment. We report the first-in-human study of AK109, a novel anti-VEGFR2 monoclonal antibody, to characterize the safety profile and pharmacokinetics/pharmacodynamics (PK/PD) properties, and explore the preliminary antitumor efficacy in patients with solid tumors. PATIENTS AND METHODS: This was a multicenter, open-label, phase I study, including dose escalation and dose expansion (NCT04547205). Patients with advanced cancers were treated 2 and 3 weekly with escalating doses of AK109. A 3 + 3 design was used to determine the maximum tolerated dose. Blood was sampled for PK/PD analysis. The primary endpoint was safety and recommended phase II dose (RP2D). RESULTS: A total of 40 patients were enrolled. No dose-limiting toxicity was observed. However, 38 patients reported treatment-related adverse events (TRAEs); grade ≥3 TRAEs occurred in 10 patients. The most common TRAEs were proteinuria (n = 24, 60%), hypertension (n = 13, 32.5%), increased aspartate transaminase (n = 11, 27.5%), thrombopenia (n = 10, 25%), and anemia (n = 10, 25%). A total of 28 patients (70%) reported adverse events of special interest (AESIs). The most common AESIs were proteinuria (60%), hypertension (32.5%), and hemorrhage (32.5%), mainly including gum bleeding and urethrorrhagia. AK109 exhibited an approximately linear PK exposure with dose escalation at 2-12 mg/kg. PD analyses showed rapid target engagement. Among the 40 patients, 4 achieved partial response and 21 achieved stable disease with an objective response rate of 10% and a disease control rate of 62.5%. Based on the safety profile, the PK/PD profile, and preliminary antitumor activities, 12 mg/kg Q2W and 15 mg/kg Q3W were selected as RP2D. CONCLUSIONS: AK109 showed manageable safety profile and promising antitumor activity, supporting further clinical development in a large population.

[Establishment of a platelet production model by bone marrow cavity transplantation of mouse primary megakaryocytes].

Objective: To establish an intramedullary transplantation model of primary megakaryocytes to evaluate the platelet-producing capacity of megakaryocytes and explore the underlying regulatory mechanisms. Methods: Donor megakaryocytes from GFP-transgenic mice bone marrow were enriched by magnetic beads. The platelet-producing model was established by intramedullary injection to recipient mice that underwent half-lethal dose irradiation 1 week in advance. Donor-derived megakaryocytes and platelets were detected by immunofluorescence staining and flow cytometry. Results: The proportion of megakaryocytes in the enriched sample for transplantation was 40 to 50 times higher than that in conventional bone marrow. After intramedullary transplantation, donor-derived megakaryocytes successfully implanted in the medullary cavity of the recipient and produce platelets, which showed similar expression of surface markers and morphology to recipient-derived platelets. Conclusion: We successfully established an in vivo platelet-producing model of primary megakaryocytes using magnetic-bead enrichment and intramedullary injection, which objectively reflects the platelet-producing capacity of megakaryocytes in the bone marrow.

Lnc-AC145676.2.1-6-3 can influence STX3-induced abnormal autophagy by sponging hsa-miR-1292-3p in intestinal aGVHD.

OBJECTIVE: Intestinal acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Abnormal autophagy levels in intestinal aGVHD have been confirmed in many studies. LncRNAs exert coregulatory functions and participate in a variety of intracellular regulatory processes. In this study, we investigated how lnc-AC145676.2.1-6-3 regulates dysregulated STX3-related autophagy in aGVHD. MATERIALS AND METHODS: First, we established a mouse model of aGVHD by transplanting a mononuclear cell suspension from Balb/c donor mice treated with 60Co X-rays into CB6F1 recipient mice. STX3-related indicators were analyzed by Western blotting (WB) and immunohistochemistry which confirmed that STX3 plays an important role in dysregulating autophagy in intestinal aGVHD. TNF-αinduced Caco-2 cells, which is an in vitro model of intestinal barrier dysfunction, were established to verify the effect of STX3. The direct interaction between the partners of lnc-AC145676.2.1-6-3-mediated hsa-miR-1292-3p and STX3 axis was evaluated by the Dual-Luciferase activity assay. We performed PCR, WB, and immunofluorescence in Caco-2 cells to determine whether the abnormal autophagy levels were influenced by lnc-AC145676.2.1-6-3. RESULTS: The results showed that lnc-AC145676.2.1-6-3 could significantly suppress the number of autophagic vacuoles, the LC3-II/I ratio, and beclin1 levels by increasing STX3 levels. CONCLUSIONS: Lnc-AC145676.2.1-6-3 may play an important role in intestinal aGVHD by targeting STX3.

[The effect of large-conductance calcium-activated potassium channels on the migration of pericytes in the mice of senile cochlear stria vascularis].

Objective: To investigate whether large conductance calcium-activated potassium channel (BK(Ca)) was involved in the migration of pericytes (PC) in the mice of senile cochlear stria vascularis capillaries PC. Methods: C57BL/6J mice were divided into 3-month (n=10) and 12-month groups (n=10). Auditory brainstem response (ABR) was used to test the hearing threshold of each group. The immunofluorescence was used to detect the expression changes of osteopontin (OPN) and ß-BK(Ca) channels on cochlear stria vascularis PC. The morphological changes of perivascular cells in cochlea were observed by transmission electron microscope (TEM). Cell experiment: The PC, which were in the stria vascularis of the cochlea were primary cultured and identified. A cell senile model was made with D-gal. The appropriate intervention concentration of low galactose (D-gal) was determined by CCK8. ß-galactosidase (SA-ß-gal) staining was used to evaluate the cell decrept level. The change of BK(Ca) channels current on PC were recorded by whole cell patch clamp technique. The expression of BK(Ca) channels on PC was detected by immunofluorescence. The migration and invasion ability of two groups were detected by using Scratch test and Transwell. The levels of OPN and ß-BK(Ca) channels were detected by Western blot. SPSS 22.0 software was used to analyze the data. Results: The ABR threshold in the 12-month group was higher than 3-month group (t=12.66, P<0.01). In the 12-month group, the expression of ß-BK(Ca) channel was lower and the expression of OPN was increased (t=14.64, P<0.01; t=20.73, P<0.01). In TEM, cochlear stria vascularis PC were tightly connected to endothelial cells in 3-month group, while PC were loosely connected to endothelial cells or PC soma were separated from the capillary in 12-month group. Cell experiment: The positive rate of PC in the primary cultured cochlear stria vascularis is above 95%. Compared with the SA-ß-gal stained cells in the control group, the positive rate of 15 mg/ml D-gal intervention PC was 85% (t=36.90, P<0.01). Whole cell patch clamp BK(Ca) channels current decreased in the D-gal group compared with the young group PC (t=12.18, P<0.05). The OPN expression in the senile group was higher than control group (t=16.30, P<0.01), while the ß-BK(Ca) channels expression was decreased (t=11.98, P<0.01; t=15.72, P<0.05), and migration ability raised (t=7.91, P<0.01;t=7.59, P<0.01). After intervened of BK(Ca) channels specific blocker IBTX in the D-gal group, the expression of OPN and migration were increased (t=4.26, P<0.05; t=5.88, P<0.01; t=21.97, P<0.01). Conclusion: PC migration capacity were increased during the senile period, and the expression of ß-BK(Ca) channel was decreased. The administration of IBTX, a specific blocker of BK(Ca) channel, at the cell level could increase the migration capacity, suggesting that BK(Ca) might be involved in the migration of PC in the stria vascularis of the aging cochlea.

[Pylorus-preserving gastrectomy and segmental gastrectomy: discrimination of concepts and surgical procedures].

Both pylorus-preserving gastrectomy (PPG) and segmental gastrectomy (SG) achieve the preservation of gastric cardia and pylorus through the circumferential resection of stomach, while concepts and surgical procedures of these two operations are obviously different. In this sense, transectional gastrectomy includes both PPG and SG. PPG is one of the standard surgical procedure for early gastric cancer (EGC). The extent of lymph node dissection (No.1, 3, 4sb, 4d, 6, 7, 8a, 9) and the retention of infrapyloric vessels, hepatic and pyloric branch of vagal nerve has formed a consensus. Meanwhile, SG is regarded as an investigational treatment according to the Japanese gastric cancer treatment guidelines. It is still controversial and may generate an ethical risk in the clinical practice. This article distinguishes the difference in the concepts and surgical procedures between PPG and SG, assisting a comprehensive evaluation in further research.

[Segmental gastrectomy with cardia preservation for early gastric cancer].

Segmental gastrectomy with cardia preservation can reduce the symptoms of postoperative gastroesophageal reflux and improve the quality of life, which is potentially advantageous among function-preserving gastrectomy procedures. However, due to the limited extent of excision, this procedure is classified as an investigational treatment in the Japanese Gastric Cancer Treatment Guidelines, without wide acceptance in clinical practice. It is generally believed that the surgical indication of segmental gastrectomy is more selected compared to the pylorus-preserving gastrectomy, and there are also differences between their therapeutic goals. The indications of cardia preservation in segmental gastrectomy mainly depend on the T stage, the distance of the resection margin and the metastasis of lymph nodes. Other points of segmental gastrectomy mainly include the scope of lymphadenectomy, the preservation of blood vessels and vagal nerves, which are still controversial in different researches. High-quality evidences are needed to confirm the safety and long-term efficacy of the segmental gastrectomy.

[Thirty-nine cases of stage 4 pressure ulcers treated by a two-stage method of debridement and skin flap transfer].

From September 2013 to October 2018, 39 patients (28 males and 11 females, aged 21 to 76 years) with stage 4 pressure ulcers were admitted to the General Hospital of Xinjiang Military Command. The area of pressure ulcers ranged from 2 cm×2 cm to 20 cm×12 cm on admission. The two-stage method of debridement and skin flap transfer was exploited to repair the wounds. In the first stage, a thorough debridement was performed (26 cases underwent debridement once, 10 cases twice, and 3 cases for three times). The skin flap transfer surgery was conducted in the second stage after 6 to 12 days (local skin flap for 16 cases, vascularized island flap for 8 cases, fascial flap for 5 cases, gluteus maximus flap for 5 cases, and biceps femoris flap for 5 cases), with flap area of 4 cm×2 cm to 16 cm×10 cm. Some donor sites were closed by direct suture and the other donor sites which can not be sutured were covered by medium-thickness skin graft from the lateral thigh. All the pressure ulcers of 39 cases were healed with no sinus. During follow-up of 6 months to 5 years, no recurrence of pressure ulcer at the surgical site was observed; the flaps achieved soft texture and good appearance. Thus, the two-stage method of debridement and skin flap transfer achieved good long-term curative effect and could be a preferable option for treating stage 4 pressure ulcers.

Evaluation of protection against bovine viral diarrhea virus type 2 after vaccination of the calves with bovine viral diarrhea virus type 1 combo inactivated vaccine / Avaliação da proteção contra o vírus da diarreia viral bovina tipo 2 após vacinação de bezerros com vacina combinada inativada do vírus da diarreia viral bovina tipo 1

This study was designed to evaluate the extent of the protection for bovine viral diarrhea virus type 2 (BVDV-2) infection, afforded by vaccination with a combo inactivated vaccine, which contains bovine viral diarrhea virus type 1 (BVDV-1) and infectious bovine rhinotracheitis virus (IBRV). Five 3-4-month-old calves were intramuscularly vaccinated with a single dose of the combo vaccine and boosted with same dose three weeks after the first vaccination, with five mock immunized calves serving as a control group. Twenty-one days after the second vaccination, all calves were challenged with BVDV-2 SX08 strain by spray into nostril. The unvaccinated animals developed typical clinical signs of high rectal temperature, diarrhoea with erosions and a dramatic drop in leukocyte counts. These signs occured markedly less in all vaccinated animals, the rectal temperature, leukopenia and virarmia of which, were significantly less than the mock immunized calves. It can be concluded that vaccination with the combo inactivated vaccine affords cross-protection against clinical effects of a challenge-infection with BVDV-2 SX08 strain, although it was part protection.(AU)

Este estudo foi desenvolvido para avaliar a extensão da proteção contra a infecção pelo vírus da diarréia viral bovina tipo 2 (BVDV-2) através da vacinação com uma vacina combinada inativada contendo o vírus da diarréia viral bovina tipo 1 (BVDV-1) e vírus da rinotraqueíte de bovinos infecciosos (IBRV). Cinco bezerros com 3 a 4 meses de idade foram vacinados via intramuscular com uma dose única da vacina combinada e reforçados com a mesma dose três semanas após a primeira vacinação, com cinco bezerros imunizados em simulação servindo como grupo controle. Vinte e um dias após a segunda vacinação, todos os bezerros foram desafiados com a cepa BVDV-2 SX08 por spray na narina. Os animais não vacinados desenvolveram sinais clínicos típicos, como alta temperatura retal, diarréia com erosões e queda drástica na contagem de leucócitos. Estes sinais tiveram ocorrência significativamente menor em todos os animais vacinados, cuja temperatura retal, leucopenia e virarmia eram significativamente menores do que os bezerros simulados. É possível concluir que a vacinação com a vacina combinada inativada proporciona proteção cruzada contra os efeitos clínicos de uma infecção provocada pela cepa BVDV-2 SX08, embora tenha sido parcialmente protegida.(AU)

[Analysis of prognosis and pregnancy outcomes of fertility-preserving treatment for patients with stage â a, grade 2 endometrial cancer].

Objective: To investigate the efficacy and pregnancy outcome of fertility-preserving treatment for patients with stage Ⅰa, grade 2 endometrial cancer (EC). Methods: Clinical data was retrospectively collected for EC or atypical endometrial hyperplasia (AEH) patients treated in Peking University People's Hospital, Foshan First People's Hospital of Guangdong Province and First Affiliated Hospital of Sun Yat-sen University, from 2010 to 2019. Inclusion criteria for fertility-preserving treatment included: (1) Age ≤45 years. (2) EC with histological differentiation of G(1), G(2) or endometrial AEH. (3) EC disease should be stage Ⅰa, confined to the endometrium without myometrial invasion, lymph node or extrauterine metastasis. Treatment regimen: patients were given oral progestin therapy and endometrial pathology was evaluated every three months. Patients were divided into three groups as G(2) EC group, G(1) EC group and AEH group based on the histological differentiation. Oncological and pregnancy outcomes were compared among them. Results: (1) Totally 57 eligible patients were included in this study, including 11 cases with G(2) EC, 22 cases with G(1) EC, and 24 cases with AEH. (2) Oncological outcome: among the three groups of G(2) EC, G(1) EC and AH, the complete remission rates (9/11, 91% and 96%, respectively) and recurrence rates (3/9, 30% and 22%, respectively) were not significantly different (all P>0.05). Median remission time was significantly longer in the G(2) EC group than those in the other two groups (8, 6 and 4 months; P=0.046). Among 9 G(2) EC patients who recurred after complete remission, three patients relapsed at 7, 18 and 53 months, respectively. All 3 patients chose fertility-sparing treatment again, and all achieved complete remission after retreatment. (3) Pregnancy outcome: among the three groups, the assisted reproduction technology rates (4/8, 5/18 and 36%, respectively) and pregnancy rates (6/8, 5/18 and 36%, respectively) had no significant difference (P>0.05). However, time interval to pregnancy was shorter in G(2) EC patientsthan the other two groups (4, 9 and 22 months, respectively; P=0.006). Conclusions: Fertility-preserving treatment for patients with stageⅠa, G(2) endometrial cancer, may obtain a relatively high remission rate and an acceptable pregnancy rate. However, further exploration is needed due to the limited number of cases.

Mechanical Signals Induce Dedifferentiation of Mature Adipocytes and Increase the Retention Rate of Fat Grafts.

BACKGROUND: Mature adipocytes dedifferentiate in vivo on application of a soft-tissue expander. Dedifferentiated adipocytes can proliferate and redifferentiate. This study used tissue expanders to pretreat adipose flaps, to increase the retention rate after fat graft. METHODS: A soft-tissue expander and silicone sheet were implanted beneath the left and right inguinal fat pads of rats, respectively. After 7 days of expansion, the adipose tissue derived from the pads was transplanted beneath dorsal skin. Samples were harvested at various time points, and histologic, immunohistochemical, and gene expression analyses were conducted. Mature adipocytes were cultured in vitro under a pressure of 520 Pa. Changes in cell morphology, the cytoskeleton, and expression of mechanical signal-related proteins were investigated. RESULTS: Pressure in adipose flaps increased to 25 kPa on expansion. Mature adipocytes dedifferentiated following expansion. At 1 week after transplantation, the expression of vascular endothelial growth factor (p < 0.05) was higher in the expanded group. The retention rate at 12 weeks after transplantation was higher in the expanded group (56 ± 3 percent) than in the control group (32 ± 3 percent) (p < 0.05), and the surviving/regenerating zones (p < 0.01) were wider. The lipid content of mature adipocytes gradually decreased on culture under increased pressure, and these cells regained a proliferative capacity. This was accompanied by increased expression of mechanical signal--related proteins (p < 0.05). CONCLUSIONS: Mechanical signals may induce dedifferentiation of mature adipocytes. Dedifferentiated adipocytes increase the retention rate of fat grafts by acting as seed cells.

CDK5 Regulates PD-L1 Expression and Cell Maturation in Dendritic Cells of CRSwNP.

The maturation of dendritic cells is critical for chronic rhinosinusitis with nasal polyps (CRSwNPs), especially eosinophilic chronic rhinosinusitis with nasal polyps (EosCRSwNPs), but the regulation mechanism of dendritic cells (DCs) maturation is still unclear. We identified nasal mucosa of 20 patients with EosCRSwNP, 16 non-EosCRSwNP patients, and inferior turbinate of 14 patients with nasal septum deviation after surgery. The expression of cyclin-dependent kinase 5 (CDK5) and programmed cell death 1 ligand 1 (PD-L1) were detected by immunofluorescent, real-time quantitative PCR, and Western blot in EosCRSwNP. The level of dendritic cell maturation was detected by flow cytometry and immunofluorescence staining after CDK5 expression interference with small interfering RNA (siRNA). The expression of CDK5 and PD-L1 in EosCRSwNP nasal mucosal tissue was significantly higher than that of non-EosCRSwNP and inferior turbinate nasal mucosa tissue, and there was a positive correlation between them. Immunofluorescence staining showed that CDK5 and PD-L1 were co-localized in dendritic cells. Synergistic stimulation of dendritic cells with LPS and TNF-α promotes the maturation of dendritic cells and increases the expression of CDK5 and PD-L1. However, blocking the expression of CDK5 in dendritic cells with siRNAs leads to a blockage of cell maturation. CDK5 can regulate the expression of PD-L1, and its presence is critical for the maturation of dendritic cells. CDK5 may play an important role in the pathogenesis of CRSwNP disease.

Micro124-mediated AHR expression regulates the inflammatory response of chronic rhinosinusitis (CRS) with nasal polyps.

MicroRNAs represent a component of the innate immune responses that can restrain inflammatory signaling, miR124 is an important member of inflammation-associated miRNAs, and abnormal miR124 expression is observed in many inflammatory diseases and immune disorders. However, the role and signaling pathways of miR124 in chronic rhinosinusitis with nasal polyps (CRSwNPs) have not been studied in detail. The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is highly conserved in evolution and plays important roles in the inflammatory response process. In our study, we describe the role of miR124 in the inflammatory response of CRS with nasal polyps. We found that the expression of miR124 was decreased in nasal polyps, and negatively correlated with the expression of AHR. MiR124 can inhibit AHR expression by directly target 3' untranslated region (3'-UTR) of AHR. To further investigate the relationship between miR124, AHR and CRS inflammatory response, we transfect HNEpC cells with miR124 mimic, miR124 inhibitors or siRNA of AHR, then all the results showed that miR124 could regulates cellular inflammatory response through negatively regulating AHR expression. This study demonstrated that the regulation of AHR expression by miR124 is critical to the development of inflammatory response in CRSwNPs.

Transbronchial biopsy in the management of pulmonary complications of hematopoietic stem cell transplantation.

The utility of transbronchial biopsy in the management of pulmonary complications following hematopoietic stem cell transplantation (HSCT) has shown variable results. Herein, we examine the largest case series of patients undergoing transbronchial biopsy following HSCT. We performed a retrospective analysis of 130 transbronchial biopsy cases performed in patients with pulmonary complications post HSCT. Logistic regression models were applied to examine diagnostic yield, odds of therapy change and complications. The most common histologic finding on transbronchial biopsy was a nonspecific interstitial pneumonitis (n=24 cases, 18%). Pathogens identified by transbronchial biopsy were rare, occurring in <5% of cases. A positive transbronchial biopsy significantly increased the odds of a subsequent change in corticosteroid therapy (odds ratio (OR)=3.12; 95% confidence interval (CI) 1.18-8.23; P=0.02) but was not associated with a change in antibiotic therapy (OR=1.01; 95% CI 0.40-2.54; P=0.98) or changes in overall therapy (OR=1.92; 95% CI 0.79-4.70; P=0.15). Patients who underwent a transbronchial biopsy had increased odds of complications related to the bronchoscopy (OR=3.33, 95% CI 1.63-6.79; P=0.001). In conclusion, transbronchial biopsy may contribute to the diagnostic management of noninfectious lung injury post HSCT, whereas its utility in the management of infectious pulmonary complications of HSCT remains low.

Risk factors associated with mortality from vascular thromboembolic events in patients diagnosed with non-small cell lung cancer: a population-based analysis.

BACKGROUND: Lung cancer patients are at increased risk for vascular events possibly due to cancer induced hypercoagulation. AIM: The purpose of this study was to evaluate risk factors associated with the mortality from vascular thromboembolic events in patients diagnosed with non-small cell lung cancer (NSCLC). DESIGN: Retrospective population-based analysis. METHODS: We used Surveillance, Epidemiology and End Results Program for 2004-13 and evaluated 199 337 patients with NSCLC. Univariate and multivariate subdistribution hazard regression models were used to identify potential risk factors for mortality from vascular thromboembolic events. Stratification analysis against clinical stage was performed to determine if the severity of the disease influenced the identified associations. RESULTS: Multivariate Cox regression analysis demonstrated that increased risk of mortality due to vascular thromboembolic events was associated with age, black race, non-adenocarcinoma histology, surgical treatment alone (all, P < 0.001) and north central region of SEER registry (P = 0.003). Female gender (P < 0.001), Asian or Pacific Islander race (P = 0.001), multiple co-existing primary cancers and late cancer stages (both, P < 0.001) were associated with significantly lower risk of mortality due to vascular thromboembolic events. The significant predictors of mortality from the vascular thromboembolic event were dependent on the stages of the disease. CONCLUSIONS: Risk factors associated with mortality from the vascular thromboembolic events in NSCLC patients identified in this study can promote awareness and may help to identify groups of patients that can benefit from anti-thrombotic prophylaxis measures.

[Study on the choice of medication time and with drawal time of intermittent endocrine therapy for prostate cancer].

Objective: To determine the best timing of discontinuance of intermittent endocrine therapy for prostate cancer (PCa). Methods: From February 2012 to September 2014, 120 PCa patients confirmed by biopsy at the Department of Urology Surgery, Beijing Shijitan Hospital Affiliated to Capital Medical University, were included. They were divided into high-, moderate- and low-risk groups according to EAU Guidelines in 2015. All patients received intermittent endocrine therapy. When the serum level of prostate-specific antigen (PSA) dropped to 0.2 µg/L, the medication was not discontinued until 3 months later for the observation group; however, the medication was immediately discontinued after reaching the above-mentioned threshold for the control group. When the PSA level during the period of medication discontinuance increased to 4 µg/L, another course of intermittent endocrine therapy was administered until the occurrence of the failure event. The Cox proportional regression model was used to compare the difference between the two groups in the androgen-independent signs, progression of PCa and severe adverse events. Result: After correction for multiple confounding factors, including severity grading before treatment, average duration of medication, average duration of medication discontinuance and the number of courses of therapy, it was found that the medication scheme adopted in the observation group was a protective factor against androgen-independent signs in the high-risk PCa patients (HR: 0.535, 95% CI: 0.458-0.612; P<0.001); it was also a protective factor against disease progression for the high- and moderate-risk patients (high-risk group, HR: 0.387, 95% CI: 0.297-0.477; P<0.001; moderate-risk group, HR: 0.697, 95% CI: 0.581-0.813; P<0.001). However, there was no significant difference in the incidence of severe adverse events among PCa patients treated by different medication schemes (HR: 1.003, 95% CI: 0.906-1.100; P=0.798). The medication scheme adopted in the observation group was an independent risk factor for severe adverse events in the low-risk PCa patients (HR: 1.489, 95% CI: 1.305-1.673; P<0.001). Conclusion: As compared with the scheme of immediately discontinuing the medication after reaching the indicator threshold, maintenance medication for another 3 months was beneficial for the high- and moderate-risk PCa cases. The maintenance medication could reduce the androgen-independent signs and disease progression, without increasing the risk of severe adverse events. However, for the low-risk patients, there was no major difference between the two medication schemes, immediate discontinuance and maintenance medication for another 3 months. Instead, further medication may bring about a higher risk of severe adverse events.

Dexmedetomidine regulate the malignancy of breast cancer cells by activating α2-adrenoceptor/ERK signaling pathway.

OBJECTIVE: Breast cancer is one of the most aggressive and pervasive cancers identified in females. Dexmedetomidine (Dex) is an efficient anesthetic used in surgery. Our study aimed to explore the role of Dex in the malignancy of breast cancer cells in vitro and in vivo. Further, we investigate the molecular mechanism involved in the function of Dex on breast cancer cells. MATERIALS AND METHODS: The methyl thiazolyl tetrazolium (MTT) assay was applied to detect cell proliferation. The migration and invasion capacity of MDA-MB-231 cells was tested by wound healing assay and transwell assay. Western blot analysis was performed to quantify the protein expression levels of α2-adrenoceptor and ERK. RESULTS: The proliferation, migration and invasion ability of MDA-MB-231 cells was gradually increased after treatment of Dex in a dose-dependent manner in vitro. In addition, Dex could significantly elevate the volume and weight of xenotransplant tumor in vivo. Furthermore, Dex up-regulated the protein level of a2-adrenoceptor and consistently enhanced the phosphorylation of ERK without changing the total level of it. Similarity, over-expression of a2-adrenoceptor via its agonist Clonidine could mimic the function of Dex on breast cancer. CONCLUSIONS: These data suggest that Dex could promote the proliferation, migration and invasion of breast cancer cells through the activation of α2B-adrenoceptor /ERK signaling.

Tramadol regulates proliferation, migration and invasion via PTEN/PI3K/AKT signaling in lung adenocarcinoma cells.

OBJECTIVE: Tramadol is used mainly for the treatment of moderate to severe chronic cancer pain. However, the effect of tramadol on lung cancer remains unclear. Therefore, it is important to explore the mechanism accounting for the function of tramadol on lung cancer. MATERIALS AND METHODS: We investigated the effects of tramadol on the proliferation, migration and invasion in human lung adenocarcinoma cells in vitro by CCK-8 assay, wound healing assay and Transwell assay, respectively. We also explored the potential mechanism of tramadol on lung cancer cells by Western blotting. RESULTS: A549 and PC-9 cells were incubated with 2 µM tramadol for different time (0, 7, 14 and 28 d). The in vitro experiments showed that tramadol treatment significantly inhibited cell proliferation, migration and invasion in a time-dependent manner. Moreover, administration of tramadol suppressed tumor growth in vivo. The data also revealed that tramadol could up-regulate the protein expression level of PTEN and consistently inhibit the phosphorylation level of PI3K and Akt, whereas the total level of PI3K and Akt remain unchanged. CONCLUSIONS: These findings indicated that tramadol inhibited proliferation, migration and invasion of human lung adenocarcinoma cells through elevation of PTEN and inactivation of PI3K/Akt signaling.

MiR-99a suppress proliferation, migration and invasion through regulating insulin-like growth factor 1 receptor in breast cancer.

OBJECTIVE: Breast cancer is one of the most common malignant tumors in women. Despite the advances made in treatments of breast cancer, the incidence and death rates of breast cancer are still on the rise. Therefore, it is essential for us to explore the potential mechanism accounting for the malignancy of breast cancer. MATERIALS AND METHODS: A lentiviral vector over-expressing miR-99a in MDA-MB-231 breast cancer cells was constructed. Cell proliferation was detected by MTT assay. Migration and invasion were measured by Scratch-wound assay and transwell assay. Direct target of miR-99a in MDA-MB-231 breast cancer cells was examined using bioinformatics and luciferase assay. The expression of endogenous insulin-like growth factor 1 receptor was quantified by qRT-PCR and Western blotting. RESULTS: In our study, we found that miR-99a could suppress the proliferation, migration and invasion of MDA-MB-231 cell in vitro and inhibited the growth of xeno-transplant tumor in vivo. We also found that insulin-like growth factor 1 receptor (IGF-1R) was a direct target of miR-99a. Furthermore, knockdown of endogenous IGF-1R by siRNA could mimic the effect of miR-99a over-expression. CONCLUSIONS: Our findings demonstrated that miR-99a could inhibit the malignancy of breast cancer cell by directly down-regulation of IGF-1R. These results indicated that miR-99a may be an important biomarker for prognosis and anticancer therapy in breast cancer in the future.