[Clinical efficacy of posterior femoral muscle flaps combined with posterior femoral cutaneous nerve nutrient vessel flap and closed lavage in the treatment of stage â £ ischial tuberosity pressure ulcers].

Objective: To explore the clinical efficacy of posterior femoral muscle flaps combined with posterior femoral cutaneous nerve nutrient vessel flap and closed lavage in the treatment of stage Ⅳ ischial tuberosity pressure ulcers. Methods: This study was a retrospective observational study. From March 2021 to March 2022, 15 patients with stage Ⅳ ischial tuberosity pressure ulcers who met the inclusion criteria were admitted to Dezhou Dongcheng Hospital, including 11 males and 4 females, aged 31 to 72 years. The pressure ulcer wound size ranged from 6.0 cm×4.5 cm to 10.0 cm×6.0 cm, with cavity diameters of 10-14 cm. Five cases were complicated with ischial tuberosity bone infection. After clearing the lesion, the biceps femoris long head muscle flap with an area of 10.0 cm×4.0 cm-18.0 cm×5.0 cm and the semitendinosus muscle flap with an area of 8.0 cm×4.0 cm-15.0 cm×5.0 cm combined with the posterior femoral cutaneous nerve nutrient vessel flap with an area of 6.5 cm×5.5 cm-10.5 cm×6.5 cm was transplanted to repair the pressure ulcer wound. The flap donor area was directly sutured, and the closed lavage with tubes inserted into the wound cavity was performed for 2-3 weeks. The postoperative survival of the muscle flaps and skin flaps, the wound healing of the donor and recipient areas were observed. The recurrence of pressure ulcers, the appearance and texture of flaps, and scar conditions of the donor and recipient areas were followed up. Results: All the muscle flaps and skin flaps in the 15 patients successfully survived after surgery. Two patients experienced incisional dehiscence at one week after surgery due to improper turning over, during which the incision in the recipient area was pressed on, and the wounds healed after dressing changes of 3 to 4 weeks; the wounds in the donor and recipient areas healed well in the other patients. All patients received follow-up after surgery. During the follow-up period of 6 to 12 months, none of the patients experienced pressure ulcer recurrence, and the texture, color, and thickness of the skin flaps closely resembled those of the surrounding skin at the recipient site, with only linear scar left in the donor and recipient areas. Conclusions: When using the posterior femoral muscle flaps combined with the posterior femoral cutaneous nerve nutrient vessel flap and closed lavage to treat stage Ⅳ ischial tuberosity pressure ulcers, the tissue flap can be used to fully fill in the dead space of the pressure ulcers. After treatment, the wound heals well, the appearance of the donor and recipient areas is better, and the pressure ulcers are less prone to reoccur.

Rapid clearing and imaging of Mohs and melanoma surgical margins using a low-cost tissue processor.

Tissue clearing methods render biological tissues transparent while maintaining tissue structure, enabling visualization of entire tissues. Recent developments in tissue clearing have predominantly emphasized preserving intrinsic fluorescent proteins or aqueous-based tissue clearing and so typically involve complex procedures and long processing times. The utilization of tissue clearing protocols in standard of care histology settings has been less well explored, and protocols for rapid clearing of human tissue specimens are limited. This study presents a novel rapid clearing protocol and demonstrates a low-cost tissue processor for high volume rapid tissue clearing that can be intergraded into standard histology workflow. We demonstrate rapid clearing in dermatological specimens, including both nonmelanoma and melanoma excisions.

Suppression of Subpixel Jitter in Resonant Scanning Systems With Phase-locked Sampling.

Resonant scanning is critical to high speed and in vivo imaging in many applications of laser scanning microscopy. However, resonant scanning suffers from well known image artifacts due to scanner jitter, limiting adoption of high-speed imaging technologies. Here, we introduce a real-time, inexpensive and all electrical method to suppress jitter more than an order of magnitude below the diffraction limit that can be applied to most existing microscope systems with no software changes. By phase-locking imaging to the resonant scanner period, we demonstrate an 86% reduction in pixel jitter, a 15% improvement in point spread function with resonant scanning and show that this approach enables two widely used models of resonant scanners to achieve comparable accuracy to galvanometer scanners running two orders of magnitude slower. Finally, we demonstrate the versatility of this method by retrofitting a commercial two photon microscope and show that this approach enables significant quantitative and qualitative improvements in biological imaging.

Phase II clinical trial of neoadjuvant anti-PD-1 (toripalimab) combined with axitinib in resectable mucosal melanoma.

BACKGROUND: The outcome of patients with resectable mucosal melanoma is poor. Toripalimab combined with axitinib has shown impressive results in metastatic mucosal melanoma with an objective response rate of 48.3% and a median progression-free survival of 7.5 months in a phase Ib trial. It was hypothesized that this combination administered in the neoadjuvant setting might induce a pathologic response in resectable mucosal melanoma, so we conducted this trial. PATIENTS AND METHODS: This single-arm phase II trial enrolled patients with resectable mucosal melanoma. Patients received toripalimab 3 mg/kg once every 2 weeks (Q2W) plus axitinib 5 mg two times a day (b.i.d.) for 8 weeks as neoadjuvant therapy, then surgery and adjuvant toripalimab 3 mg/kg Q2W starting 2 ± 1weeks after surgery for 44 weeks. The primary endpoint was the pathologic response rate according to the International Neoadjuvant Melanoma Consortium recommendations. RESULTS: Between August 2019 and October 2021, 29 patients were enrolled and received treatment, of whom 24 underwent resection. The median follow-up time was 34.2 months (95% confidence interval 20.4-48.0 months). The pathologic response rate was 33.3% (8/24; 4 pathological complete responses and 4 pathological partial responses). The median event-free survival for all patients was 11.1 months (95% confidence interval 5.3-16.9 months). The median overall survival was not reached. Neoadjuvant therapy was tolerable with 8 (27.5%) grade 3-4 treatment-related adverse events and no treatment-related deaths. Tissue samples of 17 patients at baseline and after surgery were collected (5 responders and 12 nonresponders). Multiplex immunohistochemistry demonstrated a significant increase in CD3+ (P = 0.0032) and CD3+CD8+ (P = 0.0038) tumor-infiltrating lymphocytes after neoadjuvant therapy, particularly in pathological responders. CONCLUSIONS: Neoadjuvant toripalimab combined with axitinib in resectable mucosal melanoma demonstrated a promising pathologic response rate with significantly increased infiltrating CD3+ and CD3+CD8+ T cells after therapy.

Efficacy and Safety of Programmed Death-1 (PD-1)/Programmed Death-Ligand 1 (PD-L1) Checkpoint Inhibitors in Patients With Metastatic Castration-resistant Prostate Cancer: A Systematic Review and Meta-analysis.

AIMS: The aim of this systematic review with meta-analysis was to evaluate the efficacy and safety of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: We searched PubMed, Embase and Cochrane Library until 1 July 2022 for mCRPC trials testing PD-1/PD-L1 checkpoint inhibitors. We measured the efficacy and safety using overall survival, progression-free survival (PFS), overall response rates (ORR), prostate-specific antigen (PSA) response rate or treatment-related adverse events (TRAEs). When possible, data were meta-analysed. RESULTS: Thirteen studies involving 2533 participants were included in this meta-analysis. The pooled hazard ratio for overall survival was 0.81 (95% confidence interval 0.42-1.20, I2 = 80.3%, PHeterogeneity＜0.001) and for PFS was 0.65 (95% confidence interval 0.38-0.92, I2 = 72.2%, PHeterogeneity = 0.013). Furthermore, better ORR (relative risk = 2.77, 95% confidence interval 1.25-6.13, I2 = 0%, PHeterogeneity = 0.699) was found in PD-L1-expressing tumours. However, no statistical trends between PD-L1 status on PSA response rate (relative risk = 0.79, 95% confidence interval 0.5-1.25, I2 = 0%, PHeterogeneity = 0.953) and tumour mutational burden on ORR (relative risk = 2.53, 95% confidence interval 0.49-13.12, I2 = 74.5%, PHeterogeneity = 0.02) were observed. The pooled proportions of TRAEs and ≥ grade 3 TRAEs were 85.1% (95% confidence interval = 71.7-98.5%) and 31.6% (95% confidence interval = 18.9-44.4%), respectively. CONCLUSIONS: This meta-analysis showed that among selected populations of men with mCRPC, anti-PD-1/PD-L1 combination treatment may significantly increase the PFS benefits. However, overall survival in mCRPC warrants further testing.

miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling.

INTRODUCTION: Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid ß (Aß)1-42. METHODS: To create a model of AD, SH-SY5Y cells were treated with Aß1-42 and mice received intracerebroventricular injections of Aß1-42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aß and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aß expression was analyzed by immunofluorescence and histochemical examinations. RESULTS: Aß1-42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aß1-42, in which miR-146a upregulation increased the expression of Aß, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aß deposition and ROS accumulation via the p-p38 signaling pathway. CONCLUSIONS: Our research demonstrates that miR-146a-5pa increases Aß deposition by triggering oxidative stress through activation of MAPK signaling.

miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signalingmi / R-146a empeora el deterioro cognitivo y la patología tipo Alzheimer al promover el estrés oxidativo a través de la vía de señalización MAPK

Introduction: Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid β (Aβ)1–42. Methods: To create a model of AD, SH-SY5Y cells were treated with Aβ1–42 and mice received intracerebroventricular injections of Aβ1–42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aβ and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aβ expression was analyzed by immunofluorescence and histochemical examinations. Results: Aβ1–42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aβ1–42, in which miR-146a upregulation increased the expression of Aβ, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aβ deposition and ROS accumulation via the p-p38 signaling pathway. Conclusions: Our research demonstrates that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling.(AU)

Introducción: miR-146a-5p es un elemento regulador clave en la respuesta inmune. Sin embargo, estudios recientes sugieren que miR-146a-5p también está involucrado en el desarrollo de la enfermedad de Alzheimer (EA), aunque aún no se conoce con exactitud el mecanismo por el que esto sucede. Analizamos los efectos de miR-146a en un modelo animal y en células SH-SY5Y expuestas a β-amiloide (Aβ)1-42. Métodos: Tratamos células SH-SY5Y con Aβ1-42 e inyectamos Aβ1-42 en los ventrículos cerebrales de ratones para generar un modelo celular y otro animal de EA. Estimamos los niveles transcripcionales de miR-146a mediante PCR en tiempo real. Al mismo tiempo, transfectamos temporalmente las células y los ratones con imitador/inhibidor de miR-146a-5p para evaluar el papel de miR-146a. Estudiamos el papel de algunas vías de señalización, como la de p38, y los niveles de especies reactivas de oxígeno (ERO) con inhibidores específicos. Los niveles de Aβ y de proteína precursora amiloidea (APP) se determinaron con inmunoblot. También se analizó la expresión de Aβ mediante inmunofluorescencia y análisis histoquímico. Resultados: Las células SH-SY5Y expuestas a Aβ1-42 mostraron altos niveles transcripcionales de miR-146a y APP. La vía de señalización p-38 MAPK y la producción de EROs se activaron al utilizar un imitador de miR-146a-5p. Sin embargo, el bloqueo de miR-146a-5p con un inhibidor redujo los niveles de APP, EROs y p-p38 MAPK. Se observó un fenómeno similar en los ratones tratados con Aβ1-42: la sobrerregulación de miR-146a aumentó la expresión de Aβ, p-p38 y EROs, mientras que la inhibición de miR-146a tuvo el efecto contrario. Esto sugiere que miR-146a está involucrado en el aumento de acumulación de Aβ y de producción de EROs por medio de la vía de señalización p-p38. Conclusiones: Nuestro estudio muestra que miR146a-5p aumenta la acumulación de Aβ al promover el estrés oxidativo a través de la activación de la vía de señalización MAPK.(AU)

Real-time Analysis of Skin Biopsy Specimens With 2-Photon Fluorescence Microscopy.

Importance: Nonmelanoma skin cancers (NMSCs) are primarily diagnosed through paraffin section histologic analysis of skin biopsy specimens that requires days to weeks before a formal diagnosis is reported. Two-photon fluorescence microscopy (TPFM) has the potential for point-of-care diagnosis of NMSC and other dermatologic conditions, which could enable same-visit diagnosis and treatment. Objective: To demonstrate that TPFM imaging of NMSC can occur within minutes of obtaining biopsies and provide similar histological features to those of conventional histology and evaluate TPFM diagnostic performance with respect to conventional histology. Design, Setting, and Participants: This comparative effectiveness pilot study examined 29 freshly excised biopsies from confirmed NMSC lesions in patients presenting for treatment. Biopsies underwent imaging immediately with TPFM on site at Rochester Dermatologic Surgery (Victor, New York) between October 2019 and August 2021. The imaged biopsies were subsequently submitted for paraffin histology to produce coregistered images. Twelve of these coregistered image pairs (41.4%) were used as a training set. Fifteen (51.7%) were used in a masked evaluation by a board-certified dermatopathologist. Two (6.9%) were excluded from the study before evaluation because they could not be coregistered. Main Outcomes and Measures: Sensitivity, specificity, and accuracy of TPFM for NMSC biopsies were evaluated compared with conventional histology. Results: Fourteen of the 15 biopsy specimens (93.3%) in the evaluation set were identically diagnosed with TPFM and paraffin histology. The TPFM had 100% sensitivity (95% CI, 48%-100%), 100% specificity (95% CI, 69%-100%), and 100% accuracy (95% CI, 78%-100%) for basal cell carcinoma diagnosis. For squamous cell carcinoma diagnosis, TPFM had 89% sensitivity (95% CI, 52%-100), 100% specificity (95% CI, 54%-100%), and 93% accuracy (95% CI, 68%-100%). For overall NMSC diagnosis, TPFM had a 93% sensitivity (95% CI, 66%-100%), 100% specificity (95% CI, 3%-100%), and 93% accuracy (95% CI, 68%-100%). Examination of the 1 discordant pair revealed mismatched imaging planes as the source of error. Conclusions and Relevance: The results of this comparative effectiveness pilot study suggest that TPFM captures histological characteristics of NMSC that are present in conventional histology, which reveals its potential as a rapid, point-of-care diagnostic alternative that does not need extensive sample preparation or retraining for image evaluation. Further validation of TPFM imaging performed for a larger cohort is needed to fully evaluate its diagnostic accuracy and potential effect within the field.

Toripalimab (anti-PD-1) versus high-dose interferon-α2b as adjuvant therapy in resected mucosal melanoma: a phase II randomized trial.

BACKGROUND: No standard of care for mucosal melanoma (MM) in the adjuvant setting has been established. Meanwhile, relapse-free survival (RFS) is only ∼5 months after surgery alone. This phase II trial aimed to compare toripalimab versus high-dose interferon-α2b (HDI) as an adjuvant therapy for resected MM. PATIENTS AND METHODS: From July 2017 to May 2019, 145 patients with resected MM were randomized (1 : 1) to receive HDI (n = 72) or toripalimab (n = 73) for 1 year until disease relapse/distant metastasis, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. The secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), and safety. RESULTS: After a median follow-up of 26.3 months, the number of RFS, OS, and DMFS events was 51 versus 46, 33 versus 29, and 49 versus 44 in the toripalimab arm and the HDI arm, respectively. The median RFS was 13.6 [95% confidence interval (CI) 8.31-19.02] months and 13.9 (95% CI 8.28-19.61) months in the toripalimab arm and the HDI arm, respectively. The DMFS was not significantly different between the two arms [hazard ratio (HR) 1.00; 95% CI 0.65-1.54]. The median OS was 35.1 months (95% CI 27.93 months-not reached) in the toripalimab arm, with no significant difference in all-cause death (HR 1.11, 95% CI 0.66-1.84) for the two arms. The median sums of the patients' actual infusion doses were 3672 mg and 1054.5 MIU in the toripalimab arm and the HDI arm, respectively. The incidence of treatment-emergent adverse events with a grade ≥3 was much higher in the HDI arm than in the toripalimab arm (87.5% versus 27.4%). CONCLUSIONS: Toripalimab showed a similar RFS and a more favorable safety profile than HDI, both better than historical data, suggesting that toripalimab might be the better treatment option. However, additional translational studies and better treatment regimens are still warranted to improve the clinical outcome of MM.

[Preliminary effects of toripalimab combined with axitinib in the treatment of advanced renal cell carcinoma].

Objective: To analyze the efficacy and safety of toripalimab combined with axitinib in the treatment of advanced renal cell carcinoma. Methods: Clinical data of 50 patients with advanced renal cell carcinoma who received axitinib combined with toripalimab were retrospectively collected from the database of Peking University Cancer Hospital. ORR, DCR, PFS, and OS were analyzed. Results: Among the 50 patients, 37 were males; median age was 56 (22-73) years; 38 were pathologically diagnosed as clear cell renal cell carcinoma and 12 were non-clear cell carcinoma. Common metastatic sites included lung, bone, lymph node, liver, and so on. 90% of the patients had received at least one-line of systemic therapy. With a median follow-up time of 11.9 months (0.8-24), 27 of the 50 patients are still on treatment, ORR was 34%, DCR was 86%, median PFS was 13.1 months (95%CI 5.8-20.4), and median OS has not yet reached. One-year OS rate was 84.6%. Common adverse reactions were proteinuria, diarrhea, hypertension, abnormal thyroid function, elevated transaminase, and hand-foot syndrome. Most adverse events were grade 1-2. Conclusion: Toripalimab combined with axitinib was efficient in the treatment of advanced renal cell carcinoma, and had manageable adverse reactions.

Improved microscopy with ultraviolet surface excitation (MUSE) using high-index immersion illumination.

Microscopy with ultraviolet surface excitation (MUSE) typically has an optical sectioning thickness significantly larger than standard physical sectioning thickness, resulting in increased background fluorescence and higher feature density compared to formalin-fixed, paraffin-embedded physical sections. We demonstrate that high-index immersion with angled illumination significantly reduces optical sectioning thickness through increased angle of refraction of excitation light at the tissue interface. We present a novel objective dipping cap and waveguide-based MUSE illuminator design with high-index immersion and quantify the improvement in optical sectioning thickness, demonstrating an e-1 section thickness reduction to 6.67 µm in tissue. Simultaneously, the waveguide illuminator can be combined with high or low magnification objectives, and we demonstrate a 6 mm2 field of view, wider than a conventional 10x pathology objective. Finally, we show that resolution and contrast can be further improved using deconvolution and focal stacking, enabling imaging that is robust to irregular surface profiles on surgical specimens.

miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling.

INTRODUCTION: Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid ß (Aß)1-42. METHODS: To create a model of AD, SH-SY5Y cells were treated with Aß1-42 and mice received intracerebroventricular injections of Aß1-42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aß and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aß expression was analyzed by immunofluorescence and histochemical examinations. RESULTS: Aß1-42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aß1-42, in which miR-146a upregulation increased the expression of Aß, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aß deposition and ROS accumulation via the p-p38 signaling pathway. CONCLUSIONS: Our research demonstrates that miR-146a-5pa increases Aß deposition by triggering oxidative stress through activation of MAPK signaling.

Hypoxia-responsive miR-346 promotes proliferation, migration, and invasion of renal cell carcinoma cells via targeting NDRG2.

Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. In this study, we investigated the role of miR-346 in RCC cells under hypoxia. OS-RC-2 and 786-O cells were cultured in 1% O2 or normal oxygen. Cell proliferation, migration, and invasion abilities were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, transwell migration, and invasion assays, respectively. Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of miR-346 and N-myc downstream-regulated gene 2 (NDRG2). Then bioinformatics analysis, dual-luciferase reporter assay, and RNA immunoprecipitation were carried out to determine the relationship between miR-346 and NDRG2. The protein expression of NDRG2 was detected by western blot assay. Hypoxia promoted cell proliferation, migration, and invasion in OS-RC-2 and 786-O cells. Meanwhile, we found that miR-346 was upregulated in RCC cells under hypoxia as relative to normoxia. miR-346 deletion could decrease the viability, migration, and invasion abilities of RCC cells under hypoxia. Besides, our data demonstrated that NDRG2 was a target gene of miR-346. The expression of NDRG2 in OS-RC-2 and 786-O cells was lower under hypoxia than under normal oxygen conditions. Moreover, NDRG2 overexpression could inhibit cell proliferation, migration, and invasion in RCC cells under hypoxia. And NDRG2 silencing reversed the inhibitory effects of the miR-346 inhibitor on the viability, migration, and invasion abilities of RCC cells in hypoxia conditions. miR-346 promoted the viability, migration, and invasion of RCC cells under hypoxia by targeting NDRG2.

Itraconazole inhibits proliferation of pancreatic cancer cells through activation of Bak-1.

Itraconazole is an FDA-approved antifungal agent, which has been reported to possess promising anticancer activities in recent years. This study investigates the antiproliferative effects of itraconazole on pancreatic cancer cells and the molecular mechanism of its apoptosis-inducing effects. In this study, our results showed that itraconazole inhibited the growth of pancreatic cancer cells in vitro, and it also significantly inhibited the tumor growth of CFPAC-1 xenografts in vivo. Itraconazole induced apoptosis through ROS generation and mitochondrial membrane depolarization. A Bak-1 activation dependent apoptosis was identified in CFPAC-1 cells. These data suggested that itraconazole exhibited antiproliferative effects in pancreatic cancer cells by inducing apoptosis through Bak-1 activation.

[Impact of first-line chemotherapy on renal function in patients with advanced upper tract urothelial carcinoma].

Objective: To observe the impact of first-line chemotherapy on renal function in patients with unresectable/metastatic upper tract urothelial carcinoma(UTUC). Methods: A total of 222 (130 males and 92 females) unresectable/metastatic upper tract urothelial carcinoma patients were included in the study between January 2005 and May 2017, with age of 29 to 87 (62.4±10.1) years old. The serum creatinine level and estimated glomerular filtration rate (eGFR) were compared before and after first-line chemotherapy. And predictive factors for decreased renal function were analyzed in logistic regression model. Results: After the first-line chemotherapy, the average serum creatinine level increased, with a median changing value of 1.5 µmol/L. Howerver, the eGFR improved, with a median changing value of 0.5 ml·min-1· (1.73 m2)-1, but the differences were not statistically significant (all P>0.05). In 149 patients who were treated with cisplatin-based chemotherapy, the average serum creatinine level increased by 1.31 µmol/L and eGFR improved by 0.14 ml·min-1·(1.73 m2)-1, but the differences were not statistically significant (P>0.05). In multivariate logistic regression model, age more than and equal to 60 years old (OR=0.88, P=0.745) and cisplatin-based chemotherapy (OR=0.95, P=0.893) did not increase the risk of renal dysfunction after first-line chemotherapy. If the time interval between surgery and first-line chemotherapy was more than 1 year, the risk of renal dysfunction due to chemotherapy decreased (OR=0.54, P=0.196). Eastern Cooperative Oncology Group Performance Status (ECOG PS) Scale≥1 (OR=1.81, P=0.131), anemia before treatment (OR=1.14, P=0.764), the cycles of first-line chemotherapy (OR=1.41, P=0.398) may lead to increase the risk of renal dysfunction, but the differences were not statistically significant. However in the patients who accepted nephrectomy, the risk of renal dysfunction after chemotherapy increased, but the difference was still not statistically significant (OR=3.06, P=0.089). Conclusions: First-line chemotherapy, especially the cisplatin-based regimen, had no significant impact on renal function in the patients with UTUC. Nephrectomy maybe a predictive risk factor for decreased renal function after chemotherapy. Adequate assessment of renal function before treatment, hydration and close monitoring during chemotherapy can effectively protect renal function of the patients.

Adaptation of microscopy with ultraviolet surface excitation for enhancing STEM and undergraduate education.

Microscopy with ultraviolet surface excitation (MUSE) is investigated as a means to enhance curricula and education in the life sciences based on simplicity of use, the incorporation of inexpensive hardware, and the simplest methods of tissue preparation. Ultraviolet excitation in effect replaces tissue sectioning because it penetrates only a few micrometers below the tissue surface at the single cell level, preventing the generation of out-of-focus light. Although tissue autofluorescence may be used, image quality and content can be enhanced by a brief immersion in a solution of nontoxic fluorescent dyes that selectively highlight different cellular compartments. Safe mixed-dye powder combinations have been developed to provide students who have minimal lab proficiencies with a one-step tissue staining process for rapid tissue preparation.

[Relationship between the ratio of neutrophil/lymphocyte and risk stratification, prognosis in patients with non-ST-elevation acute coronary syndrome].

Objective: To investigate the value of neutrophil to lymphocyte ratio (NLR) in predicting risk stratification and prognosis in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). Methods: A total of 227 NSTE-ACS patients after percutaneous coronary intervention (PCI) were collected from September 2012 to September 2014 in Beijing Anzhen Hospital.Groups: (1)According to NLR, the patients were divided into 3 groups: NLR<2.20 group; 2.2≤NLR<3.33 group; NLR≥3.33 group.(2)According to the global registry of acute coronary events (GRACE) score, the patients were divided into 3 groups: Low-risk group, Medium-risk group and High-risk group.(3)According to the occurrence of major adverse cardiac events (MACE), the patients were divided into 2 groups: MACE group and non MACE group.Receiver operator characteristic curve (ROC) was used to assess value of NLR for high risk NSTE-ACS patients.Then COX regression analysis was used to analyze correlation between NLR and MACE. Results: A total of 227 NSTE-ACS patients after PCI were collected and the ratio of MACE was 32.2% (73/227). The GRACE score and the incidence of MACE in NLR≥3.33 group were higher than those in 2.2≤NLR<3.33 group and NLR<2.20 group (all P<0.01). The level of NLR and the incidence of MACE in High-risk group were higher than those in Low-risk group and Medium-risk group (all P<0.05). The level of NLR and the GRACE score in MACE group were higher than those in non MACE group (all P<0.05). COX regression analysis indicated that NLR was independent risk factor for MACE occurrence in NSTE-ACS patients at 1 year after PCI (OR=1.214, 95%CI: 1.114-1.323, P=0.000). Conclusion: The level of NLR has significant correlation with High-risk NSTE-ACS patients, and NLR is an independent risk factor for poor prognosis in patients with NSTE-ACS.

BRAF inhibitors: efficacious and tolerable in BRAF-mutant acral and mucosal melanoma.

BRAF inhibitors substantially have impressive clinical efficacy in cutaneous melanoma. However, their role in acral and mucosal melanoma remains unclear. Records were reviewed of patients with metastatic or unresectable BRAF-mutant acral and mucosal melanoma hospitalized and administrated BRAF inhibitors during January 2011 and March 2016. Clinical data were collected to determine PFS, ORR, DCR, OS, and safety. Among 28 acral and 12 mucosal melanoma patients treated with BRAF inhibitors, median PFS were 3.6 (95%CI 3.0-6.4) and 4.4 (95%CI 0.8-12.7) months, median OS were 6.2 (95%CI 6.1-12.1) and 8.2 (95%CI 6.6-19.9) months; ORRs were 38.1% and 20.0%, DCRs were 81.0% and 70.0% in acral and mucosal melanoma, respectively. BRAF inhibitors were well tolerated. The most common adverse effects (AEs) were cutaneous and hematological. Grade 3/4 AEs were relatively rare. In conclusion, BRAF inhibitors have acceptable efficacy and good tolerance in BRAF mutant acral and mucosal melanoma.

The natural history and patterns of metastases from mucosal melanoma: an analysis of 706 prospectively-followed patients.

Background: We examined whether mucosal melanomas are different in their clinical course and patterns of metastases when arising from different anatomic sites. Our hypothesis was that metastatic behavior would differ from primary mucosal melanomas at different anatomical sites. Patients and methods: Clinical and pathological data from 706 patients were compared for their stage distribution, patterns of metastases, CKIT/BRAF mutation status, and overall survival for different anatomical sites. Results: The anatomic sites of the primary mucosal melanomas were from the lower GI tract (26.5%), nasal cavity and paranasal sinuses (23%), gynecological sites (22.5%), oral cavity (15%), urological sites (5%), upper GI tract (5%), and other sites (3.0%). At initial diagnosis, 14.5% were stage I disease, 41% Stage II, 21.5% Stage III, and 23.0% stage IV. Predominant metastatic sites were regional lymph nodes (21.5%), lung (21%), liver (18.5%), and distant nodes (9%). Oral cavity mucosal melanoma had a higher incidence of regional nodal metastases (31.7% versus 19.8%, P = 0.009), and a higher incidence of lung metastases (32.5% versus 18.5%, P = 0.007) compared to other primary mucosal melanomas. There was a 10% incidence of CKIT mutation and 12% BRAF mutation. Mucosal melanomas from nasal pharyngeal and oral, gastrointestinal, gynecological, and urological had a similar survival with a 1-year survival rate (88%, 83%, 86%), 2-year survival rate (66%, 57%, 61%), 5-year survival rate (27%, 16%, 20%), respectively. Conclusions: The largest sample size allows, for the first time, a comparison of primary melanoma stage and patterns of metastases across anatomical sites. With few exceptions, the presenting stages, incidence of nodal and distant metastases, the site of predilection of distant metastases, or overall survival were similar despite different primary anatomic sites. These findings suggest that clinical trials involving mucosal melanomas and the administration of systemic therapy can be applied equally to mucosal melanomas regardless of their primary anatomic site.

[Efficacy and the multivariate analysis of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma].

Objective: To investigate the efficacy and the influence factors of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma (mRCC). Methods: Clinical data of mRCC patients with sunitinib administered as the first line treatment from August 2008 to December 2015 were retrospectively reviewed. The efficacy and the influence factors of sunitinib treatment was analyzed using the Kaplan-Meier method and Cox proportional hazards models. Results: In all 166 patients who received sunitinib as first-line treatment, objective response rate was 31.9%, disease control rate was 84.3%. The median progression free survival (PFS) and overall survival (OS) were 11.0 months (95% CI: 9.0-14.0) and 28.0 months (95% CI: 19.0-33.0), respectively. Multivariate analysis showed that pathological types (clear cell carcinoma vs non clear cell carcinoma, HR: 1.889 vs 2.353), time from diagnosis to treatment(<1 year vs ≥1 year, HR: 0.293 vs 0.322) and the number of metastatic sites (1 vs ≥1, HR: 2.360 vs 4.351) were the independent prognostic factors for PFS and OS (P<0.05). Conclusions: The efficacy of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma is similar to reports at home and abroad. The patients with renal clear cell carcinoma, time from diagnosis to treatment> 1 year, and only one metastatic site would get better PFS and OS.