Diane-35 and Metformin Induce Autophagy and Apoptosis in Polycystic Ovary Syndrome Women with Early-Stage Endometrial Carcinoma

Objective: Women with polycystic ovary syndrome (PCOS) are at increased risk ofendometrial carcinoma (EC). Previous studies indicated that the combined therapy of Diane-35 and metformin significantly suppresses disease progression in PCOS patients with early EC; however, the mechanisms remain unclear. Methods: An established murine model of PCOS with early EC, clinical specimens, and human EC cells was used in this study. The levels of protein and mRNA were measured with Western blotting and RT-PCR, respectively. Cell proliferation was determined with MTT, colony formation, and flow cytometry. Proteins were analyzed with immunofluorescence and immunohistochemistry. Results: Diane-35 and metformin significantly inhibited proliferative activity and promoted apoptosis in EC cells. Additionally, cell autophagy was induced by the combined therapy. Quantitive PCR revealed that Diane-35 and metformin decreased androgen receptor (AR) expression but elevated GLUT4 expression. AR was found to repress GLUT4 expression by binding to the promoter of GLUT4. Moreover, the combined treatment mediated the onset of cellular autophagy by regulating the mTORC pathway via the suppression of IGF-1 and inhibited the development of EC by the activation of the PI3K/mTORC pathway. Conclusion: The results and previous clinical evidence support the use of Diane-35 and metformin combination therapy for patients with PCOS and early EC.

Effect of stroke etiology on endovascular thrombectomy with or without intravenous alteplase: a subgroup analysis of DIRECT-MT

BackgroundStroke etiology might influence the clinical outcomes in patients with large vessel occlusion receiving endovascular treatment (EVT) with or without thrombolysis.ObjectiveTo examine whether stroke etiology resulted in different efficacy and safety in patients treated with EVT-alone or EVT preceded by intravenous alteplase (combined therapy).MethodsWe assessed the efficacy and safety of treatment strategy based on prespecified stroke etiology, cardioembolism (CE), large-artery atherosclerosis (LAA), and undetermined cause (UC) for patients enrolled in the DIRECT-MT trial. The primary outcome was the modified Rankin Scale (mRS) score at 90 days. Multivariate ordinal logistic regression analysis was used to calculate the adjusted common OR for a shift of better mRS score for EVT-alone versus combined therapy. A term was entered to test for interaction.ResultsIn this study, 656 patients were grouped into three prespecified stroke etiologic subgroups. The adjusted common ORs for improvement in the 90-day ordinal mRS score with EVT-alone were 1.2 (95% CI 0.8 to 1.8) for CE, 1.6 (95% CI 0.8 to 3.3) for LAA, and 0.8 (95% CI 0.5 to 1.3) for UC. Compared with CE, EVT-alone was more likely to result in an mRS score of 0–1 (pinteraction=0.047) and extended Thrombolysis in Cerebral Infarction ≥2b (pinteraction=0.041) in the LAA group. The differences in mortality and symptomatic intracranial hemorrhage within 90 days were not significant between the subgroups (p＞0.05).ConclusionsThe results did not support the hypothesis that a specific treatment strategy based on stroke etiology should be used for patients with large vessel occlusion (NCT03469206).

Effect of Neoadjuvant Iodine-125 Brachytherapy Upon Resection of Glioma

Background: A more extensive surgical resection of glioma contributes to improved overall survival (OS) and progression-free survival (PFS). However, some of the patients lost the chance of surgical resection when the tumor involves critical structures. Purpose: The present study aimed to assess the feasibility of neoadjuvant 125I brachytherapy followed by total gross resection for initially inoperable glioma.Methods:Six patients diagnosed with inoperable glioma due to invasion of eloquent areas, bi-hemispheric diffusion, or large tumor volume received 125I brachytherapy. Surgical resection was performed when the tumor shrank, allowing a safe resection, assessed by the neurosurgeons. Patients were followed up after surgery.Results:Tumor shrinkage after adjuvant 125I brachytherapy enabled a total gross resection of all six patients. Four patients were still alive at the last follow-up, with the longest survival time of more than 50 months, two of which returned to a normal life with the KPS of 100. Another two patients got a neurological injury with the KPS of 80 and 50, respectively. One patient with grade Ⅱ glioma died 34 months, and another patient with grade Ⅳ glioma died 40 months later after the combined therapy.Conclusions: In the present study, the results demonstrated that 125I brachytherapy enabled a complete resection of patients with initially unresectable gliomas. 125I brachytherapy may offer a proper neoadjuvant therapy method for glioma.

Efficacy of Combined Therapy with Nitroimidazole Drugs and Broad-Spectrum Antibiotics on Intra-Abdominal Infection: A 10 Years Real-World Cohort Study

Background: Abdominal infection still has a high mortality rate, and whether the combination of nitroimidazoles against obligate anaerobe could improve the outcome of abdominal infection remains controversial. Objective: This study aimed at exploring the clinical efficacy of broad-spectrum antibiotics combined with nitroimidazoles in the treatment of abdominal infection. Methods: Clinical data of patients with abdominal infection who received broad-spectrum antibiotics alone (BSA) or broad-spectrum antibiotics in combination with nitroimidazole (NCBSA) at a single center from June 2010 to May 2020 were retrospectively reviewed. One-to-one propensity score matching (PSM) was performed to adjust the potential differences in age, gender, APACHE II score and SOFA score of the two groups. Clinical effective rate, hospitalization days and total hospitalization costs were compared between the two groups. Meanwhile, subgroup efficacy was analyzed according to disease severity (APACH II score) and whether abdominal surgery was performed. Result: A total of 149 propensity score-matched case pairs were included in this study. There was no statistical difference in clinical effective rates between the two groups (P = 0.236). The patients in BSA group had shorter hospital stays (18d vs 27d, P = 0.001) and lower hospitalization costs (85185.7 yuan vs 187898.3 yuan, P < 0.001). However, the body temperature and PCT in patients in NCBSA group were higher than those in BSA group (P = 0.007 and P = 0.045, respectively), and CRP and WBC values in NCBSA group also were higher, but there were no significant differences between the two groups (P = 0.105 and P = 0.170, respectively). And more patients (92 vs 38) in NCBSA group underwent abdominal surgery, which indicated the infection and clinical conditons in NCBSA group were probably more severe. Subgroup analysis showed that the severity of the disease and whether the patient suffered postoperative co-infection did not affect the therapeutic effect of the two groups (P > 0.05). Conclusion: The clinical efficacy of broad-spectrum antibiotics combined with nitroimidazoles for abdominal infection was similar to that of broad-spectrum antibiotics alone, and whether the combination of nitroimidazoles in these conditions still needs more lcinical evidence.

Multidisciplinary treatment of advanced or recurrent solid pseudopapillary neoplasm of the pancreas: three case reports

Background Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor that predominantly affects young females. Prognosis is excellent; however, 10–15% of patients show metastasis at the time of surgery or develop tumor recurrence after pancreatectomy. Case presentation We reviewed the clinical course of three patients with advanced or recurrent SPN and subsequently underwent multidisciplinary treatment at our institution between 2002 and 2019. The primary tumor was resected in all three patients, and metastases were also resected if indicated. Intensive combined therapy, including re-resection, chemotherapy, ablation, arterial chemoembolization, and radiation therapy, allowed all patients to survive for a long time. The literature review showed that resection seems to be more effective than other treatments for metastatic SPN. Conclusions Multidisciplinary treatment, including resection, may improve the prognosis of patients with SPN with recurrence or metastasis.

Combined Antitumor Therapy Using In Situ Injectable Hydrogels Formulated with Albumin Nanoparticles Containing Indocyanine Green, Chlorin e6, and Perfluorocarbon in Hypoxic Tumors

Combined therapy using photothermal and photodynamic treatments together with chemotherapeutic agents is considered one of the most synergistic treatment protocols to ablate hypoxic tumors. Herein, we sought to fabricate an in situ-injectable PEG hydrogel system having such multifunctional effects. This PEG hydrogel was prepared with (i) nabTM-technique-based paclitaxel (PTX)-bound albumin nanoparticles with chlorin-e6 (Ce6)-conjugated bovine serum albumin (BSA-Ce6) and indocyanine green (ICG), named ICG/PTX/BSA-Ce6-NPs (~175 nm), and (ii) an albumin-stabilized perfluorocarbon (PFC) nano-emulsion (BSA-PFC-NEs; ~320 nm). This multifunctional PEG hydrogel induced moderate and severe hyperthermia (41−42 °C and >48 °C, respectively) at the target site under two different 808 nm laser irradiation protocols, and also induced efficient singlet oxygen (1O2) generation under 660 nm laser irradiation supplemented by oxygen produced by ultrasound-triggered PFC. Due to such multifunctionality, our PEG hydrogel formula displayed significantly enhanced killing of three-dimensional 4T1 cell spheroids and also suppressed the growth of xenografted 4T1 cell tumors in mice (tumor volume: 47.7 ± 11.6 and 63.4 ± 13.0 mm3 for photothermal and photodynamic treatment, respectively, vs. PBS group (805.9 ± 138.5 mm3), presumably based on sufficient generation of moderate heat as well as 1O2/O2 even under hypoxic conditions. Our PEG hydrogel formula also showed excellent hyperthermal efficacy (>50 °C), ablating the 4T1 tumors when the irradiation duration was extended and output intensity was increased. We expect that our multifunctional PEG hydrogel formula will become a prototype for ablation of otherwise poorly responsive hypoxic tumors.

NUT midline carcinoma as a primary lung tumor treated with anlotinib combined with palliative radiotherapy: a case report

Background NUT (nuclear protein in testis) midline carcinoma (NMC) is a rapidly progressive tumor arising from midline structures. Recent cases have reported that the poor prognosis with a median survival of 6.7 months and a 2 years overall survival of 19% due to limited treatment. Based on the effect of arotinib on inhibiting tumor growth and angiogenesis. We present one patient case treated with anlotinib and radiotherapy. Case presentation Here, we describe a 33-year old patient who complained of cough and chest pain and was diagnosed as a pulmonary NMC through CT scan, FISH and immunohistochemistry. In addition, we initially demonstrated that anlotinib combined with palliative radiotherapy could significantly prevent the tumor growth in a pulmonary NMC. Conclusion The report indicated that anlotinib combined with palliative radiotherapy could inhibit the tumor progression in a pulmonary NMC, which may provide a combined therapy to pulmonary NMC in the future.

Drug Repurposing of Asparaginase and Vitamin C Targeting Glutamine Synthetase Improves Anticancer Effect in Metastatic Castration-resistant Prostate Cancer

Background: Although in North America or Europe early dignosis of prostate cancer could sucessfully improves the therapeutic outcome. However, about 70-80% of patients still suffer from metastatic castration-resistant prostate cancer (mCRPC), because of the disproportionate medical care in China. Lutetium-177 (Lu-177) or Radium-223 (Ra-223) has been suggested as the most effective therapy for mCRPC. Unfortunately, they are either not been approved in a few countries or too expensive for patients with the financial issue. Drug repurposing has been recognized as a cost-effective and relatively low-risk alternative, gains a lot interesting recently. In this study, we explored the combined treatment with asparaginase (ASNase) and/or vitamin Cas an alternative therapeutic option for mCRPC management.Methods: Prostate cancer cell lines PC3 and DU145 were used to observe the therapeutic effect of ASNase and/or vitamin C on mCRPC in vitro and in vivo. Change of cell proliferation, cell death as well as expression of glutamine synthetase eunder different treatment conditions were detected to analyzed anticancer effect of combined therapy with ASNase and vitamin C on mCRPC. Intracellular oxidation was also observed with NADPH and NADP+ assay. Male BALB/c nude mice bearing prostate carcinoma xenografts (PC3 or DU145) were used to assess treatment response to vitamin C with or without ASNase through tumor growth, small animal PET/CT scans as well as Immunohistochemistry in vivo.Results: Our in vitro studies demonstrate that ASNase synergizes with vitamin C targeting expression of glutamine synthetase enhances redox imbalance and induces anticancer effect in mCRPC cells through regulation the glutamine synthetase (GS) expression. In vivo, combination of ASnase and vitamin C could provide a significant better therapeutic outcome in comparison with controls or single treated mice. 18F-FDG PET imaging illustrated that the treatment with combined therapy could significantly reduce the 18F-FDG uptake in tumor.Conclusions: In this current study, we suggest that ASNase combined with vitamin C could be as a cost-effective strategy to manage mCRPC.18F-FDG PET/CT imaging could indicate the therapeutic response of treatment for mCRPC.

THE USE OF IONTOPHORESIS WITH HYALURONIC ACID ASSOCIATED WITH GOLD NANOPARTICLES ACCELERATES WOUND HEALING IN RATS

This study aimed to investigate the effects of iontophoresis with HA associated to GNPs solution in an epithelial lesion model. Fifty Wistar rats (n=10/group) were randomly assigned to the following groups: epithelial lesion (EL); (EL+MIC); (EL+MIC+HA); (EL+MIC+GNPs); (EL+MIC+HA-GNPs). The animals induced to an epithelial lesion and treatment started 24 hours after injury with microcurrents (300µA) containing gel with HA (0.9%) and/or GNPs (30mg/Kg) in the electrodes (1mL) for seven days. The animals were sacrificed 12 hours after the last treatment application. Results demonstrated a reduction in the levels of pro-inflammatory cytokines (IFNϒ, IL-1β, TNFα, IL6) in the group in which the therapies were combined; an increase in the levels of anti-inflammatory cytokines (IL-4, IL-10) and growth factors (FGF, TGFβ) in EL+MIC+HA and EL+MIC+HA-GNPs groups. As for dichlorofluorescein (DCF) and nitrite levels, decreased in the combined therapy group when compared to the control group, as well as the oxidative damage (carbonyl and sulfhydryl). In antioxidant defense, there was an increase in glutathione (GSH) and a decrease in superoxide dismutase (SOD) in the combination therapy group. Histological analysis showed a reduction in the inflammatory infiltrate in groups treated with MIC and in the combination therapy group. An increase in contraction of the wound area was obtained in all treated groups when compared to the control group, proving that the proposed therapies are effective in the process of epithelial healing. The results of this study demonstrated that the associated therapies favor the tissue repair process more significantly compared to the isolated therapies.