Treatment of metastatic hormone-sensitive prostate cancer: from doublet therapy to triplet therapy.

For metastatic prostate cancer, androgen deprivation therapy (ADT) is the key strategy to control the disease. However, after 18-24 months of treatment, most patients will progress from metastatic hormone-sensitive prostate cancer (mHSPC) to metastatic castration-resistant prostate cancer (mCRPC) even with ADT. Once patients enter into mCRPC, they face with significant declines in quality of life and a dramatically reduced survival period. Thus, doublet therapy, which combines ADT with new hormone therapy (NHT) or ADT with docetaxel chemotherapy, substitutes ADT alone and has become the "gold standard" for the treatment of mHSPC. In recent years, triplet therapy, which combines ADT with NHT and docetaxel chemotherapy, has also achieved impressive effects in mHSPC. This article provides a comprehensive review of the recent applications of the triplet therapy in the field of mHSPC.

GDF11 Improves Ischemia-Reperfusion-Induced Acute Kidney Injury via Regulating Macrophage M1/M2 Polarization.

INTRODUCTION: Acute kidney injury (AKI) is a clinical emergency caused by the rapid decline of renal function caused by various etiologies. Growth differentiation factor 11 (GDF11) can promote renal tubular regeneration and improve kidney function in AKI, but the specific mechanism remains unclear. Herein, we investigated the effect and mechanisms of GDF11 in ameliorating AKI induced by ischemia-reperfusion (I/R). METHODS: An animal model of AKI was established by I/R method, and the changes of serum urea nitrogen and creatinine were measured to evaluate the AKI. Enzyme-linked immunosorbent assay (ELISA) was used to measure cytokines, malondialdehyde, superoxide dismutase, nitric oxide synthase, and arginase 1 levels. Flow cytometry was used to count the M1/M2 macrophages. IHC, WB, and q-PCR experiments were used to evaluate the expression of GDF11. RESULTS: The changes in serum levels of urea nitrogen and creatinine after I/R suggest that an animal model of AKI induced by I/R was successfully established. AKI caused by I/R significantly changed the M1/M2 macrophage polarization balance, with an increase in M2 being significantly higher than M1 as well as increased oxidative stress. Treatment with GDF11 after I/R significantly increased the differentiation of M2 cells and inhibited the differentiation of M1 macrophages, as well as decreased oxidative stress. CONCLUSION: GDF11 can promote the repair of AKI caused by I/R by regulating the balance of M1/M2 polarization in macrophages and oxidative stress.

Single-port nipple-sparing subcutaneous mastectomy with immediate prosthetic breast reconstruction for breast cancer.

INTRODUCTION: This study compares the perioperative results, aesthetic outcome and oncologic safety of single-port insufflation endoscopic nipple-sparing subcutaneous mastectomy combined with immediate reconstruction using prosthesis implantation (SIE-NSM-IRPI) with those of conventional open-nipple and areola-sparing subcutaneous mastectomy combined with immediate reconstruction using prosthesis implantation (C-NSM-IRPI). METHODS: In this retrospective cohort study, 64 early-stage breast cancer patients were divided into SIE-NSM-IRPI (n = 38) and C-NSM-IRPI (n = 26) groups. Perioperative results (operation time, intraoperative blood loss, incision length, drainage duration, and recent complications) were then compared between the two groups. Differences in satisfaction with the breasts, psychosocial well-being, physical well-being (chest) and sexual well-being were analyzed according to the BREAST-Q scale, and survival outcomes were also compared. RESULTS: The median follow-up time was 51.5 months. The incision length of SIE-NSM-IRPI was shorter than that of C-NSM-IRPI (P < 0.001). SIE-NSM-IRPI achieved the same detection rate and median number of sentinel lymph nodes as C-NSM-IRPI (3.00vs. 4.00, P = 0.780). The incidence of prosthesis removal due to infection or prosthesis exposure in the SIE-NSM-IRPI group was lower than that in the C-NSM-IRPI group (P = 0.015). Satisfaction with breasts (82.00vs.59.00, P < 0.001), psychosocial well-being (93.00vs.77.00, P = 0.001) and physical well-being (chest) (89.00vs.82.00, P < 0.001) scores were higher in the SIE-NSM-IRPI group. There were no significant differences between the two groups in disease-free survival (hazard ratio = 0.829, 95% confidence interval = 0.182-3.779) and overall survival (hazard ratio = 1.919, 95% confidence interval = 0.169-21.842). CONCLUSION: In this selected cohort of patients with early breast cancer, SIE-NSM-IRPI was comparable to C-NSM-IRPI, considering oncologic safety and detection of sentinel lymph nodes. It had a lower incidence of prosthesis removal, shorter incision length, and was associated with better patient satisfaction with the breasts. More random clinical trials of this novel approach in a larger cohort of Chinese patients with an extended follow-up period are needed in the future.

Complications after radiofrequency ablation of hyperparathyroidism secondary to chronic kidney disease.

OBJECTIVE: To study the complications of ultrasound-guided radiofrequency ablation (RFA) in chronic kidney disease (CKD) patients undergoing renal replacement therapy with secondary hyperparathyroidism (SHPT). METHODS: This retrospective study reviewed the clinical data, including general information, examination results, treatment times, time interval, and postoperative complications, of 103 SHPT patients who received ultrasound-guided RFA treatment from July 2017 to January 2021. RESULTS: Of 103 patients, 52 required two sessions of RFA within a month. The incidence of recurrent laryngeal nerve injury at the second treatment was significantly higher than that at the first treatment (first session vs. second session, 5.77% vs. 21.15%; p = .021). Of all the enrolled 103 patients, 27 suffered complications after the first session of RFA. When we separated patients into complications group and non-complication group, we detected more ablated nodules in the complications group (Z = -2.222; p = .0026). Subgroup analysis further showed that the patients in the severe hypocalcemia group were younger (p = .005), had more ablated nodules (p = .003) and higher blood phosphorus (p = .012) and alkaline phosphatase (ALP) levels (p = .002). Univariate analysis showed that age, serum phosphorus, ALP, and number of ablated nodules were associated with a higher risk of severe hypocalcemia after the first session of RFA. CONCLUSIONS: An interval of more than 1 month between two treatments may help to avoid recurrent laryngeal nerve injury. Age, serum phosphorus, ALP, and number of ablated nodules were associated with a higher risk of severe hypocalcemia after the first session of RFA.

Design, Synthesis, and Biological Activity of Chalcone Analogs Containing 4-Phenylquinolin and Benzohydrazide.

A series of chalcone derivatives (3a-3m) containing 4-phenylquinoline and benzohydrazide were designed and synthesized, and their anti-inflammatory, analgesic, and antidepressant activities were evaluated. Using the classic antidepressant model, except for compounds 3a and 3d, 11 compounds all showed certain antidepressant activity at a dose of 100 mg/kg, among which compounds 3f, 3h, and 3m showed good antidepressant activity (inhibition rate, respectively 63.0 %, 73.2 %, and 76.4 %), which was equivalent to the positive control fluoxetine (inhibition rate of 70.0 %). Secondly, the inhibitory activity of these compounds on mouse MAOA was evaluated. At 10 mM, compounds 3f and 3j showed a certain selective inhibitory effect on mouse MAOA , while compounds 3b, 3d, 3g, 3i, and 3m had a good inhibitory effect on mouse MAOA (inhibition rate is 42.3-71.4 %). The mouse ear edema model was used to evaluate the anti-inflammatory activity of compounds 3a-3m. At 30 mg/kg, compounds 3b, 3c, 3e, 3f, 3g, and 3m showed certain anti-inflammatory effects (inhibition rate of 51.5-99.9 %), which was equivalent to the positive control indomethacin (inhibition rate of 69.7 %). Results of the acetic acid-induced abdominal writhing test showed that, at 30 mg/kg, excepted for compounds 3a, 3b and 3d, all the other 10 compounds can show certain analgesic activity (inhibition rate 67-99.9 %). The use of Auto dock Vina (simina) to simulate molecular target docking shows that the development of quinoline and benzohydrazide groups is of great significance to MAOA inhibitors.

Multilevel resistive random access memory achieved by MoO3/Hf/MoO3stack and its application in tunable high-pass filter.

In this work, the multilevel resistive random access memories (RRAMs) have been achieved by using the structure of Pt/MoO3/Hf/MoO3/Pt with four stable resistance states. The devices show good retention property of each state (>104s) and large memory window (>104). The simulation and experimental study reveal that the resistive switching mechanism is ascribed to combination of the conductive filament in the stack of MoO3/Hf next to the top electrode and redox reaction at the interface of Hf/MoO3next to bottom electrode. The fitting results of current-voltage characteristics under low sweep voltage indicate that the conduction of HRSs is dominated by the Poole-Frenkel emission and that of LRS is governed by the Ohmic conduction. Based on the RRAM, the tunable high-pass filter (HPF) with configurable filtering characteristics has been realized. The gain-frequency characteristics of the programmable HPF show that the filter has high resolution and wide programming range, demonstrating the viability of the multilevel RRAMs for future spiking neural network and shrinking the programmable filters with low power consumption.

Autophagy inhibition via Becn1 downregulation improves the mesenchymal stem cells antifibrotic potential in experimental liver fibrosis.

Liver fibrosis (LF) is the result of a vicious cycle between inflammation-induced chronic hepatocyte injury and persistent activation of hepatic stellate cells (HSCs). Mesenchymal stem cell (MSC)-based therapy may represent a potential remedy for treatment of LF. However, the fate of transplanted MSCs in LF remains largely unknown. In the present study, the fate and antifibrotic effect of MSCs were explored in a LF model induced by CCl4 in mouse. Additionally, MSCs were stimulated in vitro with LF-associated factors, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor-ß1 (TGF-ß1), to mimic the LF microenvironment. We unveiled that MSCs exhibited autophagy in response to the LF microenvironment through Becn1 upregulation both in vivo and in vitro. However, autophagy suppression induced by Becn1 knockdown in MSCs resulted in enhanced antifibrotic effects on LF. The improved antifibrotic potential of MSCs may be attributable to their inhibitory effects on T lymphocyte infiltration, HSCs proliferation, as well as production of TNF-α, IFN-γ, and TGF-ß1, which may be partially mediated by elevated paracrine secretion of PTGS2/PGE2 . Thus, autophagy manipulation in MSCs may be a novel strategy to promote their antifibrotic efficacy.

Inhibition of the RhoA/Rho-associated, coiled-coil-containing protein kinase-1 pathway is involved in the therapeutic effects of simvastatin on pulmonary arterial hypertension.

BACKGROUND: Recent research has shown that statins improve pulmonary arterial hypertension (PAH), but their mechanisms of action are not fully understood. This study aimed to investigate the role of RhoA/ROCK1 regulation in the therapeutic effects of simvastatin on PAH. METHODS: For in vivo experiments, rats (N = 40) were randomly assigned to four groups: control, simvastatin, monocrotaline (MCT), and MCT + simvastatin. The MCT group and MCT + simvastatin groups received proline dithiocarbamate (50 mg/kg, i.p.) on the first day of the study. The MCT + simvastatin group received simvastatin (2 mg/kg) daily for 4 weeks, after which pulmonary arterial pressure was measured by right heart catheterization. The protein and mRNA levels of Rho and ROCK1 were measured by immunohistochemistry, Western blot, and PCR. For in vitro experiments, human pulmonary endothelial cells were divided into seven groups: control, simvastatin, monocrotaline pyrrole (MCTP), MCTP + simvastatin, MCTP + simvastatin + mevalonate, MCTP + simvastatin + farnesyl pyrophosphate (FPP), and MCTP + simvastatin + FPP + geranylgeranyl pyrophosphate (GGPP). After 72 h exposed to the drugs, the protein and mRNA levels of RhoA and ROCK1 were measured by Western blot and PCR. RESULTS: The MCT group showed increased mean pulmonary arterial pressure, marked vascular remodeling, and increased protein and mRNA levels of RhoA and ROCK1 compared to the other groups (P < 0.05). In vitro, the MCTP group showed a marked proliferation of vascular endothelial cells, as well as increased protein and mRNA levels of RhoA and ROCK1 compared to the MCTP + simvastatin group. The MCTP + simvastatin + mevalonate group, MCTP + simvastatin+ FPP group, and MCTP + simvastatin + FPP + GGPP group showed increased mRNA levels of RhoA and ROCK1, as well as increased protein levels of RhoA, compared to the MCTP + simvastatin group. CONCLUSIONS: Simvastatin improved vascular remodeling and inhibited the development of PAH. The effects of simvastatin were mediated by inhibition of RhoA/ROCK1. Simvastatin decreased RhoA/ROCK1 overexpression by inhibition of mevalonate, FPP, and GGPP synthesis.

[Establishing Glioma-associated Oncogene Homolog 1 Genetic Lineage-tracing Mice for Studies on Hepatic Fibrosis].

OBJECTIVE: To establish Gli1-CreERt2; tdTomato genetic lineage-tracing mice for studies on hepatic fibrosis. METHODS: Offspring of ROSA26 td Tomato (tdTomato) mice and Gli1-CreERt2 mice (Gli1 mice) were obtained, with Gli1-CreERt2; tdTomato genotype being identified by PCR. The mice model of hepatic fibrosis was induced with CCl4. Their liver samples were taken. The formalin-fixed and paraffin-embedded samples were prepared for HE staining and Masson staining. The expression of tdTomato was observed under immunofluorescent microscope. RESULTS: An ideal number of Gli1-CreERt2; tdTomato genetic lineage-tracing mice were harvested. The differences in fertility between the parental and the offspring mice were not significant (P>0.05). Pseudolobular formation occurred in the CCl4-induced hepatic fibrosis model mice. Enhanced red fluoresce was observed in the model mice. CONCLUSION: Gli1-CreERt2; tdTomato genetic lineage-tracing mice can be used to monitor the cell source of fibrous tissues, its transition as well as the underlying mechanism of pathogenesis of hepatic fibrosis.

Inhibition of lectin-like oxidized low-density lipoprotein receptor-1 reduces cardiac fibroblast proliferation by suppressing GATA Binding Protein 4.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and GATA Binding Protein 4 (GATA4) are important for the growth of cardiac fibroblasts (CFs). When deregulated, LOX-1 and GATA4 can cause cardiac remodeling. In the present study, we found novel evidence that GATA4 was required for the LOX-1 regulation of CF proliferation. The inhibition of LOX-1 by RNA interference LOX-1 lentivirus resulted in the loss of PI3K/Akt activation and GATA4 protein expression. The overexpression of LOX-1 by lentivirus rescued CF proliferation, PI3K/Akt activation, and GATA4 protein expression. Moreover, GATA4 overexpression enhanced CF proliferation with LOX-1 inhibition. We also found that the inhibition of PI3K/Akt activation by LY294002, a PI3K inhibitor, reduced cell proliferation and protein level of GATA4. In summary, GATA4 may play an important role in the LOX-1 and PI3K/Akt regulation of CF proliferation.

Short linear shadows connecting pulmonary segmental arteries to oblique fissures in volumetric thin-section CT images: comparing CT, micro-CT and histopathology.

OBJECTIVES: To retrospectively evaluate short linear shadows connecting pulmonary segmental arteries to oblique fissures in thin-section CT images and determine their anatomical basis. METHODS: CT scanning was performed on 108 patients and 11 lung specimens with no lung diseases around the oblique fissures or hila. Two radiologists evaluated the imaging. The parameters included length, thickness of short linear shadows, pulmonary segmental artery variations, and traction interlobar fissures, etc. RESULTS: The short linear shadows were not related to sex, age, or smoking history. The lengths of the short linear shadows were generally within 10 mm. The thicknesses of the short linear shadows ranged from 1 to 2 mm. Of the patients, 26.9 % showed pulmonary segmental artery variations; 66.7 % of short linear shadows pulled oblique fissures. In three-dimensional images, the short linear shadows appeared as arc planes, with one side edge connected to the oblique fissure, one side edge connected to a pulmonary segmental artery. On the tissue slices, the short linear shadow exhibited a band structure composed of connective tissues, small blood vessels, and small lymphatic vessels. CONCLUSIONS: Short linear shadows are a type of normal intrapulmonary membranes and can maintain the integrity of the oblique fissures and hilar structure. KEY POINTS: • Volumetric thin-section CT scanning is commonly used to study lung anatomy. • Short linear shadows are a common intrapulmonary structure in thin-section CT. • Short linear shadows correlate with band structures on the correlative tissue slices.

Increased Plasma Levels of Heme Oxygenase-1 in Human Brucellosis.

BACKGROUND: Brucellosis is associated with inflammation and the oxidative stress response. Heme oxygenase-1 (HO-1) is a cytoprotective stress-responsive enzyme that has anti-inflammatory and anti-oxidant effects. Nevertheless, the role of HO-1 in human brucellosis has not yet been studied. The aim of this study was to examine the plasma levels of HO-1 in patients with brucellosis and to evaluate the ability of plasma HO-1 levels as an auxiliary diagnosis, a severity predictor, and a monitor for brucellosis treatments. METHODS: A total of 75 patients with brucellosis were divided into the acute, subacute, chronic active, and chronic stable groups. An additional 20 volunteers were included as the healthy control group. The plasma HO-1 levels and other laboratory parameters were measured in all groups. Furthermore, the plasma levels of HO-1 in the acute group were compared before and after treatment. RESULTS: The plasma HO-1 levels were considerably increased in the acute (4.97 ± 3.55), subacute (4.98 ± 3.23), and chronic active groups (4.43 ± 3.00) with brucellosis compared to the healthy control group (1.03 ± 0.63) (p < 0.01). In the acute group, the plasma HO-1 levels in the post-treatment group (2.33 ± 2.39) were significantly reduced compared to the pre-treatment group (4.97 ± 3.55) (p < 0.01). On the other hand, the plasma HO-1 levels were higher in the chronic active group (4.43 ± 3.00) than the chronic stable group (2.74 ± 2.23) (p < 0.05). However, the plasma HO-1 levels in the chronic stable group (2.74 ± 2.23) remained higher than the levels in the healthy control group (1.03 ± 0.63) (p < 0.05). The HO-1 levels were positively correlated with the C-reactive protein (CRP) levels in patients with brucellosis (r = 0.707, p < 0.01). CONCLUSIONS: The plasma HO-1 levels can reflect patients' brucellosis status and may be used as a supplementary plasma marker for diagnosing brucellosis and monitoring its treatment.

[[Urodynamic tests contribute to the choice of therapies for type-III B prostatitis].

OBJECTIVE: To analyze the parameters of urodynamic tests for patients with type-III B prostatitis and evaluate the significance of the results of urodynamic tests in the choice of therapies for this disease. METHODS: Urodynamic tests were performed for 87 type-III B prostatitis patients aged 22-45 (30.7 ± 8.5) years, who had moderate or severe lower urinary tract symptoms (LUTS) and failed to respond to routine therapy. Different treatments were administered according to the results of urodynamic tests followed by observation of the therapeutic effects. RESULTS: Urodynamic abnormalities were found in 70 of the 87 patients, bladder outlet obstruction in 28 (32.2%), detrusor overactivity in 25 (28.7%), bladder hyperesthesia in 18 (20.7%), low compliance in 10 (11.5%), detrusor-external urethral sphincter dyssynergia in 1 (1.1%), and impaired detrusor contractile function in 1 (1.1%). Treatments achieved obvious effectiveness in 26 cases (29.9%), effectiveness in 51 (58.6%), and no effectiveness in 10 (11.5%). CONCLUSION: Urodynamic tests contribute significantly to the choice of therapies for type-III B prostatitis patients with moderate or severe LUTS.

Insulin-like growth factor 1 opposes the effects of C-reactive protein on endothelial cell activation.

Emerging evidence demonstrates that high plasma C-reactive protein (CRP) levels or low plasma insulin-like growth factor 1 (IGF-1) concentrations may be separately associated with the increased risk of coronary artery disease or myocardial infarction. Interestingly, animal model studies and epidemiological investigations indicate that circulating IGF-1 and CRP levels have an inverse correlation. The present study aims to evaluate if IGF-1 can directly oppose the effects of CRP on endothelial cell (EC) activation. We found that IGF-1 rescues endothelial nitric oxide synthase activity and decreases the release of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 from ECs. We also showed that IGF-1 antagonizes the effects of CRP by activating the PI3K/Akt pathway and suppressing the JNK/c-Jun and MAPK p38/ATF2 signaling pathways, rather than inhibiting ERK1/2 activity. These findings provide evidence of the physiopathological mechanisms of endothelial activation and novel insights into the protective properties of IGF-1.

Pulmonary function differences in patients with chronic right heart failure secondary to pulmonary arterial hypertension and chronic left heart failure.

BACKGROUND: Pulmonary abnormalities are found in both chronic heart failure (CHF) and pulmonary arterial hypertension (PAH). The differences of pulmonary function in chronic left heart failure and chronic right heart failure are not fully understood. MATERIAL AND METHODS: We evaluated 120 patients with stable CHF (60 with chronic left heart failure and 60 with chronic right heart failure). All patients had pulmonary function testing, including pulmonary function testing at rest and incremental cardiopulmonary exercise testing (CPX). RESULTS: Patients with right heart failure had a significantly lower end-tidal partial pressure of CO2 (PetCO2), higher end-tidal partial pressure of O2 (PetO2) and minute ventilation/CO2 production (VE/VCO2) at rest. Patients with right heart failure had a lower peak PetCO2, and a higher peak dead space volume/tidal volume (VD/VT) ratio, peak PetO2, peak VE/VCO2, and VE/VCO2 slope during exercise. Patients with right heart failure had more changes in ∆PetCO2 and ∆VE/VCO2, from rest to exercise. CONCLUSIONS: Patients with right heart failure had worse pulmonary function at rest and exercise, which was due to severe ventilation/perfusion (V/Q) mismatching, severe ventilation inefficiency, and gas exchange abnormality.

Differences in exercise capacity in patients with chronic left heart failure and chronic right heart failure.

BACKGROUND: Exercise impairment is common in chronic left heart failure and pulmonary arterial hypertension (PAH). Exercise impairment degree is a strong predictor of clinical outcome. Our purpose was to evaluate differences in exercise capacity using cardiopulmonary exercise testing (CPX) in patients with chronic left and right heart failure, and determine which factors were related to exercise impairment. METHODS: 102 patients with class II/III New York Heart Association were involved in the study (41 with chronic left heart failure, 61 with chronic right heart failure secondary to PAH). All patients underwent CPX to evaluate exercise capacity. RESULTS: Patients with right heart failure had significantly lower peak oxygen uptake (VO2), peak VO2/kg ratio, peak oxygen uptake/heart rate (VO2/HR) ratio and increases in oxygen uptake/increase in work rate (ΔVO2/ΔWR) slope, and had higher minute ventilation/CO2 production ratio and peak dead space volume/tidal volume during exercise. In patients with left heart failure, peak VO2/HR ratio was positively correlated with ΔVO2/ΔWR slope. However, VO2 and VO2/HR ratio were positively correlated with ΔVO2/ΔWR slope in patients with right heart failure. CONCLUSIONS: Compared with left heart failure, patients with right heart failure showed worse exercise capacity resulting from worse pulmonary and cardiovascular adaptation to exercise.

A proteomic study of spike development inhibition in bread wheat.

Spike development in wheat is a complicated development process and determines the wheat propagation and survival. We report herein a proteomic study on the bread wheat mutant strain 5660M underlying spike development inhibition. A total of 121 differentially expressed proteins, which were involved in cold stress response, protein folding and assembly, cell-cycle regulation, scavenging of ROS, and the autonomous pathway were identified using MS/MS and database searching. We found that cold responsive proteins were highly expressed in the mutant in contrast to those expressed in the wild-type line. Particularly, the autonomous pathway protein FVE, which modulates flowering, was dramatically downregulated and closely related to the spike development inhibition phenotype of 5660M. A quantitative RT-PCR study demonstrated that the transcription of the FVE and other six genes in the autonomous pathway and downstream flowering regulators were all markedly downregulated. The results indicate that spike development of 5660M cannot complete the floral transition. FVE might play an important role in the spikes development of the wheat. Our results provide the theory basis for studying floral development and transition in the reproductive growth period, and further analysis of wheat yield formation.

Glycogen synthase kinase-3ß is involved in C-reactive protein-induced endothelial cell activation.

C-reactive protein (CRP) is a significant contributor to atherosclerosis and a powerful predictor of cardiovascular risk. The role of CRP in endothelial cell (EC) activation has been extensively investigated, but the underlying mechanisms have not been fully elucidated. The effect of glycogen synthase kinase-3ß (GSK-3ß) on CRP-induced EC activation was evaluated in this study. We observed that CRP decreased endothelial nitric oxide synthase (eNOS) activity during EC activation. CRP also activated GSK-3ß by dephosphorylating its Ser9 level and reducing ß-catenin protein expression in a time-dependent manner. We also found that the GSK-3ß inhibitors TDZD-8 and SB415286 partially restored eNOS activity and suppressed the release of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 from ECs. These data provide new evidence for the involvement of GSK-3ß in EC activation.

Single-port insufflation endoscopic nipple-sparing mastectomy in early breast cancer: a retrospective cohort study.

Background: Breast cancer is the most common malignancy in female patients. In recent years, more and more studies have focused on how to improve the appearance and the quality of life for patients. This study aimed to compare the oncologic safety, aesthetic results, and upper extremity function between single-port insufflation endoscopic nipple-sparing mastectomy (SIE-NSM) and conventional open mastectomy (C-OM) in early-stage breast cancer treatment. Methods: In our retrospective cohort, 285 patients with stage I and II breast cancer were categorized into the SIE-NSM group (n=71) and the C-OM group (n=214). We assessed local recurrence, distant metastasis, and upper extremity function across the two groups. The BREAST-Q scale was employed to analyze differences in aesthetic results, psychosocial well-being, and sexual health. The risk of local recurrence was evaluated using multivariable binary logistic regression, while a multivariable linear regression model gauged upper extremity function and aesthetic outcomes. Results: Local recurrence rates between the two groups were statistically similar (1/71, 1.4% for SIE-NSM vs. 2/214, 0.9% for C-OM, P=0.735), as confirmed by the multivariable binary logistic regression analysis. Neither group exhibited distant metastases. The SIE-NSM group demonstrated higher scores in satisfaction with breasts, chest wellness, psychosocial health, and sexual well-being (P<0.001). The SIE-NSM group also exhibited superior outcomes regarding chest wall/breast pain, shoulder mobility, and daily arm usage (P<0.001). No subcutaneous effusion was reported in the SIE-NSM group, whereas the C-OM group had a 10.7% incidence rate (P=0.004). Conclusions: SIE-NSM offers comparable oncologic safety to C-OM but provides enhanced satisfaction regarding breast appearance, physical comfort, psychosocial health, sexual health, and improved upper extremity functionality. Consequently, this innovative approach is a suitable surgical alternative for treating early-stage breast cancer.

Inhibition of hepatic glycogen synthesis by hyperhomocysteinemia mediated by TRB3.

Recently, epidemiological and experimental studies have linked hyperhomocysteinemia (HHcy) to insulin resistance. However, whether HHcy impairs glucose homeostasis by affecting glycogenesis in the liver is not clear. In the present study, we investigated the effect of HHcy on hepatic glycogen synthesis. Hyperhomocysteinemia was induced in mice by drinking water containing two percent methionine. Mice with HHcy showed an increase in the phosphorylation of glycogen synthase and a significant decrease in hepatic glycogen content and the rate of glycogen synthesis. The expression of TRB3 (tribbles-related protein 3) was up-regulated in the liver of mice with HHcy, concomitantly with the dephosphorylation of glycogen synthase kinase-3ß and Akt. The knockdown of TRB3 by short hairpin RNA suppressed the dephosphorylation of these two kinases. Homocysteine induced an increase in the levels of hepatic cAMP and cAMP response element-binding protein phosphorylation, which in turn up-regulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α and TRB3. The inhibition of PPAR-α by its inhibitor, MK886, or knockdown of PPAR-α by small interfering RNA significantly inhibited the expression of TRB3 induced by homocysteine. The current study demonstrates that HHcy impairs hepatic glycogen synthesis by inducing the expression of TRB3. These results provide a novel explanation for the development and progression of insulin resistance in HHcy.