Discovery of novel tetrahydrobenzothiophene derivatives as MSBA inhibitors for antimicrobial agents.

The incidence of infections caused by drug-resistant bacteria has been one of the most serious health threats in the past and is substantially increasing in an alarming rate. Therefore, the development of new antimicrobial agents to combat bacterial resistance effectively is urgent. This study focused on the design and synthesis of 40 novel tetrahydrobenzothiophene amide/sulfonamide derivatives and their antibacterial activities were evaluated. Compounds 2p, 6p, and 6 s exhibited significant inhibitory effects on the growth of bacteria. To assess their safety, the cytotoxicity of the compounds was assessed using human normal liver cells, revealing that compound 6p has lower cytotoxicity. A mouse wound healing experiment demonstrated that compound 6p effectively improved wound infection induced by trauma and accelerated the healing process. Compound 6p holds promise as a potential therapeutic agent for combating bacterial infections.

Percutaneous Intra-arterial Hyaluronidase Injection for Hyaluronic Acid Filler Embolism Threatening Skin Barrier Integrity: Implementation of a Stepwise Treatment Protocol.

BACKGROUND: Hyaluronic acid (HA) filler-induced vascular embolism that threatens skin integrity is an urgent situation. There is increasing evidence that percutaneous intra-arterial hyaluronidase injection is an effective therapeutic technique for it. However, until now, there is a lack of a unifying protocol about the technique. OBJECTIVES: This study aims to provide a conclusion of percutaneous intra-arterial hyaluronidase injection along with adjunctive measures on the treatment of occlusions precipitated by HA-based filler and develop a stepwise treatment protocol. METHODS: We searched PubMed for peer-reviewed studies, consensus statements, case series, and case reports using a variety of keywords. RESULTS: High-dose, pulsed hyaluronidase is the mainstay for the treatment of HA filler-induced embolism, but percutaneous intra-arterial hyaluronidase injection is a more effective technique. Until now, hyaluronidase is injected into three arteries percutaneously, including facial artery, supratrochlear artery, and superficial temporal artery. Furthermore, the adjunctive measures that may optimize clearance of an occlusion and/or skin barrier repair such as the use of image guidance and CGF should be considered. CONCLUSION: Vascular occlusions that threaten skin integrity are an urgent matter which requires accurate diagnosis and effective intervention. Percutaneous intra-arterial hyaluronidase injection along with adjunctive measures performed in a stepwise manner is key to an optimal outcome. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

ChlOR, a GMC family oxidoreductase that evolved independently from the actinomycete, confers resistance to amphenicol antibiotics.

Overuse of the amphenicol antibiotics chloramphenicol (CHL) and thiamphenicol (TAP) poses a great threat to ecosystem safety and human health. The strain, Nocardioides sp. LMS-CY, Nocardioides sp. QY071 and Nocardioides sp. L-11A, classified as a gram-positive actinomycete, harbours a complete CHL metabolic pathway. However, the metabolic genes (clusters) involved in the entire pathway in gram-positive actinomycetes are still limited. Here, chlORLMS , chlORQY071 and chlORL-11A completely from the actinomycete Nocardioides spp. were found to act on the C1 -OH of the CHL/TAP side chain, directly converting CHL/TAP to 4-nitrobenzaldehyde (PNBD)/4-methylsulfonyl benzaldehyde (PMBD) and transforming PNBD/PMBD into 4-nitrobenzyl alcohol (PNBM)/4-methylsulfonyl phenyl methanol (PMBM). Furthermore, oxidoreductases can transform PNBM into 4-nitrobenzoate (PNBA). The oxidoreductases ChlORLMS , ChlORQY071 and ChlORL-11A were all classified as cellobiose dehydrogenases from the glucose methanol choline (GMC) family. Based on the Swiss-Prot database, ChlORQY071 exhibited a lower identity (27.12%-35.10% similarity) with the reported oxidoreductases. Enzymatic and molecular docking analyses showed that ChlORQY071 and ChlORL-11A from the two similar genomes were remarkably more effective in metabolizing CHL than ChlORLMS . Overall, the detailed resistance mechanism of CHL/TAP by actinomycete strains isolated from soil and livestock manure will provide insights into the occurrence of CHL/TAP resistance genes in the environment, resistance risk and bioremediation of CHL/TAP-contaminated environments.

Evaluation of clinical efficacy, adverse reactions, and safety of PD-1 inhibitors combined with chemotherapy when treating advanced gastric cancer.

OBJECTIVE: This paper aimed to assess the clinical efficacy, adverse reactions, and safety of employing PD-1 inhibitors in conjunction with chemotherapy as a treatment strategy for advanced gastric cancer (GC). METHODS: Ninety patients with advanced GC from January 2020 to December 2021 were divided into the research group (n = 45) and the control group (n = 45). The control group was treated with apatinib and tigio. The study group was treated with PD-1 inhibitor combined with apatinib and tigio. The remission rate (RR), disease control rate (DCR), overall survival (OS), Eastern Oncology Collaborative Group Physical Status Assessment (ECOG-PS) score, EORTCQLQ-C30 (v3.0) score, and incidence of adverse reactions were compared between the two groups. RESULTS: The research group exhibited improved outcomes in several key metrics relative to the control group. Specifically, the RR, DCR, and OS were notably higher in the research group. Additionally, the ECOG-PS score was significantly reduced, indicating better performance. At a median follow-up of 8.7 months, the research group's functional and total health scores on the EORTC QLQ-C30 (v3.0) scale had seen significant improvement compared to their initial scores and were also superior to the control group's scores. Importantly, both groups demonstrated comparable incidence rates for adverse reactions, with no significant difference observed (P > 0.05). CONCLUSION: PD-1 inhibitor combined with chemotherapy was more effective when treating patients with advanced GC. It was more beneficial to enhance the patient's condition, promote survival time, and improve physical status and life quality. In addition, the adverse reactions could be controlled.

Genome-Wide Analysis of the Membrane Attack Complex and Perforin Genes and Their Expression Pattern under Stress in the Solanaceae.

The Membrane Attack Complex and Perforin (MACPF) proteins play a crucial role in plant development and adaptation to environmental stresses. Heretofore, few MACPF genes have been functionally identified, leaving gaps in our understanding of MACPF genes in other plants, particularly in the Solanaceae family, which includes economically and culturally significant species, such as tomato, potato, and pepper. In this study, we have identified 26 MACPF genes in three Solanaceae species and in the water lily, which serves as the base group for angiosperms. Phylogenetic analysis indicates that angiosperm MACPF genes could be categorized into three distinct groups, with another moss and spikemoss lineage-specific group, which is further supported by the examination of gene structures and domain or motif organizations. Through inter-genome collinearity analysis, it is determined that there are 12 orthologous SolMACPF gene pairs. The expansion of SolMACPF genes is primarily attributed to dispersed duplications, with purifying selection identified as the principal driving force in their evolutionary process, as indicated by the ω values. Furthermore, the analysis of expression patterns revealed that Solanaceae genes are preferentially expressed in reproductive tissues and regulated by various environmental stimuli, particularly induced by submergence. Taken together, these findings offer valuable insights into and a fresh perspective on the evolution and function of SolMACPF genes, thereby establishing a foundation for further investigations into their phenotypic and functional characteristics.

Selenium hyperaccumulator plant Cardamine enshiensis: from discovery to application.

Selenium (Se) is an essential trace element for animals and humans. Se biofortification and Se functional agriculture are emerging strategies to satisfy the needs of people who are deficient in Se. With 200 km2 of Se-excess area, Enshi is known as the "world capital of Se." Cardamine enshiensis (C. enshiensis) is a Se hyperaccumulation plant discovered in the Se mine drainage area of Enshi. It is edible and has been approved by National Health Commission of the People's Republic of China as a new source of food, and the annual output value of the Se-rich industry in Enshi City exceeds 60 billion RMB. This review will mainly focus on the discovery and mechanism underlying Se tolerance and Se hyperaccumulation in C. enshiensis and highlight its potential utilization in Se biofortification agriculture, graziery, and human health.

Efficacy of Percutaneous Superficial Temporal Arterial Hyaluronidase Injection for Hyaluronic Acid Filler-Induced Necrosis of Frontotemporal Skin and/or the Ipsilateral Scalp With Subsequent Alopecia.

BACKGROUND: Necrosis of frontotemporal skin and/or the ipsilateral scalp with subsequent alopecia after hyaluronic acid (HA) filler injection into the temple is rare complications with superficial temporal artery embolization are suspected as the major pathological mechanism. The main treatment currently is intralesional hyaluronidase (HAase) injection, but the effectiveness of percutaneous superficial temporal arterial HAase injection still lacks consensus. OBJECTIVES: To investigate the effectiveness of superficial temporal arterial HAase injection in dissolving HA filler-induced necrosis of frontotemporal skin and/or the ipsilateral scalp with subsequent alopecia. METHODS: Five recent clinical cases with necrosis of frontotemporal skin and/or the ipsilateral scalp with subsequent alopecia after HA filler injection into the temple were analyzed retrospectively. The patients underwent HAase injection via superficial temporal artery combined with adjunctive treatments, and the clinical progress was observed. RESULTS: Significant improvement was observed in terms of necrosis of frontotemporal skin and the ipsilateral scalp after treatment, and the patients were relieved of their clinical symptoms. Alopecia occurred approximately 1 to 2 weeks after HA filler injection, and the well-defined alopecia areas were formed 15 to 20 days after HAase injection. Patients were followed for 3 to 6 months. During follow-up, the skin lesions of all patients were restored to near normal appearance. Hair regrowth was observed 2 to 3 months after HAase treatment, and hair density nearly reached the normal level 3 to 4 months later. CONCLUSIONS: Percutaneous superficial temporal arterial HAase injection is an effective treatment option for HA filler-induced necrosis of frontotemporal skin and/or the ipsilateral scalp with subsequent alopecia.

Clinical Significance of Pim-1 in Human Cancers: A Meta-analysis of Association with Prognosis and Clinicopathological Characteristics.

BACKGROUND: Pim-1 is overexpressed in cancer tissues and plays a vital role in carcinogenesis. However, its clinical significance in cancers is not fully verified by meta-analysis, especially in relation to prognosis and clinicopathological features. METHODS: Four databases, PubMed, Embase, Cochrane Library, and Web of Science, were searched. Literature screening and data extraction according to the inclusion and exclusion criteria. The quality of the included literatures was evaluated using the Newcastle-Ottawa scale and the data analysis was performed using STATA and Review Manager software. RESULTS: 15 articles were finally included for meta-analysis, involving 1651 patients. Effect-size pooling analysis showed that high Pim-1 was related to poor overall survival (OS) (HR 1.68 [95% CI 1.17-2.40], P = .004) and disease-free survival (DFS) (HR 2.15 [95 %CI 1.15-4.01], P = .000). Subgroup analysis indicated that the detection techniques of Pim-1 were the main sources of heterogeneity, and 2 literatures using quantitative polymerase chain reaction (qPCR) for Pim-1mRNA had high homogeneity (I2 = .0%, P = .321) in OS. Another 13 studies that applied immunohistochemistry (IHC) for Pim-1 protein had significant heterogeneity (I2=82.2%, P = .000; I2=92%, P = .000) in OS and DFS, respectively, and further analysis demonstrated that ethnicity, sample size, and histopathological origin were considered to be the main factors affecting their heterogeneity. In addition, high Pim-1 was associated with lymph node metastasis (OR 1.40 [95% CI 1.02-1.92], P = .04), distant metastasis (OR 2.69 [95%CI 1.67-4.35], P < .0001), and clinical stage III-IV (OR .7 [95% CI .50-.96, P = .03). Sensitivity analysis suggested that the pooled results of each effect-size were stable and reliable, and there was no significant publication bias (P = .138) in all included articles. CONCLUSION: High Pim-1 can not only predict poor OS and DFS of cancer, but also help to infer the malignant clinical characteristics of tumor metastasis. Pim-1 may be a potential and promising biomarker for early diagnosis, prognostic analysis and targeted therapy of tumors.

Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long-term outcomes in COVID-19 patients.

Sustained hypercoagulability and endotheliopathy are present in convalescent COVID-19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID-19 patients were evaluated up to 16 months after recovery from COVID-19. These values were compared with a control group of healthy volunteers (n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. Elevated D-dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D-dimer 0.34 FEU µg/mL (IQR 0.28, 0.46) (p < .001) and Factor VIII 150% (IQR 171, 203) (p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) (p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) (p = 0.01) and delayed lag time 2.4 min (1.42-2.97) (p = 0.0002) versus controls. Raised vWF:Ag and ICAM-1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) (p = 0.02) and ICAM-1 54.1 ng/mL (IQR 43.8, 64.1) (p = .004) than controls. IL-6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL-6 of 1.5 pg/mL (IQR 0.6, 3.0) (p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID-19 severity and COVID-19 vaccination preceding SARS-CoV-2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID-19.

Global haemostatic tests demonstrate the absence of parameters of hypercoagulability in non-hypoxic mild COVID-19 patients: a prospective matched study.

Severe COVID-19 patients demonstrate hypercoagulability, necessitating thromboprophylaxis. However, less is known about the haemostatic profile in mild COVID-19 patients. We performed an age and gender-matched prospective study of 10 severe and 10 mild COVID-19 patients. Comprehensive coagulation profiling together with Thromboelastography and Clot Waveform Analysis were performed. FBC, PT, APTT, D-dimer, fibrinogen and CWA were repeated every 3 days for both groups and repeat TEG was performed for severe patients up till 15 days. On recruitment, severe patients had markers reflecting hypercoagulability including raised median D-dimer 1.0 µg/mL (IQR 0.6, 1.4) (p = 0.0004), fibrinogen 5.6 g/L (IQR 4.9, 6.6) (p = 0.002), Factor VIII 206% (IQR 171, 203) and vWF levels 265.5% (IQR 206, 321). Mild patients had normal values of PT, aPTT, fibrinogen and D-dimer, and slightly elevated median Factor VIII and von Willebrand factor (vWF) levels. Repeated 3-day assessments for both groups showed declining trends in D-dimer and Fibrinogen. CWA of severe COVID-19 group demonstrated hypercoagulability with an elevated median values of aPTT delta change 78.8% (IQR 69.8, 85.2) (p = 0.001), aPTT clot velocity (min1) 7.8%/s (IQR 6.7, 8.3) (p = 0.001), PT delta change 22.4% (IQR 19.4, 29.5) (p = 0.004), PT min1 7.1%/s (IQR 6.3, 9.0) (p = 0.02), PT clot acceleration (min 2) 3.6%/s2 (IQR 3.2, 4.5) (p = 0.02) and PT clot deceleration (max2) 2.9%/s2 (IQR 2.5, 3.5) (p = 0.02). TEG of severe patients reflected hypercoagulability with significant increases in the median values of CFF MA 34.6 mm (IQR 27.4,38.6) (p = 0.003), CRT Angle 78.9° (IQR 78.3, 80.0) (p = 0.0006), CRT A10 67.6 mm (IQR 65.8, 69.6) (p = 0.007) and CFF A10 32.0 mm (IQR 26.8, 34.0) (p = 0.003). Mild COVID-19 patients had absent hypercoagulability in both CWA and TEG. 2 severe patients developed thromboembolic events while none occurred in the mild COVID-19 group. Mild COVID-19 patients show absent parameters of hypercoagulability in global haemostatic tests while those with severe COVID-19 demonstrated parameters associated with hypercoagulability on the global haemostatic tests together with raised D-Dimer, fibrinogen, Factor VIII and vWF levels.

miR-30a Serves as a Tumor Suppressor for Hepatocellular Carcinoma by Downregulating ADAMTS14.

BACKGROUND: Hepatocellular carcinoma (HCC) is a very common malignancy in the world, but the effect of therapies on advanced HCC has not improved for decades. The present study aimed to investigate the role of miR-30a in the tumorigenesis of HCC. METHODS: The expression of miR-30a and ADAMTS14 in HCC tissues were determined. Luciferase reporter gene detection confirmed the correlation between miR-30a and ADAMTS14. Cell viability and apoptosis rate were examined using an MTT assay and flow cytometry. Cell migration and invasion ability were detected by a transwell assay. The protein expression of ADAMTS14, ß-catenin, GSK-3ß, and p-GSK-3ß were determined using western blotting. RESULTS: miR-30a was negatively correlated with the expression of ADAMTS14 in HCC tissues. Further research confirmed that ADAMTS14 is the direct target of miR-30a. In addition, the expression of ADAMTS14, cell viability and apoptosis were suppressed by miR-30a overexpression, while knockdown of miR-30a led to the opposite result. miR-30a also inhibits the phosphorylation of GSK-3ß and ß-catenin, without changing the total GSK-3ß level. CONCLUSIONS: miR-30a acts as a tumor suppressor in the progression of HCC and can be used as a biomarker for early prediction and diagnosis.

Efficacy of Percutaneous Intraarterial Facial/Supratrochlear Arterial Hyaluronidase Injection for Treatment of Vascular Embolism Resulting From Hyaluronic Acid Filler Cosmetic Injection.

BACKGROUND: Vascular embolism is a serious complication of hyaluronic acid (HA) filler cosmetic injection, and hyaluronidase injection has been proposed as the treatment. Until now, there has been a lack of adequate clinical evidence regarding the benefits of treatment for HA filler-induced vascular embolism by percutaneous facial or supratrochlear arterial hyaluronidase injection. OBJECTIVES: The authors sough to evaluate the efficacy of percutaneous facial or supratrochlear arterial hyaluronidase injection as a rescue treatment for HA filler-induced vascular embolism. METHODS: We included 17 patients with vascular embolism after facial HA filler injection. Intraarterial injection of 1500 units hyaluronidase was performed via facial artery for 13 cases with skin necrosis and via supratrochlear arterial for 4 cases with severe ptosis and skin necrosis but no visual impairment. Simultaneously, general symptomatic treatment and nutritional therapy were performed. RESULTS: After hyaluronidase injection, facial skin necrosis in all cases was restored and ptosis in the 4 cases was also significantly relieved. Patients were subsequently followed-up for 1 month to 1 year. The skin necrosis in 16 patients completely healed, and only 1 patient had small superficial scars. CONCLUSIONS: It is effective to alleviate skin necrosis and ptosis resulting from HA filler embolism via percutaneous facial or supratrochlear arterial hyaluronidase injection.

COVID-19 associated coagulopathy in critically ill patients: A hypercoagulable state demonstrated by parameters of haemostasis and clot waveform analysis.

Patients with COVID-19 are known to be at risk of developing both venous, arterial and microvascular thrombosis, due to an excessive immuno-thrombogenic response to the SARS-CoV-2 infection. Overlapping syndromes of COVID-19 associated coagulopathy with consumptive coagulopathy and microangiopathy can be seen in critically ill patients as well. Blood was collected from 12 Intensive Care Unit (ICU) patients with severe COVID-19 who were on either mechanical ventilation or on high flow oxygen with a PaO2/FiO2 ratio of <300 mmHg. Laboratory tests were performed for parameters of haemostasis, clot waveform analysis and anti-phospholipid antibodies. CWA parameters were raised with elevated aPTT median Min1 (clot velocity) 9.3%/s (IQR 7.1-9.9%/s), elevated PT median Min1 10.3%/s (IQR 7.1-11.1%/s), elevated aPTT median Min2 (clot acceleration) 1.5%/s2 (IQR 1.0-1.6%/s2), elevated PT median Min2 5.2%/s2 (3.6-5.7%/s2), elevated aPTT median Max2 (clot deceleration) 1.3%/s2 (IQR 0.8-1.4%/s2) elevated PT median Max2 3.8%/s2 (IQR 2.6-4.2%/s2), increased aPTT median Delta change (decreased light transmission due to increased clot formation) 87.8% (IQR 70.2-91.8%) and PT median Delta change 33.0%. This together with raised median Factor VIII levels of 262.5%, hyperfibrinogenemia (median fibrinogen levels 7.5 g/L), increased median von Willebrand factor antigen levels 320% and elevated median D-dimer levels 1.7 µg/dl support the diagnosis of COVID-19 associated coagulopathy. A lupus anticoagulant was present in 50% of patients. Our laboratory findings further support the view that severe SARS-CoV-2 infection is associated with a state of hypercoagulability.

Immune checkpoint inhibitors for the management of advanced non-small-cell lung carcinoma: a meta-analysis.

This study is a meta-analysis assessing the safety and efficacy of programmed cell death-1/cell death-ligand 1 (PD-1/PD-L1) inhibitors in order to improve their efficacy in advanced non-small-cell lung cancer. We retrieved studies of anti-PD-1/PD-L1 therapies for non-small-cell lung cancer from electronic databases; 17 clinical trials were analyzed. The pooled hazard ratios for overall and progression-free survival (PFS), and the odds ratios (ORs) for the objective response rate (ORR) and adverse effects were calculated using Review Manager 5.3. The pooled hazard ratios for overall and PFS were 0.69 and 0.74, respectively, and the pooled OR for the ORR was 1.78, implying a significant improvement in overall survival (OS), PFS, and ORR with administration of PD-1/PD-L1 inhibitors. In subgroup analysis, the ORs of the ORR were 2.48 in PD-L1 positive versus negative tumors, and 0.99 for a high dose of PD-1/PD-L1 inhibitors versus a low dose. The ORs for the occurrence of any treatment-related adverse effects and grades 3-5 treatment-related adverse effects were 0.33 and 0.30, respectively, suggesting a good safety profile. PD-1/PD-L1 immunotherapy has superior outcomes in terms of the ORR, OS, and PFS with tolerable adverse effects when compared with chemotherapy.

An Automatic Bearing Fault Diagnosis Method Based on Characteristics Frequency Ratio.

Bearing is a key component of satellite inertia actuators such as moment wheel assemblies (MWAs) and control moment gyros (CMGs), and its operating state is directly related to the performance and service life of satellites. However, because of the complexity of the vibration frequency components of satellite bearing assemblies and the small loading, normal running bearings normally present similar fault characteristics in long-term ground life experiments, which makes it difficult to judge the bearing fault status. This paper proposes an automatic fault diagnosis method for bearings based on a presented indicator called the characteristic frequency ratio. First, the vibration signals of various MWAs were picked up by the bearing vibration test. Then, the improved ensemble empirical mode decomposition (EEMD) method was introduced to demodulate the envelope of the bearing signals, and the fault characteristic frequencies of the vibration signals were acquired. Based on this, the characteristic frequency ratio for fault identification was defined, and a method for determining the threshold of fault judgment was further proposed. Finally, an automatic diagnosis process was proposed and verified by using different bearing fault data. The results show that the presented method is feasible and effective for automatic monitoring and diagnosis of bearing faults.

Isoprenylcysteine carboxylmethyltransferase regulates ovarian cancer cell response to chemotherapy and Ras activation.

Inhibition of isoprenylcysteine carboxylmethyltransferase (Icmt), which catalyzes the final step of oncoproteins' prenylation, targets growth and survival of various cancers. In this work, we systematically studied the expression, functions and molecular signaling of Icmt in ovarian cancer. We show that the upregulation of Icmt expression is a common feature in patients with epithelial ovarian cancer regardless of age and disease stage. In line with the observations in ovarian cancer patients, a panel of epithelial ovarian cancer cell lines also demonstrates the significant increase on Icmt transcript and protein levels than normal ovarian epithelial cells. In addition, ovarian cancer cell lines with higher Icmt levels are more resistant to chemotherapeutic agents. We further show that Icmt inhibition by siRNA or inhibitor cysmethynil suppresses growth and induces apoptosis in ovarian cancer cells. Importantly, Icmt inhibition significantly augments chemotherapeutic agent's efficacy in vitro and in vivo, demonstrating the translational potential of Icmt inhibition in ovarian cancer. Mechanistically, we show that Ras activation is a critical effector of Icmt in ovarian cancer cells. Using cell culturing system, mouse model and patient samples, our work is the first to demonstrate the essential roles of Icmt in ovarian cancer via Ras signaling, particularly on its response to chemotherapy. Our findings suggest that Icmt inhibition is a promising therapeutic strategy to overcome chemoresistance in ovarian cancer, in particular, those patients with high Icmt expression.

The type VI adenylyl cyclase protects cardiomyocytes from ß-adrenergic stress by a PKA/STAT3-dependent pathway.

BACKGROUND: The type VI adenylyl cyclase (AC6) is a main contributor of cAMP production in the heart. The amino acid (aa) sequence of AC6 is highly homologous to that of another major cardiac adenylyl cyclase, AC5, except for its N-terminus (AC6-N, aa 1-86). Activation of AC6, rather than AC5, produces cardioprotective effects against heart failure, while the underlying mechanism remains to be unveiled. Using an AC6-null (AC6-/-) mouse and a knockin mouse with AC6-N deletion (AC6 ΔN/ΔN), we aimed to investigate the cardioprotective mechanism of AC6 in the heart. METHODS: Western blot analysis and immunofluorescence staining were performed to determine the intracellular distribution of AC6, AC6-ΔN (a truncated AC6 lacking the first 86 amino acids), and STAT3 activation. Activities of AC6 and AC6-ΔN in the heart were assessed by cAMP assay. Apoptosis of cardiomyocytes were evaluated by the TUNEL assay and a propidium iodine-based survival assay. Fibrosis was examined by collagen staining. RESULTS: Immunofluorescence staining revealed that cardiac AC6 was mainly anchored on the sarcolemmal membranes, while AC6-ΔN was redistributed to the sarcoplasmic reticulum. AC6ΔN/ΔN and AC6-/- mice had more apoptotic myocytes and cardiac remodeling than WT mice in experimental models of isoproterenol (ISO)-induced myocardial injury. Adult cardiomyocytes isolated from AC6ΔN/ΔN or AC6-/- mice survived poorly after exposure to ISO, which produced no effect on WT cardiomyocytes under the condition tested. Importantly, ISO treatment induced cardiac STAT3 phosphorylation/activation in WT mice, but not in AC6ΔN/ΔN and AC6-/- mice. Pharmacological blockage of PKA-, Src-, or STAT3- pathway markedly reduced the survival of WT myocytes in the presence of ISO, but did not affect those of AC6ΔN/ΔN and AC6-/- myocytes, suggesting an important role of AC6 in mediating cardioprotective action through the activation of PKA-Src-STAT3-signaling. CONCLUSIONS: Collectively, AC6-N controls the anchorage of cardiac AC6 on the sarcolemmal membrane, which enables the coupling of AC6 with the pro-survival PKA-STAT3 pathway. Our findings may facilitate the development of novel therapies for heart failure.

The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients.

Pulsed low-dose cyclophosphamide (CTX) therapy has become a very effective approach in improving the clinical outcomes of lupus nephritis (LN) patients. However, variations of CTX therapeutic outcomes in LN patients are incompletely understood. We investigated the contributions of known allelic variants to CTX therapy outcomes in 77 LN patients. Then, 22 out of the 77 patients were randomly enrolled to evaluate the pharmacokinetic profiles. LN patients with a GSTA1*A mutation (CT heterozygous) had more risk of non-remission (44% vs. 20%, P=0.005). Pharmacokinetic data indicated that patients with a GSTA1*A heterozygous variant had a lower exposure to 4-hydroxycyclophosphamide (4OHCTX) compared to wild-type patients (AUC4OHCTX: 12.8 (9.8, 19.5) vs. 27.5 (18.1, 32.8) h mg/l, P=0.023). Clinical remission was significantly related to higher exposure of 4OHCTX (P=0.038). In conclusion, LN patients with GSTA1*A heterozygous genotypes had poor CTX treatment remission due to less exposure to activated metabolites of CTX.