Action Of Treatment Research Articles

Systems pharmacology-based drug discovery from Amaryllidaceae alkaloids and investigation of mechanisms of action in treatment of Alzheimer’s disease

Abstract Objectives Given the success of galanthamine in treating Alzheimer’s disease, this study aims to establish an effective method to find drugs from Amaryllidaceae alkaloids and to clarify its mechanism in treating Alzheimer’s disease. Methods The pharmacodynamic basis and mechanism of action between Amaryllidaceae alkaloids and Alzheimer’s disease were explored by constructing a compound-target-disease network, targets protein-protein interaction, gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and molecular docking verification. Key findings In total, a chemical library of 357 potential alkaloids was constructed. A total of 100 active alkaloid components were identified. Thirty-nine associated targets were yielded based on network construction, and the key targets were defined as HSP90AA1, ESR1, NOS3, PTGS2, and PPARG using protein–protein interaction network. Gene ontology items (490) and 68 Kyoto Encyclopedia of Genes and Genomes pathways were selected through the enrichment of target functions, including neuroactive ligand–receptor interaction, calcium signaling pathway, cAMP signaling pathway, Alzheimer disease, and serotonergic synapse that were related to Alzheimer’s disease. Lastly, molecular docking demonstrated good stability in combining selected alkaloids with targets. Conclusions This study explained the mechanisms of Amaryllidaceae alkaloids in preventing and treating Alzheimer’s disease and established a novel strategy to discover new drugs from biological chemical sources.

Survodutide, a promising agent with novel mechanism of action for treatment of obesity and type 2 diabetes

Activation of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) may result in synergistic effects on glycemic control and weight reduction. Survodutide is a dual agonist of GLP-1R and GCGR under development for treatment of type 2 diabetes, obesity and non-alcoholic steatohepatitis (NASH). In a phase 2 trial of 16-week duration including patients with type 2 diabetes, subcutaneous survodutide given once weekly reduced glycated hemoglobin (HbA1c) levels by 1.5% versus placebo, which was comparable to the reduction achieved by semaglutide (1.0 mg/w). In another phase 2 trial of obese subjects without diabetes, percent weight loss with the highest dose of survodutide was 12.1% versus placebo and did not reach a plateau up to the end of follow-up at 46 weeks. Use of survodutide was associated with significant reduction in systolic and diastolic blood pressure and plasma triglycerides. The most common adverse effects of survodutide were gastrointestinal (GI) disorders reported by 55% of patients (versus 22% with placebo) in the diabetes trial and by 75% (versus 42% with placebo) in the obesity trial. Drug discontinuation rates were 16-25% with survodutide, 4% with semaglutide and 4-5% with placebo. Results of a phase 2 trial including patients with NASH are pending. The major limitation of survodutide is suboptimal tolerability due to GI adverse effects attributed in part to rapid dose escalation. Overall, survodutide is a promising candidate drug with a novel mechanism of action for treatment of type 2 diabetes and obesity. Phase 3 clinical trials, with slower dose titration of survodutide should clarify its efficacy and safety in a broader population of patients with type 2 diabetes, obesity and NASH.

Case report: CBD: THC medical cannabis in the treatment of neuropathic pain

Chronic neuropathic pain affects millions of adults worldwide, creating a direct impact on quality of life. The control of neuropathic pain is a challenge in daily clinical practice. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of this pathology. The use of cannabis and cannabinoid products is a growing area of research for the treatment of different pathologies including neuropathic pain. The studies developed so far and what is observed in the clinical practice, demonstrate the importance of this medication in a pathology of such complexity and difficult control, besides of that, more randomized controlled studies are needed to confirm medical cannabis an adjunct medication in the treatment of neuropathic pain. This case report aims to demonstrate the validity of joining GMP cannabis products as an adjuvant therapy for an effective with low profile side effects treatment leading to an improvement in quality of life.

New insights into the interactions between the gut microbiota and the inflammatory response to ulcerative colitisin a mouse model of dextran sodium sulfate and possible mechanisms of action for treatment with PE&AFWE.

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation. Intestinal innate immunity, including innate immune cells, defends against pathogens and excessive entry of gut microbiota, while preserving immune tolerance to resident intestinal microbiota, and may be characterized by its capacity to produce a rapid and nonspecific reaction. The association between microbiota dysbiosis and the pathogenesis of IBD is complex and dynamic. When the intestinal ecosystem is in dysbiosis, the reduced abundance and diversity of intestinal gut microbiota make the host more vulnerable to the attack of exogenous and endogenous pathogenic gut microbiota. The aim of our study was to comprehensively assess the relationship between microbial populations within UC, the signaling pathways of pathogenic gut microbe therein and the inflammatory response, as well as to understand the effects of using PE&AFWE (poppy extract [Papaver nudicaule L.] and Artemisia frigida Willd. extract) on UC modulation. A UC mouse model was established by inducing SPF-grade C57BL/6 mice using dextrose sodium sulfate (DSS). Based on metagenomic sequencing to characterize the gut microbiome, the relationship between gut microbiota dysbiosis and gut microbiota was further studied using random forest and Bayesian network analysis methods, as well as histopathological analysis. (1) We found that the 5 gut microbiota with the highest relative abundance of inflammatory bowel disease UC model gut microbiota were consistent with the top 5 ranked natural bacteria. There were three types of abundance changes in the model groups: increases (Chlamydiae/Proteobacteria and Deferribacteres), decreases (Firmicutes), and no significant changes (Bacteroidetes). The UC model group was significantly different from the control group, with 1308 differentially expressed species with abundance changes greater than or equal to 2-fold. (2) The proportion of the fecal flora in the UC group decreased by 37.5% in the Firmicutes and increased by 14.29% in the proportion of Proteobacteria compared to the control group before treatment. (3) The significantly enriched and increased signaling pathways screened were the 'arachidonic acid metabolic pathway' and the 'phagosomal pathway', which both showed a decreasing trend after drug administration. (4) Based on the causal relationship between different OTUs and the UC model/PE&AFWE administration, screening for directly relevant OTU networks, the UC group was found to directly affect OTU69, followed by a cascade of effects on OTU12, OTU121, OTU93, and OTU7, which may be the pathway of action that initiated the pathological changes in normal mice. (5) We identified a causal relationship between common differentially expressed OTUs and PE&AFWE and UC in the pre- and post-PE&AFWE-treated groups. Thereby, we learned that PE&AFWE can directly affect OTU90, after which it inhibits UC, inhibiting the activity of arachidonic acid metabolic pathway by affecting OTU118, which in turn inhibits the colonization of gut microbiota by OTU93 and OTU7. (6) Histopathological observation and scoring (HS) of the colon showed that there was a significant difference between the model group and the control group (p < 0.001), and that there was a significant recovery in both the sulfasalazine (SASP)and the PE&AFWE groups after the administration of the drug (p < 0.0001). We demonstrated causal effects and inflammatory metabolic pathways in gut microbiota dysbiosis and IBD, with five opportunistic pathogens directly contributing to IBD. PE&AFWE reduced the abundance of proteobacteria in the gut microbiota, and histopathology showed significant improvement.

Amelioration of Oxidative Stress in Rats with Chronic Obstructive Pulmonary Disease through Shenqi Huatan Decoction Activation of Peroxisome Proliferator‐Activated Receptor Gamma‐Mediated Activated Protein Kinase/Forkhead Transcription Factor O3a Signaling Pathway

Background. Chronic obstructive pulmonary disease (COPD) is a common respiratory disease. Currently, no specific treatment strategy has been established; therefore, finding new treatment methods is essential. Clinically, Shenqi Huatan Decoction (SQHT) is a traditional Chinese medicinal formula for COPD treatment; however, its mechanism of action in treatment needs to be clarified. Methods. The COPD rat model was replicated by cigarette smoking and tracheal injection using the LPS method. The control group and the SQHT groups were treated with dexamethasone and SQHT by gavage, respectively. After treatment, superoxide dismutase (SOD) serum levels, total antioxidant capacity (TAOC), lipid peroxidation, and malondialdehyde (MDA) were detected by enzyme‐linked immunosorbent assay (ELISA). Activated protein kinase alpha (AMPK‐α), forkhead transcription factor O3a (FOXO3a), manganese SOD (MnSOD), and peroxisome proliferator‐activated receptor gamma (PPARγ) were detected using reverse transcriptase quantitative polymerase chain reaction (RT‐qPCR) and Western blot. Microribonucleic acid and protein expression levels were measured, and pathological changes in lung tissue were observed using hematoxylin and eosin staining. Results. The pathological findings suggested that SQHT substantially affects COPD treatment by enhancing alveolar fusion and reducing emphysema. ELISA results showed that SQHT could lower the blood levels of MDA and lipid peroxide and raise SOD and TAOC levels, suggesting that it could lessen oxidative stress. In the lung tissue of rats with COPD, large doses of SQHT intervention dramatically increased AMPK protein expression, AMPK‐α, FOXO3a, MnSOD, and PPARγ, indicating that SQHT may reduce oxidative stress by activating the PPARγ‐mediated AMPK/FOXO3a signaling pathway. Similar results were obtained using RT‐qPCR. Conclusion. SQHT is effective for COPD treatment. The mechanism of action may be related to the activation of the PPARγ‐mediated AMPK/FOXO3a signaling pathway to improve oxidative stress in lung tissue.

N-acetylcysteine for non-acetaminophen induced acute liver failure: A review.

The use of N-acetylcysteine (NAC) for non-acetaminophen-induced acute liver failure (NAI-ALF) has been increasing despite controversy in its efficacy. National guidelines are in disagreement for NAC use as standard of care; however, many healthcare centers continue to adopt the use of NAC outside of acetaminophen poisoning. While NAC may have multiple mechanisms of action in treatment of ALF, this has not translated to clinical benefit. Murine models have reported antioxidant and anti-inflammatory properties, as well as improvement in liver-specific microcirculation. Multiple case studies and series have reported positive outcomes of NAC treatment for ALF of various etiologies. While prospective studies suggested the benefit of NAC treatment, these studies have methodological and statistical shortcomings that affect the validity of the results. In this review, we aimed to summarize the existing literature on the efficacy of NAC for NAI-ALF including mechanism of action, case studies and series demonstrating outcomes, and prospective studies that have led to its current widespread use, along with the reported rate of adverse events.

Mechanism of Xianling Gubao Capsule in the Treatment of Steroid Induced Osteonecrosis of Femoral Head

This study aimed to obtain the main active components of Xianling Gubao capsule and identify their pharmacological characteristics and mechanism of action in treatment of steroid-induced femoral head necrosis. The chemical constituents and direct targets of Xianling Gubao capsule were obtained by the system pharmacology platform of traditional Chinese medicine. GeneCards database and gene expression omnibus database were used to obtain pathogenic genes related to steroid-induced femoral head necrosis. Through Venn diagram software, the intersection of direct drug targets and disease-related genes was obtained to obtain the potential drug targets of Xianling Gubao capsule. In the Cytoscape 3.7.1 software, the drug component-target and protein-protein interaction networks were visualized and analyzed by network analyze plugin and molecular complex detection plugin, the degree values of nodes were analyzed to screen the core genes. Finally, the database for annotation, visualization and integrated discovery database was used for gene enrichment analysis. We obtained 76 chemical components of Xianling Gubao, 583 pathogenic related genes of steroid-induced femoral head necrosis and 38 potential drug targets of Xianling Gubao capsule for the treatment of steroid-induced femoral head necrosis. A drug componenttargets network with 1001 nodes and 3661 edges, a protein-protein interaction network with 31 nodes and 67 edges were constructed. 15 core genes were obtained by network topology analysis and enrichment analysis of potential drug targets showed that they were mainly concentrated in chemokine signaling pathway. Finally, 5 optimal drug targets of Xianling Gubao capsule for steroid-induced femoral head necrosis were obtained, respectively. Xianling Gubao capsule can prevent or treat steroid-induced femoral head necrosis by promoting the reconstruction of new capillaries after necrosis, improving intravascular coagulation, accelerating the formation of callus and regulating the differentiation and direction of bone marrow stem cells.

Raloxifene as a treatment option for viral infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused corona virus disease 2019 (COVID-19) pandemic and led to mass casualty. Even though much effort has been put into development of vaccine and treatment methods to combat COVID-19, no safe and efficient cure has been discovered. Drug repurposing or drug repositioning which is a process of investigating pre-existing drug candidates for novel applications outside their original medical indication can speed up the drug development process. Raloxifene is a selective estrogen receptor modulator (SERM) that has been approved by FDA in 1997 for treatment and prevention of postmenopausal osteoporosis and cancer. Recently, raloxifene demonstrates efficacy in treating viral infections by Ebola, influenza A, and hepatitis C viruses and shows potential for drug repurposing for the treatment of SARS-CoV-2 infection. This review will provide an overview of raloxifene’s mechanism of action as a SERM and present proposed mechanisms of action in treatment of viral infections.

The Systematic Effect of Mesenchymal Stem Cell Therapy in Critical COVID-19 Patients: A Prospective Double Controlled Trial

The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, n = 10, treated conventionally), Group 2 (critical cases, n = 10, treated conventionally), and Group 3 (critical cases, n = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 106 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-β, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.

Development of the mental health cultural adaptation and contextualization for implementation (mhCACI) procedure: a systematic framework to prepare evidence-based psychological interventions for scaling.

Because of the high burden of untreated mental illness in humanitarian settings and low- and middle-income countries, scaling-up effective psychological interventions require a cultural adaptation process that is feasible and acceptable. Our adaptation process incorporates changes into both content and implementation strategies, with a focus on local understandings of distress and treatment mechanisms of action. Building upon the ecological validity model, we developed a 10-step process, the mental health Cultural Adaptation and Contextualization for Implementation (mhCACI) procedure, and piloted this approach in Nepal for Group Problem Management Plus (PM+), a task-sharing intervention, proven effective for adults with psychological distress in low-resource settings. Detailed documentation tools were used to ensure rigor and transparency during the adaptation process. The mhCACI is a 10-step process: (1) identify mechanisms of action, (2) conduct a literature desk review for the culture and context, (3) conduct a training-of-trainers, (4) translate intervention materials, (5) conduct an expert read-through of the materials, (6) qualitative assessment of intervention population and site, (7) conduct practice rounds, (8) conduct an adaptation workshop with experts and implementers, (9) pilot test the training, supervision, and implementation, and (10) review through process evaluation. For Group PM+, key adaptations were harmonizing the mechanisms of action with cultural models of 'tension'; modification of recruitment procedures to assure fit; and development of a skills checklist. A 10-step mhCACI process could feasibly be implemented in a humanitarian setting to rapidly prepare a psychological intervention for widespread implementation.

1564. Activity of bacteriophage against multidrug resistant Klebsiella pneumoniae

BackgroundThe prevalence of extended-spectrum beta-lactamase (ESBL) producing and carbapenem resistant (CR) Klebsiella pneumoniae (KP) has significantly risen in all geographic regions. Infections due to these bacteria are associated with high mortality across different infection types. Even with newer options, there remains an unmet need for safe and effective therapeutic options to treat infections caused by ESBL and CR KP. Phage therapy offers a novel approach with an unprecedented and orthogonal mechanism of action for treatment of diseases caused by pathogenic bacterial strains that are insufficiently addressed by available antibiotics. Phage-based therapies confer a high strain-level specificity and have a strong intrinsic safety profile. Here we describe the identification of novel phages that can effectively target antibiotic resistant KP strains.Host range of the 21 phages on 33 strain KP panel via solid culture infectivity assays. Red marks resistance to infection while sensitivity to phage is marked in green Methods KP clinical strains were isolated from human stool specimens preserved in glycerol. Selective culturing was carried, followed by testing of individual colonies for motility, indole and urease production, sequenced and analyzed by Kleborate tool to determine antibiotic resistant genes. Natural phages were isolated from plaques that developed on susceptible bacterial targets, sequenced and characterized.ResultsAntibiotic-resistant KP strains encoding beta lactamase genes or a carbapenemase (n=33) were isolated from healthy individuals (n=3), and patients with inflammatory bowel disease (n=26) or primary sclerosing cholangitis (n=3). Isolates sequencing revealed bla CTX-M15 and/or bla SHV encoding strains and carbapenamase KPC-2. A panel of 21 phages targeting the beta-lactamase- and carbapenemase-producing KP strains were identified. Phage sequencing revealed that all phages belong to the Caudovirales order and include 6 Siphoviridae, 14 Myoviridae, and 1 Podoviridae. In vitro lytic activity of the phages was tested on the isolated bacteria and revealed a coverage of 70% of the 33 isolated antibiotic resistant strains, >50% of which were targeted by multiple phages.ConclusionCollectively, these results demonstrate the feasibility of identifying phage with potent activity against antibiotic resistant KP strains, and may provide a novel therapeutic approach for treatment of ESBL and CR KP infections.Disclosures All Authors: No reported disclosures

A novel concept for treatment and vaccination against Covid‐19 with an inhaled chitosan‐coated DNA vaccine encoding a secreted spike protein portion

A novel concept in DNA vaccine design is the creation of an inhaled DNA plasmid construct containing a portion of the coronavirus spike protein for treatment and vaccination. The secretion of a spike protein portion will function as a competitive antagonist by interfering with the binding of coronavirus to the angiotensin‐converting enzyme 2 (ACE2) receptor. The secreted protein binding to the ACE2 receptor provides a unique mechanism of action for treatment to all strains of coronavirus in naïve patients, by blocking the ACE2 receptor site. An inhaled plasmid DNA vaccine replicates the route of lung infection taken by coronavirus with transfected cells secreting spike protein portions to induce immunity. Unlike most DNA vaccines with intracellular antigen presentation through MHC I, the current vaccine relies on the secreted proteins presentation through MHC II as well as MHC I to induce immunity. Lung specific production of vaccine particles by inhaled plasmid DNA is appealing since it may have limited systemic side effects, and may induce both humoral and cytotoxic immunity. Finally, the ease and ability to rapidly produce this plasmid construct makes this an ideal solution for managing the emerging threat of coronavirus.

Phase Ib study assessing different sequencing regimens of atezolizumab (anti-PD-L1) and sipuleucel-T (SipT)in patients who have asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer.

e17564 Background: Combining an immune checkpoint inhibitor with a tumor vaccine may leverage complementary mechanisms of action for treatment of mCRPC. Atezolizumab, a fully human anti–PD-L1 IgG1 antibody, is an approved treatment option in multiple indications; while SipT, an autologous cellular immunotherapeutic, is approved for treatment of metastatic castrate resistant prostate cancer (mCRPC). We present a phase Ib study evaluating safety, tolerability and objective response rate of atezolizumab + SipT in patients with mCRPC (NCT03024216). Methods: Eligible patients who had asymptomatic or minimally symptomatic progressive mCRPC and met standard criteria for sipuleucel-T were randomized to receive either atezolizumab 1200 mg IV every 3 weeks for 2 doses then SipT IV every 2 weeks for a total of three infusions (Arm 1) or SipT IV every 2 weeks for a total of three infusions followed by atezolizumab 1200 mg IV every 3 weeks for 2 doses (Arm 2). The primary endpoint was safety, while secondary endpoints included objective tumor response (PCWG2 and modified RECISTv1.1 criteria) and comparing systemic immune responses after induction between the arms. Results: As of February 6, 2020, 37 pts (median follow-up 7.4 months, median age 75 yrs [range 53.0–86.0]; median number of previous treatments 4 [range 1-8], 75.7% ECOG PS = 0) were enrolled. Three patients did not complete induction therapy (1 – withdrew consent, 1 developed toxicity, and 1 progressed). There were no grade 5 toxicities attributed to study drugs and grade 4 toxicities were noted in 2 patients, 1 in each arm (Arm 1 bronchitis and Arm 2 hypotension). Eight grade 3 toxicities were noted in arm 1 (hyponatremia, pulmonary embolus x3, bone pain, hypophosphatemia, shock, tooth fracture from a fall), while 4 grade 3 toxicities were noted in arm 2 (anemia, hypertension x 2, pneumonia). None of the grade 3 or 4 SAEs were noted to be irAEs. At 6 months, there were 11 SD (7 in Arm 1 and 4 in Arm 2), 18 PD and 7 unevaluable (3 withdrew from study and 4 have yet to reach 6 month evaluation). At this time, PFS was noted to be 8.2 months in Arm 1 and 5.8 months in Arm 2 (p = 0.054). Conclusions: The safety profile of the combination of atezolizumab with sipuleucel-T appears manageable in a heavily pre-treated population and consistent with those agents administered as monotherapy. Responses were seen but no CR. Immune activation studies may shed light on which sequence is optimal. Clinical trial information: NCT03024216 .

Assessing different sequencing regimens of atezolizumab (atezo) and sipuleucel-T (sipT) in patients who have asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer.

141 Background: Combining an immune checkpoint inhibitor with a vaccine may leverage complementary mechanisms of action for treatment of mCRPC. We present a randomized study evaluating atezo (anti PD-L1) + sipT in patients (pts) with mCRPC. Methods: Pts who met standard criteria for sipT were randomized to receive (Arm1): atezo 1200 mg IV every 3 weeks for 2 doses then SipT every 2 weeks for a total of 3 infusions (induction) followed by maintenance atezo every 3 weeks until toxicity or loss of clinical benefit or (Arm2) sipT every 2 weeks for a total of 3 infusions followed by atezo 1200 mg IV every 3 weeks for 2 doses (induction) followed by maintenance atezo every 3 weeks until same. The primary endpoint was safety (CTCAE v4.0); secondary endpoints were PFS by PCWG2, objective response (modified RECIST1.1) and systemic immune responses after induction. Results: 37 pts, median age 75 [range 53–86] enrolled; median prior treatments was 4 [range 1-8] and 76% had ECOG PS = 0. Three patients did not complete induction (1 withdrew consent, 1 due to toxicity, and 1 progressed). There were no delays in induction dosing for Arm1 but 9 delays (1 week) for Arm2 (collection failure=6, holiday=2 and other=1). There were no grade 5 toxicities attributed to study drugs. 1 grade 4 toxicity was noted in each arm (Arm 1 bronchitis, Arm 2 hypotension). Eight grade 3 toxicities were noted in arm 1 (hyponatremia, pulmonary embolus x3, bone pain, hypophosphatemia, shock, fall with tooth fracture), while 4 grade 3 toxicities were noted in arm 2 (anemia, hypertension x 2, pneumonia). None of the grade 3 or 4 AEs were immune related. AEs led to discontinuation in 5 patients in Arm1 and 1 patient in Arm2. In Arm1 11 patients were RECIST evaluable at 6 months, with 1 PR (5.8%), 4 SD (23.5%) and 6 PD. In Arm2 13 patients were evaluable, with 1 PR (5.8%), 6 SD (32%) and 6 PD. 10/24 evaluable patients (41.7%) had stable disease at 6 months. Conclusions: The combination of atezo with sipT was safe, AEs consistent with the agents as monotherapy, with no immune related AEs. 2 pts had RECIST PR and 10 had stable disease at 6 months, more than expected with monotherapy. Clinical trial information: 03024216.

Medicinal herbs useful in pediatric fever from the perspective of Persian medicine.

Background Fever is the most important and common symptom of pediatric diseases. Fever can be a sign or symptom or complication of disease. Considering the development of complementary and alternative medicine worldwide and the prevalence of this symptom in children, we aimed to investigate their application based on Persian medical textbooks by searching herbs used in pediatric fever. Materials and Methods In this review study, materials were extracted by searching in reliable Persian medical textbooks of the10th -20th century using related Persian medicine keywords. Then the documentations for herbs extracted were searched in the databases based on the conventional medicine. The interpretation was made based on the results. Results Based on the Persian medical textbooks, seventeen herbs have been prescribed for decreasing pediatric fever. Among them, 16herbs have proven mechanisms of action for treatment of fever, classified into five categories (diaphoretic, anti-inflammatory, anti-septic, immunomodulatory, anti-oxidant) based on literature review. On the other hand, according to Persian medicine, there were thirteen cold temperament herbs and only four hot temperament ones. They were administrated using various oral and topical methods. The maternal and neonatal treatment was emphasized. Conclusion According to this study and documentations of conventional medicine, many of these herbs can be effective in the treatment of pediatric fever, so further clinical studies are recommended for evaluating their efficacy.

First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100).

4072 Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of advanced/metastatic (a/m) hepatocellular carcinoma (HCC). Avelumab is a human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a tyrosine kinase inhibitor selective for VEGF receptors 1/2/3. VEGF Liver 100 (NCT03289533) is a phase 1b study evaluating safety and efficacy of avelumab + axitinib in treatment-naive patients (pts) with HCC; interim results are reported here. Methods: Eligible pts had confirmed a/m HCC, ≥1 measurable lesion, a fresh or archival tumor specimen, ECOG PS ≤1, and Child-Pugh class A. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and objective response (RECIST v1.1; modified [m] RECIST for HCC). Results: Interim assessment was performed after a minimum follow up of 6 months based on the released study data set (clinical cut-off date: Aug 1, 2018). As of the cut-off date, 22 pts (median age: 68.5 y) were treated with avelumab (median: 20.0 wk) and axitinib (median: 19.9 wk). The most common grade 3 treatment-related adverse events (TRAEs) (≥10% of patients) were hypertension (50.0%) and hand-foot syndrome (22.7%); no grade 4/5 TRAEs were reported. Immune-related AEs (irAEs) (≥10% of pts) were hypothyroidism (31.8%) and hyperthyroidism (13.6%). No grade ≥3 irAEs were reported; no pts discontinued treatment due to TRAEs or irAEs. Based on Waterfall plot calculations, tumor shrinkage was observed in 15 (68.2%) and 16 (72.7%) pts by RECIST and mRECIST, respectively. ORR was 13.6% (95% CI, 2.9%-34.9%) and 31.8% (95% CI, 13.9%-54.9%) by RECIST and mRECIST, respectively. OS data were immature at data cutoff. Conclusions: The preliminary safety of avelumab + axitinib in HCC is manageable and consistent with the known safety profiles of avelumab and axitinib when administered as monotherapies. This study demonstrates antitumor activity of the combination in HCC. Follow-up is ongoing. Clinical trial information: NCT03289533. [Table: see text]

Genomic and GeneChip expression profiling reveals the inhibitory effects of Amorphophalli Rhizoma in TNBC cells

Ethnopharmacological relevanceAmorphophalli Rhizoma has been widely used as an adjuvant treatment for advanced or metastatic breast cancer, pancreatic cancer, hepatoma, and malignant lymphoma, but its molecular mechanism of action for treatment of metastatic triple-negative breast cancer (TNBC) is generally poorly understood. Aim of the studyTo investigate genomic changes related to the inhibitory effect of Amorphophalli Rhizoma and to elucidate the molecular mechanism of this inhibition in MDA-MB-231 TNBC cells. Materials and methodsGene chip analysis was employed to explore genomic changes caused by Amorphophalli Rhizoma in TNBC cells. Potential classical signaling pathways, upstream regulators, functions, regulatory effects and gene interaction networks were analyzed by Ingenuity Pathway Analysis (IPA). Real-time quantitative PCR (RT-qPCR) and RNA interference (RNAi) assays were used to clarify the roles of potential target genes. ResultsIn total, 536 significantly upregulated and 648 significantly downregulated genes were identified between the group treated with Amorphophalli Rhizoma extract and that treated with vehicle. Many of these differentially expressed genes (DEGs) in TNBC cells are involved in DNA replication, recombination and repair, the cell cycle, and cellular assembly and organization. Attenuation of KNL1, OLFML2A, RTKN2 and SGO1 gene expression by Amorphophalli Rhizoma significantly induced cell cycle arrest and suppressed cell proliferation and migration. ConclusionsThe inhibitory effects of Amorphophalli Rhizoma in TNBC cells likely occur through regulation of the spindle checkpoint, chromosomal and centrosomal instability, and cell membrane stability.

Change in domain-specific but not general psychological flexibility relates to greater weight loss in acceptance-based behavioral treatment for obesity

Acceptance-based approaches have demonstrated promise for improving outcomes in behavioral treatments for obesity, but few studies have examined processes of change in these treatments. It is critical to identify mechanisms of action in treatment to further optimize this approach, refine theory, and inform future research. This study examined change in several domain-specific and general measures of psychological flexibility in a randomized controlled trial of an acceptance-based behavioral weight loss treatment. The relationships between change in these measures and weight loss outcomes were also examined. Adults (N = 283) were randomized to receive 12 months of acceptance-based (ABT) or non-acceptance-based (non-ABT) behavioral treatment and completed measures of general and weight control-specific psychological flexibility at months 0, 6, and 12. Participants in ABT demonstrated greater increases in psychological flexibility related to eating and physical activity experiences during treatment compared to participants in non-ABT, and changes in these processes were correlated with better weight loss. Parallel mediation analyses further revealed that psychological flexibility related to eating and physical activity experiences partially mediated the relationship between treatment condition and 12-month weight loss. Participants across conditions also experienced small increases in general psychological flexibility, but general psychological flexibility was not meaningfully related to weight loss outcomes. These findings indicate that domain-specific (versus general) psychological flexibility may be most impacted by ABT and most relevant to weight loss outcomes. Results also provide partial support for the theoretical model of ABT for weight management.

Targeting Cancer Metabolism and Cell Cycle by Plant-Derived Compounds.

Cancer has an increasing death rate over the world population without discriminating between the industrial and developing countries. Complexity of cancer such as ability of cancer cells to develop resistance to drugs or differential behavior of sub-types and different responses from the patients indicate the continuous need for research and development of new anticancer drugs, new formulations of drug combinations and treatment strategies. Not too surprisingly nature itself, is often the largest territorial reservoir as a source for this type of research and development. Speaking of plant variety, more than 1000 plants have already been identified to produce agents with anticancer activities. In this review, a panel of plant derived anti-cancer agents will be reiterated in terms of their mechanism of action in treatment of disease.

The Chinese herbal formula Fuzheng Quxie Decoction attenuates cognitive impairment and protects cerebrovascular function in SAMP8 mice.

PurposeThis study was designed to explore the underlying mechanism of action for a Fuzheng Quxie Decoction (FQD) in Alzheimer’s disease (AD), to validate its neuroprotective effects, and to provide experimental support for its predicted mechanism of action.MethodsAn integrative approach to network pharmacology was performed to predict the mechanism of action for treatment of AD with FQD. The predicted mechanism was validated in SAMP8 mice.ResultsWith predicted putative FQD targets and a collection of AD-related genes, 245 possible regulatory targets of FQD were identified for the treatment of AD. Pathway-enrichment analysis for the possible regulatory targets indicated that vascular endothelial growth factor (VEGF) and VEGF-receptor signaling were pivotal in the treatment of AD with FQD. In vivo experiments confirmed the neuroprotective effect and the predicted mechanism of action for treatment of AD with FQD.ConclusionThis study contributes to an understanding of the neuroprotective effect of FQD and its potential mechanism of action for the treatment of AD.