Plain language summary of the FOENIX-CCA2 study: futibatinib for people with advanced bile duct cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life. WHAT WERE THE RESULTS?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib. WHAT DO THE RESULTS MEAN?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).

Effect of Repeated Moist Heat Sterilization on Titanium Implant-Abutment Interface-An In Vitro Study.

OBJECTIVES: Sterilization eliminates microbial viability by decreasing the biological load, but likewise have the ability to deteriorate the mechanical properties of an implant material. This study intended to evaluate the effect of repeated moist heat sterilization on implant-abutment interface using two different implant systems. MATERIALS AND METHODS: Forty screw-retained titanium implant-abutment combinations (fixture 3.5 ×10 mm, abutment 2 mm diameter), twenty each from Genesis (Aktiv Implant Systems, United States) and Bredent (SKY, Germany), were divided into four different groups (n = 10) and placed in a computer-aided diagnostic model. The abutments from each group were exposed to first and second autoclave cycle (121°C for 30 minutes), connected back to the fixture and analyzed under scanning electron microscope for marginal gap and surface roughness. RESULTS: Genesis group showed higher marginal gaps on both sides (buccal/mesial [2.8 ± 0.47]; lingual/distal [2.8 ± 0.33]), while Bredent implant-abutment system (IAS) did not show any changes in marginal gaps after autoclaving. Differences within and between the group were found to be statistically significant. Surface roughness for Genesis (243.7 ± 70.30) and Bredent groups (528.9 ± 213.19) was highest at second autoclave, with Bredent implant-abutment showing higher values for surface roughness than Genesis IAS. CONCLUSION: Marginal vertical gap increased with autoclaving for Genesis IAS, while Bredent implant abutments were more stable. Surface roughness increases with autoclaving for both Genesis and Bredent group of IAS.

Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma.

BACKGROUND & AIMS: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA). METHODS: A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance mutations in the mitogen-activated protein kinase (MAPK) pathway were introduced to assess their effect on sensitivity to FGFRi in vitro. RESULTS: On retrospective analysis of 17 patients with repeat sequencing following FGFRi treatment, new FGFR2 mutations were detected in 11 (64.7%) and new alterations in MAPK pathway genes in nine (52.9%) patients, with seven (41.2%) patients developing new alterations in both the FGFR2 and MAPK pathways. In serially collected plasma samples, a patient treated with an irreversible FGFRi tested positive for previously undetected BRAF V600E, NRAS Q61K, NRAS G12C, NRAS G13D and KRAS G12K mutations upon progression. Introduction of a FGFR2-BICC1 fusion into biliary tract cells in vitro sensitized the cells to FGFRi, while concomitant KRAS G12D or BRAF V600E conferred resistance. MEK inhibition was synergistic with FGFRi in vitro. In an in vivo animal model, the combination had antitumor activity in FGFR2 fusions but was not able to overcome KRAS-mediated FGFRi resistance. CONCLUSIONS: These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi. CLINICAL TRIAL NUMBER: NCT02052778. IMPACT AND IMPLICATIONS: We evaluated tumors and plasma from patients who previously received inhibitors of fibroblast growth factor receptor (FGFR), an important receptor that plays a role in cancer cell growth, especially in tumors with abnormalities in this gene, such as FGFR fusions, where the FGFR gene is fused to another gene, leading to activation of cancer cell growth. We found that patients treated with FGFR inhibitors may develop mutations in other genes such as KRAS, and this can confer resistance to FGFR inhibitors. These findings have several implications for patients with FGFR2 fusion-positive tumors and provide mechanistic insight into emerging MAPK pathway alterations which may serve as a therapeutic vulnerability in the setting of acquired resistance to FGFRi.

Ultraviolet disinfection (UV-D) robots: bridging the gaps in dentistry.

Maintaining a microbe-free environment in healthcare facilities has become increasingly crucial for minimizing virus transmission, especially in the wake of recent epidemics like COVID-19. To meet the urgent need for ongoing sterilization, autonomous ultraviolet disinfection (UV-D) robots have emerged as vital tools. These robots are gaining popularity due to their automated nature, cost advantages, and ability to instantly disinfect rooms and workspaces without relying on human labor. Integrating disinfection robots into medical facilities reduces infection risk, lowers conventional cleaning costs, and instills greater confidence in patient safety. However, UV-D robots should complement rather than replace routine manual cleaning. To optimize the functionality of UV-D robots in medical settings, additional hospital and device design modifications are necessary to address visibility challenges. Achieving seamless integration requires more technical advancements and clinical investigations across various institutions. This mini-review presents an overview of advanced applications that demand disinfection, highlighting their limitations and challenges. Despite their potential, little comprehensive research has been conducted on the sterilizing impact of disinfection robots in the dental industry. By serving as a starting point for future research, this review aims to bridge the gaps in knowledge and identify unresolved issues. Our objective is to provide an extensive guide to UV-D robots, encompassing design requirements, technological breakthroughs, and in-depth use in healthcare and dentistry facilities. Understanding the capabilities and limitations of UV-D robots will aid in harnessing their potential to revolutionize infection control practices in the medical and dental fields.

Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).

Salivary Biomarkers in Periodontitis Post Scaling and Root Planing.

OBJECTIVES: This study was conducted to evaluate the levels of salivary uric acid and arginase in patients with periodontitis, generalized gingivitis, and in healthy individuals. Then, the effects of non-surgical periodontal therapy on levels of salivary arginase and uric acid were also investigated. METHODS: A total of 60 subjects were divided into three groups based on periodontal health: group I comprised 20 healthy individuals; group II comprised 20 subjects who had generalized gingivitis; group III comprised 20 subjects who had generalized periodontitis. On day 0, the clinical examination of periodontal status was recorded, following which saliva samples were collected. Group II and group III subjects underwent non-surgical periodontal therapy. These patients were recalled on day 30 to collect saliva samples. The periodontal parameters were reassessed on day 90, and saliva samples were collected for analysis of salivary arginase and uric acid levels. RESULTS: Group II and group III showed improvement in clinical parameters following non-surgical periodontal therapy on the 90th day. The MGI score, PPD, and CAL showed improvement. On day 0, at baseline, salivary arginase levels in group III and group II were higher than those in healthy subjects, whereas on day 0, salivary uric acid levels in group III and group II were lower than those in healthy subjects. Both on day 0 and day 90, the salivary arginase level showed a positive correlation with the periodontal parameters, whereas the salivary uric acid level was positively correlated with the periodontal parameters on day 90. CONCLUSION: the level of salivary arginase was a pro-inflammatory marker and a raised level of salivary uric acid was an anti-inflammatory marker following periodontal therapy, suggesting their pivotal role in assessing periodontal status and evaluation of treatment outcome.

Suppression of Tumorigenicity 2 Pro-Inflammatory Biomarker Linking Diabetes Mellitus and Periodontitis: A Pilot Study.

BACKGROUND Suppression of tumorigenicity 2 (ST2) is a member of the interleukin (IL)-1 family and has 2 isoforms: ST2L, a transmembrane form, and ST2, a soluble form. IL-33 can act as an immune system alarm signal when released by damaged cells, which in turn activates other cells expressing the ST2 receptor. This can cause inflammatory cytokines to be released and produced, as well as trigger osteoclastogenesis. This study aimed to investigate the levels of soluble ST2 in gingival samples. MATERIAL AND METHODS The study population consisted of 30 individuals. The participants were divided into 3 groups: healthy participants, patients with periodontitis, and patients with periodontitis and diabetes mellitus. Periodontitis was determined using probing depth, clinical attachment loss, and gingival index. Patients with stage 2 to 4 periodontitis met the inclusion criteria. Gingival crevicular fluid (GCF) was collected for quantification of samples for ST2 levels by using an enzyme immunoassay. RESULTS The mean±standard deviation of ST2 GCF concentrations was relatively high (558.87±68.99) in the group with periodontitis and diabetes mellitus, compared with that of the periodontitis group (452.06±54.18) and healthy group (252.82±87.9). CONCLUSIONS GCF ST2 values were found to be a marker of inflammatory activities. Thus, GCF ST2 could be a potential biomarker for the diagnosis of periodontitis as well as systemic diseases, such as diabetes mellitus. This pilot study was limited by a small number of participants. To confirm the associations, more large-scale investigations should be conducted.

Evaluation of Mesiodistal Root Angulation of Permanent Incisors, Canines, and First Pre-Molars by Orthopantomogram Dental Imaging Findings in 296 Children Aged 6-14 Years.

BACKGROUND Early pre-eruptive inclination changes of the first premolar (FP) and its associative changes with canine (C) inclination are important to predict canine impaction. This study aimed to evaluate the mesiodistal root angulation of permanent lateral incisors (LI), canines, and first molars by orthopantomogram dental imaging in 296 children ages 6-14 years at a single center in India. MATERIAL AND METHODS The total number of participants was 296, with equal numbers of boys and girls divided into 4 age groups: 6-8 years, 8-10 years, 10-12 years, and 12-14 years. Angles between lateral incisor, erupting canine, and first pre-premolar with midline were measured on an orthopantomogram (dental imaging which includes all the teeth with TMJ). The angle between the erupting C with LI and erupting C with FP was measured. Pearson's correlation was also evaluated between the movement of the erupting canine with lateral incisor and erupting canine with erupting first premolar. RESULTS There was a significant difference in the angular values of different age groups (P≤0.05). The movements between LI, C, and FP were moderately correlated boys and girls aged 6-12 years. CONCLUSIONS The findings from this study showed that in boys and girls aged 6-14 years, eruption of the upper canine tooth was synchronized with eruption of the LI and FP.

A phase II study of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations.

PTEN acts as a potent tumor suppressor within the PI3K/AKT/mTOR pathway. Germline mutations in the PTEN gene are a hallmark of PTEN hamartoma tumor syndrome, which includes Cowden syndrome, where they appear to elevate lifetime risk of cancer. Targeted AKT directed therapy has been proposed as an effective approach in cancer patients having germline PTEN mutations. The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I study in Japan in which activity was observed against certain tumor types. Here we describe the study protocol of an international, two-part phase II study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations.

Signaling paths control growth and activities inside cells. Overactivity in these paths can encourage many types of cancers to develop. Tumor suppressor proteins can inhibit cell signals that promote cancer. This protection can be lost if there are errors in any gene coding for a tumor suppressor protein. We are carrying out a clinical study to test TAS-117, a potential new oral medicine, in people who have solid tumors and whose cells have changes in their genes that inactivate a tumor suppressor protein called PTEN. TAS-117 targets part of a signaling path that may be overactive due to loss of PTEN activity. In early research, TAS-117 has shown promising activity against certain tumor types. Our trial will explore if TAS-117 can provide a new treatment for rare forms of cancer where genetic changes have led to a loss of PTEN activity. Clinical Trial Registration: NCT04770246 (ClinicalTrials.gov).

Effect of Fluoridated Mouthwashes on Corrosion Property of Orthodontic Appliances: A Narrative Review.

OBJECTIVE: To analyze the effects of various fluoride agents on metallic orthodontic materials. DESIGN: PubMed, Google Scholar, and Embase were searched using keyword combinations such as fluoride mouthwash and orthodontic appliance and corrosion, fluoride and fixed appliance, and metal degradation. RESULTS: Of 315 articles, 20 were selected for inclusion in the review. All types of fluoride agents, especially the acidulated form of fluoride, seemed to influence the corrosion of orthodontic metallic appliances. CONCLUSION: Since most of the studies reported suggest that fluoride ions are capable of causing corrosion of metallic orthodontic appliances, attention should be paid while prescribing fluoride agents for orthodontic patients. The degree of corrosion seems to be directly correlated with the acidity of the medium and the concentration of fluoride ions. Co-Cr brackets are resistant to corrosion by fluoride while stainless steel and Ti brackets are susceptible. CLINICAL SIGNIFICANCE: It allows making the right choice while choosing the orthodontic brackets in relation to their susceptibility to corrosion by fluoride ions.

Receptor binding domain of SARS-CoV-2 from Wuhan strain to Omicron B.1.1.529 attributes increased affinity to variable structures of human ACE2.

BACKGROUND: COVID-19 is an infectious disease declared as a global pandemic caused by SARS-CoV-2 virus. Genomic changes in the receptor binding domain (RBD) region of SARS-CoV-2 led to an increased, infectivity in humans through interaction with the angiotensin-converting enzyme2 (ACE2) receptor. Simultaneously, the genetic variants in ACE2 provide an opportunity for SARS-CoV-2 infection and severity. We demonstrate the binding efficiencies of RBDs of SARS-CoV-2 strain with ACE2 variants of the human host. METHODOLOGY: A Total of 615 SARS-CoV-2 genomes were retrieved from repository. Eighteen variations were identified contributing to structural changes in RBD that are distributed in 615 isolates. An analyses of 285 single nucleotide variances at the coding region of the ACE2 receptor showed 34 to be pathogenic. Homology models of 34 ACE2 and 18 RBD structures were constructed with 34 and 18 structural variants, respectively. Protein docking of 612 (34 *18) ACE2-RBD complexes showed variable affinities compared to wildtype Wuhan's and other SARS-CoV-2 RBDs, including Omicron B.1.1.529. Finally, molecular dynamic simulation was performed to determine the stability of the complexes. RESULTS: Among 612, the top 3 complexes showing least binding energy were selected. The ACE2 with rs961360700 variant showed the least binding energy (-895.2 Kcal/mol) on binding with the RBD of Phe160Ser variant compared to Wuhan's RBD complex. Interestingly, the binding energy of RBD of Omicron B.1.1.529 with ACE2 (rs961360700) structure showed least binding energy of -1010 Kcal/mol. Additionally, molecular dynamics showed structure stability for all the analysed complexes with the RMSD (0.22-0.26 nm), RMSF (0.11-0.13 nm), and Rg (2.53-2.56 nm). CONCLUSION: In conclusion, our investigation highlights the clinical variants contributing to structural variants in ACE2 receptors that lead to efficient binding of SARS-CoV-2. Therefore, screening of these ACE2 polymorphisms will help detect COVID-19 risk population so as to provide additional care and for safe management.

Identification of E484K and other novel SARS-COV-2 variants from the Kingdom of Bahrain.

The challenges imposed by the ongoing outbreak of severe acute respiratory syndrome coronavirus-2 affects every aspect of our modern world, ranging from our health to our socio-economic needs. Our existence highly depends on the vaccine's availability, which demands in-depth research of the available strains and their mutations. In this work, we have analyzed all the available SARS-COV2 genomes isolated from the Kingdom of Bahrain in terms of their variance and origin analysis. We have predicted various known and unique mutations in the SARS-COV2 isolated from Bahrain. The complexity of the phylogenetic tree and dot plot representation of the strains mentioned above with other isolates of Asia indicates the versatility and multiple origins of Bahrain's SARS-COV2 isolates. We have also identified two high impact spike mutations from these strains which increase the virulence of SARS-COV2. Our research could have a high impact on vaccine development and distinguishes the source of SARS-COV2 in the Kingdom of Bahrain.

Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer ("METRIC"): a randomized multicenter study.

The METRIC study (NCT#0199733) explored a novel antibody-drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1-14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.

Do We have a Satisfactory Cell Viability Assay? Review of the Currently Commercially-Available Assays.

Cell-based assays are an important part of the drug discovery process and clinical research. One of the main hurdles is to design sufficiently robust assays with adequate signal to noise parameters while maintaining the inherent physiology of the cells and not interfering with the pharmacology of target being investigated. A plethora of assays that assess cell viability (or cell heath in general) are commercially available and can be classified under different categories according to their concepts and principle of reactions. The assays are valuable tools, however, suffer from a large number of limitations. Some of these limitations can be procedural or operational, but others can be critical as those related to a poor concept or the lack of proof of concept of an assay, e.g. those relying on differential permeability of dyes in-and-out of viable versus compromised cell membranes. While the assays can differentiate between dead and live cells, most, if not all, of them can just assess the relative performance of cells rather than providing a clear distinction between healthy and dying cells. The possible impact of relatively high molecular weight dyes, used in most of the assay, on cell viability has not been addressed. More innovative assays are needed, and until better alternatives are developed, setup of current cell-based studies and data interpretation should be made with the limitations in mind. Negative and positive control should be considered whenever feasible. Also, researchers should use more than one orthogonal method for better assessment of cell health.

Some imminent but overlooked preanalytical and analytical challenges currently facing biomarkers and companion diagnostics.

An incredibly high failure rate in the pharmaceutical industry has positioned personalized medicine with its prerequisite drug-diagnostic codevelopment, commonly known as companion diagnostics (CDx), in the frontline as an potential rescuer. This hopefulness is potentiated by the recent major advances and competitiveness in molecular diagnostics, making laboratory tests widely accessible at affordable prices. If executed correctly, biomarkers and CDx can potentially help the drug industry by enhancing the probability of success and possibly accelerating time to market; help the diagnostics industry develop tests utilizing precious, clinically annotated human samples; and, more importantly, benefit patients by supporting accurate diagnosis and selection of the most efficacious and least toxic therapies. However, this spectacular road is not yet paved, and it faces an enormous number of challenges. This paper will list these challenges and highlight some critical problems with representative examples of imminent but still overlooked preanalytical and analytical variables that can defeat the whole purpose of biomarkers and CDx and mislead drug developers and clinicians. The paper will provide some suggestions for mitigation.

Ex vivo reversal of the anticoagulant effects of edoxaban.

INTRODUCTION: Edoxaban is an oral, once-daily direct factor Xa (FXa) inhibitor. Although rapidly cleared, strategies to reverse edoxaban-mediated effects on anticoagulation are needed in cases of excessive bleeding or emergency. This study evaluated the effect of two prohemostatic agents, recombinant factor VIIa (rFVIIa) and factor VIII inhibitor bypass activity (FEIBA), on the anticoagulatory effects of supratherapeutic concentrations of edoxaban in human whole blood ex vivo. MATERIALS AND METHODS: Blood samples were collected from six healthy volunteers. Edoxaban (500 or 1000 ng/mL), alone or followed by rFVIIa (0.8 or 1.8µg/mL) or FEIBA (0.75 or 1.5 U/mL), was added to an aliquot of each sample. Biomarkers, including prothrombin time (PT), activated partial thromboplastin time (aPTT), extrinsic FXa activity (anti-FXa), intrinsic factor X activity, and D-dimer, were assessed at 0.25, 0.5, 1, 2, and 4 hours after adding rFVIIa or FEIBA. RESULTS: Decreases in measures of PT (p<0.0001), aPTT (p<0.0001), and anti-FXa (p<0.0001) were observed when rFVIIa or FEIBA was added to edoxaban-containing blood samples. Intrinsic FX activity was increased up to 20% and 31% of normal in the presence of edoxaban by rFVIIa and FEIBA, respectively. The impact of these agents on the anticoagulant effects of edoxaban were observed within 15 minutes and remained relatively unchanged at each timepoint thereafter. CONCLUSIONS: The findings of this ex vivo study suggest that rFVIIa and FEIBA rapidly reversed edoxaban-mediated anticoagulation effects based on PT and aPTT, but had minimal effect based on intrinsic FX activity. No dose response was observed for rFVIIa or FEIBA.

Population pharmacokinetic-pharmacodynamic modeling analysis of intrinsic FXa and bleeding from edoxaban treatment.

Edoxaban is an oral, once-daily, direct factor Xa (FXa) inhibitor that has been evaluated for the prevention of stroke in patients with atrial fibrillation (AF) and for the treatment and prevention of venous thromboembolism (VTE) recurrence. Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and logistic regression analyses were used to explore the clinical data from phase 1 and 2 studies to determine the relationship among PK exposure, PD response, and bleeding risk. Population PK/PD modeling was performed using plasma edoxaban concentration data from combined phase 1 and 2 studies and using intrinsic FXa data from a phase 2 AF study. A 2-compartment PK model adequately described the combined PK data, and a dynamic binding model characterized the dynamics of the intrinsic factor X activity (iFXa) data. Logistic regression analysis then identified the relationship between the iFXa and the observed bleeding risk. The more protracted suppression of FXa over the dosing interval for a 30-mg twice-daily dose compared with a 60-mg once-daily dose offers an explanation for the significantly higher bleeding rate at the former dose.

The biggest challenges currently facing companion diagnostic advancement.

Low productivity in the pharmaceutical industry positions personalized medicine and companion diagnostics as an attractive approach. The oncology community is enthusiastic and optimistic that advances in molecular diagnostics have the potential to materialize the dream of personalized cancer therapy with the aim to: help the drug industry enhance the probability of success and, probably, accelerate time to market; help the diagnostics industry develop diagnostic tests utilizing precious human samples; and support accurate diagnosis and selection of the most efficacious and least toxic therapies. However, this spectacular road is not yet paved and remains facing the following biggest challenges: the need for better understanding of biology and limitations of preclinical models; pre-analytical variables that are likely to alter results; analytical discrepancies; and the wide gap between clinical/pharmaceutical and diagnostic understandings. This article explores these challenges, their possible impacts, and provides some suggestions for mitigation.

Lipid peroxidation and oxidative stress in rat erythrocytes induced by aspirin and diazinon:the protective role of selenium

Objective:To investigate the adverse effect of exposure to acetylsalicylic acid (ASA), diazinon (DIA) and their combination on oxidant/antioxidant status in rat erythrocytes and the ameliorating role of selenium (Se). Methods: Rats were oral administered ASA at the maximum administration dose (1 350 mg/personal/d=2.5 mg/kg body weight/d), DIA at a dose of 20 mg/kg body weight/d and Se at a dose of 200 μg/kg body weight/d and their combinations for 28 consecutive d. Results: Administration of DIA, ASA and ASA+DIA lead to a significant increment (P≤0.05) in lipid peroxidation as evidenced by the increase in erythrocytes MDA levels by 61.8%, 20.79%and 105.62%, respectively. Co-administration of Se to treated rats modulated the augmentation of MDA levels. Administration of DIA, ASA and ASA+DIA lead to significant decreases (P≤0.05) in the activities of catalase, superoxide dismutase and glutathione peroxidase enzymes when compared to the control group. The most influence and decreases in the activities of the aforementioned enzymes were observed in the treatments of ASA+DIA by 30.53%, 43.42%and 48.31%, respectively. However, co-administration of Se mitigated the significant decreases of superoxide dismutase, catalase and glutathione peroxidase activities to by 14.47%, 15, 36%and 12.29%. Conclusions: It can be concluded that DIA and ASA induced oxidative stress and lipid peroxidation in rat erythrocytes. The results reveal the pronounced ameliorating effect of Se in DIA and ASA intoxicated rats. It is supposed that antioxidant supplementation may be beneficial for the people using ASA for longer periods and exposure to pesticides.

Phase I study of U3-1287, a fully human anti-HER3 monoclonal antibody, in patients with advanced solid tumors.

PURPOSE: HER3 is a key dimerization partner for other HER family members, and its expression is associated with poor prognosis. This first-in-human study of U3-1287 (NCT00730470), a fully human anti-HER3 monoclonal antibody, evaluated its safety, tolerability, and pharmacokinetics in patients with advanced solid tumor. EXPERIMENTAL DESIGN: The study was conducted in 2 parts: part 1--sequential cohorts received escalating doses (0.3-20 mg/kg) of U3-1287 every 2 weeks, starting 3 weeks after the first dose; part 2--additional patients received 9, 14, or 20 mg/kg U3-1287 every 2 weeks, based on observed tolerability and pharmacokinetics from part 1. Recommended phase II dose, adverse event rates, pharmacokinetics, and tumor response were determined. RESULTS: Fifty-seven patients (part 1: 26; part 2: 31) received U3-1287. As no dose-limiting toxicities were reported, the maximum-tolerated dose was not reached. The maximum-administered dose was 20 mg/kg every 2 weeks. The most frequent adverse events related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea (10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient developed anti-U3-1287 antibodies. In these heavily pretreated patients, stable disease was maintained 9 weeks or more in 19.2% in part 1 and 10 weeks or more in 25.8% in part 2. CONCLUSION: U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. Pharmacokinetic data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing.