The Agent Pattern Driven Business Engineering (APBDE) approach enabled business-based systems

Agent design patterns form a new methodology used to improve the development of software agents. Agent design patterns can help by capturing solutions to common problems in agent design [Lange and Oshima, 1998].Agent design patterns are applied in different systems such as knowledge management systems, real-time systems, and network management systems. Agent design patterns for business-based systems, aim to support different ecommerce paradigms business-to-business (B2B) and business-to-consumer (B2C).In this paper, we developed an approach for extracting agent-based design patterns for B2C e-commerce to improve business-based processes.This approach is called an Agent Pattern Driven Business Engineering (APDBE).Based on this approach, we derived two agent-based commerce design patterns namely, the De-coupler Design Pattern (DecDP), and the Dynamic Design Pattern (DynDP). These design patterns are used to support selling/buying-based processes in e-commerce domain

Management of Large Cell Neuroendocrine Carcinoma

Background: Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive cancer with a dismal prognosis. The majority of cases occur in the lung and the gastrointestinal tract; however, it can occur throughout the body. Recently advances in the understanding of the molecular underpinnings of this disease have paved the way for additional novel promising therapies. This review will discuss the current best evidence for management of LCNEC and new directions in the classification and treatment of this rare disease. Methods: We performed a PubMed search for “Large cell neuroendocrine carcinoma” and “High grade neuroendocrine carcinoma.” All titles were screened for relevance to the management of LCNEC. Papers were included based on relevance to the management of LCNEC. Results: Papers were included reviewing both pulmonary and extra pulmonary LCNEC. We summarized the data driven best practices for the management of both early and advanced stage LCNEC. We describe emerging therapies with promising potential. Discussion: LCNEC are rare and aggressive neoplasms. In advanced disease, the historical regimen of platinum based therapy in combination with etoposide or irinotecan remains among the commonly used first line therapies, however for extra thoracic LCNEC regimens like FOLFOX, FOLFOIRI and CAPTEM can also be used. Further effective and safe treatment options are desperately needed. Recently, new advances including a new understanding of the genetic subcategories of LCNEC and immunotherapy agents may guide further treatments

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability

Thyroid hormone regulates distinct paths to maturation in pigment cell lineages

Thyroid hormone (TH) regulates diverse developmental events and can drive disparate cellular outcomes. In zebrafish, TH has opposite effects on neural crest derived pigment cells of the adult stripe pattern, limiting melanophore population expansion, yet increasing yellow/orange xanthophore numbers. To learn how TH elicits seemingly opposite responses in cells having a common embryological origin, we analyzed individual transcriptomes from thousands of neural crest-derived cells, reconstructed developmental trajectories, identified pigment cell-lineage specific responses to TH, and assessed roles for TH receptors. We show that TH promotes maturation of both cell types but in distinct ways. In melanophores, TH drives terminal differentiation, limiting final cell numbers. In xanthophores, TH promotes accumulation of orange carotenoids, making the cells visible. TH receptors act primarily to repress these programs when TH is limiting. Our findings show how a single endocrine factor integrates very different cellular activities during the generation of adult form

Immune Checkpoint Inhibitors in Large Cell Neuroendocrine Carcinoma: Current Status

Introduction: Large cell neuroendocrine carcinomas (LCNEC) are a group of rare high grade neuroendocrine tumors that often behave clinically like small cell carcinoma (SCLC) and are treated as such. No major advancement in the management of these tumors has occurred in the last 30 years. Methods: We present a case series of three cases from Markey Cancer center along with a review of 13 published cases in the literature wherein immune-checkpoint inhibitors were utilized in the management of LCNEC. Results: Immune-checkpoint inhibitors might have clinical activity in LCNEC. Conclusion: Role of immune-checkpoint inhibitors should be explored in prospective LCNEC clinical trials. We summarize current evidence regarding use of immune checkpoint inhibitors in the treatment of LCNEC

Gynecologic Large Cell Neuroendocrine Carcinoma: A Review

Large cell neuroendocrine carcinomas (LCNEC) are rare, aggressive high-grade neuroendocrine neoplasms within the neuroendocrine cell lineage spectrum. This manuscript provides a detailed review of published literature on LCNEC of gynecological origin. We performed a PubMed search for material available on gynecologic LCNEC. We analyzed 104 unique cases of gynecologic LCNECs, of which 45 were cervical primary, 45 were ovarian, 13 were uterine, and 1 was vaginal. A total of 45 cases of cervical LCNEC were identified with a median age of 36 years. Median overall survival was 16 months. We identified 45 ovarian LCNEC cases in the published literature with a median age of 54 years. Median overall survival was 8 months. 13 LCNEC cases of uterine origin were identified; 12 out of 13 were of endometrial origin and the median age was 71 years. The majority of patients presented with Stage III/IV disease (stages I–IV were 31%, 8%, 38%, and 23%, respectively). Gynecologic LCNEC is an aggressive malignancy. Our current understanding of the disease biology is very limited. Efforts are required to better understand the genomic and molecular characterizations of gynecological LCNEC. These efforts will elucidate the underlying oncogenic pathways and driver mutations as potential targets

A Commentary on Ruppeiner Metrics for Black Holes

There has been some recent controversy regarding the Ruppeiner metrics that are induced by Reissner-Nordstrom (and Reissner-Nordstrom-like) black holes. Most infamously, why does this family of metrics turn out to be flat, how is this outcome to be physically understood, and can/should the formalism be suitably modified to induce curvature? In the current paper, we provide a novel interpretation of this debate. For the sake of maximal analytic clarity and tractability, some supporting calculations are carried out for the relatively simple model of a rotating BTZ black hole.Comment: 15 pages; v2, typos corrected and a few references adde

Real World Clinicopathologic Observations of Patients with Metastatic Solid Tumors Receiving Immune Checkpoint Inhibitor Therapy: Analysis from Kentucky Cancer Registry

The state of Kentucky has the highest cancer incidence and mortality in the United States. High‐risk populations such as this are often underrepresented in clinical trials. The study aims to do a comprehensive analysis of molecular landscape of metastatic cancers among these patients with detailed evaluation of factors affecting response and outcomes to immune checkpoint inhibitor (ICI) therapy. We performed a retrospective analysis of metastatic solid tumor patients who received ICI and underwent molecular profiling at our institution. Sixty nine patients with metastatic solid tumors who received ICI were included in the study. Prevalence of smoking and secondhand tobacco exposure was 78.3% and 14.5%, respectively. TP53 (62.3%), CDKN1B/2A (40.5%), NOTCH and PIK3 (33.3%) were the most common alterations in tumors. 67.4% were PDL1 positive and 59.4% had intermediate‐high tumor mutational burden (TMB). Median TMB (12.6) was twofold to fourfold compared to clinical trials. The prevalence of mutations associated with smoking, homologous recombinant repair and PIK3/AKT/mTOR pathway mutations was higher compared to historic cohorts. PDL1 expression had no significant effect on radiologic response, but PFS improvement in patients with tumors expressing PDL1 trended toward statistical significance (median 18 vs. 40 weeks. HR = 1.43. 95%CI 0.93, 4.46). Median PFS was higher in the high‐TMB cohort compared to low‐intermediate TMB (median not reached vs. 26 weeks; HR = 0.37. 95%CI 0.13, 1.05). A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks. HR = 2.51. 95%CI 1.23, 5.14). This was independent of tumor mutational burden (TMB) status or PDL1 expression status. PIK3 mutants had a higher overall response rate than the wild type (69.6% vs. 43.5%, OR 0.34; p = 0.045). The results should prompt further evaluation of these potential biomarkers and more widespread real‐world data publications which might help determine biomarkers that could benefit specific populations

Diagnosis of Infection After Splenectomy for Trauma Should be Based on Lack of Platelets Rather Than White Blood Cell Count

Background: There is a lack of evidence-based criteria to assist the diagnosis of infection following trauma splenectomy (TS). However, the literature suggests that white blood cell count (WBC) is associated with infection in patients who undergo TS. We sought to find whether there exist key differences in laboratory and clinical parameters that can assist the diagnosis of infection after TS. Methods: We evaluated all consecutive trauma patients who had undergone TS at a Level 1 trauma center from 2005 to 2011 for the development of infection. To do this, we compared the values of demographic, laboratory, and clinical variables of infected and non-infected patients on odd post-operative days (POD) in the period from 1–15 days after TS. Results: Of 127 patients who underwent TS, 25 died within 48 h after the procedure and were excluded from our analysis, leaving, 102 patients for investigation. In the 41 (40%) patients who developed an infection, the mean day for the first infectious episode was POD 7 (range, POD 4–14). The three most common infections were pneumonia (51%), urinary tract infection (24%), and bacteremia (20%). An evaluation of laboratory and clinical parameters showed no differences in the WBC of the patients who did and did not develop infections at any time in the 15 d after TS. However, the platelet count was statistically significantly higher in non-infected patients on POD 3–9 and on POD 13, and maximal body temperature was statistically significantly higher in the infected group of patients during the first week after TS. Differences in laboratory and clinical values of the infected and non-infected patients were greatest on POD 5. Conclusions: Patients who undergo TS have high rates of infectious complications. The WBC is not a reliable predictor of infection in these patients in the 2 wks following TS. However, patients who do not develop infection after TS have statistically significantly higher absolute platelet counts and rates of change in their daily platelet counts than those who develop infection