Paul Clairmont and his connections to American surgery.

PURPOSE: To examine the life and influences of Paul Clairmont (1875-1942). METHOD: Review and analysis of published and archival information. RESULTS: The Clairmont family was associated with famous individuals in English literary history. Paul Clairmont himself was born, educated, and trained as a surgeon under Anton von Eiselsberg in Vienna. As a junior faculty member in 1908, he was the first general surgeon to publish a report for German readers on the remarkable progress of American surgery. Later, as Professor of Surgery in Zürich, he was a mentor to Alton Ochsner, who became a leader in the further development of surgery in the USA. CONCLUSION: Paul Clairmont's interesting life was an important link between the classical science and practice of surgery in Europe and its continuation in America.

The International Abstract of Surgery and the migration of scientific leadership from Europe to America.

PURPOSE: The International Abstract(s) of Surgery (IAS) was a monthly supplement to Surgery, Gynecology & Obstetrics (SG&O, later Journal of the American College of Surgeons) from 1913-1994, approximately equal in size to the journal itself. It followed the example of the Zentralblatt für Chirurgie (ZblCh), which had been compiling abstracts of the current world surgical literature since 1874 (but in the German language). This article seeks to review the relationships of these surgical abstract journals in historical context. METHODS: Citations in the IAS were systematically sampled for 1913-1990, and in the ZblCh and other American and German surgical publications for 1905-1940. Changes in the proportions of citations by language category were tabulated over time and related to concurrent international events and the publication histories of the sampled journals. RESULTS: German-language citations were most frequent until the First World War, even in America. They subsequently became less frequent in America, but remained dominant in Germany. Articles in French or other languages were occasionally cited by Americans, but in German publications, they were cited as frequently as those in English. Contemporary observations from this time confirm that the American literature was being disregarded by most German surgeons. Since the Second World War, surgical publications have become predominantly English-language, even in Germany, and printed abstract compilations have become irrelevant. CONCLUSIONS: The history of the IAS and ZblCh reflects world events of the early twentieth century, the isolation and decline of German scientific leadership, the rise of American surgery, and the transition from a multilingual print-based era to one where scientific communication is primarily electronic and in English.

Upfront resection versus neoadjuvant therapy for T1/T2 pancreatic cancer.

BACKGROUND: The role of neoadjuvant therapy remains controversial for resectable pancreatic neoplasms. We evaluated treatment outcomes for T1/T2 tumors. METHODS: Retrospective study of patients with T1/T2 (Stage I-II) pancreatic cancer within the NCDB. Treatment-sequence variables were used for classification: "surgery + chemotherapy" (S+C), "chemotherapy + surgery" (C+S), "surgery only" (SO), and "chemotherapy only" (CO). RESULTS: 13 412 patients were included; the majority had T2 tumors. 8 490 received upfront surgery; 4 922 preoperative chemotherapy. In the surgery branch, 5 684 received surgery and chemotherapy (S+C); 2 806 did not receive chemotherapy (SO). Of those intended to receive preoperative chemotherapy, 3 804 received only chemotherapy (CO); 1 118 proceeded to surgery (C+S). Median survival for S+C and C+S groups was similar (25.9 vs 26.2) [HR 0.92, p= 0.41]. Compared to the CO group, the SO group had improved median survival (13.5 vs. 10.8) [HR 0.63, p<0.001]. Branched analyses demonstrated improved median and 5-year (20.8% vs 12.7%) survival for patients receiving upfront resection [HR 0.77, p<0.001]. CONCLUSION: Patients with T1/T2 pancreatic cancer have similar survival irrespective of the timing of chemotherapy and surgery, if they receive both. Upfront resection ensures surgery is delivered, increasing the possibility of long-term survival.

Virtual Screening: Is Bigger Always Better? Or Can Small Be Beautiful?

This viewpoint is intended to counterbalance some recent publications describing large-scale virtual screening by illustrating how success in launching drug discovery projects has been achieved with much more modest resources. Two examples of small-scale virtual screening that led to the discovery of clinical candidates are cited in favor of this argument.

Automated De Novo Drug Design: Are We Nearly There Yet?

Medicinal chemistry and, in particular, drug design have often been perceived as more of an art than a science. The many unknowns of human disease and the sheer complexity of chemical space render decision making in medicinal chemistry exceptionally demanding. Computational models can assist the medicinal chemist in this endeavour. Provided here is an overview of recent examples of automated de novo molecular design, a discussion of the concepts and computational approaches involved, and the daring prediction of some of the possibilities and limitations of drug design using machine intelligence.

Procedure-based postoperative risk prediction using NSQIP data.

BACKGROUND: The National Surgical Quality Improvement Program (NSQIP) has proposed using procedure-based hierarchical models to predict adverse outcomes, but it is not clear whether this approach was used to develop the NSQIP "Surgical Risk Calculator". We therefore wished to demonstrate how procedure-based hierarchical models can be constructed and to describe their results. METHODS: NSQIP data from 2015 were used to construct statistical models predicting 30-day postoperative mortality and morbidity, using two-level logistic regression with preoperative patient-level variables as fixed effects and procedure-specific codes as a random intercept. Model performance was validated using NSQIP data from 2014. RESULTS: NSQIP for 2015 contained records for 885,502 patients, of whom 8986 died (1.0%) and 104,836 suffered a complication (11.8%). Complete model specifications and results are presented, including odds ratios for patient-level variable effects and random procedure effects. Most comorbidities were associated with increased morbidity and mortality, but overweight and obesity were associated with lower risk. Odds ratios for individual procedures ranged from 0.117 to 10.85 for mortality and from 0.615 to 8.09 for morbidity. Validation C-statistics were 0.940 for the mortality model and 0.833 for the morbidity model; Brier Scores were 0.0086 and 0.085, respectively. Graphs for 20 quantiles showed good conformity of observed and predicted risk. CONCLUSIONS: Procedure-based hierarchical logistic regression models of NSQIP outcomes had satisfactory overall performance statistics. Model specifications and results are provided for criticism and improvement, and several possible refinements are suggested.

Ethanolamine Signaling Promotes Salmonella Niche Recognition and Adaptation during Infection.

Chemical and nutrient signaling are fundamental for all cellular processes, including interactions between the mammalian host and the microbiota, which have a significant impact on health and disease. Ethanolamine is an essential component of cell membranes and has profound signaling activity within mammalian cells by modulating inflammatory responses and intestinal physiology. Here, we describe a virulence-regulating pathway in which the foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) exploits ethanolamine signaling to recognize and adapt to distinct niches within the host. The bacterial transcription factor EutR promotes ethanolamine metabolism in the intestine, which enables S. Typhimurium to establish infection. Subsequently, EutR directly activates expression of the Salmonella pathogenicity island 2 in the intramacrophage environment, and thus augments intramacrophage survival. Moreover, EutR is critical for robust dissemination during mammalian infection. Our findings reveal that S. Typhimurium co-opts ethanolamine as a signal to coordinate metabolism and then virulence. Because the ability to sense ethanolamine is a conserved trait among pathogenic and commensal bacteria, our work indicates that ethanolamine signaling may be a key step in the localized adaptation of bacteria within their mammalian hosts.

Discovery of LRRK2 inhibitors by using an ensemble of virtual screening methods.

In this paper, we present the results of a ligand- and structure-based virtual screen targeting LRRK2, a kinase that has been implicated in Parkinson's disease. For the ligand-based virtual screen, the structures of 12 competitor compounds were used as queries for a variety of 2D and 3D searches. The structure-based virtual screen relied on homology models of LRRK2, as no X-ray structure is currently available in the public domain. From the virtual screening, 662 compounds were purchased, of which 35 showed IC50 values below 10µM in wild-type and/or mutant LRRK2 (a hit rate of 5.3%). Of these 35 hits, four were deemed to have potential for medicinal chemistry follow-up.

Application of virtual screening to the discovery of novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with potential for the treatment of cancer and axonopathies.

NAMPT may represent a novel target for drug discovery in various therapeutic areas, including oncology and inflammation. Additionally, recent work has suggested that targeting NAMPT has potential in treating axon degeneration. In this work, publicly available X-ray co-crystal structures of NAMPT and the structures of two known NAMPT inhibitors were used as the basis for a structure- and ligand-based virtual screening campaign. From this, two novel series of NAMPT inhibitors were identified, one of which showed a statistically significant protective effect when tested in a cellular model of axon degeneration.

Codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival.

Stress granules aid cell survival in response to environmental stressors by acting as sites of translational repression. We report an unanticipated link between stress granules and the serine/threonine kinase RSK2. In stressed breast cells, endogenous RSK2 colocalizes in granules with TIA-1 and poly(A)-binding protein 1, and the sequestration of RSK2 and TIA-1 exhibits codependency. The RSK2 N-terminal kinase domain controls the direct interaction with the prion-related domain of TIA-1. Silencing RSK2 decreases cell survival in response to stress. Mitogen releases RSK2 from the stress granules and permits its nuclear import via a nucleocytoplasmic shuttling sequence in the C-terminal domain. Nuclear accumulation is dependent on TIA-1. Surprisingly, nuclear localization of RSK2 is sufficient to enhance proliferation through induction of cyclin D1, in the absence of other active signaling pathways. Hence, RSK2 is a pivotal factor linking the stress response to survival and proliferation.

From virtual to clinical: The discovery of PGN-1531, a novel antagonist of the prostanoid EP4 receptor.

In this Letter, we present the results of a hit-finding and lead optimization programme against the EP4 receptor (EP4R). In a short time period, we were able to discover five structurally diverse series of hit compounds using a combination of virtual screening methods. The most favoured hit, compound 6, was demonstrated to be a competitive antagonist of the EP4R. Compound 73 was identified following several rounds of optimization, which centred on improving both the primary EP4R affinity and selectivity against the related EP2R as well as the aqueous solubility. This work culminated in the preparation of PGN-1531, the sodium salt of 73, which showed a marked improvement in solubility (>10 mg/mL). PGN-1531 is a potent and selective antagonist at EP4Rs in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation.

Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV.

The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.

Canine Atopic Dermatitis: Prevalence, Impact, and Management Strategies.

Atopic dermatitis (AD) is a common inflammatory and pruritic allergic skin disease in humans and dogs worldwide. The pathogenesis of AD is multifactorial, immunologically complex, and may involve genetic factors, epidermal barrier dysfunction, microbiome changes, immune dysregulation, and allergic sensitization. Across species, prevalence of AD is on the rise. At present, there is no cure for canine AD (CAD). The treatment for CAD is multifaceted and aimed at controlling the pruritus, associated inflammation, and infections, repairing the skin barrier function, and dietary management. This review presents data on prevalence, impact, and complex immunological interactions in AD with a focus on subsequent management of the disease in the canine population. A multimodal approach for management of CAD to address varying clinical signs and responses to therapies is discussed.

EutR is a direct regulator of genes that contribute to metabolism and virulence in enterohemorrhagic Escherichia coli O157:H7.

Ethanolamine (EA) metabolism is a trait associated with enteric pathogens, including enterohemorrhagic Escherichia coli O157:H7 (EHEC). EHEC causes severe bloody diarrhea and hemolytic uremic syndrome. EHEC encodes the ethanolamine utilization (eut) operon that allows EHEC to metabolize EA and gain a competitive advantage when colonizing the gastrointestinal tract. The eut operon encodes the transcriptional regulator EutR. Genetic studies indicated that EutR expression is induced by EA and vitamin B12 and that EutR promotes expression of the eut operon; however, biochemical evidence for these interactions has been lacking. We performed EA-binding assays and electrophoretic mobility shift assays (EMSAs) to elucidate a mechanism for EutR gene regulation. These studies confirmed EutR interaction with EA, as well as direct binding to the eutS promoter. EutR also contributes to expression of the locus of enterocyte effacement (LEE) in an EA-dependent manner. We performed EMSAs to examine EutR activation of the LEE. The results demonstrated that EutR directly binds the regulatory region of the ler promoter. These results present the first mechanistic description of EutR gene regulation and reveal a novel role for EutR in EHEC pathogenesis.

Racial disparities in survival among injured drivers.

Prior studies on racial and ethnic disparities in survival after motor vehicle crashes have examined only population-based death rates or have been restricted to hospitalized patients. In the current study, we examined 3 components of crash survival by race/ethnicity: survival overall, survival to reach a hospital, and survival among those hospitalized. Nine years of data (from 2000 through 2008) from the National Automotive Sampling System Crashworthiness Data System were used to examine white non-Hispanic, black non-Hispanic, and Hispanic drivers aged ≥ 15 years with serious injuries (injury severity scores of ≥ 9). By using multivariable logistic regression, we found that a driver's race/ethnicity was not significantly associated with overall survival after being injured in a crash (for blacks, odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.36, 1.32; for Hispanics, OR = 1.00, 95% CI: 0.59, 1.72), and blacks and Hispanics were equally likely to survive to be treated at a hospital compared with whites (for blacks, OR = 1.00, 95% CI: 0.52, 1.93; for Hispanics, OR = 1.13, 95% CI: 0.71, 1.79). However, among patients who were treated at a hospital, blacks were 50% less likely to survive 30 days compared with whites (OR = 0.50, 95% CI: 0.33, 0.76). The disparity in survival after serious traffic injuries among blacks appears to occur after hospitalization, not in prehospital survival.

Effect of chronic oral anticoagulation with warfarin on the durability and outcomes of endovascular aortic aneurysm repair.

OBJECTIVE: Endoleak after endovascular aortic aneurysm repair (EVAR) can affect the durability of the repair and lead to continued sac expansion, rupture, and the need for further endovascular or open surgical interventions. The purpose of this study was to determine whether chronic anticoagulation therapy with warfarin is associated with an increased incidence of endoleak and thus increased need for reintervention after EVAR. METHODS: We reviewed the records of 401 consecutive patients who underwent EVAR at a single institution from 2003 until 2011. Patients on warfarin were compared with a control group not on warfarin. Primary endpoints included reintervention, defined as rupture, explant, or angiography; death from any cause; and a composite outcome of reintervention or death. The presence of an endoleak at last follow-up, identified by computed tomography or ultrasound scan, and increase of more than 5 mm in aneurysm sac size were secondary endpoints. Cox proportional hazards models were used to estimate the effect of warfarin use on the primary and secondary outcomes, controlling for age, gender, obesity, specific comorbidities, antiplatelet drugs, statin use, and urgency of EVAR. RESULTS: Three hundred sixty-three patients with a median follow-up period of 29 months had sufficient data for analysis. Warfarin use was not associated with an increased risk of any of the primary endpoints. Controlling for covariates and length of observation via proportional hazards models, the effect of warfarin remained insignificant. It was found, however, on regression analysis, that adverse outcomes were more prevalent after emergency EVAR and in patients deemed unfit for open surgical repair. CONCLUSIONS: Chronic oral anticoagulation does not appear to affect the incidence of endoleak after EVAR, nor does it impact the need for reintervention or degree of sac regression. We feel that warfarin may be safely used in post-EVAR patients. It appears that adverse long-term outcomes are more likely after emergency EVAR and in patients deemed unfit for open surgery.

Preoperative downstaging of pancreatic cancer is associated with improved survival after multi-agent chemotherapy, but not after radiation.

BACKGROUND: Downstaging has been associated with improved survival for many cancers. However, the implications of downstaging are unclear for pancreatic cancer in an era of effective neoadjuvant systemic chemotherapy. METHODS: NCDB retrospective cohort study of resected pancreatic carcinoma treated with neoadjuvant therapy. RESULTS: The study included 73,985 patients: 66,589 with no neoadjuvant therapy, 2,102 neoadjuvant radiation therapy (N-RT), 3,195 neoadjuvant multiagent chemotherapy (N-MAC) and 2.099 with both neoadjuvant radiation and multiagent chemotherapy. There was increased use of N-MAC over the period of this study. Patients selected for treatment with N-MAC had longer survival from surgery on univariate (23.1 vs. 18.7 months, p = < 0.01) and multivariate analyses HR 0.81 (0.76-0.87, p < 0.001) compared to those selected with N-RT. Downstaging was similar in N-RT and N-MAC groups (25.1 vs. 24.1%, p = 0.43). Downstaging following N-MAC was associated with a survival benefit, HR 0.85 (0.74-0.98). However, downstaging following N-RT was not associated with a survival advantage, HR 1.12 (0.99-0.99). CONCLUSION: Clinicians have rapidly adopted N-MAC for treatment of pancreatic cancer. Although the rates of downstaging are similar between treatment groups, response translates into increased survival only with N-MAC and not with N-RT.

Analogs of the RSK inhibitor SL0101: optimization of in vitro biological stability.

The Ser/Thr protein kinase, RSK, is important in the etiology of tumor progression including invasion and motility. The natural product kaempferol-3-O-(3″,4″-di-O-acetyl-α-l-rhamnopyranoside), called SL0101, is a highly specific RSK inhibitor. Acylation of the rhamnose moiety is necessary for high affinity binding and selectivity. However, the acetyl groups can be cleaved by esterases, which accounts for the poor in vitro biological stability of SL0101. To address this problem a series of analogs containing acetyl group replacements were synthesized and their in vitro stability evaluated. Monosubstituted carbamate analogs of SL0101 showed improved in vitro biological stability while maintaining specificity for RSK. These results should facilitate the development of RSK inhibitors derived from SL0101 as anticancer agents.