To test the diagnostic approach described in part 1 of this article, 2 exercises were completed by pathologists from multiple companies/agencies. Pathologist's examination of whole slide image (WSI) heart sections from rats using personal diagnostic approaches (exercise #1) corroborated conclusions from study #1. Using the diagnostic approach described in part 1, these pathologists examined the same WSI heart sections (exercise #2) to determine whether that approach increased consistency of diagnosis of rodent progressive cardiomyopathy (PCM) lesions. In exercise #2, there was improved consistency of categorization of small borderline morphologies and mild lesions, but a decrement in consistency of categorizing minimal lesions. Exercises 1 and 2 suggest the described diagnostic approach is representative of that in use by the majority of toxicologic pathologists across companies/agencies and that application by all may improve diagnostic consistency of PCM/like lesions. Additionally, a criterion of approximately 5% heart section involvement is suggested for separating mild from moderate or greater severity. While evidence is not absolute, until further investigation shows otherwise, microscopic changes resembling PCM, but located in the epicardial and subepicardial region of the right ventricle, may be considered as part of the spectrum of PCM.

C-H functionalization is a very active research field that has attracted the interest of scientists from many disciplines. This Outlook describes the collaborative efforts within the NSF CCI Center for Selective C-H Functionalization (CCHF) to develop catalyst-controlled selective methods to enhance the synthetic potential of C-H functionalization.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTRecent Advances in C–H FunctionalizationHuw M. L. Davies and Daniel MortonView Author Information Department of Chemistry, Emory UniversityCite this: J. Org. Chem. 2016, 81, 2, 343–350Publication Date (Web):January 15, 2016Publication History Published online15 January 2016Published inissue 15 January 2016https://pubs.acs.org/doi/10.1021/acs.joc.5b02818https://doi.org/10.1021/acs.joc.5b02818editorialACS PublicationsCopyright © 2016 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views42947Altmetric-Citations516LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (2 MB) Get e-AlertscloseSUBJECTS:Aromatic compounds,Catalysts,Chemical reactions,Functionalization,Selectivity Get e-Alerts

Dose selection for the 6-month rasH2 mouse carcinogenicity studies depends heavily on the maximum tolerated dose (MTD) obtained from 1-month range-finding studies. A retrospective evaluation of range-finding studies and pivotal 6 month rasH2 mouse studies for 11 compounds demonstrated that the MTD based on at least a 10% decrease in body weight gain, mortality, and target organ toxicity in range-finding studies appropriately identified high doses for pivotal studies for 8 of 11 compounds. Two of the selected high doses were based on decreased body weight gain alone, while 7 were based on mortality at higher doses in shorter duration range-finding studies. High-dose selection was based on the maximum feasible dose for one study. The Center for Drug Evaluation and Research, U.S. Food and Drug Administration Executive Carcinogenicity Assessment Committee often suggested different doses than those proposed by the sponsor. High mortality was observed in only one pivotal study and the high dose was lowered during the course of that study.

RETURN TO ISSUEPREVNewsNEXTA New Collaborative Approach For Chemists and Cite this: Chem. Eng. News 2015, 93, 39, 32–33Publication Date (Print):October 5, 2015Publication History Published online30 March 2016Published inissue 5 October 2015https://pubs.acs.org/doi/10.1021/cen-09339-scitech2https://doi.org/10.1021/cen-09339-scitech2newsACS PublicationsCopyright © 2015 Chemical & Engineering NewsArticle Views4Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access options SUBJECTS:Organic synthesis Get e-Alerts

Transition-metal-stabilized carbenes, or carbenoids, have been the subject of significant interest in the synthetic community, being capable and effective intermediates in a multitude of transformations. Of particular note is their ability to perform C H insertion reactions in a highly stereoand enantioselective fashion. Two key techniques have emerged that influence the reactivity of these transient intermediates: 1) variation of the steric and electronic nature of the substituents that flank the carbene carbon and 2) the design of efficient catalysts that can stabilize and mediate the reactivity of the carbene. Early work in this area focused on the dirhodium-catalyzed reaction of acceptorand acceptor–acceptor-substituted carbenoids (Figure 1). These highly electrophilic carbenoids found

The toxicity of hydroxyurea, a treatment for specific neoplasms, sickle-cell disease, polycythemia, and thrombocytosis that kills cells in mitosis, was assessed in repeat-dose, oral gavage studies in rats and dogs and a cardiovascular study in telemetered dogs. Hydroxyurea produced hematopoietic, lymphoid, cardiovascular, and gastrointestinal toxicity with steep dose response curves. In rats dosed for 10 days, 50 mg/kg/day was tolerated; 500 mg/kg/day produced decreased body weight gain; decreased circulating leukocytes, erythrocytes, and platelets; decreased cellularity of thymus, lymph nodes, and bone marrow; and epithelial degeneration and/or dysplasia of the stomach and small intestine; 1,500 mg/kg/day resulted in deaths on day 5. In dogs, a single dose at ≥ 250 mg/kg caused prostration leading to unscheduled euthanasia. Dogs administered 50 mg/kg/day for 1 month had decreased circulating leukocytes, erythrocytes, and platelets; increased bone marrow cellularity with decreased maturing granulocytes; increased creatinine kinase activity; and increased iron pigment in bone marrow and hepatic sinusoidal cells. In telemetered dogs, doses ≥ 15 mg/kg decreased systolic blood pressure (BP); 50 mg/kg increased diastolic BP, heart rate, and change in blood pressure over time (+dP/dt), and decreased QT and PR intervals and maximum left ventricular systolic and end diastolic pressures with measures returning to control levels within 24 hr.

In many fields of academic scientific research, collaborations come about quite naturally. One discipline, however, that has tended not to follow this pattern is organic synthesis. That is not to say that organic chemists don't collaborate, but synthetic organic chemistry is primarily considered an enabling science. Advances in synthesis empower research in many other fields, and synthetic organic chemists are often actively engaged in interdisciplinary collaboration. However, it is rare to find synthetic organic chemists collaborating with each other toward a goal within their own discipline. Many arguments could be put forth for this lack of cooperation, but perhaps the most convincing is that organic chemistry, compared to many other fields, when most effective, is readily accessible. It does not rely upon highly sophisticated instrumentation or facilities that are available only to a few. A fantastic new synthetic method would ideally be extremely easy to perform from readily available materials. So, what really distinguishes a research program in organic synthesis are the ideas behind the work. As a consequence, sharing one's most exciting research ideas and insights with other organic chemists is risky, because, in principle, it would not require too much effort for an organic chemist to take advantage of an open exchange of ideas with another. Hence, synthetic organic chemists need to establish a high level of trust before they can effectively collaborate within their own discipline.1 1 An area of intense interest at the heart of modern organic synthesis is CH functionalization. The development of techniques that can predictably modify CH bonds selectively would fundamentally change the logic of organic synthesis; the CH bonds would become the favored reaction partners and the "functional groups" would be relegated to structural adornments. Of course, in order to achieve such a scenario many massive challenges must be met. Certainly, free radical reactions have taught us that the selective functionalization of the least stable CH bond is possible, but the ability to precisely control product selectivity in functional-group-containing molecules possessing multiple, disparate CH bonds is the defining challenge for this field. In recent years, several significant advances have been made in the field of CH functionalization. New reagents and various transition-metal catalysts, originating from the organometallic community, have revealed the possibility of achieving truly selective CH functionalization methods. Many of the early studies focused on simple organic substrates. However, in order for this field to develop, it was necessary to move beyond simple substrates to be challenged in more complex molecular scaffolds. To make this leap and develop this transformation from a novelty into a practical synthetic process, the fundamentals of the reaction mechanism would need to be thoroughly understood. This would require advanced theoretical, mechanistic, and experimental analysis as these organometallic systems are often complex with subtle controlling factors. New catalysts, new reagents, and improved reaction engineering would be required to ensure that the methodology is robust, cost-effective, and sustainable. For CH functionalizations, predictive rules need to be developed to define what CH bonds are likely to react in a complex molecular setting; these results must be taken into account in synthesis design (retrosynthesis). Ideally these academic explorations would be conducted in partnership with industry to ensure that the developing methodologies are rapidly applied to "real world" synthetic problems (see schematic overview).1 The challenges faced when introducing a whole new way of thinking about constructing organic molecules are exponentially greater than those for developing a single new reaction and certainly beyond the grasp of a single investigator. To meet the challenges associated with bringing CH functionalization into the mainstream of synthetic chemistry, a multifaceted approach is required. Therefore, in 2009 we responded to a solicitation from the National Science Foundation for a Phase I Center in Chemical Innovation. The founding team of the Center for Selective CH Functionalization (CCHF; see http://www.nsf-cchf.com/), consisted of one computational chemist (Jamal Musaev) and five synthetic chemists with expertise in not only designing new catalysts and synthetic methods in CH functionalization, but also understanding the logic of the synthesis of complex molecules (Simon Blakey, Huw Davies, Justin Du Bois, Christina White, and Jin-Quan Yu). When we started, none of us had collaborated together, and even though our research programs were complementary, many in the field would have considered us as potential competitors rather than collaborators. Our first meeting was a very exciting affair, devoting a one-day symposium to sharing our established research programs and then a second day of brainstorming in which we had to let go of our usual scientific reservations, so that we could find some common ground, which eventually became the foundation of our Center. Phase I funding lasted three years and was considered to be a pilot project for preparing the group to apply to become a much larger Phase II Center. For us the Phase I period was crucial because we needed to build trust and to explore whether the concept of conducting one's research within a collaborative team was advantageous. During this time, we also needed to expand the team from the central core of methodology developers. The growth was carefully planned, focusing on the addition of people who were not only excellent scientists, but also likely to embrace the collaborative dynamic we were building. The current members of the Center, as well as their areas of expertise and institutions are given in Table 1. Early on, the team developed a very close partnership with Novartis Institutes for BioMedical Research, facilitated by Larry Hamann, so that results can be quickly tested for their utility in the synthesis of pharmaceuticals. During the first phase of funding this team began working together and making the connections that were compelling in the justification of a Phase II Center that was awarded in 2012. Member Area Institution John Berry Inorganic University of Wisconsin Donna Blackmond Kinetics The Scripps Research Institute, La Jolla Simon Blakey Methodology Emory University Andy Borovik Inorganic University of California, Irvine Huw Davies Methodology Emory University Justin Du Bois Methodology Stanford University Stefan France Methodology Georgia Institute of Technology Ken Houk Theory University of California, Los Angeles Chris Jones Chemical engineering Georgia Institute of Technology Jared Lewis Bioinorganic University of Chicago Christine Luscombe Organic materials University of Washington Cora MacBeth Inorganic Emory University Seth Marder Organic materials Georgia Institute of Technology John Montgomery Methodology University of Michigan Mo Movassaghi Total synthesis Massachusetts Institute of Technology Jamal Musaev Theory Emory University Richmond Sarpong Methodology University of California, Berkeley David Sherman Bioinorganic University of Michigan Matt Sigman Physical organic University of Utah Eric Sorensen Total synthesis Princeton University Brian Stoltz Total synthesis California Institute of Technology Jin-Quan Yu Methodology The Scripps Research Institute, La Jolla Richard Zare Mechanistic studies Stanford University So, how do 23 research groups, located over 15 universities, many of which could easily be in direct competition with each other, manage to collaborate? Effective, open, and stimulating communication is essential. Every week we meet over our videoconference system for technical–scientific discussions, logistical issues, and Center updates. When Phase II funding was awarded, we arranged a Center-wide symposium at Emory University to move the ideas we had on paper into real collaborations in a face-to-face setting. This was a crucial meeting because the whole group needed to gain confidence with letting down their scientific guards so that we could share ideas. This behavior is so unusual within the organic chemistry community that we spent half a day discussing our expectations and what would be best practices for engagement (look for collaborations first, avoid competition with/within the Center, be a doer not a listener, etc.). The meeting provided an excellent environment for open scientific exchanges with the experts in one's field, without fear of competition, something that can be difficult to find. We have organized the Center into six thematic areas and every week we discuss technical details around a specific theme. Even though only about six groups would be nominally connected to each theme we typically have about 20 groups joining each meeting because we encourage continuous exploration of new collaborative opportunities. The enthusiasm level of the faculty and students has been incredibly high because everyone feels that their research programs are greatly enriched from the collaborative atmosphere. This is one of the key strengths of the Center community network, ongoing research projects are presented to a large and diverse audience of faculty and student peers and the discussion and feedback generated are very helpful. Organization and engagement is also essential for such a geographically dispersed collective to operate effectively. Members have demonstrated an exceptional level of commitment to the collaborative network, not simply in terms of the scientific engagement, but also involvement in the integrative activities of the Center. This has been facilitated by a management team based at Emory University consisting of a Director (Huw Davies), Managing Director (Daniel Morton), and Education, Outreach, and Diversity Director (Monya Ruffin). A Governance Committee, a Scientific Advisory Board, and a Student Advisory Board help guide Center activities. How is this approach affecting the research? Since its inception, the Center has published over 70 papers, over half of which have multiple faculty members as co-authors. Through a combination of computational and experimental studies, we have gained not only a greater understanding of the chemistry, but also begun to develop predictive systems to lead our studies. Some excellent examples include the first characterization of a dirhodium carbenoid, the analysis, understanding and predication of site-selectivity in CH amination, and the modelling and prediction of remote CH activation templates. Collaborations between the methodology and total-synthesis groups have led to streamlined synthesis of complex targets and the design of more robust CH functionalization methods for skeletal construction and late-stage CH functionalization. The Center has also found traction with some of the "real-world" challenges brought to the community, preparing novel electron-transport polymer building blocks inaccessible through known methods and developing techniques to expand substrate scopes to more pharmaceutically applicable systems. How is this approach affecting the researchers? Cultivating a research community has revealed benefits, for faculty and students alike, beyond what we imagined. The open and free exchange of ideas and feedback provide a research environment and experience unlike that possible in an individual group setting. We hope this enables and empowers our members to be better communicators and collaborators in the future. Collaboration does not stop at the door. The Center has collaborative projects beyond its membership, with projects, either active or completed, that have included over ten different research groups from across the USA. We are currently making global connections to partners in Asia and Europe. The Center is also developing a new mechanism to facilitate engagement with industrial partners. We have benefited from an extremely fruitful partnership with Novartis that has challenged the way we think about our chemistry and while we are strengthening this relationship we are exploring ways to engage with other industries from across the chemical sciences. Ultimately through our scientific work and educational activities we aim to not only bring CH functionalization to the mainstream attention of the chemical community, but also to train chemists who can take advantage of the benefits a collaborative network creates.

Administration of lersivirine, a nonnucleotide reverse transcriptase inhibitor, daily by oral gavage to Sprague-Dawley rats for up to 2 yr was associated with decreased survival, decreased body weights, and an increase in neoplasms and related proliferative lesions in the liver, thyroid, kidney, and urinary bladder. Thyroid follicular adenoma and carcinoma, the associated thyroid follicular hypertrophy/hyperplasia, hepatocellular adenoma/adenocarcinoma, altered cell foci, and hepatocellular hypertrophy were consistent with lersivirine-related induction of hepatic microsomal enzymes. Renal tubular adenoma and renal tubular hyperplasia were attributed to the lersivirine-related exacerbation of chronic progressive nephropathy (CPN), while urinary bladder hyperplasia and transitional cell carcinoma in the renal pelvis and urinary bladder were attributed to urinary calculi. Renal tubular neoplasms associated with increased incidence and severity of CPN, neoplasms of transitional epithelium attributed to crystalluria, and thyroid follicular and hepatocellular neoplasms related to hepatic enzyme induction have low relevance for human risk assessment.

In a 2-year rat carcinogenicity study, pegvisomant injected subcutaneously on a daily basis at doses of 0, 2, 8, or 20 mg/kg/day produced malignant fibrous histiocytomas (MFHs) at the injection sites of 3 male rats (5%) given 8 mg/kg/day and 5 males (8%) given 20 mg/kg/day. MFH was characterized by unencapsulated dermal and subcutaneous sheets of fusiform and spindle-shaped cells sometimes with areas of round and/or irregular, pleomorphic cells and variable numbers of large multinucleated giant cells. Some regions of MFH had a fibroblastic appearance with streaming cells forming storiform patterns, while other areas consisted primarily of round to plump irregular cells with more giant cells. Pegvisomant did not increase the incidence of MFH in female rats and did not produce any other neoplastic responses in rats. In the dermis and subcutis at the injection sites of many males and females, pegvisomant produced dose-related increased incidences and severity of histiocytic infiltrates consisting of vacuolated macrophages with variable mature or immature fibrous tissue. Neoplasms at injection sites did not result in marketing restrictions or a label warning for human cancer risk, highlighting that injection-site neoplasms in rats have low relevance for human risk assessment.

During 2011, International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice (INHAND) Global Editorial Steering Committee representatives had discussions with representatives of the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER), Clinical Data Interchange Standards Consortium (CDISC), and the National Cancer Institute (NCI) Enterprise Vocabulary Services (EVS) to examine the potential use of INHAND terminology for SEND (Standard for Exchange of Nonclinical Data) submissions to the FDA. The interest in utilizing the INHAND nomenclature, based on input from industry and government toxicologists as well as information technology specialists, suggests that there will be wide acceptance of INHAND nomenclature. The purpose of this article is 2-fold: (1) to provide a brief historical background on the development of SEND and how it is structured and (2) to discuss the impact of SEND on toxicologic pathology and the role of INHAND.

Auf vielen Gebieten der akademischen Forschung ist Zusammenarbeit etwas ziemlich Natürliches. Eine Disziplin allerdings, auf die dieses Muster nicht unbedingt zutrifft, ist die organische Synthese. Das soll nicht bedeuten, dass Organiker nicht zusammenarbeiten, aber die präparative organische Chemie wird vorrangig so gesehen, dass Fortschritte in ihr die Forschung auf vielen anderen Gebieten unterstützen, und präparativ arbeitende Organiker sind häufig an interdisziplinären Projekten beteiligt. Doch es ist schwierig, präparativ arbeitende Organiker zu finden, die in ihrer eigenen Disziplin auf dem Weg zu einem Ziel zusammenarbeiten. Dafür gibt es viele mögliche Erklärungen, doch die vielleicht überzeugendste ist, dass die Organik anders als viele andere Bereiche, wenn sie am effektivsten ist, einfach zugänglich ist. Sie braucht keine hochkomplexen Geräte oder Ausstattungen, die nur für wenige verfügbar sind. Eine phantastische neue Synthesemethode ist im Idealfall äußerst einfach und geht von leicht zugänglichen Materialien aus. Was ein Forschungsprogramm in der organischen Synthese also wirklich kennzeichnet, sind die ihm zugrundeliegenden Ideen. Darum ist es riskant, die eigenen aufregendsten Forschungsideen und Einsichten mit anderen Organikern zu teilen, denn ein Organiker müsste sich im Prinzip nicht sonderlich anstrengen, um einen offenen Ideenaustausch mit anderen zu missbrauchen. Darum müssen präparativ arbeitende Organiker erst großes Vertrauen aufbauen, bevor sie innerhalb ihrer Disziplin effektiv zusammenarbeiten können.1 1 Großes Interesse besteht im Zentrum der modernen organischen Synthese an der C-H-Funktionalisierung. Die Entwicklung von Verfahren, um C-H-Bindungen selektiv und verhersagbar zu modifizieren, würde die Logik der organischen Synthese grundlegend ändern; C-H-Bindungen würden zu den beliebtesten Reaktionspartnern, und die “funktionellen Gruppen” würden zu einem reinen Strukturschmuck degradiert. Natürlich lässt sich ein solches Szenario nur nach Überwindung vieler Schwierigkeiten erreichen. Gewiss haben uns Reaktionen freier Radikale gelehrt, dass die selektive Funktionalisierung der am wenigsten stabilen C-H-Bindung möglich ist, doch die Fähigkeit, die Produktselektivität bei Verbindungen, die funktionelle Gruppen und mehrere ungleichartige C-H-Bindungen enthalten, gezielt einzustellen ist die Hauptherausforderung auf diesem Gebiet. In den letzten Jahren gab es eine Reihe signifikanter Fortschritte bei der C-H-Funktionalisierung. Neue Reagentien und mehrere Übergangsmetallkatalysatoren, die von der Metallorganiker-Gemeinde beigesteuert wurden, haben die Möglichkeit aufgezeigt, wirklich selektive C-H-Funktionalisierungen zu erreichen. Viele der frühen Untersuchungen konzentrierten sich auf einfache organische Substrate. Doch für eine Weiterentwicklung des Gebiets war es unabdingbar, sich der Herausforderung komplexerer Molekülgerüste zu stellen. Um diesen Sprung zu machen und die Reaktion von einem Novum in einen praktischen Syntheseprozess zu überführen, müssen zunächst die Grundlagen des Reaktionsmechanismus vollständig verstanden werden. Dazu sind aufwendige theoretische, mechanistische und experimentelle Analysen unumgänglich, da diese Organometallsysteme oft komplex sind und durch sehr feine Faktoren gesteuert werden. Neue Katalysatoren, Reagentien und ein besseres Reaktions-Engineering sind die Voraussetzung dafür, dass die Methodik robust, kostengünstig und nachhaltig ist. Für C-H-Funktionalisierungen müssen Vorhersageregeln entwickelt werden, mit denen die C-H-Bindungen in einem komplexen Molekülsystem definiert werden können, die am wahrscheinlichsten reagieren; diese Erkenntnisse müssen bei der Syntheseplanung (Retrosynthese) berücksichtigt werden. Idealerweise sollten diese akademischen Erkundungen partnerschaftlich mit der Industrie passieren, um sicherzustellen, dass die sich entwickelnden Verfahren schnell auf Synthesefragen der “wirklichen Welt” angewendet werden (siehe schematische Übersicht auf der nächsten Seite).1 Die Aufgaben, vor denen man steht, will man einen ganz neuen Denkansatz zum Aufbau organischer Verbindungen entwickeln, sind exponentiell größer als die bei der Entwicklung einer einzigen neuen Reaktion und überfordern sicherlich jeden Einzelforscher. Um die C-H-Funktionalisierung zu einem Hauptthema der Synthesechemie zu machen, ist ein vielseitiger Ansatz erforderlich. Aus diesem Grund reagierten wir 2009 auf das Ansuchen der National Science Foundation, ein Phase-I-Zentrum für chemische Innovation zu schaffen. Das Gründungsteam des Center for Selective CH Functionalization (CCHF; siehe http://www.nsf-cchf.com/) bestand aus einem Computerchemiker (Jamal Musaev) und fünf Synthesechemikern nicht nur mit Erfahrung im Entwerfen neuer Katalysatoren und in Synthesemethoden zur C-H-Funktionalisierung, sondern auch mit einem Verständnis für die Logik der Synthese komplexer Moleküle (Simon Blakey, Huw Davies, Justin Du Bois, Christina White und Jin-Quan Yu). Bis zu diesem Zeitpunkt hatten wir noch nie miteinander gearbeitet, und obwohl unsere Forschungsprogramme komplementär waren, hätten uns viele als potenzielle Konkurrenten und nicht als Teamarbeiter angesehen. Unser erstes Treffen war sehr aufregend: An einem Tag stellten wir uns gegenseitig unsere aktuellen Forschungsprogramme vor, und an einem zweiten versuchten wir herauszufinden, welche unserer üblichen wissenschaftlichen Berührungsängste wir ablegen mussten, um eine gemeinsame Basis zu finden, die letztlich die Grundlage für unser Zentrum wurde. Die Finanzierung der Phase I galt für drei Jahre und wurde als Pilotprojekt betrachtet, um die Gruppe auf die Bewerbung für ein viel größeres Phase-II-Zentrum vorzubereiten. Für uns war die Phase I entscheidend, denn wir mussten erst Vertrauen aufbauen und herausfinden, ob das Konzept, die eigene Forschung im Rahmen eines Teams zu verfolgen, Vorteile hat. Während dieser Zeit mussten wir auch das Team über den zentralen Kern der Methodenentwickler hinaus erweitern. Dieses Wachstum wurde sorgfältig geplant, wobei wir uns auf Leute konzentrierten, die nicht nur ausgezeichnete Wissenschaftler waren, sondern von denen wir auch annahmen, dass sie die Teamdynamik begrüßen würden, die wir gerade entwickelten. In Tabelle 1 sind die Wissenschaftler zusammengefasst, die dem Zentrum angehören, sowie ihre jeweiligen Fachgebiete und Arbeitsstätten genannt. Das Team konnte früh über Larry Hamann eine sehr enge Partnerschaft mit Novartis Institutes for BioMedical Research aufbauen, wodurch die Ergebnisse schnell im Hinblick auf ihren Nutzen in der Wirkstoffsynthese geprüft werden konnten. Während der ersten Förderphase begann dieses Team zusammenzuarbeiten und die Kontakte herzustellen, die als Berechtigung für ein Phase-II-Zentrum notwendig waren; dieses wurde 2012 genehmigt. Mitglied Fachgebiet Arbeitsstätte John Berry Anorganik University of Wisconsin Donna Blackmond Kinetik Scripps Research Institute, La Jolla Simon Blakey Methodenentwicklung Emory University Andy Borovik Anorganik University of California, Irvine Huw Davies Methodenentwicklung Emory University Justin Du Bois Methodenentwicklung Stanford University Stefan France Methodenentwicklung Georgia Institute of Technology Ken Houk Theorie University of California, Los Angeles Chris Jones Chemieingenieurwesen Georgia Institute of Technology Jared Lewis Bioanorganik University of Chicago Christine Luscombe Materialwissenschaften University of Washington Cora MacBeth Anorganik Emory University Seth Marder Materialwissenschaften Georgia Institute of Technology John Montgomery Methodenentwicklung University of Michigan Mo Movassaghi Totalsynthese Massachusetts Institute of Technology Jamal Musaev Theorie Emory University Richmond Sarpong Methodenentwicklung University of California, Berkeley David Sherman Bioanorganik University of Michigan Matt Sigman Physikoorganik University of Utah Eric Sorensen Totalsynthese Princeton University Brian Stoltz Totalsynthese California Institute of Technology Jin-Quan Yu Methodenentwicklung Scripps Research Institute, La Jolla Richard Zare Mechanismusaufklärung Stanford University Nun, wie schaffen es 23 Forschungsgruppen, die sich auf 15 Universitäten verteilen und von denen viele als direkte Konkurrenten angesehen werden können, im Team zusammenzuarbeiten? Effektive, offene und stimulierende Kommunikation ist essenziell. Jede Woche werden in einer Videokonferenz technisch-wissenschaftliche und logistische Themen besprochen. Als wir die Phase II genehmigt bekommmen hatten, organisierten wir ein zentrumweites Symposium an der Emory University, um aus den Ideen, die wir auf Papier hatten, im direkten persönlichen Gespräch echte Kooperationen zu machen. Das war ein entscheidendes Treffen, denn jeder in der Gruppe musste Vertrauen fassen, um seine Konkurrenzvorbehalte auszuschalten, damit ein Ideenaustausch möglich wurde. Das ist ein für Organiker so seltenes Verhalten, dass wir einen halben Tag über unsere Erwartungen und das optimale Engagement diskutierten (erst Zusammenarbeitsmöglichkeiten ausfindig machen, Konkurrenz mit dem Zentrum und innerhalb des Zentrums vermeiden, nicht nur Zuhörer sein etc.). Das Treffen schuf die ideale Umgebung für offenen wissenschaftlichen Austausch mit Experten auf dem eigenen Gebiet, ohne Konkurrenz fürchten zu müssen – etwas, das man nicht leicht findet. Wir haben das Zentrum in sechs Themenbereiche aufgeteilt, und jede Woche diskutieren wir technische Details zu einem ausgewählten Thema. Auch wenn üblicherweise nur etwa sechs Gruppen direkt mit einem bestimmten Thema verbunden sind, nehmen an diesen Treffen etwa zwanzig Gruppen teil, weil wir die kontinuierliche Erkundung neuer Möglichkeiten der Zusammenarbeit fördern wollen. Der Enthusiasmus von Professoren und Studenten war und ist sehr groß, weil jeder den Eindruck hat, das eigene Forschungsprogramm würde durch die Teamatmosphäre deutlich bereichert. Das ist eine der zentralen Stärken des Netzwerks des Zentrums: Laufende Forschungsprojekte werden einer großen und breiten Zuhörerschaft aus Kollegen und Studenten vorgestellt, und die dabei ausgelösten Diskussionen und Rückmeldungen sind sehr nützlich. Eine gute Organisation und großes Engagement sind bei einem räumlich so weit verstreuten Kollektiv für ein effektives Arbeiten ebenfalls unabdingbar. Die Mitglieder haben ein außergewöhnliches Maß an Bekenntnis zu unserem Netzwerk gezeigt, nicht nur einfach in Form ihres wissenschaftlichen Engagements, sondern auch durch ihre Beteiligung an den integrierenden Aktivitäten des Zentrums. Hier half ein an der Emory University angesiedeltes Managementteam aus einem wissenschaftlichen (Huw Davies), einem geschäftsführenden (Daniel Morton) und einem Direktor für Bildung, Kommunikation und Diversität (Monya Ruffin). Ein Aufsichtskomitee sowie ein wissenschaftliches und ein studentisches Ratgebergremium helfen beim Steuern der Zentrumsaktivitäten. Wie beeinflusst dieser Ansatz die Forschung? Seit seiner Gründung hat das Zentrum mehr als 70 Arbeiten veröffentlicht, wobei bei mehr als der Hälfte mehrere Arbeitsgruppenleiter Coautoren sind. Die Kombination von computergestützter mit experimenteller Forschung hat uns nicht nur ein besseres Verständnis der Chemie verschafft, sondern auch den Startschuss dafür gegeben, Vorhersagesysteme zur Steuerung unserer Arbeit zu entwickeln. Besonders deutlich zeigen das die erste Charakterisierung eines Dirhodiumcarbenoids, die Analyse, das Verständnis und die Vorhersage der Ortsselektivität bei der C-H-Aminierung sowie das Modellieren und die Vorhersage von Templaten für eine entfernte C-H-Aktivierung. Die Zusammenarbeit von Methodik- und Totalsynthese-Gruppen hat zur rationelleren Synthese komplexer Zielverbindungen und zum Design robusterer C-H-Funktionalisierungsmethoden für den Gerüstaufbau und späte C-H-Funktionalisierungen geführt. Das Zentrum bekam auch einige der Herausforderungen der “wirklichen Welt”, die an es herangetragen wurden, in den Griff: Es synthetisierte neuartige polymere Bausteine für den Elektronentransport, die mit bisher bekannten Methoden nicht zugänglich sind, und entwickelte Techniken, um den Substratbereich auf pharmazeutisch besser anwendbare Systeme zu erweitern. Wie beeinflusst dieser Ansatz die Forscher? Eine Forschergemeinschaft zu pflegen hat für die Professoren und die Studenten Vorteile weit über das hinaus gebracht, was wir uns vorgestellt hatten. Der offene und freie Austausch von Ideen und Rückmeldungen schafft eine Forschungsumgebung und eine Erfahrung, wie sie in Einzelgruppen nicht möglich sind. Wir hoffen, dass damit unsere Mitglieder auch künftig bessere Vermittler und Teammitglieder sein werden. Zusammenarbeit endet nicht an der Haustür. Das Zentrum arbeitet auch mit Nichtmitgliedern zusammen, wobei an den – noch aktiven oder abgeschlossenen – Projekten mehr als zehn weitere Forschungsgruppen aus den USA beteiligt waren. Derzeit bauen wir Verbindungen zu Partnern in Asien und Europa auf. Außerdem entwickeln wir einen neuen Mechanismus, der die Beteiligung von Industriepartnern erleichtern soll. Wir haben von einer äußerst fruchtbaren Partnerschaft mit Novartis profitiert, die uns dazu gebracht hat, unsere Art über Chemie nachzudenken zu hinterfragen; parallel dazu, dass wir diese Beziehung ausbauen, suchen wir nach Wegen, um mit anderen Zweigen der chemischen Industrie zu Kooperationen zu kommen. Das letztliche Ziel unserer wissenschaftlichen Arbeiten und Schulungsaktivitäten ist es nicht nur, die C-H-Funktionalisierung zu einem Hauptthema der Chemikergemeinde zu machen, sondern auch, Chemiker auszubilden, die die Vorteile eines Netzwerks von zusammenarbeitenden Forschern nutzen können.

An incidental, asymptomatic, well-circumscribed, solitary, submucosal nodular mass was detected on the mucosal surface of the inner lower lip in a female cynomolgus macaque (age, approximately 2.4 y) during a juvenile chronic toxicology study. Grossly, the nodule was soft with brown to tan discoloration and measured approximately 4 mm in diameter. Microscopically, the nodule was covered by normal stratified squamous epithelium and composed of well-circumscribed irregular lobules containing hyperplastic and normal-appearing mucinous salivary gland acini and ducts, which were separated by thick connective tissue septae. In light of the gross pathology and results of microscopic examination, salivary gland hamartoma was diagnosed. This lesion resembles adenomatoid hyperplasia of mucous salivary glands in humans, which is a rare nonneoplastic swelling. To our knowledge, this case description is the first report of a cynomolgus macaque with the rare entity of lip salivary gland hamartoma, which likely represents adenomatous hyperplasia in humans.

In vivo carcinogenicity assessment of chemicals is a long and expensive process, typically including lifetime (2-year) studies in two rodent species. The relevance of these animal data to human cancer risk assessment has been questioned, and there are numerous examples of chemically-induced rodent neoplasms that are not considered applicable to human risk. This chapter summarizes the design, planning, and execution of 2-year rodent carcinogenicity studies as well as the same features in newer alternative (6-month) studies that use mouse models with genetically engineered predispositions to develop xenobiotic-induced cancers (e.g., the rasH2 mouse and p53+/− mouse). Special considerations required when undertaking carcinogenicity assessment of proteins, small nucleic acids, and stem cell-based therapies are also reviewed.

The ICH initiated talks in June 2012 to revise regulatory guidance for carcinogenicity assessment of pharmaceutical products, stimulated in part by a proposal called Negative for Endocrine, Genotoxicity, and Chronic Study Associated Histopathologic Risk Factors for Carcinogenicity in the Rat (NEGCARC) from the Pharmaceutical Research and Manufacturing Association (PhRMA). The 2012 STP Town Hall Meeting focused on the need for change in carcinogenicity assessment strategies for pharmaceuticals. Dr. Todd Bourcier from the Division of Endocrine and Metabolic Products, U.S. FDA and a member of the FDA’s Alternative Carcinogenicity Assessment Committee, was the guest speaker and a panelist. Dr. Bourcier is also one of FDA’s representatives to the ICH S1 Expert Working Group that is discussing changes to regulatory guidelines for carcinogenicity assessment. Drs. Carl Alden and Dan Morton also participated in the panel discussion.