IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251.

Although insulin-like growth factor 1 (IGF-1) signaling promotes tumor growth and cancer progression, therapies that target the IGF-1 receptor (IGF-1R) have shown poor clinical efficacy. To address IGF-1R activity in cancer cells and how it differs from that of the closely related insulin receptor (IR), we focused on two tyrosines in the IGF-1R C-terminal tail that are not present in the IR and are essential for IGF-1-mediated cancer cell survival, migration, and tumorigenic growth. We found that Tyr1250 and Tyr1251 (Tyr1250/1251) were autophosphorylated in a cell adhesion-dependent manner. To investigate the consequences of this phosphorylation, we generated phosphomimetic Y1250E/Y1251E (EE) and nonphosphorylatable Y1250F/Y1251F (FF) mutant forms of IGF-1R. Although fully competent in kinase activity and signaling, the EE mutant was more rapidly internalized and degraded than either the wild-type or FF receptor. IGF-1 promoted the accumulation of wild-type and EE IGF-1R within the Golgi apparatus, whereas the FF mutant remained at the plasma membrane. Golgi-associated IGF-1R signaling was a feature of migratory cancer cells, and Golgi disruption impaired IGF-1-induced signaling and cell migration. Upon the formation of new cell adhesions, IGF-1R transiently relocalized to the plasma membrane from the Golgi. Thus, phosphorylation at Tyr1250/1251 promoted IGF-1R translocation to and signaling from the Golgi to support an aggressive cancer phenotype. This process distinguishes IGF-1R from IR signaling and could contribute to the poor clinical efficacy of antibodies that target IGF-1R on the cell surface.

Us, Too. Sexual Harassment Within Academic Medicine in the United States.

PURPOSE: We report on the extent of sexual harassment among residents and examine its relationship to specialty and program year and effects. METHODS: Using the C-Change Resident Survey, we surveyed residents in 34 internal medicine, pediatrics, and general surgery programs in 14 academic medical centers (AMCs). A total of 1708 residents completed the survey (70% response-rate); 51% (n = 879) were women. Respondents reported unwanted sexual comments, attention, or advances by a superior or colleagues within the last 2 years. Measures of vitality and ethical or moral distress were included in the surveys. RESULTS: Rates of sexual harassment reported by women differed across the 34 programs, with an interquartile range of 0%-11%. Residents in pediatrics had the lowest frequencies of sexual harassment (mean 2%, 95% confidence interval [CI] 0%, 4%). Residents in internal medicine had higher rates of sexual harassment (mean 7%, 95% CI 1%, 25%). Residents in surgery had the highest rates (mean 12%, 95% CI 2%, 33%). Sexual harassment was associated with lower levels of vitality and higher ethical or moral distress (both, P <0.05). CONCLUSIONS: Sexual harassment is more common for women residents in Internal Medicine and Surgery programs. The adverse effects of sexual harassment on female residents detracts from an institution's professional workforce.

FES-related tyrosine kinase activates the insulin-like growth factor-1 receptor at sites of cell adhesion.

IGF-1 receptor (IGF-1R) and integrin cooperative signaling promotes cancer cell survival, proliferation, and motility, but whether this influences cancer progression and therapy responses is largely unknown. Here we investigated the non-receptor tyrosine adhesion kinase FES-related (FER), following its identification as a potential mediator of sensitivity to IGF-1R kinase inhibition in a functional siRNA screen. We found that FER and the IGF-1R co-locate in cells and can be co-immunoprecipitated. Ectopic FER expression strongly enhanced IGF-1R expression and phosphorylation on tyrosines 950 and 1131. FER phosphorylated these sites in an IGF-1R kinase-independent manner and also enhanced IGF-1-mediated phosphorylation of SHC, and activation of either AKT or MAPK-signaling pathways in different cells. The IGF-1R, ß1 Integrin, FER, and its substrate cortactin were all observed to co-locate in cell adhesion complexes, the disruption of which reduced IGF-1R expression and activity. High FER expression correlates with phosphorylation of SHC in breast cancer cell lines and with a poor prognosis in patient cohorts. FER and SHC phosphorylation and IGF-1R expression could be suppressed with a known anaplastic lymphoma kinase inhibitor (AP26113) that shows high specificity for FER kinase. Overall, we conclude that FER enhances IGF-1R expression, phosphorylation, and signaling to promote cooperative growth and adhesion signaling that may facilitate cancer progression.

IGF-1R inhibition sensitizes breast cancer cells to ATM-related kinase (ATR) inhibitor and cisplatin.

The complexity of the IGF-1 signalling axis is clearly a roadblock in targeting this receptor in cancer therapy. Here, we sought to identify mediators of resistance, and potential co-targets for IGF-1R inhibition. By using an siRNA functional screen with the IGF-1R tyrosine kinase inhibitor (TKI) BMS-754807 in MCF-7 cells we identified several genes encoding components of the DNA damage response (DDR) pathways as mediators of resistance to IGF-1R kinase inhibition. These included ATM and Ataxia Telangiectasia and RAD3-related kinase (ATR). We also observed a clear induction of DDR in cells that were exposed to IGF-1R TKIs (BMS-754807 and OSI-906) as indicated by accumulation of γ-H2AX, and phosphorylated Chk1. Combination of the IGF-1R/IR TKIs with an ATR kinase inhibitor VE-821 resulted in additive to synergistic cytotoxicity compared to either drug alone. In MCF-7 cells with stably acquired resistance to the IGF-1R TKI (MCF-7-R), DNA damage was also observed, and again, dual inhibition of the ATR kinase and IGF-1R/IR kinase resulted in synergistic cytotoxicity. Interestingly, dual inhibition of ATR and IGF-1R was more effective in MCF-7-R cells than parental cells. IGF-1R TKIs also potentiated the effects of cisplatin in a panel of breast cancer cell lines. Overall, our findings identify induction of DDR by IGF-1R kinase inhibition as a rationale for co-targeting the IGF-1R with ATR kinase inhibitors or cisplatin, particularly in cells with acquired resistance to TKIs.

IGF-1 Receptor and Adhesion Signaling: An Important Axis in Determining Cancer Cell Phenotype and Therapy Resistance.

IGF-1R expression and activation levels generally cannot be correlated in cancer cells, suggesting that cellular proteins may modulate IGF-1R activity. Strong candidates for such modulation are found in cell-matrix and cell-cell adhesion signaling complexes. Activated IGF-1R is present at focal adhesions, where it can stabilize ß1 integrin and participate in signaling complexes that promote invasiveness associated with epithelial mesenchymal transition (EMT) and resistance to therapy. Whether IGF-1R contributes to EMT or to non-invasive tumor growth may be strongly influenced by the degree of extracellular matrix engagement and the presence or absence of key proteins in IGF-1R-cell adhesion complexes. One such protein is PDLIM2, which promotes both cell polarization and EMT by regulating the stability of transcription factors including NFκB, STATs, and beta catenin. PDLIM2 exhibits tumor suppressor activity, but is also highly expressed in certain invasive cancers. It is likely that distinct adhesion complex proteins modulate IGF-1R signaling during cancer progression or adaptive responses to therapy. Thus, identifying the key modulators will be important for developing effective therapeutic strategies and predictive biomarkers.

Implementing the 2009 Institute of Medicine recommendations on resident physician work hours, supervision, and safety.

Long working hours and sleep deprivation have been a facet of physician training in the US since the advent of the modern residency system. However, the scientific evidence linking fatigue with deficits in human performance, accidents and errors in industries from aeronautics to medicine, nuclear power, and transportation has mounted over the last 40 years. This evidence has also spawned regulations to help ensure public safety across safety-sensitive industries, with the notable exception of medicine. In late 2007, at the behest of the US Congress, the Institute of Medicine embarked on a year-long examination of the scientific evidence linking resident physician sleep deprivation with clinical performance deficits and medical errors. The Institute of Medicine's report, entitled "Resident duty hours: Enhancing sleep, supervision and safety", published in January 2009, recommended new limits on resident physician work hours and workload, increased supervision, a heightened focus on resident physician safety, training in structured handovers and quality improvement, more rigorous external oversight of work hours and other aspects of residency training, and the identification of expanded funding sources necessary to implement the recommended reforms successfully and protect the public and resident physicians themselves from preventable harm. Given that resident physicians comprise almost a quarter of all physicians who work in hospitals, and that taxpayers, through Medicare and Medicaid, fund graduate medical education, the public has a deep investment in physician training. Patients expect to receive safe, high-quality care in the nation's teaching hospitals. Because it is their safety that is at issue, their voices should be central in policy decisions affecting patient safety. It is likewise important to integrate the perspectives of resident physicians, policy makers, and other constituencies in designing new policies. However, since its release, discussion of the Institute of Medicine report has been largely confined to the medical education community, led by the Accreditation Council for Graduate Medical Education (ACGME). To begin gathering these perspectives and developing a plan to implement safer work hours for resident physicians, a conference entitled "Enhancing sleep, supervision and safety: What will it take to implement the Institute of Medicine recommendations?" was held at Harvard Medical School on June 17-18, 2010. This White Paper is a product of a diverse group of 26 representative stakeholders bringing relevant new information and innovative practices to bear on a critical patient safety problem. Given that our conference included experts from across disciplines with diverse perspectives and interests, not every recommendation was endorsed by each invited conference participant. However, every recommendation made here was endorsed by the majority of the group, and many were endorsed unanimously. Conference members participated in the process, reviewed the final product, and provided input before publication. Participants provided their individual perspectives, which do not necessarily represent the formal views of any organization. In September 2010 the ACGME issued new rules to go into effect on July 1, 2011. Unfortunately, they stop considerably short of the Institute of Medicine's recommendations and those endorsed by this conference. In particular, the ACGME only applied the limitation of 16 hours to first-year resident physicans. Thus, it is clear that policymakers, hospital administrators, and residency program directors who wish to implement safer health care systems must go far beyond what the ACGME will require. We hope this White Paper will serve as a guide and provide encouragement for that effort. RESIDENT PHYSICIAN WORKLOAD AND SUPERVISION: By the end of training, a resident physician should be able to practice independently. Yet much of resident physicians' time is dominated by tasks with little educational value. The caseload can be so great that inadequate reflective time is left for learning based on clinical experiences. In addition, supervision is often vaguely defined and discontinuous. Medical malpractice data indicate that resident physicians are frequently named in lawsuits, most often for lack of supervision. The recommendations are: The ACGME should adjust resident physicians workload requirements to optimize educational value. Resident physicians as well as faculty should be involved in work redesign that eliminates nonessential and noneducational activity from resident physician dutiesMechanisms should be developed for identifying in real time when a resident physician's workload is excessive, and processes developed to activate additional providersTeamwork should be actively encouraged in delivery of patient care. Historically, much of medical training has focused on individual knowledge, skills, and responsibility. As health care delivery has become more complex, it will be essential to train resident and attending physicians in effective teamwork that emphasizes collective responsibility for patient care and recognizes the signs, both individual and systemic, of a schedule and working conditions that are too demanding to be safeHospitals should embrace the opportunities that resident physician training redesign offers. Hospitals should recognize and act on the potential benefits of work redesign, eg, increased efficiency, reduced costs, improved quality of care, and resident physician and attending job satisfactionAttending physicians should supervise all hospital admissions. Resident physicians should directly discuss all admissions with attending physicians. Attending physicians should be both cognizant of and have input into the care patients are to receive upon admission to the hospitalInhouse supervision should be required for all critical care services, including emergency rooms, intensive care units, and trauma services. Resident physicians should not be left unsupervised to care for critically ill patients. In settings in which the acuity is high, physicians who have completed residency should provide direct supervision for resident physicians. Supervising physicians should always be physically in the hospital for supervision of resident physicians who care for critically ill patientsThe ACGME should explicitly define "good" supervision by specialty and by year of training. Explicit requirements for intensity and level of training for supervision of specific clinical scenarios should be providedCenters for Medicare and Medicaid Services (CMS) should use graduate medical education funding to provide incentives to programs with proven, effective levels of supervision. Although this action would require federal legislation, reimbursement rules would help to ensure that hospitals pay attention to the importance of good supervision and require it from their training programs. RESIDENT PHYSICIAN WORK HOURS: Although the IOM "Sleep, supervision and safety" report provides a comprehensive review and discussion of all aspects of graduate medical education training, the report's focal point is its recommendations regarding the hours that resident physicians are currently required to work. A considerable body of scientific evidence, much of it cited by the Institute of Medicine report, describes deteriorating performance in fatigued humans, as well as specific studies on resident physician fatigue and preventable medical errors. The question before this conference was what work redesign and cultural changes are needed to reform work hours as recommended by the Institute of Medicine's evidence-based report? Extensive scientific data demonstrate that shifts exceeding 12-16 hours without sleep are unsafe. Several principles should be followed in efforts to reduce consecutive hours below this level and achieve safer work schedules. The recommendations are: Limit resident physician work hours to 12-16 hour maximum shiftsA minimum of 10 hours off duty should be scheduled between shiftsResident physician input into work redesign should be actively solicitedSchedules should be designed that adhere to principles of sleep and circadian science; this includes careful consideration of the effects of multiple consecutive night shifts, and provision of adequate time off after night work, as specified in the IOM reportResident physicians should not be scheduled up to the maximum permissible limits; emergencies frequently occur that require resident physicians to stay longer than their scheduled shifts, and this should be anticipated in scheduling resident physicians' work shiftsHospitals should anticipate the need for iterative improvement as new schedules are initiated; be prepared to learn from the initial phase-in, and change the plan as neededAs resident physician work hours are redesigned, attending physicians should also be considered; a potential consequence of resident physician work hour reduction and increased supervisory requirements may be an increase in work for attending physicians; this should be carefully monitored, and adjustments to attending physician work schedules made as needed to prevent unsafe work hours or working conditions for this group"Home call" should be brought under the overall limits of working hours; work load and hours should be monitored in each residency program to ensure that resident physicians and fellows on home call are getting sufficient sleepMedicare funding for graduate medical education in each hospital should be linked with adherence to the Institute of Medicine limits on resident physician work hours. MOONLIGHTING BY RESIDENT PHYSICIANS: The Institute of Medicine report recommended including external as well as internal moonlighting in working hour limits. The recommendation is: All moonlighting work hours should be included in the ACGME working hour limitsand actively monitored. (ABSTRACT TRUNCATED)

US public opinion regarding proposed limits on resident physician work hours.

BACKGROUND: In both Europe and the US, resident physician work hour reduction has been a source of controversy within academic medicine. In 2008, the Institute of Medicine (IOM) recommended a reduction in resident physician work hours. We sought to assess the American public perspective on this issue. METHODS: We conducted a national survey of 1,200 representative members of the public via random digit telephone dialing in order to describe US public opinion on resident physician work hour regulation, particularly with reference to the IOM recommendations. RESULTS: Respondents estimated that resident physicians currently work 12.9-h shifts (95% CI 12.5 to 13.3 h) and 58.3-h work weeks (95% CI 57.3 to 59.3 h). They believed the maximum shift duration should be 10.9 h (95% CI 10.6 to 11.3 h) and the maximum work week should be 50 h (95% CI 49.4 to 50.8 h), with 1% approving of shifts lasting >24 h (95% CI 0.6% to 2%). A total of 81% (95% CI 79% to 84%) believed reducing resident physician work hours would be very or somewhat effective in reducing medical errors, and 68% (95% CI 65% to 71%) favored the IOM proposal that resident physicians not work more than 16 h over an alternative IOM proposal permitting 30-h shifts with > or =5 h protected sleep time. In all, 81% believed patients should be informed if a treating resident physician had been working for >24 h and 80% (95% CI 78% to 83%) would then want a different doctor. CONCLUSIONS: The American public overwhelmingly favors discontinuation of the 30-h shifts without protected sleep routinely worked by US resident physicians and strongly supports implementation of restrictions on resident physician work hours that are as strict, or stricter, than those proposed by the IOM. Strong support exists to restrict resident physicians' work to 16 or fewer consecutive hours, similar to current limits in New Zealand, the UK and the rest of Europe.

Weaving basic and social sciences into a case-based, clinically oriented medical curriculum: one school's approach.

Southern Illinois University School of Medicine recently completed its fourth year of a resource-session-enhanced, case-based, tutor-group-oriented curriculum. As an example of a curricular unit, the authors describe the implementation of the basic and clinical sciences in one of the four units in year one, and detail that unit's organization, logistics, content, rationale, and other characteristics. The Sensorimotor Systems and Behavior (SSB) unit is preceded by a cardio-respiratory-renal unit and is followed by an endocrine-reproductive-gastrointestinal unit. A Doctoring unit temporally spans each of these three units. The SSB unit is allotted an 11.5-week period that includes an aggregate of 2.5 weeks of available clinical time, 1.5 weeks for examinations and exam study time, and approximately 8.5 weeks for tutor-group sessions, mandatory laboratory sessions, and self-directed learning. Optional resource sessions are offered during a two- to four-hour block on a single morning each week. Clinical training in the SSB unit augments self-directed, laboratory, and tutor-group learning of neuroscience, gross anatomy, cell biology, physiology, biochemistry, behavioral and social science, embryology, limited pharmacology and genetics, and basic clinical neurology for first-year students. Although it is fast-paced and places heavy responsibility for independent learning on the students, the SSB unit culminates in significant achievement in the basic and clinical sciences. The unit provides substantial clinical training and practical experience in physical and neurological examinations that directly integrate with basic science knowledge. The unit reduces lecture-based instruction, demands self-determination, and promotes experience in team effort, professionalism, peer interaction, empathy in clinical medicine, and practical use of basic science knowledge.