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Background The Democratic Republic of the Congo (DRC) experienced its largest Ebola Virus Disease Outbreak in 2018-2020. As a result of the outbreak, significant funding and international support were provided to Eastern DRC to improve disease surveillance. The Integrated Disease Surveillance and Response (IDSR) strategy has been used in the DRC as a framework to strengthen public health surveillance, and full implementation could be critical as the DRC continues to face threats of various epidemic-prone diseases. In 2021, the DRC initiated an IDSR assessment in North Kivu province to assess the capabilities of the public health system to detect and respond to new public health threats. Methods A descriptive cross-sectional survey was conducted using mixed quantitative and qualitative methods. Performance in IDSR core functions was assessed at multiple levels of the tiered health system through observations, key informant interviews, and analysis of health data. Qualitative data were also collected through focus groups and open-ended questions to guide the interpretation of the findings. Data were collected at the North Kivu provincial public health office, five health zones, 66 healthcare facilities, and from community health workers in 15 health areas. Results Data completeness was 100% at the provincial and health zone levels, and timeliness was 100% and 97% at the provincial and health zone levels, respectively. Healthcare facility data had an average completeness of 86%, and timeliness varied between health zones from 41 to 100%. The use of electronic Integrated Disease Surveillance and Response is not widely implemented. Data analyses are conducted mainly at the provincial and health zone levels, and are regularly disseminated to all levels. Preparedness capabilities were low, with 44% of health zones in North Kivu having a preparedness and response plan and 41% having a functional rapid response team. Conclusion Comparing the results of this assessment to the last IDSR assessment conducted in DRC in 2016, slight improvements in disease reporting have been made, despite several limitations in materials, equipment, infrastructure, and workforce training. This assessment highlights the need to move from outbreak-focused support and funding to building systems that can improve the long-term functionality of the routine disease surveillance system.

Long-standing social inequities and health disparities have resulted in increased risk for coronavirus disease 2019 (COVID-19) infection, severe illness, and death among racial and ethnic minority populations. The Health Resources and Services Administration (HRSA) Health Center Program supports nearly 1,400 health centers that provide comprehensive primary health care* to approximately 30 million patients in 13,000 service sites across the United States.† In 2019, 63% of HRSA health center patients who reported race and ethnicity identified as members of racial ethnic minority populations (1). Historically underserved communities and populations served by health centers have a need for access to important information and resources for preventing exposure to SARS-CoV-2, the virus that causes COVID-19, to testing for those at risk, and to follow-up services for those with positive test results.§ During the COVID-19 public health emergency, health centers¶ have provided and continue to provide testing and follow-up care to medically underserved populations**; these centers are capable of reaching areas disproportionately affected by the pandemic.†† HRSA administers a weekly, voluntary Health Center COVID-19 Survey§§ to track health center COVID-19 testing capacity and the impact of COVID-19 on operations, patients, and personnel. Potential respondents can include up to 1,382 HRSA-funded health centers.¶¶ To assess health centers' capacity to reach racial and ethnic minority groups at increased risk for COVID-19 and to provide access to testing, CDC and HRSA analyzed survey data for the weeks June 5-October 2, 2020*** to describe all patients tested (3,194,838) and those who received positive SARS-CoV-2 test results (308,780) by race/ethnicity and state of residence. Among persons with known race/ethnicity who received testing (2,506,935), 36% were Hispanic/Latino (Hispanic), 38% were non-Hispanic White (White), and 20% were non-Hispanic Black (Black); among those with known race/ethnicity with positive test results, 56% were Hispanic, 24% were White, and 15% were Black. Improving health centers' ability to reach groups at increased risk for COVID-19 might reduce transmission by identifying cases and supporting contact tracing and isolation. Efforts to improve coordination of COVID-19 response-related activities between state and local public health departments and HRSA-funded health centers can increase access to testing and follow-up care for populations at increased risk for COVID-19.

Each year in the United States, ∼260,000 people get sick from contaminated fish. Fish is also the most commonly implicated food category in outbreaks. We reviewed the Centers for Disease Control and Prevention Foodborne Disease Outbreak Surveillance System for outbreaks resulting from consumption of fish during the period 1998-2015. We found 857 outbreaks associated with fish, resulting in 4815 illnesses, 359 hospitalizations, and 4 deaths. The median number of illnesses per outbreak was three (range: 2-425). The annual number of fish-associated outbreaks declined from an average of 62 per year during the period 1998-2006 to 34 per year during the period 2007-2015. Hawaii (221 outbreaks [26%]) and Florida (203 [24%]) reported the most outbreaks. Among 637 outbreaks (74%) with a confirmed etiology, scombrotoxin (349 [55%]) and ciguatoxin (227 [36%]) were by far most common. Most outbreak-associated illnesses were caused by scombrotoxin (1299 [34%]), Salmonella (978 [26%]), and ciguatoxin (894 [23%]). Most hospitalizations were caused by Salmonella (97 [31%]) and ciguatoxin (96 [31%]). Norovirus (105 average illnesses; range: [6-380]) and Salmonella (54 [3-425]) caused the largest outbreaks. Fish types implicated most often were tuna (37%), mahi-mahi (10%), and grouper (9%). The etiology-fish pairs responsible for the most outbreaks were scombrotoxin and tuna (223 outbreaks), scombrotoxin and mahi-mahi (64), and ciguatoxin and grouper (54). The pairs responsible for the most illnesses were scombrotoxin and tuna (720 illnesses) and Salmonella and tuna (660). Of the 840 outbreaks (98%) with a single location of food preparation, 52% were associated with fish prepared in a restaurant and 33% with fish prepared in a private home. Upstream control measures targeted to the most common etiologies and controls during processing and preparation could further reduce outbreaks caused by fish.

Objective We used experiences in multiple countries to determine that owner engagement is critical for successful evaluations of surveillance system viability. Introduction Pilot projects help determine utility and feasibility of a system, but even if considered successful, cost could prevent further scale-up. When evaluating a surveillance system pilot, cost and benefits are key factors to examine. In Cote d’Ivoire and Tanzania, Ministry of Health (MoH) and non-governmental partners receive funding under the Global Health Security Agenda to strengthen disease surveillance for earlier detection and improved response to potential infectious disease outbreaks. To this end, Community based surveillance (CBS) projects were implemented in 2016 as a means for early warning of potential events to facilitate a more rapid response. Currently, these CBS projects are being evaluated collaboratively with the primary stakeholder, the host country government (HCG), as lead, and partners such as CDC providing technical assistance. In other instances, partners may conduct an evaluation and share the results and recommendations with the HCG; however, if the HCG is not actively engaged as the primary executor, outcomes may not be endorsed or implemented. Therefore, these evaluations were approached from an owner’s (HCG) perspective. In this way, the governmental agencies develop capabilities to conduct similar activities in other areas, reduce dependencies on outside entities, and promote enactment of resulting recommendations. Methods Once the determination was made that an evaluation was necessary to decide the usefulness of the projects for future planning, key stakeholders worked together to design and execute the evaluation. For Cote d’Ivoire, the evaluation team consisted of representatives from the MoH’s National Institute of Public Health, Directorate of Informatics and Health Information, and Directorate for the Coordination of the Expanded Immunization Program, along with delegates from CDC and implementing partners. In Tanzania, evaluation team members came from the MoH, the Ministry of Agriculture, Forestries and Livestock, WHO, CDC and implementing partners. Team members participated in either planning, conducting or analyzing the evaluation, while some contributed to a combination or to all aspects. MoH members led the effort with CDC and other partners providing technical assistance, while implementing partners contributed only to planning and logistics to reduce the potential for bias. For the initial step, representatives came together to fully document the system to be evaluated. This system description details the purpose, relevant stakeholders and current operation of the pilot system. As the evaluation question should remain within the scope of the system’s purpose, it was necessary to definitively understand and confirm the goal and objectives set out for the system. Next, the sites, participants and roles, and data flows were described, noting that verification of the actual processes would occur during the site visit portion of the evaluation. Total cost of ownership was calculated by considering solution costs, implementation costs and ongoing support, and then broken down by district. The CBS pilots implemented early warning notification systems in two districts in Cote d’Ivoire and in five districts in Tanzania using a combination of paper-based and electronic reporting formats. Evaluation teams visited pilot sites and routine surveillance sites for comparison and conducted in-person interviews using questionnaires specific to the individual’s role. Data were either collected in the field on paper forms or electronically on tablets for subsequent upload to a centralized database for later analysis. Data from project and routine reporting databases were comparatively analyzed to calculate timeliness, validity, usefulness, acceptability and value of the early warning system pilots. Results Although final interpretations of the evaluation results are pending, the evaluations were successfully led by the HCG and jointly conducted with other stakeholder engagement. Leadership by the owners of the systems has already resulted in the recognition that certain aspects of the pilot surveillance systems demonstrate a successful and affordable approach, while others will need to consider more cost-effective strategies. Though further analysis will likely continue to show the utility of CBS strategies, the ownership approach is resulting in an outcome of broad stakeholder input with approval from the host country government. Conclusions Community based surveillance can help to detect events of public health importance and effect earlier introduction into the health system for more timely situational awareness and response. However, it is difficult to determine the costs associated with different strategies of implementation and operation in order to ascertain the value for public health action. Additionally, pilot implementations of these systems are often funded at a level that cannot be replicated nationally and not for a prolonged period of time. While it is believed that CBS can be a cost effective early notification system, continual monitoring and routine evaluation is required. By routinely monitoring cost and quality, sustainability of the system can be continually assessed and system adaptations made accordingly. Key to remember is that evaluation must occur from an owner’s perspective and must engage the people who are going to govern, operate and provide the ongoing resources for system operation. In this way, effectiveness and efficiency can be continually monitored within the parameter of cost so that viability of the system can be ascertained.

LKB1 is a Ser/Thr kinase, and its activity is regulated by the pseudokinase, STE20-related adaptor α (STRADα). The STRADα-LKB1 pathway plays critical roles in epithelial cell polarity, neuronal polarity, and cancer metastasis. Though much attention is given to the STRADα-LKB1 pathway, the function of STRADα itself, including a role outside of the LKB1 pathway, has not been well-studied. Data in Caenorhabditis elegans suggest that STRADα has an LKB1-independent role in regulating cell polarity, and therefore we tested the hypothesis that STRADα regulates cancer cell polarity and motility when wild-type LKB1 is absent. These results show that STRADα protein is reduced in LKB1-null cell lines (mutation or homozygous deletion) and this partial degradation occurs through the Hsp90-dependent proteasome pathway. The remaining STRADα participates in cell polarity and invasion, such that STRADα depletion results in misaligned lamellipodia, improper Golgi positioning, and reduced invasion. To probe the molecular basis of this defect, we show that STRADα associates in a complex with PAK1, and STRADα loss disrupts PAK1 activity via Thr(423) PAK1 phosphorylation. When STRADα is depleted, PAK1-induced invasion could not occur, suggesting that STRADα is necessary for PAK1 to drive motility. Furthermore, STRADα overexpression caused increased activity of the PAK1-activating protein, rac1, and a constitutively active rac1 mutant (Q61L) rescued pPAK(Thr423) and STRADα invasion defects. Taken together, these results show that a STRADα-rac1-PAK1 pathway regulates cell polarity and invasion in LKB1-null cells. It also suggests that while the function of LKB1 and STRADα undoubtedly overlap, they may also have mutually exclusive roles.

Radon exposure is the second leading cause of lung cancer after smoking and the number one cause among non-smokers. EPA estimates that one in fifteen homes nationwide has elevated radon levels. Public outreach efforts promote radon testing and subsequent mitigation when unsafe levels are found, yet due to varying state regulations, data are non-standardized, making targeted public health actions challenging. An EPA-CDC collaboration will test the feasibility for capturing, analyzing and displaying radon data from state and local health departments by conducting a pilot project to standardize previously non-systemized, uncoordinated data sources into a nationally consistent radon information resource.

The National Environmental Public Health Tracking Program facilitates the linkage of environmental information to health outcomes through development of a national standards-based public health surveillance system that provides useful information to improve where we live and work. State tracking programs have successfully used their tracking networks to identify and educate at-risk communities. Other success stories include endeavours to improve surveillance, support epidemiologic studies, target prevention efforts, and inform policymakers. Future directions include identifying knowledge gaps, developing plans for adding new data sources and collaborators to fill those gaps, and improving application and utility of the Tracking Networks.

The sensitivity and predictive value of a surveillance system (ESSENCE-FL) originally designed for syndromic data to identify possible outbreak activity using data from a reportable disease system was examined. ESSENCE-FL-generated alerts were compared with confirmed outbreak activity for different infectious diseases over a 52-week period. Results showed that although overall sensitivity of the system to detect outbreak activity was fairly low, the positive predictive value was relatively high. This evaluation concludes that the application of reportable disease data within the ESSENCE-FL syndromic surveillance system is useful for prompting users of possible outbreak activity that warrants further inquiry.

Acetylated tubulin (AT) expression has been proposed as a marker for sensitivity to taxane chemotherapy. We wanted to explore AT as a prognostic marker in squamous cell carcinoma of the head and neck (SCCHN). We assessed AT expression in archival tissue from our institutional tissue bank of primary SCCHN specimens. We also examined AT expression on pre-therapy tissues of patients with SCCHN receiving induction chemotherapy with docetaxel, cisplatin and 5FU (TPF IC). AT expression was assessed on archival cases of SCCHN with (N = 63) and without (N = 82) locoregional lymph node metastases (LNM). The predominant tumor site was oral cavity (52 %). Immunohistochemistry staining was based on staining intensity and percentage of tumor cells stained to create a weighted index (WI). A total of nine patients who received TPF IC were evaluable for response by RECIST and also had pre-therapy tissues available. A significant independent correlation between AT and tumor grade (p = 0.001) and primary location (p = 0.008) was noted. There was a trend of higher AT in patients with presence of LNM (p = 0.052) and a trend in improved OS for patients with an AT WI below the median compared to those above the median for patients with no LNM (p = 0.054). For patients treated with induction TPF, we observed an inverse correlation between AT expression and response to TPF IC (p = 0.0071). AT expression is correlated with tumor grade and primary site. There was an observed trend correlating AT with presence nodal metastases. The observed inverse correlation with response to taxane based chemotherapy needs validation in a larger sample size.

Objective The Florida Department of Health (FDOH), Bureau of Epidemiology, partnered with the U.S. Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response (ASPR) to improve surveillance methods in post disaster or response events. A new process was implemented for conducting surveillance to monitor injury and illness for those presenting for care to ASPR assets such as Disaster Medical Assistance Team (DMAT) sites when they are operational in the state. The purpose of the current work was to field test and document the operational experience of the newly implemented ASPR data module in ESSENCE-FL (syndromic surveillance system) to receive near real-time automated data feeds when ASPR federal assets were deployed in Florida during the 2012 Republican National Convention (RNC). Introduction Florida has implemented various surveillance methods to augment existing sources of surveillance data and enhance decision making with timely evidence based assessments to guide response efforts post-hurricanes. Historically, data collected from deployed federal assets have been an integral part of this effort. However, a number of factors have made this type of surveillance challenging: logistical issues of field work in a post-disaster environment, the resource intensive manual data collection process from DMAT sites, and delayed analysis and interpretation of these data to inform decision makers. The ESSENCE-FL system is an automated and secure web-based application accessed by FDOH epidemiologists and staff at participating hospitals. Methods ESSENCE-FL was configured by the Johns Hopkins University Applied Physics Laboratory (JHU/APL) to receive ASPR electronic medical record (EMR) data. A scheduled program to generate data files for FDOH was created using SAS Enterprise Business Intelligence (EBI) software and a script was set up on the ASPR server to send an updated file via secure file transfer protocol (sftp) every 15 minutes. A case definition was created by ASPR field teams to identify which encounter visits would be entered into the electronic medical record (EMR) and received in ESSENCE-FL. To assess completeness of data elements and total patient encounters received in ESSENCE-FL, DMAT field teams maintained Excel line lists of patient encounters and emailed them to FDOH three times daily during the RNC. ASPR data were reviewed and analyzed by FDOH staff multiple times a day in near real time utilizing the existing ESSENCE-FL robust analysis tools. Results Three separate ASPR missions were deployed to Florida to support the RNC. ASPR EMR data files were received at 15-minute intervals by ESSENCE-FL from the ASPR central server during each day of the 2012 RNC (August 26–31). Reduced patient counts within ESSENCE-FL as compared with DMAT-maintained Excel line lists indicated an incomplete input, upload, or transfer of patient data from one of two ASPR sites to the central ASPR servers. Although only 11 of 34 total patient encounters were received by ESSENCE-FL during the event, the system design enabled users to run specific queries and display the results of their queries in time series graphs, pie and bar charts, GIS maps, dashboards, and statistical tables. Conclusions There is a great need to have timely access to data sources to enhance disease surveillance efforts and help guide decision makers’ situational awareness and disease control efforts during a response. The FDOH, Bureau of Epidemiology’s collaboration with JHU/APL and ASPR takes advantage of ASPR’s EMR-S to make data sharing and analysis efficient as evidenced during the RNC. Automated data feeds to ESSENCE-FL removed resource intensive manual data collection by public health, improved standardization of syndrome and demographic categorizations, increased access to these data by local, state, and federal epidemiologists in a timely manner, and expedited analysis and interpretation for situational awareness. Future recommendations include pre-event testing of the entire data flow process, establishing an on-site specialist to immediately assist with any issues, greater understanding of the field team use of the EMR-S, and ensuring field staff is aware of data quality needs for effective public health surveillance.

Objective In light of recent outbreaks of pertussis, the ability of Florida Department of Health’s (FDOH) Electronic Surveillance System for the Early Notification of Community-based Epidemics (ESSENCE-FL) to detect emergent disease outbreaks was examined. Through a partnership with the Johns Hopkins University Applied Physics Laboratory (JHU/APL), FDOH developed a syndromic surveillance system, ESSENCE-FL, with the capacity to monitor reportable disease case data from Merlin, the FDOH Bureau of Epidemiology’s secure webbased reporting and epidemiologic analysis system for reportable diseases. The purpose of this evaluation is to determine the utility and application of ESSENCE-FL system generated disease warnings and alerts originally designed for use with emergency department chief complaint data to reportable disease data to assist in timely detection of outbreaks in promotion of appropriate response and control measures. Introduction Reportable disease case data are entered into Merlin by all 67 county health departments in Florida and assigned confirmed, probable, or suspect case status. De-identified reportable disease data from Merlin are sent to ESSENCE-FL once an hour for further analysis and visualization using tools in the surveillance system. These data are available for ad hoc queries, allowing users to monitor disease trends, observe unusual changes in disease activity, and to provide timely situational awareness of emerging events. Based on system algorithms, reportable disease case weekly tallies are assigned an awareness status of increasing intensity from normal to an alert category. These statuses are constantly scrutinized by county and state level epidemiologists to guide disease control efforts in a timely manner, but may not signify definitive actionable information. Methods Within the ESSENCE-FL query portal, the Merlin Reportable Diseases Data Source was selected with a weekly time resolution by event date. Case Classification included all confirmed, probable and suspect cases, reported and not yet reported, during the time period of week 35, 2011, to week 35, 2012. The ESSENCE Weighted Moving Average (EWMA 1.2) detector was used to classify weekly counts as either of normal, warning or alert status based on previous weeks’ counts, indicating the possibility of an emerging outbreak. These weekly statuses were then compared with outbreaks reported in Merlin’s fully integrated outbreak reporting system and with outbreak reports submitted to EpiCom, Florida’s EpiX or health alert network. An ESSENCE-FL generated warning or alert was considered valid if a corresponding outbreak of 2 or more epi-linked pertussis cases were reported in either Merlin’s outbreak module or in EpiCom. For the sake of brevity in this abstract, the analysis of pertussis is presented, while other reportable disease conditions of immediate interest will be presented at the conference. Results Examination of 494 pertussis cases reported from September 2011 to September 2012 showed that of 53 weeks, 38 weeks contained normal case counts, 11 weeks generated warnings, and 4 weeks produced alerts. The number of warnings that corresponded to actual outbreaks was 6 of 11, whereas 2 of the 4 alerts matched reported outbreaks. Of the remaining 38 weeks, 12 had outbreaks reported with no warning or alert generated by ESSENCE-FL. When comparing confirmed outbreak status with ESSENCE-FL weekly data count status, warning/alert versus normal, it was found that the sensitivity of ESSENCE-FL to detect a true outbreak was 40.0% while the specificity was 78.8%. This comparison generated a positive-predictive value of 53.3% and a negative predictive value of 68.4%. Conclusions The ability of ESSENCE-FL to act as a first alert system for emerging disease events using Merlin reportable disease data should be considered with constraint. While warnings or alerts about potential pertussis outbreaks were generated correctly about half the time, the nearly one-third of reported outbreaks with no warning or alert makes the utility of the alerts questionable as far as initiating immediate action without prior verification of the alert. Florida does not currently have a requirement for centrally documenting all outbreaks, so it is likely that outbreaks occurred but were not recorded, precluding verification of all outbreaks.

The proper orientation of the mitotic spindle is essential for mitosis; however, how these events unfold at the molecular level is not well understood. AMP-activated protein kinase (AMPK) regulates energy homeostasis in eukaryotes, and AMPK-null Drosophila mutants have spindle defects. We show that threonine(172) phosphorylated AMPK localizes to the mitotic spindle poles and increases when cells enter mitosis. AMPK depletion causes a mitotic delay with misoriented spindles relative to the normal division plane and a reduced number and length of astral microtubules. AMPK-depleted cells contain mitotic actin bundles, which prevent astral microtubule-actin cortex attachments. Since myosin regulatory light chain (MRLC) is an AMPK downstream target and mediates actin function, we investigated whether AMPK signals through MRLC to control spindle orientation. Mitotic levels of serine(19) phosphorylated MRLC (pMRLC(ser19)) and spindle pole-associated pMRLC(ser19) are abolished when AMPK function is compromised, indicating that AMPK is essential for pMRLC(ser19) spindle pole activity. Phosphorylation of AMPK and MRLC in the mitotic spindle is dependent upon calcium/calmodulin-dependent protein kinase kinase (CamKK) activity in LKB1-deficient cells, suggesting that CamKK regulates this pathway when LKB1 function is compromised. Taken together, these data indicate that AMPK mediates spindle pole-associated pMRLC(ser19) to control spindle orientation via regulation of actin cortex-astral microtubule attachments.

Background: Triple negative (TN) breast cancers are a heterogeneous group of breast cancers with a poor prognosis in part due to a lack of effective targeted agents. Insulin-like growth factor-1 receptor (IGF-1R) has been shown to play a role in breast cancer cell proliferation, adhesion, invasion, and migration and is overexpressed in more than a third of TN breast tumors. We hypothesized that IGF-1R could be a therapeutic target for a subset of TN breast cancers. Methods: We evaluated the effects of IGF-1R silencing on the metastatic properties of TN breast cancer cells by knock down in two morphologically distinct TN breast cancer cell lines using shRNA lentiviral techniques. Reverse-transcription polymerase chain reaction (RT-PCR) and immunoblotting were used to detect mRNA and protein expression levels, respectively, of IGF-1R signaling molecules. Anchorage-dependent growth and Matrigel chamber assays were performed to assess the effects of IGF-1R silencing on colony formation and invasion of TN breast cancer cells, respectively; wound-healing and spheroid migration were also performed to assess the effects of IGF-1R inhibition on TN breast cancer cell motility. Results: Stably transfected mesenchymal MDA-MB-231 TN cells showed effective downregulation of IGF-1R protein expression, which resulted in mesenchymal-to-epithelial transition (MET), confirmed by upregulation of the epithelial marker E-cadherin and downregulation of the mesenchymal marker vimentin. Importantly, this MET resulted in reduced colony formation (p Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-02-06.

Next to skin cancer, breast cancer is the second most common cancer diagnosed among American women and affects nearly 1.3 million women worldwide each year. Aggressive, metastatic disease is directly responsible for the majority of breast cancer-related deaths. Breast tumors lacking expression of three receptors, estrogen receptor (ER), progesterone receptor (PR), and HER2, are commonly referred to as triple negative breast cancers (TNBCs) and make up 15-20% of all diagnosed breast cancers cases. Disparities exist in terms of survival following diagnosis of TNBC, and a devastating reality is that this diagnosis is highly correlated with incurable, metastatic disease. Despite tremendous advantages in treatments for hormone-sensitive breast tumors, a significant number of women with TNBC experience disease progression due to the unavailability of targeted therapies. Insulin-like growth factor-1 receptor (IGF1R) plays a role in breast cancer proliferation, adhesion, invasion, and migration. Overexpression of IGF1R has been noted in 50% of primary breast tumors and in nearly 65% of TNBCs. Consequently, high IGF1R expression in breast cancers correlates well with, high tumor grade, shorter disease-free survival, and poor prognosis. We report the in vitro effects of IGF1R inhibition on the metastatic properties of mesenchymal TNBC cells lines using two methods: (1) shRNA lentiviral system and (2) picropodophyllin (PPP), an IGF1R tyrosine kinase inhibitor. Stably transfected mesenchymal TNBC cells showed down-regulation of IGF1R protein levels, which resulted in mesenchymal-epithelial-transition (MET), as confirmed by up-regulation of epithelial marker, E-cadherin, and down-regulation of mesenchymal marker, vimentin. Importantly, this MET was accompanied by reduced colony formation, cell motility, and invasion. Cell survival assays and fluorescence-activated cell sorting (FACS) analysis revealed that PPP also effectively decreased cell viability and induced cell death, respectively, in TNBC cells. Furthermore, PPP dramatically inhibited cell invasion and migration. Our findings indicate that inhibitors of IGF1R exhibit promising anti-cancer activity in TNBC cells of mesenchymal origin by triggering MET, inducing cell death, and reducing invasive and metastatic properties. Given the very poor outcomes for patients with metastatic TNBCs, we believe the use of IGF1R inhibitors warrant further investigation as prospective anti-cancer options for treating a subset of mesenchymal TN breast carcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 342. doi:1538-7445.AM2012-342

The kinase LKB1 is mutated in multiple tumor types with a high mutation rate in non-small cell lung cancer. LKB1 activity is regulated by the pseudokinase, STE20-related adaptor alpha (STRADα), and the STRADα-LKB1 pathway plays critical roles in cell polarity and metastasis. Though much attention is given to the STRADα-LKB1 pathway, the function of STRADα itself, including a role outside of the LKB1 pathway, has not been well-studied. Data in C. elegans suggest that STRADα has an LKB1-independent role in regulating cell polarity, and therefore we tested the hypothesis that STRADα regulates cancer cell polarity and motility when wild-type LKB1 is absent. These results show that STRADα protein is reduced in LKB1-null cell lines (mutation or homozygous deletion) and this partial degradation occurs through the Hsp90-dependent proteasome pathway. The remaining STRADα participates in cell polarity and invasion, such that STRADα depletion results in misaligned lamellipodia, improper Golgi positioning, and reduced invasion. To probe the molecular basis of this defect, we show that STRADα associates in a complex with PAK1, and STRADα loss disrupts PAK1 activity via thr423 PAK1 phosphorylation. When STRADα is depleted, PAK1-induced invasion could not occur, suggesting that STRADα is necessary for PAK1 to drive motility. Based upon these data, we conclude that STRADα regulates PAK1 in LKB1-null cells to oversee cancer cell polarity and invasion.

Docetaxel acts by binding to β-tubulin, stabilizing microtubules, and causing cell cycle arrest in the G2/M phase of mitosis. Previous reports by our group suggest the absence of acetylated tubulin in tumor samples is a predictor for disease control in patients treated on a phase I trial with Docetaxel and Lonafarnib[1]. In this study, we hypothesize that patients with HNSCC with low levels of microtubule acetylation (i.e. highly dynamic microtubules) as measured by immunohistochemistry (IHC) would respond better to induction therapy with TPF (Docetaxel, Cisplatin and 5FU), and hence the level of acetylated tubulin (AT) would be a predictor of response to TPF. Method: Between July 5th 2006 and September 29th2009, 14 patients with HNSCC were enrolled in a Phase II clinical trial of induction chemotherapy with 3 cycles of TPF followed by local therapy. Patients underwent a biopsy of their primary tumor site prior to initiation of induction TPF. The IHC staining for AT expression was performed on formalin fixed paraffin embedded tissue. The scoring was based on intensity only since tumor cells displayed a homogeneous staining pattern. An AT score of 4 was considered to be high, whereas a stain of 0, 1, 2 or 3 was considered low. Primary tumor sites included oral cavity (OC; n=6), oropharynx (OP; n=5), larynx (L; n=1), sinus (S; n=1), and unknown primary (UP; n=1). All patients had stage IVa or IVb at presentation and had a performance status of 0-2 (Eastern Cooperative Oncology Group ECOG scale). All had at least one uni- or bi-dimensional measurable lesion on imaging. The study closed prematurely due to slow accrual and increased observed complications. A total of 9 patients were evaluated: OC/4, OP/5. Results: After 3 cycles of TPF induction chemotherapy, complete remission (CR) was achieved in 4/9(44.5%), partial remission (PR) in 4/9(44.5%), and progressive disease (PD) in 1/9(11%) of patients. There was a significant correlation between AT staining intensity and response to TPF (p=0.0476). Patients with complete response (CR) or good partial response (GPR) (>60% reduction in tumor measurement) had a significantly lower staining intensity. No correlation was observed between staining intensity and progression free survival (PFS) or overall survival (OS) perhaps due to the small sample size. Conclusion: AT expression seems to correlate with response to TPF chemotherapy in HNSCC. Predicting response to TPF may prove to be useful in customizing care for patients with HNSCC. We are planning a larger scale retrospective analysis of the value of AT expression in predicting outcome for patients with HNSCC. 1. Kauh J, et al., Defining the Interaction of Docetaxel and Lonafarnib in Patients with Advanced Malignancies. AACR meeting, 2008, LB-67, 2008. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3744.

5560 Background: We previously established that AT expression predicts for response to chemotherapy in SCCHN (Saba et al, AACR 2010 meeting abstr 3744). We wanted to further examine the relation of AT expression and nodal metastases in SCCHN. Methods: We assessed AT expression in archival tissue specimens from primary SCCHN cases with (50 cases) and without (53 cases) lymph node metastases (NM) using standard immunohistochemistry (IHC). Clinical characteristics of patients were retrieved from the department of pathology under the guidelines of the institutional review board (IRB). IHC staining for AT was scored based on intensity and percentage of tumor cells stained: 0 = no staining, 1+ = weak, 2+ = moderate, 3+ = moderate to high, 4+ = high and a weighted index (WI) was calculated as percent stain x stain intensity. Wilcoxon two-sample test and Kruskal-Wallis test were used to estimate the relationships of the WI with nodal metastasis, node status, primary tumor location, grade, and stage. Log-rank test was used to examine the difference in OS and DFS among four groups based on quartiles of the WI. A Cox proportional hazard model was employed to estimate the adjusted effect of WI on OS and DFS. Results: A higher AT expression was associated with nodal metastasis (p=0.0155) and higher stage (p=0.0311). A lower AT expression was associated with oral cavity primary (p=0.0107). After adjusting for age, gender, race, and smoking status, a lower AT expression was significantly associated with better DFS in the subset of patients with NM by multivariate analysis (HR=1.008; 95% CI=1.002- 1.014; p=0.0123). Among patients with no NM there was a marginally significant difference in OS among four different groups based on quartiles of AT expression (p=0.0765). Conclusions: High AT expression is associated with nodal metastases in SCCHN and may be a marker of poor prognosis in patients with node positive disease. The value of AT as a prognostic marker in SCCHN needs to be better defined. This work is supported by a SPORE CDP Grant P50 CA128613-03 to NFS.