Gastric cancer (GC) is one of the most common malignancies with high mortality and substantial morbidity. Although the traditional treatment strategies for GC revolve around surgery, radiotherapy, and chemotherapy, none have been able to optimally treat most affected patients. To improve clinical outcomes and overcome potential GC resistance, we established a three-dimensional (3D) culturing platform that accurately predicts drug responses in a time- and cost-effective manner. We collected tumor tissues from patients following surgeries and cultured them for 3 days using our protocol. We first evaluated cell proliferation, viability, and apoptosis using the following markers: Ki67 and cleaved caspase 3 (Cas3). We demonstrated that cell viability was maintained for 72 h in culture and that the tumor microenvironments and vascular integrities of the tissues were intact throughout the culture period. We then administered chemotherapeutics to assess drug responses and found differential sensitivity across different patient-derived tissues, enabling us to determine individualized medication plans. Overall, our study validated this rapid, cost-effective, scalable, and reproducible protocol for GC tissue culture that can be employed for drug response assessments. Our 3D culture platform paves a new way for personalized medication in GC and other tumors and can greatly impact future oncological research.

Abnormal expression and remodeling of cytoskeletal regulatory proteins are important mechanisms for tumor development and chemotherapy resistance. This study systematically analyzed the relationship between differential expression of cytoskeleton genes and prognosis in gastric cancer (GC). We found the Arf GTP-activating protein ASAP1 plays a key role in cytoskeletal remodeling and prognosis in GC patients. Here we analyzed the expression level of ASAP1 in tissue microarrays carrying 564 GC tissues by immunohistochemistry. The results showed that ASAP1 expression was upregulated in GC cells and can be served as a predictor of poor prognosis. Moreover, ASAP1 promoted the proliferation, migration, and invasion of GC cells both in vitro and in vivo. We also demonstrated that ASAP1 inhibited the ubiquitin-mediated degradation of IQGAP1 and thus enhanced the activity of CDC42. The activated CDC42 upregulated the EGFR-MAPK pathway, thereby promoting the resistance to chemotherapy in GC. Taken together, our results revealed a novel mechanism by which ASAP1 acts in the progression and chemotherapy resistance in GC. This may provide an additional treatment option for patients with GC.

Vibrio vulnificus (V. vulnificus) is an estuarine bacterium that is capable of causing rapidly fatal infection in humans. Proper polarization and bactericidal activity of macrophages play essential roles in defending against invading pathogens. How macrophages limit V. vulnificus infection remains not well understood. Here we report that tuberous sclerosis complex 1 (TSC1) is crucial for the regulation of V. vulnificus-induced macrophage polarization, bacterial clearance, and cell death. Mice with myeloid-specific deletion of TSC1 exhibit a significant reduction of survival time after V. vulnificus infection. V. vulnificus infection induces both M1 and M2 polarization. However, TSC1 deficient macrophages show enhanced M1 response to V. vulnificus infection. Interestedly, the absence of TSC1 in myeloid cells results in impaired bacterial clearance both in vivo and in vitro after V. vulnificus infection. Inhibition of the mammalian target of rapamycin (mTOR) activity significantly reverses V. vulnificus-induced hypersensitive M1 response and resistant bactericidal activity both in wild-type and TSC1-deficient macrophages. Moreover, V. vulnificus infection causes cell death of macrophages, possibly contributes to defective of bacterial clearance, which also exhibits in a mTORC1-dependent manner. These findings highlight an essential role for the TSC1-mTOR signaling in the regulation of innate immunity against V. vulnificus infection.

Background: Recent studies show that treating aggressive subtypes of breast cancer (BC) with neoadjuvant chemotherapy (NAC) improves clinical outcomes in addition to breast conservation therapy (BCT) rates. Yet a large multi-site population-level analysis shows that only 5.5% of NCCN-guideline eligible patients receive NAC (Ontilo et al, 2013). Multi-level interventions are needed to improve concordance with NCCN guidelines for NAC consideration in women who meet criteria for BCT (clinical stage IIA, IIB, and IIIA BC). Methods: A 2-part intervention was undertaken to improve adherence to NAC guidelines. Certified medical education (CME) was first provided on BC diagnostics and treatment (Tx), including NAC. Next patients were recruited to a point of care technology-based intervention. Eligibility included a new diagnosis of invasive BC, clinical stage T1c and/or N1 or greater, and no prior Tx. Patients interact with an electronic care planning system (CPS) at the time of surgical consultation to report preferences for decision-making and concerns, such as distress over losing a breast. The CPS displays these findings along with a draft care plan (CP) that suggests guideline based referrals and provides patient education about BC diagnosis and Tx options. After editing, surgeons finalize and deliver CPs at the visit. The goal is to describe referral rates to medical oncology for discussion of and receipt of NAC. Outcomes from chart abstraction are compared to historical rates in the literature and where available, the institution. Results: Data on 39 of 75 women are mature (remaining to be presented at meeting). Median age is 60 years (range 37-92) and clinical stage is IA=41% (N=16), IIA= 41% (N=16), IIB=8% (N=3), and III=10% (N=4). Of 39 patients, 44% were HR+HER2+, 10% were HR+HER2-, 13% had triple negative BC, and 33% had incomplete data. Per NCCN stage, 59% (N =23) were eligible for NAC evaluation. 96% (N=22) of those eligible were referred to MO. Follow up 2 months post-surgical appointment revealed 91% (N=21) of referred patients had completed a MO consultation. 39% (N=9) of those referred for evaluation (N=23) had a prescription for NAC and all prescriptions were guideline adherent, including regimens combining chemotherapy with trastuzumab and pertuzumab for HER2+ disease. Overall, 30.4% of women eligible for referral went on to receive NAC. Distress related to loss of breast was moderate (0-10 scale, M=4.83) and was significantly related to whether patients received a referral for NAC (B= -.304, Wald's=4.61, p=.03). Most of participating providers (80%, N=5) felt the CP was valuable to help with Tx decision-making. Conclusions: Preliminary results show CME and an electronic CPS may improve NAC uptake. Rates of prescription were clearly higher in this analysis than in a 4-center population database study, both overall (23.1% vs. 3.8%) and by NCCN eligibility (30.4% vs. 5.5%), and compared to baseline in 1 (of 3 planned) centers in the study who had a baseline rate of overall NAC prescription of 8.7% in the year prior to the study. The higher the distress over the loss of a breast, the more likely the patient received a referral for NAC. These data provide preliminary support for improving NAC uptake and warrant investigation in a RCT. Citation Format: Gary M, Keeler V, Rush S, Parsons P, Zhong X, Stricker CT, Wujcik D, DiGiovanni L, Davis A, Han LK. Improving neoadjuvant breast cancer therapy rates uptake with education and technology [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-11-05.

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