Abstract Background Challenges remain in discerning microbiologic etiology and disease severity in childhood pneumonia. Defining host transcriptomic profiles during illness may facilitate improved diagnostic and prognostic approaches. Methods Using whole blood RNA sequencing from 222 hospitalized children with radiographic pneumonia and 45 age-matched controls, we identified differentially expressed (DE) genes that best identified children according to detected microbial pathogens (viral only vs bacterial only and typical vs atypical bacterial [with or without [±] viral co-detection]) and an ordinal measure of phenotypic severity (moderate, severe, very severe). Results Overall, 135 (61%) children had viral-only detections, 15 (7%) had typical bacterial detections (± viral co-detections), and 26 (12%) had atypical bacterial detections (± viral co-detections). Eleven DE genes distinguished between viral-only and bacterial-only detections. Sixteen DE genes distinguished between atypical and typical bacterial detections (± viral co-detections). Nineteen DE genes distinguished between levels of pneumonia severity, including 4 genes also identified in the viral-only versus bacterial-only model (IGHGP, PI3, CD177, RAP1GAP1) and 4 genes from the typical versus atypical bacterial model (PRSS23, IFI27, OLFM4, ABO). Conclusions We identified transcriptomic biomarkers associated with microbial detections and phenotypic severity in children hospitalized with pneumonia. These DE genes are promising candidates for validation and translation into diagnostic and prognostic tools.
NSCLC treatment includes targeting of EGFR with tyrosine kinase inhibitors (TKIs) such as Erlotinib; however, resistance to TKIs is commonly acquired through T790M EGFR mutations or overexpression of vascular endothelial growth factor receptor-2 (VEGFR-2). We investigated the mechanisms of EGFR-TKI resistance in NSCLC cell lines with EGFR mutations or acquired resistance to Erlotinib. These studies showed upregulated gene and protein expression of VEGF, VEGFR-2, and a VEGF co-receptor neuropilin-1 (NP-1) in Erlotinib-resistant (1.4–5.3-fold) and EGFR double-mutant (L858R and T790M; 4.1–8.3-fold) NSCLC cells compared to parental and EGFR single-mutant (L858R) NSCLC cell lines, respectively. Immunofluorescence and FACS analysis revealed increased expression of VEGFR-2 and NP-1 in EGFR-TKI-resistant cell lines compared to TKI-sensitive cell lines. Cell proliferation assays showed that treatment with a VEGFR-2 inhibitor combined with Erlotinib lowered cell survival in EGFR double-mutant NSCLC cells to 9% compared to 72% after treatment with Erlotinib alone. Furthermore, Kaplan–Meier analysis revealed shorter median survival in late-stage NSCLC patients with high vs. low VEGFR-2 expression (14 mos vs. 21 mos). The results indicate that VEGFR-2 may play a key role in EGFR-TKI resistance and that combined treatment of Erlotinib with a VEGFR-2 inhibitor may serve as an effective therapy in NSCLC patients with EGFR mutations.
Abstract Background: Lung cancer is the leading cause of cancer-related deaths in the United States. In 2021, it is anticipated that there will be 235,760 cases and 131,880 deaths due to lung cancer in the US, accounting for close to 22% of all cancer related deaths. Lung cancer's high mortality rate is largely due to the fact that approximately 75% of new cases are diagnosed in late stages. On a local level, Winnebago County has 17% higher incidence and mortality rates due to lung cancer than the corresponding national rates. Low-dose computed tomography (LDCT) is a valuable lung screening technique that utilizes 90% less ionizing radiation than a conventional chest CT scan. Hypothesis/Aims: Increased awareness of LDCT in clinical and community settings will lead to increased detection of lung cancer at its early stages and decreased mortality rates attributed to the disease. Study Design: This project harnessed the power of education, specifically through informational seminars and booths at community events, to promote LDCT screening in our community. We spread information on the new U.S. Preventive Services Task Force guidelines to both smokers and physicians in Winnebago County. We evaluated the number of LDCT screenings in Winnebago County between June 2015 and October 2021, and we recorded the number and stage classifications of lung cancer cases detected as a result of these screenings. Lastly, we created a Facebook page (Northern Illinois Lung Cancer Screening Project) to continue promoting LDCT screening in a socially distanced manner. Results: 16 seminars and 42 public awareness booths targeting an estimated 400 physicians and 2,000 smokers were conducted to increase knowledge of LDCT. 4,170 patients underwent LDCT screening at local hospitals during the timeframe of our study. 90 patients were diagnosed with lung cancer, with 50 cases being early stage. 1,264 additional individuals were found to have small lung nodules and are being followed up on in accordance with Lung RADS Criteria on pulmonary nodules detected using LDCT. These studies are being done in Boone, Ogle, and Stephenson Counties, which are also characterized by alarmingly high incidence and mortality rates attributed to lung cancer. In an alternative effort to promote lung cancer screening in Northern Illinois, we created a Facebook page where we publish posts weekly and have reached over 2,177 people and garnered 176 engagements from Facebook users. Conclusions: 50 local community members were diagnosed with early stage lung cancer, thus improving their prognosis and increasing therapy options. Physicians and smokers in the community are more educated on the clinical benefits of LDCT. These community-based studies are being expanded to surrounding areas, and new screening techniques are being implemented to expand the reach and effectiveness of our studies. Citation Format: Shruti Gautam, Roberto E. DeVera IV, Meet Patel, Neelu Puri. Promotion of low-dose computed tomography for early-stage lung cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6347A.
Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, and nivolumab, are the treatment options for malignant melanoma. Several biomarkers involved in tumorigenesis have been identified as potential targets for molecularly targeted melanoma therapy, such as tyrosine kinase inhibitors (TKIs). Unfortunately, melanoma quickly acquires resistance to these molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been employed and have been shown to improve the prognosis of melanoma patients compared to monotherapy. This review discusses several combination therapies that target melanoma biomarkers, such as BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K. Several of these regimens are already FDA-approved for treating metastatic melanoma, while others are still in clinical trials. Continued research into the causes of resistance and factors influencing the efficacy of these combination treatments, such as specific mutations in oncogenic proteins, may further improve the effectiveness of combination therapies, providing a better prognosis for melanoma patients.
Objectives: In India, tobacco consumption is responsible for half of all the cancers in men and a quarter in women. The present study focuses on the expression of cyclooxygenase-2 (COX-2), P53, vascular endothelial growth factor (VEGF), and nitric oxide synthase (NOS) and their relationship with the growth and angiogenesis of tobacco-related malignancies of the oral cavity, esophagus, lungs, and stomach. It further evaluates the carcinogenic action of nicotine and examines whether COX-2 and NOS-2 overexpression is responsible for tumor growth and associated angiogenic VEGF expression via its receptor. Materials and Methods: A cross-sectional study on 140 biopsies, resected specimens of cancer of oral cavity, esophagus, stomach, and lungs, was done. Immunohistochemical evaluation for p53, COX-2, VEGF, and inducible NOS was done. Relevant statistical analysis was applied for the significance of the findings. Statistical Analysis: Relevant statistical analysis was done using SPSS, chi-square and Fisher's exact tests were applied for the significance of the findings. A p-value of < 0.05 was considered as significant value. Results: Immunohistochemical evaluation of pattern of expression of COX-2, NOS-2, VEGF, and p53 was done in both tobacco- and nontobacco-associated cases. The results of the present study revealed an upregulation of COX-2, NOS-2, VEGF, and p53 in all the malignancies. Conclusion: The present results indicated that p53 protein accumulation and increased expression of COX-2, NOS-2, and VEGF might be responsible for carcinogenesis and tumor aggressiveness by enhancing angiogenesis. A possible significant effect of nicotine on COX-2 and P53 expression in tumorigenesis is revealed. These data might have important implications for the therapeutic use of COX-2, NOS-2, and VEGF inhibitors as well as of p53 gene therapy in future anticancer therapeutic strategies in tobacco-related malignancies.
