Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model

<p>Abstract</p> <p>Background</p> <p>There is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs) leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC).</p> <p>Methods</p> <p>We selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2. Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed <it>in vitro</it>. <it>In vivo </it>experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without radiotherapy) were also carried out.</p> <p>Results</p> <p>Lapatinib dramatically reduced cell proliferation (<it>P </it>< 0.0001), DNA synthesis (<it>P </it>< 0.006), and colony formation capacity (<it>P </it>< 0.0001) in A549 cells <it>in vitro</it>. Furthermore, lapatinib induced G1 cell cycle arrest (<it>P </it>< 0.0001) and apoptotic cell death (<it>P </it>< 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages, respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc and PCNA levels. <it>In vivo </it>experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly less active tumors (as assessed by PET analysis) (<it>P </it>< 0.04) and smaller in size than controls. In addition, tumors from lapatinib-treated mice showed a dramatic reduction in angiogenesis (<it>P </it>< 0.0001).</p> <p>Conclusion</p> <p>Overall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer.</p

Elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell-mediated endothelial cell tube formation: implications for prostate cancer progressioan

<p>Abstract</p> <p>Background</p> <p>Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR1C enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we propose a novel pathological function of AKR1C3 in tumor angiogenesis and its potential role in promoting PCa progression.</p> <p>Methods</p> <p>To recapitulate elevated AKR1C3 expression in cancerous prostate, the human PCa PC-3 cell line was stably transfected with an AKR1C3 expression construct to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analysis were performed to identify AKR1C3-mediated pathways of activation and their potential biological consequences in PC-3 cells. Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and an <it>in vitro </it>Matrigel angiogenesis assays were applied to validate the pro-angiogenic activity of PC3-AKR1C3 transfectants identified by bioinformatics analysis.</p> <p>Results</p> <p>Microarray and bioinformatics analysis suggested that overexpression of AKR1C3 in PC-3 cells modulates estrogen and androgen metabolism, activates insulin-like growth factor (IGF)-1 and Akt signaling pathways, as well as promotes tumor angiogenesis and aggressiveness. Levels of IGF-1 receptor (IGF-1R) and Akt activation as well as vascular endothelial growth factor (VEGF) expression and secretion were significantly elevated in PC3-AKR1C3 transfectants in comparison to PC3-mock transfectants. PC3-AKR1C3 transfectants also promoted endothelial cell (EC) tube formation on Matrigel as compared to the AKR1C3-negative parental PC-3 cells and PC3-mock transfectants. Pre-treatment of PC3-AKR1C3 transfectants with a selective IGF-1R kinase inhibitor (AG1024) or a non-selective phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) abolished ability of the cells to promote EC tube formation.</p> <p>Conclusions</p> <p>Bioinformatics analysis followed by functional genomics demonstrated that AKR1C3 overexpression promotes angiogenesis and aggressiveness of PC-3 cells. These results also suggest that AKR1C3-mediated tumor angiogenesis is regulated by estrogen and androgen metabolism with subsequent IGF-1R and Akt activation followed by VEGF expression in PCa cells.</p

Fatal police violence by race and state in the USA, 1980–2019: a network meta-regression

Background: The burden of fatal police violence is an urgent public health crisis in the USA. Mounting evidence shows that deaths at the hands of the police disproportionately impact people of certain races and ethnicities, pointing to systemic racism in policing. Recent high-profile killings by police in the USA have prompted calls for more extensive and public data reporting on police violence. This study examines the presence and extent of under-reporting of police violence in US Government-run vital registration data, offers a method for correcting under-reporting in these datasets, and presents revised estimates of deaths due to police violence in the USA. Methods: We compared data from the USA National Vital Statistics System (NVSS) to three non-governmental, open-source databases on police violence: Fatal Encounters, Mapping Police Violence, and The Counted. We extracted and standardised the age, sex, US state of death registration, year of death, and race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic of other races, and Hispanic of any race) of each decedent for all data sources and used a network meta-regression to quantify the rate of under-reporting within the NVSS. Using these rates to inform correction factors, we provide adjusted estimates of deaths due to police violence for all states, ages, sexes, and racial and ethnic groups from 1980 to 2019 across the USA. Findings: Across all races and states in the USA, we estimate 30 800 deaths (95% uncertainty interval [UI] 30 300–31 300) from police violence between 1980 and 2018; this represents 17 100 more deaths (16 600–17 600) than reported by the NVSS. Over this time period, the age-standardised mortality rate due to police violence was highest in non-Hispanic Black people (0·69 [95% UI 0·67–0·71] per 100 000), followed by Hispanic people of any race (0·35 [0·34–0·36]), non-Hispanic White people (0·20 [0·19–0·20]), and non-Hispanic people of other races (0·15 [0·14– 0·16]). This variation is further affected by the decedent's sex and shows large discrepancies between states. Between 1980 and 2018, the NVSS did not report 55·5% (54·8–56·2) of all deaths attributable to police violence. When aggregating all races, the age-standardised mortality rate due to police violence was 0·25 (0·24–0·26) per 100 000 in the 1980s and 0·34 (0·34–0·35) per 100 000 in the 2010s, an increase of 38·4% (32·4–45·1) over the period of study. Interpretation: We found that more than half of all deaths due to police violence that we estimated in the USA from 1980 to 2018 were unreported in the NVSS. Compounding this, we found substantial differences in the age-standardised mortality rate due to police violence over time and by racial and ethnic groups within the USA. Proven public health intervention strategies are needed to address these systematic biases. State-level estimates allow for appropriate targeting of these strategies to address police violence and improve its reporting. Funding: Bill & Melinda Gates Foundation, National Institute on Minority Health and Health Disparities, and National Heart, Lung, and Blood Institute

Randomized Trial of Case-Finding for Depression in Elderly Primary Care Patients

OBJECTIVE: To determine the effect of case-finding for depression on frequency of depression diagnoses, prescriptions for antidepressant medications, prevalence of depression, and health care utilization during 2 years of follow-up in elderly primary care patients. DESIGN: Randomized controlled trial. SETTING: Thirteen primary care medical clinics at the Kaiser Permanente Medical Center, an HMO in Oakland, Calif, were randomly assigned to intervention conditions (7 clinics) or control conditions (6 clinics). PARTICIPANTS: A total of 2,346 patients aged 65 years or older who were attending appointments at these clinics and completed the 15-item Geriatric Depression Scale (GDS). GDS scores of 6 or more were considered suggestive of depression. INTERVENTIONS: Primary care physicians in the intervention clinics were notified of their patients' GDS scores. We suggested that participants with severe depressive symptoms (GDS score ≥ 11) be referred to the Psychiatry Department and participants with mild to moderate depressive symptoms (GDS score of 6 –10) be evaluated and treated by the primary care physician. Intervention group participants with GDS scores suggestive of depression were also offered a series of organized educational group sessions on coping with depression led by a psychiatric nurse. Primary care physicians in the control clinics were not notified of their patients' GDS scores or advised of the availability of the patient education program (usual care). Participants were followed for 2 years. MEASUREMENTS AND MAIN RESULTS: Physician diagnosis of depression, prescriptions for antidepressant medications, prevalence of depression as measured by the GDS at 2-year follow-up, and health care utilization were determined. A total of 331 participants (14%) had GDS scores suggestive of depression (GDS ≥ 6) at baseline, including 162 in the intervention group and 169 in the control group. During the 2-year follow-up period, 56 (35%) of the intervention participants and 58 (34%) of the control participants received a physician diagnosis of depression (odds ratio [OR], 1.0; 95% confidence interval [CI], 0.6 to 1.6; P = .96). Prescriptions for antidepressants were received by 59 (36%) of the intervention participants and 72 (43%) of the control participants (OR, 0.8; 95% CI, 0.5 to 1.2; P = .3). Two-year follow-up GDS scores were available for 206 participants (69% of survivors): at that time, 41 (42%) of the 97 intervention participants and 54 (50%) of the 109 control participants had GDS scores suggestive of depression (OR, 0.7; 95% CI, 0.4 to 1.3; P = .3). Comparing participants in the intervention and control groups, there were no significant differences in mean GDS change scores (−2.4 ± SD 3.7 vs −2.1 SD ± 3.6; P = .5) at the 2-year follow-up, nor were there significant differences in mean number of clinic visits (1.8 ± SD 3.1 vs 1.6 ± SD 2.8; P = .5) or mean number of hospitalizations (1.1 ± SD 1.6 vs 1.0 ± SD 1.4; P =.8) during the 2-year period. In participants with initial GDS scores >11, there was a mean change in GDS score of −5.6 ± SD 3.9 for intervention participants (n =13) and −3.4 ± SD 4.5 for control participants (n = 21). Adjusting for differences in baseline characteristics between groups did not affect results. CONCLUSIONS: We were unable to demonstrate any benefit from case-finding for depression during 2 years of follow-up in elderly primary care patients. Studies are needed to determine whether case-finding combined with more intensive patient education and follow-up will improve outcomes of primary care patients with depression

Underdiagnosis of Depression in HIV: Who Are We Missing?

OBJECTIVE: To determine the sociodemographic and service delivery correlates of depression underdiagnosis in HIV. DESIGN: Cross-sectional survey. PATIENTS/PARTICIPANTS: National probability sample of HIV-infected persons in care in the contiguous United States who have available medical record data. MEASUREMENTS AND MAIN RESULTS: We interviewed patients using the Composite International Diagnostic Interview (CIDI) survey from the Mental Health Supplement. Patients also provided information regarding demographics, socioeconomic status, and HIV disease severity. We extracted patient medical record data between July 1995 and December 1997, and we defined depression underdiagnosis as a diagnosis of major depressive disorder based on the CIDI and no recorded depression diagnosis by their principal health care provider in their medical records between July 1995 and December 1997. Of the 1,140 HIV Cost and Services Utilization Study patients with medical record data who completed the CIDI, 448 (37%) had CIDI-defined major depression, and of these, 203 (45%) did not have a diagnosis of depression documented in their medical record. Multiple logistic regression analysis revealed that patients who had less than a high school education (P < .05) were less likely to have their depression documented in the medical record compared to those with at least a college education. Patients with Medicare insurance coverage compared to those with private health insurance (P < .01) and those with ≥3 outpatient visits (P < .05) compared to <3 visits were less likely to have their depression diagnosis missed by providers. CONCLUSIONS: Our results suggest that providers should be more attentive to diagnosing comorbid depression in HIV-infected patients