Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon and pancreatic cancers combined. Current research suggests that standard ...chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway-involving AKT, CREB, Bcl-xL, survivin, and Bcl-2-downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that short hairpin RNA (shRNA) knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl have complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.
Background
The immune response in cancer is increasingly understood to be important in determining clinical outcomes, including responses to cancer therapies. New insights into the mechanisms ...underpinning the immune microenvironment in colorectal cancer are helping to develop the role of immunotherapy and suggest targeted approaches to the management of colorectal cancer at all disease stages.
Method
A literature search was performed in PubMed, MEDLINE and Cochrane Library databases to identify relevant articles. This narrative review discusses the current understanding of the contributors to immunogenicity in colorectal cancer and potential applications for targeted therapies.
Results
Responsiveness to immunotherapy in colorectal cancer is non‐uniform. Several factors, both germline and tumour‐related, are potential determinants of immunogenicity in colorectal cancer. Current approaches target tumours with high immunogenicity driven by mutations in DNA mismatch repair genes. Recent work suggests a role for therapies that boost the immune response in tumours with low immunogenicity.
Conclusion
With the development of promising therapies to boost the innate immune response, there is significant potential for the expansion of the role of immunotherapy as an adjuvant to surgical treatment in colorectal cancer.
Antecedentes
La respuesta inmune en el cáncer se considera cada vez más importante por su influencia sobre los resultados clínicos, incluidas las respuestas a las diferentes modalidades de tratamiento. Los nuevos conocimientos sobre los mecanismos implicados en el microambiente inmunitario en el cáncer colorrectal están ayudando a definir el papel de la inmunoterapia y el desarrollo de terapias dirigidas para el tratamiento del cáncer colorrectal en todos los estadios de la enfermedad.
Métodos
Se realizó una búsqueda bibliográfica en las bases de datos PubMed, Medline y Cochrane para identificar artículos relevantes. Esta revisión descriptiva discute la comprensión actual de los factores que contribuyen a la inmunogenicidad en el cáncer colorrectal y las posibles aplicaciones en terapias dirigidas.
Resultados
La capacidad de respuesta a la inmunoterapia en el cáncer colorrectal no es uniforme. Varios factores, tanto relacionados con la línea germinal, como con el tumor son determinantes potenciales de la inmunogenicidad en el cáncer colorrectal. Los estudios actuales están dirigidos a tumores con alta inmunogenicidad provocada por mutaciones en los genes de reparación de apareamientos erróneos en el ADN. Trabajos recientes sugieren un papel para los tratamientos que estimulan la respuesta inmune en tumores con baja inmunogenicidad.
Conclusión
Con el desarrollo de tratamientos prometedores para estimular la respuesta inmune innata, existe un potencial significativo para la expansión del papel de la inmunoterapia como adyuvante del tratamiento quirúrgico en el cáncer colorrectal.
This narrative review highlights current understanding of the mechanisms of immunogenicity in colorectal cancer. The roles of germline, somatic and epigenetic factors in determining the immune environment in colorectal cancer are considered, and the significant potential for targeted immune therapies to improve patient outcomes is discussed.
Role for the future
Complex defects in neuronal signaling may underlie the dysfunctions that characterize schizophrenia. Using cDNA microarrays, we discovered that the transcript encoding regulator of G-protein ...signaling 4 (RGS4) was the most consistently and significantly decreased in the prefrontal cortex of all schizophrenic subjects examined. The expression levels of ten other RGS family members represented on the microarrays were unchanged and hierarchical data analysis revealed that as a group, 274 genes associated with G-protein signaling were unchanged. Quantitative in situ hybridization verified the microarray RGS4 data, and demonstrated highly correlated decreases in RGS4 expression across three cortical areas of ten subjects with schizophrenia. RGS4 expression was not altered in the prefrontal cortex of subjects with major depressive disorder or in monkeys treated chronically with haloperidol. Interestingly, targets for 70 genes mapped to the major schizophrenia susceptibility locus 1q21--22 were present on the microarrays, of which only RGS4 gene expression was consistently altered. The combined data indicate that a decrease in RGS4 expression may be a common and specific feature of schizophrenia, which could be due either to genetic factors or a disease- specific adaptation, both of which could affect neuronal signaling.
•CFTR-related disorders (RD) are a group of conditions caused by CFTR protein dysfunction, but to a level of dysfuncton not satisfying the diagnostic crtieria for cystic fibrosis (CF).•This paper ...discusses the individual disorders, including congenital absence of the vas deferens (CAVD), diffuse bronchiectasis, chronic or acute recurrent pancreatitis, allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling of the palms.•The CFTR functional and genetic evidence in support of each condition being a CFTR-RD are discussed and guidance for reaching the diagnosis is provided.•Gaps in our knowledge and future areas of research, including the role of CFTR modulators, are highlighted.
This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.
We report on a comprehensive reinterpretation of the existing cross-section data for elastic electron-proton scattering obtained by the initial-state radiation technique, resulting in a significantly ...improved accuracy of the extracted proton charge radius. By refining the external energy corrections we have achieved an outstanding description of the radiative tail, essential for a detailed investigation of the proton finite-size effects on the measured cross sections. This development, together with a novel framework for determining the radius, based on a regression analysis of the cross sections employing a polynomial model for the form factor, led us to a new value for the charge radius, which is
(
0.878
±
0
.
011
stat
.
±
0
.
031
sys
.
±
0
.
002
mod
.
)
fm
BackgroundIn patients with pulmonary arterial hypertension (PAH) hospital-based risk stratification is used to aid decision making and guide treatment. Risk stratification based on remote monitored ...parameters may facilitate early evaluation of clinical efficacy following treatment change or indicate clinical stability/deterioration, thereby permitting early intervention.MethodsPatients with pulmonary hypertension were identified from the ASPIRE database (6/YH/0352). Univariate Cox Regression and stepwise forward multivariate analysis were undertaken in a derivation cohort (n=3832) to identify parameters associated with mortality. Mortality weighted z-scores of age, incremental shuttle walk test (ISWT), heart rate (HR) and total pulmonary resistance (TPR) were summed to give an individual remote risk score value and LOESS regression used to determine risk thresholds. Patients enrolled in FIT-PH (NCT04078243) were implanted with a pulmonary artery pressure (CardioMEMS, Abbott) and insertable cardiac monitors (LinQ, Medtronic) and remote monitored physiology observed following clinically indicated therapeutic escalation (TE) and clinical worsening events (CWE).ResultsMultivariate analysis of the derivation cohort demonstrated that ISWT, HR and TPR had statistically significant relationships to mortality. Survival analysis demonstrated increased mortality with each decile of baseline risk score (p<0.01). In the validation cohort of patients with PAH (n=590), remote risk score thresholds identified low-, intermediate-low-, intermediate-high- and high-risk groups with Kaplan-Meier estimated 1-year mortality of 4.4%, 8.0%, 10.3% and 17.8% respectively (p<0.001 for between group comparisons, figure 1A) that were consistent COMPERA 2.0 risk stratification (Cohen’s weighted Kappa 0.61). In patients with remote monitoring devices implanted, following TE, mean pulmonary artery pressure and TPR were reduced and cardiac output (CO) and physical activity increased compared to baseline at days 7, 4, 22 and 42 respectively (p<0.05). The developed remote risk score was improved following TE (p<0.0001, figure 1B) and worsened at the time of a CWE (p<0.05) consistent with established measures of risk (WHO FC, right ventricular ejection fraction, ISWT and NTpro-BNP).Abstract S92 Figure 1A. Risk stratification of patients with pulmonary arterial hypertension by baseline remote risk score, B. Effects of clinically indicated therapeutic escalation on remote PAH risk score A. Kaplan-Meier analysis of mortality stratified by baseline 4-strata remote risk score. Kaplan-Meier estimated survival rates 1, 3 and 5 years after diagnosis for the low-risk group were 95.6%, 85.8% and 80.0%, respectively; for the intermediate-low risk group, 92.0%, 75.8% and 60.3%, respectively; for the intermediate-high risk group, 89.7%, 60.2% and 42.6%, respectively; and for the high-risk group, 82.2%, 44.6% and 28.0%, respectively (p<0.001 for between group comparisons). B. Individual risk scores were calculated by summation of the mortality weighted z-score for age, resting heart rate, total pulmonary resistance, and physical activity. Data is presented with therapeutic escalation (TE) at day 0 with days -30 to day -1 as days preceding (left of the Y-axis), and days +1 to day +30 as days following TE (right of the Y-axis). Control group comprises 60-day periods from patients with no TE. TE n=18, control n=24, mean +/-SEM, one-way ANOVA with Dunnetts’s correction, ***p<0.0001)ConclusionA remote risk score of mortality-associated parameters accurately categorised patients as low-, intermediate-low-, intermediate-high- and high-risk. Implementation of this score, to daily remote monitored data, identified improvement following TE and deterioration with CWE.
PDF
