RESUMO
Transition-metal-based approaches to selectively modify proteins hold promise in addressing challenges in chemical biology. Unique bioorthogonal chemistry can be achieved with preformed metal-based compounds; however, their utility in native protein sites within cells remain underdeveloped. Here, we tune the ancillary ligands of cyclometalated gold(III) as a reactive group, and the gold scaffold allows for rapid modification of a desired cysteine residue proximal to the ligand binding site of a target protein. Moreover, evidence for a ligand association mechanism toward C-S bond formation by X-crystallography is established. The observed reactivity of cyclometalated gold(III) enables the rational design of a cysteine-targeted covalent inhibitor of mutant KRAS. This work illustrates the potential of structure-activity relationship studies to tune kinetics of cysteine arylation and rational design of metal-mediated ligand affinity chemistry (MLAC) of native proteins.
Assuntos
Cisteína/farmacologia , Inibidores Enzimáticos/farmacologia , Ouro/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Cisteína/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ouro/química , Humanos , Ligantes , Estrutura Molecular , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismoRESUMO
Fulvestrant, which degrades ER, is used after AI failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mTOR, a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis. Of 33 patients enrolled two were ruled ineligible after enrollment and were excluded from study analysis, for a total of 31 evaluable patients. Median age was 54 years (range 45-85). Prior therapy included tamoxifen (81 %), chemotherapy (71 %), with 26 % of patients having received 3 or more endocrine agents. Median TTP was 7.4 months (95 % CI 1.9-12.1) with an objective response rate of 13 % and CBR of 49 %. Of particular note, 32 % of patients exhibited de novo resistance to study treatment with disease progression as their best response. Most common adverse events (AEs) were elevated AST (87 %) and ALT (77 %), anemia (74 %), hyperglycemia (71 %), and hypercholesterolemia (68 %). Prominent clinical toxicities were mucositis (58 %), weight loss (48 %), and rash (42 %). Most AEs were grade 1 or 2 and largely reversible with infrequent need for everolimus dose reduction. To conclude, everolimus plus fulvestrant is effective after AI failure in heavily pretreated metastatic ER-positive breast cancer and has manageable toxicity. Further study of this combination is warranted in randomized studies. Since not all patients experience benefit, and in view of potential toxicities, biomarker examination is critical to help select patients most likely to benefit from this strategy in future studies.
Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Estradiol/análogos & derivados , Sirolimo/análogos & derivados , Falha de Tratamento , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estradiol/efeitos adversos , Estradiol/uso terapêutico , Everolimo , Feminino , Fulvestranto , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores de Estrogênio/metabolismo , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
BACKGROUND: Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer. MATERIALS & METHODS: A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual. RESULTS: Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-α. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways. CONCLUSION: The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Biomarcadores Tumorais/sangue , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Niacinamida/uso terapêutico , Projetos Piloto , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Estrogênio/metabolismo , Sorafenibe , Tamoxifeno/uso terapêutico , Resultado do TratamentoRESUMO
Oncogenic mutations of ras and B-raf frequently occur in many cancer types and are critical for cell transformation and tumorigenesis. Death receptor 5 (DR5) is a cell surface pro-apoptotic death receptor for tumor necrosis factor-related apoptosis-inducing ligand and has been targeted in cancer therapy. The current study has demonstrated induction of DR5 expression by the oncogenic proteins Ras and B-Raf and revealed the underlying mechanisms. We demonstrated that both Ras and B-Raf induce DR5 expression by enforced expression of oncogenic Ras (e.g. H-Ras12V or K-Ras12V) or B-Raf (i.e. V600E) in cells and by analyzing gene expression array data generated from cancer cell lines and from human cancer tissues. This finding is further supported by our results that knockdown of endogenous K-Ras or B-Raf (V600E) reduced the expression of DR5. Importantly, we have elucidated that Ras induces DR5 expression through co-activation of ERK/RSK and JNK signaling pathways and subsequent cooperative effects among the transcriptional factors CHOP, Elk1, and c-Jun to enhance DR5 gene transcription. Moreover, we found that the majority of cancer cell lines highly sensitive to the DR5 agonistic antibody AMG655 have either Ras or B-Raf mutations. Our findings warrant further study on the biology of DR5 regulation by Ras and B-Raf, which may provide new insight into the biology of Ras and B-Raf, and on the potential impact of Ras or B-Raf mutations on the outcome of DR5-targeted cancer therapy.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Transdução de Sinais , Proteínas ras/metabolismo , Linhagem Celular Tumoral , Humanos , Mutação , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Proteínas Quinases S6 Ribossômicas/metabolismo , Fator de Transcrição CHOP/metabolismo , Transcrição Gênica , Proteínas Elk-1 do Domínio ets/metabolismoRESUMO
OBJECTIVE: To study curricular outcomes for the purpose of holistic improvement of the curriculum. METHODS: A single-institution retrospective cohort study evaluated 3 cohorts of Doctor of Pharmacy students entering the program through performance in Advanced Pharmacy Practice Experience (APPE) rotations. Assessment scores and pass/fail outcomes were collected from the 3 examinations to use as predictors, and the numbers of "needs improvement" (NI) and "unsatisfactory" (U) ratings from preceptors during the APPE rotations served as outcome measures. RESULTS: Pharmacy mathematics competency and Milemarker 1 (MM1) examination first-time scores, but not those from Milemarker 2 (MM2), were significantly associated with NI or U scores on required APPE rotations. Significant correlations for all examinations (pharmacy mathematics competency, MM1, and MM2) were found for the Acute Care/Inpatient APPE rotation for each cohort and the combined cohorts. Significant correlations were also found between all examinations and the APPE rotation courses Advanced Hospital and Ambulatory Care, with the exception of the 2021 cohort. Performance in the Advanced Community rotation was not associated with any of the examinations. MM1 and MM2 are both reliable measures of competence in our didactic curriculum and predictive of scoring an NI or U rating in the APPE Acute Care/Inpatient rotation. CONCLUSION: The longitudinal milestone examinations used in our institution provide a mechanism to identify students likely to struggle in required APPE rotations and target them for remediation activities.
Assuntos
Educação em Farmácia , Farmácia , Estudantes de Farmácia , Humanos , Estudos Retrospectivos , Avaliação Educacional , CurrículoRESUMO
The identification of novel therapies, new strategies for combination of therapies, and repurposing of drugs approved for other indications are all important for continued progress in the fight against lung cancers. Antibodies that target immune checkpoints can unmask an immunologically hot tumor from the immune system of a patient. However, despite accounts of significant tumor regression resulting from these medications, most patients do not respond. In this study, we sought to use protein expression and RNA sequencing data from The Cancer Genome Atlas and two smaller studies deposited onto the Gene Expression Omnibus (GEO) to advance our hypothesis that inhibition of SHP-2, a tyrosine phosphatase, will improve the activity of immune checkpoint inhibitors (ICI) that target PD-1 or PD-L1 in lung cancers. We first collected protein expression data from The Cancer Proteome Atlas (TCPA) to study the association of SHP-2 and PD-L1 expression in lung adenocarcinomas. RNA sequencing data was collected from the same subjects through the NCI Genetic Data Commons and evaluated for expression of the PTPN11 (SHP-2) and CD274 (PD-L1) genes. We then analyzed RNA sequencing data from a series of melanoma patients who were either treatment naïve or resistant to ICI therapy. PTPN11 and CD274 expression was compared between groups. Finally, we analyzed gene expression and drug response data collected from 21 non-small cell lung cancer (NSCLC) patients for PTPN11 and CD274 expression. From the three studies, we hypothesize that the activity of SHP-2, rather than the expression, likely controls the expression of PD-L1 as only a weak relationship between PTPN11 and CD274 expression in either lung adenocarcinomas or melanomas was observed. Lastly, the expression of CD274, not PTPN11, correlates with response to ICI in NSCLC.
Assuntos
Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Genômica , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adenocarcinoma de Pulmão/genética , Antígeno B7-H1/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Melanoma/genética , Fosforilação , Receptor de Morte Celular Programada 1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
The pandemic caused by the novel coronavirus identified in 2019 (COVID-19) has resulted in seismic changes throughout society. Accordingly, academia has been forced to adapt. Changes across all aspects of teaching and instruction have occurred. Students have departed campuses and prospects of their return remain unclear. The Academy, which is generally reluctant to change, has been forced to make rapid adjustments. Among other issues, pharmacy schools and colleges have been forced to mitigate changes to experiential education. Tremendous resources and energy have been invested to actuate the changes that have occurred. In many ways, the disruptions forced upon pharmacy education may usher in a new normal. The likelihood for even a partial return to the customary way of doing things appears increasingly unlikely.
Assuntos
Infecções por Coronavirus/epidemiologia , Educação em Farmácia/organização & administração , Pneumonia Viral/epidemiologia , Aprendizagem Baseada em Problemas/organização & administração , Faculdades de Farmácia/organização & administração , Betacoronavirus , COVID-19 , Humanos , Pandemias , SARS-CoV-2RESUMO
Lung cancers demonstrate loss of cellular signaling control pathways. EGFR-mutant non-small cell lung cancer cell lines constitutively express active ERK1/2 and require ERK activity for survival. DUSP4 is a negative regulator of ERK activity and is up-regulated in EGFR-mutant lung cancer cell lines relative to K-ras mutant cells. Both DUSP4 and family member, DUSP1, can bind ERK in vitro. However, only DUSP1 has detectable binding to ERK in vivo in cell lines of either genotype. Depletion of DUSP4 in EGFR-mutant cells unexpectedly results in loss of pERK whereas loss of DUSP4 in K-ras mutant cells predictably yields increased pERK. These data support a role for DUSP4, and perhaps DUSP1, as a positive activator of ERK in EGFR-mutant lung cancer cell lines independent of the ability to bind to ERK.
Assuntos
Fosfatase 1 de Especificidade Dupla/metabolismo , Fosfatases de Especificidade Dupla/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/enzimologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Linhagem Celular Tumoral , Fosfatase 1 de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/genética , Receptores ErbB/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Transdução de SinaisRESUMO
Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in human cancer including lung cancer and has been implicated in transformation, tumorigenicity, and metastasis. One putative downstream gene regulated by Stat3 is MUC1 which also has important roles in tumorigenesis. We determined if Stat3 regulates MUC1 in lung cancer cell lines and what function MUC1 plays in lung cancer cell biology. We examined MUC1 expression in non-small cell lung cancer (NSCLC) cell lines and found high levels of MUC1 protein expression associated with higher levels of tyrosine phosphorylated STAT3. STAT3 knockdown downregulated MUC1 expression whereas constitutive STAT3 expression increased MUC1 expression at mRNA and protein levels. MUC1 knockdown induced cellular apoptosis concomitant with reduced Bcl-XL and sensitized cells to cisplatin treatment. MUC1 knockdown inhibited tumor growth and metastasis in an orthotopic mouse model of lung cancer by activating apoptosis and inhibiting cell proliferation in vivo. These results demonstrate that constitutively activated STAT3 regulates expression of MUC1, which mediates lung cancer cell survival and metastasis in vitro and in vivo. MUC1 appears to be a cooperating oncoprotein with multiple oncogenic tyrosine kinase pathways and could be an effective target for the treatment of lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Mucina-1/fisiologia , Fator de Transcrição STAT3/fisiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular , Cisplatino/uso terapêutico , Proteína-Tirosina Quinases de Adesão Focal/fisiologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Mucina-1/genética , Invasividade Neoplásica , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de SinaisRESUMO
BACKGROUND: The anti-EGFR monoclonal antibody cetuximab is used in metastatic colorectal cancer (CRC), and predicting responsive patients garners great interest, due to the high cost of therapy. Mutations in the KRAS gene occur in ~40% of CRC and are a negative predictor of response to cetuximab. However, many KRAS-wildtype patients do not benefit from cetuximab. We previously published a gene expression predictor of sensitivity to erlotinib, an EGFR inhibitor. The purpose of this study was to determine if this predictor could identify KRAS-wildtype CRC patients who will benefit from cetuximab therapy. METHODS: Microarray data from 80 metastatic CRC patients subsequently treated with cetuximab were extracted from the study by Khambata-Ford et al. The study included KRAS status, response, and PFS for each patient. The gene expression data were scaled and analyzed using our predictive model. An improved predictive model of response was identified by removing features in the 180-gene predictor that introduced noise. RESULTS: Forty-three of eighty patients were identified as harboring wildtype-KRAS. When the model was applied to these patients, the predicted-sensitive group had significantly longer PFS than the predicted-resistant group (median 88 days vs. 56 days; mean 117 days vs. 63 days, respectively, p = 0.008). Kaplan-Meier curves were also significantly improved in the predicted-sensitive group (p = 0.0059, HR = 0.4109. The model was simplified to 26 of the original 180 genes and this further improved stratification of PFS (median 147 days vs. 56.5 days in the predicted sensitive and resistant groups, respectively, p < 0.0001). However, the simplified model will require further external validation, as features were selected based on their correlation to PFS in this dataset. CONCLUSION: Our model of sensitivity to EGFR inhibition stratified PFS following cetuximab in KRAS-wildtype CRC patients. This study represents the first true external validation of a molecular predictor of response to cetuximab in KRAS-WT metastatic CRC. Our model may hold clinical utility for identifying patients responsive to cetuximab and may therefore minimize toxicity and cost while maximizing benefit.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB/imunologia , Regulação Neoplásica da Expressão Gênica , Proteínas ras/genética , Anticorpos Monoclonais Humanizados , Cetuximab , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Perfilação da Expressão Gênica , Genótipo , Humanos , Mutação , Metástase Neoplásica , Valor Preditivo dos TestesRESUMO
In the current study, novel paclitaxel-loaded cross-linked hyaluronan nanoparticles were engineered for the local delivery of paclitaxel as a prototype drug for cancer therapy. The nanoparticles were prepared using a desolvation method with polymer cross-linking. In vitro cytotoxicity studies demonstrated that less than 75% of the MDA-MB-231 and ZR-75-1 breast cancer cells were viable after 2-day exposure to paclitaxel-loaded hyaluronan nanoparticles or free paclitaxel, regardless of the dose. These results suggest that hyaluronan nanoparticles maintain the pharmacological activity of paclitaxel and efficiently deliver it to the cells. Furthermore, in vivo administration of the drug-loaded nanoparticles via direct intratumoral injection to 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor in female rats was studied. The paclitaxel-loaded nanoparticles treated group showed effective inhibition of tumor growth in all treated rats. Interestingly, there was one case of complete remission of tumor nodule and two cases of persistent reduction of tumor size that was observed on subsequent days. In the case of free paclitaxel-treated group, the mean tumor volume increased almost linearly (R(2) = 0.93) with time to a size that was 4.9-fold larger than the baseline volume at 57 days post-drug administration. Intratumoral administration of paclitaxel-loaded hyaluronan nanoparticles could be a promising treatment modality for solid mammary tumors.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Ácido Hialurônico/administração & dosagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , 9,10-Dimetil-1,2-benzantraceno , Animais , Química Farmacêutica , Feminino , Paclitaxel/química , Paclitaxel/farmacologia , Ratos , Ratos Sprague-Dawley , SolubilidadeRESUMO
Many external drivers may be influencing a paradigm shift in graduate education. Workforce dynamics are driving a re-examination of what is instructed in graduate programs as well as how curricula are delivered. Most graduate programs have made incremental changes in their philosophical approaches, but new and more dramatic paradigms may be needed to sufficiently address the future needs of employers and students alike.
Assuntos
Educação de Pós-Graduação/organização & administração , Educação em Farmácia/tendências , Avaliação de Programas e Projetos de Saúde/tendências , Currículo , Educação de Pós-Graduação/tendências , Humanos , Pesquisa Farmacêutica , Desenvolvimento de ProgramasRESUMO
KRAS-activation mutations occur in 25% to 40% of lung adenocarcinomas and are a known mechanism of epidermal growth factor receptor inhibitor (EGFRI) resistance. There are currently no targeted therapies approved specifically for the treatment of KRAS-active non-small cell lung cancers (NSCLC). Attempts to target mutant KRAS have failed in clinical studies leaving no targeted therapy option for these patients. To circumvent targeting KRAS directly, we hypothesized that targeting proteins connected to KRAS function rather than targeting KRAS directly could induce cell death in KRAS-active NSCLC cells. To identify potential targets, we leveraged 2 gene expression data sets derived from NSCLC cell lines either resistant and sensitive to EGFRI treatment. Using a Feasible Solutions Algorithm, we identified genes with deregulated expression in KRAS-active cell lines and used STRING as a source for known protein-protein interactions. This process generated a network of 385 deregulated proteins including KRAS and other known mechanisms of EGFRI resistance. To identify candidate drug targets from the network for further study, we selected proteins with the greatest number of connections within the network and possessed an enzymatic activity that could be inhibited with an existing pharmacological agent. Of the potential candidates, the pharmacological impact of targeting casein kinase 2 (CK2) as a single target was tested, and we found a modest reduction in viability in KRAS-active NSCLC cells. MEK was chosen as a second target from outside the network because it lies downstream of KRAS and MEK inhibition can overcome resistance to CK2 inhibitors. We found that CK2 and MEK inhibition demonstrates moderate synergy in inducing apoptosis in KRAS-active NSCLC cells. These results suggest promise for a combination inhibitor strategy for treating KRAS-active NSCLC.
RESUMO
BACKGROUND AND PURPOSE: Opioid overdose is a leading cause of death across the United States. Rho Chi Pharmacy Honor Society students at the University of Kentucky initiated a project to provide fellow students a volunteer opportunity to educate at-risk patients about naloxone using a physician-approved protocol. The goal was to improve student counseling skills by allowing them to apply knowledge learned during didactic and simulated training. EDUCATIONAL ACTIVITY AND SETTING: Third and fourth year pharmacy students at the University of Kentucky voluntarily provided opioid overdose and naloxone counseling to patients at the health department and other locations. Students who counseled at the health department were asked to complete an Institutional Review Board (IRB)-approved, anonymous, electronic survey at the end to gauge their perceptions of the experience. FINDINGS: Thirty-five of forty-five participating students responded to the survey, indicating a 78% response rate. The results suggested that student comfort with naloxone counseling increased after real-world counseling, compared with their perceived comfort levels entering the experience. The majority of the respondents (77%, nâ¯=â¯27) reported a change in their personal views on drug addiction and the associated patient population. Ninety-one percent (nâ¯=â¯32) of students plan to pursue certification to dispense naloxone as part of their future pharmacy practice. Most (94%, nâ¯=â¯33) perceived the counseling experience as practical application of their didactic education. DISCUSSION AND CONCLUSIONS: As opioid addiction and accidental overdose plagues the nation, pharmacists are prepared to lead the battle against this disease. Pharmacy education and hands-on opportunities provide students with the practical knowledge and skills necessary to have impact on their patients and the opioid epidemic.
Assuntos
Aconselhamento/normas , Naloxona/administração & dosagem , Percepção , Estudantes de Farmácia/psicologia , Adulto , Aconselhamento/métodos , Overdose de Drogas/tratamento farmacológico , Overdose de Drogas/psicologia , Feminino , Humanos , Kentucky , Masculino , Pessoa de Meia-Idade , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/psicologia , Inquéritos e QuestionáriosRESUMO
Our previous work identified a 13-gene miRNA signature predictive of response to the epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in Non-Small Cell Lung Cancer cell lines. Bioinformatic analysis of the signature showed a functional convergence on TGFß canonical signalling. We hypothesized that TGFß signalling controls expression of the miRNA genes comprising an erlotinib response signature in NSCLC. Western analysis revealed that TGFß signalling via Smad2/3/4 occurred differently between erlotinib-resistant A549 and erlotinib- sensitive PC9 cells. We showed that TGFß induced an interaction between Smad4 and putative Smad Binding Elements in PC9. However, qRT-PCR analysis showed that endogenous miR-140/141/200c expression changes resulted from time in treatments, not the treatments themselves. Moreover, flow cytometry indicated that cells exited the cell cycle in the same manner. Taken together these data indicated that the miRNA comprising the signature are likely regulated by the cell cycle rather than by TGFß. Importantly, this work revealed that TGFß did not induce EMT in PC9 cells, but rather TGFß-inhibition induced an EMT-intermediate. These data also show that growth/proliferation signals by constitutively-activated EGFR may rely on TGFß and a possible relationship between TGFß and EGFR signalling may prevent EMT progression in this context rather than promote it.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Cloridrato de Erlotinib/uso terapêutico , Perfilação da Expressão Gênica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , MicroRNAs/genética , Fator de Crescimento Transformador beta/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática , Transição Epitelial-Mesenquimal/genética , Cloridrato de Erlotinib/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Fenótipo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Smad/metabolismo , Fatores de TempoRESUMO
Objective. To determine whether admissions data alone adequately predicts student success in the first-year doctor of pharmacy (PharmD) curriculum or whether academic monitoring and intervention has greater value toward successful completion of first-year coursework. Methods. A systematic evaluation of the literature assessing student success was performed to ascertain historical evidence of student success metrics. We then retrospectively analyzed internal admissions data and first-year outcomes for our pharmacy classes of 2016-2019 using available data. We conducted an interim evaluation of voluntary academic monitoring and mentoring with the hypothesis that admission data alone cannot predict student success in early foundational coursework, and intentional intervention might improve success. Results. Pre-pharmacy grade point average (GPA), science GPA, Pharmacy College Admission Test (PCAT) score, and prior degree status each retain some predictive value regarding success, and combinations of these factors may improve the ability to predict student success in early foundational coursework. There remains a significant, and perhaps insurmountable, gap in identifying quantitative metrics that forecast student success. Although admission data can stratify incoming students based on predicted academic ability, early monitoring and intervention provide an actionable means for enhancing student success in first-year coursework. Conclusion. Quantitative academic measures, such as PCAT scores and GPA, historically have demonstrated limited value in predicting student success. While these measures allow stratification of predicted academic performance among incoming students, monitoring of first-year, institution-specific data, such as midterm grades, can direct intentional intervention and remediation strategies that may provide more benefit to ensure students succeed.
Assuntos
Educação de Pós-Graduação em Farmácia , Educação em Farmácia , Avaliação Educacional/métodos , Teste de Admissão Acadêmica , Humanos , Critérios de Admissão EscolarRESUMO
PURPOSE: Immune checkpoint inhibition reactivates the immune response against cancer cells in multiple tissue types and has been shown to induce durable responses. However, for patients with autoimmune disorders, their conditions can worsen with this reactivation. We sought to identify, among patients with lung and renal cancer, how many harbor a comorbid autoimmune condition and may be at risk of worsening their condition while on immune checkpoint inhibitors such as nivolumab and pembrolizumab. METHODS: An administrative health care claims database, Truven MarketScan, was used to identify patients diagnosed with lung and renal cancer from 2010 to 2013. We assessed patients for diagnosis of autoimmune diseases 1 year prior to or after diagnosis of cancer using International Classification of Diseases, Ninth Revision codes for 41 autoimmune diseases. Baseline characteristics and other comorbid conditions were recorded. RESULTS: More than 25% of patients with both lung and renal cancer had a comorbid autoimmune condition between 2010 and 2013 and were more likely to be women, older, and have more baseline comorbidities. CONCLUSIONS: This population presents a dilemma to physicians when deciding to treat with immune checkpoint inhibitors and risk immune-related adverse events. Future evaluation of real-world use of immune checkpoint inhibitors in patients with cancer with autoimmune diseases will be needed.
RESUMO
PURPOSE: Cohort studies report associations between statin use and improved survival in patients with cancer. We used pharmacoepidemiologic methods to evaluate the survival of patients with cancer who received statins alone or in ostensibly synergistic drug combinations. MATERIALS AND METHODS: Patients with cancer who were diagnosed from 2010 to 2013 were identified in a large health care claims database. The rate of all-cause death up to 1 year after diagnosis was compared by Cox proportional hazard regression. Sensitivity analyses included age stratification, statin type and intensity, and comparison with or without bisphosphonates and dipyridamole. RESULTS: Among 312,907 identified patients with cancer, treatment groups included statin users (n = 65,440), nonstatin users who received medications that block cholesterol absorption (n = 9,289), and nonusers (n = 226,007). Statin use before diagnosis was associated with improved overall survival compared with no treatment (hazard ratio [HR], 0.85; 95% CI, 0.80 to 0.91) and specifically in patients with leukemia, lung, or renal cancers. Nonstatin users had increased overall survival compared with no treatment (HR, 0.73; 95% CI, 0.62 to 0.85); when stratified, this difference held true only for pancreatic cancer and leukemia. No differences were observed between statin and nonstatin groups. Bisphosphonate use alone had no effect (n = 4,528), but patients who used both statins and bisphosphonates (n = 4,090) had increased survival compared with no treatment (HR, 0.60; 95% CI, 0.45 to 0.81). The effect of the combination of dipyridamole and statin use (n = 651) was not significant compared with no treatment. CONCLUSION: This study suggests that the combination of statins with drugs that affect isoprenylation, such as bisphosphonates, improves survival in patients with cancer. Consideration of pathway-specific pharmacology allows for hypotheses testing with the pharmacoepidemiologic approach. Prospective evaluation of these findings warrants clinical investigation and preclinical mechanistic studies.
Assuntos
Neoplasias/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Bases de Dados Factuais , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Gerenciamento Clínico , Quimioterapia Combinada , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/mortalidade , Neoplasias/terapia , Prognóstico , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Statins have been shown to have a protective effect for venous thromboembolism (VTE) in the general population. This study sought to assess the association between statins and the risk for cancer-associated deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: Patients with newly diagnosed cancer were followed for up to one year in a healthcare claims database (2010-2013). Three treatment groups included statin users, non-statin cholesterol lowering medication users, and an untreated group with pre-existing indications for statin therapy (hyperlipidemia, diabetes, or heart disease). Propensity score matched groups were compared using competing risks survival models for DVT and PE outcomes reporting the hazard ratios (HR) between the treatment groups. Sensitivity analyses assessed the influence of age and individual medications. RESULTS: The total cohort included 170,459 patients, which, after matching, were similar on baseline characteristics. The overall model showed a statistically significant protective effect for statins compared to no treatment attributed only to leukemia for DVT (HR=0.77, 95% CI 0.61-0.99) and colorectal cancers for PE (HR=0.80, 95% CI 0.64-0.99) in stratified analyses. There were generally no differences in outcomes between statins and non-statins and no individual statin use showed results different from the class effect. CONCLUSIONS: In this propensity score matched sample of patients with cancer, statins were shown to have a small protective effect in some cancers for DVT or PE compared to no treatment and little difference compared to an active control group. The lack of effect was consistent across statins and was also not found for any of the sensitivity analyses included.