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1.
Anticancer Res ; 40(1): 67-73, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892553

RESUMO

BACKGROUND/AIM: Aberrant expression of the SEI1 oncogene has been prevalently found in a variety of human cancers, including oral squamous cell carcinoma (OSCC). Recent studies have shown that cisplatin up-regulates the expression of SEI1 in breast and bladder cancer cells, thus inhibiting apoptosis and cell death in these cells. In the present study, we investigated the impact of cisplatin on the expression of SEI1 in OSCC cells. MATERIALS AND METHODS: Four OSCC cell lines, CAL27, SCC4, SCC15, and SCC22A were treated with cisplatin and 5-fluorouracil, and changes in SEI1 expression in these cells were evaluated using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. RESULTS: Cisplatin significantly induced SEI1 expression in the tested OSCC cells. Contrarily, cisplatin treatment did not affect the expression of gankyrin and BMI1, two oncogenes frequently overexpressed in a coordinate manner with SEI1 in OSCC. Additionally, 5-fluorouracil did not bring about any detectable changes in SEI1 expression in these cells. CONCLUSION: Cisplatin-induced up-regulation of SEI1 expression in OSCC is specific, and such induction could underlie the development of resistance to cisplatin in OSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Bucais/genética , Oncogenes , Fatores de Transcrição/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos
2.
Anticancer Res ; 40(1): 133-141, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892561

RESUMO

BACKGROUND/AIM: Aberrant expression of the BMI1 oncogene has been prevalently found in a variety of human cancers, including cervical cancer. Recent studies have shown that PTC209, a specific BMI1 inhibitor, exhibits high potency in inhibiting the growth of colon, breast, oral cancer cells and cancer-initiating cells, indicative of its chemotherapeutic potential. In the current study, we evaluated the inhibitory abilities of PTC209 in cervical cancer cells. MATERIALS AND METHODS: Three cervical cell lines, C33A, HeLa, and SiHa were treated with PTC209. The impacts of PTC209 on BMI1 were investigated using quantitative reverse-transcription PCR assay (qRT-PCR) and western blotting; changes in cell viability, cell cycle distribution, and apoptosis were assessed using cell viability testing, colony formation assay and flow cytometry analyses, respectively. RESULTS: PTC209 exhibited considerably high short-term and long-term cytotoxicities in all tested cervical cancer cell lines regardless of their HPV infection status, TP53 and pRb statuses. PTC209 significantly downregulated the expression of BMI1 in cervical cancer cell lines, and such downregulation led to G0/G1 arrest (p<0.05). Moreover, PTC209 drove more cells into apoptosis (p<0.05). CONCLUSION: PTC209 (BMI1-targeting agents, in general) represents a novel chemotherapeutic agent with potential in cervical cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Complexo Repressor Polycomb 1/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
3.
Surg Infect (Larchmt) ; 21(1): 23-28, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31381489

RESUMO

Background: Type III open fractures are associated with an infection rate as high as 50%. The optimal antibiotic for open fracture prophylaxis remains unclear, and the literature comparing the safety and efficacy of different antibiotic regimens is limited. The aim of this study was to compare the composite adverse events (AEs) in patients before and after a change in prophylactic antibiotic management for these injuries from a tobramycin- to a piperacillin/tazobactam-based regimen. Methods: This was a retrospective single-center cohort study of patients with Type III open fractures admitted from January 2010 to December 2016. Patients were included if they received either tobramycin plus cefazolin or clindamycin or piperacillin/tazobactam for fracture prophylaxis. The primary outcome was the rate of composite AEs, which included nephrotoxicity, surgical site infection (SSI), and hospital re-admission with surgical intervention. Secondary outcomes included the rate of SSI within 30 and 60 days after injury. Data were analyzed using the Student t-, Mann-Whitney U, and Fisher exact tests. Results: Eighty-five patients were included. There were 29 events in the tobramycin group compared with three in the piperacillin/tazobactam group. At 30 days, SSI had occurred in 17 patients (27.5%) in the tobramycin group and 1 patient (4.3%) in the piperacillin/tazobactam group (p = 0.033). At 60 days, SSI had occurred in three additional patients in the tobramycin group (p = 0.009). Conclusion: There was no difference in the composite AEs in the piperacillin/tazobactam compared with the tobramycin group. However, SSI within 30 and 60 days was significantly more common with tobramycin.

4.
Bioorg Med Chem Lett ; 30(1): 126725, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732409

RESUMO

Cyanine compounds have previously shown excellent in vitro and promising in vivo antileishmanial efficacy, but the potential toxicity of these agents is a concern. A series of 22 analogs of thiazole orange ((Z)-1-methyl-4-((3-methylbenzo[d]thiazol-2(3H)-ylidene)methyl)quinolin-1-ium salt), a commercial cyanine dye with antileishmanial activity, were synthesized in an effort to increase the selectivity of such compounds while maintaining efficacy. Cyanines possessing substitutions on the quinolinium ring system displayed potency against Leishmania donovani axenic amastigotes that differed little from the parent compound (IC50 12-42 nM), while ring disjunction analogs were both less potent and less toxic. Changes in DNA melting temperature were modest when synthetic oligonucleotides were incubated with selected analogs (ΔTm ≤ 5 °C), with ring disjunction analogs showing the least effect on this parameter. Despite the high antileishmanial potency of the target compounds, their toxicity and relatively flat SAR suggests that further information regarding the target(s) of these molecules is needed to aid their development as antileishmanials.

5.
Curr Pharm Teach Learn ; 11(11): 1190-1195, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31783968

RESUMO

BACKGROUND: As collaborative team-based healthcare expands, there is a need for effective interprofessional education (IPE). Although the desired outcomes of IPE are defined by the Interprofessional Education Collaborative (IPEC), resources often limit IPE implementation. The purpose of this study is to assess the effectiveness of a novel interprofessional activity in improving health professions students' interprofessional competencies using team-based learning (TBL). INTERPROFESSIONAL EDUCATION ACTIVITY: Teams of second year pharmacy and medical students participated in a novel IPE session targeting roles and responsibilities. This activity was designed and implemented by a small number of faculty and used TBL to educate a large number of students using limited resources. Class averages for individual and team readiness assurance test (iRAT/tRAT) scores were collected, and students were invited to complete the Interprofessional Collaborative Competencies Attainment Survey (ICCAS) to evaluate the effectiveness of the activity. DISCUSSION: On average, tRAT scores were 20% higher than iRAT scores. While there was significant improvement for all items on the ICCAS, questions within the roles and responsibilities domain of the ICCAS were most affected. IMPLICATIONS: This novel IPE activity was successful in teaching a large group of professional students in the targeted domain of roles and responsibilities in a single session. This activity was a rich experience in which students learned together using limited resources which can be easily replicated at other institutions to help professional students gain proficiency in interprofessional competencies.

6.
Nano Res ; 12(4): 855-861, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31737223

RESUMO

Triple-negative breast cancer (TNBC) is one type of the most aggressive breast cancers with poor prognosis. It is of great urgency to develop new therapeutics for treating TNBC. Based on current treatment guideline and genetic information of TNBC, a combinational therapy platform integrating chemotherapy drugs and mRNA encoding tumor suppressor proteins may become an efficacious strategy. In this study, we developed paclitaxel amino lipid (PAL) derived nanoparticles (NPs) to incorporate both chemotherapy drugs and P53 mRNA. The PAL P53 mRNA NPs showed superior properties compared to Abraxane® and Lipusu® used in the clinic including high paclitaxel loading capacity (24 wt.%, calculated by paclitaxel in PAL), PAL encapsulation efficiency (94.7% ± 6.8%) and mRNA encapsulation efficiency (88.7% ± 0.7%). Meanwhile, these NPs displayed synergetic cytotoxicity of paclitaxel and P53 mRNA in cultured TNBC cells. More importantly, we demonstrated in vivo anti-tumor efficacy of PAL P53 mRNA NPs in an orthotopic TNBC mouse model. Overall, these chemotherapy drugs derived mRNA NPs provide a new platform to integrate chemotherapy and personalized medicine using tumor genetic information, and therefore represent a promising approach for TNBC treatment.

7.
Mol Carcinog ; 58(12): 2327-2339, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31544312

RESUMO

Autologous stem cell transplant (ASCT) with high-dose melphalan (HDM) is the standard treatment for fit multiple myeloma (MM) patients. It is generally believed that some DNA repair proteins impact the activity to repair melphalan-induced DNA damage, thus potentially contributing to the patient's clinical response. However, knowledge of these proteins is limited. In the current study, we investigated the roles of XRCC1, a protein involved in base excision repair and single-strand break repair, in melphalan response in MM cells. Small interfering RNA knockdown of XRCC1 significantly increased the accumulation of melphalan-induced DNA damage in MM cells and sensitized them to melphalan treatment, indicating that genetic variation in XRCC1 may impact response to melphalan treatment. We then evaluated the association between an XRCC1 variant with reduced activity, rs25487 (R399Q), and clinical outcomes of 108 MM patients with melphalan therapy. Our results showed that XRCC1 rs25487 was associated with prolonged progression-free survival (PFS) in MM patients. The adjusted hazard ratio for PFS between patients carrying rs25487 AA/AG and GG was 0.42 (95% confidence interval: 0.25, 0.84, P = .014). Taken together, these results indicate that XRCC1 is involved in the repair of melphalan-induced DNA damage and XRCC1 rs25487 variant with impaired DNA repair function influences the clinical responses of HDM in MM patients.

8.
Clin Breast Cancer ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31451366

RESUMO

BACKGROUND: Additional use of cyclin-dependent kinase 4/6 inhibitors with endocrine therapy improves progression-free survival (PFS) in advanced hormone receptor (HR)-positive HER2-negative breast cancer. However, neutropenia is a common reason for dose reductions, leading to concerns about palbociclib efficacy at lower doses. A safety analysis confirmed no PFS differences between palbociclib doses in the second-line setting, but to our knowledge, this has not been evaluated for first-line treatment. PATIENTS AND METHODS: In this retrospective, single-center cohort study we evaluated real-world use of first-line palbociclib with aromatase inhibitor (AI) treatment in HR-positive, HER2-negative metastatic breast cancer patients who received treatment between February 2015 and July 2017. The primary objective was to determine PFS of treatment with palbociclib and an AI in a real-world first-line setting. Secondary objectives included determining the PFS for patients treated with palbociclib on the basis of final doses, time to first dose reduction, time to treatment failure (TTF), and safety. RESULTS: Seventy patients were included in the final analysis. Median PFS was 26.4 months. No significant differences in PFS were observed on the basis of final doses of palbociclib (P = .77). Time to first dose reduction was 2.3 months. Median TTF was 26.1 months. Dose delays, reductions, and Grade 3/4 neutropenia were common (63%, n = 44; 57%, n = 40; and 62%, n = 43, respectively). CONCLUSION: Real-world first-line palbociclib treatment produced outcomes similar to those in PALOMA-2 (Palbociclib and Letrozole in Advanced Breast Cancer) (median PFS 26.4 months vs. 24.8 months) despite more dose reductions (57%, n = 40 vs. 36%, n = 160) and shorter time to first dose reduction (2.3 vs. 3.0 months). No significant differences in PFS were observed for the varying palbociclib doses. Palbociclib dose reductions might not significantly affect PFS in the first-line setting.

9.
J Oncol Pharm Pract ; : 1078155219857800, 2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31256745

RESUMO

BACKGROUND: Pertuzumab-based neoadjuvant chemotherapy (NAC) has demonstrated successful pathologic complete response (pCR) rates when administered to patients with human epidermal growth factor receptor 2 (HER2)-positive, locally advanced breast cancer and has become standard of care. This study aimed to identify pCR rates in patients receiving a variety of pertuzumab-based NAC regimens. The effect of the addition of an anthracycline and impact of anthracycline and taxane sequencing on pCR was also assessed. METHODS: A retrospective, single-center review was conducted on patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer that received one of five pertuzumab-containing NAC regimens followed by definitive surgery. RESULTS: Ninety-six patients were included in the analysis; overall, pCR was attained in 49 patients (51%). Of the 61 patients who received an anthracycline-containing NAC regimen, 30 (49%) attained a pCR. Of the 35 patients who received the non-anthracycline NAC regimen, 19 (54%) attained a pCR; difference in pCR was not statistically significant (p = 0.63). Anthracycline/taxane sequence analysis showed that of the patients attaining pCR with an anthracycline-containing NAC, 77% of patients received the taxane portion upfront (p = 0.17). Relative dose intensity of the anthracycline portion was similar irrespective of treatment sequence. However, relative dose intensity of the taxane portion was decreased with upfront anthracycline administration. CONCLUSION: These findings support current recommendations of adding pertuzumab to established regimens for treatment of locally advanced, HER2-positive, early stage breast cancer. The benefit of adding an anthracycline in the neoadjuvant setting remains unclear. Patients treated with the taxane portion of NAC upfront appeared to have a higher rate of pCR and better relative dose intensity than patients who received the anthracycline portion upfront, but differences were not statistically significant. These findings should be verified in a prospective clinical trial.

10.
J Am Pharm Assoc (2003) ; 59(4S): S19-S24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080150

RESUMO

OBJECTIVES: The objectives of this study were to assess how a charitable pharmacy model affects patient perception of health care insecurity, physical and emotional functioning, and medication access in an underserved population. METHODS: New patients presenting for medication at their initial pharmacy visit at Charitable Pharmacy of Central Ohio were screened for eligibility during a 12-week enrollment period. Participants completed a baseline survey containing the Health Care Insecurity Measure (HCIM), Veterans RAND 12-Item Health Survey (VR-12), and medication access questions. The follow-up survey, which contained the HCIM and VR-12 only, was administered during a pharmacy visit at least 14 days after the patient's initial visit. Survey data were analyzed with the use of descriptive statistics. RESULTS: A total of 105 patients met eligibility criteria, and 17 patients declined to participate. Of the 88 remaining participants, 33 (38%) completed the study (both baseline and follow-up survey). Of the 33 participants who completed the study, there was a statistically significant decrease from the baseline health care insecurity score (23.2 ± 11.1) to the follow-up score (17.9 ± 8.5; P = 0.0031). CONCLUSION: This study demonstrated that pharmacists working in a charitable pharmacy can have a positive impact on the sense of security patients feel about their health care and can better understand their medication-related needs.

11.
Leuk Lymphoma ; 60(9): 2223-2229, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30764681

RESUMO

Acute graft-versus-host-disease (aGVHD) is a complication after allogeneic stem cell transplant. After the failure of treatment with high dose corticosteroids, steroid-refractory aGVHD (SR aGVHD) is associated with high rates of mortality. Tocilizumab has evidence of activity in SR aGVHD. For patients ineligible for trials, the OSU James Comprehensive Cancer Center has been utilizing tocilizumab as first-line therapy for SR aGVHD. We retrospectively report on 15 patients who received tocilizumab. aGVHD grading and responses were based on consensus criteria. Median age at transplant was 49 years. Median time to tocilizumab administration was 9 days (range, 3-16). Six patients had complete responses (40%) with a resolution of aGVHD. From the last contact, median overall survival for responders was not yet reached vs. 31 days for non-responders (p = .0002). Patients with skin and/or GI aGVHD demonstrated the greatest benefit. Patients with liver aGVHD did not respond. Future studies are needed to evaluate tocilizumab prior to steroid failure.

12.
Air Med J ; 38(1): 39-44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30711084

RESUMO

OBJECTIVE: The aim of this study was to evaluate the difference in the time to postintubation sedation between patients receiving etomidate and either succinylcholine or rocuronium in the prehospital setting. SETTING: Patients who received rapid sequence intubation medications from transport service personnel and were subsequently intubated were included. The critical care transport agency operates 8 helicopter- and 3 ground-based emergency medical service units. METHODS: This retrospective cohort study compared the time to the first sedative in patients intubated with etomidate and succinylcholine versus etomidate and rocuronium. Enrollment of 64 patients per arm was needed to achieve 80% power with a 2-tailed alpha of 0.05. RESULTS: Sixty-four and 38 patients received succinylcholine or rocuronium, respectively. The median time to postetomidate sedation was 10 (range, 5.0-16.0) and 13.5 (range, 7.0-20.8) minutes for succinylcholine and rocuronium patients, respectively (P = .13). Given the average duration of effect of etomidate, succinylcholine, and rocuronium, 0 (0%) succinylcholine versus 33 (86.8%) rocuronium patients were found to be at risk of wakeful paralysis. CONCLUSIONS: This study suggests rocuronium's long duration of effect puts patients at risk for wakeful paralysis once the short effects of etomidate have subsided.

13.
Biomed Microdevices ; 21(1): 8, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30617619

RESUMO

Current therapeutic options against cutaneous leishmaniasis are plagued by several weaknesses. The effective topical delivery of an antileishmanial drug would be useful in treating some forms of cutaneous leishmaniasis. Toward this end, a microneedle based delivery approach for the antileishmanial drug amphotericin B was investigated in murine models of both New World (Leishmania mexicana) and Old World (Leishmania major) infection. In the L. mexicana model, ten days of treatment began on day 35 post infection, when the area of nodules averaged 9-15 mm2. By the end of the experiment, a significant difference in nodule area was observed for all groups receiving topical amphotericin B at 25 mg/kg/day after application of microneedle arrays of 500, 750, and 1000 µM in nominal length compared to the group that received this dose of topical amphotericin B alone. In the L. major model, ten days of treatment began on day 21 post infection when nodule area averaged 51-65 mm2 in the groups. By the end of the experiment, there was no difference in nodule area between the group receiving 25 mg/kg of topical amphotericin B after microneedle application and any of the non-AmBisome groups. These results show the promise of topical delivery of amphotericin B via microneedles in treating relatively small nodules caused by L. mexicana. These data also show the limitations of the approach against a disseminated L. major infection. Further optimization of microneedle delivery is needed to fully exploit this strategy for cutaneous leishmaniasis treatment.


Assuntos
Anfotericina B/farmacologia , Sistemas de Liberação de Medicamentos , Leishmania mexicana/metabolismo , Leishmaniose Cutânea/tratamento farmacológico , Agulhas , Animais , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Feminino , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/patologia , Camundongos , Camundongos Endogâmicos BALB C
14.
Anticancer Res ; 39(1): 67-72, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591441

RESUMO

BACKGROUND/AIM: SLC7A5 is recognized as the major mediator of melphalan uptake into multiple myeloma (MM) cells; however, its contribution to the inter-patient variability of melphalan efficacy and toxicity is yet to be well elucidated. This study aimed to investigate the impact of a single nucleotide polymorphism (SNP) rs4240803 in SLC7A5 on the gene expression, ex vivo sensitivity to melphalan, and clinical outcomes in MM patients who were undergoing autologous stem cell transplantation with high-dose melphalan. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 108 MM patients prior to melphalan therapy. Clinical data were also collected from these patients following melphalan therapy. RESULTS: rs4240803 was associated with elevated expression of SLC7A5 mRNA, higher ex vivo sensitivity to melphalan in PBMCs, and positive 90-day response in these patients (p=0.047, 0.10, 0.049, respectively). CONCLUSION: rs4240803 impacted the expression of SLC7A5, thus contributing to the clinical response of MM patients to melphalan therapy.


Assuntos
Transportador 1 de Aminoácidos Neutros Grandes/genética , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Terapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Polimorfismo de Nucleotídeo Único , Transplante Autólogo/efeitos adversos , Resultado do Tratamento
15.
CPT Pharmacometrics Syst Pharmacol ; 7(11): 748-758, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30343510

RESUMO

High-dose melphalan (HDM) is part of the conditioning regimen in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT). However, individual sensitivity to melphalan varies, and many patients experience severe toxicities. Prolonged severe neutropenia is one of the most severe toxicities and contributes to potentially life-threatening infections and failure of ASCT. Granulocyte-colony stimulating factor (G-CSF) is given to stimulate neutrophil proliferation after melphalan administration. The aim of this study was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model capable of predicting neutrophil kinetics in individual patients with MM undergoing ASCT with high-dose melphalan and G-CSF administration. The extended PK/PD model incorporated several covariates, including G-CSF regimen, stem cell dose, hematocrit, sex, creatinine clearance, p53 fold change, and race. The resulting model explained portions of interindividual variability in melphalan exposure, therapeutic effect, and feedback regulation of G-CSF on neutrophils, thus enabling simulation of various doses and prediction of neutropenia duration.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Neutropenia/induzido quimicamente , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/farmacologia , Área Sob a Curva , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Meia-Vida , Humanos , Masculino , Melfalan/efeitos adversos , Melfalan/farmacocinética , Melfalan/farmacologia , Pessoa de Meia-Idade , Modelos Biológicos , Neutropenia/terapia
16.
Am J Transl Res ; 10(8): 2669-2676, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210703

RESUMO

Colon cancer is one of the most fatal cancers in the United States, and is characterized by the presence of chromosomal instability (CIN), causes of which are largely unclear. Emerging evidence indicates that abnormal spindle geometry and supernumerary centrosomes lead to CIN in cells. However, if and how spindle geometry defects and centrosomes amplification occur in colon cancer remains unknown. Here we show that decrease in the cell cycle regulatory protein, cyclin A2, induces spindle geometry defects in colon cancer cells. In mechanistic studies, we found that cyclin A2 is located at the centrosomes, and its depletion reduces phosphorylation of EG5, which is important for centrosome localization and movement of duplicated centrosomes to opposite poles. We also found that cyclin A2 silencing leads to centrosome amplification in the cells. Collectively, these findings demonstrate previously unrecognized role for cyclin A2 in preventing centrosomal defects in colon cancer cells and provide insights into mechanisms that may potentially cause CIN in these tumors.

17.
J Pharm Pract ; : 897190018799218, 2018 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-30222031

RESUMO

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to lower atherogenic lipid markers in patients with statin intolerance; however, external validity of these findings is unclear in patients with self-reported statin intolerance. OBJECTIVE: The objective of this study was to describe the tolerability of evolocumab and alirocumab in patients with self-reported statin intolerance. Secondary objectives were to describe their efficacy and obtainability. METHODS: A retrospective chart review was completed and included adult patients with self-reported statin intolerance who were prescribed a PCSK9 inhibitor. Patient-reported side effects, laboratory values, and insurance information were collected for assessment of study objectives. RESULTS: During the study period, 55 patients were prescribed PCSK9 inhibitor, 42 started therapy, and 34 had at least 1 follow-up visit. While myalgias occurred in 14.7% (n = 5) of patients, flu-like symptoms in 11.8% (n = 4), and fatigue in 2.9% (n = 1), only 5.9% (n = 2) of prescriptions for PCSK9 inhibitors were discontinued. Low-density lipoprotein cholesterol (LDL-C) was reduced 48.7% (95% confidence interval [CI]: -1.7%-99.1%), and 20 (58.8%) patients achieved a ≥50% reduction in LDL-C. Regarding obtainability, of the 57 prescriptions written, 77.2% (n = 44) required prior authorization and 5.3% (n = 3) were denied by insurance. CONCLUSION: PCSK9 inhibitors were well tolerated in patients with self-reported statin intolerance.

18.
Chem Biol Interact ; 289: 9-14, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29660302

RESUMO

MicroRNAs (miRNAs) can function as tumor suppressor or oncogenic genes. The putative targets of miR-223 include tumor suppressor gene, RhoB. Here we sought to investigate the role of miR-223-RhoB signaling pathway in proliferation of colon cancer. We used Western blot, immunofluorescence staining, or RT-PCR to detect expression levels of miR-223 and RhoB in colon adenocarcinoma and adjacent non-cancerous tissue samples, or in human colon adenocarcinoma cell lines. MTT assay was used to determine proliferation and apoptosis in cell lines. We further used Western blot to determine levels of cell cycle regulators CDK1 and Cyclin B1 with anti-miR-223 or apoptosis with overexpression of RhoB. The expression level of miR-223 was significantly upregulated in clinical samples and cell lines of colon adenocarcinoma, in contrast to down-regulation of RhoB. In addition, we showed that inhibition of miR-223 led to upregulation of RhoB and in turn suppression of proliferation of colon adenocarcinoma. Moreover, inhibition of miR-223 or overexpression of RhoB induced cell arrest or apoptosis in colon adenocarcinoma. These results suggest that miR-223-RhoB signaling pathway plays an important role in modulation of proliferation, cell arrest, and apoptosis in colon cancer.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Apoptose , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , MicroRNAs/metabolismo , Transdução de Sinais , Proteína rhoB de Ligação ao GTP/metabolismo , Adenocarcinoma/genética , Apoptose/genética , Sequência de Bases , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/genética , Regulação para Baixo/genética , Feminino , Fase G2/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Mitose/genética , Regulação para Cima/genética
19.
Leuk Lymphoma ; 59(10): 2377-2382, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29424601

RESUMO

Aminocaproic acid is frequently used in patients with hematologic malignancy that present with thrombocytopenia with or without hemorrhage. We conducted a retrospective study to evaluate the safety of aminocaproic acid in 109 patients with hematologic malignancies. Patients were included if aminocaproic acid had been administered for at least 24 hours for the prevention or treatment of thrombocytopenic hemorrhage. Our primary outcome was thromboembolic complications defined as arterial or venous thrombotic events objectively confirmed by imaging studies. Thromboembolic complications occurred in five patients (4.6%) and all were venous thromboses. Other than the underlying malignancy, these patients also had many concurrent risk factors including indwelling central venous catheters, which could have contributed to thromboses. In conclusion, in our population of patients with a variety of hematological malignancies, aminocaproic acid does not appear to be associated with a high incidence of thromboembolic complications.


Assuntos
Ácido Aminocaproico/efeitos adversos , Antifibrinolíticos/efeitos adversos , Neoplasias Hematológicas/complicações , Hemorragia/tratamento farmacológico , Trombocitopenia/tratamento farmacológico , Tromboembolia/epidemiologia , Adulto , Idoso , Cateterismo Venoso Central/efeitos adversos , Cateteres de Demora/efeitos adversos , Feminino , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Trombocitopenia/etiologia , Trombocitopenia/prevenção & controle , Tromboembolia/induzido quimicamente , Resultado do Tratamento
20.
J Prim Care Community Health ; 9: 2150132718759213, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29468934

RESUMO

OBJECTIVES: The primary objective of this study was to determine the effect of a pharmacist-provided spirometry service within a federally qualified health center on the percentage of spirometry referrals completed with results reviewed by the ordering provider. Secondary objectives evaluated differences between internal and external referrals, medication recommendations made by the pharmacist, and revenue brought in by the service. METHODS: Chart reviews were completed to determine the referral completion rates between patients who received a spirometry referral before (December 2014-September 2015) and after (January 2016-October 2016) the implementation of the pharmacy-provided spirometry service. Chart reviews were also used to determine the number and completion rate among referrals for internal and external services in the postimplementation time frame. Chart reviews also assessed medication recommendations made by the pharmacist. RESULTS: The results demonstrate an increase in referral completion rate from 38.1% to 47.0% ( P = .08) between the pre- and postimplementation time frames. In the postimplementation time frame, there was a statistically significant difference in the percentage of referrals completed between in-house referrals and external referrals (70.0% and 40.9%, respectively, P = .0004). Comparing clinics with and without the spirometry service, there was a statistically significant difference in the total number of spirometry referrals (1.13% and 0.59%, respectively, P < .0001) and the percent of referrals completed (0.55% and 0.27%, respectively, P = .0002). CONCLUSION: The results suggest that offering spirometry within the primary care setting helps to increase the rate of completed spirometry tests with results available to the primary care provider. Additionally, the results show that there is an increased completion rate in patients who receive an internal spirometry referral, which may be due to reduced barriers in obtaining this testing. Overall, these results demonstrate that providing spirometry in the primary care setting helps to increase spirometry results obtained and could be beneficial in other primary care settings.


Assuntos
Serviços Comunitários de Farmácia/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Provedores de Redes de Segurança/organização & administração , Espirometria/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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