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Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal storage disease caused by mutations in the gene that encodes the protein N-acetyl-glucosaminidase (NAGLU). Defective NAGLU activity results in aberrant retention of heparan sulfate within lysosomes leading to progressive central nervous system (CNS) degeneration. Intravenous treatment options are limited by the need to overcome the blood-brain barrier and gain successful entry into the CNS. Additionally, we have demonstrated that AAV8 provides a broader transduction area in the MPS IIIB mouse brain compared with AAV5, 9 or rh10. A triple-capsid mutant (tcm) modification of AAV8 further enhanced GFP reporter expression and distribution. Using the MPS IIIB mouse model, we performed a study using either intracranial six site or intracisterna magna injection of AAVtcm8-codon-optimized (co)-NAGLU using untreated MPS IIIB mice as controls to assess disease correction. Disease correction was evaluated based on enzyme activity, heparan sulfate storage levels, CNS lysosomal signal intensity, coordination, activity level, hearing and survival. Both histologic and enzymatic assessments show that each injection method results in supranormal levels of NAGLU expression in the brain. In this study, we have shown correction of lifespan and auditory deficits, increased CNS NAGLU activity and reduced lysosomal storage levels of heparan sulfate following AAVtcm8-coNAGLU administration and partial correction of NAGLU activity in several peripheral organs in the murine model of MPS IIIB.
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Mucopolissacaridose III , Animais , Camundongos , Mucopolissacaridose III/genética , Mucopolissacaridose III/terapia , Mucopolissacaridose III/metabolismo , Capsídeo/metabolismo , Acetilglucosaminidase/genética , Acetilglucosaminidase/metabolismo , Heparitina Sulfato/metabolismoRESUMO
BACKGROUND: Endocrine therapy is the mainstay treatment for breast cancer (BC) to reduce BC recurrence risk. During the first year of endocrine therapy use, nearly 30% of BC survivors are nonadherent, which may increase BC recurrence risk. This study is to examine the association between endocrine therapy adherence trajectories and BC recurrence risk in nonmetastatic BC survivors. METHODS: This retrospective cohort study included Medicare beneficiaries in the United States (US) with incident nonmetastatic BC followed by endocrine therapy initiation in 2010-2019 US Surveillance, Epidemiology, and End Results linked Medicare data. We calculated monthly fill-based proportion of days covered in the first year of endocrine therapy. We applied group-based trajectory models to identify distinct endocrine therapy adherence patterns. After the end of the first-year endocrine therapy trajectory measurement period, we estimated the risk of time to first treated BC recurrence within 4 years using Cox proportional hazards models. RESULTS: We identified 5 trajectories of adherence to endocrine therapy in BC Stages 0-I subgroup (n = 28,042) and in Stages II-III subgroup (n = 7781). A trajectory of discontinuation before 6 months accounted for 7.0% in Stages 0-I and 5.8% in Stages II-III subgroups, and this trajectory was associated with an increased treated BC recurrence risk compared to nearly perfect adherence (Stages 0-I: adjusted hazard [aHR] = 1.84, 95% CI = 1.46-2.33; Stages II-III: aHR = 1.38, 95% CI = 1.07-1.77). CONCLUSIONS: Nearly 7% of BC survivors who discontinued before completing 6 months of treatment was associated with an increased treated BC recurrence risk compared to those with nearly perfect adherence among Medicare nonmetastatic BC survivors.
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Antineoplásicos Hormonais , Neoplasias da Mama , Sobreviventes de Câncer , Adesão à Medicação , Recidiva Local de Neoplasia , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Sobreviventes de Câncer/estatística & dados numéricos , Idoso , Recidiva Local de Neoplasia/epidemiologia , Estados Unidos/epidemiologia , Estudos Retrospectivos , Antineoplásicos Hormonais/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Idoso de 80 Anos ou mais , Medicare , Programa de SEER , Fatores de RiscoRESUMO
PURPOSE: To examine the association between prescription opioid use trajectories and risk of opioid use disorder (OUD) or overdose among nonmetastatic breast cancer survivors by treatment type. METHODS: This retrospective cohort study included female nonmetastatic breast cancer survivors with at least 1 opioid prescription fill in 2010-2019 Surveillance, Epidemiology and End Results linked Medicare data. Opioid mean daily morphine milligram equivalents (MME) calculated within 1.5 years after initiating active breast cancer therapy. Group-based trajectory models identified distinct opioid use trajectory patterns. Risk of time to first OUD/overdose event within 1 year after the trajectory period was calculated for distinct trajectory groups using Cox proportional hazards models. Analyses were stratified by treatment type. RESULTS: Four opioid use trajectories were identified for each treatment group. For 38,030 survivors with systemic endocrine therapy, 3 trajectories were associated with increased OUD/overdose risk compared with early discontinuation: minimal dose (< 5 MME; adjusted hazard ratio [aHR] = 1.73 [95% CI 1.43-2.09]), very low dose (5-25 MME; 2.67 [2.05-3.48]), and moderate dose (51-90 MME; 6.20 [4.69-8.19]). For 9477 survivors with adjuvant chemotherapy, low-dose opioid use was associated with higher OUD/overdose risk (aHR = 7.33 [95% CI 2.52-21.31]) compared with early discontinuation. For 3513 survivors with neoadjuvant chemotherapy, the differences in OUD/OD risks across the 4 trajectories were not significant. CONCLUSIONS: Among Medicare nonmetastatic breast cancer survivors receiving systemic endocrine therapy or adjuvant chemotherapy, compared with early discontinuation, low-dose or moderate-dose opioid use were associated with six- to sevenfold higher OUD/overdose risk. Breast cancer survivors at high-risk of OUD/overdose may benefit from targeted interventions (e.g., pain clinic referral).
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Neoplasias da Mama , Sobreviventes de Câncer , Overdose de Drogas , Endrin/análogos & derivados , Transtornos Relacionados ao Uso de Opioides , Humanos , Feminino , Idoso , Estados Unidos/epidemiologia , Analgésicos Opioides/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Estudos Retrospectivos , Medicare , Transtornos Relacionados ao Uso de Opioides/complicações , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Overdose de Drogas/tratamento farmacológico , Overdose de Drogas/epidemiologia , Prescrições , SobreviventesRESUMO
Sanfilippo syndrome Type-B, also known as mucopolysaccharidosis IIIB (MPS IIIB), accounts for approximately one-third of all Sanfilippo syndrome patients and is characterized by a similar natural history as Type-A. Patients suffer from developmental regression, bone malformation, organomegaly, GI distress, and profound neurological deficits. Despite human trials of enzyme replacement therapy (ERT) (SBC-103, AX250) in MPS IIIB, there is currently no FDA approved treatment and a few palliative options. The major concerns of ERT and gene therapy for the treatment of bone malformation are the inadequate biodistribution of the missing enzyme, N-acetyl-α-glucosaminidase (NAGLU), and that the skeleton is a poorly hit target tissue in ERT and gene therapy. Each of the four known human types of MPS III (A, B, C, and D) is usually regarded as having mild bone manifestations, yet it remains poorly characterized. This study aimed to determine bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties in femurs MPS IIIB C57BL/6 mice compared to phenotypic control C57BL/6 mice. Significant differences were observed in MPS IIIB mice within various cortical and cancellous bone parameters for both males and females (p < 0.05). Here, we establish some osteogenic manifestations of MPS IIIB within the mouse model by radiographic and biomechanical tests, which are also differentially affected by age and sex. This suggests that some skeletal features of the MPS IIIB mouse model may be used as biomarkers of peripheral disease correction for preclinical treatment of MPS IIIB.
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Mucopolissacaridose III , Masculino , Feminino , Humanos , Animais , Camundongos , Mucopolissacaridose III/genética , Distribuição Tecidual , Camundongos Endogâmicos C57BL , Acetilglucosaminidase , Modelos Animais de Doenças , Fêmur/metabolismoRESUMO
Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal disease caused by defective production of the enzyme α-N-acetylglucosaminidase. It is characterized by severe and complex central nervous system degeneration. Effective therapies will likely target early onset disease and overcome the blood-brain barrier. Modifications of adeno-associated viral (AAV) vector capsids that enhance transduction efficiency have been described in the retina. Herein, we describe for the first time, a transduction assessment of two intracranially administered adeno-associated virus serotype 8 variants, in which specific surface-exposed tyrosine (Y) and threonine (T) residues were substituted with phenylalanine (F) and valine (V) residues, respectively. A double-mutant (Y444 + 733F) and a triple-mutant (Y444 + 733F + T494V) AAV8 were evaluated for their efficacy for the potential treatment of MPS IIIB in a neonatal setting. We evaluated biodistribution and transduction profiles of both variants compared to the unmodified parental AAV8, and assessed whether the method of vector administration would modulate their utility. Vectors were administered through four intracranial routes: six sites (IC6), thalamic (T), intracerebroventricular, and ventral tegmental area into neonatal mice. Overall, we conclude that the IC6 method resulted in the widest biodistribution within the brain. Noteworthy, we demonstrate that GFP intensity was significantly more robust with AAV8 (double Y-F + T-V) compared to AAV8 (double Y-F). This provides proof of concept for the enhanced utility of IC6 administration of the capsid modified AAV8 (double Y-F + T-V) as a valid therapeutic approach for the treatment of MPS IIIB, with further implications for other monogenic diseases.
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Capsídeo , Mucopolissacaridose III , Animais , Encéfalo , Dependovirus/genética , Vetores Genéticos/genética , Camundongos , Mucopolissacaridose III/genética , Mucopolissacaridose III/terapia , Distribuição Tecidual , Transdução GenéticaRESUMO
BACKGROUND: Breast cancer-related lymphedema (BCRL) is a source of postoperative morbidity for breast cancer survivors. Lymphatic microsurgical preventive healing approach (LYMPHA) is a technique used to prevent BCRL at the time of axillary lymph node dissection (ALND). We report the 5-year experience of a breast surgeon trained in LYMPHA and investigate the outcomes of patients who underwent LYMPHA following ALND for treatment of cT1-4N1-3M0 breast cancer. METHODS: A retrospective review of patients with cT1-4N1-3M0 breast cancer was performed in patients who underwent ALND with and without LYMPHA. Diagnosis of BCRL was made by certified lymphedema therapists. Descriptive statistics and lymphedema surveillance data were analyzed using results of Fisher's exact or Wilcoxon rank-sum tests. Logistic regression and propensity matching were performed to assess the reduction of BCRL occurrence following LYMPHA. RESULTS: In a 5-year period, 132 patients met inclusion criteria with 76 patients undergoing LYMPHA at the time of ALND and 56 patients undergoing ALND alone. Patients who underwent LYMPHA at the time of ALND were significantly less likely to develop BCRL than those who underwent ALND alone (p = 0.045). Risk factors associated with BCRL development were increased patient age (p = 0.007), body mass index (BMI) (p = 0.003), and, in patients undergoing LYMPHA, number of positive nodes (p = 0.026). CONCLUSIONS: LYMPHA may be successfully employed by breast surgeons trained in lymphatic-venous anastomosis at the time of ALND. While research efforts should continue to focus on prevention and surveillance of BCRL, LYMPHA remains an option to reduce BCRL and improve patient quality of life.
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Neoplasias da Mama , Linfedema , Cirurgiões , Axila , Neoplasias da Mama/cirurgia , Feminino , Humanos , Excisão de Linfonodo/efeitos adversos , Linfedema/etiologia , Linfedema/prevenção & controle , Linfedema/cirurgia , Qualidade de Vida , Estudos Retrospectivos , Biópsia de Linfonodo SentinelaRESUMO
BACKGROUND: During their work on the cerebrospinal fluid (CSF) circulatory system of human nerves and brain, the authors applied imaging and tissue techniques that complemented basic anatomical dissection. OBJECTIVES: The authors sought to show how integrating fluorescent imaging and basic immunohistochemistry (IHC) with facial anatomy can address current problems in aesthetic surgery. METHODS: The authors developed an algorithm and a set of principles from their work on the CSF circulatory system and applied these to 3 problems in aesthetic surgery: the functional anatomy of the vermilion-cutaneous junction; chemosis; and the functional anatomy of periosteal fixation. RESULTS: Integrating fluorescent imaging and IHC with anatomical dissection characterizes structural and functional anatomy. Fluorescent imaging helps to identify and locate easily missed structures. IHC defines cell type and function. The vermilion-cutaneous junction is defined by a major lymphatic vessel. Lymphatic flow from the medial limbus to the lateral canthus suggests the etiology of chemosis. Periosteal sites of fixation prevent shear where dural CSF vessels drain directly to subcutaneous lymphatics. CONCLUSIONS: Integrating anatomical dissection with fluorescent imaging and basic IHC characterizes structural and functional anatomy and helps to better understand many problems encountered in aesthetic surgery.
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Sistema Cardiovascular , Vasos Linfáticos , Cirurgia Plástica , Encéfalo , Humanos , Imuno-Histoquímica , Vasos Linfáticos/diagnóstico por imagem , Vasos Linfáticos/cirurgiaRESUMO
The most aggressive and invasive tumor cells often reside in hypoxic microenvironments and rely heavily on rapid anaerobic glycolysis for energy production. This switch from oxidative phosphorylation to glycolysis, along with up-regulation of the glucose transport system, significantly increases the release of lactic acid from cells into the tumor microenvironment. Excess lactate and proton excretion exacerbate extracellular acidification to which cancer cells, but not normal cells, adapt. We have hypothesized that carbonic anhydrases (CAs) play a role in stabilizing both intracellular and extracellular pH to favor cancer progression and metastasis. Here, we show that proton efflux (acidification) using the glycolytic rate assay is dependent on both extracellular pH (pHe) and CA IX expression. Yet, isoform-selective sulfonamide-based inhibitors of CA IX did not alter proton flux, which suggests that the catalytic activity of CA IX is not necessary for this regulation. Other investigators have suggested the CA IX co-operates with the MCT transport family to excrete protons. To test this possibility, we examined the expression patterns of selected ion transporters and show that members of this family are differentially expressed within the molecular subtypes of breast cancer. The most aggressive form of breast cancer, triple-negative breast cancer, appears to co-ordinately express the monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CA IX). This supports a possible mechanism that utilizes the intramolecular H+ shuttle system in CA IX to facilitate proton efflux through MCT4.
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Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Glicólise , Proteínas de Neoplasias/metabolismo , Neoplasias de Mama Triplo Negativas/enzimologia , Animais , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
This article presents current best knowledge to assess the projected outcomes benefit of adding multi-modality surveillance imaging to standard follow-up care for breast cancer patients at high risk (>30%) for developing future metastases. This analysis is motivated by recent preliminary clinical studies that have suggested that augmenting systemic treatment of early-stage metastases with targeted surgery and/or radiosurgery achieves significant overall survival and disease-free survival benefit. Our primary aims are to: (a) describe the clinical motivation and scan parameters needed to identify the early onset of metastatic progression in breast cancer patients for effective surgical or radiosurgical treatment; (b) estimate the anticipated survival benefit for high-risk patients under this recommended protocol; and (c) estimate the radiation risks associated with the repeated body imaging of this protocol.
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Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Adulto , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Detecção Precoce de Câncer , Feminino , Humanos , Pessoa de Meia-Idade , Mortalidade , Tomografia por Emissão de Pósitrons , RadiocirurgiaRESUMO
Sanfilippo Syndrome or Mucopolysaccharidosis Ill (MPS Ill) is a group of lysosomal storage diseases resulting from a deficiency of one of four lysosomal enzymes: Type A - heparan N-sulfatase (SGSH), Type B - a-N-acetylglucosaminidase (NAGLU), Type C - acetyl CoA a-glucosaminide acetyltransferase (HGSNAT) and Type D - N-acetylglucosamine-6-sulfatase (GNS). Each of these enzymes is necessary for degradation of heparan sulfate. Deficiency of any of these enzymes manifests as a neurodegenerative disorder with accompanying somatic manifestations. Typically this presents early in life with developmental delays followed by developmental regression and usually results in death sometime during the second decade of life, though several less severe cases have been described living into late adulthood (30's to 60's). Often there is a delay of several years from time of symptom onset to diagnosis. Currently treatment is limited to supportive care. We will briefly discuss the typical natural history and presumed pathophysiology of the disease. We will also discuss current experimental therapies being pursued for treatment of this devastating disease. These include enzyme replacement, gene therapy, stem cell therapy, and substrate reduction approaches.
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Terapia de Reposição de Enzimas , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/terapia , Terapias em Estudo , Humanos , Mucopolissacaridose III/tratamento farmacológico , Mucopolissacaridose III/cirurgiaRESUMO
Purpose: In breast cancer, improved treatment approaches that reduce injury to lung tissue and early diagnosis and intervention for lung toxicity are increasingly important in survivorship. The aims of this study are to (1) compare lung tissue radiographic changes in women treated with conventional photon radiation therapy and those treated with proton therapy (PT), (2) assess the volume of lung irradiated to 5 Gy (V5) and 20 Gy (V20) by treatment modality, and (3) quantify the effects of V5, V20, time, and smoking history on the severity of tissue radiographic changes. Patients and Methods: A prospective observational study of female breast cancer patients was conducted to monitor postradiation subclinical lung tissue radiographic changes. Repeated follow-up x-ray computed tomography scans were acquired through 2 years after treatment. In-house software was used to quantify an internally normalized measure of pulmonary tissue density change over time from the computed tomography scans, emphasizing the 6- and 12-month time points. Results: Compared with photon therapy, PT was associated with significantly lower lung V5 and V20. Lung V20 (but not V5) correlated significantly with increased subclinical lung tissue radiographic changes 6 months after treatment, and neither correlated with lung effects at 12 months. Significant lung tissue density changes were present in photon therapy patients at 6 and 12 months but not in PT patients. Significant lung tissue density change persisted at 12 months in ever-smokers but not in never-smokers. Conclusion: Patients treated with PT had significantly lower radiation exposure to the lungs and less statistically significant tissue density change, suggesting decreased injury and/or improved recovery compared to photon therapy. These findings motivate additional studies in larger, randomized, and more diverse cohorts to further investigate the contributions of treatment modality and smoking regarding the short- and long-term radiographic effects of radiation on lung tissue.
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Introduction: Sanfilippo syndrome is a rare disease and fatal genetic disorder with no FDA-approved treatment in the United States (US), and no comprehensive assessment of economic disease burden is available. Objectives: To develop a model to estimate the economic burden associated with Sanfilippo syndrome in the US using direct costs, indirect costs and valued intangibles (disability-adjusted life years, or DALYs) from 2023 onward. Design and Setting: A multistage comorbidity model was generated based on Sanfilippo syndrome symptoms, and disability weights from the 2010 Global Burden of Disease Study. Attributable increase in caregiver mental health burden were estimated using data from the CDC National Comorbidity Survey and retrospective studies on caregiver burden. Direct costs were approximated from the 2019 EveryLife Foundation survey, and indirect costs were estimated from Federal income data. Monetary valuations were adjusted to USD 2023 and given a 3% discount rate from 2023 onward. Main Outcome Measures: Incidence of Sanfilippo syndrome was calculated for each year, and year-over-year DALYs due to patient years lived with disability (YLDs) and years life lost (YLLs) were calculated by comparing to the health-adjusted life expectancy (HALE) in the US. Direct and indirect costs were calculated for each simulated patient from onset of symptoms to death. Results: From 2023-2043, overall economic burden in the US attributable to Sanfilippo syndrome was estimated to be $2.04 billion USD present value (2023) with current standard of care. The burden to individual families exceeded $8 million present value from time of birth per child born with Sanfilippo syndrome. Conclusion: Sanfilippo syndrome is a rare lysosomal storage disease, however the severe burden associated with the disease for individual families demonstrates a considerable cumulative impact. Our model represents the first disease burden value estimate associated with Sanfilippo syndrome, and underscores the substantial morbidity and mortality burden of Sanfilippo syndrome.
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BACKGROUND: Real-world evidence on the comparative effectiveness of pegfilgrastim biosimilars compared with the originator product is limited. OBJECTIVE: To compare the risk of febrile neutropenia (FN) among users of pegfilgrastim biosimilars (pegfilgrastim-jmdb and pegfilgrastim-cbqv) and the originator product. METHODS: A retrospective cohort study was conducted using 2019 IBM MarketScan databases to assess comparative effectiveness of pegfilgrastim originator and biosimilars for prevention of FN among patients receiving myelosuppressive chemotherapy. Patients with cancer, including breast, lung, colorectal, esophageal and gastric, pancreatic, prostate, ovarian, and non-Hodgkin lymphomas, initiating myelosuppressive chemotherapy courses were selected. We further selected patients who used pegfilgrastim originator and biosimilars within 3 days of chemotherapy completion. FN-associated hospitalizations were measured by International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes. After 1:1 propensity score matching, we used equivalence (with a margin of 6%) hypothesis tests to compare FN-related hospitalization risk in the first cycle and across all cycles between biosimilars and originator users. RESULTS: A total of 2,045 patients were included, of which 445 (21.8%) used pegfilgrastim-jmdb, 636 (31.1%) used pegfilgrastim-cbqv, and 964 (47.1%) used pegfilgrastim originator. After matching, 13 out of 445 originator users and 17 out of 445 pegfilgrastim-jmdb users developed FN after the first chemotherapy cycle (risk difference was 0.9%; P < 0.001 for equivalence test indicating statistical equivalence). After matching, 14 out of 633 originator users and 16 out of 633 pegfilgrastim-cbqv users developed FN (risk difference was 0.32%; P < 0.001 for equivalence test indicating statistical equivalence). Results across all cycles (including the first cycle) were consistent with that in the first cycle. CONCLUSIONS: In this real-world study of patients with cancer receiving myelosuppressive chemotherapy, there was no difference in FN risk between patients receiving pegfilgrastim originator and biosimilars in the first cycle and across all cycles. These results add further to the current evidence on pegfilgrastim biosimilars and support wider adoption of pegfilgrastim biosimilars among payers, providers, and patients. Future studies assessing the tolerability, side effects, and other safety issues of pegfilgrastim biosimilars are needed.
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Antineoplásicos , Medicamentos Biossimilares , Neutropenia Febril , Filgrastim , Neoplasias , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/uso terapêutico , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/tratamento farmacológico , Neutropenia Febril/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Neoplasias/tratamento farmacológico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes , Estudos Retrospectivos , Pesquisa Comparativa da Efetividade , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Filgrastim/efeitos adversos , Filgrastim/uso terapêuticoRESUMO
Background: Behavioral, social, and physical characteristics are posited to distinguish the sexes, yet research on transcription-level sexual differences in the brain is limited. Here, we investigated sexually divergent brain transcriptomics in prepubertal cynomolgus macaques, a commonly used surrogate species to humans. Methods: A transcriptomic profile using RNA sequencing was generated for the temporal lobe, ventral midbrain, and cerebellum of 3 female and 3 male cynomolgus macaques previously treated with an Adeno-associated virus vector mix. Statistical analyses to determine differentially expressed protein-coding genes in all three lobes were conducted using DeSeq2 with a false discovery rate corrected P value of .05. Results: We identified target genes in the temporal lobe, ventral midbrain, and cerebellum with functions in translation, immunity, behavior, and neurological disorders that exhibited statistically significant sexually divergent expression. Conclusions: We provide potential mechanistic insights to the epidemiological differences observed between the sexes with regards to mental health and infectious diseases, such as COVID19. Our results provide pre-pubertal information on sexual differences in non-human primate brain transcriptomics and may provide insight to health disparities between the biological sexes in humans.
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BACKGROUND: Breast cancer is the most diagnosed cancer in the United States, and half of breast cancer survivors experience major depressive disorders (hereafter depression). Healthcare Effectiveness Data and Information Set (HEDIS) quality measures evaluating depression treatment practices recommend uninterrupted antidepressant treatment for 3 months in the acute phase and 3 months in the continuation phase for the general population. However, little is known about the extent of and trends in antidepressant nonadherence among breast cancer survivors with depression, which may impact adherence to breast cancer treatment, potentially leading to breast cancer recurrence and other adverse outcomes. OBJECTIVE: To examine the trends and characteristics associated with antidepressant nonadherence among breast cancer survivors with depression in the United States. METHODS: We conducted cross-sectional analyses of Surveillance, Epidemiology, and End Results linked with Medicare data (2010-2019) for women with breast cancer and depression who newly initiated antidepressant use. Using HEDIS measures of nonadherence (ie, antidepressant prescription coverage ≤84 days of the 114-day acute phase or ≤180 days of the 231-day continuation phase), we calculated the annual crude prevalence of antidepressant nonadherence and examined trends using unadjusted logistic regression. Multivariable logistic regression identified characteristics associated with antidepressant nonadherence. RESULTS: Among 9,452 eligible breast cancer survivors with depression (aged ≥65 years = 84% and White race = 82%), the crude prevalence of antidepressant nonadherence decreased from 2010 to 2019 for both the acute (49% to 40%; Ptrend<0.001) and continuation (67% to 57%; Ptrend<0.001) phases. Factors significantly associated with higher odds of antidepressant nonadherence in both the acute and continuation phases included Black race (odds ratios [ORs] [95% CI] for the acute/continuation phases: 2.0 [1.7-2.4]/2.0 [1.7-2.3]) and Hispanic ethnicity (1.5 [1.1-1.9]/2.2 [1.6-2.9]) compared with White race; receiving the first antidepressant from an oncologist vs a psychiatrist (1.4 [1.1-1.8]/1.6 [1.2-2.0]); and using antidepressants not recommended for older adults by the Beers criteria (2.2 [1.6-2.9]/2.0 [1.4-2.7]). Factors associated with lower odds of antidepressant nonadherence in both phases included receiving lymph node dissection (0.7 [0.5-0.9]/0.7 [0.5-0.9]), receiving endocrine therapy (0.9 [0.8-0.9]/0.8 [0.7-0.9]), having a higher National Cancer Institute comorbid index (0.8 [0.7-0.8]/0.9 [0.8-0.9]), having a follow-up visit with a psychiatrist (0.9 [0.8-0.9]/0.9 [0.8-0.9]), and switching to different antidepressants (0.7 [0.6-0.8]/0.7 [0.7-0.8]). CONCLUSIONS: Despite antidepressant nonadherence prevalence decreasing from 2010 to 2019, over half of breast cancer survivors with depression and Medicare were nonadherent in the continuation phase. Patients with identified nonadherence risk factors may benefit from close monitoring and targeted interventions. DISCLOSURES: Wei-Hsuan Lo-Ciganic reported grants from the National Institute on Drug Abuse (R01DA044985 and R01DA050676), the National Institute on Aging (R21AG060308), the National Institute of Mental Health (R01MH121907), Merck Sharp & Dohme, Bristol Myers Squibb, the Richard King Mellon Foundation at the University of Pittsburgh, the Clinical and Translational Science Institute of the University of Florida, the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation, and the US Department of Veterans Affairs outside the submitted work; in addition, Wei-Hsuan Lo-Ciganic has a patent pending for U1195.70174US00. Haesuk Park reported grants from Bristol Myers Squibb/Pfizer Alliance American Thrombosis Investigator Initiated Research Program (ARISTA-USA) outside the submitted work. Juan M. Hincapie-Castillo reported grants from Merck outside the submitted work. Debbie Wilson reported grants from the National Institute on Drug Abuse, the National Institute on Aging, Merck Sharp & Dohme, and Bristol Myers Squibb outside the submitted work; and serving as an editorial board member for the Journal of Pharmacy Technology. Ching-Yuan Chang's contributions to this manuscript were made while at the University of Florida College of Pharmacy. Ching-Yuan Chang is currently employed by Vertex Pharmaceuticals, Inc. Vertex did not fund or have any involvement in this study or publication. Vakaramoko Diaby is currently employed by Otsuka, Inc. Otsuka did not fund or have any involvement in this study or publication. No other disclosures were reported.
Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Transtorno Depressivo Maior , Humanos , Idoso , Feminino , Estados Unidos , Depressão/tratamento farmacológico , Depressão/epidemiologia , Transtorno Depressivo Maior/tratamento farmacológico , Etnicidade , Neoplasias da Mama/tratamento farmacológico , Estudos Transversais , Medicare , Recidiva Local de Neoplasia/tratamento farmacológico , Antidepressivos/uso terapêuticoRESUMO
BACKGROUND: It is unknown whether using pegfilgrastim biosimilars is cost saving in a real-world setting. OBJECTIVE: To compare medical costs including pegfilgrastim drug costs and febrile neutropenia (FN) treatment and management costs between pegfilgrastim biosimilars (pegfilgrastim-jmdb, pegfilgrastim-cbqv) and originator users for primary prophylaxis of febrile neutropenia. METHODS: A retrospective cohort study using 2019 IBM MarketScan Commercial and Medicare Supplemental databases was conducted in adult patients with cancer initiating myelosuppressive chemotherapy courses. At least 2 diagnoses of the same cancer (at least 7 days apart) were required within 30 days of the chemotherapy initiation date. Pegfilgrastim (excluding on-body injector) costs included drug costs only (excluding administration fees). FN-related costs included all FN-related health care utilizations that were defined as having neutropenia, fever, or infection diagnosis. Per-patient per-cycle (PPPC) out-of-pocket (OOP) costs, health plan costs, and total costs were compared between originator (excluding on-body injector) and biosimilars users in the first cycle. A generalized linear model and a 2-part model were used. RESULTS: A total of 1,930 patients were included, of whom 884 (45.8%) used pegfilgrastim originator, 427 (22.1%) used pegfilgrastim-jmdb, and 619 (32.1%) used pegfilgrastim-cbqv. Adjusted PPPC OOP pegfilgrastim costs in the first cycle were significantly lower for the biosimilars vs the originator ($182 for pegfilgrastim-jmdb and $159 for pegfilgrastim-cbqv vs $299 for originator, P < 0.0001 for both comparisons). However, there was no difference in health plan costs ($5,783 for pegfilgrastim-jmdb and $5,845 for pegfilgrastim-cbqv vs $5,618 for originator) and total costs. In addition, no difference was observed for adjusted PPPC FN treatment and management OOP costs, health plan costs, and total costs in the first cycle. FN treatment OOP costs were $192 for originator, $197 for pegfilgrastim-jmdb (P = 0.958), and $240 for pegfilgrastim-cbqv (P = 0.680). FN treatment health plan costs were $2,804 for originator, $2,970 for pegfilgrastim-jmdb (P = 0.692), and $2,745 for pegfilgrastim-cbqv (P = 0.879). CONCLUSIONS: In a commercially insured population, using pegfilgrastim biosimilars in the first cycle for primary prophylaxis of FN led to cost savings for patients but not payers. No difference in FN-related costs was observed.
Assuntos
Medicamentos Biossimilares , Neutropenia Febril , Neoplasias , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neutropenia Febril/tratamento farmacológico , Neutropenia Febril/prevenção & controle , Filgrastim , Humanos , Medicare , Neoplasias/tratamento farmacológico , Polietilenoglicóis , Estudos Retrospectivos , Estados UnidosRESUMO
Breast cancer mortality remains unacceptably high, indicating a need for safer and more effective therapeutic agents. Disulfide bond Disrupting Agents (DDAs) were previously identified as a novel class of anticancer compounds that selectively kill cancers that overexpress the Epidermal Growth Factor Receptor (EGFR) or its family member HER2. DDAs kill EGFR+ and HER2+ cancer cells via the parallel downregulation of EGFR, HER2, and HER3 and activation/oligomerization of Death Receptors 4 and 5 (DR4/5). However, the mechanisms by which DDAs mediate these effects are unknown. Affinity purification analyses employing biotinylated-DDAs reveal that the Protein Disulfide Isomerase (PDI) family members AGR2, PDIA1, and ERp44 are DDA target proteins. Further analyses demonstrate that shRNA-mediated knockdown of AGR2 and ERp44, or expression of ERp44 mutants, enhance basal DR5 oligomerization. DDA treatment of breast cancer cells disrupts PDIA1 and ERp44 mixed disulfide bonds with their client proteins. Together, the results herein reveal DDAs as the first small molecule, active site inhibitors of AGR2 and ERp44, and demonstrate roles for AGR2 and ERp44 in regulating the activity, stability, and localization of DR4 and DR5, and activation of Caspase 8.
Assuntos
Neoplasias da Mama , Dissulfetos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Morte Celular , Dissulfetos/metabolismo , Dissulfetos/uso terapêutico , Receptores ErbB/metabolismo , Feminino , Humanos , Proteínas de Membrana , Chaperonas Moleculares/metabolismo , Mucoproteínas , Proteínas Oncogênicas/genética , Isomerases de Dissulfetos de Proteínas/genética , Isomerases de Dissulfetos de Proteínas/metabolismo , Proteínas , Receptores de Morte CelularRESUMO
Sanfilippo syndrome type B (MPS IIIB) is a lysosomal storage disease resulting from a deficiency of N-acetyl-glucosaminidase (NAGLU) activity. In an attempt to correct the disease in the murine model of MPS IIIB, neonatal mice were treated with intracranial AAV2/5-NAGLU (AAV), syngeneic bone marrow transplant (BMT), or both (AAV/BMT). All treatments resulted in some improvement in clinical phenotype. Adeno-associated viral (AAV) treatment resulted in improvements in lifespan, motor function, hearing, time to activity onset, and daytime activity level, but no reduction of lysosomal storage. BMT resulted in improved hearing by 9 months, and improved circadian measures, but had no effect on lifespan, motor function, or central nervous system (CNS) lysosomal storage. AAV/BMT treatment resulted in improvements in hearing, time to activity onset, motor function, and reduced CNS lysosomal storage, but had no effect on lifespan. Combination therapy compared to either therapy alone resulted in synergistic effects on hearing and CNS lysosomal inclusions but antagonistic effects on motor function and lifespan. AAV alone is more efficacious than BMT or AAV/BMT treatment for lifespan. BMT was the least efficacious treatment by all measures. CNS-directed AAV treatment alone appears to be the preferred treatment, combining the most efficacy with the least toxicity of the approaches assessed.