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Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. In treatment-naïve mice, MYCN overexpression promoted cell cycle progression, suppressed infiltration of cytotoxic T cells, and accelerated SCLC. MYCN overexpression also suppressed response to cisplatin-etoposide chemotherapy, with similar findings made upon MYCL overexpression. We extended these data to genetically perturb chemosensitive patient-derived xenograft (PDX) models of SCLC. In chemosensitive PDX models, overexpression of either MYCN or MYCL also conferred a switch to chemoresistance. To identify therapeutic strategies for MYCN-overexpressing SCLC, we performed a genome-scale CRISPR-Cas9 sgRNA screen. We identified the deubiquitinase USP7 as a MYCN-associated synthetic vulnerability. Pharmacological inhibition of USP7 resensitized chemoresistant MYCN-overexpressing PDX models to chemotherapy in vivo. Our findings show that MYCN overexpression drives SCLC chemoresistance and provide a therapeutic strategy to restore chemosensitivity.
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Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Peptidase 7 Específica de Ubiquitina/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Xenoenxertos , Humanos , Neoplasias Pulmonares/enzimologia , Camundongos , Proteína Proto-Oncogênica N-Myc/genética , Carcinoma de Pequenas Células do Pulmão/enzimologia , Carcinoma de Pequenas Células do Pulmão/genéticaRESUMO
Developing robot control software systems is difficult because of a wide variety of requirements, including hardware systems and sensors, even though robots are demanding nowadays. Middleware systems, such as Robot Operating System (ROS), are being developed and widely used to tackle this difficulty. Streaming data Sharing Manager (SSM) is one of such middleware systems that allow developers to write and read sensor data with timestamps using a Personal Computer (PC). The timestamp feature is essential for the robot control system because it usually uses multiple sensors with their own measurement cycles, meaning that measured sensor values with different timestamps become useless for the robot control. Using SSM allows developers to use measured sensor values with the same timestamps; however, SSM assumes that only one PC is used. Thereby, if one process consumes CPU resources intensively, other processes cannot finish their assumed deadlines, leading to the unexpected behavior of a robot. This paper proposes an SSM middleware, named Distributed Streaming data Sharing Manager (DSSM), that enables distributing processes on SSM to different PCs. We have developed a prototype of DSSM and confirmed its behavior so far. In addition, we apply DSSM to an existing real SSM based robot control system that autonomously controls an unmanned vehicle robot. We then reveal its advantages and disadvantages via several experiments by measuring resource usages.
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The rearrangement of carbon-carbon (C-C) single bonds in readily available carbocyclic scaffolds can yield uniquely substituted carbocycles that would be challenging to construct otherwise. This is a powerful and often non-intuitive approach for complex molecule synthesis. The transition-metal-mediated cleavage of C-C bonds has the potential to broaden the scope of this type of skeletal remodeling by providing orthogonal selectivities compared to more traditional pericyclic and carbocation-based rearrangements. To highlight this emerging technology, a unified, asymmetric, total synthesis of the phomactin terpenoids was developed, enabled by the selective C-C bond cleavage of hydroxylated pinene derivatives obtained from carvone. In this full account, the challenges, solutions, and intricacies of Rh(I)-catalyzed cyclobutanol C-C cleavage in a complex molecule setting are described. In addition, details of the evolution of strategies that ultimately led to the total synthesis of phomactins A, K, P, R, and T, as well as the synthesis and structural reassignment of Sch 49027, are given.
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Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Terpenos/química , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura Molecular , Ródio/químicaRESUMO
BACKGROUND: Atazanavir causes plasma indirect bilirubin to increase. We evaluated associations between Gilbert's polymorphism and bilirubin-related atazanavir discontinuation stratified by race/ethnicity. PATIENTS AND METHODS: Patients had initiated atazanavir/ritonavir-containing regimens at an HIV primary care clinic in the southeastern USA, and had at least 12 months of follow-up data. Metabolizer group was defined by UGT1A1 rs887829 CâT. Genome-wide genotype data were used to adjust for genetic ancestry in combined population analyses. RESULTS: Among 321 evaluable patients, 15 (4.6%) had bilirubin-related atazanavir discontinuation within 12 months. Homozygosity for rs887829 T/T was present in 28.1% of Black, 21.4% of Hispanic, and 8.6% of White patients. Among all patients the hazard ratio (HR) for bilirubin-related discontinuation with T/T versus C/C genotype was 7.3 [95% confidence interval (CI): 1.7-31.5; P=0.007]. Among 152 White patients the HR was 14.4 (95% CI: 2.6-78.7; P=0.002), but among 153 Black patients the HR was 0.8 (95% CI: 0.05-12.7; P=0.87). CONCLUSION: Among patients who initiated atazanavir/ritonavir-containing regimens, UGT1A1 slow metabolizer genotype rs887829 T/T was associated with increased bilirubin-related discontinuation of atazanavir in White but not in Black patients, this despite T/T genotype being more frequent in Black patients.
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Sulfato de Atazanavir/efeitos adversos , Glucuronosiltransferase/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/etnologia , Inibidores da Protease de HIV/efeitos adversos , Icterícia/etnologia , Adulto , Negro ou Afro-Americano/genética , Bilirrubina/sangue , Feminino , Estudos de Associação Genética , Genótipo , Infecções por HIV/sangue , Hispânico ou Latino/genética , Humanos , Icterícia/sangue , Icterícia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
BACKGROUND: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings. METHODS: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per µL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080. FINDINGS: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per µL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5-7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4-7·8); absolute risk difference of -0·06% (95% CI -3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group. INTERPRETATION: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease. FUNDING: National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.
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Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Fármacos Anti-HIV/uso terapêutico , Antituberculosos/uso terapêutico , Isoniazida/uso terapêutico , Tuberculose/prevenção & controle , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Adulto , Instituições de Assistência Ambulatorial , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Resultado do Tratamento , Tuberculose/imunologiaRESUMO
BACKGROUND: Efavirenz frequently causes central nervous system (CNS) symptoms. We evaluated genetic associations with efavirenz discontinuation for CNS symptoms within 12 months of treatment initiation. METHODS: Patients had initiated efavirenz-containing regimens at an HIV primary care clinic in the Southeastern United States and had at least 12 months of follow-up data. Polymorphisms in CYP2B6 and CYP2A6 defined efavirenz metabolizer categories. Genome-wide genotyping enabled adjustment for population stratification. RESULTS: Among 563 evaluable patients, 99 (17.5%) discontinued efavirenz within 12 months, 29 (5.1%) for CNS symptoms. The hazard ratio (HR) for efavirenz discontinuation for CNS symptoms in slow versus extensive metabolizers was 4.9 [95% confidence interval (CI): 1.9-12.4; P=0.001]. This HR in Whites was 6.5 (95% CI: 2.3-18.8; P=0.001) and 2.6 in Blacks (95% CI: 0.5-14.1; P=0.27). Considering only slow metabolizers, the HR in Whites versus Blacks was 3.1 (95% CI: 0.9-11.0; P=0.081). The positive predictive value of slow metabolizer genotypes for efavirenz discontinuation was 27% in Whites and 11% in Blacks. CONCLUSION: Slow metabolizer genotypes were associated significantly with efavirenz discontinuation for reported CNS symptoms. This association was considerably stronger in Whites than in Blacks.
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Hidrocarboneto de Aril Hidroxilases/genética , Benzoxazinas/efeitos adversos , Doenças do Sistema Nervoso Central/induzido quimicamente , Citocromo P-450 CYP2B6/genética , Etnicidade/genética , Polimorfismo de Nucleotídeo Único , Inibidores da Transcriptase Reversa/efeitos adversos , Esteroide Hidroxilases/genética , Adulto , Alcinos , Doenças do Sistema Nervoso Central/genética , Ciclopropanos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Valor Preditivo dos Testes , Suspensão de TratamentoRESUMO
Progress toward the total syntheses of a diverse set of fawcettimine-type Lycopodium alkaloids via a "Heathcock-type" 6-5-9 tricycle is disclosed. This route features an intermolecular Diels-Alder cycloaddition to rapidly furnish the 6-5-fused bicycle and a highly chemoselective directed hydrogenation to build the azonane fragment. While conducting these synthetic studies, trimethylsilyl iodide was found to effect a hydroamination reaction to furnish the tetracyclic core of serratine and related natural products. This observation has been expanded into a general method for the room temperature hydroamination of unactivated olefins with tosylamides utilizing catalytic "anhydrous" HI (generated in situ from trimethylsilyl iodide and water). The presence of the iodide anion is critical to the success of this Brønsted acid catalyzed protocol, possibly due to its function as a weakly coordinating anion. These conditions also effect the analogous hydroetherification reaction of alcohols with unactivated olefins.
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Alcenos/química , Hidrogênio/química , Iodetos/química , Aminação , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
AIMS: Genetic factors, notably CYP2B6 516GâT [rs3745274] and 983TâC [rs28399499], explain much of the interindividual variability in efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations in HIV-infected Black South African adults and children. METHODS: Steady-state mid-dosing interval efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3. RESULTS: Among 113 participants (59 adults and 54 children), minor allele frequencies for CYP2B6 516GâT, 983TâC, and 15582CâT [rs4803419] were 0.36, 0.07, and 0.09, respectively. Based on composite CYP2B6 15582/516/983 genotype, there were 33 extensive metabolizer, 62 intermediate metabolizer and 18 slow metabolizer genotypes. Median (IQR) mid-dose efavirenz concentrations were 1.44 (1.21-1.93) µg ml(-1), 2.08 (1.68-2.94) µg ml(-1) and 7.26 (4.82-8.34) µg ml(-1) for extensive, intermediate and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted efavirenz concentrations (ß = 0.28, 95% CI 0.21, 0.35, P = 2.4 × 10(-11)). Among individual CYP2B6 polymorphisms, 516GâT best predicted efavirenz concentrations (ß = 0.22, 95% CI 0.13, 0.30, P = 1.27 × 10(-6)). There was also associations with 983TâC (ß = 0.27, 95% CI 0.10, 0.44, P = 0.002) and 15582CâT (ß = 0.11, 95% CI 0.01, 0.22, P = 0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with efavirenz concentrations. CONCLUSIONS: Composite CYP2B6 genotype based on CYP2B6 516GâT, 983TâC, and 15582CâT best described efavirenz exposure in HIV-infected Black South African adults and children.
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Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Benzoxazinas/sangue , Benzoxazinas/farmacocinética , Citocromo P-450 CYP2B6/genética , Infecções por HIV/genética , Adolescente , Adulto , Alcinos , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , População Negra/genética , Criança , Pré-Escolar , Receptor Constitutivo de Androstano , Ciclopropanos , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , África do Sul , Adulto JovemRESUMO
Stavudine (d4T) was, until recently, one of the most widely prescribed antiretroviral drugs worldwide. While there has been a major shift away from d4T use in resource-limited countries, a large number of patients have previously received (or continue to receive) d4T, and many have developed peripheral neuropathy. The identification of genetic predictors of increased risk might suggest novel therapeutic targets for such patients. In AIDS Clinical Trials Group protocol 384, antiretroviral-naïve patients were randomized to d4T/didanosine (ddI)- or zidovudine/lamivudine-containing regimens. Data from d4T/ddI recipients were analyzed for genome-wide associations (approximately 1 million genetic loci) with new onset distal sensory peripheral neuropathy. Analyses involved 254 patients (49 % White, 34 % Black, 17 % Hispanic), comprising 90 peripheral neuropathy cases (32 grade 1, 35 grade 2, 23 grade 3) and 164 controls. After correcting for multiple comparisons, no polymorphism was consistently associated with neuropathy among all patients, among White, Black, and Hispanic patients analyzed separately, both in genome-wide analyses (threshold, P < 5.0 × 10(-8)) and focused on 46 neuropathy-associated genes (threshold, P < 3.5 × 10(-5)). In the latter analyses, the lowest P values were in KIF1A among Whites (rs10199388, P = 8.4 × 10(-4)), in LITAF among Blacks (rs13333308, P = 6.0 × 10(-6)), and in NEFL among Hispanics (rs17763685, P = 5.6 × 10(-6)). Susceptibility to d4T/ddI-associated neuropathy is not explained by a single genetic variant with a marked effect.
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Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/genética , Lamivudina/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/genética , Estavudina/uso terapêutico , Zidovudina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Estudos de Casos e Controles , Combinação de Medicamentos , Quimioterapia Combinada , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Estudos Multicêntricos como Assunto , Polimorfismo Genético , Análise de Componente Principal , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Androgen deprivation therapy (ADT) improves local cancer control in unfavorable localized prostate cancer treated with radiotherapy. ADT is known to cause hormonally related symptoms that resolve with testosterone recovery. Hot flashes are particularly burdensome. This study sought to evaluate the timeline of hot flashes following short-course ADT and stereotactic body radiotherapy (SBRT) as well as its relationship with testosterone recovery. METHODS: Institutional IRB approval was obtained for this retrospective review of prospectively collected data (IRB#: 2009-510). ADT was initiated three months prior to the start of SBRT. Hot flashes were self-reported via question 13a of the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (one, three, six, nine, 12, 18, 24, and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem, and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up. RESULTS: From 2007 to 2010, 122 localized prostate cancer patients (nine low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (three to six months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Thirty-two percent were Black and 27% were obese. Seventy-seven percent of patients received three months of ADT. At baseline, 2% of men experienced hot flashes that were a "moderate to big problem" and that proportion peaked at the start of SBRT (45%) before returning to baseline (2%) nine months post-SBRT with a cumulative incidence of 52.4%. The median baseline EPIC-26 hot flash score of 94 declined to 50 at the start of SBRT but this returned to baseline (92) by six months post SBRT. These changes were both statistically and clinically significant (MID = 9.5083, p<0.01). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. Resolution of hot flashes correlated with testosterone recovery. CONCLUSION: Bothersome hot flashes occur in greater than 50% of men treated with neoadjuvant ADT. Resolution of hot flashes occurs in the majority of patients within one year after treatment. Reassurance of the temporary nature of hot flashes may assist in reducing patient anxiety. Measuring testosterone levels at follow-up visits may allow for anticipatory counseling that may limit the associated bother.
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Introduction: Sexual function following local treatment for prostate cancer is an important quality of life concern. Relugolix is a novel oral GnRH receptor antagonist used in combination with radiation therapy in the treatment of unfavorable prostate cancer. It has been shown to achieve rapid and profound testosterone suppression. As a result, these very low testosterone levels may impact both sexual functioning and perceptions. This prospective study sought to assess neoadjuvant relugolix-induced sexual dysfunction prior to stereotactic body radiation therapy (SBRT). Methods: Between March 2021 and September 2023, 87 patients with localized prostate cancer were treated with neoadjuvant relugolix followed by SBRT per an institutional protocol. Sexual function and bother were assessed via the sexual domain of the validated Expanded Prostate Index Composite (EPIC-26) survey. Responses were collected for each patient at pre-treatment baseline and after several months of relugolix. A Utilization of Sexual Medications/Devices questionnaire was administered at the same time points to assess erectile aid usage. Results: The median age was 72 years and 43% of patients were non-white. The median baseline Sexual Health Inventory for Men (SHIM) score was 13 and 41.7% of patients utilized sexual aids prior to relugolix. Patients initiated relugolix at a median of 4.5 months (2-14 months) prior to SBRT. 95% and 87% of patients achieved effective castration (≤ 50 ng/dL) and profound castration (< 20 ng/dl) at SBRT initiation, respectively. Ability to have an erection, ability to reach orgasm, quality of erections, frequency of erections, and overall sexual function significantly declined following relugolix. There was a non- significant increase in sexual bother. Discussion: In concordance with known side effects of androgen deprivation therapy (ADT), neoadjuvant relugolix was associated with a significant decline in self-reported sexual function. However, patients indicated only a minimal and non-significant increase in bother. Future investigations should compare outcomes while on relugolix directly to GnRH agonist-induced sexual dysfunction.
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JavaScript Web applications are a common product in industry. As with most applications, Web applications can acquire software flaws (known as bugs), whose symptoms are seen during the development stage and, even worse, in production. The use of debuggers is beneficial for detecting bugs. Unfortunately, most JavaScript debuggers (1) only support the "step into/through" feature in an execution program to detect a bug, and (2) do not allow developers to go back-in-time at the application execution to take actions to detect the bug accurately. For example, the second limitation does not allow developers to modify the value of a variable to fix a bug while the application is running or test if the same bug is triggered with other values of that variable. Using concepts such as continuations and static analysis, this article presents a usable debugger for JavaScript, named DeloreanJS, which enables developers to go back-in-time in different execution points and resume the execution of a Web application to improve the understanding of a bug, or even experiment with hypothetical scenarios around the bug. Using an online and available version, we illustrate the benefits of DeloreanJS through five examples of bugs in JavaScript. Although DeloreanJS is developed for JavaScript, a dynamic prototype-based object model with side effects (mutable variables), we discuss our proposal with the state-of-art/practice of debuggers in terms of features. For example, modern browsers like Mozilla Firefox include a debugger in their distribution that only support for the breakpoint feature. However DeloreanJS uses a graphical user interface that considers back-in-time features. The aim of this study is to evaluate and compare the usability of DeloreanJS and Mozilla Firefox's debugger using the system usability scale approach. We requested 30 undergraduate students from two computer science programs to solve five tasks. Among the findings, we highlight two results. First, we found that 100% (15) of participants recommended DeloreanJS, and only 53% (eight) recommended Firefox's debugger to complete the tasks. Second, whereas the average score for DeloreanJS is 71.6 ("Good"), the average score for Firefox's debugger is 55.8 ("Acceptable").
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Introduction: Injectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy. Prostate SBRT offers an abbreviated treatment course with comparable efficacy to conventionally fractionated radiotherapy. Relugolix is a new oral GnRH receptor antagonist which achieves rapid, sustained testosterone suppression. This prospective study sought to evaluate early testosterone suppression and PSA response following relugolix and SBRT for intermediate to high prostate cancer. Methods: Relugolix was initiated at least 2 months prior to SBRT. Interventions to improve adherence were not utilized. PSA and total testosterone levels were obtained prior to and 1-4 months post SBRT. Profound castration was defined as serum testosterone ≤ 20 ng/dL. Early PSA nadir was defined as the lowest PSA value within 4 months of completion of SBRT. Per prior trials, we examined the percentage of patients who achieved PSA level of ≤ 0.5 ng/mL and ≤ 0.2 ng/mL during the first 4 months post SBRT. Results: Between July 2021 and January 2023, 52 men were treated at Georgetown with relugolix (4-6 months) and SBRT (36.25-40 Gy in 5 fractions) per an institutional protocol (IRB 12-1775). Median age was 71 years. 26.9% of patients were African American and 28.8% were obese (BMI ≥30 kg/m2). The median pretreatment PSA was 9.1 ng/ml. 67% of patients were ≥ Grade Group 3. 44 patients were intermediate- and 8 were high-risk. Patients initiated relugolix at a median of 3.6 months prior to SBRT with a median duration of 6.2 total months. 92.3% of patients achieved profound castration during relugolix treatment. Poor drug adherence was observed in 2 patients. A third patient chose to discontinue relugolix due to side effects. By post-SBRT month 4, 87.2% and 74.4% of patients achieved PSA levels ≤ 0.5 ng/ml and ≤ 0.2 ng/ml, respectively. Discussion: Relugolix combined with SBRT allows for high rates of profound castration with low early PSA nadirs. We observed a 96% testosterone suppresion rate without the utilization of scheduled cues/reminders. This finding supports the notion that patients with localized prostate cancer can consistently and successfully follow an oral ADT protocol without daily reminders. Given relugolix's potential benefits over injectable GnRH receptor agonists, its usage may be preferred in specific patient populations (fear of needles, prior cardiovascular events). Future studies should focus on boundaries to adherence in specific underserved populations.
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OBJECTIVE: In a previous analysis involving protocol ANRS 12154, interindividual variability in steady-state nevirapine clearance among HIV-infected Cambodians was partially explained by CYP2B6 516GâT (CYP2B6*6). Here, we examine whether additional genetic variants predict nevirapine clearance in this cohort. METHODS: Analyses included Phnom Penh ESTHER (Ensemble pour une Solidarité Thérapeutique Hospitalière en Réseau) cohort participants who had consented for genetic testing. All participants were receiving nevirapine plus two nucleoside analogs. The mean individual nevirapine clearance estimates were derived from a population model developed on nevirapine concentrations at 18 and 36 months of therapy. Polymorphisms were assayed in ABCB1, CYP2A6, CYP2B6, CYP2C19, CYP3A4, CYP3A5, and NR1I2. RESULTS: Of 198 assayed loci, 130 were polymorphic. Among 129 individuals with evaluable genetic data, nevirapine clearance ranged from 1.06 to 5.00 l/h in 128 individuals and was 7.81 l/h in one individual. In bivariate linear regression, CYP2B6 516GâT (CYP2B6*6) was associated with lower nevirapine clearances (P=3.5×10). In a multivariate linear regression model conditioned on CYP2B6 516GâT, independent associations were identified with CYP2B6 rs7251950, CYP2B6 rs2279343, and CYP3A4 rs2687116. The CYP3A4 association disappeared after censoring the outlier clearance value. A model that included CYP2B6 516GâT (P=1.0×10), rs7251950 (P=4.8×10), and rs2279343 (P=7.1×10) explained 11% of interindividual variability in nevirapine clearance. CONCLUSION: Among HIV-infected Cambodians, several CYP2B6 polymorphisms were associated independently with steady-state nevirapine clearance. The prediction of nevirapine clearance was improved by considering several polymorphisms in combination.
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Fármacos Anti-HIV/farmacocinética , Povo Asiático , Variação Genética , Infecções por HIV/tratamento farmacológico , Nevirapina/farmacocinética , Adulto , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Feminino , Genótipo , Infecções por HIV/genética , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Nevirapina/uso terapêutico , Polimorfismo de Nucleotídeo ÚnicoRESUMO
General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound 39 engages GCN2 at levels ≥80% with an oral dose of 15 mg/kg BID. We also demonstrate the ability of compound 39 to alleviate MDSC-related T cell suppression and restore T cell proliferation, similar to the effect seen in MDSCs from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI) as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced by treatment with compound 39 demonstrating the complementarity of these two mechanisms.
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Células Supressoras Mieloides , eIF-2 Quinase , Animais , Heme , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases , Linfócitos T/metabolismo , eIF-2 Quinase/metabolismoRESUMO
BACKGROUND: Laboratory monitoring for toxicity among patients receiving antiretroviral therapy (ART) in less-developed settings is technically challenging and consumes significant resources. METHODS: We conducted a cohort study of the 1800 adult patients who initiated ART at the Haitian Study Group for Kaposi's Sarcoma and Opportunistic Infections (GHESKIO) in Haiti from 2003 to 2006, using baseline data to establish the prevalence and using follow-up data to establish the incidence of hepatitis, renal insufficiency, hyperglycemia, anemia, neutropenia, and thrombocytopenia. We determined how frequently routine (not symptom-driven) testing detected significant laboratory abnormalities and calculated the cost per disability-adjusted life year (DALY) averted by detection of these events in the asymptomatic stage, compared with a strategy of symptom-prompted testing only. RESULTS: Forty-eight patients (3.5%) had severe anemia at baseline testing and consequently did not receive zidovudine. Fifty-three patients receiving zidovudine therapy developed severe anemia during follow-up (incidence, 2.5 cases/100 person-years). Monitoring for asymptomatic anemia with hematocrit testing was cost-saving at baseline and had a cost-effectiveness ratio of US$317/DALY averted during follow-up; with a complete blood count, costs increased to US$1182 and $10,781/DALY averted, respectively. With glucose monitoring, 11 patients were diagnosed with new-onset hyperglycemia during follow-up (incidence, 0.7 cases/100 person-years), resulting in a cost-effectiveness ratio of US$9845 per DALY averted. Monitoring for asymptomatic hepatitis and renal insufficiency was expensive and rarely affected care. CONCLUSIONS: Resource-poor countries should select which laboratory tests to perform on the basis of the cost-effectiveness of each test. This will depend on the national ART drug regimen and the prevalence of other comorbidities. Routine monitoring with multitest hematological and chemistry panels is unlikely to be cost-effective.
Assuntos
Fármacos Anti-HIV/economia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/economia , Zidovudina/economia , Zidovudina/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Glicemia/efeitos dos fármacos , Técnicas de Laboratório Clínico/economia , Estudos de Coortes , Análise Custo-Benefício , Países em Desenvolvimento/economia , Infecções por HIV/epidemiologia , Haiti , Recursos em Saúde/economia , Humanos , Hiperglicemia/induzido quimicamente , Fatores SocioeconômicosRESUMO
Lymph node recurrent prostate cancer is a common clinical scenario that is likely to increase significantly with the widespread adoption of novel positron emission tomography (PET) agents. Despite increasing evidence that localized therapy is disease modifying, most men with lymph node recurrent prostate cancer receive only systemic therapy with androgen deprivation therapy (ADT). For men who receive localized therapy the intent is often to delay receipt of systemic therapy. Little evidence exists on the optimal combination of local and systemic therapy in this patient population. In this hypothesis generating review, we will outline the rationale and propose a framework for combining involved field SBRT with risk adapted intermittent ADT for hormone sensitive nodal recurrent prostate cancer. In patients with a limited number of nodal metastases, involved field stereotactic body radiation therapy (SBRT) may have a role in eliminating castrate-resistant clones and possibly prolonging the response to intermittent ADT. We hypothesize that in a small percentage of patients, such a treatment approach may lead to long term remission or cure.
RESUMO
USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases. The succinimide was identified as a key potency-driving motif, forming two strong hydrogen bonds to the allosteric pocket of USP7. Redesign of an initial benzofuran-amide scaffold yielded a simplified ether series of inhibitors, utilizing acyclic conformational control to achieve proper amine placement. Further improvements were realized upon replacing the ether-linked amines with carbon-linked morpholines, a modification motivated by free energy perturbation (FEP+) calculations. This led to the discovery of compound 41, a highly potent, selective, and orally bioavailable USP7 inhibitor. In xenograft studies, compound 41 demonstrated tumor growth inhibition in both p53 wildtype and p53 mutant cancer cell lines, demonstrating that USP7 inhibitors can suppress tumor growth through multiple different pathways.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Descoberta de Drogas/métodos , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Peptidase 7 Específica de Ubiquitina/química , Administração Oral , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X/métodos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Estrutura Terciária de Proteína , Peptidase 7 Específica de Ubiquitina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. Thus, USP7 inhibition may decrease oncogene function, increase tumor suppressor function, and sensitize tumors to DNA-damaging agents. We have discovered a novel chemical series that potently and selectively inhibits USP7 in biochemical and cellular assays. Our inhibitors reduce the viability of multiple TP53 wild-type cell lines, including several hematologic cancer and MYCN-amplified neuroblastoma cell lines, as well as a subset of TP53-mutant cell lines in vitro Our work suggests that USP7 inhibitors upregulate transcription of genes normally silenced by the epigenetic repressor complex, polycomb repressive complex 2 (PRC2), and potentiate the activity of PIM and PI3K inhibitors as well as DNA-damaging agents. Furthermore, oral administration of USP7 inhibitors inhibits MM.1S (multiple myeloma; TP53 wild type) and H526 (small cell lung cancer; TP53 mutant) tumor growth in vivo Our work confirms that USP7 is a promising, pharmacologically tractable target for the treatment of cancer.
Assuntos
Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Modelos MolecularesRESUMO
We analyzed mortality among 201 patients with AIDS and tuberculosis in Haiti. Patients who received a diagnosis of tuberculosis during the first 3 months after the initiation of antiretroviral therapy were 3.25 times more likely to die than were other patients with AIDS and tuberculosis. Failure to recognize active tuberculosis at initiation of antiretroviral therapy leads to increased mortality.