Targeted biopsy added to systematic biopsy improves cancer detection in prostate cancer screening.

BACKGROUND: Magnetic resonance imaging (MRI)/ultrasound targeted biopsy has frequently been used together with a 12-core systematic biopsy for prostate cancer screening in the past few years. However, the efficacy of targeted biopsy compared to systematic biopsy, as well as its clinical-histologic correlation, has been assessed by a limited number of studies and is further investigated in this study. DESIGN: We collected 960 cases with both targeted and systematic prostate biopsies from 04/2019 to 04/2022 (Table 1). We compared cancer detection rates between targeted and systematic prostate biopsies in different grade groups. Correlations with the size of prostate lesions, prostate-specific antigen (PSA) level, and Prostate Imaging-Reporting and Data System (PI-RADS) scale were also analyzed for each of these biopsy methods. RESULTS: Among the 960 men who underwent targeted biopsy with systematic biopsy, prostatic adenocarcinoma was diagnosed in 652 (67.9%) cases. 489 (50.9%) cases were diagnosed by targeted biopsy and 576 (60.0%) cases were diagnosed by systematic biopsy. In the 384 cases diagnosed negative by systematic biopsy, targeted biopsy identified cancer in 76 (8%) cases. Systematic biopsy was able to detect 163 cancer cases that were missed by targeted biopsy. Systematic biopsy detected more grade group 1 cancers compared to targeted biopsy. However, for higher grade cancers, the differences between the cancer detection rates of targeted biopsy and systematic biopsy became negligible. Targeted biopsy upgraded the grade group categorized by systematic biopsy in several cases (3.8%, 7.0%, 2.6%, 1.1% and 0.9% in Grade Groups 1, 2, 3, 4, and 5 respectively). Targeted biopsy was more likely to detect cancer in larger lesions (13.17 mm VS 11.41 mm, P=0.0056) and for higher PI-RADS scales (4.19 VS 3.68, P<0.0001). The cancers detected by targeted biopsy also had higher PSA levels (10.38 ng/ml VS 6.39 ng/ml, P=0.0026). CONCLUSION: Targeted biopsy with systematic biopsy improved cancer detection rate compared to systematic biopsy alone. Targeted biopsy is not more sensitive for grade groups 1, 4, or 5 cancers but is as sensitive as systematic biopsy for detecting grade group 2 and 3 cancers. Targeted biopsy is more effective at detecting cancers when patients have larger lesions, higher PI-RADS scales, and higher PSA levels.

Correction: Implementation of Genomic Surveillance of SARS-CoV-2 in the Caribbean: Lessons learned for sustainability in resource-limited settings.

[This corrects the article DOI: 10.1371/journal.pgph.0001455.].

Implementation of genomic surveillance of SARS-CoV-2 in the Caribbean: Lessons learned for sustainability in resource-limited settings.

The COVID-19 pandemic highlighted the importance of global genomic surveillance to monitor the emergence and spread of SARS-CoV-2 variants and inform public health decision-making. Until December 2020 there was minimal capacity for viral genomic surveillance in most Caribbean countries. To overcome this constraint, the COVID-19: Infectious disease Molecular epidemiology for PAthogen Control & Tracking (COVID-19 IMPACT) project was implemented to establish rapid SARS-CoV-2 whole genome nanopore sequencing at The University of the West Indies (UWI) in Trinidad and Tobago (T&T) and provide needed SARS-CoV-2 sequencing services for T&T and other Caribbean Public Health Agency Member States (CMS). Using the Oxford Nanopore Technologies MinION sequencing platform and ARTIC network sequencing protocols and bioinformatics pipeline, a total of 3610 SARS-CoV-2 positive RNA samples, received from 17 CMS, were sequenced in-situ during the period December 5th 2020 to December 31st 2021. Ninety-one Pango lineages, including those of five variants of concern (VOC), were identified. Genetic analysis revealed at least 260 introductions to the CMS from other global regions. For each of the 17 CMS, the percentage of reported COVID-19 cases sequenced by the COVID-19 IMPACT laboratory ranged from 0·02% to 3·80% (median = 1·12%). Sequences submitted to GISAID by our study represented 73·3% of all SARS-CoV-2 sequences from the 17 CMS available on the database up to December 31st 2021. Increased staffing, process and infrastructural improvement over the course of the project helped reduce turnaround times for reporting to originating institutions and sequence uploads to GISAID. Insights from our genomic surveillance network in the Caribbean region directly influenced non-pharmaceutical countermeasures in the CMS countries. However, limited availability of associated surveillance and clinical data made it challenging to contextualise the observed SARS-CoV-2 diversity and evolution, highlighting the need for development of infrastructure for collecting and integrating genomic sequencing data and sample-associated metadata.

From Rhesus macaque to human: structural evolutionary pathways for immunoglobulin G subclasses.

The Old World monkey, Rhesus macaque (Macaca mulatta, Mm), is frequently used as a primate model organism in the study of human disease and to test new vaccines/antibody treatments despite diverging before chimpanzees and orangutans. Mm and humans share 93% genome identity with substantial differences in the genes of the adaptive immune system that lead to different functional IgG subclass characteristics, Fcγ receptors expressed on innate immune cells, and biological interactions. These differences put limitations on Mm use as a primary animal model in the study of human disease and to test new vaccines/antibody treatments. Here, we comprehensively analyzed molecular properties of the Fc domain of the four IgG subclasses of Rhesus macaque to describe potential mechanisms for their interactions with effector cell Fc receptors. Our studies revealed less diversity in the overall structure among the Mm IgG Fc, with MmIgG1 Fc being the most structurally like human IgG3, although its CH2 loops and N297 glycan mobility are comparable to human IgG1. Furthermore, the Fcs of Mm IgG3 and 4 lack the structural properties typical for their human orthologues that determine IgG3's reduced interaction with the neonatal receptor and IgG4's ability for Fab-arm exchange and its weaker Fcγ receptor interactions. Taken together, our data indicate that MmIgG1-4 are less structurally divergent than the human IgGs, with only MmIgG1 matching the molecular properties of human IgG1 and 3, the most active IgGs in terms of Fcγ receptor binding and Fc-mediated functions. PDB accession numbers for deposited structures are 6D4E, 6D4I, 6D4M, and 6D4N for MmIgG1 Fc, MmIgG2 Fc, MmIgG3 Fc, and MmIgG4 Fc, respectively.

Managing acute ischaemic stroke in a small island developing state: meeting the guidelines in Barbados.

BACKGROUND: We describe hospital-based management of acute ischaemic stroke patients in 2010-2013 in Barbados, by comparing documented treatment given in the single tertiary public hospital with international guideline recommendations. METHODS: Evidence-based stroke management guidelines were identified through a systematic literature search. Comparisons were made between these guidelines and documented diagnostic practice (all strokes) and prescribed medication (ischaemic stroke only), using a combination of key informant interviews and national stroke registry data for 2010-2013. RESULTS: Several published international guidelines for the acute management of ischaemic stroke recommended patient management in a dedicated stroke unit or nearest hospital specialised in stroke care. Further, patients should receive clinical diagnosis, CT brain scan, specialist evaluation by a multidisciplinary team and, if eligible, thrombolysis with alteplase within 3-3.5 h of symptom onset. Subsequent secondary prophylaxis, with a platelet aggregation inhibitor and a statin was advised. Barbados had no stroke unit or stroke team, and no official protocol for acute stroke management during the study period. Most of the 1735 stroke patients were managed by emergency physicians at presentation; if admitted, they were managed on general medical wards. Most had a CT scan (1646; 94.9%). Of 1406 registered ischaemic stroke patients, only 6 (0.4%) had been thrombolysed, 521 (37.1%) received aspirin within 24 h of admission and 670 (47.7%) were prescribed aspirin on discharge. CONCLUSIONS: Acute ischaemic stroke diagnosis was consistent with international recommendations, although this was less evident for treatment. While acknowledging the difficulty in implementing international guidelines in a low-resource setting, there is scope for improvement in acute ischaemic stroke management and/or its documentation in Barbados. A stroke unit was established in August 2013 and written clinical protocols for acute stroke care were in development at the time of the study; future registry data will evaluate their impact. Our findings have implications for other low-resource settings with high stroke burden.

Investing in non-communicable diseases: an estimation of the return on investment for prevention and treatment services.

The global burden of non-communicable diseases (NCDs) is growing, and there is an urgent need to estimate the costs and benefits of an investment strategy to prevent and control NCDs. Results from an investment-case analysis can provide important new evidence to inform decision making by governments and donors. We propose a methodology for calculating the economic benefits of investing in NCDs during the Sustainable Development Goals (SDGs) era, and we applied this methodology to cardiovascular disease prevention in 20 countries with the highest NCD burden. For a limited set of prevention interventions, we estimated that US$120 billion must be invested in these countries between 2015 and 2030. This investment represents an additional $1·50 per capita per year and would avert 15 million deaths, 8 million incidents of ischaemic heart disease, and 13 million incidents of stroke in the 20 countries. Benefit-cost ratios varied between interventions and country-income levels, with an average ratio of 5·6 for economic returns but a ratio of 10·9 if social returns are included. Investing in cardiovascular disease prevention is integral to achieving SDG target 3.4 (reducing premature mortality from NCDs by a third) and to progress towards SDG target 3.8 (the realisation of universal health coverage). Many countries have implemented cost-effective interventions at low levels, so the potential to achieve these targets and strengthen national income by scaling up these interventions is enormous.

Establishing national noncommunicable disease surveillance in a developing country: a model for small island nations.

Objective To describe the surveillance model used to develop the first national, population-based, multiple noncommunicable disease (NCD) registry in the Caribbean (one of the first of its kind worldwide); registry implementation; lessons learned; and incidence and mortality rates from the first years of operation. Methods Driven by limited national resources, this initiative of the Barbados Ministry of Health (MoH), in collaboration with The University of the West Indies, was designed to collect prospective data on incident stroke and acute myocardial infarction (MI) (heart attack) cases from all health care facilities in this small island developing state (SIDS) in the Eastern Caribbean. Emphasis is on tertiary and emergency health care data sources. Incident cancer cases are obtained retrospectively, primarily from laboratories. Deaths are collected from the national death register. Results Phased introduction of the Barbados National Registry for Chronic NCDs ("the BNR") began with the stroke component ("BNR-Stroke," 2008), followed by the acute MI component ("BNR-Heart," 2009) and the cancer component ("BNR-Cancer," 2010). Expected case numbers projected from prior studies estimated an average of 378 first-ever stroke, 900 stroke, and 372 acute MI patients annually, and registry data showed an annual average of about 238, 593, and 349 patients respectively. There were 1 204 tumors registered in 2008, versus the expected 1 395. Registry data were used to identify public health training themes. Success required building support from local health care professionals and creating island-wide registry awareness. With spending of approximately US$ 148 per event for 2 200 events per year, the program costs the MoH about US$ 1 per capita annually. Conclusions Given the limited absolute health resources available to SIDS, combined surveillance should be considered for building a national NCD evidence base. With prevalence expected to increase further worldwide, Barbados' experiences are offered as a "road map" for other limited-resource countries considering national NCD surveillance.

Establishing national noncommunicable disease surveillance in a developing country: a model for small island nations / Introducción de la vigilancia nacional de las enfermedades no transmisibles en un país en desarrollo: un modelo para las pequeñas naciones insulares

Objective. To describe the surveillance model used to develop the first national, populationbased, multiple noncommunicable disease (NCD) registry in the Caribbean (one of the first of its kind worldwide); registry implementation; lessons learned; and incidence and mortality rates from the first years of operation. Methods. Driven by limited national resources, this initiative of the Barbados Ministry of Health (MoH), in collaboration with The University of the West Indies, was designed to collect prospective data on incident stroke and acute myocardial infarction (MI) (heart attack) cases from all health care facilities in this small island developing state (SIDS) in the Eastern Caribbean. Emphasis is on tertiary and emergency health care data sources. Incident cancer cases are obtained retrospectively, primarily from laboratories. Deaths are collected from the national death register. Results. Phased introduction of the Barbados National Registry for Chronic NCDs (“the BNR”) began with the stroke component (“BNR–Stroke,” 2008), followed by the acute MI component (“BNR–Heart,” 2009) and the cancer component (“BNR–Cancer,” 2010). Expected case numbers projected from prior studies estimated an average of 378 first-ever stroke, 900 stroke, and 372 acute MI patients annually, and registry data showed an annual average of about 238, 593, and 349 patients respectively. There were 1 204 tumors registered in 2008, versus the expected 1 395. Registry data were used to identify public health training themes. Success required building support from local health care professionals and creating island-wide registry awareness. With spending of approximately US$ 148 per event for 2 200 events per year, the program costs the MoH about US$ 1 per capita annually. Conclusions. Given the limited absolute health resources available to SIDS, combined surveillance should be considered for building a national NCD evidence base. With prevalence expected to increase further worldwide, Barbados’ experiences are offered as a “road map” for other limitedresource countries considering national NCD surveillance.

Objetivo. Describir el modelo de vigilancia que se utilizó para crear el primer registro poblacional nacional de múltiples enfermedades no transmisibles en el Caribe (uno de los primeros registros de esta clase en el mundo), la ejecución del registro, las lecciones aprendidas y las tasas de incidencia y mortalidad desde sus primeros años de funcionamiento. Métodos. Esta iniciativa del Ministerio de Salud de Barbados, realizada en colaboración con la Universidad de las Indias Occidentales e impulsada por la limitación de los recursos nacionales, tuvo por finalidad recoger datos prospectivos sobre los casos nuevos de accidente cerebrovascular e infarto agudo de miocardio en todos los establecimientos de atención de salud de este pequeño estado insular en desarrollo del Caribe oriental. El análisis se centró en las fuentes de datos sobre la atención de salud terciaria y de urgencia. La información sobre los casos nuevos de cáncer se obtuvo de manera retrospectiva, principalmente de los laboratorios. Los datos sobre las defunciones se tomaron del registro nacional de mortalidad. Resultados. La introducción progresiva del Registro Nacional de Enfermedades Crónicas no Transmisibles de Barbados se inició con el componente de los accidentes cerebrovasculares en 2008, seguido del componente de infarto agudo de miocardio en 2009 y el componente de cáncer en 2010. Las estimaciones previstas con base en los estudios anteriores fueron en promedio de 378 casos de un primer accidente cerebrovascular, 900 casos de accidente cerebrovascular y 372 pacientes con infarto agudo de miocardio cada año; los datos del registro mostraron un promedio anual cercano a 238, 593 y 349 casos respectivamente. En el 2008, se registraron 1204 casos de cáncer, frente a los 1395 previstos. En función de los datos del registro se definieron los temas de capacitación en salud pública. El éxito de la iniciativa exigió fomentar el apoyo de los profesionales de salud a nivel local y dar a conocer la existencia del registro en toda la isla. Con un gasto cercano a 148 dólares por episodio y 2200 episodios por año, el programa cuesta al Ministerio de Salud alrededor de un dólar por habitante cada año. Conclusiones. Dada la limitación de los recursos absolutos destinados a la salud en los pequeños estados insulares en desarrollo, es preciso analizar la posibilidad de realizar una vigilancia combinada, con el objeto de crear una base nacional de datos fidedignos sobre las enfermedades no transmisibles. Ante la perspectiva de un aumento continuo de la prevalencia mundial, la experiencia en Barbados se ofrece como una “hoja de ruta” destinada a otros países con recursos limitado

Establishing national noncommunicable disease surveillance in a developing country: a model for small island nations / Introducción de la vigilancia nacional de las enfermedades no transmisibles en un país en desarrollo: un modelo para las pequeñas naciones insulares

ABSTRACT Objective To describe the surveillance model used to develop the first national, population-based, multiple noncommunicable disease (NCD) registry in the Caribbean (one of the first of its kind worldwide); registry implementation; lessons learned; and incidence and mortality rates from the first years of operation. Methods Driven by limited national resources, this initiative of the Barbados Ministry of Health (MoH), in collaboration with The University of the West Indies, was designed to collect prospective data on incident stroke and acute myocardial infarction (MI) (heart attack) cases from all health care facilities in this small island developing state (SIDS) in the Eastern Caribbean. Emphasis is on tertiary and emergency health care data sources. Incident cancer cases are obtained retrospectively, primarily from laboratories. Deaths are collected from the national death register. Results Phased introduction of the Barbados National Registry for Chronic NCDs (“the BNR”) began with the stroke component (“BNR–Stroke,” 2008), followed by the acute MI component (“BNR–Heart,” 2009) and the cancer component (“BNR–Cancer,” 2010). Expected case numbers projected from prior studies estimated an average of 378 first-ever stroke, 900 stroke, and 372 acute MI patients annually, and registry data showed an annual average of about 238, 593, and 349 patients respectively. There were 1 204 tumors registered in 2008, versus the expected 1 395. Registry data were used to identify public health training themes. Success required building support from local health care professionals and creating island-wide registry awareness. With spending of approximately US$ 148 per event for 2 200 events per year, the program costs the MoH about US$ 1 per capita annually. Conclusions Given the limited absolute health resources available to SIDS, combined surveillance should be considered for building a national NCD evidence base. With prevalence expected to increase further worldwide, Barbados’ experiences are offered as a “road map” for other limited-resource countries considering national NCD surveillance.

RESUMEN Objetivo Describir el modelo de vigilancia que se utilizó para crear el primer registro poblacional nacional de múltiples enfermedades no transmisibles en el Caribe (uno de los primeros registros de esta clase en el mundo), la ejecución del registro, las lecciones aprendidas y las tasas de incidencia y mortalidad desde sus primeros años de funcionamiento. Métodos Esta iniciativa del Ministerio de Salud de Barbados, realizada en colaboración con la Universidad de las Indias Occidentales e impulsada por la limitación de los recursos nacionales, tuvo por finalidad recoger datos prospectivos sobre los casos nuevos de accidente cerebrovascular e infarto agudo de miocardio en todos los establecimientos de atención de salud de este pequeño estado insular en desarrollo del Caribe oriental. El análisis se centró en las fuentes de datos sobre la atención de salud terciaria y de urgencia. La información sobre los casos nuevos de cáncer se obtuvo de manera retrospectiva, principalmente de los laboratorios. Los datos sobre las defunciones se tomaron del registro nacional de mortalidad. Resultados La introducción progresiva del Registro Nacional de Enfermedades Crónicas no Transmisibles de Barbados se inició con el componente de los accidentes cerebrovasculares en 2008, seguido del componente de infarto agudo de miocardio en 2009 y el componente de cáncer en 2010. Las estimaciones previstas con base en los estudios anteriores fueron en promedio de 378 casos de un primer accidente cerebrovascular, 900 casos de accidente cerebrovascular y 372 pacientes con infarto agudo de miocardio cada año; los datos del registro mostraron un promedio anual cercano a 238, 593 y 349 casos respectivamente. En el 2008, se registraron 1204 casos de cáncer, frente a los 1395 previstos. En función de los datos del registro se definieron los temas de capacitación en salud pública. El éxito de la iniciativa exigió fomentar el apoyo de los profesionales de salud a nivel local y dar a conocer la existencia del registro en toda la isla. Con un gasto cercano a 148 dólares por episodio y 2200 episodios por año, el programa cuesta al Ministerio de Salud alrededor de un dólar por habitante cada año. Conclusiones Dada la limitación de los recursos absolutos destinados a la salud en los pequeños estados insulares en desarrollo, es preciso analizar la posibilidad de realizar una vigilancia combinada, con el objeto de crear una base nacional de datos fidedignos sobre las enfermedades no transmisibles. Ante la perspectiva de un aumento continuo de la prevalencia mundial, la experiencia en Barbados se ofrece como una “hoja de ruta” destinada a otros países con recursos limitados que planean introducir la vigilancia nacional de las enfermedades no transmisibles.

Social distribution of diabetes, hypertension and related risk factors in Barbados: a cross-sectional study.

OBJECTIVE: To describe the distribution of diabetes, hypertension and related behavioural and biological risk factors in adults in Barbados by gender, education and occupation. DESIGN: Multistage probability sampling was used to select a representative sample of the adult population (≥ 25 years). Participants were interviewed using standard questionnaires, underwent anthropometric and blood pressure measurements, and provided fasting blood for glucose and cholesterol measurements. Standard WHO definitions were used. Data were weighted for sampling and non-response, and were age and sex standardised to the 2010 Barbados population. Weighted prevalence estimates were calculated, and prevalence ratios were calculated for behavioural and biological risk factors by demographic and socioeconomic group. RESULTS: Study response rate was 55.0%, with 764 women, 470 men. Prevalence of obesity was 33.8% (95% CI 30.7% to 37.1%); hypertension 40.6% (95% CI 36.5% to 44.9%); and diabetes 18.7% (95% CI 16.2% to 21.4%). Compared with women, men were less likely to be obese (prevalence ratio 0.5; 95% CI 0.4 to 0.7), or physically inactive (0.5; 0.4 to 0.6), but more likely to smoke tobacco (4.1; 2.5 to 6.7) and consume large amounts of alcohol in a single episode (4.6; 2.7 to 7.6). Both diabetes (0.83; 0.65 to 1.05) and hypertension (0.89; 0.79 to 1.02) were lower in men, but not significantly so. In women, higher educational level was related to higher fruit and vegetable intake, more physical activity, less diabetes and less hypercholesterolaemia (p 0.01-0.04). In men, higher education was related only to less smoking (p 0.04). Differences by occupation were limited to smoking in men and hypercholesterolaemia in women. CONCLUSIONS: In this developing country population, sex appears to be a much stronger determinant of behavioural risk factors, as well as obesity and its related risks, than education or occupation. These findings have implications for meeting the commitments made in the 2011 Rio Political Declaration, to eliminate health inequities.

Synthesis and structure-activity relationships of benzophenone-bearing diketopiperazine-type anti-microtubule agents.

KPU-105 (4), a potent anti-microtubule agent that contains a benzophenone was derived from the diketopiperazine-type vascular disrupting agent (VDA) plinabulin 3, which displays colchicine-like tubulin depolymerization activity. To develop derivatives with more potent anti-microtubule and cytotoxic activities, we further modified the benzophenone moiety of 4. Accordingly, we obtained a 4-fluorobenzophenone derivative 16j that inhibited tumor cell growth in vitro with a subnanomolar IC(50) value against HT-29 cells (IC(50)=0.5 nM). Next, the effect of 16j on mitotic spindles was evaluated in HeLa cells. Treatment with 3nM of 16j partially disrupted the interphase microtubule network. By contrast, treatment with the same concentration of CA-4 barely affected the microtubule network, indicating that 16j exhibited more potent anti-mitotic effects than did CA-4.

Synthesis and structure-activity relationship study of antimicrotubule agents phenylahistin derivatives with a didehydropiperazine-2,5-dione structure.

Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.

Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model.

Our previous study showed that the novel proteasome inhibitor NPI-0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM-xenografts demonstrated that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase-1 clinical trial of NPI-0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI-0052 using human MM xenograft murine model. Our results showed that NPI-0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin-like (CT-L, beta5), trypsin-like (T-L, beta2), and caspase-like (C-L, beta1) activities in extra-vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs (<24 h). Tissue distribution analysis of radiolabeled compound (3H-NPI-0052) in mice demonstrated that NPI-0052 left the vascular space and entered organs as the parent compound. Importantly, treatment of MM.1S-bearing mice with NPI-0052 showed reduced tumour growth without significant toxicity, which was associated with prolonged inhibition of proteasome activity in tumours and PWB but not normal tissues.

Identification of an X-linked locus modifying mouse skin tumor susceptibility.

The enhancing effect of overexpression of an ornithine decarboxylase (Odc) transgene on skin tumor susceptibility can be modified by genetic loci present in several inbred mouse strains. The BALB/cJ strain is among the most resistant strains so far examined; tumor multiplicity following 7,12-dimethylbenz(a)anthracene (DMBA) treatment is reduced by 90% when the K6/ODC transgene is expressed on a BALB/cJ background versus the susceptible C57BL/6J background. Further, transgenic BALB/cJ males developed more tumors than females, indicating the presence of sex-dependent modifier pathway. Analysis of 263 F2 intercross mice revealed significant linkage of markers on the X chromosome to tumor multiplicity. This analyses as well as a similar genome-wide scan of 136 backcross mice found evidence for other modifier loci on chromosomes 4, 6, and 17. Identification of these modifier genes should reveal the effector pathways responsive to Odc overexpression that mediate susceptibility to skin tumorigenesis.

20 years of HIV treatment: past, present, and future.

Twenty years after the recognition of HIV and AIDS, no cure is in sight. Antiretroviral therapy is effective in delaying progression of HIV infection and AIDS, but the quality of life provided is only marginally better than the disease itself. To avoid therapeutic failures and viral resistance, medication adherence is critically important when patients are taking antiretroviral agents, but it is difficult to achieve. Pharmacists have a key role to play in managing adverse effects and drug interactions, providing adherence counseling, and monitoring regimens for needed therapeutic response and resistance tests.