Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile

We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.     

Somatisation Disorder and Its Associated Factors in Multiethnic Primary Care Clinic Attenders

Background

Somatisation disorder (SD) has been reported as common in all ethnic groups, but the estimates of its prevalence have varied and the evidence for its associated factors has been inconsistent.

Purpose

This study seeks to determine the prevalence of SD and its associated factors in multiethnic primary care clinic attenders.

Methods

This cross-sectional study was on clinic attenders aged 18?years and above at three urban primary care clinics in Malaysia. The operational definition of SD was based on ICD-10 criteria for SD for research, frequent attendance, and excluded moderate to severe anxiety and depression. The instruments used were the ICD-10 symptom list, the Hospital Anxiety and Depression Scale, a semi-structured questionnaire, and SF-36.

Results

We recruited 1,763 patients (response rate 63.8%). The mean age of respondents was 44.7?±?15.8?years, 807 (45.8%) were male; there were 35.3% Malay, 30.1% Chinese and 34.6% Indian. SD prevalence was 3.7%; the prevalence in Malay was 5.8%, Indian 3.0% and Chinese 2.1%. Significant associations were found between SD prevalence and ethnicity, family history of alcoholism, blue-collar workers and the physical component summary (PCS) score of SF-36. Multivariate analysis showed that SD predictors were Malay ethnicity (OR 2.7, 95% CI 1.6, 4.6), blue-collar worker (OR 2.0, 95% CI 1.2, 3.5) and impaired PCS score of SF-36 (OR 0.92, 95% CI 0.90, 0.95).

Conclusion

The prevalence of SD was relatively uncommon with the stringent operational criteria used. SD preponderance in blue-collar workers may be attributable to secondary gain from getting sickness certificates and being paid for time off work.     

Nerve injury causes long-term attentional deficits in rats

Human chronic pain sufferers frequently report problems with attention and concentration that affect daily functioning and quality of life. Chronic pain is also commonly associated with anxiety and depression. It is currently not known if the pain causes these co-morbidities, or if they are pre-disposing risk factors for the development of chronic pain. Animal studies suggest a possible causative effect of pain on cognition, but usually tests are conducted during acute ongoing pain when the pain may act as a distracter to normal cognitive and emotional processing. Here we examine long-term effects of nerve injury on cognitive functioning in a rat model, which contributes to better understanding of the relationship between cognitive impairment and chronic pain experience in human populations. This study investigated attentional capability, anxiety-like behavior and sensory functioning 6 months after spared nerve injury (SNI) surgery—a time-point well beyond the acute pain phase and akin to decades of pain experience in humans. Male Long Evans rats subjected to nerve injury remained hypersensitive to sensory stimuli from the time of injury to the 6-month post-injury assessment. At 6 months they were impaired on a visual non-selective, non-sustained attention task and displayed anxiety-like behaviors in the elevated plus maze. These findings show that cognitive disturbances observed during acute pain persist for months in a rodent chronic pain model and suggest that cognitive alterations in chronic pain patients are at least partially caused by the chronic pain state.     

Antidiabetic and haematological effect of aqueous extract of stem bark of Afzelia africana (Smith) on streptozotocin-induced diabetic Wistar rats

Objective

To investigate the antidiabetic properties of aqueous extract of stem bark of Afzelia africana (A. africana) and its beneficial effect on haematological parameters in streptozotocin induced diabetic rats.

Methods

A total of 30 rats including 24 diabetic and 6 normal rats were used for this study. Diabetes was induced in male Wistar rats by intraperitoneal injection of streptozotocin. After being confirmed diabetic, animals were orally treated with distilled water or extracts at 100 or 200 mg/kg body weight daily for 10 days. The haematological parameters including red blood and white blood cells and their functional indices were evaluated in diabetic treated groups compared with the controls.

Results

The extract significantly reduced the blood glucose levels while the best result was obtained at 200 mg/kg body weight. The feed and water intake in diabetic rats were significantly reduced while weight loss was minimized at both dosages. Similarly, the levels of red blood, white blood cells and their functional indices were significantly improved after extract administration at both doses.

Conclusions

It can be concluded that the aqueous extract of bark of A. africana possesses antihyperglycemic properties. In addition, the extract can prevent various complications of diabetes and improve some haematological parameters. Further experimental investigation is needed to exploit its relevant therapeutic effect to substantiate its ethnomedicinal usage.     

Antibiotic Prophylaxis Prevents the Development of a Post-Infectious Phenotype in a New Rat Model of Post-Infectious IBS

Background  

A recent post-infectious rat model with Campylobacter jejuni 81-176 has replicated the events noted in humans with post-infectious irritable bowel syndrome (IBS). In this study, we test whether prophylactic treatment with the antibiotic rifaximin will prevent the development of long-term altered bowel function in this model.     

Pulmonary sclerosing hemangioma: pitfalls in management

Pulmonary sclerosing hemangioma is a rare benign tumor for which surgical excision is curative with an excellent prognosis. It often mimics malignancy, making it a diagnostic and management challenge. We reviewed the clinical, radiological, and histopathological characteristics as well as the surgical management of our patients to assess the potential pitfalls in management. All 19 patients who underwent surgical biopsy between January 1999 and December 2009 with a final histopathological diagnosis of pulmonary sclerosing hemangioma were reviewed retrospectively. The median age was 48 years, 89.5% were female, 89.5% were Chinese, and 68.4% were asymptomatic. There were no specific diagnostic radiological characteristics; 1 of 3 patients who underwent combined positron-emission and computed tomography had a false-positive result. Preoperative attempts at establishing a diagnosis were successful in 20% of patients who had invasive procedures. Intraoperative frozen-section evaluation for pulmonary sclerosing hemangioma had an error rate of 25% and a deferred rate of 31%, resulting in nearly half of our patients undergoing unnecessary extensive surgical procedures. We hope to heighten awareness of this diagnosis, thereby increasing the index of suspicion and minimizing errors in diagnosis.     

Epigenetic epidemiology: the rebirth of soft inheritance

Non-communicable diseases (NCDs), such as cardiovascular disease and type 2 diabetes, constitute the main cause of death worldwide. Eighty percent of these deaths occur in low- and middle-income countries, especially as these countries undergo socio-economic improvement following reductions in the burden of infectious disease. The World Health Organization predicts a substantial increase in the incidence of NCDs over the next decade globally. NCDs are generally preventable, but current approaches are clearly inadequate. New initiatives are needed to implement such prevention, and there needs to be greater recognition that early-life interventions are likely to be the most efficacious. Devising appropriate prevention strategies necessitates an understanding of how the developmental environment influences risk. Progress in this field has been slow due to an excessive emphasis on fixed genomic variations (hard inheritance) as the major determinants of disease susceptibility. However, new evidence demonstrates the much greater importance of early-life developmental factors, involving epigenetic processes and 'soft' inheritance in modulating an individual's vulnerability to NCD. This also offers opportunities for novel epigenetic biomarkers of risk or interventions targeting epigenetic pathways to be devised for use in early life. This may pave the way to much more effective, customised interventions to promote health across the life course.     

Distinct signatures of diversifying selection revealed by genome analysis of respiratory tract and invasive bacterial populations

Many pathogens colonize different anatomical sites, but the selective pressures contributing to survival in the diverse niches are poorly understood. Group A Streptococcus (GAS) is a human-adapted bacterium that causes a range of infections. Much effort has been expended to dissect the molecular basis of invasive (sterile-site) infections, but little is known about the genomes of strains causing pharyngitis (streptococcal "sore throat"). Additionally, there is essentially nothing known about the genetic relationships between populations of invasive and pharyngitis strains. In particular, it is unclear if invasive strains represent a distinct genetic subpopulation of strains that cause pharyngitis. We compared the genomes of 86 serotype M3 GAS pharyngitis strains with those of 215 invasive M3 strains from the same geographical location. The pharyngitis and invasive groups were highly related to each other and had virtually identical phylogenetic structures, indicating they belong to the same genetic pool. Despite the overall high degree of genetic similarity, we discovered that strains from different host environments (i.e., throat, normally sterile sites) have distinct patterns of diversifying selection at the nucleotide level. In particular, the pattern of polymorphisms in the hyaluronic acid capsule synthesis operon was especially different between the two strain populations. This finding was mirrored by data obtained from full-genome analysis of strains sequentially cultured from nonhuman primates. Our results answer the long-standing question of the genetic relationship between GAS pharyngitis and invasive strains. The data provide previously undescribed information about the evolutionary history of pathogenic microbes that cause disease in different anatomical sites.