The leishmaniases are a group of four vector-borne neglected tropical diseases (NTDs) with 1.6 billion people in some 100 countries at risk. They occur in certain eco-epidemiological foci that reflect manipulation by human activities, such as migration, urbanization and deforestation, of which poverty, conflict and climate change are key drivers. Given their synergistic impacts, risk factors and the vulnerabilities of poor populations and the launch of a new 2030 roadmap for NTDs in the context of the global sustainability agenda, it is warranted to update the state of knowledge of the leishmaniases and their effects. Using existing literature, we review socioeconomic and psychosocial impacts of leishmaniasis within a framework of risk factors and vulnerabilities to help inform policy interventions. Studies show that poverty is an overarching primary risk factor. Low-income status fosters inadequate housing, malnutrition and lack of sanitation, which create and exacerbate complexities in access to care and treatment outcomes as well as education and awareness. The co-occurrence of the leishmaniases with malnutrition and HIV infection further complicate diagnosis and treatment, leading to poor diagnostic outcomes and therapeutic response. Even with free treatment, households may suffer catastrophic health expenditure from direct and indirect medical costs, which compounds existing financial strain in low-income communities for households and healthcare systems. The dermatological presentations of the leishmaniases may result in long-term severe disfigurement, leading to stigmatization, reduced quality of life, discrimination and mental health issues. A substantial amount of recent literature points to the vulnerability pathways and burden of leishmaniasis on women, in particular, who disproportionately suffer from these impacts. These emerging foci demonstrate a need for continued international efforts to address key risk factors and population vulnerabilities if leishmaniasis control, and ultimately elimination, is to be achieved by 2030.

No abstract

Introduction: PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells. As such, Talazoparib (TLZ), a potent PARP inhibitor, offers a way to target the biology of a number of cancers with DNA repair defects until these tumors develop resistance. PARP inhibitors must be used in combination with other inhibitors or chemotherapeutics to reverse resistance and sensitize non-responsive tumors. Dinaciclib, a potent cyclin dependent kinase (CDK) inhibitor, has been shown to sensitize both BRCA wild-type tumors and PARP inhibitor resistant tumors to PARP inhibition through disruption of homologous recombination. In clinical trials, Talazoparib and Dinaciclib have both demonstrated hematologic toxicities, suggesting a combination of these drugs would result in compounded toxicity, leading to dose reduction and an ineffective combination. Nanoparticle delivery systems offer a means to modify the toxicity profiles of these drugs and enhance the therapeutic window, therefore allowing for effective combination treatment. Methods: Separate nanoformulations of Talazoparib (NanoTLZ) and Dinaciclib (NanoDCB) were optimized, and pharmacokinetics and pharmacodynamics assessed. Nanoformulations were tested alone and in combination in vitro to ensure NanoDCB could sensitize a model with no known DNA repair defects to NanoTLZ. The combination of the two nanoformulations was then assessed for efficacy and toxicity in orthotopic MDA-MB-231 xenografts. Results: Robust formulations of NanoTLZ and NanoDCB were developed. Each nanoformulation extended the half-life of the drug it encapsulates. A constant low dose of Dinaciclib sensitized MDA-MB-231 cells to Talazoparib, significantly lowering the IC50 value. As a single agent NanoDCB was more effective in vitro than free Dinaciclib. In vivo, the combination of the two nanoformulations was more effective than either single nanoformulation or the combination of the two free drugs. Assessments of hematologic toxicities are underway, but thus far, there were no signs of gross toxicity in the combination therapy group. Conclusions: The combination of NanoDCB and NanoTLZ has provided an effective method for sensitizing tumors to PARP inhibition that are otherwise nonresponsive to this therapy. The development of two separate nanoformulations has allowed for tailored dosing. These long-circulating nanoformulations have proven more effective than the free drugs in stabilizing tumor growth and were well tolerated. This work was supported by ARMY/W81XWH-16-1-0731. Citation Format: Paige Baldwin, Adrienne Orriols, Srinivas Sridhar. Combination nanotherapy using the PARP inhibitor talazoparib and cyclin dependent kinase inhibitor dinaciclib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3642.

No abstract

Background Carpal bone tumors are rare in the literature, making it difficult to identify their clinical presentation. Purpose This systematic review analyzes the characteristics of published carpal bone tumor cases to identify the most frequent patterns in diagnoses. Attention is paid to the carpal bone involved and type, and patient demographics was performed to summarize published findings. Methods A systematic review was searched on PubMed, Ovid, and Cochrane databases gathering literature on carpal bone tumors. After applying specific criteria, final analysis of the literature yielded 151 patients with 156 carpal bone neoplasms. Results The most common carpal bones involved were the scaphoid (48, 31%), capitate (31, 20%), and hamate (24, 15%). Benign tumors represented the largest majority (133, 85%), followed by metastatic (17, 11%) and primary malignant (7, 5%). The most frequent tumor types were osteoid osteoma (37, 24%), osteoblastoma or giant cell tumor (24, 15%), intraosseous ganglia (21, 13%), and chondroblastoma (14, 9%). Within the metastatic category, most tumors derived from lung carcinoma (10, 59%), followed by renal cell carcinoma (2, 12%). There were three types within the malignant category: chondrosarcoma (3, 43%), hemangioendothelial sarcoma (3, 43%), and osteosarcoma (1, 14%). Conclusion The most frequent carpal bones observed were the scaphoid, capitate, and hamate. Most tumors were benign. The most common tumor types were osteoid osteoma, osteoblastoma, and giant cell tumor. Metastatic carpal tumors were most commonly from lung carcinoma. Chondrosarcoma and hemangioendothelial sarcoma were the most common primary malignancies.