Throwing the Book at the CSG

We estimate the effect of the child support grant on mothers' labour supply in South Africa. Identification is based on the use of specific samples, such as black mothers, aged 20 to 45, whose youngest child is aged within 2 years of the age eligibility cut-off, and unanticipated variation over the years in the age eligibility cut-off. Balancing tests across the age cut-o s are used to show that there are no significant differences between mothers of eligible and ineligible children in the samples used, over the years. Different techniques are used to estimate the effect of the child support grant from many angles, including simple OLS as a bench mark, a difference in difference estimator, using appropriately constructed treatment and control groups, instrumental variables estimates, and descriptive analysis. The effect of having an age eligible child is large. Mothers who become recipients in their twenties see an average increase in employment probability of 15%, and in labour force participation of 9%. Many robustness and specification checks are used, including placebo regressions in the pre-treatment years, to ensure the estimated effect is not due to age or another variable.

Alternative splicing of TIA-1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance

© 2014 The Authors. The angiogenic capability of colorectal carcinomas (CRC), and their susceptibility to anti-angiogenic therapy, is determined by expression of vascular endothelial growth factor (VEGF) isoforms. The intracellular protein T-cell Intracellular Antigen (TIA-1) alters post-transcriptional RNA processing and binds VEGF-A mRNA. We therefore tested the hypothesis that TIA-1 could regulate VEGF-A isoform expression in colorectal cancers. TIA-1 and VEGF-A isoform expression was measured in colorectal cancers and cell lines. We discovered that an endogenous splice variant of TIA-1 encoding a truncated protein, short TIA-1 (sTIA-1) was expressed in CRC tissues and invasive K-Ras mutant colon cancer cells and tissues but not in adenoma cell lines. sTIA-1 was more highly expressed in CRC than in normal tissues and increased with tumour stage. Knockdown of sTIA-1 or over-expression of full length TIA-1 (flTIA-1) induced expression of the anti-angiogenic VEGF isoform VEGF-A 165 b. Whereas flTIA-1 selectively bound VEGF-A 165 mRNA and increased translation of VEGF-A 165 b, sTIA-1 prevented this binding. In nude mice, xenografted colon cancer cells over-expressing flTIA-1 formed smaller, less vascular tumours than those expressing sTIA-1, but flTIA-1 expression inhibited the effect of anti-VEGF antibodies. These results indicate that alternative splicing of an RNA binding protein can regulate isoform specific expression of VEGF providing an added layer of complexity to the angiogenic profile of colorectal cancer and their resistance to anti-angiogenic therapy

Inhaled recombinant human IL-15 in dogs with naturally occurring pulmonary metastases from osteosarcoma or melanoma: a phase 1 study of clinical activity and correlates of response.

PurposeAlthough recombinant human interleukin-15 (rhIL-15) has generated much excitement as an immunotherapeutic agent for cancer, activity in human clinical trials has been modest to date, in part due to the risks of toxicity with significant dose escalation. Since pulmonary metastases are a major site of distant failure in human and dog cancers, we sought to investigate inhaled rhIL-15 in dogs with naturally occurring lung metastases from osteosarcoma (OSA) or melanoma. We hypothesized a favorable benefit/risk profile given the concentrated delivery to the lungs with decreased systemic exposure.Experimental designWe performed a phase I trial of inhaled rhIL-15 in dogs with gross pulmonary metastases using a traditional 3+3 cohort design. A starting dose of 10 µg twice daily × 14 days was used based on human, non-human primate, and murine studies. Safety, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) were the primary objectives, while response rates, progression-free and overall survival (OS), and pharmacokinetic and immune correlative analyses were secondary.ResultsFrom October 2018 to December 2020, we enrolled 21 dogs with 18 dogs reaching the 28-day response assessment to be evaluable. At dose level 5 (70 μg), we observed two DLTs, thereby establishing 50 µg twice daily × 14 days as the MTD and recommended phase 2 dose. Among 18 evaluable dogs, we observed one complete response >1 year, one partial response with resolution of multiple target lesions, and five stable disease for an overall clinical benefit rate of 39%. Plasma rhIL-15 quantitation revealed detectable and sustained rhIL-15 concentrations between 1-hour and 6 hour postnebulization. Decreased pretreatment lymphocyte counts were significantly associated with clinical benefit. Cytotoxicity assays of banked peripheral blood mononuclear cells revealed significant increases in peak cytotoxicity against canine melanoma and OSA targets that correlated with OS.ConclusionsIn this first-in-dog clinical trial of inhaled rhIL-15 in dogs with advanced metastatic disease, we observed promising clinical activity when administered as a monotherapy for only 14 days. These data have significant clinical and biological implications for both dogs and humans with refractory lung metastases and support exploration of combinatorial therapies using inhaled rhIL-15

School Enrolment and the Child Support Grant: Evidence from South Africa

The extension of the Child Support Grant in South Africa to all children aged 17 or under gives the opportunity to evaluate this type of social transfer and its effect on school enrolment. Using exogenous variation in the fraction of life exposed to the grant, we find the grant is associated with a higher probability of enrolment, especially for older children. Other methods of identification presented provide supporting evidence for these conclusions.Katherine Eyal - Southern Africa Labour & Development Research Unit (SALDRU) Aliate. Doctoral Candidate, University of Cape Town. Lecturer, School of Economics, University of Cape Town, Ingrid Woolard - Co-PI: National Income Dynamics Study. PD Hahn Level 7. Southern Africa Labour & Development Research Unit (SALDRU). Associate Professor, University of Cape Town

Throwing the book at the CSG

We estimate the effect of the child support grant on mothers' labour supply in South Africa. Identification is based on the use of specific samples, such as black mothers, aged 20 to 45, whose youngest child is aged within 2 years of the age eligibility cut-off, and unanticipated variation over the years in the age eligibility cut-off. Balancing tests across the age cut-o s are used to show that there are no significant differences between mothers of eligible and ineligible children in the samples used, over the years. Different techniques are used to estimate the effect of the child support grant from many angles, including simple OLS as a bench mark, a difference in difference estimator, using appropriately constructed treatment and control groups, instrumental variables estimates, and descriptive analysis. The effect of having an age eligible child is large. Mothers who become recipients in their twenties see an average increase in employment probability of 15%, and in labour force participation of 9%. Many robustness and specification checks are used, including placebo regressions in the pre-treatment years, to ensure the estimated effect is not due to age or another variable

More than just a black-board: Cash transfers and adolescent education in South Africa

Please note: This paper has been updated. Cash transfers are a well-known tool in the developing world to alleviate poverty. However, much of the research evaluating these programs has focussed on short term outcomes, in populations of younger children. Using exogenous changes in the age eligibility limit of an unconditional cash transfer to South African children, this paper examines the current and cumulative impact of grant receipt on the educational outcomes of older adolescents. We find that while current grant receipt raises enrolment rates, longer exposure to this cash transfer does not predict higher years of education attained, or other similar measures of cumulative attainment. This finding emphasises the crucial nature of school quality for educational attainment - a hypothesis that the data supports. It is clear that education is a function of more than just a blackboard - quality of school matters too

Spectrum of activity of Salmonella anti-biofilm compounds: Evaluation of activity against biofilm-forming ESKAPE pathogens

The ESKAPE pathogens are a group of bacteria that are a leading cause of health-care associated infections and are known to be agents of chronic, biofilm-mediated infections. These chronic bacterial infections often respond poorly to antibiotics and in some cases may require surgical intervention in order to cure the infection. As biofilms are often the critical mediator of a chronic infection, it is essential to develop therapies that target bacteria within the biofilm state. Herein, we report the development of a rapid, 96-well plate-based assay that employs conditions specific for each species to optimize biofilm production and allow for easy identification of differences in biofilm mass after treatment with anti-biofilm candidates. We used these ESKAPE-specific biofilm assays to test our previously identified Salmonella anti-biofilm small molecule compounds, JG-1 and M4, for anti-biofilm activity. The results demonstrated that JG-1 and M4 have anti-biofilm activity against Enterobacter spp., S. aureus, E. faecium, P. aeruginosa, and A. baumannii. In addition, we identified that M4 has significant antimicrobial activity against S. aureus and E. faecium at concentrations >10 μM (X μg/mL). These findings support the claim that JG-1 and M4 have broad-spectrum anti-biofilm activity, while M4 has antimicrobial activity against the Gram-positive members of the ESKAPE pathogens. Thus, these compounds have the potential to have a significant impact on treating multiple types of commonly encountered biofilm-mediated infections

A dual-therapy approach for the treatment of biofilm-mediated Salmonella gallbladder carriage.

Asymptomatic carriage of Salmonella Typhi continues to facilitate the transmission of typhoid fever, resulting in 14 million new infections and 136,000 fatalities each year. Asymptomatic chronic carriage of S. Typhi is facilitated by the formation of biofilms on gallstones that protect the bacteria from environmental insults and immune system clearance. Here, we identified two unique small molecules capable of both inhibiting Salmonella biofilm growth and disrupting pre-formed biofilm structures without affecting bacterial viability. In a mouse model of chronic gallbladder Salmonella carriage, treatment with either compound reduced bacterial burden in the gallbladder by 1-2 logs resulting in bacterial dissemination to peripheral organs that was associated with increased mortality. Co-administration of either compound with ciprofloxacin not only enhanced compound efficacy in the gallbladder by a further 1-1.5 logs for a total of 3-4.5 log reduction, but also prevented bacterial dissemination to peripheral organs. These data suggest a dual-therapy approach targeting both biofilm and planktonic populations can be further developed as a safe and efficient treatment of biofilm-mediated chronic S. Typhi infections