Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re-induction chemotherapy

Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials were used to test the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients. The bone marrow samples were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts. We found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies.     

Obstetric fistula in Niger: 6-month postoperative follow-up of 384 patients from the Danja Fistula Center

Introduction and hypothesis

The impoverished West African country of Niger has high rates of obstetric fistula. We report a 6-month postoperative follow-up of 384 patients from the Danja Fistula Center and assess factors associated with operative success or failure.

Methods

The medical records of 384 women who had completed a 6-month follow-up after fistula surgery were reviewed. Cases were categorized as “easy,” “of intermediate complexity,” or “difficult” based on a preoperative points system. Data were analyzed using simple chi-squared statistics and logistic regression.

Results

The patients were predominantly of Hausa ethnicity (73%), married young (average 15.9 years), had teenage first pregnancies (average first delivery 16.9 years), and experienced prolonged labor (average 2.3 days) with poor outcomes (89% stillbirth rate). The average parity was four. Patients commonly developed their fistula during their first delivery (43.5%), but over half sustained a fistula during a subsequent delivery (56.5%). Prior fistula surgery elsewhere (average 1.75 operations) was common. The overall surgical success (“closed and dry”) was 54%. When the 134 primary operations were analyzed separately, the overall success rate was 80%. Increasing success was seen with decreasing surgical difficulty: 92% success for “easy” cases, 68% for “intermediate” cases, and 57% success for “difficult” cases. Success decreased with increasing numbers of previous attempts at surgical repair.

Conclusions

These data provide further evidence that clinical outcomes are better when primary fistula repair is performed by expert surgeons in specialist centers with the support of trained fistula nurses.

     

Purkinje cell survival in organotypic cultures: implication of Rho and its downstream effector ROCK

Organotypic cultures of postnatal day 1 (P1) to P7 mouse cerebella are well-established models for studying cell survival. In the present work, we investigate the involvement of the Rho/ROCK intracellular pathway in Purkinje cell survival by using organotypic cultures of P3 Swiss mice. Specific inhibitors of Rho or ROCK were applied at different concentrations to the slice cultures, which were maintained for 5 days in vitro. We show that the bacterial exoenzyme C3 transferase, a specific inhibitor of the small GTPase Rho, increases Purkinje cell survival. There is a 4.5- and 2.5-fold increase in Purkinje cell survival when C3 intracellular uptake is promoted either by the PEP-1 peptide or by the C2IN carrier protein, respectively, and not with the commonly used TAT peptide. Moreover, treatment with Y27632 and H-1152, two specific inhibitors of the Rho kinase ROCK, also strongly reduces apoptotic cell death and results in 6.5- and 8.5-fold increases in cell survival, respectively. In immunohistochemical analysis, we also show that H-1152 did not change either glial fibrillary acidic protein or isolectin-B4 staining, indicating that this compound did not alter the cellular composition in our cultures. Thus, our data demonstrate that inhibition of Rho and its downstream effector ROCK may be used to enhance cell survival in neurodegenerative diseases.     

Factors contributing to motivation of volunteer community health workers in Ethiopia: the case of four woredas (districts) in Oromia and Tigray regions

Background

The use of community health workers (CHWs) has been considered as one of the strategies to address the growing shortage of health workers, predominantly in low-income countries. They are playing a pivotal role in lessening health disparities through improving health outcomes for underserved populations. Yet, little is known about what factors motivate and drive them to continue working as CHWs. In this study, we aimed to examine factors contributing to the motivation of volunteer CHWs (vCHWs) in Ethiopia currently known as one-to-five network leaders (1to5NLs) and explore variations between attributes of social and work-related determinants.

Method

We conducted a cross-sectional study in four selected woredas (the second lowest administrative structure in Ethiopia, and similar to a district) of Oromia and Tigray regions and interviewed 786 1to5NLs. The effects of each motivational factor were explored using percentage of respondents who agreed and strongly agreed to each of them and Mann-Whitney U test.

Results

Individual, community, and health system factors contributed to the motivation of 1to5NLs in this study. Intrinsic desire to have a good status in the community as a result of their volunteer service (81.86%) followed by a commitment to serve the community (81.61%) and to gain satisfaction by accomplishing something worthwhile to the community (81.61%) were some of the factors motivating 1to5NLs in our study. Despite these motivational items, factors such as lack of career development (51.47%), unclear health development army guideline (59.26%), limited supervision and support (62.32%), and lack of recognition and appreciation of accomplishments (63.22%) were the factors negatively affecting motivation of 1to5NLs. Lack of career development, limited supervision and support, and lack of recognition and appreciation of accomplishments were significantly varied between attributes of educational level, marital status, service year as 1to5NLs, and previous volunteer engagement (at P?< 0.05).

Conclusion

Findings of our study indicated that non-financial incentives such as the creation of career development models is the key to motivating and retaining CHWs where they are not receiving stipends. Sustainability of CHW program should consider exploring enhanced innovations to strengthen supportive supervision, development of better mechanisms to publicize the role of CHWs, and improvement of recognition and appreciation schemes for CHWs’ efforts and accomplishments.