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.     

Pre-transplant co-infusion of donor-adipose tissue derived mesenchymal stem cells and hematopoietic stem cells may help in achieving tolerance in living donor renal transplantation

Transplantation tolerance is still a Utopian dream for many transplanters. Mesenchymal stem cells (MSC) have shown immuno-modulatory and tolerogenic effects in experimental models. We present a 29-year-old male with end stage renal disease (ESRD) who was transplanted with HLA 4/6 matched kidney from 51-year-old father in June 2010 preceded by co-infusion of donor-adipose tissue derived mesenchymal stem cells (AD-MSC) and bone marrow derived hematopoietic stem cells (BM-HSC) under non-myeloablative conditioning for deleting rejecting T and B-cells. He has maintained fairly stable graft function with serum creatinine (SCr) between 1.5 and 1.8?mg/dL at 3 years post-transplant with absence of donor specific antibodies (DSA), normal protocol graft biopsy, and peripheral T-regulatory cell levels (pTregs) (CD127^low/?CD25^highCD4⁺) of 4.57% on zero immunosuppression since 6 months.     

Single-stage earlobe reconstruction: a simple method with promising results

Various methods have been described in the literature for earlobe reconstruction in one or many stages. Authors describe here a simple, single-stage technique to reconstruct the loss of the earlobe. The technique is clearly illustrated in a step-by-step manner and produces a natural-looking earlobe without an unpleasant secondary deformity with desirable texture and color match. Level of Evidence: Level IV, therapeutic study.     

World Witnesses a Tumultuous Year while India Reports an Eventful Decade in the Long Story of Polio Eradication

With recent outbreaks in Syria and Horn of Africa, silent circulation of wild poliovirus type 1 (WPV1) in Israel, West Bank, and Gaza, and fresh spate of violence against vaccinators and their security personnel in Pakistan, the world is facing a turbulent final ascent to the summit of polio eradication. On the positive side, we may also be witnessing the end of wild poliovirus type 3 (WPV3) and defused programmatic crisis caused by funding gaps, while India registers third consecutive polio-free year. Having a cogent endgame plan 2013-2018, informed by some cardinal lessons learned from an eventful decade in India, is also a very significant development. Now, there is a parallel pursuit against WPV and vaccine-derived poliovirus (VDPV). Endgame would also involve integration of at least one dose of affordable inactivated polio vaccine (IPV) to up-scaled routine immunization (RI), switch from trivalent oral polio vaccine (tOPV) to bivalent oral polio vaccine (bOPV) in 144 countries before 2018, stockpiling of mOPV, and simultaneous global cessation of bOPV before 2020. Role of antivirals in post-eradication era is still unclear. Some specific threats emerging at this stage are as follows: Global buildup of new birth cohorts in non-endemic countries with weak RI and downscaled supplementary immunization activities (SIAs), tremendous pressure on peripheral health workers, and fatigued systems. Cultural resistance to transnational programs is taking a violent shape in some areas. Differential interpretations of ‘right to say no’, on both sides of the divide, are damaging a global cause. Amidst all these concerns, let us not forget to underline the sacrifice made by frontline vaccinators working in some of the most challenging circumstances.     

DiceCT Analysis of the Extreme Gouging Adaptations Within the Masticatory Apparatus of the Aye-Aye (Daubentonia madagascariensis)

Relative to all other primates, the aye-aye (Daubentonia madagascariensis) exists at the extremes of both morphology and behavior. Its specialized anatomy—which includes hypselodont incisors and highly derived manual digits—reflects a dietary niche, unique among primates, which combines tap-foraging with gouging to locate and extract wood-boring larvae. Here, we explore the impact of this extreme dietary ecology upon the masticatory musculature of this taxon with reference to a second, similarly sized but highly generalist lemuriform—the mongoose lemur (Eulemur mongoz). Using non-destructive, high-resolution diffusible iodine-based contrast-enhanced computed tomography techniques, we reconstruct the three-dimensional volumes of eight masticatory muscles, and, for the first time in strepsirrhines, isolate and visualize their constituent muscle fascicles in situ and in three dimensions. Using these data, we report muscle volumes, forces, and fascicle lengths from each muscle portion, as well as their orientation relative to two standardized anatomical planes. Our findings demonstrate the overbuilt nature of the aye-aye's masticatory apparatus, in which each muscle possesses an absolutely and relatively larger muscle volume and PCSA than its counterpart in the mongoose lemur. Likewise, for several adductor muscles, aye-ayes also possess relatively greater fascicle lengths. Finally, we note several unusual features within the lateral pterygoid of the aye-aye—the muscle most responsible for jaw protrusion—that relate to force maximization and reorientation. As this jaw motion is critical to gouging, we interpret these differences to reflect highly specific specializations that facilitate the aye-aye's extreme subsistence strategy. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:282–294, 2020. © 2019 American Association for Anatomy     

Study on influence of age,gender and genetic variants on lactose intolerance and its impact on milk intake in adult Asian Indians

Background: Lactase non-persistence (LNP) has been associated with the CC genotype of ?13910C?>?T and GG genotype of ?22018G?>?A polymorphisms present upstream of the lactase gene. Lactose intolerance (LI) is caused when gastrointestinal symptoms develop in individuals with low lactase activity.

Objective: To analyse association of LNP genotype and LI symptoms with milk intake and determine whether factors such as age, gender and genotype affect LI status.

Subjects and methods: Genetic analysis and lactose tolerance test (LTT) were performed on 205 healthy Indian adults. The pattern of milk consumption was recorded using a dietary questionnaire.

Results: LI was strongly associated with ?13910CC genotype (OR?=?10.28, 95% CI?=?2.32–45.55, p?=?0.002). Females were found to be at a higher risk of developing LI (OR?=?2.47, 95% CI?=?1.33–4.59, p?=?0.004). The association of the ≥50 years age group with LI was marginally significant (OR?=?1.86, 95% CI?=?0.995–3.47, p?=?0.05). Frequency and quantity of milk intake were lower in subjects belonging to the LNP genotype and LI groups (p?Conclusions: Subject study suggests that gender and genotype may be associated with development of LI. Association of age with LI was marginal. The data also indicate that LNP genotype and LI may play a role in influencing milk intake in individuals.     

Synthesis of high surface area porous carbon from anaerobic digestate and it's electrochemical study as an electrode material for ultracapacitors

The remnants of the anaerobic digestion process, ‘the digestate,’ mainly consist of fibrous lignin and cellulose like molecules, as a significant carbon repository along with some other inorganic impurities. The present work demonstrates the potential use of anaerobically treated fruit and vegetable waste (FVW) as a source of porous carbon for supercapacitor electrode materials. This work suggests that the FVW digestate can inherit silicon (Si) and calcium (Ca) based inorganic impurities, which play an essential role as structure directing agents for digestate derived carbon. These contaminants act as hard templates during carbonization to create hierarchical pores and contribute to an enhancement in surface area. Different batches from an anaerobic biogas digester plant are converted to porous carbon and examined as a potential supercapacitor electrode material. A maximum capacitance of 235 F g⁻¹ is achieved from DDHPC-4kh carbon with a specific surface area of 2502 m² g⁻¹ at a current density of 1 A g⁻¹ in an acidic aqueous electrolyte. The results are significant in comparison to other bio-sourced precursors studied previously.

The remnants of the anaerobic digestion process, ‘the digestate,’ mainly consist of fibrous lignin and cellulose like molecules, as a significant carbon repository along with some other inorganic impurities.