Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria.

Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children1, yet the promise of an effective vaccine has not been fulfilled. Here, using our previously described differential screening method to analyse the proteome of blood-stage P. falciparum parasites2, we identify P. falciparum glutamic-acid-rich protein (PfGARP) as a parasite antigen that is recognized by antibodies in the plasma of children who are relatively resistant-but not those who are susceptible-to malaria caused by P. falciparum. PfGARP is a parasite antigen of 80 kDa that is expressed on the exofacial surface of erythrocytes infected by early-to-late-trophozoite-stage parasites. We demonstrate that antibodies against PfGARP kill trophozoite-infected erythrocytes in culture by inducing programmed cell death in the parasites, and that vaccinating non-human primates with PfGARP partially protects against a challenge with P. falciparum. Furthermore, our longitudinal cohort studies showed that, compared to individuals who had naturally occurring anti-PfGARP antibodies, Tanzanian children without anti-PfGARP antibodies had a 2.5-fold-higher risk of severe malaria and Kenyan adolescents and adults without these antibodies had a twofold-higher parasite density. By killing trophozoite-infected erythrocytes, PfGARP could synergize with other vaccines that target parasite invasion of hepatocytes or the invasion of and egress from erythrocytes.

Immunization with PfGBP130 generates antibodies that inhibit RBC invasion by P. falciparum parasites.

Background: Despite decades of effort, Plasmodium falciparum malaria remains a leading killer of children. The absence of a highly effective vaccine and the emergence of parasites resistant to both diagnosis as well as treatment hamper effective public health interventions. Methods and results: To discover new vaccine candidates, we used our whole proteome differential screening method and identified PfGBP130 as a parasite protein uniquely recognized by antibodies from children who had developed resistance to P. falciparum infection but not from those who remained susceptible. We formulated PfGBP130 as lipid encapsulated mRNA, DNA plasmid, and recombinant protein-based immunogens and evaluated the efficacy of murine polyclonal anti-PfGBP130 antisera to inhibit parasite growth in vitro. Immunization of mice with PfGBP130-A (aa 111-374), the region identified in our differential screen, formulated as a DNA plasmid or lipid encapsulated mRNA, but not as a recombinant protein, induced antibodies that inhibited RBC invasion in vitro. mRNA encoding the full ectodomain of PfGBP130 (aa 89-824) also generated parasite growth-inhibitory antibodies. Conclusion: We are currently advancing PfGBP130-A formulated as a lipid-encapsulated mRNA for efficacy evaluation in non-human primates.

Rare Pleomorphic Liposarcoma Presented as Jejunal Obstruction.

Pleomorphic liposarcoma (PLS) is typically found in the lower and upper extremities. PLS arising in the gastrointestinal (GI) tract is extremely rare. Here, we reported a case of a 71-year-old female with a history of rectal adenocarcinoma presenting with small bowel obstruction. Small bowel resection was performed and revealed a 7.8 cm transmural mass in the jejunum. Histology reviewed a heterogenous epithelioid malignant tumor with intracytoplasmic fatty droplets scalloping the nucleus consistent with lipoblasts in some cells and others with numerous PAS/diastase+intracytoplasmic eosinophilic globules. Scattered multinucleated giant cells were also present. Mitotic count was up to 80/10 HPFs including some bizarre mitotic figures, and Ki67 proliferation index was approximately 60%. Immunohistochemistry demonstrated that the malignant cells were negative for pancytokeratin, CD117, DOG1, SMA, desmin, MyoD1, ERG1, CD34, CD31, SOX10, Melan A, and S100. INI1 was retained. Beta-catenin showed normal membranous staining. P53 was diffusely positive suggestive of mutant phenotype. Fluorescence in situ hybridization (FISH) assay was negative for MDM2 amplification and DDIT3 rearrangement. The overall morphologic and immunohistochemical features supported a diagnosis of high-grade pleomorphic liposarcoma. Diagnosis of PLS can be challenging due to its rarity in GI tract and lack of specific biomarkers, and histomorphology with identification of lipoblasts remains the gold standard.