A Lab-On-chip Tool for Rapid, Quantitative, and Stage-selective Diagnosis of Malaria

Malaria remains the most important mosquito-borne infectious disease worldwide, with 229 million new cases and 409.000 deaths in 2019. The infection is caused by a protozoan parasite which attacks red blood cells by feeding on hemoglobin and transforming it into hemozoin. Despite the WHO recommendation of prompt malaria diagnosis, the quality of microscopy-based diagnosis is frequently inadequate while rapid diagnostic tests based on antigens are not quantitative and still affected by non-negligible false negative/positive results. PCR-based methods are highly performant but still not widely used in endemic areas. Here, a diagnostic tool (TMek), based on the paramagnetic properties of hemozoin nanocrystals in infected red blood cells (i-RBCs), is reported on. Exploiting the competition between gravity and magnetic forces, i-RBCs in a whole blood specimen are sorted and electrically detected in a microchip. The amplitude and time evolution of the electrical signal allow for the quantification of i-RBCs (in the range 10–105 i-RBC µL−1) and the distinction of the infection stage. A preliminary validation study on 75 patients with clinical suspect of malaria shows on-field operability, without false negative and a few false positive results. These findings indicate the potential of TMek as a quantitative, stage-selective, rapid test for malaria

Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor

<p>Abstract</p> <p>Background</p> <p>Traumatic brain injury (TBI) induces activation of microglia. Activated microglia can in turn increase secondary injury and impair recovery. This innate immune response requires hours to days to become fully manifest, thus providing a clinically relevant window of opportunity for therapeutic intervention. Microglial activation is regulated in part by poly(ADP-ribose) polymerase-1 (PARP-1). Inhibition of PARP-1 activity suppresses NF-kB-dependent gene transcription and thereby blocks several aspects of microglial activation. Here we evaluated the efficacy of a PARP inhibitor, INO-1001, in suppressing microglial activation after cortical impact in the rat.</p> <p>Methods</p> <p>Rats were subjected to controlled cortical impact and subsequently treated with 10 mg/kg of INO-1001 (or vehicle alone) beginning 20 - 24 hours after the TBI. Brains were harvested at several time points for histological evaluation of inflammation and neuronal survival, using markers for microglial activation (morphology and CD11b expression), astrocyte activation (GFAP), and neuronal survival (NeuN). Rats were also evaluated at 8 weeks after TBI using measures of forelimb dexterity: the sticky tape test, cylinder test, and vermicelli test.</p> <p>Results</p> <p>Peak microglial and astrocyte activation was observed 5 to 7 days after this injury. INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus. No rebound inflammation was observed in rats that were treated with INO-1001 or vehicle for 12 days followed by 4 days without drug. The reduced inflammation was associated with increased neuronal survival in the peri-lesion cortex and improved performance on tests of forelimb dexterity conducted 8 weeks after TBI.</p> <p>Conclusions</p> <p>Treatment with a PARP inhibitor for 12 days after TBI, with the first dose given as long as 20 hours after injury, can reduce inflammation and improve histological and functional outcomes.</p

Overcoming barriers to tumor genomic profiling through direct-to-patient outreach

Purpose: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. Experimental design: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype. Results: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6-40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. Conclusions: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment. See related commentary by Desai and Subbiah, p. 2339Y.L. has received research funding from AstraZeneca, GSK, and REPARE Therapeutics unrelated to this work. C.A. has received consulting fees from Eisai, Merk, Roche/Genentech, Abbvie, AstraZeneca and Repare Therapeutics and clinical trial funding from AstraZeneca. M.Y. has served as a consultant for Janssen Research and Development. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, and Janssen, Loxo Oncology/Lilly and is on the Scientific Advisory Board of Envisagenics Inc and Harmonic Discovery Inc.; O.A.-W. has received prior research funding from H3B Biomedicine, Loxo Oncology/Lilly, and Nurix Therapeutics unrelated to the current manuscript. M.B. has served as a consultant for Eli Lilly, PetDx and received research funding from Grail. J.G.B has served as a consultant for Jazz Pharmaceuticals, was an uncompensated consultant on a DSMB for Springworks, Merck and Pfizer and served on pediatric advisory boards for BMS and Eisai. She receives institutional research support (but no salary support) for clinical trials from Roche, Merck, Amgen, Lilly, BMS, Eisai, Novartis, Loxo-oncology, Cellectar and Bayer. S.A.F. has received research support from AstraZeneca, Genentech/Roche, and Decibel Therapeutics is a consultant/advisory board member for Merck and BioNTech, and owns stock in Urogen, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, ByHeart, 76Bio, Vida Ventures, Inconovir, and Doximity. A.D. served as a consultant for Incyte, EUSA Pharma, Loxo Oncology and receives research support from Roche and Takeda. R.A.S. was paid annually for serving as assistant editor for one of the USCAP society journals. H.A-A. has served as a consultant for AstraZeneca and Paige.AI. D.R.F. has received research funding from Telix Pharmaceuticals, Decibel Therapeutics, Astellas, Royalties from Up-to-Date, and has served as a consultant for BioNTech. E.M.V. has served as an advisor/Consultant to Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics, Serinus Bio, has received research support from Novartis, BMS, Sanofi, and has equity interests in Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, Serinus Bio. E.L.D. discloses unpaid editorial support from Pfizer, Inc, and paid advisory board membership with Day One Biopharmaceuticals and Springworks Therapeutics. D.B.S. has served as a consultant for/received honorarium from Pfizer, Loxo Oncology/Lilly, Vividion Therapeutics, Scorpion Therapeutics, FORE Therapeutics, Fog Pharma, Elsie Biotechnologies, and BridgeBio. The remaining authors declare no potential conflicts of interest