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The plasmodium genome project aims at the development of more effective antimalarial drugs to fight against the human malaria caused by Plasmodium falciparum, one among four specie of Plasmodium genus. Therefore, identifying the different checkpoints enzymes represents a systematic way to identify potential metabolic drug targets.

Non-neural granular cell tumor (NNGCT; also known as primitive polypoid granular cell tumor) is a rare neoplasm composed of large ovoid cells with abundant granular cytoplasm, variable nuclear pleomorphism, and the potential for regional lymph node spread. In contrast to conventional granular cell tumor (GCT), NNGCT lacks S100 expression and can exhibit greater nuclear atypia and mitotic activity. Therefore, we investigated clinicopathologic features of 12 NNGCT, and also used next-generation sequencing to identify potential driver events in a subset of NNGCT and 6 GCT. NNGCT demonstrated mild-to-moderate nuclear pleomorphism, variable mitotic activity (0 to 10/10 high-power fields), and were S100−. Genetic analysis of 5 cutaneous NNGCT revealed gene fusions involving the anaplastic lymphoma kinase gene (ALK) in 3 cases (60%). Specifically, an interstitial deletion of chromosome 2 resulting in an in-frame fusion of dyanactin 1 (DCTN1) to ALKwas identified in 2 cases, and a translocation resulting in a fusion between sequestosome 1 (SQSTM1) on chromosome 5 and ALKwas identified in one case. Two of 6 GCT (33%) showed gains of chromosome 7. No other molecular or chromosomal alterations were detected in NNGCT and GCT. ALK immunohistochemistry revealed weak-to-moderate positivity in 4/9 cutaneous NNCGT (44%) including all 3 tumors with ALKfusions. Three oral NNGCT lacked ALK expression. NNGCT with ALK immunostaining did not have morphologic features distinguishing them from those without ALK staining. Our results demonstrate that a subset of NNGCT harbor ALKfusions, suggest that NNGCT are molecularly diverse, and further substantiate NNGCT as distinct from GCT.

Adenomatoid tumors are the most common neoplasm of the epididymis, and histologically similar adenomatoid tumors also commonly arise in the uterus and fallopian tube. To investigate the molecular pathogenesis of these tumors, we performed genomic profiling on a cohort of 31 adenomatoid tumors of the male and female genital tracts. We identified that all tumors harbored somatic missense mutations in the TRAF7gene, which encodes an E3 ubiquitin ligase belonging to the family of tumor necrosis factor receptor-associated factors (TRAFs). These mutations all clustered into one of five recurrent hotspots within the WD40 repeat domains at the C-terminus of the protein. Functional studies in vitrorevealed that expression of mutant but not wild-type TRAF7led to increased phosphorylation of nuclear factor-kappa B (NF-kB) and increased expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation. Immunohistochemistry demonstrated robust L1CAM expression in adenomatoid tumors that was absent in normal mesothelial cells, malignant peritoneal mesotheliomas and multilocular peritoneal inclusion cysts. Together, these studies demonstrate that adenomatoid tumors of the male and female genital tract are genetically defined by TRAF7mutation that drives aberrant NF-kB pathway activation.

We report a series of 58 melanocytic tumors that harbor an activating fusion of BRAF, a component of the MAP kinase signaling cascade. Cases were diagnosed as melanocytic nevus (n=12, 21%), diagnostically ambiguous favor benign (n=22, 38%), diagnostically ambiguous concerning for melanoma (n=12, 21%) or melanoma (n=12, 21%). Three main histopathological patterns were observed. The first pattern (“buckshot fibrosis”) was characterized by large, epithelioid melanocytes arrayed as single cells or “buckshot” within marked stromal desmoplasia. The second pattern (“cords in whorled fibrosis”) demonstrated polypoid growth with a whorled arrangement of cords and single melanocytes within desmoplasia. The third pattern (“spindle-cell fascicles”), showed fascicular growth of spindled melanocytes. Cytomorphologic features characteristic of Spitz nevi were observed in most cases (n=50, 86%). Most cases (n=54, or 93%) showed stromal desmoplasia. Histomorphology alone was not sufficient in distinguishing benign from malignant BRAF-fused melanocytic tumors since the only histopathologic features more commonly associated with a diagnosis of malignancy included dermal mitoses (p=0.046) and transepidermal elimination of melanocytes (p=0.013). BRAFfusion kinases are targetable by kinase inhibitors and thus should be considered as relevant genetic alterations in the molecular work-up of melanomas. Recognizing the three main histopathologic patterns of BRAF-fused melanocytic tumors will aid in directing ancillary testing.

Desmoplastic melanoma is a subtype of melanoma characterised by amelanotic fusiform melanocytes dispersed in a collagenous stroma. Cell-poor and fibrous stroma-rich ‘pure’ variants have been distinguished from ‘mixed’ variants with areas of higher cell density and/or less desmoplastic stroma. This distinction is relevant because patients whose tumours display a pure phenotype have a lower risk for regional lymph node metastasis and distant recurrence. However, little is known about interobserver agreement among pathologists in the subclassification of desmoplastic melanoma. To address this issue, we conducted a study in which eleven dermatopathologists independently evaluated whole slide scanned images of excisions from 30 desmoplastic melanomas. The participating pathologists were asked to classify the tumours as pure or mixed. They were also asked to record the presence or absence of neurotropism and angiotropism. We found substantial interobserver agreement between the 11 dermatopathologists in the classification of tumours as pure versus mixed desmoplastic melanoma (kappa=0.64; p<0.0001). There was fair agreement between the 11 dermatopathologists in the evaluation of presence versus absence of neurotropism (kappa=0.26; p<0.0001), and slight agreement in the assessment of angiotropism (kappa=0.13; p<0.0001). The level of concordance in the subclassification of desmoplastic melanomas is encouraging for the acceptance of this prognostic parameter in the real-world practice of melanoma pathology.

KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron–activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.