Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure activity relationship and the selectivity mechanism.

Depression in Women With Inflammatory Bowel Disease: A Multifaceted Approach for a Multidimensional Problem.

The prevalence of depression is higher in patients with inflammatory bowel disease (IBD) than in the general population. Women are more significantly affected by depression among those with IBD and in the general population. This review presents evidence on sex-based differences in depression pathogenesis and the effect of depression on various factors associated with IBD that affect women's lives, including sexual dysfunction, body image dissatisfaction, fertility, and overall quality of life. We also discuss sex-specific effects on IBD treatment, disease activity, and health care costs. Interestingly, women with IBD tend to seek and are more receptive to depression-related information. Given the underdiagnosis and undertreated nature of depression in individuals with IBD, effective screening and an optimal integrative treatment approach with relevant sex-specific needs are discussed. Evidence regarding the efficacy of psychotherapy, antidepressant pharmacotherapy, and IBD-specific therapy for depression is discussed. This review summarizes evidence of the effect of depression on both personal and professional aspects of the daily lives of women with IBD, which extends beyond negative moods. It applies this information to screening and integrative treatment, resulting in a holistic approach to this multidimensional problem. We also discuss how depression affects males with IBD differently from females. Finally, we discuss the need for gender-based studies on depression in individuals with IBD.

Depression, an important comorbidity of IBD, occurs more frequently in females and impairs quality of life. Depression screening in IBD patients is crucial, as it is widely underdiagnosed. A multifaceted treatment approach, accounting for sex- and gender-based differences, is optimal.

RASGRF1-rearranged Cutaneous Melanocytic Neoplasms With Spitzoid Cytomorphology: A Clinicopathologic and Genetic Study of 3 Cases.

Spitz neoplasms, according to 2018 WHO Blue Book, are morphologically defined by spindled and/or epithelioid melanocytes and genetically by either HRAS mutations or kinase gene fusions. The terminology "spitzoid" refers to lesions with similar morphology but with alternate or undefined genetic anomalies. Herein, we present 3 melanocytic neoplasms with a spitzoid cytomorphology, variable nuclear atypia, and harboring undescribed fusions involving RASGRF1. Two cases presented as unpigmented papules on the heel of a 26-year-old female (case 1) and the forearm of a 13-year-old boy (case 2). They were classified as low-grade melanocytomas (WHO 2018). The third case appeared as a pigmented ulcer on the sole of a 72-year-old female (case 3) that displayed diagnostic features of an invasive melanoma (Breslow thickness 6 mm, Clark level V). A wide skin reexcision identified an epidermotropic metastasis, and sentinel lymph node biopsy displayed multiple subcapsular metastatic deposits. RNA sequencing revealed CD63::RASGRF1, EHBP1::RASGRF1, and ABCC2::RASGRF1 fusions in cases 1 to 3, respectively. They were confirmed by a RASGRF1 break-apart fluorescence in situ hybridization technique. Translocations of RASGRF1, a gene coding a guanine nucleotide exchange factor but not a kinase, have rarely been reported in tumors. While all these cases showed spitzoid cytomorphology, it is too early to tell if they are true Spitz neoplasms as currently defined.

"HTLV-I Infection" Twenty-Year Research in Neurology Department of Mashhad University of Medical Sciences.

Human T-cell lymphotropic virus (HTLV) types 1 and 2 belong to the Oncorna group of retroviridae, a large family of viruses, grouped initially by pathogenic features, but later revised on the basis of genome structure and nucleotide sequence. HTLV-I was the first discovered human retrovirus to be associated with a malignancy in 1980. The malignancy, first described by Uchiyama and co-workers in southwestern Japan, was named Adult T-cell Leukemia/Lymphoma (ATL) and characterized with cutaneous and respiratory involvement, hepatosplenomegaly, lymphadenopathy and various metabolic abnormalities such as hypercalcemia. The HTLV-I has been known to be endemic to certain parts of Iran like the province of Khorasan in the northeast since 1990, with a 2.3% prevalence rate of infection. The main manifestations of HTLV-I infection are neurologic and hematologic (such as ATL) disorders, but it has also other manifestations such as uveitis, arthritis, dermatitis, vitiligo and lymphocytic alveolitis. Its main neurologic manifestation is a chronic progressive myelopathy that is referred to HTLV-I Associated Myelopathy (HAM) in Japan and Tropical Spastic Paraparesis (TSP) in Caribbean. But other disorders such as peripheral neuropathy, polyradiculoneuropathy, myopathy, peripheral facial paresis, and so on have been reported too. In this review we wish to give some brief information on the different aspects (including epidemiology, pathogenesis and pathology, clinical findings, and treatment) of HTLV-I infection according to our twenty-year researches. The department of neurology of Mashhad University of Medical Sciences has been a pioneer in researches on HTLV-I in the last twenty years.

Efficacy of Mohs micrographic surgery for the treatment of dermatofibrosarcoma protuberans: systematic review.

OBJECTIVE To summarize evidence about the recurrence of dermatofibrosarcoma protuberans (DFSP) following Mohs micrographic surgery (MMS). DATA SOURCES MEDLINE, Cochrane Library, EMBASE, Pascal, Biosis, CisMef, BDSP, Scopus, and Web of Knowledge databases were searched for the period January 1, 1995, to August 31, 2011. Search terms were Mohs micrographic surgery, dermatofibrosarcoma protuberans, and their synonyms. No language restriction was used. STUDY SELECTION Two of us selected randomized controlled trials or nonrandomized trials comparing the recurrence of DFSP among patients undergoing MMS vs wide local excision. The search retrieved 384 references, of which 31 were reviewed in detail. DATA EXTRACTION Twenty-three nonrandomized trials (4 comparative and 19 noncomparative) were included, from which data were extracted by 2 of us independently. The methodological quality was assessed using the Cochrane Handbook for Systematic Reviews of Interventions. DATA SYNTHESIS Moderate-quality evidence (level B) was found for recurrence of DFSP after MMS (1.11%; 95% CI, 0.02%-6.03%) vs after wide local excision (6.32%, 95% CI, 3.19%-11.02%). A mean raw recurrence rate of 1.03% (95% CI, 0.37%-2.22%) was found after MMS among 19 nonrandomized noncomparative trials (low-quality evidence [level C]). The mean follow-up periods ranged from 26 to 127 months. The mean time to recurrence was 68 months. CONCLUSIONS A weak recommendation is given in favor of MMS or similar surgical techniques with meticulous histologic evaluation of all margins as the first-line therapy for DFSP, particularly in recurrence-prone regions. Attention should be given to longer than a 5-year follow-up period. High-quality trials with sufficient follow-up periods should be encouraged.