BackgroundAmong the neglected tropical diseases, leishmaniasis continues to be prevalent in many tropical and subtropical countries despite international, national, and local efforts towards its control and elimination over the last decade. This warrants a critical evaluation of such factors as under-reporting, asymptomatic infections, post kala azar dermal leishmaniasis (PKDL) cases, and drug resistance. In this review, we highlight lesser-understood atypical presentations of the disease involving atypical parasite strains against a background of classical leishmaniasis with a focus on the Indian subcontinent.Methods and findingsA literature review based on endemic areas, the nature of disease manifestation, and underlying causative parasite was performed with data collected from WHO reports for each country. Searches on PubMed included the term ‘‘leishmaniasis” and “leishmaniasis epidemiology” alone and in combination with each of the endemic countries, Leishmania species, cutaneous, visceral, endemic, non-endemic, typical, classical, atypical, and unusual with no date limit and published in English up to September 2017. Our findings portray a scenario with a wider distribution of the disease in new endemic foci, with new discoveries of parasite-driven atypical disease manifestations in different regions of the world. Unlike the classical picture, some Leishmania species are associated with more than one disease presentation, e.g., the L. donovani complex, generally associated with the visceral form, is now also associated with a cutaneous disease presentation, while L. tropica species complex, known to cause cutaneous disease, can cause viscerotropic disease. This phenomenon points towards the discovery of novel parasite variants as etiologic agents of atypical disease manifestations and represents an excellent opportunity to identify and study genes that control disease virulence and tropism.ConclusionsThe increased recognition of atypical leishmaniasis as an outcome of parasite variants has major implications for leishmaniasis control and elimination. Identifying molecular correlates of parasite isolates from distinct regions associated with different disease phenotypes is required to understand the current epidemiology of leishmaniasis in regions with atypical disease.

The five-year survival rate of esophageal cancer patients is less than 20%. This may be due to increased resistance (acquired or intrinsic) of tumor cells to chemo/radiotherapies, often caused by aberrant cell cycle, deregulated apoptosis, increases in growth factor signaling pathways, and/or changes in the proteome network. In addition, deregulation in non-coding RNA-mediated signaling pathways may contribute to resistance to therapies. At the molecular level, these resistance factors have now been linked to various microRNA (miRNAs), which have recently been shown to control cell development, differentiation and neoplasia. The increased stability and dysregulated expression of miRNAs have been associated with increased resistance to various therapies in several cancers, including esophageal cancer. Therefore, miRNAs represent the next generation of molecules with tremendous potential as biomarkers and therapeutic targets. Yet, a detailed studies on miRNA-based therapeutic intervention is still in its infancy. Hence, in this review, we have summarized the current status of microRNAs in dictating the resistance/sensitivity of tumor cells against chemotherapy and radiotherapy. In addition, we have discussed various strategies to increase radiosensitivity, including targeted therapy, and the use of miRNAs as radiosensitive/radioresistance biomarkers for esophageal cancer in the clinical setting.

L eishmaniasis is a complex disease with cutaneous, mucocutaneous, or visceral manifestations depending on the parasite species and host immunity. Despite continued elimination efforts, leishmaniasis continues to afflict known and newer endemic regions, where 0.5-0.9 million new cases of visceral leishmaniasis (VL) and 0.6-1.0 million new cases of cutaneous leishmaniasis (CL) occur every year (1). An increase in VL and CL cases from newer foci and atypical disease manifestation pose a challenge to leishmaniasis control programs (2-7). Unlike the known species-specific disease phenotype, parasite variants can cause atypical disease, so that Leishmania species generally associated with VL can cause CL and vice versa. In India, VL caused by L. donovani parasites in the northeastern region and CL caused by L. tropica in the western Thar Desert represent the prevalent forms of the disease (2). Himachal Pradesh is a more recently leishmaniasis-endemic state in northwest where VL and CL coexist; CL incidence is higher than VL incidence and most cases are attributable to L. donovani instead of L. tropica infection (8,9). Sharma et al. conducted limited molecular analysis of a few CL cases and reported preliminary findings (8). For an in-depth study on the involvement of L. donovani parasites in CL cases, we conducted a comprehensive molecular analysis of CL cases in Himachal Pradesh. The Study During 2014-2018, an increase in CL cases occurred in Himachal Pradesh; case reports came from different tehsils (i.e., townships) in Kinnaur, Shimla, and Kullu and the previously nonendemic districts of Mandi and Solan (Appendix Table 1, Figure 1, https://wwwnc.cdc.gov/EID/article/26/8/19-1761-App1.pdf). We confirmed 60 CL cases indigenous to the state with detailed patient information, demonstration of the presence of Leishman-Donovan bodies and CL-specific histopathologic changes in skin lesional specimens, and PCR detection of parasitic infection (Appendix). We conducted PCR and restriction fragmentlength polymorphism (RFLP) analysis of parasite species-specific internal transcribed spacer 1 (ITS1) sequences by using appropriate standard controls. We detected the expected ≈320-bp product with a HaeIII RFLP pattern specific to L. donovani complex in all patient biopsy specimens, indicating L. donovani, L. infantum, or both as the causative agent of infection (Appendix Figure 4) (10). BLAST analysis (https://blast.ncbi.nlm.nih. gov/Blast.cgi) of 44 ITS1 test sequences showed all the samples to be closest to L. donovani, having maximum identity to L. donovani isolates from Bhutan (GenBank accession nos. JQ730001-2) and possibly L. infantum. None of the CL cases were consistent with L. tropica infection, unlike in a previous report (8). To distinguish whether HP isolates were L. donovani, L. infantum, or both and to infer genetic and geographic relatedness between

Himachal Pradesh in India is a newer endemic state with coexistence of cutaneous and visceral leishmaniasis. The cutaneous leishmaniasis cases are on an increase in the region and reported to be unusually caused by Leishmania donovani with limited molecular validation. In order to molecularly characterize the causative parasite of the cutaneous disease, parasite specific Internal-Transcribed Spacer 1 (ITS1) PCR RFLP and sequence analysis was performed on skin lesional biopsies from cutaneous leishmaniasis patients. Interestingly, we found the presence of Leptomonas seymouri in 38.5% (22/57) of the patients along with L. donovani detected in all the samples. L. seymouri is a monoxenous insect trypanosomatid, generally incapable of infecting humans. In recent years, the parasite is also reported to co-infect humans with L. donovani in visceral and post kala-azar dermal leishmaniasis (PKDL) cases prevalent in northeastern India. The finding of L. seymouri-L. donovani co-infection in unusual cutaneous cases from Himachal Pradesh is the first ever to our knowledge and imply a newer disease paradigm. There is an urgent need to understand the biology of Leptomonas co-infection with L. donovani and its possible role in visceral and/or dermotropic disease outcome. Importantly, L. seymouri co-infection in cutaneous cases and previously reported visceral and PKDL cases needs to be recognized as a newer phenomenon by the leishmaniasis surveillance program in India.

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