Serotype-specific clinical features and spatial distribution of dengue in northern Kerala, India.

Background: Collection and compilation of spatial, meteorological, entomological, and virological data are critical in mitigating climate-sensitive emerging infections like dengue. This study was a holistic attempt to understand the dengue situation in the Kasaragod district of Kerala, India. Methods: This cross-sectional study was conducted in 13 health institutions from June to July 2021. Adult patients presenting with fever and testing positive for NS1 ELISA were subjected to Dengue RT-PCR and serotyping. The spatial and clinical features of the RT-PCR-positive patients, the district's meteorological data, and the vector indices were studied. Results: The pre-epidemic months were marked by intermittent rainfall, peak ambient temperature and high larval indices. Among the 136 dengue RT-PCR patients studied, 41.2% had DENV2 followed by DENV1 (22.8%), DENV3 (5.9%) and DENV4 (4.4%); with 25% mixed infections. DENV1 showed a higher risk of gastrointestinal manifestations (80.6%, p=0.019) and musculoskeletal symptoms (77.4%, p=0.026) compared with other serotypes. Conclusions: In the context of dengue hyperendemicity, the possibility of an emerging serotype's dominance coupled with the mixing up of strains should warn the health system regarding future outbreaks. Furthermore, the study emphasizes the importance of monitoring larval indices and the window of opportunity to intervene between environmental predictors and dengue outbreaks.

Sensitization of cancer cells towards Cisplatin and Carboplatin by protein kinase D inhibitors through modulation of ATP7A/B (copper transport ATPases).

Drug resistance of cancer cells is a significant impediment to effective chemotherapy. One primary reason for this is copper exporters - ATPase copper transporting alpha (ATP7A) and ATPase copper transporting beta (ATP7B). These molecular pumps belong to P-type ATPases and dispose off the Platinum (Pt) based anticancer drugs from cancer cells, causing resistance in them. For the disposal of Pt-drugs, copper exporters require phosphorylation mediated by protein kinase D (PKD) for their activation and trafficking. Even though various research works are underway to overcome resistance to anticancer drugs, the role of PKD is mainly ignored. In this study, we have found a significant upregulation of ATP7A and ATP7B in cervical cancer cells (HeLa) and Liver Hepatocellular Carcinoma cells (HepG2) in the presence of Cisplatin or Carboplatin; both at transcriptional as well as translational levels. Interestingly, the expression of ATP7A and ATP7B were significantly downregulated in the presence of a PKD inhibitor (CID2011756), resulting in the reduction of PKD mediated phosphorylation of ATP7A/7B. This causes enhancement of proteasome-mediated degradation of ATP7A/7B and thereby sensitizes the cells towards Cisplatin and Carboplatin. Similarly, the treatment of Cisplatin resistant HepG2 cells with PKD inhibitor causes enhanced sensitivity towards Cisplatin drug. However, the presence of proteasome inhibitor (MG132) reversed the effect of the PKD inhibitor on the expression level of ATP7A/7B, indicating the necessity of phosphorylation for its stability. Hence, we conclude that the combinatorial usage of Cisplatin with drugs targeting PKD can be developed as an effective chemotherapeutic approach to overcome drug resistance.