From molecular insight to therapeutic strategy: The holistic approach for treating triple negative breast cancer.

Aim of the present study was to analyze the molecular pathogenesis of TNBC, therapeutic practice, challenges, and future goals in treatment strategies. Based on the alterations of distinct pathways, Lehmann's subgroups of TNBCs were further categorized. Those with defective DNA damage repair and replication pathways, viz. Basal Like 1 & 2 (BL1, BL2) were found susceptible to DNA intercalating drugs while those with upregulated cell signalling & motility (mesenchymal (M), mesemchymal stem like (MSL)), cell survival (BL2, M, MSL), angiogenesis (BL2, MSL), T cell signalling (Immunomodulatory/IM) pathways required targeted therapies. Our Meta-analysis categorized 12 randomized previous trial cases, solely under the following drug regimens: [1] DNA destabilizers, [2] PARP inhibitors, [3] Microtubule stabilizers, [4] Angiogenesis inhibitors, [5] Antimetabolite, [6] T cell targeted therapy; as single or combinational therapy. Best therapeutic efficacies of DNA destabilizers with angiogenesis inhibitors in combination than monotherapy with either (OR: 5.011-7.286; p value<0.001) indicated a significant prevalence of BL1 type TNBCs in populations. Statistical significance with antimetabolites as combination therapy (OR: 2.343; p value: 0.018) and not with microtubule stabilizer (OR: 0.377) were observed. Thus, for best ORR in TNBC, personalized medicine should be the therapeutic choice for the clinicians.

Differential modulation of intracellular survival of cytosolic and vacuolar pathogens by curcumin.

Curcumin, a principal component of turmeric, acts as an immunomodulator regulating the host defenses in response to a diseased condition. The role of curcumin in controlling certain infectious diseases is highly controversial. It is known to alleviate symptoms of Helicobacter pylori infection and exacerbate that of Leishmania infection. We have evaluated the role of curcumin in modulating the fate of various intracellular bacterial pathogens. We show that pretreatment of macrophages with curcumin attenuates the infections caused by Shigella flexneri (clinical isolates) and Listeria monocytogenes and aggravates those caused by Salmonella enterica serovar Typhi CT18 (a clinical isolate), Salmonella enterica serovar Typhimurium, Staphylococcus aureus, and Yersinia enterocolitica. Thus, the antimicrobial nature of curcumin is not a general phenomenon. It modulated the intracellular survival of cytosolic (S. flexneri and L. monocytogenes) and vacuolar (Salmonella spp., Y. enterocolitica, and S. aureus) bacteria in distinct ways. Through colocalization experiments, we demonstrated that curcumin prevented the active phagosomal escape of cytosolic pathogens and enhanced the active inhibition of lysosomal fusion by vacuolar pathogens. A chloroquine resistance assay confirmed that curcumin retarded the escape of the cytosolic pathogens, thus reducing their inter- and intracellular spread. We have demonstrated that the membrane-stabilizing activity of curcumin is crucial for its differential effect on the virulence of the bacteria.

Acidic pH induced STM1485 gene is essential for intracellular replication of Salmonella.

During the course of infection, Salmonella has to face several potentially lethal environmental conditions, one such being acidic pH. The ability to sense and respond to the acidic pH is crucial for the survival and replication of Salmonella. The physiological role of one gene (STM1485) involved in this response, which is upregulated inside the host cells (by 90- to 113-fold) is functionally characterized in Salmonella pathogenesis. In vitro, the ΔSTM1485 neither exhibited any growth defect at pH 4.5 nor any difference in the acid tolerance response. The ΔSTM1485 was compromised in its capacity to proliferate inside the host cells and complementation with STM1485 gene restored its virulence. We further demonstrate that the surface translocation of Salmonella pathogenicity island-2 (SPI-2) encoded translocon proteins, SseB and SseD were reduced in the ΔSTM1485. The increase in co-localization of this mutant with lysosomes was also observed. In addition, the ΔSTM1485 displayed significantly reduced competitive indices (CI) in spleen, liver and mesenteric lymph nodes in murine typhoid model when infected by intra-gastric route. Based on these results, we conclude that the acidic pH induced STM1485 gene is essential for intracellular replication of Salmonella.

Cationic amino acid transporters and Salmonella Typhimurium ArgT collectively regulate arginine availability towards intracellular Salmonella growth.

Cationic amino acid transporters (mCAT1 and mCAT2B) regulate the arginine availability in macrophages. How in the infected cell a pathogen can alter the arginine metabolism of the host remains to be understood. We reveal here a novel mechanism by which Salmonella exploit mCAT1 and mCAT2B to acquire host arginine towards its own intracellular growth within antigen presenting cells. We demonstrate that Salmonella infected bone marrow derived macrophages and dendritic cells show enhanced arginine uptake and increased expression of mCAT1 and mCAT2B. We show that the mCAT1 transporter is in close proximity to Salmonella containing vacuole (SCV) specifically by live intracellular Salmonella in order to access the macrophage cytosolic arginine pool. Further, Lysosome associated membrane protein 1, a marker of SCV, also was found to colocalize with mCAT1 in the Salmonella infected cell. The intra vacuolar Salmonella then acquire the host arginine via its own arginine transporter, ArgT for growth. The argT knockout strain was unable to acquire host arginine and was attenuated in growth in both macrophages and in mice model of infection. Together, these data reveal survival strategies by which virulent Salmonella adapt to the harsh conditions prevailing in the infected host cells.