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Furthermore, SQ109 has synergistic activities with other conventional anti-tubercular drugs such as INH, rifampicin and bedaquillin, and thereby reduces the length of treatment by 30% or more12,13,14. In addition, a recent study indicated that a new regimen constituting SQ109 achieved a relapse free cure in 3 weeks in murine model of tuberculosis15. SQ109 has successfully completed phase 1 and phase 2 clinical trials for treatment of TB13,16,17,18, and the Food and Drug Administration (FDA) approved its fast track designation and orphan drug status. Based on these clinical studies SQ109 is a highly promising adjunct drug for TB treatment.
Refugees reported limited barriers to care as international organizations provide comprehensive health care free of charge in the refugee camp. PU-AMI provides TB services to the general camp population and IOM screens and treats individuals who have been accepted into the resettlement program. TB and TB/HIV treatment is provided at a residential TB village and MDR-TB cases are referred outside the camp to SMRU. PU-AMI provides transportation to SMRU for all referred patients.
We found that legal status has important implications for where patients are eligible to receive free or low-cost care. Participants explained that general healthcare entitlements differed between refugees, undocumented migrants and documented migrants who had registered in the Thai migrant health insurance scheme. For example, migrants with health insurance can access TB treatment at the Thai government hospitals. In contrast, migrants without this insurance have to pay directly for treatment at the government hospitals or can access treatment free of charge where a third party donor funds their treatment.
Participants identified legal status as an overarching barrier for migrants from Myanmar who need to travel to access TB treatment in Thailand. Migrants without proper documents are in Thailand illegally and were concerned about their security while travelling to get treatment. Undocumented migrants are more susceptible to police extortion. On the other hand, having the correct documentation permits migrants to travel freely without concern for their personal safety. Documentation ranges from having a day pass to travel in Thailand to having a passport and work permit.
We found that although most migrant patients did not initially know where to seek TB treatment in Mae Sot, this does not affect their ability to seek care as they were able to seek referral services from Mae Tao Clinic (MTC). MTC, a well know clinic that provides free healthcare services to migrants, refers TB patients to SMRU for treatment. Some of the migrant participants in our study went directly to the Thai government hospital for TB treatment.
Availability of free or low cost treatment services for TB, TB/HIV and MDR-TB in Tak province is an enabler for migrants to access treatment. While TB treatment is available to documented and undocumented migrants in Tak province, participants reported lack of affordable and accessible treatment in Bangkok and within Myanmar contributed to their decision seek care in Tak province. MDR-TB treatment is very expensive and would be unaffordable for most migrants if they had to pay for it directly. One course of treatment is 200,000 Thai baht (USD 5950). It is not only the cost for treatment that is a barrier but also the fees associated with tests necessary to determine that they have TB.
Human hepatocarcinoma HepG2 cells from the AmericanType Culture Collection (ATCC; Manassas, VA, USA) were maintainedin Dulbecco's modified Eagle's medium (DMEM) supplemented with 10%fetal bovine serum (FBS) from HyClone (Logan, UT, USA) at 37°C with5% CO2. IR was induced in HepG2 cells according to apreviously described method (12).Briefly, the cells were incubated in serum-free DMEM for 6 h, andthen treated with 0.5 µmol/l insulin for 72 h. The resultantcells were named as HepG2/IR cells. HepG2/IR cells were thentreated with PH (10 mmol/l) for 24 h to reverse IR, and theresultant cells were called HepG2/IR/PH cells.
In 2008, the influence of reversion mutations on PARPi resistance was independently discovered by two groups. Ashworth et al derived PARPi-resistant clones by deleting the BRCA2 c.6174delT frameshift mutation of human CAPAN1 pancreatic cancer cell line, a BRCA2-deficient cell line. Consequently, the reconstituted BRCA2-deficient cells acquired PARPi resistance . Meanwhile, Sakai et al demonstrated that secondary mutations restored the wild-type BRCA2 reading frame was a major clinical mediator of acquired resistance to platinum and PARPi . By using liquid biopsy or circulating cell-free DNA (cfDNA), lots of BRCA reversion mutations have been discovered to restore the open reading frame (ORF) of BRCA1/2 and confer resistance to PARPi-based therapy in various cancers [84,85,86,87,88,89,90] (Table 1).
In the past few decades, PARPi was successfully developed in treating BRCA mutation patients, which provided proof-of concept that synthetic lethal interactions could be translated into cancer therapy. However, the preclinical and clinical investigation of PRARi is far from complete. In terms of PARPi resistance, multiple potential resistance mechanisms, such as HR restoration and protection of DNA replication fork have been identified. Nonetheless, the contribution weight of them to PARPi resistance is incomprehensible. Recently, the PRIMA trial results suggested that among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival (PFS) than those who received placebo, regardless of the presence or absence of HRD . Based on it, we assumed that PARPi might kill cancer cells in ways other than DNA repair. The association between PARPi resistance and protection of DNA replication fork confirmed this conjecture. Therefore, we should comprehensively understand how PARPi functions, especially, how do the roles of PARPi in processes unrelated to DNA repair influence the anti-cancer activity of PARPi, which would be conductive to understand the development of resistance. Also, to overcome PARPi resistance and increase PARPi sensitivity, the optimal combination of PARPi and other treatment regimens are urgently needed to identify.
There are limited studies of bacterial factors as key drivers of DR-TB prevalence and persistence in PNG. Prior analysis of clinical isolates from Daru, a town in Western Province that is located approximately 500 km from Port Moresby in the NCD, provided critical insight of MTB population dynamics and molecular causes of drug resistance . With a modern Beijing highly resistant strain identified to be responsible for the majority of DR TB in Daru, the potential spread of this strain to other PNG settings needed to be investigated. Furthermore, knowledge provided by whole genome sequencing (WGS) of the prevalent mutations associated with drug resistance is important to inform recommendations for the choice of effective treatment regimens. There have been major changes in recent years to the recommendations by the World Health Organization (WHO) for the treatment of MDR/RR-TB, with a welcome shift to shorter and safer, injectable-free regimens when possible . An improved understanding of the drug-resistance patterns of MTB strains in PNG will inform the development of national guidelines for PNG and improve treatment outcomes.
The principal actions of anthracyclines are DNA intercalation, inhibition of topoisomerase II and the formation of free radicals . Resistance mechanisms specific to topoisomerase II inhibitors have been identified and include enhanced levels of efflux and alterations to the expression of the topoisomerase II . Resistance to therapeutics can be caused by numerous factors, associated with either acquired or de novo mechanisms. Acquired mechanisms of resistance progress in response to exposure to the therapeutics, whereas de novo resistance relates specifically to the characteristics of a tumour that exist prior to the application of anti-cancer agents . De novo resistance can be mediated by environmental influences, such as tumour cell attachment to elements of the stroma, including the extracellular matrix (ECM) [8, 9].
Human lung adenocarcinoma A549 cells, drug-resistant A549 cells overexpressing P-gp (A549/ADR), and drug-resistant mouse breast cancer 4T1 (4T1/ADR) cells (College of Pharmaceutical Science, Guangzhou Medical University, Guangzhou, China) were grown in RPMI-1640 supplemented with 10% FBS and 1% antibiotics (100 U/mL penicillin and 100 mg/mL streptomycin). For maintenance of drug resistance, A549/ADR and 4T1/ADR cells were cultured in the presence of 4 µM CDDP, and CDDP-free medium was used for 1 week prior to initiation of the experiments . Cell cultivation was performed in a humidified incubator maintained at 37 °C containing 5% CO2. All of the cell studies were approved by the Institutional Animal Care Committee and the Local Veterinary Office and Ethics Committee at Guangzhou Medical University (GZMUC 10-05010).
The in vitro biocompatibility of TP and TPH polymer was further studied by performing the hemo-compatibility test (Fig. 3c). The hemolysis levels of TP and TPH nanomicelles were negligible with hemolytic ratios of 0.001 vitro biocompatibility of TP and TPH polymer was further studied by performing the hemo-cafter co-cultured with PBS, TP (0.25 mg/mL, 0.5 mg/mL, 1.25 mg/mL), TPH (0.25 mg/mL, 0.5 mg/mL, 1.25 mg/ml), respectively. In addition, the cytotoxicity of drug free nanomicelles (for example, TP, TPH), were also assayed in lung cancer cells, and cell cytotoxicity was hardly observed, indicating that these vectors are biocompatible and non-toxic to tissues and cells (Additional file 1: Figure S1). 2b1af7f3a8