Antigen-induced production of inflammatory cytokines such as TNFalpha within the DRG identifies a potential novel mechanism for MS-induced NPP.

Multiple sclerosis (MS) is characterized by focal destruction of the white matter of the brain and spinal cord. The exact mechanisms underlying the pathophysiology of the disease are unknown. Many studies have shown that MS is predominantly an autoimmune disease with an inflammatory phase followed by a demyelinating phase. Recent studies alongside current treatment strategies, including glatiramer acetate, have revealed a potential role for brain-derived neurotrophic factor (BDNF) in MS. However, the exact role of BDNF is not fully understood. We used the experimental autoimmune encephalomyelitis (EAE) model of MS in adolescent female Lewis rats to identify the role of BDNF in disease progression. Dorsal root ganglia (DRG) and spinal cords were harvested for protein and gene expression analysis every 3 days post-disease induction (pdi) up to 15 days. We show significant increases in BDNF protein and gene expression in the DRG of EAE animals at 12 dpi, which correlates with peak neurological disability. BDNF protein expression in the spinal cord was significantly increased at 12 dpi, and maintained at 15 dpi. However, there was no significant change in mRNA levels. We show evidence for the anterograde transport of BDNF protein from the DRG to the dorsal horn of the spinal cord via the dorsal roots. Increased levels of BDNF within the DRG and spinal cord in EAE may facilitate myelin repair and neuroprotection in the CNS. The anterograde transport of DRG-derived BDNF to the spinal cord may have potential implications in facilitating central myelin repair and neuroprotection.

SummaryBangladesh has attained notable progress in most of the health indicators, but still, health system of the country is suffering badly from poor funding. Issues like burden of out‐of‐pocket expenditure, low per capita share in health, inadequate service facilities, and financial barriers in reducing malnutrition are being overlooked due to inadequacy and inappropriate utilization of allocated funds. We aimed to review the current status of health care spending in Bangladesh in response to national health policy (NHP) and determine the future challenges towards achieving universal health coverage (UHC). National health policy suggested a substantial increase in budgetary allocation for health care, although government health care expenditures in proportion to total public spending plummeted down from 6.2% to 4.04% in the past 8 years. Overall, 67% of the health care cost is being paid by people, whereas global standard is below 32%. Only one hospital bed is allocated per 1667 people, and 34% of total posts in health sector are vacant due to scarcity of funds. The country is experiencing demographic dividend with a concurrent rise of aged people, but there seems no financial protection schemes for the aged and working age populations. Such situation results in multiple obstacles in achieving financial risk protection as well as UHC. Policy makers must think effectively to develop and adapt systems in order to achieve UHC and ensure health for all.

Neuropathic pain (NPP) is a frequently reported symptom described by 50-80% of multiple sclerosis (MS) patients. Although Th1 cell activation is known to drive the pathology of MS, this critical step has also been suggested to be involved in the neuroimmune induction of NPP. The release of pain inducing inflammatory cytokines such as tumour necrosis factor alpha (TNFα) from activated Th1 cells may have key implications in the development of MS-induced pain. We hypothesize that immune mediated antigenic induction of inflammatory cytokines such as TNFα within dorsal root ganglia (DRG) and spinal cord (SC) facilitate the cellular events underlying induction of pain. A rat experimental autoimmune encephalomyelitis (EAE) model of MS was utilized to identify the cellular source and expression changes of TNFα protein and mRNA in the DRG and SC. The TNFα levels in the DRG and SC were correlated with the behavioral testing indicative of NPP. We show significant increases in TNFα protein and mRNA expression in DRG and SC of EAE animals at 12 days post induction (EAE12) relative to naïve control (NC) and active control (AC) groups. Further, we show increased TNFα protein and mRNA expression at the dorsal root entry point, which suggests the anterograde transport of both protein and mRNA. Further, the onset of NPP coincides with increased TNFα expression in the SC. These results demonstrate that the elevated expression of TNFα in the DRG and SC may be associated with the pathological induction of NPP in an animal model of MS.

No abstract

Poly(ADP‐ribose) polymerase 1 inhibitors alone or in combination with DNA damaging agents are promising clinical drugs in the treatment of cancer. However, there is a need to understand the molecular mechanisms of resistance to PARP1 inhibitors. Expression of HMGA2 in cancer is associated with poor prognosis for patients. Here, we investigated the novel relationship between HMGA2 and PARP1 in DNA damage‐induced PARP1 activity. We used human triple‐negative breast cancer and fibrosarcoma cell lines to demonstrate that HMGA2 colocalizes and interacts with PARP1. High cellular HMGA2 levels correlated with increased DNA damage‐induced PARP1 activity, which was dependent on functional DNA‐binding AT‐hook domains of HMGA2. HMGA2 inhibited PARP1 trapping to DNA and counteracted the cytotoxic effect of PARP inhibitors. Consequently, HMGA2 decreased caspase 3/7 induction and increased cell survival upon treatment with the alkylating methyl methanesulfonate alone or in combination with the PARP inhibitor AZD2281 (olaparib). HMGA2 increased mitochondrial oxygen consumption rate and spare respiratory capacity and increased NAMPT levels, suggesting metabolic support for enhanced PARP1 activity upon DNA damage. Our data showed that expression of HMGA2 in cancer cells reduces sensitivity to PARP inhibitors and suggests that targeting HMGA2 in combination with PARP inhibition may be a promising new therapeutic approach.

The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) plays important roles in the repair and protection of genomic DNA in embryonic stem cells and cancer cells. Here we show that HMGA2 localizes to mammalian telomeres and enhances telomere stability in cancer cells. We present a novel interaction of HMGA2 with the key shelterin protein TRF2. We found that the linker (L1) region of HMGA2 contributes to this interaction but the ATI-L1-ATII molecular region of HMGA2 is required for strong interaction with TRF2. This interaction was independent of HMGA2 DNA-binding and did not require the TRF2 interacting partner RAP1 but involved the homodimerization and hinge regions of TRF2. HMGA2 retained TRF2 at telomeres and reduced telomere-dysfunction despite induced telomere stress. Silencing of HMGA2 resulted in (i) reduced binding of TRF2 to telomere DNA as observed by ChIP, (ii) increased telomere instability and (iii) the formation of telomere dysfunction-induced foci (TIF). This resulted in increased telomere aggregation, anaphase bridges and micronuclei. HMGA2 prevented ATM-dependent pTRF2T188 phosphorylation and attenuated signaling via the telomere specific ATM-CHK2-CDC25C DNA damage signaling axis. In summary, our data demonstrate a unique and novel role of HMGA2 in telomere protection and promoting telomere stability in cancer cells. This identifies HMGA2 as a new therapeutic target for the destabilization of telomeres in HMGA2+ cancer cells.

Highlights► We used an ovine prenatal exposure model to a mixture of environmental chemicals. ► Male fetal thyroids of mixed exposure groups have reduced follicle counts. ► Fetal thyroids of animals in mixed exposure groups show increased proliferation. ► Thyroid glands of exposed fetuses showed regions with impaired differentiation. ► Fetal plasma levels of free thyroid hormones were normal.