Our work has focused on understand the signaling pathways that regulate the choice between stem cell renewal and commitment, and define how the same signals are subverted in cancer. We have ...specifically studied developmental signals such as Wnt, Notch and Hedgehog which are critical regulators of normal development in a variety of systems, and a major target of mutation in human cancer. Our research using knockout and transgenic approaches suggests that these signals are activated in hematopoietic stem cells, and that they functionally contribute to stem cell self-renewal in vivo. In addition our data also shows that inhibition of these signals can block leukemia development and propagation in mouse models of the disease as well as in human leukemia cells.
RIF1 is a multifunctional protein that plays key roles in the regulation of DNA processing. During repair of DNA double-strand breaks (DSBs), RIF1 functions in the 53BP1-Shieldin pathway that ...inhibits resection of DNA ends to modulate the cellular decision on which repair pathway to engage. Under conditions of replication stress, RIF1 protects nascent DNA at stalled replication forks from degradation by the DNA2 nuclease. How these RIF1 activities are regulated at the post-translational level has not yet been elucidated. Here, we identified a cluster of conserved ATM/ATR consensus SQ motifs within the intrinsically disordered region (IDR) of mouse RIF1 that are phosphorylated in proliferating B lymphocytes. We found that phosphorylation of the conserved IDR SQ cluster is dispensable for the inhibition of DSB resection by RIF1, but is essential to counteract DNA2-dependent degradation of nascent DNA at stalled replication forks. Therefore, our study identifies a key molecular feature that enables the genome-protective function of RIF1 during DNA replication stress.
The progress of sensor devices, digital communication, and computing techniques enhances the functionalities of e-healthcare, where the medical facilities are manageable based on the Internet. Now a ...days, e-healthcare not only helps in disease diagnosis, or tele-medicine, but also implies to general medical scope and medical resource management. Thus, Internet-of-Medical Thing (IoMT) becomes an umbrella term to connect e-healthcare, tele-medicine, and medical supply chain management. In the recent past, the outbreak of COVID-19 pandemic has shown the loopholes in the existing medical systems such as the mismanagement of medical resources and the unavailability of the basic requirements for patients. The medical infrastructure urges for the new frameworks to handle accountability and transparent governance in a medical emergency situation. This motivates us to address medical resource accountability in e-healthcare.
In the present work, we introduce the first resource accountability framework to balance the demand–supply of medical facilities in an e-healthcare and IoMT ecosystem. Our solution is based on blockchain and we call it bloCkchained framework for resOUrce accouNTability (COUNT). We use a customized Proof of Vote (PoV) for consensus in COUNT. We call this consensus COUNT-PoV, which is another direction of novelty in our solution. The blocks in the proposed COUNT contain the resource requirements and their availability–production–supply status. Multiple stakeholders are involved in the process based on providing pre-attained credentials; thus, COUNT supports consortium blockchain. Existing literature shows a number of studies for blockchain-based frameworks for e-healthcare; however, those works do not address the accountability and transparency issues of medical e-governance and balancing the demand–supply of the medical facilities/resources. Therefore, our proposed COUNT is beneficial for e-healthcare and IoMTs. We use signcryption process to reduce the complexity of the cryptographic processes, which is an add-on to the contribution. We evaluate our proposed framework based on the Hyperledger Caliper benchmark test with latency, throughput, and resource consumption. Additionally, we also analyse the cost of the implementation. The comparative analysis of our consensus with other stake-based consensus protocols on the COUNT framework shows that our consensus, COUNT-PoV is efficient and suitable for the use of e-healthcare and IoMTs. Moreover, being a generic framework, COUNT is helpful for the e-governance of medical facilities, the vaccination process, and COVID passports.
Although the role of Hedgehog (Hh) signalling in embryonic pattern formation is well established, its functions in adult tissue renewal and maintenance remain unclear, and the relationship of these ...functions to cancer development has not been determined. Here we show that the loss of Smoothened (Smo), an essential component of the Hh pathway, impairs haematopoietic stem cell renewal and decreases induction of chronic myelogenous leukaemia (CML) by the BCR-ABL1 oncoprotein. Loss of Smo causes depletion of CML stem cells-the cells that propagate the leukaemia-whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, we show that the cell fate determinant Numb, which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacological inhibition of Hh signalling impairs not only the propagation of CML driven by wild-type BCR-ABL1, but also the growth of imatinib-resistant mouse and human CML. These data indicate that Hh pathway activity is required for maintenance of normal and neoplastic stem cells of the haematopoietic system and raise the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML might be avoided by targeting this essential stem cell maintenance pathway.
National guidelines recommend twice-yearly hepatitis C virus (HCV) screening for patients receiving in-center hemodialysis. However, studies examining the cost-effectiveness of HCV screening methods ...or frequencies are lacking.
We populated an HCV screening, treatment, and disease microsimulation model with a cohort representative of the US in-center hemodialysis population. Clinical outcomes, costs, and cost-effectiveness of the Kidney Disease Improving Global Outcomes (KDIGO) 2018 guidelines-endorsed HCV screening frequency (every 6 months) were compared with less frequent periodic screening (yearly, every 2 years), screening only at hemodialysis initiation, and no screening. We estimated expected quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) between each screening strategy and the next less expensive alternative strategy, from a health care sector perspective, in 2019 US dollars. For each strategy, we modeled an HCV outbreak occurring in 1% of centers. In sensitivity analyses, we varied mortality, linkage to HCV cure, screening method (ribonucleic acid versus antibody testing), test sensitivity, HCV infection rates, and outbreak frequencies.
Screening only at hemodialysis initiation yielded HCV cure rates of 79%, with an ICER of $82,739 per QALY saved compared with no testing. Compared with screening at hemodialysis entry only, screening every 2 years increased cure rates to 88% and decreased liver-related deaths by 52%, with an ICER of $140,193. Screening every 6 months had an ICER of $934,757; in sensitivity analyses using a willingness-to-pay threshold of $150,000 per QALY gained, screening every 6 months was never cost-effective.
The KDIGO-recommended HCV screening interval (every 6 months) does not seem to be a cost-effective use of health care resources, suggesting that re-evaluation of less-frequent screening strategies should be considered.
The integration between blockchains, Internet-of-Thing (IoT), and smart contracts is an emerging and promising technology. The advantages of this technology have raised the importance of Industrial ...Internet-of-Thing (IIoT) and have paved the pathway for "Industry 4.0." Surprisingly, access control has received less attention in IIoTs. Though there are some solutions coming forward to use blockchains for IIoT to enable secure and resilient access control management, the challenge is to satisfy the low-latency requirements of IIoTs for validating and adding the blocks to the chain. Besides, role-based and rule-based access controls in the existing systems can be forged without organizational access controls and compliance. Therefore, we address these problems in this article. In the present work, we propose DHACS , a Decentralized Hybrid Access Control for Smart contract , for IIoTs. DHACS aims to provide transparency, reliability, and robustness to the existing access control mechanism in IIoTs. The framework is based on blockchain feasibilities that contribute to an interconnected hybrid access control through smart contract provision. It is a novel idea in the domain of IIoTs. We use three access control strategies, role-based, rule-based, and organization-based, to develop a hybrid approach for smart contract in DHACS. The operational transactions along with their access controls are accounted and blocks are made by the transaction pooler and block creator. We use a private blockchain environment; however, it can be extended to a public blockchain or consortium blockchain for geographical distributed dependency. We compare DHACS with three existing approaches in recent time. We measure the performance in terms of computational costs, storage complexity, and energy consumption. DHACS outperforms the others approaches and is considered to be efficient for IIoT applications with more than 30% better efficiency in access control management. To the best of our knowledge, DHACS is the first attempt to use decentralized blockchains with smart contract for hybrid access control in IIoTs.
In a screen of drugs previously tested in humans we identified itraconazole, a systemic antifungal, as a potent antagonist of the Hedgehog (Hh) signaling pathway that acts by a mechanism distinct ...from its inhibitory effect on fungal sterol biosynthesis. Systemically administered itraconazole, like other Hh pathway antagonists, can suppress Hh pathway activity and the growth of medulloblastoma in a mouse allograft model and does so at serum levels comparable to those in patients undergoing antifungal therapy. Mechanistically, itraconazole appears to act on the essential Hh pathway component Smoothened (SMO) by a mechanism distinct from that of cyclopamine and other known SMO antagonists, and prevents the ciliary accumulation of SMO normally caused by Hh stimulation.
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► Itraconazole identified as Hh pathway inhibitor in screen of human-experienced drugs ► Itraconazole appears to act on Smoothened at distinct site from cyclopamine ► Itraconazole inhibits accumulation of Smoothened in primary cilium ► Itraconazole suppresses Hh-dependent tumor growth in vivo
While it has long been speculated that mammalian stem cells undergo asymmetric and symmetric division, whether this actually occurs has not been clearly demonstrated. We have used a transgenic Notch ...reporter mouse, in which the GFP status of a cell acts as a sensor for the differentiated state, to image how mammalian hematopoietic stem cells divide and respond to signals during growth, differentiation, and oncogenic transformation. We show that mammalian hematopoietic stem cells have the ability to undergo both symmetric and asymmetric divisions and that the balance between these divisions is not hardwired in precursors but, instead, responsive to extrinsic and intrinsic cues. In addition, we show that oncoproteins can also influence a cell's choice between symmetric and asymmetric division. Cumulatively, this work not only establishes a novel system in which division of early hematopoietic precursor cells can not only be tracked in real time, but also indicates that the distribution of symmetric and asymmetric division can be modulated in response to the microenvironment and subverted by oncogenes.
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