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The Cutting-edge of CRISPR for Cancer Treatment and its Future Prospects

Kah Man L, An Gie O, Chian Huey M, Yong P, Siik Kee L, Cheng Ze L, et al.

Curr Pharm Biotechnol, 2023 Oct 25.
PMID: 37921129 DOI: 10.2174/0113892010258617231020062637

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a versatile technology that allows precise modification of genes. One of its most promising applications is in cancer treatment. By targeting and editing specific genes involved in cancer development and progression, CRISPR has the potential to become a powerful tool in the fight against cancer. This review aims to assess the recent progress in CRISPR technology for cancer research and to examine the obstacles and potential strategies to address them. The two most commonly used CRISPR systems for gene editing are CRISPR/Cas9 and CRISPR/Cas12a. CRISPR/Cas9 employs different repairing systems, including homologous recombination (HR) and nonhomologous end joining (NHEJ), to introduce precise modifications to the target genes. However, off-target effects and low editing efficiency are some of the main challenges associated with this technology. To overcome these issues, researchers are exploring new delivery methods and developing CRISPR/Cas systems with improved specificity. Moreover, there are ethical concerns surrounding using CRISPR in gene editing, including the potential for unintended consequences and the creation of genetically modified organisms. It is important to address these issues through rigorous testing and strict regulations. Despite these challenges, the potential benefits of CRISPR in cancer therapy cannot be overlooked. By introducing precise modifications to cancer cells, CRISPR could offer a targeted and effective treatment option for patients with different types of cancer. Further investigation and development of CRISPR technology are necessary to overcome the existing challenges and harness its full potential in cancer therapy.
A carbon conductive filament-induced robust resistance switching behavior for brain-inspired computing

Yu T, Wang D, Liu M, Lei W, Shafie S, Mohtar MN, et al.

Mater Horiz, 2024 Mar 04;11(5):1334-1343.
PMID: 38175571 DOI: 10.1039/d3mh01762a

Memristors have revolutionized the path forward for brain-inspired computing. However, the instability of the nucleation process of conductive filaments based on active metal electrodes leads to the discrete distribution of switching parameters, which hinders the realization of high-performance and low-power devices for neuromorphic computing. In response, a carbon conductive filament-induced robust memristor is demonstrated with variation coefficients as low as 3.9%/-1.18%, a threshold power as low as 10-9 W, and 3 × 106 s retention and 107 cycle endurance behaviors can be maintained. The recognition accuracy for Modified National Institute of Standards and Technology (MNIST) handwriting is as high as 96.87%, attributed to the high linearity of the iterative updating of synaptic weights. The demodulation and storage functions of the American Standard Code for Information Interchange (ASCII) are demonstrated by programmable pulse modulation. Notably, the transmission electron microscopy (TEM) images allow the observation of carbon conductive filament paths formed in the low resistance state. First-principles calculations analyze the energetics of defects involved in the diffusion of carbon atoms into MoTe2 films. This work presents a novel guideline for studying memristor-based neuromorphic computing.
Fulltext A Matrilineal Genetic Perspective of Hanging Coffin Custom in Southern China and Northern Thailand

Zhang X, Li C, Zhou Y, Huang J, Yu T, Liu X, et al.

iScience, 2020 Apr 24;23(4):101032.
PMID: 32304863 DOI: 10.1016/j.isci.2020.101032

Hanging Coffin is a unique and ancient burial custom that has been practiced in southern China, Southeast Asia, and near Oceania regions for more than 3,000 years. Here, we conducted mitochondrial whole-genome analyses of 41 human remains sampled from 13 Hanging Coffin sites in southern China and northern Thailand, which were dated between ∼2,500 and 660 years before present. We found that there were genetic connections between the Hanging Coffin people living in different geographic regions. Notably, the matrilineal genetic diversity of the Hanging Coffin people from southern China is much higher than those from northern Thailand, consistent with the hypothesized single origin of the Hanging Coffin custom in southern China about 3,600 years ago, followed by its dispersal in southern China through demic diffusion, whereas the major dispersal pattern in Southeast Asia is cultural assimilation in the past 2,000 years.
Fulltext A phase 3, randomised, placebo-controlled study of erenumab for the prevention of chronic migraine in patients from Asia: the DRAGON study

Yu S, Kim BK, Wang H, Zhou J, Wan Q, Yu T, et al.

J Headache Pain, 2022 Nov 21;23(1):146.
PMID: 36404301 DOI: 10.1186/s10194-022-01514-9

ABSTACT: BACKGROUND: DRAGON was a phase 3, randomised, double-blind, placebo-controlled study which evaluated the efficacy and safety of erenumab in patients with chronic migraine (CM) from Asia not adequately represented in the global pivotal CM study.
METHODS: DRAGON study was conducted across 9 Asian countries or regions including mainland China, India, the Republic of Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. Patients (N = 557) with CM (aged 18-65 years) were randomised (1:1) to receive once-monthly subcutaneous erenumab 70 mg or matching placebo for 12 weeks. The primary endpoint was the change in monthly migraine days (MMD) from baseline to the last 4 weeks of the 12-week double-blind treatment phase (DBTP). Secondary endpoints included achievement of ≥ 50% reduction in MMD, change in monthly acute headache medication days, modified migraine disability assessment (mMIDAS), and safety. Study was powered for the primary endpoint of change from baseline in MMD.
RESULTS: At baseline, the mean (SD) age was 41.7 (± 10.9) years, and 81.5% (n = 454) patients were women. The mean migraine duration was 18.0 (± 11.6) years, and the mean MMD was 19.2 (± 5.4). 97.8% (n = 545) randomised patients completed the DBTP. Overall, demographics and baseline characteristics were balanced between the erenumab and placebo groups except for a slightly higher proportion of women in the placebo group. At Week 12, the adjusted mean change from baseline in MMD was - 8.2 days for erenumab and - 6.6 days for placebo, with a statistically significant difference for erenumab versus placebo (adjusted mean difference vs placebo: - 1.57 [95%CI: - 2.83, - 0.30]; P = 0.015). A greater proportion of patients treated with erenumab achieved ≥ 50% reduction in MMD versus placebo (47.0% vs 36.7%, P = 0.014). At Week 12, greater reductions in monthly acute headache medication days (- 5.34 vs - 4.66) and mMIDAS scores (- 14.67 vs - 12.93) were observed in patients treated with erenumab versus placebo. Safety and tolerability profile of erenumab was comparable to placebo, except the incidence of constipation (8.6% for erenumab vs 3.2% for placebo).
CONCLUSION: DRAGON study demonstrated the efficacy and safety of erenumab 70 mg in patients with CM from Asia. No new safety signals were observed during the DBTP compared with the previous trials.
TRIAL REGISTRATION: NCT03867201.
Fulltext Timosaponin AIII promotes non-small-cell lung cancer ferroptosis through targeting and facilitating HSP90 mediated GPX4 ubiquitination and degradation

Zhou C, Yu T, Zhu R, Lu J, Ouyang X, Zhang Z, et al.

Int J Biol Sci, 2023;19(5):1471-1489.
PMID: 37056925 DOI: 10.7150/ijbs.77979

Timosaponin AIII (Tim-AIII), a steroid saponin, exhibits strong anticancer activity in a variety of cancers, especially breast cancer and liver cancer. However, the underlying mechanism of the effects of Tim-AIII-mediated anti-lung cancer effects remain obscure. In this study, we showed that Tim-AIII suppressed cell proliferation and migration, induced G2/M phase arrest and ultimately triggered cell death of non-small cell lung cancer (NSCLC) cell lines accompanied by the release of reactive oxygen species (ROS) and iron accumulation, malondialdehyde (MDA) production, and glutathione (GSH) depletion. Interestingly, we found that Tim-AIII-mediated cell death was reversed by ferroptosis inhibitor ferrostatin-1 (Fer-1). Meanwhile, the heat shock protein 90 (HSP90) was predicted and verified as the direct binding target of Tim-AIII by SwissTargetPrediction (STP) and surface plasmon resonance (SPR) assay. Further study showed that Tim-AIII promoted HSP90 expression and Tim-AIII induced cell death was blocked by the HSP90 inhibitor tanespimycin, indicating that HSP90 was the main target of Tim-AIII to further trigger intracellular events. Mechanical analysis revealed that the Tim-AIII-HSP90 complex further targeted and degraded glutathione peroxidase 4 (GPX4), and promoted the ubiquitination of GPX4, as shown by an immunoprecipitation, degradation and in vitro ubiquitination assay. In addition, Tim-AIII inhibited cell proliferation, induced cell death, led to ROS and iron accumulation, MDA production, GSH depletion, as well as GPX4 ubiquitination and degradation, were markedly abrogated when HSP90 was knockdown by HSP90-shRNA transfection. Importantly, Tim-AIII also showed a strong capacity of preventing tumor growth by promoting ferroptosis in a subcutaneous xenograft tumor model, whether C57BL/6J or BALB/c-nu/nu nude mice. Together, HSP90 was identified as a new target of Tim-AIII. Tim-AIII, by binding and forming a complex with HSP90, further targeted and degraded GPX4, ultimately induced ferroptosis in NSCLC. These findings provided solid evidence that Tim-AIII can serve as a potential candidate for NSCLC treatment.
Hybridization state transition-driven carbon quantum dot (CQD)-based resistive switches for bionic synapses

Yu T, Fang Y, Chen X, Liu M, Wang D, Liu S, et al.

Mater Horiz, 2023 Jun 06;10(6):2181-2190.
PMID: 36994553 DOI: 10.1039/d3mh00117b

As an emerging carbon-based material, carbon quantum dots (CQDs) have shown unstoppable prospects in the field of bionic electronics with their outstanding optoelectronic properties and unique biocompatible characteristics. In this study, a novel CQD-based memristor is proposed for neuromorphic computing. Unlike the models that rely on the formation and rupturing of conductive filaments, it is speculated that the resistance switching mechanism of CQD-based memristors is due to the conductive path caused by the hybridization state transition of the sp2 carbon domain and sp3 carbon domain induced by the reversible electric field. This avoids the drawback of uncontrollable nucleation sites leading to the random formation of conductive filaments in resistive switching. Importantly, it illustrates that the coefficient of variation (CV) of the threshold voltage can be as low as -1.551% and 0.083%, which confirms the remarkable uniform switching characteristics. Interestingly, the Pavlov's dog reflection as an important biological behavior can be demonstrated by the samples. Finally, the accuracy recognition rate of MNIST handwriting can reach up to 96.7%, which is very close to the ideal number (97.8%). A carbon-based memristor based on a new mechanism presented provides new possibilities for the improvement of brain-like computing.
Platform presentations

Pereda J, Niimi G, Kaul JM, Mishra S, Pangtey B, Peri D, et al.

Surg Radiol Anat, 2009 Sep;31 Suppl 1:49-93.
PMID: 27392491 DOI: 10.1007/BF03371485
Fulltext Search for standard model production of four top quarks with same-sign and multilepton final states in proton-proton collisions at s = 13 TeV

Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.

Eur Phys J C Part Fields, 2018;78(2):140.
PMID: 31265001 DOI: 10.1140/epjc/s10052-018-5607-5

A search for standard model production of four top quarks ( t t ¯ t t ¯ ) is reported using events containing at least three leptons ( e , μ ) or a same-sign lepton pair. The events are produced in proton-proton collisions at a center-of-mass energy of 13 TeV at the LHC, and the data sample, recorded in 2016, corresponds to an integrated luminosity of 35.9 fb - 1 . Jet multiplicity and flavor are used to enhance signal sensitivity, and dedicated control regions are used to constrain the dominant backgrounds. The observed and expected signal significances are, respectively, 1.6 and 1.0 standard deviations, and the t t ¯ t t ¯ cross section is measured to be 16 . 9 - 11.4 + 13.8 fb , in agreement with next-to-leading-order standard model predictions. These results are also used to constrain the Yukawa coupling between the top quark and the Higgs boson to be less than 2.1 times its expected standard model value at 95% confidence level.
Fulltext Measurement of the Z / γ ∗ → τ τ cross section in pp collisions at s = 13 TeV and validation of τ lepton analysis techniques

Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.

Eur Phys J C Part Fields, 2018;78(9):708.
PMID: 30956559 DOI: 10.1140/epjc/s10052-018-6146-9

A measurement is presented of the Z / γ ∗ → τ τ cross section in pp collisions at s = 13 TeV , using data recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 2.3 fb - 1 . The product of the inclusive cross section and branching fraction is measured to be σ ( pp → Z / γ ∗ +X ) B ( Z / γ ∗ → τ τ ) = 1848 ± 12 ( stat ) ± 67 (syst \,+\,lumi) pb , in agreement with the standard model expectation, computed at next-to-next-to-leading order accuracy in perturbative quantum chromodynamics. The measurement is used to validate new analysis techniques relevant for future measurements of τ lepton production. The measurement also provides the reconstruction efficiency and energy scale for τ decays to hadrons + ν τ final states, determined with respective relative uncertainties of 2.2 and 0.9%.