Publications by authors named "Ming Tan"

566 Publications

Set-regression with applications to subgroup analysis.

Stat Med 2021 Oct 20. Epub 2021 Oct 20.

Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, District of Columbia, USA.

Regression is a commonly used statistical model. It is the conditional mean of the response given covariates . However, in some practical problems, the interest is the conditional mean of the response given the covariates belonging to some set A. Notably, in precision medicine and subgroup analysis in clinical trials, the aim is to identify subjects who benefit the most from the treatment, or identify an optimal set in the covariate space which manifests treatment favoritism if a subject's covariates fall in this set and the subject is classified to the favorable treatment subgroup. Existing methods for subgroup analysis achieve this indirectly by using classical regression. This motivates us to develop a new type of regression: set-regression, defined as which directly addresses the subgroup analysis problem. This extends not only the classical regression model but also improves recursive partitioning and support vector machine approaches, and is particularly suitable for objectives involving optimization of the regression over sets, such as subgroup analysis. We show that the new versatile set-regression identifies the subgroup with increased accuracy. It is easy to use. Simulation studies also show superior performance of the proposed method in finite samples.
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http://dx.doi.org/10.1002/sim.9229DOI Listing
October 2021

A Phase I Trial of Dasatinib and Osimertinib in TKI Naïve Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer.

Front Oncol 2021 8;11:728155. Epub 2021 Sep 8.

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, United States.

Background: Osimertinib is an effective first-line therapy option for -mutant NSCLC, but virtually all patients develop resistance. CRIPTO, through Src activation, has been implicated in resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Dasatinib, a Src inhibitor, has shown preclinical synergy with EGFR-TKI therapy.

Method: This is a single-arm phase I/II trial of osimertinib and dasatinib in TKI-naïve advanced -mutant NSCLC (NCT02954523). A 3 + 3 design was used in the phase I to establish the recommended phase II dose (RP2D). Osimertinib 80 mg QD was combined with dasatinib 70 mg BID (DL2), 50 mg BID (DL1), 70 mg QD (DL-1), and 50 mg QD (DL-2).

Results: Ten patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches/body pain, neutropenia, rash, one each). Common treatment-related adverse events included pleural effusion (n=10), diarrhea (n=8), rash (n=7), transaminitis (n=7), thrombocytopenia (n=7), and neutropenia (n=7). While the MTD was not determined by protocol-defined DLT criteria, DL-2 was chosen as the RP2D, considering overall tolerability. Nine (90%) patients had a PR, including 1 unconfirmed PR. Median PFS was 19.4 months and median OS 36.1 months. The trial was closed to accrual prematurely due to slow accrual after the approval of osimertinib as first-line therapy.

Conclusions: The combination of dasatinib and osimertinib demonstrated anticancer activity. The treatment was limited by chronic toxicities mainly attributed to dasatinib. To improve the safety and tolerability of Src and EGFR co-inhibition, Src inhibitors with a more favorable safety profile should be utilized in future studies.

Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02954523.
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http://dx.doi.org/10.3389/fonc.2021.728155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457399PMC
September 2021

Critical Period After Stroke Study (CPASS): A phase II clinical trial testing an optimal time for motor recovery after stroke in humans.

Proc Natl Acad Sci U S A 2021 09;118(39)

Department of Kinesiology, University of Wisconsin-Madison, Madison, WI 53706.

Restoration of human brain function after injury is a signal challenge for translational neuroscience. Rodent stroke recovery studies identify an optimal or sensitive period for intensive motor training after stroke: near-full recovery is attained if task-specific motor training occurs during this sensitive window. We extended these findings to adult humans with stroke in a randomized controlled trial applying the essential elements of rodent motor training paradigms to humans. Stroke patients were adaptively randomized to begin 20 extra hours of self-selected, task-specific motor therapy at ≤30 d (acute), 2 to 3 mo (subacute), or ≥6 mo (chronic) after stroke, compared with controls receiving standard motor rehabilitation. Upper extremity (UE) impairment assessed by the Action Research Arm Test (ARAT) was measured at up to five time points. The primary outcome measure was ARAT recovery over 1 y after stroke. By 1 y we found significantly increased UE motor function in the subacute group compared with controls (ARAT difference = +6.87 ± 2.63, = 0.009). The acute group compared with controls showed smaller but significant improvement (ARAT difference = +5.25 ± 2.59 points, = 0.043). The chronic group showed no significant improvement compared with controls (ARAT = +2.41 ± 2.25, = 0.29). Thus task-specific motor intervention was most effective within the first 2 to 3 mo after stroke. The similarity to rodent model treatment outcomes suggests that other rodent findings may be translatable to human brain recovery. These results provide empirical evidence of a sensitive period for motor recovery in humans.
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http://dx.doi.org/10.1073/pnas.2026676118DOI Listing
September 2021

Significantly enhanced coupling effect and gap plasmon resonance in a MIM-cavity based sensing structure.

Sci Rep 2021 09 16;11(1):18515. Epub 2021 Sep 16.

Department of Optoelectronics and Materials Technology, National Taiwan Ocean University, Keelung, 20224, Taiwan.

Herein, we design a high sensitivity with a multi-mode plasmonic sensor based on the square ring-shaped resonators containing silver nanorods together with a metal-insulator-metal bus waveguide. The finite element method can analyze the structure's transmittance properties and electromagnetic field distributions in detail. Results show that the coupling effect between the bus waveguide and the side-coupled resonator can enhance by generating gap plasmon resonance among the silver nanorods, increasing the cavity plasmon mode in the resonator. The suggested structure obtained a relatively high sensitivity and acceptable figure of merit and quality factor of about 2473 nm/RIU (refractive index unit), 34.18 1/RIU, and 56.35, respectively. Thus, the plasmonic sensor is ideal for lab-on-chip in gas and biochemical analysis and can significantly enhance the sensitivity by 177% compared to the regular one. Furthermore, the designed structure can apply in nanophotonic devices, and the range of the detected refractive index is suitable for gases and fluids (e.g., gas, isopropanol, optical oil, and glucose solution).
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http://dx.doi.org/10.1038/s41598-021-98001-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445917PMC
September 2021

Structural basis of P[II] rotavirus evolution and host ranges under selection of histo-blood group antigens.

Proc Natl Acad Sci U S A 2021 Sep;118(36)

Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056;

Group A rotaviruses cause severe gastroenteritis in infants and young children worldwide, with P[II] genogroup rotaviruses (RVs) responsible for >90% of global cases. RVs have diverse host ranges in different human and animal populations determined by host histo-blood group antigen (HBGA) receptor polymorphism, but details governing diversity, host ranges, and species barriers remain elusive. In this study, crystal structures of complexes of the major P[II] genogroup P[4] and P[8] genotype RV VP8* receptor-binding domains together with Lewis epitope-containing LNDFH I glycans in combination with VP8* receptor-glycan ligand affinity measurements based on NMR titration experiments revealed the structural basis for RV genotype-specific switching between ββ and βα HBGA receptor-binding sites that determine RV host ranges. The data support the hypothesis that P[II] RV evolution progressed from animals to humans under the selection of type 1 HBGAs guided by stepwise host synthesis of type 1 ABH and Lewis HBGAs. The results help explain disease burden, species barriers, epidemiology, and limited efficacy of current RV vaccines in developing countries. The structural data has the potential to impact the design of future vaccine strategies against RV gastroenteritis.
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http://dx.doi.org/10.1073/pnas.2107963118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433580PMC
September 2021

Prevalence and Evolution of Noroviruses between 1966 and 2019, Implications for Vaccine Design.

Pathogens 2021 Aug 11;10(8). Epub 2021 Aug 11.

Key Laboratory of Medical Molecular Virology of MoE & MoH and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

Noroviruses (NoVs), a group of single-stranded RNA viruses causing epidemic acute gastroenteritis in humans, are highly diverse, consisting of multiple genogroups with >30 genotypes. Their continual evolutions make NoV vaccine design and development difficult. Here, we report a study of NoV sequences obtained from a population-based diarrhea surveillance in Zhengding County of Hebei Province spanning from 2001 to 2019 and those available in the GenBank database from 1966 to 2019. NoV genotypes and/or variants that may evade immunity were screened and identified based on primary and conformational structures for vaccine design. We selected 366, 301, 139, 74 and 495 complete VP1-coding nucleotide sequences representing the predominant genotypes of GII.4, GII.2, GII.3, GII.6 and GII.17, respectively. A total of 16 distinct GII.4 variants were identified, showing a typical linear evolutionary pattern of variant replacement, while only 1-4 variants of the other genotypes were found to co-circulate over the 40-50-year period without typical variant replacement. The vaccine strain GII.4c is close to variant Sydney_2012 (0.053) in their primary structure, but they are distinct at epitopes A and E in conformations. Our data suggested GII.4 variant Sydney_2012, GII.2 variant A, a GII.3 strain, GII.6 variants B and C and GII.17 variant D are primary candidate strains for NoV vaccine development.
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http://dx.doi.org/10.3390/pathogens10081012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400007PMC
August 2021

Bis{'-[3-(4-nitro-phen-yl)-1-phenyl-prop-2-en-1-yl-idene]--phenyl-carbamimido-thio-ato}zinc(II): crystal structure, Hirshfeld surface analysis and computational study.

Acta Crystallogr E Crystallogr Commun 2021 Aug 27;77(Pt 8):839-846. Epub 2021 Jul 27.

Research Centre for Crystalline Materials, School of Medical and Life Sciences, Sunway University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.

The title zinc bis-(thio-semicarbazone) complex, [Zn(CHNOS)], comprises two ,-donor anions, leading to a distorted tetra-hedral NS donor set. The resultant five-membered chelate rings are nearly planar and form a dihedral angle of 73.28 (3)°. The configurations about the endocyclic- and exocyclic-imine bonds are and , respectively, and that about the ethyl-ene bond is . The major differences in the conformations of the ligands are seen in the dihedral angles between the chelate ring and nitro-benzene rings [40.48 (6) . 13.18 (4)°] and the -bound phenyl and nitro-benzene ring [43.23 (8) and 22.64 (4)°]. In the crystal, a linear supra-molecular chain along the -axis direction features amine-N-H⋯O(nitro) hydrogen bonding. The chains assemble along the 2-screw axis through a combination of phenyl-C-H⋯O(nitro) and π(chelate ring)-π(phen-yl) contacts. The double chains are linked into a three-dimensional architecture through phenyl-C-H⋯O(nitro) and nitro-O⋯π(phen-yl) inter-actions.
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http://dx.doi.org/10.1107/S2056989021007398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340977PMC
August 2021

1-{()-[4-(4-Hy-droxy-phen-yl)butan-2-yl-idene]amino}-3-phenyl-thio-urea: crystal structure, Hirshfeld surface analysis and computational study.

Acta Crystallogr E Crystallogr Commun 2021 Aug 13;77(Pt 8):788-794. Epub 2021 Jul 13.

Research Centre for Crystalline Materials, School of Medical and Life Sciences, Sunway University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.

The title thio-urea derivative, CHNOS, adopts a U-shaped conformation with the dihedral angle between the terminal aromatic rings being 73.64 (5)°. The major twist in the mol-ecule occurs about the ethane bond with the C-C-C-C torsion angle being -78.12 (18)°; i = imine, e = ethane and b = benzene. The configuration about the imine bond is , the N-bound H atoms lie on opposite sides of the mol-ecule and an intra-molecular amine-N-H⋯N(imine) hydrogen bond is evident. In the mol-ecular packing, hydroxyl-O-H⋯S(thione) and amine-N-H⋯O hydrogen bonding feature within a linear, supra-molecular chain. The chains are connected into a layer in the plane by a combination of methyl-ene-C-H⋯S(thione), methyl-ene-C-H⋯O(hydrox-yl), methyl-C-H⋯π(phen-yl) and phenyl-C-H⋯π(hy-droxy-benzene) inter-actions. The layers stack without directional inter-actions between them. The analysis of the calculated Hirshfeld surface highlights the presence of weak methyl-C-H⋯O(hydrox-yl) and H⋯H inter-actions in the inter-layer region. Computational chemistry indicates that dispersion energy is the major contributor to the overall stabilization of the mol-ecular packing.
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http://dx.doi.org/10.1107/S2056989021006666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340978PMC
August 2021

Structured Training for Lap Appendectomy for Residents (STAR Trial)-A Randomized Pilot Study.

J Surg Res 2021 Aug 13;268:363-370. Epub 2021 Aug 13.

Department of Surgery, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Objective: Laparoscopic appendectomy is a common operation that is frequently performed by junior surgical residents. We investigated the effect of a structured training program on the proficiency of junior residents in acquiring skills necessary in this operation.

Design And Participants: This is a randomized pilot trial. Between December 2014 and July 2018, twenty junior residents were recruited for this study. 11 were randomized to receive a structured training program of supervised, task-specific training. Each resident subsequently performed ten cases of laparoscopic appendectomy with their performance assessed for the last 5. The GOALS scale was used as the primary endpoint. Secondary endpoints were perioperative outcomes. The effect of intervention on these outcomes were evaluated assuming a linear mixed effect multi-level model. The study was single-blinded as the assessors did not know which group each resident belonged to.

Results: There were no statistically significant differences in the total GOALS score or any of its individual domains. After adjusting for the number of operations done within the trial, the mean difference between the total GOALS score was 0.07 (95% CI -0.76 to 0.90, P=0.866). Blood loss, hospital stay and postoperative complication rates were similar. There was suggestion of a shorter operative time (effect estimate -9.03, 95% CI -19.56 to 1.50) in the intervention arm although statistical significance was not achieved. No avoidable adverse events due to this study were recorded.

Conclusion: Structured training program did not significantly improve surgical performance and outcomes in laparoscopic appendectomy in this pilot trial. Despite these findings, residents can still potentially mount their learning curves in laparoscopy earlier in a safe environment with such a program which is especially important in the era of minimally invasive surgery.
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http://dx.doi.org/10.1016/j.jss.2021.06.073DOI Listing
August 2021

Characterization of Functional Components in Bovine Colostrum That Inhibit Norovirus Capsid Protruding Domains Interacting with HBGA Ligands.

Pathogens 2021 Jul 7;10(7). Epub 2021 Jul 7.

State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.

Human noroviruses (huNoVs) cause epidemic acute gastroenteritis with significant mortality and morbidity worldwide. However, there are no commercial vaccines or antivirals against these important pathogens so far. In this study, we found that bovine colostrum (bCM) inhibited huNoV VLPs and their capsid-protruding (P) domains binding to histo-blood group antigens (HBGAs) that are huNoV receptor or attachment factors for infection, suggesting that bCM may function as a natural antiviral against huNoVs. We then characterized the bCM for the functional inhibition components by sequentially separating bCM into multiple fractions through various chromatography approaches, followed by determining their inhibitory abilities against huNoV receptor-binding P protein interacting with HBGAs. The protein components of bCM functional fractions were examined by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Our data suggested that some milk proteins, likely in the form of glycoproteins, contribute to the observed blocking effects of bCM. Our findings lay an important foundation to further develop bCM into a potential natural antiviral against huNoVs.
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http://dx.doi.org/10.3390/pathogens10070857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308730PMC
July 2021

Accelerated RNA detection using tandem CRISPR nucleases.

Nat Chem Biol 2021 09 5;17(9):982-988. Epub 2021 Aug 5.

Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA, USA.

Direct, amplification-free detection of RNA has the potential to transform molecular diagnostics by enabling simple on-site analysis of human or environmental samples. CRISPR-Cas nucleases offer programmable RNA-guided RNA recognition that triggers cleavage and release of a fluorescent reporter molecule, but long reaction times hamper their detection sensitivity and speed. Here, we show that unrelated CRISPR nucleases can be deployed in tandem to provide both direct RNA sensing and rapid signal generation, thus enabling robust detection of ~30 molecules per µl of RNA in 20 min. Combining RNA-guided Cas13 and Csm6 with a chemically stabilized activator creates a one-step assay that can detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA extracted from respiratory swab samples with quantitative reverse transcriptase PCR (qRT-PCR)-derived cycle threshold (C) values up to 33, using a compact detector. This Fast Integrated Nuclease Detection In Tandem (FIND-IT) approach enables sensitive, direct RNA detection in a format that is amenable to point-of-care infection diagnosis as well as to a wide range of other diagnostic or research applications.
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http://dx.doi.org/10.1038/s41589-021-00842-2DOI Listing
September 2021

Robust estimates of regional treatment effects in multiregional randomized clinical trials with semiparametric logistic model.

Pharm Stat 2021 Aug 4. Epub 2021 Aug 4.

Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, District of Columbia, USA.

In multiregional randomized clinical trials (MRCTs), determining the regional treatment effect of a new treatment over an existing one is important to both the sponsor and related regulatory agencies. Also of particular interest is to test the null hypothesis that the treatment benefit is the same among all the regions. Existing methods are mainly for continuous endpoint and use parametric models, which are not robust. MRCTs are known for facing increased variation and heterogeneity and a robust model for its design and analysis would be desirable. We consider clinical trials with a binary primary endpoint and propose a robust semiparametric logistic model which has a known parametric and an unknown nonparametric component. The parametric component represents our prior knowledge about the model, and the nonparametric part reflects uncertainty. Compared to the classic logistic model for this problem, the proposed model has the following advantages: robust to model assumption, more flexible and accurate to model the relationship between the response and covariates, and possibly more accurate parameter estimates. The model parameters are estimated by profile maximum likelihood approach, and the null hypothesis of regional treatment difference being the same is tested by the profile likelihood ratio statistic. Asymptotic properties of the estimates are derived. Simulation studies are conducted to evaluate the performance of the proposed model, which demonstrated clear advantages over the classic logistic model. The method is then applied to analyzing a real MRCT.
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http://dx.doi.org/10.1002/pst.2157DOI Listing
August 2021

Whole genome sequencing identifies rare germline variants enriched in cancer related genes in first degree relatives of familial pancreatic cancer patients.

Clin Genet 2021 Nov 3;100(5):551-562. Epub 2021 Aug 3.

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

First-degree relatives (FDRs) of familial pancreatic cancer (FPC) patients have increased risk of developing pancreatic ductal adenocarcinoma (PDAC). Investigating and understanding the genetic basis for PDAC susceptibility in FPC predisposed families may contribute toward future risk-assessment and management of high-risk individuals. Using a Danish cohort of 27 FPC families, we performed whole-genome sequencing of 61 FDRs of FPC patients focusing on rare genetic variants that may contribute to familial aggregation of PDAC. Statistical analysis was performed using the gnomAD database as external controls. Through analysis of heterozygous premature truncating variants (PTV), we identified cancer-related genes and cancer-driver genes harboring multiple germline mutations. Association analysis detected 20 significant genes with false discovery rate, q < 0.05 including: PALD1, LRP1B, COL4A2, CYLC2, ZFYVE9, BRD3, AHDC1, etc. Functional annotation showed that the significant genes were enriched by gene clusters encoding for extracellular matrix and associated proteins. PTV genes were over-represented by functions related to transport of small molecules, innate immune system, ion channel transport, and stimuli-sensing channels. In conclusion, FDRs of FPC patients carry rare germline variants related to cancer pathogenesis that may contribute to increased susceptibility to PDAC. The identified variants may potentially be useful for risk prediction of high-risk individuals in predisposed families.
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http://dx.doi.org/10.1111/cge.14038DOI Listing
November 2021

New species of Phaloria (Orthoptera: Phalangopsidae: Phaloriinae) from West Papua (Indonesia).

Zootaxa 2021 Jun 16;4985(4):513530. Epub 2021 Jun 16.

Institut de Systématique, Evolution et Biodiversité (ISYEB), Muséum national d'Histoire naturelle, CNRS, SU, EPHE, UA, 57 rue Cuvier, CP 50, 75231 Paris Cedex 05, France.

The genus Phaloria belongs to the monophyletic cricket subfamily Phaloriinae. It is s speciose group comprising 68 species found across Southeast Asia and New Guinea and Australia. The numerical diversity of Phaloria in New Guinea is impressive, but more species still await discovery owing to the large size and remoteness of the island. Based on new material collected from Lobo and Kumawa in West Papua (Indonesia), we describe six new species: Phaloria dischidia Tan Robillard, sp. nov. from Lobo; Phaloria paradischidia Tan Robillard, sp. nov. from Kumawa; Phaloria tukul Tan Robillard, sp. nov. from Lobo; Phaloria brevis Tan Robillard, sp. nov. from Kumawa; Phaloria berbeda Tan Robillard, sp. nov. from Lobo; Phaloria lobulata Tan Robillard, sp. nov. from Kumawa. We also record new localities for a species widespread in Lobo and Kumawa: Phaloria nr. aspersa Gorochov, 1996.
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http://dx.doi.org/10.11646/zootaxa.4985.4.5DOI Listing
June 2021

A new species of Heminicsara (Orthoptera: Tettigoniidae: Agraeciini) from West Papua (New Guinea).

Zootaxa 2021 Jun 23;4991(1):161-168. Epub 2021 Jun 23.

Institut de Systématique, Evolution, Biodiversité (ISYEB), Muséum national d'Histoire naturelle, CNRS, SU, EPHE, UA, 57 rue Cuvier, CP 50, 75231 Paris Cedex 05, France..

Heminicsara Karny, 1912 is a katydid genus of Agraeciini from the Axylus genus group. It currently comprises 62 species from mainly New Guinea and surrounding archipelagos. Based on recent fieldwork in Lobo in West Papua, Indonesia, a new species of Heminicsara is described here: Heminicsara incrassata sp. nov. It is most readily characterised from congeners and other species of the Axylus genus group by the male tenth abdominal tergite forming a large shield-shaped plate. This represents the first species of Heminicsara described and known from the south-west of New Guinea.
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http://dx.doi.org/10.11646/zootaxa.4991.1.8DOI Listing
June 2021

Cohort profile and heritability assessment of familial pancreatic cancer: a nation-wide study.

Scand J Gastroenterol 2021 Aug 24;56(8):965-971. Epub 2021 Jun 24.

Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

Background: Familial Pancreatic Cancer (FPC) is responsible for up to 10% of all cases of pancreatic ductal adenocarcinoma (PDAC). Individuals predisposed for FPC have an estimated lifetime risk of 16-39% of developing PDAC. While heritability of PDAC has been estimated to be 36% in a Nordic twin study, no heritability estimate specific on FPC has been reported.

Methods: A national cohort of Danish families with predisposition for FPC is currently included in a screening program for PDAC at Odense University Hospital. Family members included in the screening program were interviewed for pedigree data including: cases of PDAC among first-degree relatives (FDRs) and number of affected/unaffected siblings. Heritability for FPC in the predisposed families was assessed by doubling the estimated intra-class correlation coefficient (ICC) from a random intercept logistic model fitted to data on FDRs.

Results: Among families with predisposition for FPC, 83 cases of PDAC were identified. The median age at diagnosis of PDAC was 66 years, and median time from diagnosis to death was 7.6 months. A total of 359 individuals were found as unaffected FDRs of the 83 PDAC cases. The retrieved FDRs included a total of 247 individuals in sibship and 317 individuals in parent-offspring relatedness. We estimated an ICC of 0.25, corresponding to a narrow sense additive heritability estimate of 0.51 in the FPC family cohort.

Conclusion: We have established a nation-wide cohort of FPC families to facilitate clinical and genetic studies on FPC. The estimated heritability of 51% prominently underlines a strong genetic background of FPC.
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http://dx.doi.org/10.1080/00365521.2021.1937697DOI Listing
August 2021

Hematologic safety of palbociclib in combination with endocrine therapy in patients with benign ethnic neutropenia and advanced breast cancer.

Cancer 2021 Oct 22;127(19):3622-3630. Epub 2021 Jun 22.

Georgetown Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia.

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC.

Methods: PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status.

Results: Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively).

Conclusions: These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.
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http://dx.doi.org/10.1002/cncr.33620DOI Listing
October 2021

A Hybrid Treatment via MHz Acoustic Waves and Plasma to Enhance Seed Germination in Mung Bean.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Jun 21;PP. Epub 2021 Jun 21.

We investigate a hybrid treatment-consists of an atmospheric pressure plasma pre-treatment, followed by an MHz surface acoustic waves treatment (SAW) with either DI water or plasma activated water (PAW)-on mung beans to accelerate the germination process, as mung bean sprout is one of the important food staples. For the early growth rate (after 320 mins), we observe that the hybrid treatment with PAW can lead to approximately 217% higher moisture content for the treated beans as compared to that without the hybrid treatment. Additionally, the hybrid treated beans germinate in around 120 mins, while the untreated beans only germinate in around 420 mins, i.e., 3.5-fold faster for treated beans. This can be attributed to the dominant effect of SAW that accelerates stage 1 water absorption process, and, the effect of direct plasma as well as plasma activated water both that promotes stage 2 metabolism process, leading to the enhancement in stage 3 germination process in early growth rate. For the post growth rate (after 24 hours), we observe that the hybrid treatment with DI water can lead to an approximately 44.20% in higher moisture and 71.17% in radicle length as compared to untreated beans. Interestingly, the hybrid treatment with plasma activated water, on the other hand, is observed to have an adverse effect on germination after 24 hours, i.e., approximately 14.51% lower in moisture content and 43.49% lower in radicle length for the hybrid treated beans with PAW as compared to that with DI water.
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http://dx.doi.org/10.1109/TUFFC.2021.3091155DOI Listing
June 2021

Molecular mechanism of MdWUS2-MdTCP12 interaction in mediating cytokinin signaling to control axillary bud outgrowth.

J Exp Bot 2021 06;72(13):4822-4838

College of Life Science, Northwest A & F University, Yangling, Shaanxi 712100, China.

Shoot branching is an important factor that influences the architecture of apple trees and cytokinin is known to promote axillary bud outgrowth. The cultivar 'Fuji', which is grown on ~75% of the apple-producing area in China, exhibits poor natural branching. The TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) family genes BRANCHED1/2 (BRC1/2) are involved in integrating diverse factors that function locally to inhibit shoot branching; however, the molecular mechanism underlying the cytokinin-mediated promotion of branching that involves the repression of BRC1/2 remains unclear. In this study, we found that apple WUSCHEL2 (MdWUS2), which interacts with the co-repressor TOPLESS-RELATED9 (MdTPR9), is activated by cytokinin and regulates branching by inhibiting the activity of MdTCP12 (a BRC2 homolog). Overexpressing MdWUS2 in Arabidopsis or Nicotiana benthamiana resulted in enhanced branching. Overexpression of MdTCP12 inhibited axillary bud outgrowth in Arabidopsis, indicating that it contributes to the regulation of branching. In addition, we found that MdWUS2 interacted with MdTCP12 in vivo and in vitro and suppressed the ability of MdTCP12 to activate the transcription of its target gene, HOMEOBOX PROTEIN 53b (MdHB53b). Our results therefore suggest that MdWUS2 is involved in the cytokinin-mediated inhibition of MdTCP12 that controls bud outgrowth, and hence provide new insights into the regulation of shoot branching by cytokinin.
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http://dx.doi.org/10.1093/jxb/erab163DOI Listing
June 2021

Transport of Amino Acids in Soy Sauce Desalination Process by Electrodialysis.

Membranes (Basel) 2021 May 29;11(6). Epub 2021 May 29.

College of Environment and Safety Engineering, Qingdao University of Science and Technology, 53 Zhengzhou Road, Qingdao 266042, China.

Soy sauce is a common condiment that has a unique flavor, one that is derived from its rich amino acids and salts. It is known that excessive intake of high-sodium food will affect human health, causing a series of diseases such as hypertension and kidney disease. Therefore, removing sodium from the soy sauce and retaining the amino acids is desirable. In this study, electrodialysis (ED) was employed for the desalination of soy sauce using commercial ion exchange membranes (IEMs). The influence of the current density and initial pH on the desalination degree of the soy sauce was explored. Results showed that the optimal desalination condition for ED was reached at a current density of 5 mA/cm and pH of 5, with the desalination degree of 64% and the amino acid loss rate of 29.8%. Moreover, it was found that the loss rate of amino acids was related to the initial concentration and molecular structure. In addition, the amino acid adsorption by IEMs was explored. Results implied that the molecular weight and structure affect amino acid adsorption. This study illustrated that the ED process can successfully reduce the salt content of the soy sauce and retain most of the amino acids without compromising the original flavor.
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http://dx.doi.org/10.3390/membranes11060408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228157PMC
May 2021

Anti-HBV therapeutic potential of small molecule 3,5,6,7,3',4'-Hexamethoxyflavone in vitro and in vivo.

Virology 2021 Aug 22;560:66-75. Epub 2021 May 22.

The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address:

Current treatment methods for hepatitis B are mainly antiviral drug therapy and immunotherapy, in which antiviral drugs are mainly nucleoside analogue and interferon. They can significantly reduce the viral load but rarely achieve hepatitis B surface antigen (HBsAg) loss. 3,5,6,7,3',4'-Hexamethoxyflavone was screened out from a small molecule compound library for its lower cytotoxic effect and greater HBsAg inhibition activity. Meanwhile, we further performed experiments in HepG2.2.15, HepG2-NTCP cells, PHHs and HBV transgenic mouse model to evaluate the anti-HBV effects of 3,5,6,7,3',4'-Hexamethoxyflavone. Our study found that 3,5,6,7,3',4'-Hexamethoxyflavone can significantly reduce the level of HBV RNAs, HBV DNA and HBsAg, in addition, the activity of four HBV promoters and the ratio of total RNAs/cccDNA and 3.5 kb RNA/cccDNA were decreased by 3,5,6,7,3',4'-Hexamethoxyflavone. Mechanistically, we found HNF3α plays important roles in Hex mediated HBV transcription inhibition. Our study indicated Hex was a potential anti-HBV therapeutic drug.
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http://dx.doi.org/10.1016/j.virol.2021.05.007DOI Listing
August 2021

Intra-species sialic acid polymorphism in humans: a common niche for influenza and coronavirus pandemics?

Emerg Microbes Infect 2021 Dec;10(1):1191-1199

Department of Chemistry and Biochemistry, Miami University, Oxford, OH, USA.

The ongoing COVID-19 pandemic has led to more than 159 million confirmed cases with over 3.3 million deaths worldwide, but it remains mystery why most infected individuals (∼98%) were asymptomatic or only experienced mild illness. The same mystery applies to the deadly 1918 H1N1 influenza pandemic, which has puzzled the field for a century. Here we discuss dual potential properties of the 1918 H1N1 pandemic viruses that led to the high fatality rate in the small portion of severe cases, while about 98% infected persons in the United States were self-limited with mild symptoms, or even asymptomatic. These variations now have been postulated to be impacted by polymorphisms of the sialic acid receptors in the general population. Since coronaviruses (CoVs) also recognize sialic acid receptors and cause severe acute respiratory syndrome epidemics and pandemics, similar principles of influenza virus evolution and pandemicity may also apply to CoVs. A potential common principle of pathogen/host co-evolution of influenza and CoVs under selection of host sialic acids in parallel with different epidemic and pandemic influenza and coronaviruses is discussed.
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http://dx.doi.org/10.1080/22221751.2021.1935329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208123PMC
December 2021

LINC01116 regulates proliferation, migration, and apoptosis of keloid fibroblasts by the TGF-β1/SMAD3 signaling via targeting miR-3141.

Anal Biochem 2021 Aug 25;627:114249. Epub 2021 May 25.

Department of Plastic and Cosmetic Surgery, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, China.

Background: Keloids are benign fibroproliferative skin tumors. Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of keloid formation. In this paper, we explored the precise actions of LINC01116 in keloid formation.

Methods: The targeted relationship between microRNA (miR)-3141 and LINC01116 or transforming growth factor β1 (TGF-β1) was verified by dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays. The expression levels of LINC01116, miR-3141, TGF-β1, and SMAD family member 3 (SMAD3) were gauged by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Cell proliferation, migration, and apoptosis were assessed by the Cell Counting Kit-8 (CCK-8) assay, wound-healing assay, and flow cytometry, respectively. Animal studies were used to assess the role of LINC01116 in the subcutaneous keloid growth in vivo.

Results: Our data showed that LINC01116 targeted miR-3141 by directly binding to miR-3141. LINC01116 was up-regulated and miR-3141 was down-regulated in human keloid tissues and fibroblasts. LINC01116 knockdown or miR-3141 overexpression suppressed keloid fibroblast proliferation, migration, and promoted cell apoptosis. Moreover, miR-3141 was a downstream mediator of LINC01116 function. MiR-3141 regulated the TGF-β1/SMAD3 signaling by directly targeting TGF-β1. Furthermore, TGF-β1 was identified as a direct and functional target of miR-3141. LINC01116 regulated the TGF-β1/SMAD3 signaling through miR-3141. Additionally, LINC01116 knockdown diminished the subcutaneous keloid growth in vivo.

Conclusion: Our findings demonstrated a novel mechanism, the miR-3141/TGF-β1/SMAD3 regulatory pathway, at least partially for the oncogenic role of LINC01116 in keloid formation.
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http://dx.doi.org/10.1016/j.ab.2021.114249DOI Listing
August 2021

Advances in the surgical outcomes of 300 cases of pure laparoscopic living donor right hemihepatectomy divided into three periods of 100 cases: a single-centre case series.

Ann Transl Med 2021 Apr;9(7):553

Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.

Background: Minimally invasive surgery has been widely used for hepatobiliary operations. This study aimed to determine the safety and feasibility of pure laparoscopic living donor right hepatectomy.

Methods: From November 2015 to April 2019, 300 cases of adult pure laparoscopic living donor right hepatectomy performed at Seoul National University Hospital were divided into three subgroups of periods 1-3 of 100 cases each: 1-100, 101-200, and 201-300, respectively. We retrospectively reviewed and analysed the safety and feasibility outcomes.

Results: The operative time (period 1: 318.9±62.2 min, period 2: 256.7±71.4 min, period 3: 227.7±57.4 min) and blood loss (period 1: 419.7±196.5 mL, period 2: 198.9±197.2 mL, period 3: 166.0±130.0 mL) gradually decreased (P<0.01). Similarly, the length of hospital stay decreased (period 1: 8.1±2.0 days, period 2: 7.3±3.1 days, period 3: 6.9±2.4 days, P<0.01). There was no requirement for intraoperative transfusions or care in the intensive care unit. The overall complication rate was 20/300 (6.7%), of which 8/300 (2.7%) were Clavien-Dindo grade III and above. Complications were not different among the three periods. In terms of anatomical variations, the incidences of multiple portal veins, multiple hepatic arteries, and multiple bile ducts were 32/300 (10.7%), 11/300 (3.7%), and 161/300 (53.7%), respectively. No differences were found among the three periods.

Conclusions: Owing to the technical improvements over time, pure laparoscopic living donor hepatectomy is currently feasible and safe even for donors with anatomical variations.
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http://dx.doi.org/10.21037/atm-20-6886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105826PMC
April 2021

Stereotactic radiosurgery with whole brain radiotherapy combined with bevacizumab in the treatment of brain metastases from NSCLC.

Int J Neurosci 2021 Sep 24:1-8. Epub 2021 Sep 24.

Sichuan Cancer Hospital & Institute, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.

Objective: Non-small cell lung cancer (NSCLC) patients who experience brain metastases are usually associated with poor prognostic outcomes. Whole-brain radiotherapy (WBRT) is one of the standard treatment strategies for NSCLC. It is interesting to combine angiogenesis inhibitors such as bevacizumab with radiation therapy. This study aimed to explore the efficacy and safety of stereotactic radiosurgery (SRS) with WBRT combined with bevacizumab in the treatment of brain metastases.

Methods: A total of 21 patients with brain metastases from NSCLC were treated with bevacizumab and WBRT-SRS, while 28 patients were treated with WBRT-SRS only. The bevacizumab average dose was 5-7.5 mg/kg, approximately 2 cycles during radiotherapy. Tumor responses were evaluated every 3 months based on Response Evaluation Criteria in Solid Tumors version 1.1.

Results: The median follow-up time was 13.5 months (range 2.7-88.4 months). The ORR and DCR of patients who received WBRT-SRS with or without bevacizumab were similar ( = 0.458,  = 0.382). OS(42.63 years VS 25.23 years,  = 0.02)and LPFS (39.53 years VS 23 years,  = 0.047)were better in WBRT-SRS with bevacizumab groups. After radiotherapy and 3 months after radiotherapy, the volume of peritumoral edema was significantly reduced in WBRT-SRS with bevacizumab groups(45.62 ± 24.03 cm vs 63.03 ± 25.44 cm,  = 0.036;8.63 ± 6.87 cm vs 15.62 ± 10.58 cm,  = 0.021). The main adverse reactions were similar in the two groups except for Venous thrombosis with bevacizumab (0 patients vs 5 patients,  = 0.006).

Conclusion: Bevacizumab with radiotherapy improved the overall efficacy and reduced the peritumoral edema of BM from NSCLC.
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http://dx.doi.org/10.1080/00207454.2021.1916490DOI Listing
September 2021

Three-dimensional positional accuracy of intraoral and laboratory implant scan bodies.

J Prosthet Dent 2021 Apr 6. Epub 2021 Apr 6.

Associate Professor, Faculty of Dentistry, National University of Singapore, Singapore, Republic of Singapore. Electronic address:

Statement Of Problem: In the implant digital workflow, scan bodies provide the 3D position of digital implants in the virtual dental arch. However, limited evidence is available on scan body accuracy, selection, and usage.

Purpose: The purpose of this in vitro study was to evaluate the 3D positional accuracy of 4 intraoral and 6 laboratory scan body systems to the implants and laboratory replicas of an implant system under various torque magnitudes.

Material And Methods: Ten test groups comprising 4 intraoral (I): Medentika L-Series (MS), Straumann CARES Mono (SM), Core 3D (CO), Straumann RC (SS); and 6 laboratory (L): Nobel Procera Pos Locator (NP), Sirona InPost (SR), Amann Girrbach (AG), Straumann CARES Mono (SM), Core 3D (CO), Straumann RC (SS) scan bodies were derived from 7 scan body systems. Of these, 3 systems (SM, CO, SS) are used for both intraoral and laboratory applications. The scan bodies were tested on Straumann Bone Level Regular CrossFit implants or laboratory replicas. Eight test groups allowed for the variation of torque application (5, 10, and 15 Ncm), while 2 test groups (NP, SR) were hand positioned only. Prefabricated metal abutments (ME) for both implants and laboratory replicas served as controls. A coordinate measuring machine measured four 3D positional accuracy variables: vertical linear distortion (d), 2D tolerance displacement (d), global linear distortion (d), and scan body height discrepancy (ΔH) (n=10). The data were analyzed with 2-way analysis of variance tests and post hoc analysis with Tukey tests (α=.05).

Results: For both intraoral and laboratory test groups, 2-way ANOVA found that the system had a significant effect on all distortion variables (P<.001), while torque magnitude had a significant effect only on d and ΔH (P<.001). Overall, mean d ranged from 5 ±12 μm for L-AG at 15 Ncm to 23 ±14 μm for L-AG at 5 Ncm. Mean d ranged from 5 ±4 μm for I-SM at 15 Ncm to 73 ±41 μm for L-SS at 10 Ncm, and mean d ranged from 11 ±6 μm for I-SM at 10 Ncm to 74 ±41 μm for L-SS at 10 Ncm. Mean ΔH ranged from -5 ±10 μm for I-SM at 15 Ncm to 23 ±14 μm for L-AG at 5 Ncm. Among intraoral test groups, for d and ΔH, all the test groups except for I-SM at 15 Ncm and I-MS at 10 and 15 Ncm were significantly more positive than the control (P<.001). For d, I-SS at 5, 10, and 15 Ncm was significantly different from the control (P<.001). For d, only I-SS at 5 Ncm was significantly different from the control (P<.001). Among laboratory test groups, for d and ΔH, L-AG at 5 Ncm and L-CO at 15 Ncm were significantly more positive than the control (P<.001). For d, L-SS at 10 and 15 Ncm were significantly different from the control (P<.001). For d, only L-SS at 10 Ncm was significantly different from the control (P<.001). Intraoral and laboratory systems show comparable 3D positional accuracy.

Conclusions: Overall, I-SS and L-SS were the least accurate. The system tested had a significant effect on 3D positional accuracy, while torque magnitude had no consistent effect across all systems.
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http://dx.doi.org/10.1016/j.prosdent.2020.09.057DOI Listing
April 2021

The Small Molecule H89 Inhibits Inclusion Growth and Production of Infectious Progeny.

Infect Immun 2021 06 16;89(7):e0072920. Epub 2021 Jun 16.

Department of Developmental and Cell Biology, University of California, Irvine, California, USA.

is an obligate intracellular bacterium and the most common reportable cause of human infection in the United States. This pathogen proliferates inside a eukaryotic host cell, where it resides within a membrane-bound compartment called the chlamydial inclusion. It has an unusual developmental cycle, marked by conversion between a replicating form, the reticulate body (RB), and an infectious form, the elementary body (EB). We found that the small molecule H89 slowed inclusion growth and decreased overall RB replication by 2-fold but caused a 25-fold reduction in infectious EBs. This disproportionate effect on EB production was mainly due to a defect in RB-to-EB conversion and not to the induction of chlamydial persistence, which is an altered growth state. Although H89 is a known inhibitor of specific protein kinases and vesicular transport to and from the Golgi apparatus, it did not cause these anti-chlamydial effects by blocking protein kinase A or C or by inhibiting protein or lipid transport. Thus, H89 is a novel anti-chlamydial compound that has a unique combination of effects on an intracellular infection.
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http://dx.doi.org/10.1128/IAI.00729-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373235PMC
June 2021

Accelerated RNA detection using tandem CRISPR nucleases.

medRxiv 2021 Mar 24. Epub 2021 Mar 24.

Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA, USA.

Direct, amplification-free detection of RNA has the potential to transform molecular diagnostics by enabling simple on-site analysis of human or environmental samples. CRISPR-Cas nucleases offer programmable RNA-guided recognition of RNA that triggers cleavage and release of a fluorescent reporter molecule , but long reaction times hamper sensitivity and speed when applied to point-of-care testing. Here we show that unrelated CRISPR nucleases can be deployed in tandem to provide both direct RNA sensing and rapid signal generation, thus enabling robust detection of ∼30 RNA copies/microliter in 20 minutes. Combining RNA-guided Cas13 and Csm6 with a chemically stabilized activator creates a one-step assay that detected SARS-CoV-2 RNA from nasopharyngeal samples with PCR-derived Ct values up to 29 in microfluidic chips, using a compact imaging system. This Fast Integrated Nuclease Detection In Tandem (FIND-IT) approach enables direct RNA detection in a format amenable to point-of-care infection diagnosis, as well as to a wide range of other diagnostic or research applications.
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http://dx.doi.org/10.1101/2021.03.19.21253328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010768PMC
March 2021
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