Publications by authors named "Bo Feng"

665 Publications

HBeAg-positive patients with HBsAg  < 100 IU/mL and negative HBV RNA have lower risk of virological relapse after nucleos(t)ide analogues cessation.

J Gastroenterol 2021 Jul 22. Epub 2021 Jul 22.

Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology On NAFLD Diagnosis, Peking University Hepatology Institute, Peking University People's Hospital, Beijing, 100044, China.

Background: Nucleos(t)ide analogues (NAs) cessation is not widely practiced and remains a controversial, but highly relevant subject in patients infected with hepatitis B virus (HBV). We aimed to explore the related factors for safe NAs cessation.

Methods: This is a multicenter prospective cohort study. Overall, 139 initially HBV e antigen (HBeAg)-positive patients meeting the stopping criteria were included in 12 hospitals in China. Enrolled patients ceased NAs and were followed up every 3 months for 24 months or until clinical relapse (CR).

Results: The 24 month cumulative rates of virological relapse (VR), CR, HBeAg reversion and HBV surface antigen (HBsAg) loss were 50.4, 24.5, 11.5 and 9.4%, respectively. Patients with end of treatment (EOT) HBsAg  < 100 IU/mL plus negative HBV RNA had the lowest 24 month cumulative VR rate (5 vs 58%, p < 0.001). EOT HBsAg  ≥ 2 log IU/mL [odds ratio (OR) = 6.686, p = 0.006], EOT positive HBV RNA (OR = 3.453, p = 0.008) and EOT hepatitis B core-related antigen (HBcrAg)  ≥ 4log U/mL (OR = 3.702, p = 0.002) were found to independently predict the risk of VR. To predict VR, the area under the receiver-operating characteristic (AUROC) value of the EOT HBsAg  < 100 IU/mL plus EOT HBV RNA negative was 0.698 (p < 0.001), which was higher than other parameters alone or combinations.

Conclusions: NAs cessation is suitable only for a small and selected patients. An EOT HBsAg  < 100 IU/mL and EOT negative HBV RNA identified a patient with low risk of off-treatment VR.
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http://dx.doi.org/10.1007/s00535-021-01812-0DOI Listing
July 2021

A Broadband Photoelectronic Detector in a Silicon Nanopillar Array with High Detectivity Enhanced by a Monolayer Graphene.

Nano Lett 2021 Jul 28;21(13):5655-5662. Epub 2021 Jun 28.

Nanolithography and Application Research Group, State Key Lab of ASIC and System, School of Information Science and Technology, Fudan University, Shanghai, 200433, China.

To meet the fast-growing need for broad applications in remote sensing, novel optoelectronic devices with high detectivity in full bands and room temperature operation are urgently desired. This paper reports our progress in developing a specially designed photovoltaic detector by integrating a monolayer graphene onto a silicon-based nanopillar array standing on a p-n junction. Optoelectronic measurements of the fabricated detectors show that the monolayer graphene plays a critical role in device performance. Compared with the one without the graphene covering, the new device demonstrates significant improvements in the specific detectivity of 1.43 × 10 Jones and the responsivity exceeding ∼10 V/W with a reduced leakage current corresponding to a quantum efficiency of 74.8% at 860 nm wavelength. Moreover, such sensing performance remained unaffected over the entire band from 450 to 1100 nm at room temperature, which is suitable for broadband imaging applications.
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http://dx.doi.org/10.1021/acs.nanolett.1c01244DOI Listing
July 2021

Asymptomatic traumatic rupture of an intracranial dermoid cyst: A case report.

World J Clin Cases 2021 Jun;9(16):4046-4051

Department of Radiology, Hangzhou Ninth People's Hospital, Hangzhou 310006, Zhejiang Province, China.

Background: Previous studies reported that most of the intracranial dermoid cyst ruptures were spontaneous, and only a few were traumatic, with asymptomatic much rarer than the symptomatic ruptures. Hence, how to deal with the asymptomatic traumatic rupture of intracranial dermoid cyst remains a challenge in the clinic.

Case Summary: A 59-year-old man was accidentally diagnosed with intracranial dermoid cyst through a cranial computed tomography (CT) scan due to a car accident. A mixed-density lesion with fat and a calcified margin was observed in the midline of the posterior fossa, accompanied with lipid droplet drifts in brain sulci, fissures, cisterns, and ventricles. After 1 wk of conservative observation, no change was observed on the updated cranial CT scan. After 2 wk of conservative observation, magnetic resonance imaging examination confirmed that the lesion was a traumatic rupture of a posterior fossa dermoid cyst with lipid droplet drifts. As the patient exhibited no adverse symptoms throughout the 2 wk, a 6-mo follow-up visit was arranged for him instead of aggressive treatment. Nonetheless, the patient did not show any abnormal neurological symptoms in the 6 mo of follow-up visits.

Conclusion: Asymptomatic traumatic rupture of intracranial dermoid cyst could be just followed or treated conservatively rather than treated aggressively.
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http://dx.doi.org/10.12998/wjcc.v9.i16.4046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180201PMC
June 2021

Combined Percutaneous Kyphoplasty/Pediculoplasty by Posterolateral Transpedicular Approach for Painful Cervical Spine Metastases: A Single-Center Prospective Study.

J Pain Res 2021 10;14:1699-1706. Epub 2021 Jun 10.

Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.

Purpose: In patients requiring percutaneous kyphoplasty (PKP) for painful cervical spine metastases (PCSMs), the surgical approach is of utmost importance. Anterolateral and transoral routes are generally used at present, whereas PKP as well as percutaneous pediculoplasty (PPP) via posterolateral transpedicular approach (PTPA) has yet to be pursued in the treatment of PCSMs. The study was designed to evaluate safety and efficacy of PKP procedures combined with PPP via PTPA as treatment of PCSMs.

Patients And Methods: The patients with PCSMs were enrolled and housed in a database. The pain intensity of enrolled patients was gauged by Visual Analog Scale (VAS), ranging from 0 (none) to 10 (extreme). After preprocedural imaging assessment, combined PKP/PPP via PTPA was performed under the guidance of CT and fluoroscopic monitoring. Postprocedural VAS scores, complications, cement dosage, and hospitalization were recorded in the database for analysis. All cases were followed up for 6 months.

Results: Adult enrollees (7 women, 4 men) with PCSMs successfully underwent PKP/PPP via PTPA between February 2019 and January 2020, injected with 3.7±0.7 mL (range, 2.5-4.8 mL) of cement on average. Other than a single instance of asymptomatic cement leakage into paravertebral soft tissues, no complications ensued. Significant analgesic effects observed 24 hours after procedures were sustained for up to 6 months in follow-up surveys. Postprocedural hospitalizations were as brief as 2.2±0.8 days.

Conclusion: Combined PKP/PPP via PTPA is safe and effective as treatment of PCSMs, enabling quick pain relief and patient recovery.
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http://dx.doi.org/10.2147/JPR.S310446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203187PMC
June 2021

Systematic analysis of lysine 2-hydroxyisobutyrylation posttranslational modification in wheat leaves.

PLoS One 2021 17;16(6):e0253325. Epub 2021 Jun 17.

Crop Research Institute, Shandong Academy of Agricultural Sciences, Ji'nan, Shandong, P. R. China.

Lysine 2-hydroxyisobutyrylation (Khib) is a recently discovered post-translational modification (PTM) showing diverse biological functions and effects in living organisms. However, the study of Khib in plant species is still relatively limited. Wheat (Triticum aestivum L.) is a global important cereal plant. In this study, the systematic Khib analysis was performed in wheat leave tissues. A total of 3004 Khib sites in 1104 proteins were repeatedly identified. Structure characterization of these Khib peptides revealed 12 conserved sequence motifs. Function classification and enrichment analysis indicated these Khib proteins showed a wide function and pathway distribution, of which ribosome activity, protein biosynthesis and photosynthesis were the preferred biological processes. Subcellular location predication indicated chloroplast was the dominant subcellular compartment where Khib was distributed. There may be some crosstalks among Khib, lysine acetylation and lysine succinylation modification because some proteins and sites were modified by all these three acylations. The present study demonstrated the critical role of Khib in wheat biological and physiology, which has expanded the scope of Khib in plant species. Our study is an available resource and reference of Khib function demonstration and structure characterization in cereal plant, as well as in plant kingdom.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253325PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211214PMC
June 2021

"Felodipine-indomethacin" co-amorphous supersaturating drug delivery systems: "Spring-parachute" process, stability, in vivo bioavailability, and underlying molecular mechanisms.

Eur J Pharm Biopharm 2021 Sep 10;166:111-125. Epub 2021 Jun 10.

School of Pharmacy, Jilin Medical University, Jilin City 132013, Jilin Province, China. Electronic address:

Amorphous solid dispersions (ASD) are one of most commonly used supersaturating drug delivery systems (SDDS) to formulate insoluble active pharmaceutical ingredients. However, the development of polymer-guided stabilization of ASD systems faces many obstacles. To overcome these shortcomings, co-amorphous supersaturable formulations have emerged as an alternative formulation strategy for poorly soluble compounds. Noteworthily, current researches around co-amorphous system (CAS) are mostly focused on preparation and characterization of these systems, but more detailed investigations of their supersaturation ("spring-parachute" process), stability, in vivo bioavailability and molecular mechanisms are inadequate and need to be clarified. In present study, we chose pharmacological relevant BCS II drugs to fabricate and characterize "felodipine-indomethacin" CAS. To enrich the current inadequate but key knowledge on CAS studies, we carried out following highlighted investigations including dissolution/solubility, semi-continuous "spring-parachute" process, long-term stability profile of amorphous state, in vivo bioavailability and underlying molecular mechanisms (molecular interaction, molecular miscibility and crystallization inhibition). Generally, the research provides some key information in the field of current "drug-drug" CAS supersaturable formulations.
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http://dx.doi.org/10.1016/j.ejpb.2021.05.030DOI Listing
September 2021

Evaluation of Long-Term Outcomes and Toxicity After Stereotactic Phosphorus-32-Based Intracavitary Brachytherapy in Patients With Cystic Craniopharyngioma.

Int J Radiat Oncol Biol Phys 2021 May 29. Epub 2021 May 29.

Department of Radiation Oncology, Geisinger Health Care, Danville, Pennsylvania; Division of Neurosurgery, McMaster University and Hamilton General Hospital, Hamilton, Ontario, Canada. Electronic address:

Purpose: Interstitial brachytherapy based on phosphorus-32 (P-32) has an established role as a minimally invasive treatment modality for patients with cystic craniopharyngioma. However, reporting on long-term outcomes with toxicity profiles for large cohorts is lacking in the literature. The purpose of this study is therefore to evaluate the long-term visual, endocrinal, and neurocognitive functions in what is the largest patient series having received this treatment to date.

Methods And Materials: We retrospectively evaluated 90 patients with cystic craniopharyngiomas who were treated with stereotactic intracavitary brachytherapy between 1998 and 2010. Colloidal activity of injected radioisotope P-32 was based on an even distribution within the tumor. After treatment, patients were followed-up for a minimum of 5 years and over a mean of 121 months (60-192 months) to assess radiographic and clinical responses.

Results: The 90 patients included in our study cohort underwent a total of 108 stereotactic surgical procedures for 129 craniopharyngioma-related cysts. Of the included tumors, 65 (72.2%) were associated with a single cyst, 15 (16.7%) were associated with 2 cysts, and 10 (11.1%) tumors had developed septations with 3 to 4 cysts. Stereotactic cyst puncture and content aspiration were used to drain a mean cyst fluid volume of 21.4 mL (1.0-55.0 mL). Each cyst was then instilled for interstitial brachytherapy with colloidal P-32 solution. Based on radiographic follow-up assessments, 56 cysts (43.4%) showed resolution and/or nonrecurrence, which was classified as a complete response to treatment; 47 cysts (36.4%) showed a partial response; and 5 cysts (3.9%) displayed a stable appearance. Treatment resulted in immediate and clinically significant vision improvement in 54 of 63 (86%) symptomatic patients, and this improvement was maintained. Progression-free survival rates at 5 and 10 years were 95.5% and 84.4%, respectively.

Conclusions: P-32-based interstitial brachytherapy can play an effective role in managing patients with cystic craniopharyngiomas. It can be considered a valid alternative to surgery in select patients with a favorable toxicity profile and long-term clinical outcomes.
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http://dx.doi.org/10.1016/j.ijrobp.2021.05.123DOI Listing
May 2021

Graphene oxide-regulated low-background aptasensor for the "turn on" detection of tetracycline.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Nov 4;260:119898. Epub 2021 May 4.

College of Environment and Resources, Xiangtan University, Xiangtan 411105, Hunan Province, China. Electronic address:

Tetracyclines (TC) are a common antibiotic for using in livestock breeding and healthcare; however, due to the inappropriate application of TCs, more than 75% of TCs are excreted and released into the environment in an active form through human and animal urine and feces, which results in high levels of TCs in the ecological system, causing adverse effects on the food safety and human health. Thus, the high-performance monitoring of TC pollution is necessary. In this work, a highly sensitive fluorescent aptasensor was developed that was based on graphene oxide (GO) regulation of low background signal and target-induced fluorescence restoration. In the absence of analyte, the DNA probe (TC aptamer) was adsorbed completely by GO and failed to enhance the fluorescence of SYBR gold (SG), thereby resulting in a low background signal. When the TC-included samples were added, the DNA probe formed an aptamer-TC complex, thereby separating from the surface of the GO and inducing the fluorescence of SG. Under optimal conditions, the proposed strategy could detect TC concentrations of less than 6.2 × 10 ng mL, which is four orders of magnitude better than the detection limit of the "turn off" mode (53.9511 ng mL). Moreover, this aptasensor has been used to detect TC from milk samples and wastewater samples, and its satisfactory performances demonstrate that the proposed strategy can be applied in practice for TC monitor in food safety and environmental protection. Therefore, we believe that this work is meaningful in pollution monitoring, environment restoration and emergency treatment.
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http://dx.doi.org/10.1016/j.saa.2021.119898DOI Listing
November 2021

Optimization study of metallic hole arrays as the multi-channel spectral filters in long-infrared wavelengths.

Appl Opt 2021 May;60(13):3830-3835

The development of miniaturized multi-channel infrared filters based on plasmonic metasurfaces is attracting growing attention, driven by its potential applications in infrared imaging, photodetectors, and spectroscopy. However, the advance of such filters in long-infrared wavelengths has rarely been reported. This paper reports our recent progress on developing multi-channel spectral filters based on micrometer metallic hole arrays in the long-infrared band of 10-15 µm. The effects of structural parameters and the shapes of metallic hole arrays on filtering performance are investigated by numerical simulations with the finite-difference time-domain method and then experimentally verified by optical characterizations of fabricated filters using electron beam lithography. The transmission peaks of the filter on a zinc selenide substrate were optimized with a maximum transmittance of 63%. A comparison of the hole shapes shows that elliptical holes give rise to sharper transmission peak quality than round ones by 28%. The progress achieved in this work should be a promising step in the development of metallic hole-based spectral filters with miniaturized dimensions.
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http://dx.doi.org/10.1364/AO.422224DOI Listing
May 2021

Application Value of 4K High-Definition System in Laparoscopic Gastrectomy: Preliminary Results and Initial Experience.

J Laparoendosc Adv Surg Tech A 2021 May 7. Epub 2021 May 7.

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

To investigate the application value of 4K high definition (HD) in laparoscopic gastrectomy by comparing the short-term outcomes and subjective perception with three-dimensional (3D) and HD vision systems. A retrospective study was conducted between September 2018 and February 2019; a total of 87 patients who underwent laparoscopic gastrectomy were enrolled and divided into three groups in terms of different type of vision system used for surgery: 4K, 3D, and HD. Demographic and clinicopathological data as well as short-term outcomes were collected and analyzed. A questionnaire survey was completed by the team of surgeons to evaluate the subjective perception of different vision systems. There was no significant difference in gender, body mass index, age, American Society of Anesthesiologists (ASA) score and history of abdominal surgery, tumor location as well as type of operation, and anastomosis between the 4K, 3D, and HD groups. All patients underwent laparoscopic gastrectomy without conversion to laparotomy. There was no difference between the three groups regarding operation time (4K versus 3D versus two-dimensional (2D), 183.60 ± 52.5 versus 189.69 ± 69.87 versus 211.00 0 ± 49.33,  = .145) and estimated blood loss (4K versus 3D versus 2D, 123.60 ± 119.51 versus 150.62 ± 105.46 versus 129.00 ± 103.57,  = .602), no difference was found in time to first flatus and postoperative hospital stay between the three groups. No significant difference was found in postoperative complications between the three groups. As for pathological results, there was no difference in tumor size and tumor-node-metastasis (TNM) stage. In 4K group, the number of lymph node harvested was 32.60 ± 10.28, no difference was found compared with that of 3D (29.81 ± 8.94) and HD groups (27.69 ± 10.96). The score of group 3D was the lowest concerning asthenopia and motion sickness. On the contrary, 3D group achieved the highest score in topographical orientation and depth description. 4K group was graded the highest in terms of control co-ordination of visual angle, visual acuity, radiance, resolution ratio and frames, and refresh rate. HD group was graded significantly lower in sense of control compared with that of 4K and 3D group. No significant difference was found in color resolution and contrast. In conclusion, the short-term effect of 4K HD laparoscopic system is comparable with that of HD and 3D laparoscopy, whereas 4K could reduce adverse effect than traditional instrument and improve quality of surgery. The Clinical Trial Registration number is NCT01441336.
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http://dx.doi.org/10.1089/lap.2020.0931DOI Listing
May 2021

A dual-target molecular mechanism of pyrethrum repellency against mosquitoes.

Nat Commun 2021 05 5;12(1):2553. Epub 2021 May 5.

Department of Entomology, Michigan State University, East Lansing, MI, USA.

Pyrethrum extracts from flower heads of Chrysanthemum spp. have been used worldwide in insecticides and repellents. While the molecular mechanisms of its insecticidal action are known, the molecular basis of pyrethrum repellency remains a mystery. In this study, we find that the principal components of pyrethrum, pyrethrins, and a minor component, (E)-β-farnesene (EBF), each activate a specific type of olfactory receptor neurons in Aedes aegypti mosquitoes. We identify Ae. aegypti odorant receptor 31 (AaOr31) as a cognate Or for EBF and find that Or31-mediated repellency is significantly synergized by pyrethrin-induced activation of voltage-gated sodium channels. Thus, pyrethrum exerts spatial repellency through a novel, dual-target mechanism. Elucidation of this two-target mechanism may have potential implications in the design and development of a new generation of synthetic repellents against major mosquito vectors of infectious diseases.
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http://dx.doi.org/10.1038/s41467-021-22847-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099882PMC
May 2021

Alginate/chitosan modified immunomodulatory titanium implants for promoting osteogenesis in vitro and in vivo.

Mater Sci Eng C Mater Biol Appl 2021 May 31;124:112087. Epub 2021 Mar 31.

Key Laboratory of Advanced Technology for Materials (Ministry of Education), School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China. Electronic address:

The essentiality of macrophages for biomaterial-mediated osteogenesis has been increasingly recognized. However, it is still unclear what is the specific role and molecular mechanisms of macrophages and material properties in the regulation of osteogenesis. As an interdisciplinary field exploring the cross-talk between immune and skeletal systems, osteoimmunology has shifted the perspective of bone substitute materials from immunosuppressive materials to immunomodulatory materials. To fabricate an immunomodulatory Ti implant, alginate/chitosan multilayer films were fabricated on the surface of titania nanotubes (TNTs) to control the release of an anti-inflammatory cytokine interleukin (IL)-4 according to our previous work. The osteogenic effects and regulation mechanisms of the immunomodulatory Ti implants were investigated in vitro in different BMSCs culture modes. Alginate/chitosan multilayer-coated samples (with or without IL-4 loading) showed better direct osteogenic ability than TNTs by promoting biomineralization and up-regulating osteogenic gene expression (BMP1α, ALP, OPN, OCN) of BMSCs. Notably, material-induced macrophage polarization, M1 and M2, enhanced early and mid-stage osteogenesis of BMSCs via distinct pathways: M1 activated both BMP6/SMADs and Wnt10b/β-catenin pathways; while M2 activated TGF-β/SMADs pathway. Material surface properties dominated in regulating late osteogenesis probably due to the surface chemical composition (alginate, chitosan and Ca, etc.). Due to synergistic effects of material-induced inflammatory microenvironment and material surface properties, IL-4-loaded samples exhibited superior osteogenic capability through co-activation of three signaling pathways. The in vivo studies in rat bone defect model revealed that IL-4-loaded immunomodulatory implants successfully achieved macrophage phenotypic transition from pro-inflammatory M1 to anti-inflammatory M2 and subsequently improved new bone formation.
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http://dx.doi.org/10.1016/j.msec.2021.112087DOI Listing
May 2021

Adsorption-improved MoSe nanosheet by heteroatom doping and its application for simultaneous detection and removal of mercury (II).

J Hazard Mater 2021 07 19;413:125470. Epub 2021 Feb 19.

College of Environment and Resources, Xiangtan University, Xiangtan 411105, Hunan, China. Electronic address:

Water pollution arising from heavy metal ions continues to be a major environmental problem, which represents a serious threat to human beings and animals worldwide. New materials that can simultaneously detect and remove these toxic ions are urgently required. Herein, nitrogen and sulfur co-doped molybdenum selenide nanosheets (N, S-MoSe) were prepared and found to be fluorescently responsive to mercury (II) with an improved adsorption capacity (208.33 mg g), thereby providing the possibility for the simultaneous detection and removal of mercury (II) in water samples. The great affinity was the result of the complexation of mercury (II) with Se and S atoms in N, S-MoSe as well as the electrostatic adsorption of cation mercury (II) on negatively charged N, S-MoSe. Besides good sensitivity and selectivity toward mercury (II), N, S-MoSe displayed a relatively consistent performance under a wide pH range from 3 to 10. The removal efficiency reached 87.5% with fast adsorption kinetics, and N, S-MoSe could be reused after simple treatment. Thus, this work is expected to provide new material for the detection and removal of mercury (II) in an aqueous solution and offer an insight into the interaction between heavy metal ions and inorganic nanomaterials.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125470DOI Listing
July 2021

Fluorescent and colorimetric dual-mode detection of tetracycline in wastewater based on heteroatoms-doped reduced state carbon dots.

Environ Pollut 2021 Aug 9;283:117109. Epub 2021 Apr 9.

College of Environment and Resources, Xiangtan University, Xiangtan, 411105, Hunan Province, China. Electronic address:

A large amount of tetracycline (TC) persists in water, soil, food, and feed due to the overuse of antibiotics, causing serious environmental problems such as damage to ecosystems and posing risks to human health. Thus, there is an urgent need to find a method to detect TC that is practical, rapid, sensitive, and offers ready visualization of TC levels so that adequate remediation measures can be immediately implemented. Herein, we report a fluorescent and colorimetric dual-mode nanosensor for the detection of TC based on reduced state carbon dots (r-CDs). In the presence of TC, the emission fluorescence of r-CDs was quenched by the Förster resonance energy transfer mechanism to achieve high-sensitivity detection of TC with a low limit of detection (LOD) of 1.73 nM. Moreover, TC was also detected by r-CDs via a noticeable color change of the solution (from colorless to red) with the naked eye, having an LOD of 0.46 μM. Furthermore, r-CDs have excellent selectivity and sensitivity in detecting TC in wastewater, and therefore, have practical applications in wastewater treatment. The fluorescent and colorimetric dual-mode proposed in this work may offer a unique idea for the detection of TC, with great prospects for environmental wastewater applications.
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http://dx.doi.org/10.1016/j.envpol.2021.117109DOI Listing
August 2021

Efficient combination of Human Papillomavirus Genotyping for the triage of women with Atypical Squamous Cells of Undetermined Significance in Chinese rural population: A population-based study.

J Cancer 2021 14;12(10):2815-2824. Epub 2021 Mar 14.

Department of Obstetrics and Gynecology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China.

In this prospective, population-based study, we evaluated the utility of high-risk human papillomavirus (HR-HPV) genotyping for triaging women with atypical squamous cells of undetermined significance (ASC-US) in the Chinese rural area. A total of 40,000 women were recruited from rural areas of Shanxi Province, China, between June 2014 and December 2014. Women with Pap results of ASC-US underwent HPV genotyping, colposcopy and histopathological examination. For those with normal cervixes or cervical intraepithelial neoplasia (CIN) 1 on the initial evaluation, a 2-year follow-up study was performed. The reporting rate of ASC-US was 5.76% (2,304/40,000) in the study population. The detection rates of CIN 2 or above (CIN2+) and CIN 3 or above (CIN3+) in women with ASC-US were 7.28% and 1.75%, respectively. HPV 16 (39.53%), HPV 58 (17.83%), and HPV 52 (15.50%) were the three most prevalent HR-HPV genotypes among all women with ASC-US cytology. The five most common HR-HPV genotypes in CIN3+ lesions were HPV16, HPV58, HPV33, HPV31 and HPV18. Compared with the 15 HR-HPV testing, genotyping for a combination of HPV16/18/31/33/58 increased specificity significantly with virtually no loss of sensitivity for detecting CIN2+ and CIN3+ lesions, as well as significantly reduced colposcopy referral rate (23.15% vs 33.70%, p<0.01). In addition, in the 2-year follow-up period, women with infection of HPV16, 18, 31, 33 or 58 genotypes were the most likely population (92%, 23/25) to develop CIN2 lesion. Our results demonstrate that genotyping for a combination of HPV16/18/31/33/58 provides a more efficient and cost-effective model to risk-stratify women with ASC-US in the Chinese rural population.
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http://dx.doi.org/10.7150/jca.55771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040879PMC
March 2021

β-1,3-Glucan from Euglena gracilis as an immunostimulant mediates the antiparasitic effect against Mesanophrys sp. on hemocytes in marine swimming crab (Portunus trituberculatus).

Fish Shellfish Immunol 2021 Jul 10;114:28-35. Epub 2021 Apr 10.

Key Laboratory of Applied Marine Biotechnology, Ministry of Education; Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculture; School of Marine Sciences, Ningbo University, 818 Fenghua Road, Ningbo, 315211, PR China. Electronic address:

β-1,3-glucans, natural polysaccharide groups, exert immunomodulatory effects to improve the innate response and disease resistance in aquatic species and mammals. However, this β-glucan stimulant is yet to be assayed in swimming crab (Portunus trituberculatus) hemocytes. In this study, we explored the immunomodulatory effect of β-1,3-glucans (derived from Euglena gracilis) via in vitro 24 h stimulation assays in swimming crab hemocytes. We found that this algal β-1,3-glucans in crab hemocytes significantly elevated cellular enzymes related parameters, including phenoloxidase (PO), lysozyme, acid phosphatase (ACP) activities, and superoxide anion generation (O) rate both at intracellular (P < 0.05) and extracellular (P < 0.05) levels. Besides, alkaline phosphatase (AKP) in hemocytes exhibited no significant differences across the groups (P > 0.05). β-glucan significantly influenced (P < 0.05) the activities of the antioxidant enzyme, superoxide dismutase (SOD) in hemocytes. Moreover, the relative mRNA expression of numerous immune-related genes, including proPO, TLR-2, Alf-1, NOX, Lysozyme, Crustin-1, and Cuznsod, was significantly higher stimulated hemocytes than in control (P < 0.05). We also reported the dose-dependent antiparasitic activity against Mesanophyrs sp., in stimulated hemocytes than in the control (P < 0.05). The present study collectively demonstrated that β-glucan potentially stimulates innate immunity by elevating cellular enzyme responses and up-regulating the mRNA expression of genes associated with crab innate immunity. Thus, β-glucan is a promising immunostimulant for swimming crab farming in crustaceans aquaculture.
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http://dx.doi.org/10.1016/j.fsi.2021.04.005DOI Listing
July 2021

Longitudinal Peripheral Blood Transcriptional Analysis Reveals Molecular Signatures of Disease Progression in COVID-19 Patients.

J Immunol 2021 05 12;206(9):2146-2159. Epub 2021 Apr 12.

State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China;

Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients developing severe illness or even death. Disease severity has been associated with increased levels of proinflammatory cytokines and lymphopenia. To elucidate the atlas of peripheral immune response and pathways that might lead to immunopathology during COVID-19 disease course, we performed a peripheral blood RNA sequencing analysis of the same patient's samples collected from symptom onset to full recovery. We found that PBMCs at different disease stages exhibited unique transcriptome characteristics. We observed that SARS-CoV-2 infection caused excessive release of inflammatory cytokines and lipid mediators as well as an aberrant increase of low-density neutrophils. Further analysis revealed an increased expression of RNA sensors and robust IFN-stimulated genes expression but a repressed type I IFN production. SARS-CoV-2 infection activated T and B cell responses during the early onset but resulted in transient adaptive immunosuppression during severe disease state. Activation of apoptotic pathways and functional exhaustion may contribute to the reduction of lymphocytes and dysfunction of adaptive immunity, whereas increase in , , and may facilitate the recovery of the number and function of lymphocytes. Our study provides comprehensive transcriptional signatures of peripheral blood response in patients with moderate COVID-19.
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http://dx.doi.org/10.4049/jimmunol.2001325DOI Listing
May 2021

The story vs the storyteller: Factors associated with the effectiveness of brief video-recorded patient stories for promoting opioid tapering.

Health Expect 2021 Jun 9;24(3):991-999. Epub 2021 Apr 9.

Department of Public Health Sciences, University of California, Davis, Davis, CA, USA.

Background: Narrative communication is often more persuasive for promoting health behaviour change than communication using facts and figures; the extent to which narrative persuasiveness is due to patients' identification with the storyteller vs engagement with the story is unclear.

Objective: To examine the relative impacts of patient engagement, age concordance and gender concordance on perceived persuasiveness of video-recorded narrative clips about opioid tapering.

Methods: Patient raters watched and rated 48 brief video-recorded clips featuring 1 of 7 different storytellers describing their experiences with opioid tapering. The dependent variable was clips' perceived persuasiveness for encouraging patients to consider opioid tapering. Independent variables were rater engagement with the clip, rater-storyteller gender concordance and rater-storyteller age concordance (<60 vs ≥60). Covariates were rater beliefs about opioids and opioid tapering, clip duration and clip theme. Mixed-effects models accounted for raters viewing multiple clips and clips nested within storytellers.

Results: In multivariable models, higher rater engagement with the clip was associated with higher perceived persuasiveness (coefficient = 0.46, 95% CI 0.39-0.53, P < .001). Neither age concordance nor gender concordance significantly predicted perceived persuasiveness. The theme Problems with opioids also predicted perceived persuasiveness.

Conclusion: Highly engaging, clinically relevant stories are likely persuasive to patients regardless of the match between patient and storyteller age and gender. When using patient stories in tools to promote health behaviour change, stories that are clinically relevant and engaging are likely to be persuasive regardless of storytellers' demographics.

Patient Or Public Contribution: Patients were involved as storytellers (in each clip) and assessed the key study variables.
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http://dx.doi.org/10.1111/hex.13243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235893PMC
June 2021

Rheumatoid arthritis coexisting with ankylosing spondylitis: A report of 22 cases with delayed diagnosis.

Medicine (Baltimore) 2021 Apr;100(13):e25051

The Rheumatology and Clinical Immunology Department, the Affiliated Hospital of Qingdao University.

Abstract: Coexisting rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in the same patient is often thought to be rare, and thus misdiagnosis is common. The aim of our study was to describe the main characteristics of RA coexisting with AS in patients with delayed diagnoses and improve awareness of the disease association.Between 2012 and 2018, data from 22 patients who had RA and AS (RA/AS) were retrospectively reviewed. All patients had a history of delayed diagnosis for RA or AS. The clinical features and radiographic changes of RA and AS patients were obtained at baseline and after 2 years. Disease activity score 28 (DAS28) or bath ankylosing spondylitis disease activity index (BASDAI) were used as outcome measures. The mean age at the time of diagnosis of RA/AS was 51.8 years, while the mean duration of diagnostic delay was 5.5 years. Middle-aged women were the most common subgroup among the RA/AS cohort. The common clinical manifestations were systemic, symmetric, peripheral, and axial arthritis. The erythrocyte sedimentation rate and C-reactive protein levels in RA/AS patients were elevated at the time diagnosis of RA/AS. The typical radiologic changes for the 2 diseases coexisted in RA/AS patients. The DAS28 and BASDAI scores at the 2-year follow-up evaluation were lower than the initial assessment.Coexisting RA and AS is often misdiagnosed for many years; a lack of recognition of RA and AS together is one of the most common reasons. Systemic, symmetric, peripheral, and axial arthritis in middle-aged women were the most frequent presentations at onset.
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http://dx.doi.org/10.1097/MD.0000000000025051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021346PMC
April 2021

Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders.

Eur J Med Chem 2021 Jun 11;218:113341. Epub 2021 Mar 11.

Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. Electronic address:

SHP2, a non-receptor tyrosine phosphatase, plays a pivotal role in numerous oncogenic cell-signaling cascades like RAS-ERK, PI3K-AKT and JAK-STAT. On the other hand, proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for the degradation of disease-related protein of interest (POI). SHP2 degradation via the PROTAC strategy will provide an alternative startegy for SHP2-mediated cancer therapy. Herein we described the design, synthesis and evaluation of a series of thalidomide-based heterobifunctional molecules and identified 11(ZB-S-29) as the highly efficient SHP2 degrader with a DC of 6.02 nM. Further mechanism investigation illustrated that 11 came into function through targeted SHP2 protein degradation.
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http://dx.doi.org/10.1016/j.ejmech.2021.113341DOI Listing
June 2021

Transanal vs laparoscopic total mesorectal excision for rectal cancer: a multicenter randomized phase III clinical trial (TaLaR trial) protocol.

Gastroenterol Rep (Oxf) 2021 Jan 14;9(1):71-76. Epub 2020 Dec 14.

Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.

Background: Total mesorectum excision (TME) is considered the standard surgical procedure for rectal-cancer treatment. Transanal TME (taTME) is a new procedure to treat low rectal cancer. Some published studies have proven that taTME can provide a better-quality resected specimen in low-rectal-cancer patients in comparison to the transabdominal procedure, yet long-term outcomes must be investigated. We designed this non-inferiority trial (TaLaR trial) to compare short-term and long-term outcomes between taTME and laparoscopic TME (lapTME) for rectal cancer.

Methods: The TaLaR trial is a phase III open-labeled multicenter randomized-controlled trial. Patients who are diagnosed with rectal cancer with no more than T3N2 stage, and with the tumor location below the peritoneal reflection by magnetic resonance imaging scan, digital rectal examination, or colonoscopy, qualify for this study. After calculating, a total of 1,114 patients (557 per group) will be randomly allocated to either the taTME or the lapTME group. Primary endpoints are the 3-year disease-free survival (DFS) rate and the 5-year overall survival (OS) rate. Secondary endpoints include specimen quality, perioperative results, pelvic and anal function, and quality of life.

Discussion: The TaLaR trial is expected to clarify whether taTME can achieve comparable oncological outcomes, as well as improve specimen quality and recovery conditions in rectal-cancer patients compared with lapTME.
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http://dx.doi.org/10.1093/gastro/goaa083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962745PMC
January 2021

Effect of different reinforcement methods on anastomotic leakage prevention after laparoscopic double anastomosis.

J Surg Oncol 2021 May 19;123 Suppl 1:S81-S87. Epub 2021 Mar 19.

Department of General Surgery, Shanghai Jiao Tong University, Shanghai, 200025, China.

Background And Objectives: To investigate the effects of different suture reinforcement methods for anastomotic leakage and other postoperative complications after the use of a laparoscopic double stapling technique (DST).

Methods: We collected the data of 124 patients who underwent laparoscopic radical resection of colorectal cancer from July 2017 to September 2018 at our institution. Patients were divided into three groups according to the suture reinforcement methods: intermittent, continuous suture reinforcement, and non-reinforcement (n = 41, 41, and 42, respectively). One-way analysis of variance, χ , Fisher's exact, and nonparametric tests were used for statistical analysis.

Results: Among the 124 patients, there were no statistically significant differences in operation times, intraoperative blood loss, postoperative hospital stays and recovery of bowel movement. Nine patients were diagnosed with anastomotic leakage (AL). The incidences of serious AL in the intermittent and continuous suture reinforcement groups were lower than that in the control group, with lower reoperation rate, shorter average lengths of stay and lower treatment costs of two experimental groups.

Conclusion: Intermittent and continuous sutures after laparoscopic DST is effective, safe, and feasible on anastomotic leakage prevention. These procedures could be popularized in rectal surgery on patients with high risk of AL.
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http://dx.doi.org/10.1002/jso.26333DOI Listing
May 2021

Efficient induction of neural progenitor cells from human ESC/iPSCs on Type I Collagen.

Sci China Life Sci 2021 Mar 16. Epub 2021 Mar 16.

CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.

A stable, rapid and effective neural differentiation method is essential for the clinical applications of human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) in treating neurological disorders and diseases. Herein, we established a novel and robust monolayer differentiation method to produce functional neural progenitor cells (NPCs) from human ESC/iPSCs on Type I Collagen. The derived cells not only displayed the requisite markers, but also behaved similarly to classic NPCs both in vitro and in vivo. Upon transplantation into traumatic brain injury model, the derived NPCs facilitated recovery from injury. We also found that SMAD signaling stayed down throughout the differentiation process on Type I Collagen, and the pluripotent signals were rapidly downregulated along with raising up of neural early markers on the third day. Meanwhile, ATAC-seq data showed the related mediation of distinct transcriptome and global chromatin dynamics during NPC induction. Totally, our results thus provide a convenient way to generate NPCs from human ESC/iPSCs for neural diseases' treatment.
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http://dx.doi.org/10.1007/s11427-020-1897-0DOI Listing
March 2021

Global analysis of lysine 2-hydroxyisobutyrylation in wheat root.

Sci Rep 2021 Mar 18;11(1):6327. Epub 2021 Mar 18.

Crop Research Institute, Shandong Academy of Agricultural Sciences, Ji'nan, Shandong, 250100, People's Republic of China.

Lysine 2-hydroxyisobutyrylation (Khib) is a novel naturally occurring post-translational modification. The system Khib identification at proteomics level has been performed in various species and tissues to characterize the role of Khib in biological activities. However, the study of Khib in plant species is relatively less. In the present study, the first plant root tissues lysine 2-hydroxyisobutyrylome analysis was performed in wheat with antibody immunoprecipitation affinity, high resolution mass spectrometry-based proteomics and bioinformatics analysis. In total, 6328 Khib sites in 2186 proteins were repeatedly identified in three replicates. These Khib proteins showed a wide subcellular location distribution. Function and pathways characterization of these Khib proteins indicated that many cellular functions and metabolism pathways were potentially affected by this modification. Protein and amino acid metabolism related process may be regulated by Khib, especially ribosome activities and proteins biosynthesis process. Carbohydrate metabolism and energy production related processes including glycolysis/gluconeogenesis, TCA cycle and oxidative phosphorylation pathways were also affected by Khib modification. Besides, root sulfur assimilation and transformation related enzymes exhibited Khib modification. Our work illustrated the potential regulation role of Khib in wheat root physiology and biology, which could be used as a useful reference for Khib study in plant root.
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http://dx.doi.org/10.1038/s41598-021-85879-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973580PMC
March 2021

Identification of hub genes associated with neutrophils infiltration in colorectal cancer.

J Cell Mol Med 2021 Apr 5;25(7):3371-3380. Epub 2021 Mar 5.

Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Colorectal cancer (CRC) is the leading cause of cancer-related mortality in the world. Accumulating evidence indicate that tumour infiltrating immune cells participated in cancer progression. Among them, tumour infiltrating neutrophils (TINs) are reported to play crucial role in various cancers. In this study, we used CIBERSORTx, a digital cytometry tool to evaluate the neutrophils infiltration in CRC based on gene expression data of CRC tissues from GSE39582 data set and The Cancer Genome Atlas data set (TCGA-COAD and TCGA-READ). Weighted gene co-expression network analysis (WGCNA) was conducted in GSE39582 data set to identify hub genes associated with neutrophil infiltration. The association of hub gene and neutrophils was then validated in TCGA cohorts and an independent RJ cohort. Functional analysis was performed to investigate the molecular mechanisms of the interested hub gene. We found that neutrophil infiltration is elevated in CRC tissues, and it is related to a poorer prognosis. A total of 18 gene modules are identified by WGCNA in GSE39582 data set, among which lightcyan module is significantly correlated with neutrophils infiltration. Furthermore, Superoxide Dismutase 2 (SOD2) in lightcyan module was proved to correlated with neutrophils infiltration in various cancer types. In addition, SOD2 expression is highly associated with several chemokines, including CXCL8, a neutrophils-related attractant, and functional analysis revealed that SOD2 is involved in neutrophils recruitment biological process. These results indicate that an 'SOD2-CXCL8-neutrophil recruitment' axis plays a potential role in colorectal cancer progression.
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http://dx.doi.org/10.1111/jcmm.16414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034475PMC
April 2021

H -free Plastic Conversion: Converting PET back to BTX by Unlocking Hidden Hydrogen.

ChemSusChem 2021 Mar 4. Epub 2021 Mar 4.

Shanghai Key Laboratory of Functional Materials Chemistry and Research, Research Institute of Industrial Catalysis, School of Chemistry and Molecular Engineering, East China University of Science and Technology, No. 130 Meilong Road, Shanghai, 200237, P.R. China.

The strong desire for a circular economy makes obtaining fuels and chemicals via plastic degradation an important research topic in the 21st century. Here, the first example of the H -free polyethylene terephthalate (PET) conversion to BTX (benzene, toluene and xylene) was achieved by unlocking hidden hydrogen in the ethylene glycol part over Ru/Nb O catalyst. Among the whole process (hydrolysis, reforming and hydrogenolysis/decarboxylation), the parallel hydrogenolysis and decarboxylation were competing and the rate-determining step. Ru/Nb O exhibited superior hydrogenolysis and poorer decarboxylation performance in direct comparison with Ru/NiAl O , accordingly contributing to the distinct selectivity to alkyl aromatics among BTX. Ru species on Nb O , unlike those on NiAl O , showed more Ru species owing to the strong interaction between Ru and Nb O , restricting the undesired decarboxylation. Along with NbO species for C-O bond activation, excellent reactivity towards the H -free conversion of PET back to BTX with alkyl aromatics as dominant species was achieved. This H -free system was also capable of converting common real PET plastics back to BTX, adding new options in the circular economy of PET.
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http://dx.doi.org/10.1002/cssc.202100196DOI Listing
March 2021

By Endowing Polyglutamic Acid/Polylysine Composite Hydrogel with Super Intrinsic Characteristics to Enhance its Wound Repair Potential.

Macromol Biosci 2021 May 3;21(5):e2000367. Epub 2021 Mar 3.

Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P. R. China.

In this study, multifunctional porous composite hydrogels are prepared via composite technology and using poly(glutamic acid) and (polylysine) as precursors, casein as foaming agent, and calcium ions as coagulant. The results show that the as-prepared hydrogels have high porosity and water absorbency, and good mechanical, inherent antibacterial, and bioadhesive properties. The results show such high water absorption, bioadhesion, and porosity of the as-prepared hydrogel can effectively concentrate blood components and seal wounds better. The release of calcium ions in the as-prepared hydrogels can activate coagulation factors. Both factors can play an important role in hemostasis. The excellent hydroscopicity, moisture retention, adhesion, and inherent antibacterial properties of the as-prepared hydrogel can create a moist, sterile, and closed microenvironment for the wound healing. The experimental results of a deep skin defect model have verified its good effect of promoting wound repair. These inherent excellent properties can endow the as-prepared hydrogel with a wide range of application values.
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http://dx.doi.org/10.1002/mabi.202000367DOI Listing
May 2021

Robust pricing for airlines with partial information.

Ann Oper Res 2021 Feb 26:1-39. Epub 2021 Feb 26.

Miami Business School, University of Miami, Coral Gables, FL 33146 USA.

In the spot market for air cargo, airlines typically adopt dynamic pricing to tackle demand uncertainty, for which it is difficult to accurately estimate the distribution. This study addresses the problem where a dominant airline dynamically sets prices to sell its capacities within a two-phase sales period with only partial information. That partial information may show as the moments (upper and lower bounds and mean) and the median of the demand distribution. We model the problem of dynamic pricing as a distributional robust stochastic programming, which minimizes the expected regret value under the worst-case distribution in the presence of partial information. We further reformulate the proposed non-convex model to show that the closed-form formulae of the second-stage maximal expected regret are well-structured. We also design an efficient algorithm to characterize robust pricing strategies in a polynomial-sized running time. Using numerical analysis, we present several useful managerial insights for airline managers to strategically collect demand information and make prices for their capacities in different market situations. Moreover, we verify that additional information will not compromise the viability of the pricing strategies being implemented. Therefore, the method we present in this paper is easier for airlines to use.
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http://dx.doi.org/10.1007/s10479-020-03926-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907347PMC
February 2021

Harnessing Preclinical Data as a Predictive Tool for Human Brain Tissue Targeting.

ACS Chem Neurosci 2021 03 2;12(6):1007-1017. Epub 2021 Mar 2.

Medicine Design, Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, Massachusetts 02139, United States.

One of the objectives within the medicinal chemistry discipline is to design tissue targeting molecules. The objective of tissue specificity can be either to gain drug access to the compartment of interest (, the CNS) for Neuroscience targets or to restrict drug access to the CNS for all other therapeutic areas. Both neuroscience and non-neuroscience therapeutic areas have struggled to quantitatively estimate brain penetration or the lack thereof with compounds that are substrates of efflux transport proteins such as P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) that are key components of the blood-brain barrier (BBB). It has been well established that drug candidates with high efflux ratios (ER) of these transporters have poor penetration into brain tissue. In the current work, we outline a parallel analysis to previously published models for the prediction of brain penetration that utilize an alternate MDR1-MDCK cell line as a better predictor of brain penetration and whether a correlation between , rodent data, non-human primate (NHP), and human brain penetration data could be established. Analysis of structural and physicochemical properties in conjunction with parameters and preclinical data has been highlighted in this manuscript as a continuation of the previously published work.
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http://dx.doi.org/10.1021/acschemneuro.0c00807DOI Listing
March 2021
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