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1.
Chembiochem ; : e202400417, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38923227

ABSTRACT

MicroRNAs (miRNAs) regulate gene expression through RNA interference. Consequently, miRNA inhibitors, such as anti-miRNA oligonucleotides (AMOs), have attracted attention for treating miRNA overexpression. To achieve efficient inhibition, we developed 2-amino-6-vinylpurine (AVP) nucleosides that form covalent bonds with uridine counterparts in RNA. We demonstrated that mRNA cross-linked with AVP-conjugated antisense oligonucleotides with AVP were protected from gene silencing by exogenous miRNA. However, endogenous miRNA function could not be inhibited in cells, probably because of slow cross-linking kinetics. We recently developed ADpVP, an AVP derivative bearing a 7-propynyl group-which boasts faster reaction rate than the original AVP. Here, we synthesized dADpVP-a deoxy analog of ADpVP-through a simplified synthesis protocol. Evaluation of the cross-linking reaction revealed that the reaction kinetics of dADpVP were comparable to those of ADpVP. In addition, structural analysis of the cross-linked adduct discovered N3 linkage against uridine. Incorporating dADpVP into two types of miRNA inhibitors revealed a marginal impact on AMO efficacy yet improved the performance of target site blockers. These results indicate the potential of cross-linking nucleosides for indirect miRNA function inhibition.

2.
J Phys Chem Lett ; 15(21): 5689-5695, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38767955

ABSTRACT

Lead-chloride perovskites are promising candidates for optoelectronic applications, such as visible-blind UV photodetection. It remains unclear how the deep defects in this wide-bandgap material impact the carrier recombination dynamics. In this work, we study the defect properties of MAPbCl3 (MA = CH3NH3) based on photoluminescence (PL) measurements. Our investigations show that apart from the intrinsic emission, four sub-bandgap emissions emerge, which are very likely to originate from the radiative recombination of excitons bound to several intrinsic vacancy and interstitial defects. The intensity of various emission features can be tuned by adjusting the type and ratio of precursors used during synthesis. Our study not only provides important insights into the defect property and carrier recombination mechanism in this class of material but also demonstrates efficient strategies for defect passivation and engineering, paving the way for further development of lead-chloride perovskite-based optoelectronic devices.

3.
Sci Total Environ ; 926: 171941, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38527544

ABSTRACT

Anthropogenic activities over the past half-century have had a negative impact on the wetland ecosystem in the Nile Delta, which provides essential provisioning and regulating services. Therefore, it is crucial to systematically investigate pollution levels and their ecological consequences at both spatial and temporal scales in order to promote sustainable development. In this study, data on metal pollution in the Manzala Lake were compiled through a systematic review of all published literature from 1968 to 2020. Additionally, agricultural data (including land use, pesticide and fertilizer usage, and discharge) and economic data for the same time period were collected to identify the main drivers of pollution. The results indicated an overall increasing trend in heavy metal concentrations during the study period. The average concentrations of metals, arranged in descending order, were as follows: Fe (15,115.5 µg/g) > Mn (722 µg/g) > Zn (115.4 µg/g) > Cu (65.9 µg/g) > Ni (62.5 µg/g) > Cr (58.1 µg/g) > Pb (54.1 µg/g) > Cd (4.7 µg/g) > Hg (0.1 µg/g). A linear regression model revealed that wastewater discharge, water reuse, and the use of pesticides and fertilizers are the main sources of heavy metal pollution in the Manzala Lake. Consequently, there has been a dramatic decrease in the biodiversity of fish and molluscan communities. The study also found a correlation between heavy metal pollution and socio-economic development, highlighting the urgent need for attention to the conservation, management, and sustainable development of the lake.


Subject(s)
Metals, Heavy , Pesticides , Water Pollutants, Chemical , Ecosystem , Water Pollutants, Chemical/analysis , Environmental Monitoring/methods , Geologic Sediments , Risk Assessment , Metals, Heavy/analysis , Lakes , China
4.
N Engl J Med ; 390(5): 432-441, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38294975

ABSTRACT

BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose. METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).


Subject(s)
Angioedemas, Hereditary , CRISPR-Cas Systems , Gene Editing , Adult , Humans , Angioedema , Angioedemas, Hereditary/blood , Angioedemas, Hereditary/drug therapy , Angioedemas, Hereditary/genetics , Complement C1 Inhibitor Protein/therapeutic use , Dose-Response Relationship, Drug , Gene Editing/methods , Plasma Kallikrein/genetics , Treatment Outcome
5.
Environ Sci Pollut Res Int ; 30(58): 122642-122662, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37973780

ABSTRACT

Heavy metal and pesticide pollution of freshwater ecosystems, i.e., rivers, raises significant concerns worldwide, where practical solutions to reduce the threats become urgent need. Heavy metals and pesticides are top of the list of environmental toxicants endangering nature; therefore, pesticides and heavy metals were measured at 10 stations along the Al-Zennar agricultural drain and the Nile River at Assiut city in Upper Egypt, to assess potential negative impact on the water/sediment's quality. The sediment of the streambed is a sink for pesticides and heavy metals, where both water and sediments have higher contamination factor (CF) for Cd, Pb, Cr, Cu, and Zn. In addition, the Nile water is highly contaminated by PCBs. The distance to the point source and hydrodynamics (flow rate and stream gradient) has major influences in pollutant concentrations as indicated by regression models. Dilution effect and rapid sedimentation may comment on the lower concentrations of the pollutants in the Nile comparatively to the drain and on the water comparatively to the sediments. The physiochemistry of the stations has minor effect on the metal/pesticide concentration, where the variable importance of projection (VIP) of the partial least square model indicated that total dissolved solids (TDS), total suspended solids (TSS), SO42-, and BOD/TOC/COD are the main contributors to the metal/pesticide concentration. Concentrations were not correlated between water and sediment suggesting a historical accumulation in sediments and temporal variation in the pollution load in the Al-Zennar drain. Bray-Curtis clustering confirmed that heavy metals have the same anthropogenic source in contrast to natural source of both Mn and Fe.


Subject(s)
Environmental Pollutants , Metals, Heavy , Pesticides , Water Pollutants, Chemical , Rivers , Water , Water Pollutants, Chemical/analysis , Egypt , Ecosystem , Environmental Monitoring , Geologic Sediments , Fresh Water , Metals, Heavy/analysis , Water Quality
6.
J Phys Chem Lett ; 14(40): 9136-9144, 2023 Oct 12.
Article in English | MEDLINE | ID: mdl-37795957

ABSTRACT

The surface quality of lead halide perovskite crystals can extremely influence their optoelectronic properties and device performance. Here, we report a surface engineering crystallization technique in which we in situ grow a polycrystalline methylammonium lead tribromide (MAPbBr3) film on top of bulk mm-sized single crystals. Such MAPbBr3 crystals with a MAPbBr3 passivating film display intense green emission under UV light. X-ray photoelectron spectroscopy demonstrates that these crystals with emissive surfaces are compositionally different from typical MAPbBr3 crystals that show no emission under UV light. Time-resolved photoluminescence and electrical measurements indicate that the MAPbBr3 film/MAPbBr3 crystals possess less surface defects compared to the bare MAPbBr3 crystals. Therefore, X-ray detectors fabricated using the surface-engineered MAPbBr3 crystals provide an almost 5 times improved sensitivity to X-rays and a more stable baseline drift with respect to the typical MAPbBr3 crystals.

7.
Mar Pollut Bull ; 194(Pt B): 115368, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37572433

ABSTRACT

To monitor the changes in fish biodiversity and to elucidate the factors responsible for these changes, the landings composition (LC) over the past 30 years in the Nile-Delta lakes was quantitatively analyzed. The LC data indicates a shift in target species towards demersal opportunistic species. A significant difference (P < 0.001) between two main intervals highlighted in both PERMANOVA and PCA plot; the first interval (1991-2002) is dominated by Tilapia and rare species, while the second interval (2003-2020) is dominated by the opportunistic catfish and mullet species. Noticeable declines in species richness and landings of rare species were observed, where rare taxa either have been overexploited or they may be positively affected by increasing pollution levels than do other dominated species such as Tilapia. In contrast, opportunistic fish species such as catfish and mullet, have flourished in such polluted water due to their ability to tolerate seasonal pollution-related hypoxia.


Subject(s)
Catfishes , Smegmamorpha , Tilapia , Animals , Lakes , Fishes , Biodiversity , Water Pollution
8.
Clin Pharmacol Ther ; 114(3): 591-603, 2023 09.
Article in English | MEDLINE | ID: mdl-37429825

ABSTRACT

Genome editing holds the potential for curative treatments of human disease, however, clinical realization has proven to be a challenging journey with incremental progress made up until recently. Over the last decade, advances in clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) systems have provided the necessary breakthrough for genome editing in the clinic. The progress of investigational CRISPR therapies from bench to bedside reflects the culmination of multiple advances occurring in parallel, several of which intersect with clinical pharmacology and translation. Directing the CRISPR therapy to the intended site of action has necessitated novel delivery platforms, and this has resulted in special considerations for the complete characterization of distribution, metabolism, and excretion, as well as immunogenicity. Once at the site of action, CRISPR therapies aim to make permanent alterations to the genome and achieve therapeutically relevant effects with a single dose. This fundamental aspect of the mechanism of action for CRISPR therapies results in new considerations for clinical translation and dose selection. Early advances in model-informed development of CRISPR therapies have incorporated key facets of the mechanism of action and have captured hallmark features of clinical pharmacokinetics and pharmacodynamics from phase I investigations. Given the recent emergence of CRISPR therapies in clinical development, the landscape continues to evolve rapidly with ample opportunity for continued innovation. Here, we provide a snapshot of selected topics in clinical pharmacology and translation that has supported the advance of systemically administered in vivo and ex vivo CRISPR-based investigational therapies in the clinic.


Subject(s)
CRISPR-Cas Systems , Pharmacology, Clinical , Humans , CRISPR-Cas Systems/genetics , Gene Editing/methods
9.
ACS Appl Mater Interfaces ; 15(23): 28166-28174, 2023 Jun 14.
Article in English | MEDLINE | ID: mdl-37259773

ABSTRACT

One major concern toward the performance and stability of halide perovskite-based optoelectronic devices is the formation of metallic lead that promotes nonradiative recombination of charge carriers. The origin of metallic lead formation is being disputed whether it occurs during the perovskite synthesis or only after light, electron, or X-ray beam irradiation or thermal annealing. Here, we show that the quantity of metallic lead detected in perovskite crystals depends on the concentration and composition of the precursor solution. Through a controlled crystallization process, we grew black-colored mixed dimethylammonium (DMA)/methylammonium (MA) lead tribromide crystals. The black color is suggested to be due to the presence of small lead clusters. Despite the unexpected black coloring, the crystals show higher crystallinity and less defect density with respect to the standard yellow-colored DMA/MAPbBr3 crystals, as indicated by X-ray rocking curve and dark current measurements, respectively. While the formation of metallic lead could still be induced by external factors, the precursor solution composition and concentration can facilitate the formation of metallic lead during the crystallization process. Our results indicate that additional research is required to fully understand the perovskite precursor solution chemistry.

10.
Neurologist ; 28(5): 310-315, 2023 Sep 01.
Article in English | MEDLINE | ID: mdl-37027177

ABSTRACT

BACKGROUND: Intracerebral hemorrhage (ICH) has worse clinical outcomes than other stroke types. The risk factors contributing to ICH outcomes are not entirely understood, and published literature from Saudi Arabia on ICH outcomes is limited. Our goal was to study the specific clinical and imaging determinants of ICH outcomes. METHODS: We retrospectively retrieved all patients with spontaneous ICH (SICH) from a prospective King Fahd Hospital University registry between 2017 and 2019. The clinical characteristics of ICH events and data on clinical outcomes (6 to 12 mo) were recorded. Groups of patients with a favorable modified Rankin Scale of 0 to 2 and nonfavorable outcomes of a modified Rankin Scale of 3 to 6 were investigated. The relationship between the clinical characteristics of the SICH event and its outcomes was assessed using linear and logistic regression analyses. RESULTS: A total of 148 patients with a mean age of 60.3 years (±15.2) and a median follow-up of 9 months were included. Unfavorable outcomes were reported in 98 patients (66.2%). The ICH event variables associated with unfavorable outcomes were impaired renal function, Glasgow Coma Score <8, hematoma volume, hematoma expansion, and intraventricular extension (IVE). CONCLUSIONS: Our study demonstrated important clinical and radiologic features in patients with ICH that may affect their clinical long-term functional outcomes. A larger multicenter study is required to validate our results and evaluate the methods to improve health care in patients with SICH.


Subject(s)
Cerebral Hemorrhage , Hematoma , Humans , Middle Aged , Treatment Outcome , Retrospective Studies , Prospective Studies , Saudi Arabia/epidemiology , Cerebral Hemorrhage/diagnostic imaging , Cerebral Hemorrhage/epidemiology , Cerebral Hemorrhage/therapy , Hematoma/complications , Hospitals
11.
Curr Rheumatol Rev ; 19(2): 189-196, 2023.
Article in English | MEDLINE | ID: mdl-35984025

ABSTRACT

BACKGROUND: Pulmonary involvement is the most common leading cause of morbidity and mortality associated with systemic sclerosis. Therefore, identifying the various patterns of pulmonary affection is crucial in the clinical management of these patients. In the current study, we aim to investigate the patterns of interstitial lung disease (ILD) associated with SSc patients (SSc- ILD) and their relation to serologic markers and clinical parameters. METHODS: A cross-sectional study was undertaken on thirty-four adult SSc patients who met the 2013 ACR/EULAR criteria for SSc and Forty healthy controls of matched age and sex. The patients were subjected to history taking, clinical examination, skin assessment using the modified Rodnan Skin Score (mRSS), chest x-ray (CXR), pulmonary function test (PFTs), and high resolution computed tomography of the chest (HRCT). Routine laboratory tests were conducted in addition to immunologic tests and an enzyme-linked immunosorbent assay (ELISA) to determine the IL-33 level. RESULTS: ILD was found in 23 SSc patients (67.6%); 20 patients had diffuse type while 3 patients had limited type. Non-specific interstitial pneumonia (NSIP) was found in 56.5%, usual interstitial pneumonia (UIP) was found in 21.7%, pleuroparenchymal fibroelastosis (PPFE) was found in 8.7%, and organizing pneumonia (OP) with the mixed pattern was found in 13% of SSc patients. Additionally, the mean IL-33 level in SSc patients was 98±12.7 compared to 66.2±10.6 in the control group (p < 0.001), with ILD patients having a significantly higher level (101.7±13.4) than those without (90.4±6.2), and a strong positive correlation with mRSS. CONCLUSION: Even in asymptomatic patients with SSc, ILD is prevalent, with NSIP being the most common pattern. IL-33 could be considered a potential biomarker for predicting the presence of ILD in SSc patients.


Subject(s)
Lung Diseases, Interstitial , Scleroderma, Systemic , Adult , Humans , Interleukin-33 , Cross-Sectional Studies , Egypt/epidemiology , Lung Diseases, Interstitial/etiology , Scleroderma, Systemic/complications , Scleroderma, Systemic/diagnosis
12.
Prz Gastroenterol ; 17(4): 332-337, 2022.
Article in English | MEDLINE | ID: mdl-36514448

ABSTRACT

Introduction: Extra-pulmonary manifestations of the Coronavirus disease of 2019 (COVID-19) have been increasingly reported, especially gastrointestinal and hepatic system dysfunction. The concern of faecal-oral transmission for COVID-19 was raised. Aim: To study the trend of faecal calprotectin in COVID-19 patients with intestinal symptoms. Material and methods: Forty confirmed cases of COVID-19 infection presenting with diarrhoea were subjected to a thorough history taking, clinical examination, and routine laboratory investigations. They were treated according to the Egyptian MOH guidelines. Faecal calprotectin (FC) concentration was measured at initial presentation and after 3 months. Those who had persistently elevated levels ≥ 200 µg/g were subjected to colonoscopic examination and histopathological examination. Forty confirmed cases of COVID-19 without diarrhoea were recruited as a control group in the initial FC evaluation. Results: Faecal calprotectin was found to be significantly elevated in the studied COVID-19 patients who presented with diarrhoea, with a mean value 260 ±80 µg/g compared to the those without diarrhoea, with a mean value of 31.6 ±12.9 µg/g (p < 0.001). Moreover, 20% (8 patients) had an elevated level exceeding 200 µg/g 3 months after recovery; among them, 5 patients showed mild colonoscopic changes whereas 3 patients showed severe ileocolitis. Out of the 3 patients with marked ileocolitis, 2 showed histopathological changes raising the diagnosis of Crohn's disease. Conclusions: Faecal calprotectin was found to be elevated in COVID-19 patients with intestinal symptoms, especially diarrhoea, with or without colonoscopic and histopathological changes.

13.
Sci Rep ; 12(1): 10753, 2022 06 24.
Article in English | MEDLINE | ID: mdl-35750705

ABSTRACT

During the coronavirus disease 2019 lockdown period, a surge in sandflies and cutaneous leishmaniasis (CL) cases was observed in Al-Ahsa, Saudi Arabia. Skin punch biopsies were obtained from 100 patients clinically diagnosed with CL in Al-Ahsa who had no travel history in the last 6 months. Impression smears were used following a three-step polymerase chain reaction (PCR) protocol using genus-specific primers targeting kDNA and ITS1. Leishmania speciation was determined by ITS1 PCR/nested PCR-restriction fragment length polymorphism and sequencing. A phylogenetic tree was constructed. The associated patient characteristics were analyzed. Using internal transcribed spacer one (ITS1)-PCR/nested PCR, 98 cases were considered true-positive CL. Leishmania major was the predominant species, and Leishmania tropica was identified in three cases. Microscopy had poor sensitivity and perfect specificity. Direct ITS1-PCR missed nine cases. Sex, residence, and treatment outcome were significantly associated with the occurrence of Leishmania; distribution of skin lesion(s) and treatment outcome were significantly associated with Leishmania genotype. This is the first time that L. tropica was identified as a cause of CL in human in Al-Ahsa, in addition to the predominant zoonotic species, L. major. We recommend using ITS1-nested PCR for negative cases by ITS1-PCR. Further exploration of Leishmania transmission dynamics in vectors and reservoir animals is essential for designing effective preventive measures.


Subject(s)
COVID-19 , Leishmania major , Leishmania tropica , Leishmaniasis, Cutaneous , Animals , COVID-19/epidemiology , Communicable Disease Control , Genotype , Humans , Leishmania major/genetics , Leishmania tropica/genetics , Leishmaniasis, Cutaneous/diagnosis , Leishmaniasis, Cutaneous/epidemiology , Pandemics , Phylogeny , Polymorphism, Restriction Fragment Length , Saudi Arabia/epidemiology
14.
Acta Crystallogr B Struct Sci Cryst Eng Mater ; 78(Pt 3 Pt 2): 425-435, 2022 Jun 01.
Article in English | MEDLINE | ID: mdl-35702960

ABSTRACT

The crystal structures of (CH3NH3)2Cu(Cl1-xBrx)4 compounds have been investigated by means of synchrotron powder X-ray diffraction and pair distribution function analysis at room temperature. As a result, new insights are gained about the structural properties of these compounds, suggesting a monoclinic symmetry (space group No. 14: P21/c - C_{2h}^{5}) induced by the co-operative orbital ordering produced by the Jahn-Teller distortion characterizing the 3d9 Cu2+ ion. In contrast to previous studies, a significant amount of vacancies is found at halogen positions, a feature that can be likely ascribed to the synthesis technique adopted in the present study. Br atoms preferentially occupy axial positions, likely on account of reduced steric hindrance at these sites.

15.
Org Biomol Chem ; 20(23): 4699-4708, 2022 06 15.
Article in English | MEDLINE | ID: mdl-35622064

ABSTRACT

The interstrand crosslinking and threaded structures of nucleic acids have high potential in oligonucleotide therapeutics, chemical biology, and nanotechnology. For example, properly designed crosslinking structures provide high activity and nuclease resistance for anti-miRNAs. The noncovalent labeling and modification by the threaded structures are useful as new chemical biology tools. Photoreversible crosslinking creates smart materials, such as reversible photoresponsive gels and DNA origami objects. This review introduces the creation of interstrand crosslinking and threaded structures, such as catenanes and rotaxanes, based on hybridization-specific chemical reactions and their functions and perspectives.


Subject(s)
Nucleic Acids , Rotaxanes , DNA/chemistry , Nanotechnology , Nucleic Acid Conformation , Nucleic Acid Hybridization , Rotaxanes/chemistry
16.
Curr Protoc ; 2(3): e386, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35316581

ABSTRACT

Crosslinking reactions to nucleic acids are an effective way to prepare stable complexes formed by covalent bonding. We demonstrated that fully 2'-O-methylated (2'-OMe) RNAs having a 2-amino-6-vinylpurine (AVP) exhibited an efficient crosslinking to uracil in the target RNA. Recently, we reported the preparation of crosslinked 2'-OMe RNA duplexes using AVP and the anti-miRNA oligonucleotides (AMOs) containing crosslinked duplexes at the terminal positions. These AMOs exhibited efficient microRNA (miRNA) inhibition at very low concentrations. In this article, we describe the chemical synthesis of 2'-OMe oligonucleotides containing AVP and preparation of the AMOs bearing crosslinked 2'-OMe RNA duplexes using AVP. In addition, we describe in detail the miRNA inhibition assay using these AMOs. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of phosphoramidite of 2-amino-6-vinylguanosine derivative Basic Protocol 2: Synthesis of AVP-2'-OMe RNA Basic Protocol 3: Evaluation of the crosslink reactivity of CFO containing AVP to the 2'-OMe RNA and preparation of AMOs containing crosslinked duplex Basic Protocol 4: miRNA inhibition assays.


Subject(s)
MicroRNAs , Oligonucleotides/chemistry , Purines/chemistry , Vinyl Compounds/chemistry
17.
Lung Cancer ; 166: 170-177, 2022 04.
Article in English | MEDLINE | ID: mdl-35298959

ABSTRACT

BACKGROUND: Preclinical data show that the combination of an ALK inhibitor (ALKi) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) may act synergistically to overcome drug resistance mechanisms. Here, we assessed the safety, tolerability, and preliminary clinical activity of ceritinib, an ALKi in combination with ribociclib, a CDK4/6i, in patients with ALK-rearranged non-small cell lung cancer (NSCLC). METHODS: This was a multicenter, open-label, phase Ib/II dose-escalation study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for ceritinib plus ribociclib therapy. RESULTS: Twenty-seven adult patients with ALK-rearranged advanced NSCLC with an ECOG PS ≤ 2 were enrolled into five cohorts to receive various dose combinations of ceritinib (range, 300-450 mg/day) and ribociclib (range, 100-300 mg/day). Median age of patients was 57 years. MTDs were not reached in this study. Enrollment into phase Ib was terminated early and phase II was not opened due to changes in the ALK-rearranged NSCLC treatment landscape. Ceritinib 300 mg/day and ribociclib 200 mg/day (3-weeks-on/1-week-off schedule) was identified as the RP2D. Among the 27 evaluable patients, the overall response rate (ORR) was 37.0% (95% CI, 19.4-57.6) and median progression-free survival (mPFS) was 21.5 months (95% CI, 5.5-25.0). At RP2D, the ORR was 50.0%, disease control rate was 75%, and mPFS was 24.8 months (95% CI, 5.5-25.1). Safety profile of the combination therapy was consistent with single-agent safety data. CONCLUSION: Combination of ceritinib and ribociclib showed clinical activity with a manageable safety profile in patients with advanced ALK-rearranged NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Adult , Aminopyridines , Anaplastic Lymphoma Kinase/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Middle Aged , Protein Kinase Inhibitors/adverse effects , Purines , Pyrimidines , Receptor Protein-Tyrosine Kinases , Sulfones
18.
J Org Chem ; 87(5): 2267-2276, 2022 03 04.
Article in English | MEDLINE | ID: mdl-34978198

ABSTRACT

Specific chemical reactions by enzymes acting on a nucleobase are realized by flipping the target base out of the helix. Similarly, artificial oligodeoxynucleotides (ODNs) can also induce the base flipping and a specific chemical reaction. We now report an easily prepared and unique structure-providing photo-cross-linking reaction by taking advantage of the base-flipping-out field formed by alkene-type base-flipping-inducing artificial bases. Two 3-arylethenyl-5-methyl-2-pyridone nucleosides with the Ph or An group were synthesized and incorporated into the ODNs. We found that the two Ph derivatives provided the cross-linked product in a high yield only by a 10 s photoirradiation when their alkenes overlap each other in the duplex DNA. The highly efficient reaction enabled forming a cross-linked product even when using the duplex with a low Tm value.


Subject(s)
Alkenes , DNA , Nucleic Acid Conformation , Nucleosides , Oligodeoxyribonucleotides
19.
Adv Mater ; 34(7): e2106160, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34856033

ABSTRACT

The solvent acidolysis crystallization technique is utilized to grow mixed dimethylammonium/methylammonium lead tribromide (DMA/MAPbBr3 ) crystals reaching the highest dimethylammonium incorporation of 44% while maintaining the 3D cubic perovskite phase. These mixed perovskite crystals show suppression of the orthorhombic phase and a lower tetragonal-to-cubic phase-transition temperature compared to MAPbBr3 . A distinct behavior is observed in the temperature-dependent photoluminescence properties of MAPbBr3 and mixed DMA/MAPbBr3 crystals due to the different organic cation dynamics governing the phase transition(s). Furthermore, lateral photodetectors based on these crystals show that, at room temperature, the mixed crystals possess higher detectivity compared to MAPbBr3 crystals caused by structural compression and reduced surface trap density. Remarkably, the mixed-crystal devices exhibit large enhancement in their detectivity below the phase-transition temperature (at 200 K), while for the MAPbBr3 devices only insignificant changes are observed. The high detectivity of the mixed crystals makes them attractive for visible-light communication and for space applications. The results highlight the importance of the synthetic technique for compositional engineering of halide perovskites that governs their structural and optoelectronic properties.

20.
Cureus ; 13(8): e17232, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34540459

ABSTRACT

Background The incidence of surgical site infection (SSI) in colorectal surgery is high, which can complicate and delay postoperative recovery. This study mainly aims to evaluate the efficacy of subcutaneous drains in decreasing superficial surgical site infection in colorectal surgery patients.  Study design This is a retrospective cohort study that included patients over 16 years old who underwent colorectal surgery from the 1st of January 2015 till the 31st of December 2020. Patients were divided into two groups, with and without a subcutaneous drain. The incidence of superficial SSI was measured as the primary objective, and the incidence of other complications like seromas, hematomas, and wound dehiscence was measured as the secondary objectives or outcomes. Chi-square and Fisher's exact were used to analyze the data, and a p-value less than 0.05 was accepted for significance. Results A total of 208 patients who underwent colorectal surgery in our hospital were included. Of these, 29 had a subcutaneous drain, and 179 did not have a subcutaneous drain. Although the incidence of dehiscence was higher in the drain group, the overall incidence of superficial SSI (20.7%) and seroma/hematoma (3.4%) in patients with subcutaneous drains was lower than without subcutaneous drains (25.7% and 7.8%, respectively). However, no statistical significance was found between drain presence and complications. Conclusion In conclusion, this study demonstrated a lower incidence of superficial SSI and seroma/hematoma in patients with a subcutaneous drain than those who did not have a drain.

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