Multi-center study of COVID-19 infection in elderly patients with lymphoma: on behalf of Jiangsu Cooperative Lymphoma Group (JCLG).

Elderly patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we retrospectively described the clinical features and outcomes of the first time infection of Omicron SARS-CoV-2 in 364 elderly patients with lymphoma enrolled in Jiangsu Cooperative Lymphoma Group (JCLG) between November 2022 and April 2023 in China. Median age was 69 years (range 60-92). 54.4% (198/364) of patients were confirmed as severe and critical COVID-19 infection. In univariable analysis, Age > 70 years (OR 1.88, p = 0.003), with multiple comorbidities (OR 1.41, p = 0.005), aggressive lymphoma (OR 2.33, p < 0.001), active disease (progressive or relapsed/refractory, OR 2.02, p < 0.001), and active anti-lymphoma therapy (OR 1.90, p < 0.001) were associated with severe COVID-19. Multiple (three or more) lines of previous anti-lymphoma therapy (OR 3.84, p = 0.021) remained an adverse factor for severe COVID-19 in multivariable analysis. Moreover, CD20 antibody (Rituximab or Obinutuzumab)-based treatments within the last 6 months was associated with severe COVID-19 in the entire cohort (OR 3.42, p < 0.001). Continuous BTK inhibitors might be protective effect on the outcome of COVID-19 infection (OR 0.44, p = 0.043) in the indolent lymphoma cohort. Overall, 7.7% (28/364) of the patients ceased, multiple lines of previous anti-lymphoma therapy (OR 3.46, p = 0.016) remained an adverse factor for mortality.

ROS-Responsive Selenopolypeptide Micelles: Preparation, Characterization, and Controlled Drug Release.

Sulfur-containing polypeptides, capable of reactive oxygen species (ROS)-responsive structural change, are one of the most important building blocks for the construction of polypeptide-based drug delivery systems. However, the relatively low ROS sensitivity of side-chain thioethers limits the biomedical applications of these polypeptides because they usually require a high concentration of ROS beyond the pathological ROS level in the tumor microenvironment. Herein, we report the design and synthesis of a selenium-containing polypeptide, which undergoes random coil-to-extended helix and hydrophobic-to-hydrophilic transitions in the presence of 0.1% H2O2, a concentration that is much lower than the ROS requirement for thioether. ROS-responsive micelles were thus prepared from the amphiphilic copolymer consisting of the hydrophilic poly(ethylene glycol) (PEG) segment and hydrophobic selenopolypeptide segment and were used to encapsulate doxorubicin (DOX). The micelles could be sensitively dissociated inside tumor cells in consequence of ROS-triggered oxidation of side-chain selenoether and structural change of the micelles, thereby efficiently and selectively releasing the encapsulated DOX to kill cancer cells. This work provides an alternative design of ROS-responsive polypeptides with higher sensitivity than that of the existing sulfur-containing polypeptides, which may expand the biomedical applications of polypeptide materials.

Site-Specific Conjugation of a Selenopolypeptide to Alpha-1-antitrypsin Enhances Oxidation Resistance and Pharmacological Properties.

Human alpha-1-antitrypsin (A1AT), a native serine-protease inhibitor that protects tissue damage from excessive protease activities, is used as an augmentation therapy to treat A1AT-deficienct patients. However, A1AT is sensitive to oxidation-mediated deactivation and has a short circulating half-life. Currently, there is no method that can effectively protect therapeutic proteins from oxidative damage in vivo. Here we developed a novel biocompatible selenopolypeptide and site-specifically conjugated it with A1AT. The conjugated A1AT fully retained its inhibitory activity on neutrophil elastase, enhanced oxidation resistance, extended the serum half-life, and afforded long-lasting protective efficacy in a mouse model of acute lung injury. These results demonstrated that conjugating A1AT with the designed selenopolymer is a viable strategy to improve its pharmacological properties, which could potentially further be applied to a variety of oxidation sensitive biotherapeutics.

Redox-Mediated Reversible Supramolecular Assemblies Driven by Switch and Interplay of Peptide Secondary Structures.

The construction of reversible supramolecular self-assembly in vivo remains a significant challenge. Here, we demonstrate the redox-triggered reversible supramolecular self-assembly governed by the "check and balance" of two secondary conformations within a brushlike peptide-selenopolypeptide conjugate. The conjugate constitutes a polypeptide backbone whose side chain contains selenoether functional moieties and double bonds to be readily grafted with ß-sheet-prone short-peptide NapFFC. The backbone of the conjugate initially assumes a robust and rigid α-helical conformation, which inhibits the supramolecular assembly of the short peptide in the side chain and yields an overall irregular aggregate morphology under native/reduced conditions. Upon oxidation of the selenoether to more hydrophilic selenoxide, the backbone helix switches to a flexible and disordered conformation, which unleashes the side-chain NapFFC self-assembly into nanofibrils via the adoption of ß-sheet conformation. The reversible switch of the supramolecular morphology enables efficient loading and tumor-microenvironment-triggered release of anticancer drugs for in vivo cancer treatment with satisfactory efficacy and biocompatibility. The interplay and interaction between two well-defined secondary structures within one scaffold offer tremendous opportunity for the design and construction of functional supramolecular biomaterials.

DNA Origami-Enabled Engineering of Ligand-Drug Conjugates for Targeted Drug Delivery.

Effective drug delivery systems that can systematically and selectively transport payloads to disease cells remain a challenge. Here, a targeting ligand-modified DNA origami nanostructure (DON) as an antibody-drug conjugate (ADC)-like carrier for targeted prostate cancer therapy is reported. Specifically, DON of six helical bundles is modified with a ligand 2-[3-(1,3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) against prostate-specific membrane antigen (PSMA), to serve as the antibody for drug conjugation in ADC. Doxorubicin (Dox) is then loaded to DON through intercalation to dsDNA. This platform features in spatially controllable organization of targeting ligands and high drug loading capacity. With this nanocomposite, selective delivery of Dox to the PSMA+ cancer cell line LNCaP is readily achieved. The consequent therapeutic efficacy is critically dependent on the numbers of targeting ligand assembled on DON. This target-specific and biocompatible drug delivery platform with high maximum tolerated doses shows immense potential for developing novel nanomedicine.

PEGylated gene carriers in serum under shear flow.

The behaviour of drug/gene carriers in the blood stream under shear is still a puzzle. In this work, using the complexes formed by 21 bp DNA and poly(ethylene glycol)-b-poly(l-lysine) (PEG-PLL) of varying PEG lengths, we studied the dynamic behaviour of the complexes in the presence of fetal bovine serum (FBS) and under flow at different shear rates, a condition mimicking the internal physical environment of blood vessels. The PEG5k-PLL/DNA complex possesses a dense DNA/PLL core and a loose PEG5k protecting layer. The PEGylated DNA complexes exhibit multiple responses to external shear in the presence of FBS. The loose PEG5k layer is firstly disturbed at a shear rate below 30 s-1. The exposure of the charged core to the environment results in a secondary aggregation of the complex with FBS. The size of the aggregate is limited to a certain range as the shear rate increases to 50 s-1. The dense DNA/PLL core starts to withstand the shear force as the shear rate reaches 500 s-1. The reorganization of the core to accommodate more serum molecules leads to tertiary aggregation of the complexes. If PEG cannot form a valid layer around the complex, as in PEG2k-PLL/DNA, the complex forms an aggregate even without shear, and the first shear dependent region is missing. If the PEG layer is too stable around the complex, as in PEG10k-PLL/DNA, no tertiary aggregation occurs. The mechanism of shear on the behaviour of delivery particles in serum helps to design gene carriers with high efficacy.

Efficient Synthesis of Topologically Linked Three-Ring DNA Catenanes.

Topologically controlled DNA catenanes are promising elements for the construction of molecular machines but present a significant effort in DNA nanotechnology. We report an efficient approach for preparing linear three-ring catenanes (L3C) composed of single-stranded DNA. The linking number was strictly controlled by using short complementary regions (6 nt) between each two DNA rings. High efficiency of forming three-ring catenanes (yield as high as 63 %) was obtained by using an 80 nt oligonucleotide as the scaffold to draw close the three pre-rings for hybridization between short complementary DNA. After assembly, three pre-rings were closed by DNA ligation using three 12 nt oligonucleotides as splints to form interlocked three-ring catenanes. L3C nanostructures were imaged in air by AFM: the catenane exhibited a smooth circular shape and was arranged in a line with well-defined structure, as expected.

Metabolome regulation and restoration mechanism of different varieties of rice (Oryza sativa L.) after lindane stress.

There is a lack of studies on the ability of plants to metabolize chlorinated organic pollutants (COPs) and the dynamic expression changes of metabolic molecules during degradation. In this study, hybrid rice Chunyou 927 (CY) and Zhongzheyou 8 (ZZY), traditional rice subsp. Indica Baohan 1 (BH) and Xiangzaoxian 45 (XZX), and subsp. Japonica Yangjing 687 (YJ) and Longjing 31 (LJ) were stressed by a typical COPs of lindane and then transferred to a lindane-free culture to incubate for 9 days. The cumulative concentrations in the roots of BH, XZX, CY, ZZY, YJ and LJ were 71.46, 65.42, 82.06, 80.11, 47.59 and 56.10 mg·kg-1, respectively. And the degradation ratios on day 9 were 87.89 %, 86.92 %, 94.63 %, 95.49 %, 72.04 % and 82.79 %, respectively. On the 0 day after the release of lindane stress, the accumulated lindane inhibited the normal physiological activities of rice by affecting lipid metabolism in subsp. Indica BH, amino acid metabolism and synthesis and nucleotide metabolism in hybrid CY. Carbohydrate metabolism of subsp. Japonica YJ also was inhibited, but with low accumulation of lindane, YJ regulated amino acid metabolism to resist stress. With the degradation of lindane in rice, the amino acid metabolism of BH and CY, which had high degradation ratios on day 9, was activated to compound biomolecules required for the organism to recover from the damage. Amino acid metabolism and carbohydrate metabolism were disturbed and inhibited mainly in YJ with low degradation ratios. This study provides the difference of the metabolic capacity of the metabolic capacity of different rice varieties to lindane, and changes at the molecular level and metabolic response mechanism of rice during the metabolism of lindane.

Combined magnetic biochar and ryegrass enhanced the remediation effect of soils contaminated with multiple heavy metals.

Biochar is a very promising material for soil remediation. However, most studies mainly focus on the adsorption ability of biochar on one heavy metal, which is difficult to evaluate the actual remediation effect since soils were contaminated with multiple heavy metals. In order to improve the soil remediation efficiency, we used the joint remediation method of magnetically modified biochar and ryegrass to remediate the soil polluted by compound heavy metals (chromium, nickel, copper, zinc, arsenic and cadmium), and evaluate the effect on the process of organic carbon mineralization in polluted soils. It was found that magnetic biochar and ryegrass together decreased the concentrations of Cr, Ni, Cu, Zn, As, and Cd in soils by 24.12 %, 23.30 %, 22.01 %, 9.98 %, 14.83 %, and 15.08 %, respectively, and reduced the available fractions. Ryegrass roots were the main accumulation part of heavy metals, and the order of enrichment effect was ranked as Zn > As > Cr > Cu > Ni > Cd. In addition, magnetic biochar can maintained the stability of the organic carbon pool, and inhibited the emission of volatile organic compounds from ryegrass. Overall, this study indicates that magnetic biochar spheres combined with ryegrass is an effective method for heavy metals co-contaminated soils, and has the excellent remediation ability for actual co-contaminated soils.

A Unique Three-Way Variant Philadelphia Chromosome t(6;9;22)(p21.3;q34;q11.2) in a Newly Diagnosed Patient with Chronic Myeloid Leukemia Responded to Flumatinib.

Background: Chronic myeloid leukaemia (CML) is a clonal malignant disorder of a pluripotent hematopoetic stem cell characterized by the presence of Philadelphia (Ph) chromosome in more than 90% of patients. However, about 5-10% of CML patients show a variant Ph translocation, involving one or more chromosomes in addition to 9 and 22. The treatment and prognostic impact of such additional abnormalities is not known. Herein, we report a unique case of a three-way translocation variant in CML and responded to flumatinib. Case Presentation: A 22-year-old Asian female who presented with leukocytosis was diagnosed with CML. Cytogenetic karyotyping analysis showed 46,XX,t(6;9;22)(p21.3;q34;q11.2). She was treated with flumatinib, and MR5.0 (BCR-ABL1 IS≤0.001%, international scale) was achieved after three months of continuous treatment. Conclusion: This was the 5th case of t(6;9;22), in particular, a new variant Ph translocation, and the first successful case treated with flumatinib in the world.

Synthesis of water soluble and multi-responsive selenopolypeptides via ring-opening polymerization of N-carboxyanhydrides.

We report here the synthesis of water soluble selenopolypeptides via the ring-opening polymerization of N-carboxyanhydrides. The oligoethylene glycol-bearing selenopolypeptides are thermally responsive in aqueous solutions with tunable lower critical solution temperatures. The polymers can also undergo rapid and reversible helix-coil transitions upon responding to the added redox cycle.

Topology- and linking number-controlled synthesis of a closed 3 link chain of single-stranded DNA.

In spite of remarkable progress in synthetic methodology, a closed three-link chain (one of the simplest but the most important topological isomers of [3]catenane) has never been prepared. Here we synthesized this isomer in high yield from three oligonucleotides which are designed to optimize various chemical and steric factors in their mutual hybridization.