Comparison of the effects of different functional exercise sequences on lymphedema in breast cancer: protocol for an exploratory randomised controlled cross-over trial.

INTRODUCTION: Breast cancer-related lymphedema (BCRL) is a common postoperative complication of breast cancer. It develops in a chronic and vicious cycle. Once lymphedema occurs, it cannot be cured and bring serious physiological, psychological, social and economic burden to patients. Upper limb functional exercises are an effective and convenient intervention for managing lymphedema. However, the optimal exercise sequence remains unclear. Therefore, we aim to compare the effects of exercise sequences under the guidance of commonly used exercise sequences and lymphatic flow theory. METHODS: An exploratory randomised controlled cross-over trial will be conducted. 32 patients with BCRL are randomly allocated into two groups (group A and group B). Group A patients will perform functional exercise from wrist joint to shoulder joint, and the exercise direction of group B is opposite to that of group A, that is, from shoulder joint to wrist joint end. Exercise time is once a day, each 20-30 min, for 2 weeks. After 2 weeks of washout period, A and B groups of exchange exercise sequences (exercise frequency and duration unchanged). The primary outcome is upper limb circumference, and secondary outcomes are upper limb function and lymphedema symptoms. ETHICS AND DISSEMINATION: This study protocol is presented in accordance with the Standard Protocol Items: Recommendations for Interventional Trials guidelines. All participants will sign a written informed consent. The research ethics regional committee of Shanghai Seventh People's Hospital has approved the study. Regardless of the outcome of this study, the results will be published in open-access journals to ensure public access. TRIAL REGISTRATION NUMBER: ChiCTR2200066463.

Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities.

We report the design and synthesis of a series of proline-derived quinoline formamide compounds as human urate transporter 1 (URAT1) inhibitors via a ligand-based pharmacophore approach. Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad. Compounds 21c, 21e, 24b, 24c, and 23a exhibit potent activities against URAT1 with IC50 values ranging from 0.052 to 0.56 µM. Furthermore, compound 23a displays improved selectivity towards organic anion transporter 1 (OAT1), good microsomal stability, low potential for genotoxicity and no inhibition of the hERG K+ channel. Compounds 21c and 23a, which have superior pharmacokinetic properties, also demonstrate significant uric acid-lowering activities in a mouse model of hyperuricemia. Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout.

Identification of Piperazinyl-Difluoro-indene Derivatives Containing Pyridyl Groups as Potent FGFR Inhibitors against FGFR Mutant Tumor: Design, Synthesis, and Biological Evaluation.

The fibroblast growth factor receptor (FGFR) signaling pathway plays important roles in cellular processes such as proliferation, differentiation, and migration. In this study, we highlighted the potential of FGFR inhibitors bearing the (S)-3,3-difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene scaffold containing a crucial 3-pyridyl group for the treatment of FGFR mutant cancers. The representative compound (S)-23, which was identified through comprehensive evaluation, exhibited potent antiproliferative activity with GI50 in the range of 6.4-10.4 nM against FGFR1 fusion protein-carrying, FGFR2-amplified, and FGFR2 mutant cancer cell lines and good antiproliferative activity against FGFR3 translocation and mutant FGFR4 cancer cell lines, as well as potency assessment against FGFR1-4 kinases. Moreover, compound (S)-23 exhibited favorable pharmacokinetic properties, low potential for drug-drug interactions, and very potent antitumor activity in MFE-296 xenograft mouse models with a TGI of 99.1% at the dose of 10 mg/kg. These findings demonstrate that compound (S)-23 is a potential therapeutic agent for FGFR mutant tumors.

Design, synthesis and biological evaluation of 3-substituted-2-thioxothiazolidin-4-one (rhodanine) derivatives as antitubercular agents against Mycobacterium tuberculosis protein tyrosine phosphatase B.

Mycobacterium tuberculosis infections still pose a serious threat to human health. Combination therapies are effective medical solutions to the problem. Mycobacterium tuberculosis is an intracellular pathogen that mainly depends on a virulence factor (Mycobacterium tuberculosis protein tyrosine phosphatase B, MptpB) for its survival in the host. Therefore, MptpB inhibitors are potential components of tuberculosis combination treatments. Herein, a new series of MptpB inhibitors bearing a rhodanine group were developed using a structure-based strategy based on the virtual screening hit. The new MptpB inhibitors displayed potent MptpB inhibitory activities and great improvements in cell membrane permeability. The optimal compounds reduced the bacterial burden in a dose-dependent manner in a macrophage infection model, especially, a combination of compound 20 and rifampicin led to a bacterial burden reduction of more than 95%, greater than the reductions achieved with compound 20 or rifampicin alone. This research provides new insights into the rational design of new MptpB inhibitors and verifies that the MptpB inhibitor has a promising potential as a component of tuberculosis treatment.

Pathogen detection in suspected spinal infection: metagenomic next-generation sequencing versus culture.

PURPOSE: The aim is to compare the pathogen detection performance of metagenomic next-generation sequencing (mNGS) and the culturing of percutaneous needle biopsy samples obtained from an individual with a suspected spinal infection. METHODS: A retrospective study of 141 individuals with a suspected spinal infection was conducted, and mNGS was performed. The microbial spectra and detection performance between mNGS and the culturing-based method were compared, and the effects of antibiotic intervention and biopsy on the detection performance were assessed. RESULTS: The microorganisms isolated most commonly via the culturing-based method were Mycobacterium tuberculosis (n = 21), followed by Staphylococcus epidermidis (n = 13). The most common microorganisms detected via mNGS were Mycobacterium tuberculosis complex (MTBC) (n = 39), followed by Staphylococcus aureus (n = 15). The difference in the type of detected microorganisms between culturing and mNGS was observed only in Mycobacterium (P = 0.001). mNGS helped identify potential pathogens in 80.9% of cases, which was significantly higher than the positivity rate of 59.6% observed for the culturing-based method (P < 0.001). Moreover, mNGS had a sensitivity of 85.7% (95% CI, 78.4% to 91.3%), a specificity of 86.7% (95% CI, 59.5% to 98.3%), and sensitivity gains of 35% (85.7% vs. 50.8%; P < 0.001) during culturing, while no differences were observed in the specificity (86.7% vs. 93.3%; P = 0.543). In addition, antibiotic interventions significantly lowered the positivity rate of the culturing-based method (66.0% vs. 45.5%, P = 0.021) but had no effects on the results of mNGS (82.5% vs. 77.3%, P = 0.467). CONCLUSION: The use of mNGS could result in a higher detection rate compared to that observed with the culturing-based method in an individual with spinal infection and is particularly valuable for evaluating the effects of a mycobacterial infection or previous antibiotic intervention.

Design, synthesis and biological evaluation of alkynyl-containing maleimide derivatives for the treatment of drug-resistant tuberculosis.

A series of alkynyl-containing maleimides with potent anti-tuberculosis (TB) activity was developed through a rigid group substitution strategy based on our previous study. Systematic optimization of the two side chains flanking the maleimide core led to new compounds with potent activity against Mycobacterium tuberculosis (MIC < 1 µg/mL) and low cytotoxicity (IC50 > 64 µg/mL). Among them, compound 29 not only possessed good activity against extensively drug-resistant TB and favorable hepatocyte stability, but also displayed good intracellular antimycobacterial activity in macrophages. This study lays a good foundation for identifying new alkynyl-containing maleimides as promising leads for treating drug-resistant TB.

An arc profile-based approach to evaluate gas pollutants in welding.

Welding is widely used to make assembly of structural components and it will trigger serious environmental pollution, especially waste gas, i.e., carbon dioxide (CO2), ozone (O3), nitrogen oxide (NOx), and particulate matter (PM). It is hard to accurately measure gas pollutants because of their fluidity and diffusivity. However, the pollutants could be evaluated by exploring its generation procedure, i.e., how these pollutants are produced and how to quantify these pollutants. In this paper, an arc profile-based approach to evaluate the emissions of gas pollutants in welding was proposed. The emission of gas pollutants in welding can be calculated according to the chemical reaction and corresponding reaction condition, i.e., the intensity of discharge that determines the coverage volume of the welding arc. To obtain the coverage volume, the welding arc was observed using a high-speed camera and the arc edge was extracted and reconstructed by a binarization processing based method. A welding experiment was performed for recording the arc shape and measuring the emission of gas pollutants. Results show that the measured concentrations of NOx and O3 are 70% and 79% of the calculated emissions of gas pollutants, respectively. It demonstrates the proposed method is credible and feasible, which can help quantitatively analyze the emission of gas pollutants. Meanwhile, the influence of welding time, welding current, and arc length on the emission of gas pollutants was investigated for lowering emission of gas pollution in welding, in order to support the development of sustainable manufacturing processes.

Solubility-driven optimization of benzothiopyranone salts leading to a preclinical candidate with improved pharmacokinetic properties and activity against Mycobacterium tuberculosis.

Solubility-driven optimization of the salts of nitro benzothiopyranone 1, which targets DprE1, led to an antimycobacterial preclinical candidate 2. Five pharmaceutically acceptable salts, including the maleate (2), fumarate (3), citrate (4, 5), and l-malate (6) of compound 1, were prepared via the salt formation reaction and evaluated for their physicochemical and pharmacokinetic properties. Compared with 1, all the target salts exhibited greatly increased aqueous solubility and improved oral bioavailability in mice. Maleate salt 2, which displayed higher chemical stability and lower log P, showed substantially improved bioavailability in rats and a much better in vivo effect compared with free base 1 at the same dose. The X-ray crystal structure of 2 revealed that the exposed hydrophilic piperazine-maleate moiety in the crystal structure cell may be critical in increasing the solubility of 2. Thus, this maleate salt 2 overcame the poor druggability of benzothiopyranone derivatives and was identified as a promising preclinical candidate for treating tuberculosis.

A novel nano material for anti-cerebral ischaemia: preparation and application of borneol angelica polysaccharide liposomes.

OBJECTIVE: To investigate the preparation of novel nanoliposomes (Borneol Angelica Polysaccharide Liposomes, BAPL) for anti-cerebral ischaemia and verify its curative effects and mechanism. METHODS: By applying a uniform experiment design to investigate the fitting combination of BAPL. Encapsulation Efficiency Evaluation of BAPL Preparation; Particle Size and Surface Potential Evaluation of BAPL Biological activity; Cerebral ischaemia models of rats Evaluation of BAPL curative effects and mechanism. RESULTS: (1) The fitting combination of lecithin, Cholesterol, AP mass and the borneol mass was 60 mg, 60 mg, 45 mg and 5 mg. the highest encapsulation efficiency was 80.4%, the particle size was 179.1 nm, and the surface zeta potential was -17.2 mV. It conforms to the nano-material standards. (2) The results of animal experiments show that: In the BAPL group, the infarct volume of TTC staining was significantly decreased, and the expression levels of NF-κBp65, TLR-4, IL-8, IL-6, IL-1ß in brain tissue were significantly decreased, while the expression levels of ZO-1, ZO-2, IL-10 were significantly increased after cerebral ischaemia-reperfusion. CONCLUSION: BAPL is a novel nano and effective material for anti-cerebral ischaemia.

Discovery of biphenyls bearing thiobarbiturate fragment by structure-based strategy as Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitors.

Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) is an important virulence factor that blocks the host immune response and facilitates M. tuberculosis growth in host cells. MptpB inhibitors are potential components of tuberculosis combination treatment. Herein, we present the development of new biphenyls MptpB inhibitors with greatly improved MptpB inhibition based on our reported thiobarbiturate lead 6 by rational design with the structure-based strategy. The eight biphenyls bearing thiobarbiturate fragment target compounds showed more potent MptpB inhibition (IC50: 1.18-14.13 µM) than the lead compound 6. Further molecular docking studies showed that compounds 13, 26, 27 and 28 had multiple interactions with active sites. Among them, compound 13 exhibited dose-dependent increased antituberculosis activity in mouse macrophages. The results displayed that the strategy of modification utilizing biphenyl scaffold was efficient. Our study identifies biphenyls bearing thiobarbiturate fragment as new MptpB inhibitors and verifies the therapeutic potential of antimycobacterial agent targeting MptpB.

Design, Synthesis, and Biological Evaluation of Pyrrole-2-carboxamide Derivatives as Mycobacterial Membrane Protein Large 3 Inhibitors for Treating Drug-Resistant Tuberculosis.

In this work, pyrrole-2-carboxamides were designed with a structure-guided strategy based on the crystal structure of MmpL3 and a pharmacophore model. The structure-activity relationship studies revealed that attaching phenyl and pyridyl groups with electron-withdrawing substituents to the pyrrole ring and attaching bulky substituents to the carboxamide greatly improved anti-TB activity. Most compounds showed potent anti-TB activity (MIC < 0.016 µg/mL) and low cytotoxicity (IC50 > 64 µg/mL). Compound 32 displayed excellent activity against drug-resistant tuberculosis, good microsomal stability, almost no inhibition of the hERG K+ channel, and good in vivo efficacy. Furthermore, the target of the pyrrole-2-carboxamides was identified by measuring their potency against M. smegmatis expressing wild-type and mutated variants of the mmpL3 gene from M. tuberculosis (mmpL3tb) and determining their effect on mycolic acid biosynthesis using a [14C] acetate metabolic labeling assay. The present study provides new MmpL3 inhibitors that are promising anti-TB agents.

An Encapsulation-Based Sodium Storage via Zn-Single-Atom Implanted Carbon Nanotubes.

The properties of high theoretical capacity, low cost, and large potential of metallic sodium (Na) has strongly promoted the development of rechargeable sodium-based batteries. However, the issues of infinite volume variation, unstable solid electrolyte interphase (SEI), and dendritic sodium causes a rapid decline in performance and notorious safety hazards. Herein, a highly reversible encapsulation-based sodium storage by designing a functional hollow carbon nanotube with Zn single atom sites embedded in the carbon shell (ZnSA -HCNT) is achieved. The appropriate tube space can encapsulate bulk sodium inside; the inner enriched ZnSA sites provide abundant sodiophilic sites, which can evidently reduce the nucleation barrier of Na deposition. Moreover, the carbon shell derived from ZIF-8 provides geometric constraints and excellent ion/electron transport channels for the rapid transfer of Na+ due to its pore-rich shell, which can be revealed by in situ transmission electron microscopy (TEM). As expected, Na@ZnSA -HCNT anodes present steady long-term performance in symmetrical battery (>900 h at 10 mA cm-2 ). Moreover, superior electrochemical performance of Na@ZnSA -HCNT||PB full cells can be delivered. This work develops a new strategy based on carbon nanotube encapsulation of metallic sodium, which improves the safety and cycling performance of sodium metal anode.

[Design and Verification of Human Metabolic Measurement System Based on STM32].

A high-precision human metabolic measurement system is designed. The system uses STM32F103 as the main control chip to acquire oxygen, carbon dioxide and flow signals to calculate four quantitative indicators: oxygen consumption(VO2), carbon dioxide production(VCO2), respiratory entropy(RQ) and resting energy metabolism(REE), and finally uses an upper computer to display the calculation results.In this paper, the signal acquisition circuit design was carried out for the oxygen sensor, carbon dioxide sensor and flow sensor, and the validity of the device was verified with the American machine MGCDiagnositcs using Bland-Altman analysis method, and the results showed that the four parameters of VO2,VCO2, RQ and REE of both devices fell in the agreement interval of more than 95%. The device thus provides accurate metabolic measurements and offers an effective tool for the field of general health and clinical nutrition support in China.

Facile Fabrication of 3D-Printed Porous Ti6Al4V Scaffolds with a Sr-CaP Coating for Bone Regeneration.

To improve osseointegration caused by the stress-shielding effect and the inert nature of titanium-based alloys, in this work, we successfully constructed a strontium calcium phosphate (Sr-CaP) coating on three-dimensional (3D)-printed Ti6Al4V scaffolds to address this issue. The energy-dispersive X-ray spectroscopy (EDS) and X-ray diffraction (XRD) results indicated that the coatings with and without Sr doping mainly consisted of CaHPO4. The bonding strength of Sr doping coating met the required ISO 13 779-4-2018 standard (≥15 MPa). The in vitro results suggested that the Sr-CaP-modified Ti6Al4V scaffolds were found to effectively promote mice bone-marrow stem cell (mBMSC) adhesion, spreading, and osteogenesis. The in vivo experiments also showed that the Sr-CaP-modified Ti6Al4V scaffolds could significantly improve bone regeneration and osseointegration. More importantly, Sr-doped CaP-coated Ti6Al4V scaffolds were found to accelerate bone healing in comparison to CaP-coated Ti6Al4V scaffolds. The Sr-CaP-modified Ti6Al4V scaffolds are considered a promising strategy to develop bioactive surfaces for enhancing the osseointegration between the implant and bone tissue.

Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis.

A series of thiophene-benzenesulfonamide derivatives was designed and synthesized by exploring the structure-activity relationship of lead compounds 2,3-disubstituted thiophenes 25a and 297F as antituberculosis agents, which displayed potent antimycobacterial activity against drug-susceptible and clinically isolated drug-resistant tuberculosis. In particular, compound 17b, which had improved activity (minimum inhibitory concentration of 0.023 µg/mL) compared with the lead compounds, displayed good intracellular antimycobacterial activity in macrophages with a reduction of 1.29 log10 CFU. A druggability evaluation indicated that compound 17b had favorable hepatocyte stability, low cytotoxicity, and low hERG channel inhibition. Moreover, compound 17b exhibited modest in vivo efficacy in an acute mouse model of tuberculosis. In addition, the molecular docking study elucidated the binding mode of compound 17b in the active site of DprE1. Therefore, compound 17b may be a promising antituberculosis lead for further research.

An Active-Oxygen-Scavenging Oriented Cathode-Electrolyte-Interphase for Long-Life Lithium-Rich Cathode Materials.

Lithium-rich layered oxides with high energy density are promising cathode materials, thus having attracted a large number of researchers. However, the materials cannot be commercialized for application so far. The crucial problem is the releasing of lattice oxygen at high voltage and resulting consequence, such as decomposition of electrolyte, irreversible phase transition of crystal structure, capacity degradation, and voltage decay. Therefore, capturing active-oxygen and further constructing a cathode-electrolyte-interface (CEI) protective layer via the scavenging effects should be a fundamental step to solve these issues. Herein, ß-carotene with antioxidant properties is used as a scavenging molecule to achieve this goal. The control of active oxygen species effectively alleviates the decomposition of carbonate electrolyte under high voltage. The introduction of ß-carotene additives can also be adjusted in situ to generate a customized CEI film, which is a double-layer structure with external organic components and internal inorganic components. Moreover, the ß-carotene-containing electrolyte system exhibits better thermal stability. Benefited from these, Lithium-rich cathode of ß-carotene-containing electrolyte shows outstanding long-life cycle stability, with 93.4% capacity retention rate after 200 cycles at 1 C; this electrochemical stability is superior to other electrolyte additive systems reported at present.

In Vitro and In Vivo Activity of Oxazolidinone Candidate OTB-658 against Mycobacterium tuberculosis.

In this work, we assess antituberculosis activity of OTB-658 in vitro and in vivo. In vitro, OTB-658 showed bacteriostatic effectiveness with a lower MIC than linezolid against Mycobacterium tuberculosis. The minimal bactericidal concentrations and time-kill curves for OTB-658 indicated inhibition activity similar to that of linezolid. OTB-658 entered macrophages to inhibit M. tuberculosis growth. OTB-658 had a low mutation frequency (10-8), which would prevent drug-resistant mutations from emerging in combination regimens. In vivo, OTB-658 reduced CFU counts in the lungs and slightly inhibited bacterial growth in the spleen in the early stage and steady state in acute and chronic murine TB models. These results support the preclinical evaluation of OTB-658 and further clinical trials in China.

Synthesis of 2-Aryl-4H-thiochromen-4-one Derivatives via a Cross-Coupling Reaction.

A concise and efficient cross-coupling synthetic strategy has been developed to construct 2-aryl-4H-thiochromen-4-one derivatives from 2-sulfinyl-thiochromones and arylboronic acids. This reaction proceeds via a catalyst system of Lewis acid and palladium(II) combined with XPhos as an optimal ligand in moderate to good yields. Besides, this flexible methodology provides a wide scope for the synthesis of different functionally substituted thiochromone scaffolds and can be further exploited to construct diverse thioflavone libraries for pharmaceutical research.

Identification of novel benzothiopyranones with ester and amide motifs derived from active metabolite as promising leads against Mycobacterium tuberculosis.

We reported three distinct series of novel benzothiopyranones, derived from an active metabolite (M-1) of anti-TB agent 6b. These small molecules were evaluated for their biological activities against a range of Mycobacterium tuberculosis (M. tuberculosis) strains. Preliminary druggability evaluation demonstrated that M-1 showed good aqueous solubility and hepatocyte stability. Benzothiopyranones with acyl, sulfonyl and phosphoryl groups exhibited potent in vitro inhibitory activity against M. tuberculosis H37Rv and low cytotoxicity. In particular, compound 3d, containing a benzoate fragment, displayed marked metabolic stability and potent in vitro activity against drug-resistant tuberculosis clinical strains. Further druggability evaluation based on the identified compounds 3d, 4e and 5b is ongoing for the discovery of promising anti-TB agents.

Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase Including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia.

BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABLT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K+, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABLT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.