Nilotinib boosts the efficacy of anti-PDL1 therapy in colorectal cancer by restoring the expression of MHC-I.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs. METHODS: Dual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated. RESULTS: Nilotinib induces MHC-I expression in CRC cells, enhances CD8+ T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-κB pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects. CONCLUSION: This study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC.

Application of S-transform-based nonlinear processing for accurate LIBS quantitative analysis of iron ore slurry.

Real-time Fe content monitoring in iron ore slurry is crucial for evaluating concentrate quality and enhancing mineral processing efficiency. Laser-induced breakdown spectroscopy (LIBS) is a promising technique for the online monitoring of elemental content at industrial sites. However, LIBS measurements are hampered by the matrix effect and the self-absorption effect, limiting the precision of linear analytical processes. To overcome this, we propose to introduce a nonlinear processing unit based on the S-transform to incorporate nonlinearity into the data analysis process. This approach integrates a feature selection unit based on the spectral distance variable selection method (SDVS), a nonlinear processing unit based on the S-transform (ST), and a partial least squares regression model (PLS). To demonstrate the improvement in accuracy achieved through nonlinear processing, a comparative analysis involving five models, Raw-PLS, SDVS-PLS, ST-PLS, SDVS-ANN, and SDVS-ST-PLS, is conducted. The results reveal a significant improvement in the performance of the SDVS-ST-PLS model, effectively facilitating the successful application of the LIBSlurry analyzer to the mineral flotation process.

Estimation of linezolid exposure in patients with hepatic impairment using machine learning based on a population pharmacokinetic model.

PURPOSE: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure. METHODS: Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included. RESULTS: A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid. CONCLUSION: In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.

Tumor derived exosomal ENTPD2 impair CD8+ T cell function in colon cancer through ATP-adenosine metabolism reprogramming.

BACKGROUND: Extracellular ATP-AMP-adenosine metabolism plays a pivotal role in modulating tumor immune responses. Previous studies have shown that the conversion of ATP to AMP is primarily catalysed by Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), a widely studied ATPase, which is expressed in tumor-associated immune cells. However, the function of ATPases derived from tumor cells themselves remains poorly understood. The purpose of this study was to investigate the role of colon cancer cell-derived ATPases in the development and progression of colon cancer. METHODS: Bioinformatic and tissue microarray analyses were performed to investigate the expression of ATPase family members in colon cancer. An ATP hydrolysis assay, high-performance liquid chromatography (HPLC), and CCK8 and colony formation assays were used to determine the effects of ENTPD2 on the biological functions of colon cancer cells. Flow cytometric and RNA-seq analyses were used to explore the function of CD8+ T cells. Immunoelectron microscopy and western blotting were used to evaluate the expression of ENTPD2 in exosomes. Double-labelling immunofluorescence and western blotting were used to examine the expression of ENTPD2 in serum exosomes and colon cancer tissues. RESULTS: We found that ENTPD2, rather than the well-known ATPase CD39, is highly expressed in cancer cells and is significantly positively associated with poor patient prognosis in patients with colon cancer. The overexpression of ENTPD2 in cancer cells augmented tumor progression in immunocompetent mice by inhibiting the function of CD8+ T cells. Moreover, ENTPD2 is localized primarily within exosomes. On the one hand, exosomal ENTPD2 reduces extracellular ATP levels, thereby inhibiting P2X7R-mediated NFATc1 nuclear transcription; on the other hand, it facilitates the increased conversion of ATP to adenosine, hence promoting adenosine-A2AR pathway activity. In patients with colon cancer, the serum level of exosomal ENTPD2 is positively associated with advanced TNM stage and high tumor invasion depth. Moreover, the level of ENTPD2 in the serum exosomes of colon cancer patients is positively correlated with the ENTPD2 expression level in paired colon cancer tissues, and the ENTPD2 level in both serum exosomes and tissues is significantly negatively correlated with the ENTPD2 expression level in tumor-infiltrating CD8+ T cells. CONCLUSION: Our study suggests that exosomal ENTPD2, originated from colon cancer cells, contributes to the immunosuppressive microenvironment by promoting ATP-adenosine metabolism. These findings highlight the importance of exosome-derived hydrolytic enzymes as independent entities in shaping the tumor immune microenvironment.

Efficacy of a novel affitoxin targeting MOMP against Chlamydia trachomatis in vitro and in vivo.

Targeted therapy is an attractive approach for treating infectious diseases. Affibody molecules have similar capability to antibodies that facilitate molecular recognition in both diagnostic and therapeutic applications. Targeting major outer membrane protein (MOMP) for treating infection of Chlamydia trachomatis, one of the most common sexually transmitted pathogens, is a promising therapeutic approach. Previously, we have reported a MOMP-specific affibody (ZMOMP:461) from phage display library. Here, we first fused it with modified Pseudomonas Exotoxin (PE38KDEL) and a cell-penetrating peptide (CPP) to develop an affitoxin, Z461X-CPP. We then verified the addition of both toxin and CPPs that did not affect the affinitive capability of ZMOMP:461 to MOMP. Upon uptake by C.trachomatis-infected cells, Z461X-CPP induced cell apoptosis in vitro. In animal model, Z461X significantly shortened the duration of C. trachomatis infection and prevented pathological damage in mouse reproductive system. These findings provide compelling evidence that the MOMP-specific affitoxin has great potential for targeting therapy of C. trachomatis infection.

HIF-1α Mediates Immunosuppression and Chemoresistance in Colorectal Cancer by Inhibiting CXCL9, -10 and -11.

Uncertainty exists regarding the mechanisms by which hypoxia-inducible factors (HIFs) control CD8+T-cell migration into tumor microenvironments. Here, we found that HIF-1α knockdown or overexpression resulted in increased or decreased CXCL9, -10, and -11 expression in vitro, respectively. Gene Set Variation Analysis revealed that elevated HIF-1α levels correlated with a poor prognosis, severe pathological stage, and an absence of CD8+ T cells in the tumor microenvironment in colorectal cancer (CRC) patients. HIF-1α was inversely associated with pathways beneficial to anti-tumor immunotherapy and cytokine/chemokine function. In vivo, inhibiting HIF-1α or its upstream regulator BIRC2 significantly suppressed tumor growth and promoted CD8+ T-cell infiltration. CXCR3 neutralizing antibodies reversed these effects, implicating the involvement of CXCL9, -10, and -11/CXCR3 axis. The presence of HIF-1α weakened the upregulation of CXCL9, -10, and -11 by bleomycin and doxorubicin. Combining HIF-1α inhibition with bleomycin promoted CD8+ T-cell infiltration and tumor suppression in vivo. Moreover, doxorubicin could upregulate CXCL9, -10 and -11 by suppressing HIF-1α. Our findings highlight the potential of HIF-1α inhibition to improve CRC microenvironments and increase chemotherapy sensitivity.

Magnesium Oxychloride and Magnesium Oxysulfate Cements as Temporary Plugging Agents in Geothermal Drilling.

The development and utilization of geothermal resources are effective ways to alleviate the current haze situation, adjust the energy structure, and achieve energy conservation and emission reduction. Geothermal formations typically contain extensive fracture networks, with fracture openings. These fracture networks can result in substantial losses of the drilling fluid and increased costs for geothermal drilling. Temporary plugging cements are used to solve the problem of lost circulation due to their high strength and high acid solubility. In this paper, two types of temporary plugging materials, magnesium oxysulfate (MOS) cement and magnesium oxychloride (MOC) cement, were prepared. The influence of the plugging agent on the flow field and the force exerted on the solid under the action of the fluid was analyzed using fluid-solid coupling software. The simulation results show that when subjected to a flow rate of 10 m/s, the edge of the cement experiences a significant force, while the stress is not widely transmitted to the middle and rear of the cement. This indicates that the cement has a strong resistance to the fluid flow. The fundamental characteristics of MOC cement and MOS cement, such as compressive strength and setting time, were investigated. The test results show that adjusting the molar ratio of the two types of cements can shorten the setting time by 60% and increase the compressive strength to up to 23 MPa. In addition, the acid solubility of the cement with different ratios of raw materials is above 95%. The plugging performance of these two cements as loss circulation materials was evaluated by using a physical simulation device. The pressure bearing capacity of the MOC cement with different MgO/MgCl2·6H2O/H2O molar ratios ranged between 13.4 and 23.6 MPa. The maximum bearing capacity of the MOS cement can reach up to 18.6 MPa. The results showed that both cements possess excellent plugging and pressure bearing capacity.

Efficacy, Safety, and Cost-effectiveness Analysis of Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with higher non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). But the preferred drug for preventing cytomegalovirus infection is still controversial. We evaluate the efficacy, safety, and cost-effectiveness of antiviral agents based on the most recent studies. METHODS: A pairwise and network meta-analysis was conducted to obtain direct and indirect evidence of antivirals. The cost of allo-HSCT recipients in a teaching hospital was collected, and a cost-effectiveness analysis using a decision tree combined with Markov model was completed from the perspective of allo-HSCT recipients over a lifetime horizon. RESULTS: A total of 19 RCTs involving 3565 patients (8 antivirals) were included. In the network meta-analysis, relative to placebo, letermovir, valacyclovir, and ganciclovir significantly reduced CMV infection incidence; ganciclovir significantly reduced CMV disease incidence; ganciclovir significantly increased the incidence of serious adverse event; none of antivirals significantly reduced all-cause mortality. Based on meta-analysis and Chinese medical data, the incremental cost-effectiveness ratios (ICER) per quality-adjusted life year (QALY) saved for maribavir, acyclovir, valacyclovir, ganciclovir, and letermovir relative to placebo corresponded to US$216 635.70, US$11 590.20, US$11 816.40, US$13 049.90, and US$12 189.40, respectively. One-way sensitivity analysis showed the most influential parameter was discount rate. The probabilistic sensitivity analysis indicated a 53.0% probability of letermovir producing an ICER below the willingness-to-pay threshold of US$38 824.23/QALY. The scenario analysis demonstrated prophylaxis with letermovir is considered cost-effective in the United States. CONCLUSIONS: Currently, letermovir is an effective and well-tolerated treatment for preventing CMV infection, and it might be a cost-effective choice in allo-HSCT recipients in China.

A new insight into fluoride induces cardiotoxicity in chickens: Involving the regulation of PERK/IRE1/ATF6 pathway and heat shock proteins.

Fluorosis poses a significant threat to human and animal health and is an urgent public safety concern in various countries. Subchronic exposure to fluoride has the potential to result in pathological damage to the heart, but its potential mechanism requires further investigation. This study investigated the effects of long-term exposure to sodium fluoride (0, 500, 1000, and 2000 mg/kg) on the hearts of chickens were investigated. The results showed that an elevated exposure dose of sodium fluoride led to congested cardiac tissue and disrupted myofiber organisation. Sodium fluoride exposure activated the ERS pathways of PERK, IRE1, and ATF6, increasing HSP60 and HSP70 and decreasing HSP90. The NF-κB pathway and the activation of TNF-α and iNOS elicited an inflammatory response. BAX, cytc, and cleaved-caspase3 were increased, triggering apoptosis and leading to cardiac injury. The abnormal expression of HSP90 and HSP70 affected the stability and function of RIPK1, RIPK3, and MLKL, which are crucial necroptosis markers. HSPs inhibited TNF-α-mediated necroptosis and apoptosis of the death receptor pathway. Sodium fluoride resulted in heart injury in chickens because of the ERS and variations in HSPs, inducing inflammation and apoptosis. Cardiac-adapted HSPs impeded the activation of necroptosis. This paper may provide a reference for examining the potential cardiotoxic effects of sodium fluoride.

Cobalt-Catalyzed Asymmetric Reductive Alkenylation and Arylation of Heterobiaryl Tosylates: Kinetic Resolution or Dynamic Kinetic Resolution?

Herein, we report a cobalt-catalyzed atroposelective reductive cross-coupling of racemic heterobiaryl tosylates with a C(sp2)-X type electrophile. Both aryl and alkenyl halides are competent precursors for this reaction, providing a variety of heterobiaryls as the products in a highly enantioselective manner with high functionality tolerance. The related asymmetric arylation and alkenylation are discovered to proceed with divergent mechanisms. The reaction pathway changes from kinetic resolution (KR) when alkenyl bromides and aryl iodides bearing strong electron-withdrawing substitution on the para-position are employed as the starting materials to an enantioconvergent transformation via dynamic KR of configurationally labile cobaltacycles when relatively electron-rich aryl iodides are used. The change of the reaction mechanisms turns out to arise from the relative rates of two competing elementary steps, which are the epimerization of the cyclic Co(I) intermediates and their trapping by the coupling electrophiles of the C(sp2)-type via oxidative addition.

Zinc-Mediated Endoplasmic Reticulum Stress and Metallothionein Alleviate Arsenic-Induced Cardiotoxicity in Cyprinus Carpio.

Arsenic (As) is a natural component of the Earth's crust, and its inorganic form is highly toxic. The problem of As pollution in water is extremely urgent, and its impact on aquatic organisms should be widely considered. Here, 120 common carp were selected as the test subjects and were exposed to environmentally relevant concentrations of As (2.83 mg L- 1) for 30 days. Histomorphological observations showed the adverse effects of As on the heart: irregular arrangement of myocardial fibers, rupture of muscle fiber bundles, inflammatory infiltration, and hemorrhages. Mechanistically, abnormal expression of factors related to As-induced inflammation (TLR4/MYD88/NF-κB pathway), endoplasmic reticulum stress (CHOP, GRP78, ATF6, PERK, IRE1) and oxidative stress (SOD, CAT, Nrf2, HO-1) was observed. Then, we tried to find a protective agent against As-induced myocardial injury. As one of the important metal elements for maintaining cell growth and immunity, zinc (Zn, 1 mg L- 1) significantly alleviated the pathological abnormalities induced by As, and the changes in physiological and biochemical indices in response to As exposure were significantly alleviated by Zn administration, which was accompanied by the restoration of metallothionein (ZIP8, Znt1, Znt5, Znt7) and heat shock protein (HSP60, HSP70, HSP90) expression. These results suggest for the possibilty of developing Zn as a candidate therapeutic agent for As induced aquatic toxicology.

Atomic-Level Insights into Hollow Silica-Based Materials for Drug Delivery: Effects of Wettability and Porosity.

Experimental evidence has demonstrated that the drug carrier capacity can be significantly enhanced through the use of hollow silica particles. Nevertheless, the effects of varying functional drug carrier surfaces and porous structures remain ambiguous. This study employs molecular dynamics simulations to examine the effects of varying the surface wettability, pore size, and flow velocity on the transfer process. The different levels of wettability of the silica surface with the coarse-grained water model is illustrated by adjusted interaction parameters. The effect of wettability is investigated. With weak interactions, the flow molecules form a nanodroplet to transfer through the porous structure. A strong interaction will lead to molecules flowing as a liquid film to transfer through the structure. Interestingly, the "contradiction effect" is observed when the flow molecules fail to penetrate the porous structure with weak interactions, during which surface tension dominates their flow behavior. Moreover, different porous structures are considered. The flow behaviors are divided into three processes: (1) fast flowing, (2) transient point, and (3) penetration flowing. Furthermore, the concept of surface molecules is defined to quantitatively measure the effect of porosity. A recommended contact angle is proposed. The results will pave the way for more carrier structures in medical engineering.

Effect of Platelet Parameters on Linezolid-Related Thrombocytopenia in Hospitalized Patients.

Background: Linezolid-induced thrombocytopenia incidence varies considerably. Linezolid-related thrombocytopenia in patients has received few studies which have investigated risk factors including platelet parameters except for platelet counts. The study aims to analyze the effect of platelet parameters, including mean platelet volume and platelet large cell ratio, on linezolid-related thrombocytopenia in patients. Methods: The effect of platelet parameters on linezolid-related thrombocytopenia was identified by univariate and multivariate logistic regressions. A Kaplan-Meier survival analysis was carried out to compare the survival of patients who developed linezolid-related thrombocytopenia with patients who did not. Results: Thrombocytopenia occurred at a rate of 41.5% (66/159) after linezolid therapy in hospitalized patients. Platelet parameters, including the difference in mean platelet volume (MPV/fL=0.08 (-1.2-0.9)vs-0.5 (-1.5-0.3), (OR, 0.459; P = 0.001), the difference in platelet large cell ratio (PLCR/fL=0.9 (-5.1-6.2)vs-3.8 (-8.6-2.4), (OR, 1.156; P = 0.001), baseline platelet counts (OR, 0.995; P = 0.006) and duration of linezolid therapy≥10d (OR, 1.346; P = 0.007), were significantly associated with linezolid-related thrombocytopenia in hospitalized patients. In addition, other risk factors which also are associated with linezolid-related thrombocytopenia include baseline red blood cells, co-medication with parecoxib and co-medication with caspofungin. Accumulated in-hospital mortality of patients with thrombocytopenia was significantly higher than that of patients without thrombocytopenia during linezolid treatment (19.7% vs 8.6%, P = 0.003). Conclusion: The difference in mean platelet volume, the difference in large platelet ratio, baseline platelet counts and duration of linezolid therapy≥10d significantly affected the development of linezolid-related thrombocytopenia in hospitalized patients.

Imaging of pancreatic desmoid fibromatosis by endoscopic ultrasound.

Desmoid type fibromatosis (DTF) is a rare intermediate soft tissue tumor. Here we report a case of DTF located in the tail of pancreas. A 39-year-old female presented epigastric pain of 1 week duration. An abdominal magnetic resonance imaging revealed a 3.4-cm irregular contour solid mass in the tail of the pancreas that was interpreted by radiology as suspicious for a benign pancreatic tumor. Endoscopic ultrasound (EUS) showed an irregularly shaped hypoechoic, heterogeneous mass within the tail of pancreas invading the adjacent gastric wall, suggesting a diagnosis of malignant pancreatic tumor. Subsequently, surgery consisted of a distal pancreatectomy, splenectomy and combined partial resection of the stomach, was performed. The immunohistochemistry and histopathological features were consistent with a diagnosis of pancreatic desmoid type fibromatosis. EUS is very useful for visually defining the location and character of pancreatic DTF and to determine whether the major vessels and the adjacent organs are infiltrated.

[Preparation and identification of rabbit anti-cyclin dependent kinase 6 (CDK6) antibodies].

Objective To prepare and identify rabbit anti-cyclin dependent kinase 6 (CDK6) antibody. Methods The recombinant pET21a (+)/CDK6 was successfully constructed, then the recombinant plasmid was transformed into E.coli BL21 (DE3) competent cells and was induced by isopropyl-ß-D-thiogalactopyranoside (IPTG) for protein expression, which was detected by SDS-PAGE and Western blot analysis. The expressed protein was purified by nickel-chelating nitrilotriacetic acid (Ni-NTA) agarose and then analyzed by SDS-PAGE. Japanese white rabbits were immunized with purified CDK6 protein for many times every two weeks. The blood was collected at 0, 2, 4 and 6 weeks after immunization, and serum was separated from blood. The titer was detected by indirect ELISA. Western blot analysis, immunofluorescence assay and immunohistochemistry were employed to determine the specificity. Results High purity CDK6 protein and high specificity of rabbit anti-CDK6 antibody were successfully prepared. The titer of CDK6 rabbit serum antibody reached 1:30 000 after immunization, which could specifically recognize the CDK6 protein expressed in cervical cancer cell line and cervical cancer tissues. Conclusion The high titer and specificity of rabbit anti-CDK6 antibody is successfully prepared.

Balancing the Efficiency and Synthetic Accessibility of Organic Solar Cells with Isomeric Acceptor Engineering.

With the continuous development of organic semiconductor materials and on-going improvement of device technology, the power conversion efficiencies (PCEs) of organic solar cells (OSCs) have surpassed the threshold of 19%. Now, the low production cost of organic photovoltaic materials and devices have become an imperative demand for its practical application and future commercialization. Herein, the feasibility of simplified synthesis for cost-effective small-molecule acceptors via end-cap isomeric engineering is demonstrated, and two constitutional isomers, BTP-m-4Cl and BTP-o-4Cl, are synthesized and compared in parallel. These two non-fullerene acceptors (NFAs) have very similar optoelectronic properties but nonuniform morphological and crystallographic characteristics. Consequently, the OSCs composed of PM6:BTP-m-4Cl realize PCE of 17.2%, higher than that of the OSCs with PM6:BTP-o-4Cl (≈16%). When ternary OSCs are fabricated with PM6:BTP-m-4Cl:BTP-o-4Cl, the averaged PCE value reaches 17.95%, presenting outstanding photovoltaic performance. Most excitingly, the figure of merit (FOM) values of PM6:BTP-m-4Cl, PM6:BTP-o-4Cl, and PM6:BTP-m-4Cl:BTP-o-4Cl based devices are 0.190, 0.178, and 0.202 respectively. The FOM values of these systems are all among the top ones of the current high-efficiency OSC systems, revealing high cost-effectiveness of the two NFAs. This work provides a general but accessible strategy to minimize the efficiency-cost gap and promises the economic prospects of OSCs.

Digital adherence technologies to improve tuberculosis treatment outcomes in China: a cluster-randomised superiority trial.

BACKGROUND: Drug-sensitive tuberculosis treatment requires 6 months of therapy, so adherence problems are common. Digital adherence technologies might improve tuberculosis treatment outcomes. We aimed to evaluate the effect of a daily reminder medication monitor, monthly review of adherence data by the health-care provider, and differentiated care for patients with adherence issues, on tuberculosis treatment adherence and outcomes. METHODS: We did a cluster-randomised superiority trial across four prefectures in China. 24 counties or districts (clusters) were randomly assigned (1:1) to intervention or control groups. We enrolled patients aged 18 years or older with GeneXpert-positive, rifampicin-sensitive pulmonary tuberculosis, who were receiving daily fixed-dose combination treatment. Patients in the intervention group received a medication monitor for daily drug-dosing reminders, monthly review of adherence data by health-care provider, and management of poor adherence; and patients in the control group received routine care (silent-mode monitor-measured adherence). Only the independent endpoints review committee who assessed endpoint data for some participants were masked to study group assignment. Patients were followed up (with sputum solid culture) at 12 and 18 months. The primary outcome was a composite of death, loss to follow-up, treatment failure, switch to multidrug-resistant tuberculosis treatment, or tuberculosis recurrence by 18 months from treatment start, analysed in the intention-to-treat population. Analysis accounted for study design with multiple imputation for the primary outcome. This trial is now complete and is registered with ISRCTN, 35812455. FINDINGS: Between Jan 26, 2017, and April 3, 2019, 15 257 patients were assessed for eligibility and 3074 were enrolled, 2686 (87%) of whom were included in the intention-to-treat population. 1909 (71%) of 2686 patients were male, 777 (29%) were female, and the median age was 44 years (IQR 29-58). By 18 months from treatment start, using multiple imputation for missing outcomes, 239 (16% [geometric mean of cluster-level proportion]) of 1388 patients in the control group and 224 (16%) of 1298 in the intervention group had a primary composite outcome event (289 [62%] of 463 events were loss to follow-up during treatment and 42 [9%] were tuberculosis recurrence). The intervention had no effect on risk of the primary composite outcome (adjusted risk ratio 1·01, 95% CI 0·73-1·40). INTERPRETATION: Our digital medication monitor intervention had no effect on unfavourable outcomes, which included loss to follow-up during treatment, tuberculosis recurrence, death, and treatment failure. There was a failure to change patient management following identification of treatment non-adherence at monthly reviews. A better understanding of adherence patterns and how they relate to poor outcomes, coupled with a more timely review of adherence data and improved implementation of differentiated care, may be required. FUNDING: Bill & Melinda Gates Foundation.

Nanocarrier of Pin1 inhibitor based on supercritical fluid technology inhibits cancer metastasis by blocking multiple signaling pathways.

Cancer metastasis is the primary cause of all cancer-related deaths due to the lack of effective targeted drugs that simultaneously block multiple signaling pathways that drive the dissemination and growth of cancer cells. The unique proline isomerase Pin1 activates numerous cancer pathways, but its role in cancer metastasis and the inhibitory efficacy of Pin1 inhibitors on cancer metastasis are unknown. Moreover, the applicability of Pin1 inhibitor-all-trans retinoic acid (ATRA) is limited due to its several drawbacks. Herein, uniform ATRA-loaded polylactic acid-polyethylene glycol block copolymer nanoparticles (ATRA-NPs) with high encapsulation efficiency, good cellular uptake, excellent controlled release performance and pharmacokinetics are developed using supercritical carbon dioxide processing combined with an optimized design. ATRA-NPs exhibited excellent biosafety and significant inhibition on the growth and metastasis of hepatocellular carcinoma. Pin1 played a key role in cancer metastasis and was the main target of ATRA-NPs. ATRA-NPs exerted their potent anti-metastatic effect by inhibiting Pin1 and then simultaneously blocking multiple signaling pathways and cancer epithelial-mesenchymal progression. Since ATRA-NPs could effectively couple the inhibition of cancer cell dissemination with cancer growth, it provided a novel therapeutic strategy for efficiently inhibiting cancer metastasis.

Virtual screening and structure-activity relationship study of novel BTK inhibitors in Traditional Chinese Medicine for the treatment of rheumatoid arthritis.

Bruton tyrosine kinase (BTK) is a known drug target for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). In this study, a series of 1-amino-1H-imidazole-5-carboxamide derivatives with good inhibitory activity against BTK were selected to explore the structure-activity relationships of these BTK inhibitors (BTKIs). Furthermore, we concentrated on 182 prescriptions of Traditional Chinese Medicine with therapeutic effects on RA. 54 herbs with a frequency of ≥10 were counted to establish a database containing 4027 ingredients for virtual screening. Five compounds with relatively higher docking scores and better absorption, distribution, metabolism, elimination and toxicity (ADMET) parameters were then selected for higher precision docking. The results demonstrated that the potentially active molecules form hydrogen bond interactions with the hinge region residues Met477, Glu475, glycine-rich P-loop residue Val416, Lys430 and DFG motif Asp539. In particular, they also interact with the key residues Thr474 and Cys481 of BTK. The molecular dynamics (MD) results demonstrated that all five compounds above could bind with BTK stably as its cognate ligand in dynamic conditions. This work identified several potential BTKIs using a computer-aided drug design approach and may provide crucial information for developing novel BTKIs.Communicated by Ramaswamy H. Sarma.

Iron-Catalyzed Reductive Ring Opening/gem-Difluoroallylation of Cyclopropyl Ketones.

By merging C-C and C-F bond cleavage, we developed a regioselective ring opening/gem-difluoroallylation of cyclopropyl ketones with α-trifluoromethylstyrenes, which proceeds under the catalysis of iron with the combination of manganese and TMSCl as the reducing agents, providing a new entry to the synthesis of carbonyl-containing gem-difluoroalkenes. Remarkably, the ketyl radical-induced selective C-C bond cleavage and the following generation of more-stable carbon-centered radicals enable complete regiocontrol of this ring opening reaction for various substitution patterns of the cyclopropane ring.