Study on the Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactone Derivatives.

With the emergence of drug-resistant strains, the treatment of tuberculosis (TB) is becoming more difficult and there is an urgent need to find new anti-TB drugs. Mycobacterium marinum, as a model organism of Mycobacterium tuberculosis, can be used for the rapid and efficient screening of bioactive compounds. The 14-membered resorcylic acid lactones (RALs) have a wide range of bioactivities such as antibacterial, antifouling and antimalarial activity. In order to further study their bioactivities, we initially constructed a 14-membered RALs library, which contains 16 new derivatives. The anti-M. marinum activity was evaluated in vitro. Derivatives 12, 19, 20 and 22 exhibited promising activity with MIC90 values of 80, 90, 80 and 80 µM, respectively. The preliminary structure-activity relationships showed that the presence of a chlorine atom at C-5 was a key factor to improve activity. Further studies showed that 12 markedly inhibited the survival of M. marinum and significantly reduced the dosage of positive drugs isoniazid and rifampicin when combined with them. These results suggest that 12 is a bioactive compound capable of enhancing the potency of existing positive drugs, and its effective properties make it a very useful leads for future drug development in combating TB resistance.

Bioinspired "cage traps" for closed-loop lead management of perovskite solar cells under real-world contamination assessment.

Despite the remarkable progress made in perovskite solar cells, great concerns regarding potential Pb contamination risk and environmental vulnerability risks associated with perovskite solar cells pose a significant obstacle to their real-world commercialization. In this study, we took inspiration from the ensnaring prey behavior of spiders and chemical components in spider web to strategically implant a multifunctional mesoporous amino-grafted-carbon net into perovskite solar cells, creating a biomimetic cage traps that could effectively mitigate Pb leakage and shield the external invasion under extreme weather conditions. The synergistic Pb capturing mechanism in terms of chemical chelation and physical adsorption is in-depth explored. Additionally, the Pb contamination assessment of end-of-life perovskite solar cells in the real-world ecosystem, including Yellow River water and soil, is proposed. The sustainable closed-loop Pb management process is also successfully established involving four critical steps: Pb precipitation, Pb adsorption, Pb desorption, and Pb recycling. Our findings provide inspiring insights for promoting green and sustainable industrialization of perovskite solar cells.

The mRNA binding-mediated self-regulatory function of small heat shock protein IbpA in γ-proteobacteria is conferred by a conserved arginine.

Bacterial small heat shock proteins, such as inclusion body-associated protein A (IbpA) and IbpB, coaggregate with denatured proteins and recruit other chaperones for the processing of aggregates thereby assisting in protein refolding. In addition, as a recently revealed uncommon feature, Escherichia coli IbpA self-represses its own translation through interaction with the 5'-untranslated region of the ibpA mRNA, enabling IbpA to act as a mediator of negative feedback regulation. Although IbpA also suppresses the expression of IbpB, IbpB does not have this self-repression activity despite the two Ibps being highly homologous. In this study, we demonstrate that the self-repression function of IbpA is conserved in other γ-proteobacterial IbpAs. Moreover, we show a cationic residue-rich region in the α-crystallin domain of IbpA, which is not conserved in IbpB, is critical for the self-suppression activity. Notably, we found arginine 93 (R93) located within the α-crystallin domain is an essential residue that cannot be replaced by any of the other 19 amino acids including lysine. We observed that IbpA-R93 mutants completely lost the interaction with the 5' untranslated region of the ibpA mRNA, but retained almost all chaperone activity and were able to sequester denatured proteins. Taken together, we propose the conserved Arg93-mediated translational control of IbpA through RNA binding would be beneficial for a rapid and massive supply of the chaperone on demand.

Prospects and feasibility of synergistic therapy with radiotherapy, immunotherapy, and DNA methyltransferase inhibitors in non-small cell lung cancer.

The morbidity and mortality of lung cancer are increasing, seriously threatening human health and life. Non-small cell lung cancer (NSCLC) has an insidious onset and is not easy to be diagnosed in its early stage. Distant metastasis often occurs and the prognosis is poor. Radiotherapy (RT) combined with immunotherapy, especially with immune checkpoint inhibitors (ICIs), has become the focus of research in NSCLC. The efficacy of immunoradiotherapy (iRT) is promising, but further optimization is necessary. DNA methylation has been involved in immune escape and radioresistance, and becomes a game changer in iRT. In this review, we focused on the regulation of DNA methylation on ICIs treatment resistance and radioresistance in NSCLC and elucidated the potential synergistic effects of DNA methyltransferases inhibitors (DNMTis) with iRT. Taken together, we outlined evidence suggesting that a combination of DNMTis, RT, and immunotherapy could be a promising treatment strategy to improve NSCLC outcomes.

A case of late and lethal Trousseau's syndrome induced by pembrolizumab in lung adenocarcinoma.

Trousseau's syndrome is a relatively rare reported event in immunotherapy-related clinical trials, mostly occurring in the early period of immune checkpoint inhibitor (ICI) therapy. Here, we report an unusual case of late and lethal Trousseau's syndrome during pembrolizumab maintenance therapy in a lung adenocarcinoma harboring tumor protein p53 (TP53) mutation. The patient has experienced severe coagulation abnormalities manifesting as cerebral infarction, partial infarction of both kidneys and spleen after 23 cycles of pembrolizumab use and was resistant to anticoagulants. The late occurrence of coagulation abnormalities in this case reveals a possible correlation between TP53 mutations and Trousseau's syndrome when patients are treated with ICIs.

In clinical practice, symptoms associated with abnormal coagulation or fibrinolytic function in malignant tumors are known as Trousseau's syndrome. Its main clinical features include cerebral infarction, myocardial infarction, peripheral arterial embolism, etc. Trousseau's syndrome is a relatively rare reported event in immune checkpoint inhibitors (ICIs)-related clinical studies, mostly occurring in the early period of ICI therapy. Here, we report an unusual case of late and lethal Trousseau's syndrome during pembrolizumab, one of the ICI agents, maintenance therapy in a lung adenocarcinoma harboring tumor protein p53 (TP53) mutation. This patient has experienced severe coagulation abnormalities manifesting as cerebral infarction, partial infarction of both kidneys and spleen after 23 cycles of pembrolizumab use and was resistant to anticoagulants. The late occurrence of coagulation abnormalities in this case reveals a possible correlation between TP53 mutations and Trousseau's syndrome when patients are treated with ICIs.

Pivotal Routes for Maximizing Semitransparent Perovskite Solar Cell Performance: Photon Propagation Management and Carrier Kinetics Regulation.

Semitransparent perovskite solar cells (ST-PSCs) are ideal candidates for building-integrated photovoltaics (BIPV) and tandem solar cells (TSCs) owing to their tunable bandgap and high visible transparency. The best power conversion efficiency (PCE) of ST-PSCs is close to 15% with an average visible transmittance of over 20%, which still lags far behind the PCE of normal opaque PSCs. This can be attributed to the poor light utilization efficiency (LUE) of ST-PSCs. Herein, the pivotal routes for maximizing LUE of ST-PSCs in terms of photon propagation management and carrier kinetics regulation are systematically rationalized. First, the fundamental theoretical analyses on optical processes and electronic properties are provided. Then, insights on photon propagation management measures and carrier kinetics regulation strategies are provided. Furthermore, a summary of the promising commercial application of ST-PSCs in BIPV and TSCs is provided. Finally, the main progress of ST-PSCs is briefly summarized, and the directions for the commercialization of ST-PSCs are proposed.

SAMHD1 silencing cooperates with radiotherapy to enhance anti-tumor immunity through IFI16-STING pathway in lung adenocarcinoma.

BACKGROUND: Sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) is a DNA end resection factor, which is involved in DNA damage repair and innate immunity. However, the role of SAMHD1 in anti-tumor immunity is still unknown. This study investigated the effects of SAMHD1 on stimulator of interferon genes (STING)-type I interferon (IFN) pathway and radiation-induced immune responses. METHODS: The roles of SAMHD1 in the activation of cytosolic DNA sensing STING pathway in lung adenocarcinoma (LUAD) cells were investigated with flow cytometry, immunofluorescence, immunoblotting and qPCR. The combined effects of SAMHD1 silencing and radiation on tumor cell growth and STING pathway activation were also evaluated with colony formation and CCK8 assay. The Lewis lung cancer mouse model was used to evaluate the combined efficiency of SAMHD1 silencing and radiotherapy in vivo. Macrophage M1 polarization and cytotoxic T cell infiltration were evaluated with flow cytometry. RESULTS: The single-stranded DNA (ssDNA) accumulated in the cytosol of SAMHD1-deficient lung adenocarcinoma (LUAD) cells, accompanied by upregulated DNA sensor IFN-γ-inducible protein 16 (IFI16) and activated STING pathway. The translocation of IFI16 from nucleus to cytosol was detected in SAMHD1-deficient cells. IFI16 and STING were acquired in the activation of STING-IFN-I pathway in SAMHD1-deficient cells. SAMHD1 silencing in LUAD cells promoted macrophage M1 polarization in vitro. SAMHD1 silencing synergized with radiation to activate ssDNA-STING-IFN-I pathway, inhibit proliferation, promote apoptosis and regulate cell cycle. SAMHD1 silencing cooperated with radiotherapy to inhibit tumor growth and increase CD86+MHC-IIhigh M1 proportion and CD8+ T cell infiltration in vivo. CONCLUSIONS: SAMHD1 deficiency induced IFN-I production through cytosolic IFI16-STING pathway in LUAD cells. Moreover, SAMHD1 downregulation and radiation cooperated to inhibit tumor growth and enhance anti-tumor immune responses through macrophage M1 polarization and CD8+ T cell infiltration. Combination of SAMHD1 inhibition and radiotherapy may be a potentially therapeutic strategy for LUAD patients.

Is ICI-based therapy better than chemotherapy for metastatic NSCLC patients who develop EGFR-TKI resistance? A real-world investigation.

Purpose: To evaluate the outcomes of immune checkpoint inhibitor (ICI)-based treatments versus classical chemotherapy for metastatic non-small cell lung cancer (NSCLC) patients who develop epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance and to explore the population that may benefit from ICI-based therapy. Materials and methods: All patients who had previously received EGFR-TKI therapy at two cancer centers in China and developed resistance to targeted therapies were included. Progression-free survival (PFS) and overall survival (OS) were utilized to evaluate the outcomes of the study cohort. Results: A total of 132 patients were included. The median follow-up time for this cohort was 21.7 months (IQR, 14.8-28.8 months), calculated from the date of EGFR-TKI resistance. The median PFS and OS were 4.9 months (IQR, 2.8-9.2) and 13.5 months (IQR, 6.6-26.5 months), respectively. Multivariate analysis showed that ICI-based therapy could significantly improve OS when compared to the classic chemotherapy (hazard ratio [HR], 0.55; 95% CI, 0.34-0.88; P = 0.01) after adjusting for variables such as gender, age, mutation status, and brain or liver metastasis status. The combined modality of ICI plus chemotherapy could offer a long-term OS benefit in most subgroups, such as young (<65 years) patients, and those without secondary T790M mutations or absence of liver and brain metastases, and the populations with good Eastern Cooperative Oncology Group (ECOG) scores. Conclusion: For patients presenting with EGFR-TKI resistance, ICI-based therapy could offer a more favorable survival than classical chemotherapy. The combination of ICI with chemotherapy may be the optimal modality for those with good ECOG PS scores.

Designing of CuS growing on Bi2WO6 nanosheet heterostructures based on a photoelectrochemical aptasensor for detecting ofloxacin.

Bi2WO6 (BW) was compounded with different contents of copper sulfide (CuS) by a two-step procedure. The chemical composition and morphology of the materials were characterized by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, and transmission electron microscopy. The results of photoelectrochemical (PEC) tests showed that CuS can improve the PEC performance of semiconductor materials and it has the best performance when the CuS mass fraction is 5%. Therefore, CuS/BW-5% nanocomposite has been constructed as ofloxacin (OFL) drug PEC aptasensors by binding of aptamer receptors. The PEC aptasensor based on CuS/BW-5% has a linear relationship for OFL of 1-12,000 nM and a determination limit of 0.35 nM. Since the photoelectron potential generated by CuS/BW-5% heterojunction reduces the combination of photogenerated electrons and holes CuS/BW-5% has a better photoelectrocatalytic performance. Graphical abstract Schematic presentation of a photoelectrochemical aptasensor based on CuS/Bi2WO6 for the determination of OFL.

Ink Engineering of Inkjet Printing Perovskite.

Inkjet printing method is one of the most effective ways for fabricating large-area perovskite solar cells (PSCs). However, because ink crystallizes rapidly during printing, the printed perovskite film is discontinuous with increasing defects. It severely restricts the application of the inkjet printing technology to the fabrication of perovskite photovoltaic devices. Here, we designed a new mixed-cation perovskite ink system that can controllably retard the crystallization rate of perovskite. In this new ink system, the printing solvent is composed of n-methyl pyrrolidone (NMP) and dimethyl formamide (DMF), and PbX2 is replaced by PbX2-DMSO (X = Br, I) complex as a printing precursor to create a high-quality perovskite layer. Accordingly, the printed Cs0.05MA0.14FA0.81PbI2.55Br0.45 perovskite film exhibited high homogeneity with a large grain size (over 500 nm). Besides, the printed perovskite film possessed lower defects with improved carrier lifetime compared to the control sample. Combining these advantages, the printed PSC delivers decent power conversion efficiencies (PCEs) of 19.6% (0.04 cm2) and 17.9% (1.01 cm2). The large-area device can still retain its original efficiency of 89% when stored in air with humidity less than 20% for 1000 h.

An ssDNA aptamer selected by Cell-SELEX for the targeted imaging of poorly differentiated gastric cancer tissue.

Gastric cancer (GC) is associated with high morbidity and mortality rates worldwide. Poorly differentiated GC predicts a poor prognosis and is related to patients' response to chemotherapy and targeted therapy. Therefore, it is very important to accurately evaluate the tumour differentiation status for the treatment of poorly differentiated GC. To develop a molecular probe to analyse poorly differentiated GC, we selected aptamers against poorly differentiated GC by subtractive Cell-SELEX using the poorly differentiated GC cell line BGC-823 as the target and the moderately differentiated GC cell line SGC-7901 as the negative control. After 15 rounds of selection, aptamer PDGC21 exhibited the highest affinity, and the Kd value of the truncated aptamer PDGC21-T was 35.2 ±â€¯1.1 nM. Aptamer PDGC21-T not only specifically bound to the target cells but also bound to other poorly differentiated GC cells. When combined with fluorescent nanoparticle quantum dots (QDs), the PDGC21-T-QD probe could distinguish poorly differentiated GC cells in mixed culture cells and clinical specimens. Furthermore, in a tissue microarray containing 15 cases from patients, there was a higher positive rate in GC tissues compared with adjacent normal tissues; in poorly differentiated tissues, in particular, the fluorescence signal was significantly higher than that in well/moderately differentiated tissues. Therefore, aptamer PDGC21-T holds great potential for use as a molecular imaging probe for the detection of poorly differentiated GC, which is of great significance for diagnosis and treatment.

Identification of LEA, a podocalyxin-like glycoprotein, as a predictor for the progression of colorectal cancer.

Large external antigen (LEA) is considered as a colorectal cancer (CRC)-associated antigen, which was found via mAb ND-1 generated using hybridoma technology, but its molecular features remain unknown. To facilitate the clinical application of LEA, we identified LEA as a podocalyxin-like protein 1 (PODXL) with molecular weight of approximately 230 kDa, a hyperglycosylated protein, using immunoprecipitation and mass spectrometry in combination, and verified that ND-1-recognized epitope is on the terminal sialic acid of LEA. Correlation analysis between LEA and PODXL in molecular weight, immunological cross-reactivity, and gene expression dependence supported the PODXL identity of the LEA. Moreover, we assessed the clinical significance of the LEA in 89 pairs of primary CRC tissues and adjacent nontumor colorectal tissues using ND-1 by quantum dot-based immunohistochemistry (QD-IHC). High LEA expression was correlated significantly with T stage (P = 0.010). Patients with high LEA expression showed significantly poorer prognosis than those with LEA low expression (P = 0.007). Multivariate analysis indicated LEA expression as an independent predictor. Furthermore, the comparative analysis showed that mAb ND-1-based IHC analysis toward sugar residue of PODXL has higher sensitivity and specificity to evaluate the LEA/PODXL expression than mAb 3D3-based method toward core protein of PODXL in CRC cell lines and clinical samples. In addition, we first found that LEA/PODXL can be secreted in exosomes from cancer cells and CRC patient peripheral blood. Our results demonstrate that LEA is an independent predictor for CRC progression and has the potential to be applied for clinical setting with high sensitivity, high specificity, and noninvasive access.

Effect of VEGF-targeted antisense gene therapy on retinoblastoma cell line SO-RB50 in vitro and in vivo.

AIM: To evaluate the possibility of generation 4 polyamidoamine (G4PAMAM) dendrimers acting as the delivery system of vascular endothelial growth factor (VEGF) antisense oligodeoxynucleotides (VEGFASODN), and to investigate the anti-tumor effect of G4PAMAM/VEGFASODN complex on the cultured cells and the mouse tumor xenograft model. METHODS: The transfection efficiency was assessed by Flow cytometry (FCM). Thiazolyl tetrazolium (MTT) assay was performed to determine the relative growth rate (RGR) of the cells after transfection. Then a mouse tumor xenograft model of human retinoblastoma was established. Different interventions were given to the mice by intratumoral injection and the tumor growth was monitored. The expression of VEGF mRNA was detected by reverse transcription PCR (RT-PCR), the expression of VEGF protein was determined by western blot analysis, and the microvessel density (MVD) was measured by immunohistochemistry (IHC) staining. RESULTS: G4PAMAM/VEGFASODN exhibited a high transfection rate in vitro, and the transfection rates of different doses of G4PAMAM/VEGFASODN groups increased with higher doses. This effect was accompanied by a dose-depended reduction in cell viability. The tumor growth in the tumor-bearing athymic mice was significantly inhibited in the G4PAMAM/VEGFASODN group. The expressions of VEGF mRNA and protein were obviously inhibited in the G4PAMAM/VEGFASODN group (P<0.05), and the MVD of the G4PAMAM/VEGFASODN group was lower than that of the other groups (P<0.05). CONCLUSION: VEGFASODN can be delivered into the cultured and transplanted retinoblastoma cells efficiently by G4PAMAM, suppress the expressions of VEGF mRNA and protein, and reduce the MVD of tumor tissues. The G4PAMAM/VEGFASODN complex has antitumor properties in vitro and in vivo.

[A retrospective survey of childhood corporal punishment by school teachers in students].

OBJECTIVE: To ascertain the prevalence of childhood corporal punishment by teachers in students, to explore the influencing factors and associations between childhood corporal punishment and psychological problems. METHODS: Five hundred and twenty-eight students from a college and a technical secondary school in Hebei province were surveyed by self-administered questionnaire anonymously in Dec. 2004. The questionnaire used for this survey mainly included (1) general demographic information; (2) 5 forms of childhood corporal punishments, in this study, cases of teachers' corporal punishments were defined as those who answered positively one or more of the 5 questions relating to childhood corporal punishment by school teachers occurring before the age of 16 years; (3) Symptom Checklist-90 (SCL-90); (4) Youth Risk Behaviours. RESULTS: Overall, 57.6% of students reported having been corporally punished at least one time, one of four forms of corporal punishment by teachers before age of 16 years, the four forms corporal punishment were non-contact corporal punishment, e.g., running for punishment, repeat-doing homework many times for punishment, standing for punishment, kneel down for punishment, not allowing to eat, sending outside in winter, etc. (53.4%), hitting/kicking/pushing very hard with open hands/fist/feet/other part of body (16.1%), beating with an object (10.2%), and locking in a small compartment/tying with rope (0.2%). No students reported having been choked, or burned/scalded, or stabbed with a sharp object by the teachers. Males had a significantly higher overall prevalence rate than females (66.4% vs. 46.6%, chi(2) = 21.01, P = 0.000). There was no statistically significant association between a history of childhood corporal punishment and the three other demographic indicators, which included residence region (rural and non-rural area) prior to 16 years of age, parental education level, and whether the respondent lived in a single or multiple children family. Compared with their peers who had not experienced childhood corporal punishment by teachers, the students with two or more forms of corporal punishments by teachers showed significantly higher scores (punished group vs. unpunished group) of psychological symptoms of somatization (0.78 vs. 0.42), obsessiveness (1.22 vs. 0.98), interpersonal sensitivity (1.24 vs. 0.89), depression (1.06 vs. 0.76), anxiety (0.90 vs. 0.64), hostility (1.11 vs. 0.68), paranoid ideation (1.11 vs. 0.71) and psychoticism (0.84 vs. 0.56), and showed significantly higher rates in sadness (54.7% vs. 26.3%), drunk (37.2% vs. 20.1%), involving in physical fighting (15.1% vs. 3.6%) in the past year and current smoking (36.0% vs. 14.5%). CONCLUSIONS: The problem of corporal punishment by teachers is common in schools, and the problem has a significant correlation with youth mental health problems. The results highlighted urgent needs to increase public awareness on children rights, creating learning-friendly environment in school.