Role of targeting ferroptosis as a component of combination therapy in combating drug resistance in colorectal cancer.

Colorectal cancer (CRC) is a form of cancer that is often resistant to chemotherapy, targeted therapy, radiotherapy, and immunotherapy due to its genomic instability and inflammatory tumor microenvironment. Ferroptosis, a type of non-apoptotic cell death, is characterized by the accumulation of iron and the oxidation of lipids. Studies have revealed that the levels of reactive oxygen species and glutathione in CRC cells are significantly lower than those in healthy colon cells. Erastin has emerged as a promising candidate for CRC treatment by diminishing stemness and chemoresistance. Moreover, the gut, responsible for regulating iron absorption and release, could influence CRC susceptibility through iron metabolism modulation. Investigation into ferroptosis offers new insights into CRC pathogenesis and clinical management, potentially revolutionizing treatment approaches for therapy-resistant cancers.

Design, synthesis, antibacterial and antitumor activities of novel pyrazolo3,4-bpyridine-4-one-5-carboxylic acid derivatives / 药学学报

To discover new structural hits, based on the important role of pyrazole ring and fragment of pyridinone carboxylic acid in drug design, novel title pyrazolo[3,4-b]pyridine-4-one-5-carboxylic acid derivatives (10a-10p) were designed and synthesized, the structures were confirmed by spectral data and elemental analyses. The antibacterial and antitumor activities were evaluated by the measured minimum inhibitory concentration (MIC) values against the tested four strains and half inhibitory concentration (IC50) values against the tested four cancer cells, respectively. The results displayed markedly poor antibacterial activity and observably potent antitumor activity. In particularly, the title difluorophenyl (10d, 10e, 10f), pyridyl (10j), ethyl (10k) and cycloproyl (10l) compounds exhibited comparable activity against Capan-1 and A549 cells to that of the comparison doxorubicin. Thus, pyrazolo[3,4-b]pyridine-4-one-5-carboxylic acid derivatives as promising antitumor hits need to be developed.

Effect of peripheral cannulation for cardiopulmonary bypass in patients with congenital heart disease undergoing reoperation: A retrospective cohort study / 中国胸心血管外科临床杂志

@#Objective    To evaluate the safety and efficacy of peripheral cannulation for cardiopulmonary bypass (CPB) in patients with reoperation of congenital heart disease. Methods    The perioperative data of patients with congenital heart disease who underwent reoperation in Fuwai Hospital from 2019 to 2020 were retrospectively collected. They were divided into two groups according to the cannulation methods: a central group and a peripheral group. The prognosis of the patients was analyzed. Results     A total of 80 patients were collected, including 43 patients in the central group, and 37 pateints in the peripheral group. In the central group, the median age was 18 (14, 32) years, and 21 patients were male. The median age of the peripheral group was 16 (10, 27 ) years, and 18 patients were male. The CPB time in the peripheral group was 201 (164, 230) min, which was longer than that in the central group [143 (97, 188 ) min, P<0.001]. The lactate after CPB in the peripheral group was statistically higher than that in the central group [2 (1, 2 ) mmol/L vs. 1 (1, 1) mmol/L, P=0.002]. The dosage of albumin use during CPB in the peripheral group was statistically higher than that in the central group [10 (0, 20) g vs. 0 (0, 0) g, P=0.004]. There was no statistical difference in the postoperative dosage of red blood cells use [0 (0, 2) U vs. 0 (0, 0) U, P=0.117], mechanical ventilation time [14 (11, 19) h vs. 13 (10, 15) h, P=0.296], ICU stay time [43 (23, 80) h vs. 40 (20, 67) h, P=0.237] or postoperative hospital stay time [10 (7, 12) d vs. 8 (7, 10) d, P=778] between the two groups. Conclusion    It’s safe and efficient to establish CPB through peripheral cannulation in patients with complex congenital heart disease undergoing reoperation.

Role of suPAR in the Pathogenesis of Podocyte Injury of Primary Focal Segmental Glomerulosclerosis / 中山大学学报(医学科学版)

ObjectiveThis study aims to investigate the role of suPAR in the pathogenesis of podocyte injury in FSGS. Methods① The sera of primary FSGS patients （17 cases） were collected. Healthy volunteers （10 cases） and patients with other types of primary nephrotic syndrome （10 cases） were set as normal and disease controls. SuPAR levels were detected by ELISA； ② Podocytes were stimulated by suPAR in vitro， and cells were collected to analyze apoptosis by flow cytometry and for RNAseq analysis； ③ Differentially expressed genes （DEGs） were screened from RNAseq data. Both up-regulated and down-regulated genes were analyzed by KEGG and GO enrichment analysis. Heat map was used to show expression of genes related to podocyte focal adhesion， slit diaphragm and actin dynamics and endocytosis. Differentially expressed genes were verified by qPCR. Results① The level of suPAR in FSGS patients was significantly increased， and that in other nephrotic syndrome（NS） patients was also significantly increased； ② suPAR stimulation significantly altered the transcriptome pattern of human podocytes. A total of 272 up-regulated genes and 288 down-regulated genes were screened； ③ KEGG and GO enrichment analysis of up-regulated and down-regulated genes showed that Focal adhesion and DNA replication and DNA repair related pathways were significantly down-regulated； ④ suPAR did not increase podocyte apoptosis. ConclusionThe level of suPAR is significantly increased in patients with primary FSGS. SuPAR may promote podocyte injury by interfering with genomic homeostasis and disrupting focal adhesion， slit diaphragm， actin dynamics and endocytosis-related functional molecules of podocytes.

A map of the spatial distribution and tumour-associated macrophage states in glioblastoma and grade 4 IDH-mutant astrocytoma.

Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.

Research advances on antitumor mechanism of NK cells and its application in cancer targeted therapy / 药学学报

Natural killer (NK) cells, as an essential part of innate immunity, can directly identify and kill tumor cells after being activated by the synergistic action of surface inhibitory receptors and activated receptors. It can secrete cytokines to recruit dendritic cells (DCs), induce DCs maturation and enhance adaptive immune response. It can target cancer stem cells (CSCs) and circulating tumor cells (CTCs) to inhibit cancer metastasis. NK cells have a unique inflammatory tendency, which can respond to cytokines and chemokines released from tumor sites and migrate to tumor sites, making them occupy an important advantage in cancer targeted therapy. The research on cancer targeted therapy of NK cells as drug delivery carriers, NK cell membrane-coated biomimetic nanoparticles, and NK cell extracellular vesicles (NKEVs) has attracted more and more attention. The article will focus on the mechanism of NK cells inhibiting cancer, and summarize the research progress of cancer targeted therapy of NK cells.

Comparison of IgG Antibody Levels in Mice Immunized with SARS-CoV-2 RBD Proteins Produced from Two Expression Systems / 中国生物化学与分子生物学报

The COVID-19 pandemic is still spreading around the world,posing a severe challenge to public health security and economic development in China and beyond. The pivotal process of SARS-COV-2 invasion is that the receptor binding domain (RBD) of Coronavirus spike protein binds with the angioten-sin converting enzyme 2 (ACE2) receptor on host cells. Therefore, RBD is closely related to our major anti-epidemic strategies such as rapid pathogen detection and development of vaccines and antiviral drugs. In this study, we aim to compare the anti-RBD IgG by immunizing mice with the recombinant RBDs of novel Coronavirus spike protein, and evaluate the antibody titers and duration elicited by RBD produced from different host cells and used in different doses, which can be used for vaccine evaluation, drug development, and pathogen detection. SDS-PAGE and mass spectrometry analysis showed that the molecular weight of bRBD (produced by insect cells) and hRBD (produced by mammalian cells) were slightly different, which are mainly caused by different glycosylation modification. Flow cytometry revealed that the binding rates of bRBD and hRBD to HEK293-ACE2-overexpressing cells were 88. 5% and 92. 7%, respectively, indicating that both antigens have favorable bioactivity. Balb/ c mice are immunized intramuscularly with 10 μg and 20 μg per mouse of RBD proteins, which were mixed with Quick Antibody adjuvant previously, and blood samples collected from the tail at 2, 4, 6, 8, 12 and 24 weeks after the primary immunization. Enzyme-linked immunosorbent assay (ELISA) showed that both RBD immunization with 10 μg or 20 μg could induce a rapid immune response to produce IgG antibodies. The antibody titers reached the peak at 4-6 weeks post first immunization, and persisted over a long time up to 6 months. No significant difference was observed in the induced antibody titers by bRBD and hRBD as well as their different doses. Virus Neutralization Assays showed that specific antibodies induced by RBD-immunized mice could inhibit the infection of ACE2-positive cells by SARS-CoV-2 pseudovirus. These results suggest that both RBD proteins through commendable adjuvant inoculation can rapidly induce an effective humoral immune response and generate specific neutralizing antibodies. It is expected to be helpful for rapid preparation of antibodies against the future various RBD mutants during the pandemic.

Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling.

Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.

Cognition on diagnosis and treatments of bronchiectasis among respiratory specialists / 中华健康管理学杂志

Objective:To investigate the cognition of the diagnosis and management of bronchiectasis among respiratory specialists.Methods:Between May and June 2020, a questionnaire survey based on expert consensus and guidelines was conducted among respiratory specialists from 50 hospitals from Sichuan and Yunnan provinces. Total 691 questionnaires were distributed and 641 were received. 601 valid questionnaires were chosen for further analysis with an effective recovery rate of 87.0%. The respondents were required to finish the e-questionnaires independently in terms of cognition of diagnosing, severity assessment, treatments and Chinese medicines of bronchiectasis. The responses were collected online and the cognitive levels were evaluated by calculating the correct rates of corresponding questions.Results:540 (89.9%) of the respondents agreed that high-resolution computed tomography (HRCT) was the gold standard for diagnosing of bronchiectasis, but 318 (52.9%) had an incomplete understanding of common radiographic manifestations of bronchiectasis, and different cognitive degrees of common radiographic manifestations of bronchiectasis existed among respondents with different qualifications or working in different levels of hospitals ( P<0.05). Only 118 (19.6%) of the respondents were familiar with severity assessments of bronchiectasis, but 65 (55.1%) of the 118 respondents said they won′t apply these severity assessments to patient during their clinical works. For the treatment of patients with stable bronchiectasis, airway clearance techniques were most recommended by specialists surveyed [410 (68.2%)], among which, postural drainage was the most known method [559 (93.0%)]. For patients undergoing an acute exacerbation, most respondents recommended antibiotics [600 (99.8%)] as the primary treatment, and examinations such as sputum culture [544 (90.5%)], inflammatory markers [523 (87.0%)] should be performed as well. 504 (83.9%) thought that pseudomonas aeruginosa was the most common conditioned pathogen for bronchiectasis. For patients with frequent exacerbations (≥3 per year), 385 (64.1%) of the respondents supported the therapeutic effect of long-term antibiotics, however, among the 385 respondents supporting long-term antibiotics, only [113 (29.4%)] were willing to recommend long-term antibiotic treatment actively during their clinical practice. Besides, 304 (50.6%) respondents held a positive attitude to the clinical effect of traditional Chinese medicine therapies. Among 304 respondents holds the point of supporting, only 86 (28.3%) were willing to recommend traditional Chinese medicine to patients actively, differences about the attitude and clinical behaviors were found between respondents working in different levels of hospitals ( P<0.05). Conclusions:Respiratory specialists′ cognition on diagnosis and treatments of bronchiectasis remains inadequate, and cognitive levels differ among respondents working in different levels of hospitals. There is a gap between respondents′ cognition and clinical practice. Further education and trainings are necessary for improving respiratory specialists′ knowledge for timely diagnosis and standard treatment of bronchiectasis.

Preparation of personalized traditional Chinese medicine condensed water pill without excipients based on correlation between concentrate viscosity and molding quality / 中国中药杂志

To explore the correlation between concentrate viscosity and molding quality of personalized traditional Chinese medicine(TCM) condensed water pill, this study established a concentrate viscosity characterization method with rotational rheometry. Seven model prescriptions were respectively concentrated to different degrees and the viscosity of each concentrate was determined. The pre-sence of 'viscosity jump' in the middle stage of 'flag hanging' of all the model prescriptions implied that there might be an ideal viscosity range in the preparation of condensed water pill. The further study of 22 model prescriptions demonstrated that the optimum viscosity range of concentrate was 5-15 Pa·s(25 ℃) for approximately 82% of the prescriptions. About 18% of the prescriptions had a wide range, which might be caused by the high proportions of mineral and crustacean drugs in the crushing part and sugar and fibrous drugs in the decocting part. This study clarified the optimum viscosity range for concentrates of personalized TCM condensed water pills and achieved a preparation technology without any excipient, laying a foundation for the on-line control of the preparation.

Long Time Efficacy and Safety of Microvascular Decompression Combined with Internal Neurolysis for Recurrent Trigeminal Neuralgia

Objective@#: To explore the clinical efficacy and safety of microvascular decompression (MVD) combined with internal neurolysis (IN) in the treatment of recurrent trigeminal neuralgia (TN) after MVD. @*Methods@#: Sixty-four patients with recurrent TN admitted to the hospital from January 2014 to December 2017 were divided into two groups according to the surgical method. Twenty-nine patients, admitted from January 2014 to December 2015, were treated with MVD alone, whereas 35 admitted from January 2016 to December 2017 were treated with MVD+IN. The postoperative efficacy, complications, and pain recurrence rate of the two groups were analyzed. @*Results@#: The efficacy of the MVD+IN and MVD groups were 88.6% and 86.2%, and the cure rates were 77.1% and 65.5% respectively. There was no statistically significant difference between the two groups (p>0.05). The cure rate (83.3%) of patients in the MVD+IN group, who were only found thickened arachnoid adhesions during the operation that could not be fully released, was significantly higher than that of the MVD group (30.0%) (p0.05). For patients whose arachnoid adhesions were completely released, there had no significant difference (p>0.05) in the efficacy (87% vs. 94.7%) and recurrence rate (5.0% vs. 11.1%). The incidence of postoperative facial numbness (88.6%) in the MVD+IN group was higher than that in the MVD group (10.3%) (p0.05). In the 18–36 months follow-up, the recurrence rate of patients in the MVD+IN group (9.7%) and in the MVD group (16%) were not statistically different (p>0.05). @*Conclusion@#: A retrospective comparison of patients with recurrent TN showed that both MVD and MVD combined with IN can effectively treat recurrent TN. Compared with MVD alone, MVD combined with IN can effectively improve the pain cure rate of patients with recurrent TN who have only severe arachnoid adhesions. The combination does not increase the incidence of long-term facial numbness and other complications.

Meta-analysis of long-term efficacy of vitrectomy combined with anti-VEGF in the treatment of proliferative diabetic retinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To explore the long-term efficacy of vitrectomy combined with or without anti-VEGF in the treatment of proliferative diabetic retinopathy(PDR).<p>METHODS: Randomized controlled trials(RCTs)comparing the efficacy of vitrectomy combined with or without anti-VEGF therapy for PDR were retrieved from databases including PUBMED, EMBASE, Cochrane Central Register of Controlled Trials(CENTRAL)and Web of Science. The retrieval time was from the establishment of the databases to July 2020. According to the inclusion and exclusion criteria, the literature was selected, then data extraction and quality evaluation was completed. Primary evaluation measures included postoperative incidence of retinal detachment, central retinal thickness(CRT), and best corrected visual acuity(BCVA). <p>RESULTS: In this article, 11 randomized controlled studies(880 eyes)were included. Meta-analysis results showed that the incidence of retinal detachment after vitrectomy was significantly lower in PDR patients who received anti-VEGF injection before vitrectomy than in patients who did not receive anti-VEGF injection \〖Risk ratio(<i>RR</i>)=0.39, 95% Confidence interval(<i>CI</i>)0.22 to 0.71, <i>P</i>=0.002\〗. There were significant differences in the incidence of retinal detachment after vitrectomy between the anti-VEGF group and the non-VEFG group in both Asian and non-Asian populations(Asian:<i> RR</i>=0.20, 95%<i>CI</i> 0.05 to 0.87, <i>P</i>=0.03; Non-Asian:<i> RR</i>=0.46, 95%<i>CI</i> 0.24 to 0.89, <i>P</i>=0.02). The central retinal thickness of PDR patients who received preoperative anti-VEGF therapy was significantly lower than that of patients who did not receive anti-VEGF therapy 3 and 6mo after PPV(<i>MD</i>=-78.49, 95%<i>CI</i> -94.81 to -62.17, <i>P</i><0.00001. <i>MD</i>= -39.62, 95%<i>CI</i> -48.44 to -30.80, <i>P</i><0.00001). The BCVA at 6mo after PPV in PDR patients with preoperative anti-VEGF treatment was better than that in patients without preoperative anti-VEGF treatment(<i>MD</i>=-0.16, 95%<i>CI</i> -0.21 to -0.10, <i>P</i><0.00001).<p>CONCLUSION: Anti-VEGF injection before PPV can effectively reduce the incidence of retinal detachment, alleviate postoperative macular edema, reduce the central retinal thickness, and improve BCVA in PDR patients.

Pathways of the COVID-19 Pandemic with Human Mobility across Countries

This study develops a holistic view of the novel coronavirus (COVID-19) transmission worldwide through a spatial-temporal model with network dynamics. By using a unique human mobility dataset containing 547,166 flights with a total capacity of 101,455,913 passengers among 22 countries during the past three months, we analyze the associations between international travel movement in six continents and the new infections in these countries. Results show that policymakers should move away from the previous practices that focus only on restricting hotspot areas with high transmission rates. Instead, they should develop a new holistic view of global human mobility to adjust the international movement restriction. The study highlights that international human mobility is the key to understand the transmission pathways and the small world phenomenon in the global network of COVID-19 pandemic.