Knowledge, attitudes, and practice of physicians and pharmacists regarding the prevention and treatment of cardiovascular toxicity associated with cancer treatment.

This study aimed to explore physicians' and pharmacists' knowledge, attitudes, and practice (KAP) regarding the prevention and treatment of cardiovascular toxicity associated with cancer treatment. A multicenter cross-sectional study included physicians and pharmacists between April 2023 and June 2023. The study included 918 participants (514 physicians and 404 pharmacists). The average scores of knowledge, attitudes, and practice were 11.6 ± 3.39, 24.7 ± 2.6, and 26.3 ± 6.8 points. Sufficient knowledge was significantly associated with age ≥ 41 years (odds ratio (OR) = 2.745, 95% confidence interval (CI) 1.086-6.941, P = 0.033), male (OR = 2.745, 95% CI 1.150-2.223, P = 0.005), bachelor's degree (OR = 0.084, 95% CI 0.013-0.533, P = 0.009), master's degree and above (OR = 0.096, 95% CI 0.015-0.609, P = 0.013), physician occupation (OR = 7.601, 95% CI 1.337-43.207, P = 0.022), pharmacy department (OR = 18.858, 95% CI 3.245-109.57, P = 0.001), oncology department (OR = 4.304, 95% CI 2.426-7.634, P < 0.001), cardiology department (OR = 3.001, 95% CI 1.387-6.492, P = 0.005), hospitals located in Eastern China (OR = 1.957, 95% CI 1.120-3.418, P = 0.018), and hospitals located in Western China (OR = 3.137, 95% CI 1.783-5.518, P < 0.001). Positive attitudes were significantly associated with a senior professional title (OR = 2.989, 95% CI 1.124-7.954, P = 0.028) and hospitals located in Eastern China (OR = 0.424, 95% CI 0.257-0.698, P = 0.001), Western China (OR = 0.231, 95% CI 0.136-0.394, P < 0.001), and Southern China (OR = 0.341, 95% CI 0.198-0.587, P < 0.001). Proactive practice was significantly associated with male (OR = 1.414, 95% CI 1.029-1.943, P = 0.033), senior professional title (OR = 3.838, 95% CI 1.176-12.524, P = 0.026), oncology department (OR = 3.827, 95% CI 2.336-6.272, P < 0.001), and cardiology department (OR = 2.428, 95% CI 1.263-4.669, P = 0.008). Both physicians and pharmacists had positive attitudes toward the prevention and treatment of cardiovascular toxicity associated with cancer treatment, while their knowledge and practice were not as proactive.

DNA damage induced by CDK4 and CDK6 blockade triggers anti-tumor immune responses through cGAS-STING pathway.

CDK4/6 are important regulators of cell cycle and their inhibitors have been approved as anti-cancer drugs. Here, we report a STING-dependent anti-tumor immune mechanism responsible for tumor suppression by CDK4/6 blockade. Clinical datasets show that in human tissues, CDK4 and CDK6 are over-expressed and their expressions are negatively correlated with patients' overall survival and T cell infiltration. Deletion of Cdk4 or Cdk6 in tumor cells significantly reduce tumor growth. Mechanistically, we find that Cdk4 or Cdk6 deficiency contributes to an increased level of endogenous DNA damage, which triggers the cGAS-STING signaling pathway to activate type I interferon response. Knockout of Sting is sufficient to reverse and partially reverse the anti-tumor effect of Cdk4 and Cdk6 deficiency respectively. Therefore, our findings suggest that CDK4/6 inhibitors may enhance anti-tumor immunity through the STING-dependent type I interferon response.

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OBJECTIVES: To develop a risk prediction model for severe adenovirus pneumonia (AVP) in children, and to explore the appropriate timing for intravenous immunoglobulin (IVIG) therapy for severe AVP. METHODS: Medical data of 1 046 children with AVP were retrospectively analyzed, and a risk prediction model for severe AVP was established using multivariate logistic regression. The model was validated with 102 children with AVP. Then, 75 children aged ≤14 years who were considered at risk of developing severe AVP by the model were prospectively enrolled and divided into three groups (A, B and C) in order of visit, with 25 children in each group. Group A received symptomatic supportive therapy only. With the exception of symptomatic supportive therapy, group B received IVIG treatment at a dose of 1g/(kg·d) for 2 consecutive days, before progressing to severe AVP. With the exception of symptomatic supportive therapy, group C received IVIG treatment at a dose of 1 g/(kg·d) for 2 consecutive days after progressing to severe AVP. Efficacy and related laboratory indicators were compared among the three groups after treatment. RESULTS: Age<18.5 months, underlying diseases, fever duration >6.5 days, hemoglobin level <84.5 g/L, alanine transaminase level >113.5 U/L, and co-infection with bacteria were the six variables that entered into the risk prediction model for severe AVP. The model had an area under the receiver operating characteristic curve of 0.862, sensitivity of 0.878, and specificity of 0.848. The Hosmer-Lemeshow test showed good consistency between the predicted values and the actual observations (P>0.05). After treatment, group B had the shortest fever duration and hospital stay, the lowest hospitalization costs, the highest effective rate of treatment, the lowest incidence of complications, the lowest white blood cell count and interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10 levels, and the highest level of tumor necrosis factor alpha (P<0.05). CONCLUSIONS: The risk model for severe AVP established in this study has good value in predicting the development of severe AVP. IVIG therapy before progression to severe AVP is more effective in treating AVP in children.

HDAC3 Inhibition Promotes Antitumor Immunity by Enhancing CXCL10-Mediated Chemotaxis and Recruiting of Immune Cells.

It is generally believed that histone deacetylase (HDAC) inhibitors, which represent a new class of anticancer agents, exert their antitumor activity by directly causing cell-cycle arrest and apoptosis of tumor cells. However, in this study, we demonstrated that class I HDAC inhibitors, such as Entinostat and Panobinostat, effectively suppressed tumor growth in immunocompetent but not immunodeficient mice. Further studies with Hdac1, 2, or 3 knockout tumor cells indicated that tumor-specific inactivation of HDAC3 suppressed tumor growth by activating antitumor immunity. Specifically, we found that HDAC3 could directly bind to promotor regions and inhibit the expression of CXCL9, 10, and 11 chemokines. Hdac3-deficient tumor cells expressed high levels of these chemokines, which suppressed tumor growth in immunocompetent mice by recruiting CXCR3+ T cells into the tumor microenvironment (TME). Furthermore, the inverse correlation between HDAC3 and CXCL10 expression in hepatocellular carcinoma tumor tissues also suggested HDAC3 might be involved in antitumor immune regulation and patient survival. Thus, our studies have illustrated that HDAC3 inhibition suppresses tumor growth by enhancing immune cell infiltration into the TME. This antitumor mechanism may be helpful in guiding HDAC3 inhibitor-based treatment.

Efficacy of quadratus lumborum block on postoperative pain and side effects in patients who underwent urological surgery: A meta-analysis.

BACKGROUND: Ultrasound-guided quadratus lumborum block (QLB) is considered a novel nerve block for postoperative pain control. However, its efficacy after urological surgery remains unclear. OBJECTIVES: The purpose of the current meta-analysis was to evaluate the effects of the QLB block versus control (placebo or no injection) on postoperative pain and other adverse outcomes after urological surgery, providing extensive evidence of whether quadratus lumborum block is suitable for pain management after urological surgery. STUDY DESIGN: Systematic review with meta-analysis of randomized clinical trials. METHODS: We searched PubMed, Cochrane Library, Embase, Web of Science, and ClinicalTrials.gov to collect studies investigating the effects of QLB on analgesia after urological surgery. The primary outcomes included visual analog scale (VAS) at rest and during movement, 24-h postoperative morphine consumption, and the incidence of postoperative nausea and vomiting (PONV). RESULTS: Overall, 13 randomized controlled trials (RCTs) were reviewed, including 751 patients who underwent urological surgery. The QLB group exhibited a lower VAS score postoperatively at rest or on movement at 0, 6, 12, and 24 h, with less 24-h postoperative morphine consumption and lower incidence of PONV. LIMITATIONS: Although the result is stable, heterogeneity exists in the current research. CONCLUSIONS: QLB exhibited a favorable effect of postoperative analgesia with reduced postoperative complications at rest or during movement after urological surgery. However, it is still a novel technology at a primary stage, which needs further research to develop.

Effects of Ultrasound-Guided Transversus Thoracic Muscle Plane Block on Postoperative Pain and Side Effects: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The effects of the transversus thoracic muscle plane (TTP) block on postoperative pain have become increasingly controversial. This meta-analysis compared the effects of the TTP block versus no block on postoperative analgesia and side effects to determine whether this new technique is a reliable alternative for pain management. PubMed, Cochrane Library, Embase, Web of Science, ClinicalTrials.gov, China National Knowledge Infrastructure, Chongqing VIP information, and Wanfang Data were searched for clinical studies investigating the analgesic effect of the TTP block compared to controls. The primary outcomes included the postoperative pain scores at rest and during movement, morphine consumption in 24 hours, and the rate of postoperative nausea and vomiting (PONV). Eleven randomized controlled trials (RCTs), including 682 patients, were reviewed. The meta-analysis showed that the TTP block significantly could reduce the pain scores at 0 (at rest: mean difference [MD], -2.28; 95% CI: -2.67 to -1.90) (during movement: MD: -2.09, 95% CI: -2.62 to -1.56) and 12 hours (at rest: -1.42, 95% CI: -2.03 to -0.82) (during movement: MD: -2.13, 95% CI: -2.80 to -1.46) after surgery, 24-hour postoperative analgesic consumption (MD: -23.18, 95% CI: -33.71 to -12.66), and the incidence of PONV (odds ratio, 0.36, 95% CI: 0.15-0.88). Furthermore, the trial sequence analysis confirmed the result of less 24-hour postoperative analgesic consumption in the TTP block group. As a novel technique, the TTP block exhibited a superior postoperative analgesic effect during the early postoperative period. Nevertheless, additional well-designed RCTs are needed.

6-Benzyladenine alleviates NaCl stress in watermelon (Citrullus lanatus) seedlings by improving photosynthesis and upregulating antioxidant defences.

Soil salinity is a growing problem in agriculture, plant growth regulators (PGRs) can regulate plant response to stress. The objective of this study was to evaluate the effects of exogenous 6-benzyladenine (6-BA) on photosynthetic capacity and antioxidant defences in watermelon (Citrullus lanatus L.) seedlings under NaCl stress. Two watermelon genotypes were subjected to four different treatments: (1) normal water (control); (2) 20mgL-1 6-BA; (3) 120mmolL-1 NaCl; and (4) 120mmolL-1 NaCl+20mgL-1 6-BA. Our results showed that NaCl stress inhibited the growth of watermelon seedlings, decreased their photosynthetic capacity, promoted membrane lipid peroxidation, and lowered the activity of protective enzymes. Additionally the salt-tolerant Charleston Gray variety fared better than the salt-sensitive Zhengzi NO.017 variety under NaCl stress. Foliar spraying of 6-BA under NaCl stress significantly increased biomass accumulation, as well as photosynthetic pigment, soluble sugar, and protein content, while decreasing malondialdehyde levels, H2 O2 content, and electrolyte leakage. Moreover, 6-BA enhanced photosynthetic parameters, including net photosynthetic rate, stomatal conductance, intercellular CO2 concentration, and transpiration rate; activated antioxidant enzymes, such as superoxide dismutase, catalase, and peroxidase; and improved the efficiency of the ascorbate-glutathione cycle by stimulating glutathione reductase, dehydroascorbate reductase, and monodehydroascorbate reductase, as well as ascorbic acid and glutathione content. Principal component analysis confirmed that 6-BA improved salt tolerance of the two watermelon varieties, particularly Zhengzi NO.017, albeit through two different regulatory mechanisms. In conclusion, 6-BA treatment could alleviate NaCl stress-induced damage and improve salt tolerance of watermelons by regulating photosynthesis and osmoregulation, activating the ascorbate-glutathione cycle, and promoting antioxidant defences.

Isoliquiritigenin attenuates pathological cardiac hypertrophy via regulating AMPKα in vivo and in vitro.

Isoliquiritigenin (ISL) is a type of flavonoid, derived from the root of the legume plant Glycyrrhiza, that has multiple pharmacological properties. However, its role in cardiac remodeling induced by pressure overload has yet to be fully elucidated. Aortic banding (AB) surgery was used to establish a cardiac hypertrophy model in male C57BL/6 mice. Mice were randomly divided into four groups (n = 20 per group) as follows: Sham + vehicle, sham + ISL, AB + vehicle and AB + ISL. ISL was administered to the mice intragastrically for 1 week after the operation. To evaluate the role of ISL in mice challenged with AB, echocardiography, histological analysis and molecular biochemistry examinations were performed. ISL treatment decreased cardiac hypertrophy and improved cardiac dysfunction induced by pressure overload. In addition, ISL decreased the cross-sectional area of cardiomyocytes. Furthermore, ISL reversed the AB-mediated increase in phosphorylated (p-)mTOR and p-ERK protein levels and further increased the protein expression of p-AMP-activated protein kinase (AMPK)α in response to AB, whereas knockout of AMPKα abolished the protective effects of ISL. The present study suggested that ISL could suppress pressure overload-induced cardiac hypertrophy through the activation of AMPKα. Therefore, ISL may serve as a therapeutic target for cardiac remodeling.

The Role of Dexmedetomidine in Tumor-Progressive Factors in the Perioperative Period and Cancer Recurrence: A Narrative Review.

Dexmedetomidine, a specific α2 adrenergic receptor agonist, is highly frequently used in the perioperatively for its favorable pharmacology, such as mitigating postoperative cognitive dysfunction. Increasing attention has been recently focused on the effect of whether dexmedetomidine influences cancer recurrence, which urges the discussion of the role of dexmedetomidine in tumor-progressive factors. The pharmacologic characteristics of dexmedetomidine, the tumor-progressive factors in the perioperative period, and the relationships between dexmedetomidine and tumor-progressive factors were described in this review. Available evidence suggests that dexmedetomidine could reduce the degree of immune function suppression, such as keeping the number of CD3+ cells, NK cells, CD4+/CD8+ ratio, and Th1/Th2 ratio stable and decreasing the level of proinflammatory cytokine (interleukin 6 and tumor necrosis factor-alpha) during cancer operations. However, dexmedetomidine exhibits different roles in cell biological behavior depending on cancer cell types. The conclusions on whether dexmedetomidine would influence cancer recurrence could not be currently drawn for the lack of strong clinical evidence. Therefore, this is still a new area that needs further exploration.

CDK2 Inhibition Enhances Antitumor Immunity by Increasing IFN Response to Endogenous Retroviruses.

Inhibitors of cyclin-dependent kinase-2 (CDK2) are commonly used against several solid tumors, and their primary mechanisms of action were thought to include cell proliferation arrest, induction of cancer cell apoptosis and induction of differentiation. Here, we found that CDK2 inhibition by either small molecular inhibitors or genetic Cdk2 deficiency promoted antitumor immunity in murine models of fibrosarcoma and lung carcinoma. Mechanistically, CDK2 inhibition reduced phosphorylation of RB protein and transcription of E2F-mediated DNA methyltransferase 1 (DNMT1), which resulted in increased expression of endogenous retroviral RNA and type I IFN (IFN-I) response. The increased IFN-I response subsequently promoted antitumor immunity by enhancing tumor antigen presentation and CD8+ T-cell infiltration. Our studies provide evidence that inhibition of CDK2 in cancer cells suppresses tumor growth by enhancing antitumor immune responses in the tumor microenvironment, suggesting a new mechanism to enhance antitumor immunity by CDK2 inhibitors.

Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1.

BACKGROUND: In 2015, herpes simplex virus 1 (HSV-1)-derived talimogene laherparepvec (T-VEC) was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment. However, its antitumor application is limited to local treatment of melanoma, and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity. We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus. METHODS: We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1. Then, we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1. Furthermore, we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models. RESULTS: We identified eight IFN-stimulated genes (ISGs) controlling HSV-1 replication, among which BTB and CNC homology 1 (BACH1) suppressed HSV-1 replication by inhibiting the transcription of ICP4, ICP27, and UL39. Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis, HMGB1 secretion, and calreticulin exposure in tumor cells. More importantly, hemin, an FDA-approved drug known to downregulate BACH1, significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site. CONCLUSIONS: Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.

Homeoprotein SIX1 compromises antitumor immunity through TGF-ß-mediated regulation of collagens.

The tumor microenvironment (TME), including infiltrated immune cells, is known to play an important role in tumor growth; however, the mechanisms underlying tumor immunogenicity have not been fully elucidated. Here, we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment. Based on analyses of patient datasets, we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients. Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME. Mechanistically, SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway, and collagen deposition in the TME hampered immune cell infiltration and activation. Thus, our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.

Efficacy and safety profile of avelumab monotherapy.

Avelumab can kill cancer cells through immune checkpoint inhibition and antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we analyzed the clinical efficacy and adverse events (AEs) in 3935 cancer patients from 21 trials. Compared with conventional treatment, avelumab monotherapy was associated with more tumor responses and less AEs. The pooled objective response rate was 14.18 % (95 % CI, 10.68 %-18.08 %). More PD-L1 positive patients responded to avelumab monotherapy compared to PD-L1 negative patients. The overall incidence was 73.78 % for all-grade treatment-related AE (TRAE), 14.44 % for high-grade TRAE, 6.07 % for serious adverse event, 0.44 % for fatal adverse event, 17.86 % for all-grade immune-related AE (irAE), and 3.22 % for high-grade irAE. In summary, avelumab monotherapy presents an active anti-tumor activity, shows no sign of increased toxicity due to the ADCC. These characteristics provide rational for further application of avelumab in cancer treatment.

1,8-cineole ameliorates ischaemic brain damage via TRPC6/CREB pathways in rats.

OBJECTIVES: A previous in vitro study reported that the monoterpene oxide 1,8-cineole (cineole) attenuates neuronal caused by oxygen-glucose deprivation/reoxygenation in culture. However, to date, there is no in vivo evidence showing neuroprotective effects of cineole against stroke. This study aimed to investigate whether cineole attenuates cerebral ischaemic damage in rats. METHODS: A rat model of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion was applied. Male rats were treated with oral cineole (100 mg/kg) for 7 consecutive days, then subjected to MCAO surgery. Infarct volume, neurologic deficits, apoptosis and expression levels of all-spectrin breakdown products of 145 kDa (SBDP145), transient receptor potential canonical (subtype) 6 (TRPC6) and phosphorylated CREB (p-CREB) were measured in ischaemic brain tissues. KEY FINDINGS: Cineole treatment significantly reduced infarct volume, neurological dysfunction, neuronal apoptosis, SBDP145 formation and TRPC6 degradation and enhanced p-CREB expression in MCAO rats compared with vehicle treatment. These neuroprotective effects were markedly suppressed by pharmacological inhibition of MEK or CaMKIV signalling. CONCLUSIONS: Our study provides in vivo evidence demonstrating that cineole pretreatment attenuates ischaemic stroke-induced brain damage, mainly through blocking calpain-induced TRPC6 degradation and activating CREB via MEK/CREB and CaMKIV/CREB signalling pathways.

Transplantation of GMP-grade human iPSC-derived retinal pigment epithelial cells in rodent model: the first pre-clinical study for safety and efficacy in China.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly due in large part to age-dependent atrophy of retinal pigment epithelium (RPE) cells. RPE cells form a monolayer located between the choroid and the outer segments of photoreceptors, playing multifarious roles in maintenance of visual function. Allogeneically induced pluripotent stem cell-derived RPE (iPSC-RPE or iRPE) has become a potential approach for providing an abundant source of donors for clinical cell products. Transplantation of iRPE has been proven effective in rescuing impaired retinas in Royal College of Surgeons (RCS) rats after approximately 5 to 6 weeks. Here, we explore the long-term (19 weeks) safety and efficacy of human iRPE cell transplantation in pre-clinical animal models. METHODS: The expression of human RPE-specific markers in iRPE cells was determined using immunofluorescence staining. For the proliferative test, Ki-67 expression was also verified by immunofluorescence and flow cytometric analysis. Then, iRPE cells were transplanted into the subretinal space of immune-deficient NOD/SCID/IL-2Rgcnull (NSG) mice to assess their safety. To evaluate whether the transplanted cells could survive and rescue visual function, we performed color fundus photography, focal electroretinogram and immunostaining after delivering iRPE cells into the subretinal space of RCS rats. RESULTS: Human iRPE cells expressed native RPE-specific markers, such as microphthalmia-associated transcription factor (MiTF), retinal pigment epithelium-specific 65-kDa protein (RPE65) and tight-junction associated structural protein (ZO-1), and their proliferative capacity (Ki-67 expression) was poor after 25 days of induction. A tumorigenicity test revealed no tumor formation or abnormal proliferation in the immunodeficient mice after subretinal injection of 5×105 iRPE cells. The transplanted iRPE cells survived for at least 19 weeks and maintained visual function for 15 weeks. CONCLUSIONS: In the present study, we provided further evidence for the use of human iRPE transplantation to treat retinal degenerative disease in pre-clinical animal models. Therefore, we consider human iRPE cells a promising source of cell replacement therapy for AMD.

COCO enhances the efficiency of photoreceptor precursor differentiation in early human embryonic stem cell-derived retinal organoids.

BACKGROUND: Significant progress has been made in cell replacement therapy for neural retinal diseases using retinal cells differentiated from human pluripotent stem cells. Low tumorigenicity and the ability to mature to form synaptic junctions make precursor cells a promising donor source. Here, we attempted to improve the yield of photoreceptor precursor cells in three-dimensional retinal organoids from human embryonic stem cells (hESCs). METHODS: A CRX-tdTomato-tagged hESC line was generated to track retinal precursors in 3D retinal organoids. COCO, a multifunctional antagonist of the Wnt, TGF-ß, and BMP pathways, was employed to 3D organoid differentiation schemes for enhanced photoreceptor precursor cells. Organoid fluorescence intensity measurement was used to monitor retinalization tendency with the number of precursors further checked by flow cytometry. Signature gene expression during organoid differentiation were assessed by qPCR and immunocytochemistry after COCO supplementation. RESULTS: CRX-positive cells can be spatiotemporally tracked by tdTomato without affecting retinalization during retinal organoid differentiation. Fluorescence intensity of organoids, which turned out highly consistent with flow cytometry measurement, allowed us to determine the differentiation efficiency of precursors during organoid culturing directly. Using COCO as an auxiliary supplement, rather than alone, can yield an increased number of photoreceptor precursors in the early stage of organoid differentiation. Over a longer time-frame, photoreceptor precursors enhanced their fate of cones and decreased fate of rods after treatment with COCO. CONCLUSIONS: Tracing with the CRX-reporter system showed that in retinal organoids derived from human pluripotent stem cells, COCO increased the differentiation efficiency of photoreceptor precursors and cones.

Targeting NLRP3 and Staphylococcal pore-forming toxin receptors in human-induced pluripotent stem cell-derived macrophages.

Staphylococcus aureus causes necrotizing pneumonia by secreting toxins such as leukocidins that target front-line immune cells. The mechanism by which leukocidins kill innate immune cells and trigger inflammation during S. aureus lung infection, however, remains unresolved. Here, we explored human-induced pluripotent stem cell-derived macrophages (hiPSC-dMs) to study the interaction of the leukocidins Panton-Valentine leukocidin (PVL) and LukAB with lung macrophages, which are the initial leukocidin targets during S. aureus lung invasion. hiPSC-dMs were susceptible to the leukocidins PVL and LukAB and both leukocidins triggered NLPR3 inflammasome activation resulting in IL-1ß secretion. hiPSC-dM cell death after LukAB exposure, however, was only temporarily dependent of NLRP3, although NLRP3 triggered marked cell death after PVL treatment. CRISPR/Cas9-mediated deletion of the PVL receptor, C5aR1, protected hiPSC-dMs from PVL cytotoxicity, despite the expression of other leukocidin receptors, such as CD45. PVL-deficient S. aureus had reduced ability to induce lung IL-1ß levels in human C5aR1 knock-in mice. Unexpectedly, inhibiting NLRP3 activity resulted in increased wild-type S. aureus lung burdens. Our findings suggest that NLRP3 induces macrophage death and IL-1ß secretion after PVL exposure and controls S. aureus lung burdens.

Effects of erector spinae plane block on postoperative pain and side-effects in adult patients underwent surgery: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Recently, the effects of erector spinae plane block on postoperative pain have become increasingly controversial. This meta-analysis compared the effects of ESP block versus placebo on postoperative analgesia and side effects to determine whether the new technique is a reliable alternative for pain management. METHODS: PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang Database were searched for clinical studies investigating the analgesic effect of ESP block versus placebo. The primary outcomes included the visual analogue scale (VAS) at rest and during movement, as well as the postoperative morphine consumption in 24 h, and the secondary outcome was the rate of postoperative nausea and vomiting (PONV). The choice of using the fixed or random-effects model depended on whether the heterogeneity tested by I2 statistic was more than 50%. Seeking sources of heterogeneity and exploring the effect of clinical details on the final result were performed by subgroup analysis. Additionally, the test for stability of the pooled result was realized by sensitivity analysis. Finally, we evaluated the quality of the evidence for the outcomes. STATA 13.0 software was selected as the main analysis software in the meta-analysis. RESULTS: Eighteen randomized controlled trials (RCTs) comprising 1041 patients were reviewed. This meta-analysis showed that ESP block could significantly reduce patients' pain scores at 1 h, 6 h, 12 h, and 24 h after surgery at rest or during movement; 24-h postoperative morphine consumption; and the incidence of PONV. CONCLUSIONS: ESP block as a novel technique exhibited superior postoperative analgesic effects, reducing the postoperative complications in spinal, thoracic, and abdominal surgeries during the early postoperative period. However, as a new nerve block technique, numerous large-sized RCTs are needed for further research.

Transversus Abdominis Plane Block versus Wound Infiltration with Conventional Local Anesthetics in Adult Patients Underwent Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: How to effectively control the postoperative pain of patients is extremely important to clinicians. Transversus abdominis plane (TAP) block is a novel analgesic method reported to greatly decrease postoperative pain. However, in many areas, there still exists a phenomenon of surgeons using wound infiltration (WI) with conventional local anesthetics (not liposome anesthetics) as the main means to decrease postoperative pain because of traditional wisdom or convenience. Here, we compared the analgesic effectiveness of the two different methods to determine which method is more suitable for adult patients. Materials and methods. A systematic review and meta-analysis of randomized controlled trials (RCTs) comparing TAP block and WI without liposome anesthetics in adult patients were performed. Frequently used databases were extensively searched. The main outcomes were postoperative pain scores in different situations (at rest or during movement) and the time until the first use of rescue analgesics. The secondary outcomes were postoperative nausea and vomiting (PONV) incidence and patient satisfaction scores. RESULTS: Fifteen studies with 983 participants met the inclusion criteria and were included in the present study. The heterogeneity in the final analysis regarding the pain score was low to moderate. The major results of the sensitivity analysis were stable. WI had the same analgesic effect as TAP block only at the one-hour postoperative time point (mean difference = -0.32, 95% confidence interval (-0.87, 0.24), P = 0.26) and was associated with a shorter time until the first rescue analgesic and poorer patient satisfaction. CONCLUSION: TAP block results in a more effective and steady analgesic effect than WI with conventional local anesthetics in adult patients from the early postoperative period and obtains higher patient satisfaction.