Nickel-Catalyzed Direct Sulfonylation of Styrenes and Unactivated Aliphatic Alkenes with Sulfonyl Chlorides.

A nickel-catalyzed direct sulfonylation of alkenes with sulfonyl chlorides has been developed using 1,10-phenanthroline-5,6-dione as the ligand. Unactivated alkenes and styrenes including 1,1-, 1,2-disubstituted alkenes can be subjected to the protocol, and a wide range of vinyl sulfones was obtained in high to excellent yields with good functional group compatibility. Notably, the process did not allow the desulfonylation of sulfonyl chloride or chlorosulfonylation of alkenes. Radical-trapping experiment supported that a sulfonyl free-radical was likely produced and triggered subsequent transformation in the process.

Harnessing nanomedicine for modulating microglial states in the central nervous system disorders: Challenges and opportunities.

Microglia are essential for maintaining homeostasis and responding to pathological events in the central nervous system (CNS). Their dynamic and multidimensional states in different environments are pivotal factors in various CNS disorders. However, therapeutic modulation of microglial states is challenging due to the intricate balance these cells maintain in the CNS environment and the blood-brain barrier's restriction of drug delivery. Nanomedicine presents a promising avenue for addressing these challenges, offering a method for the targeted and efficient modulation of microglial states. This review covers the challenges faced in microglial therapeutic modulation and potential use of nanoparticle-based drug delivery systems. We provide an in-depth examination of nanoparticle applications for modulating microglial states in a range of CNS disorders, encompassing neurodegenerative and autoimmune diseases, infections, traumatic injuries, stroke, tumors, chronic pain, and psychiatric conditions. This review highlights the recent advancements and future prospects in nanomedicine for microglial modulation, paving the way for future research and clinical applications of therapeutic interventions in CNS disorders.

Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis.

CONTEXT.­: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children. OBJECTIVE.­: To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH. DESIGN.­: We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients. RESULTS.­: A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor. CONCLUSIONS.­: Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.

Risk Factors of Chemotherapy-Induced Thrombocytopenia After Oxaliplatin-Containing Chemotherapy for Gastrointestinal Malignancies.

PURPOSE: Thrombocytopenia is among the most common chemotherapy-related hematologic toxicities. We aim to determine the predictors of oxaliplatin chemotherapy-induced thrombocytopenia in patients with gastrointestinal tumors to guide the clinic. METHODS: Clinical data of 750 patients with a malignant gastrointestinal tumor were included as the primary cohort. Basic clinical data, serological indices, and anthropometric indices of these patients were collected. According to the presence or absence of CIT, univariate analysis was performed to identify significant factors for multivariate analysis. In R language software, nomogram was constructed based on the results of multi-factor analysis, and the calibration curve and ROC curve were drawn. RESULTS: Univariate analysis identified 17 factors as closely related to CIT occurrence, namely age, lymph node metastasis (N) stage, metastasis (M) stage, lung metastasis, other site metastasis, chemotherapy regimen, course of treatment, total dose of oxaliplatin, AST, albumin, neutrophils, monocytes, baseline platelets, transferrin, natural killer (NK) cell, phase angle, and SMI (P < 0.10). The binary logistic multivariate regression analysis revealed five independent risk factors for developing CIT (P < 0.05), including the M stage, total dose of oxaliplatin, albumin, baseline thrombocyte count, and NK cell. Based on the results of multivariate logistic regression analysis, R software was used to establish a nomogram model. The calibration curve shows that the combined predictor has good consistency. The area under the ROC curve was 0.877 and the best cut-off value was 0.3579613 (sensitivity, 78.9%; specificity, 81.8%), which showed the better prediction efficiency. CONCLUSION: The total dose of oxaliplatin, M stage, albumin, baseline platelet count, and NK cell was independent risk factors for CIT. The sequentially constructed histogram model had a good predictive effect on the risk of thrombocytopenia caused by oxaliplatin chemotherapy in patients with gastrointestinal malignancies.

Association between CFTR modulators and changes in iron deficiency markers in cystic fibrosis.

BACKGROUND: Iron deficiency (ID) is a common extrapulmonary manifestation in cystic fibrosis (CF). CF transmembrane conductance regulator (CFTR) modulator therapies, particularly highly-effective modulator therapy (HEMT), have drastically improved health status in a majority of people with CF. We hypothesize that CFTR modulator use is associated with improved markers of ID. METHODS: In a multicenter retrospective cohort study across 4 United States CF centers 2012-2022, the association between modulator therapies and ID laboratory outcomes was estimated using multivariable linear mixed effects models overall and by key subgroups. Summary statistics describe the prevalence and trends of ID, defined a priori as transferrin saturation (TSAT) <20 % or serum iron <60 µg/dL (<10.7 µmol/L). RESULTS: A total of 568 patients with 2571 person-years of follow-up were included in analyses. Compared to off modulator therapy, HEMT was associated with +8.4 % TSAT (95 % confidence interval [CI], +6.3-10.6 %; p < 0.0001) and +34.4 µg/dL serum iron (95 % CI, +26.7-42.1 µg/dL; p < 0.0001) overall; +5.4 % TSAT (95 % CI, +2.8-8.0 %; p = 0.0001) and +22.1 µg/dL serum iron (95 % CI, +13.5-30.8 µg/dL; p < 0.0001) in females; and +11.4 % TSAT (95 % CI, +7.9-14.8 %; p < 0.0001) and +46.0 µg/dL serum iron (95 % CI, +33.3-58.8 µg/dL; p < 0.0001) in males. Ferritin was not different in those taking modulator therapy relative to off modulator therapy. Hemoglobin was overall higher with use of modulator therapy. The prevalence of ID was high throughout the study period (32.8 % in those treated with HEMT). CONCLUSIONS: ID remains a prevalent comorbidity in CF, despite availability of HEMT. Modulator use, particularly of HEMT, is associated with improved markers for ID (TSAT, serum iron) and anemia (hemoglobin).

Characteristics of patients with recurrent retinoblastoma: a survival analysis.

BACKGROUND: Management guidelines and corresponding survival data for patients with recurrent retinoblastoma (RB) are lacking. This study aimed to summarize the clinical characteristics of patients with recurrent RB and analyze their survival outcomes. METHODS: We retrospectively analyzed 68 patients with recurrent RB who underwent treatment in our institution from January 2016 to December 2020. Patients were grouped according to location of recurrence: intraocular, orbital, and distant metastasis. RESULTS: The male:female ratio was 1.3:1 and the median age at recurrence was 37.5 months (range, 30.3-62.8). The number of patients in the intraocular recurrence, orbital recurrence, and metastasis groups was 13 (19.1%), 23 (33.8%), and 32 (47.1%), respectively. Thirty patients died, 36 were alive at last follow-up, and two were lost to follow-up. Eye enucleation was performed in 94.1% of patients. Five-year overall survival in patients with intraocular recurrence, orbital recurrence, and metastasis was 84.6%, 69.6%, and 31.3%, respectively (P = 0.001). Most deaths occurred within 2 years of recurrence. Presence of high-risk pathological factors, central nervous system invasion, and absence of combination therapy were independent predictors of worse 5-year overall survival. CONCLUSION: The rate of eye preservation in survivors of recurrent RB was very low. Although 5-year overall survival in patients who underwent treatment for intraocular and orbital recurrence was high, it was low in those with metastasis. RB patients may need lifelong follow-up for recurrence and secondary malignancy.

Pro-tumorigenic activity of PYCR1 in gastric cancer through regulating the PI3K/AKT signaling.

Background: The primary objective of this investigation was to assess the impact of pyrroline-5-carboxylate reductase 1 (PYCR1) on the progression of gastric cancer (GC), specifically focusing on tumor growth and metastatic potential. Methods: Surgical specimens from patients with different stages of GC were assayed for PYCR1 expression using immunohistochemistry. PYCR1 expression was manipulated by depletion or overexpression approaches in GC cells, and these cells were applied to explore the functional roles of PYCR1. Expression of apoptosis- and metastasis-related markers was quantified through quantitative real-time PCR and Western blot. Results: Higher PYCR1 expression was ascertained in surgical specimens from patients with GC as compared to noncancerous adjacent tissues. Additionally, PYCR1 overexpression in GC tissues was linked to adverse clinical outcomes. The depletion of PYCR1 in GC cells resulted in a pronounced reduction in proliferation, the induction of apoptosis, and the attenuation of invasion and metastasis. Conversely, its ectopic expression notably augmented proliferation, restricted apoptosis, and stimulated invasion and metastasis. In addition, the knockdown of PYCR1 resulted in a significant elevation in the activation of caspase 3, a key protein involved in apoptosis. This depletion also led to a decrease in the activation or expression of proteins associated with metastasis, such as phosphorylated (p)-phosphatidylinositol 3-kinase (PI3K), p-AKT serine/threonine kinase (AKT), and snail family transcriptional repressor 1 (Snail). Additionally, it resulted in an upregulation of E-cadherin expression. Conversely, the overexpression of PYCR1 notably increased the levels of p-PI3K, p-AKT, and Snail, while simultaneously reducing E-cadherin expression. Conclusion: PYCR1, by activating PI3K/AKT signaling, assumes a crucial role in governing malignant characteristics of GC cells, including proliferation, apoptosis, and metastasis. These findings underscore the promising potential of PYCR1 as a diagnostic biomarker and a target for tailored therapeutic interventions in patients with GC.

Nutrient availability regulates the secretion and function of immune cell-derived extracellular vesicles through metabolic rewiring.

Extracellular vesicle (EV)-based immunotherapeutics have emerged as promising strategy for treating diseases, and thus, a better understanding of the factors that regulate EV secretion and function can provide insights into developing advanced therapies. Here, we report that nutrient availability, even changes in individual nutrient components, may affect EV biogenesis and composition of immune cells [e.g., macrophages (Mφs)]. As a proof of concept, EVs from M1-Mφ under glutamine-depleted conditions (EVGLN-) had higher yields, functional compositions, and immunostimulatory potential than EVs from conventional GLN-present medium (EVGLN+). Mechanistically, the systemic metabolic rewiring (e.g., altered energy and redox metabolism) induced by GLN depletion resulted in up-regulated pathways related to EV biogenesis/cargo sorting (e.g., ESCRT) and immunostimulatory molecule production (e.g., NF-κB and STAT) in Mφs. This study highlights the importance of nutrient status in EV secretion and function, and optimizing metabolic states and/or integrating them with other engineering methods may advance the development of EV therapeutics.

The mitochondria‒paraspeckle axis regulates the survival of transplanted stem cells under oxidative stress conditions.

Rationale: Stem cell-based therapies have emerged as promising tools for tissue engineering and regenerative medicine, but their therapeutic efficacy is largely limited by the oxidative stress-induced loss of transplanted cells at injured tissue sites. To address this issue, we aimed to explore the underlying mechanism and protective strategy of ROS-induced MSC loss. Methods: Changes in TFAM (mitochondrial transcription factor A) signaling, mitochondrial function, DNA damage, apoptosis and senescence in MSCs under oxidative stress conditions were assessed using real-time PCR, western blotting and RNA sequencing, etc. The impact of TFAM or lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) knockdown or overexpression on mitochondrial function, DNA damage repair, apoptosis and senescence in MSCs was also analyzed. The effect of mitochondrion-targeted antioxidant (Mito-TEMPO) on the survival of transplanted MSCs was evaluated in a mouse model of renal ischemia/reperfusion (I/R) injury. Results: Mitochondrial ROS (mtROS) bursts caused defects in TFAM signaling and overall mitochondrial function, which further impaired NEAT1 expression and its mediated paraspeckle formation and DNA repair pathways in MSCs, thereby jointly promoting MSC senescence and death under oxidative stress. In contrast, targeted inhibition of the mtROS bursts is a sufficient strategy for attenuating early transplanted MSC loss at injured tissue sites, and coadministration of Mito-TEMPO improved the local retention of transplanted MSCs and reduced oxidative injury in ischemic kidneys. Conclusions: This study identified the critical role of the mitochondria‒paraspeckle axis in regulating cell survival and may provide insights into developing advanced stem cell therapies for tissue engineering and regenerative medicine.

Expression profile analysis of LncRNAs and mRNAs in pre-receptive endometrium of women with polycystic ovary syndrome undergoing in vitro fertilization-embryo transfer.

BACKGROUND: To compare the expression levels of long non-coding RNA (lncRNA) and messenger RNA (mRNA) in pre-receptive endometrium between patients with Polycystic Ovary Syndrome (PCOS)and normal ovulation undergoing in vitro fertilization-embryo transfer (IVF-ET). METHODS: Endometrial tissues were collected with endometrial vacuum curette in pre-receptive phase (3 days after oocytes retrieval) from PCOS and control groups. LncRNAs and mRNAs of endometrium were identified via RNA sequencing and alignments. A subset of 9 differentially expressed lncRNAs and 11 mRNAs were validated by quantitative reverse transcription polymerase chain reaction(qRT-PCR)in 22 PCOS patients and 18 ovulation patients. The function of mRNAs with differential expression patterns were explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: We found out 687 up-regulated and 680 down-regulated mRNAs, as well as 345 up-regulated and 63 down-regulated lncRNAs in the PCOS patients in contrast to normal ovulation patients. qRT-PCR was used to detect the expression of 11 mRNAs, and validated that the expression of these 6 mRNAs CXCR4, RABL6, OPN3, SYBU, IDH1, NOP10 were significantly elevated among PCOS patients, and the expression of ZEB1 was significantly decreased. qRT-PCR was performed to detect the expression of 9 lncRNAs, and validated that the expression of these 7 lncRNAs IDH1-AS1, PCAT14, FTX, DANCR, PRKCQ-AS1, SNHG8, TPT1-AS1 were significantly enhanced among PCOS patients. Bioinformatics analysis showed that differentially expressed genes (DEGs) involved KEGG pathway were tyrosine metabolism, PI3K-Akt pathway, metabolic pathway, Jak-STAT pathway, pyruvate metabolism, protein processing in endoplasmic reticulum, oxidative phosphorylation and proteasome. The up-regulation of GO classification was involved in ATP metabolic process, oxidative phosphorylation, RNA catabolic process, and down-regulation of GO classification was response to corticosteroid, steroid hormone, and T cell activation. CONCLUSION: Our results determined the characteristics and expression profile of endometrial lncRNAs and mRNAs in PCOS patients in pre-receptive phase, which is the day 3 after oocytes retrival. The possible pathways and related genes of endometrial receptivity disorders were found, and those lncRNAs may be developed as a predictive biomarker of endometrium in pre-receptive phase.

Injectable Multifunctional Composite Hydrogel as a Combination Therapy for Preventing Postsurgical Adhesion.

Postsurgical adhesion (PA) is a common and serious postoperative complication that affects millions of patients worldwide. However, current commercial barrier materials are insufficient to inhibit diverse pathological factors during PA formation, and thus, highly bioactive materials are needed. Here, this work designs an injectable multifunctional composite hydrogel that can serve as a combination therapy for preventing PA. In brief, this work reveals that multiple pathological events, such as chronic inflammatory and fibrotic processes, contribute to adhesion formation in vivo, and such processes can not be attenuated by barrier material (e.g., hydrogel) alone treatments. To solve this limitation, this work designs a composite hydrogel made of the cationic self-assembling peptide KLD2R and TGF-ß receptor inhibitor (TGF-ßRi)-loaded mesenchymal stem cell-derived nanovesicles (MSC-NVs). The resulting composite hydrogel displays multiple functions, including physical separation of the injured tissue areas, antibacterial effects, and local delivery and sustained release of anti-inflammatory MSC-NVs and antifibrotic TGF-ßRi. As a result, this composite hydrogel effectively inhibited local inflammation, fibrosis and adhesion formation in vivo. Moreover, the hydrogel also exhibits good biocompatibility and biodegradability in vivo. Together, the results highlight that this "all-in-one" composite hydrogel strategy may provide insights into designing advanced therapies for many types of tissue injury.

Exploration and validation of the Ki67, Her-2, and mutant P53 protein-based risk model, nomogram and lymph node metastasis model for predicting colorectal cancer progression and prognosis.

Introductions: Identifying biological markers of colorectal cancer (CRC) development and prognosis and exploring the intrinsic connection between these molecular markers and CRC progression is underway. However, a single molecular tumor marker is often difficult to assess and predict the progression and prognosis of CRC. Consequently, a combination of tumor-related markers is much needed. Ki67, Her-2, and mutant P53 (MutP53) proteins play pivotal roles in CRC occurrence, progression and prognosis. Methods: Based on the expressions by immunochemistry, we developed a risk model, nomogram and lymph node metastasis model by R software and Pythons to explore the value of these proteins in predicting CRC progression, prognosis, and examined the relationship of these proteins with the CRC clinicopathological features from 755 (training set) and 211 CRC (validation set) patients collected from the hospital. Results: We found that Ki67 expression was significantly correlated with T-stage, N-stage, TNM-stage, vascular invasion, organization differentiation, and adenoma carcinogenesis. Moreover, Her-2 expression was significantly correlated with T-stage, N-stage, TNM-stage, vascular and nerve invasion, pMMR/dMMR, signet ring cell carcinoma, and organization differentiation. MutP53 expression was significantly correlated with T-stage, N-stage, TNM-stage, vascular and nerve invasion, adenoma carcinogenesis, signet ring cell carcinoma, organization differentiation, and pMMR/dMMR. Increased expression of each of the protein indicated a poor prognosis. The established risk model based on the three key proteins showed high predictive value for determining the pathological characteristics and prognosis of CRC and was an independent influencer for prognosis. The nomogram prediction model, which was based on the risk model, after sufficient evaluation, showed more premium clinical value for predicting prognosis. Independent cohort of 211 CRC patients screened from the hospital verified the strong predictive efficacy of these models. The utilization of the XGBoost algorithm in a lymph node metastasis model, which incorporates three crucial proteins, demonstrated a robust predictive capacity for lymph node metastasis. Discussion: The risk model, nomogram and lymph node metastasis model have all provided valuable insights into the involvement of these three key proteins in the progression and prognosis of CRC. Our study provides a theoretical basis for further screening of effective models that utilize biological markers of CRC.

Prognostic factors for intermediate- or high-risk neuroblastomas in children in China.

BACKGROUND: Evidence regarding the characteristics and prognosis of neuroblastoma (NBL) in China is limited. We aimed to investigate the characteristics and prognosis of intermediate- or high-risk NBL in children in China. METHODS: We included 147 patients with intermediate- or high-risk NBL evaluated from January 2006 to March 2015. The patients were aged 1 month to 15.5 years, 66% of them were boys, and 117 (79.6%) were diagnosed with high-risk NBL. RESULTS: After a median follow-up of 32.5 months, 80 (45.6%) patients survived, with a median survival time of 48 months (95% confidence interval [CI]: 36.41-59.59). High-risk patients (hazard ratio [HR]: 12.467; 95% CI: 11.029-12.951), partial response (PR) (HR: 1.200; 95% CI: 1.475-2.509) or progression disease (PD) (HR: 1.924; 95% CI: 1.623-3.012) after induction chemotherapy, and intracranial metastasis (HR: 3.057; 95% CI: 0.941-4.892) were independent risk factors for survival (p < 0.05) and postrelapse survival (p < 0.05). NBL relapse, male sex, and PR or PD after induction chemotherapy were risk factors for event-free survival (p < 0.05). CONCLUSIONS: In addition to previously established independent risk factors, such as age, risk group, and relapse, efficacy of induction chemotherapy and intracranial metastasis play significant roles in the prognosis of NBL.

Tyrosine phosphorylation of IRF3 by BLK facilitates its sufficient activation and innate antiviral response.

Viral infection triggers the activation of transcription factor IRF3, and its activity is precisely regulated for robust antiviral immune response and effective pathogen clearance. However, how full activation of IRF3 is achieved has not been well defined. Herein, we identified BLK as a key kinase that positively modulates IRF3-dependent signaling cascades and executes a pre-eminent antiviral effect. BLK deficiency attenuates RNA or DNA virus-induced ISRE activation, interferon production and the cellular antiviral response in human and murine cells, whereas overexpression of BLK has the opposite effects. BLK-deficient mice exhibit lower serum cytokine levels and higher lethality after VSV infection. Moreover, BLK deficiency impairs the secretion of downstream antiviral cytokines and promotes Senecavirus A (SVA) proliferation, thereby supporting SVA-induced oncolysis in an in vivo xenograft tumor model. Mechanistically, viral infection triggers BLK autophosphorylation at tyrosine 309. Subsequently, activated BLK directly binds and phosphorylates IRF3 at tyrosine 107, which further promotes TBK1-induced IRF3 S386 and S396 phosphorylation, facilitating sufficient IRF3 activation and downstream antiviral response. Collectively, our findings suggest that targeting BLK enhances viral clearance via specifically regulating IRF3 phosphorylation by a previously undefined mechanism.

FOXQ1 inhibits breast cancer ferroptosis and progression via the circ_0000643/miR-153/SLC7A11 axis.

Dysregulation of ferroptosis is involved in breast cancer progression and therapeutic responses. Inducing ferroptosis can be a potential therapeutic strategy for breast cancer treatment. Forkhead box Q1 (FOXQ1) is an oncogenic transcription factor that highly expressed and related with poor outcomes in various tumors. However, the specific effects of FOXQ1 on ferroptosis in breast cancer is unclear. In this study, we intended to explore the functions and potential mechanisms of FOXQ1 in breast cancer ferroptosis. By CCK-8, colony formation, wound healing, transwell and ferroptosis related assays, we explored the functions of FOXQ1 in breast cancer ferroptosis and progression. Through bioinformatics analysis of public database, luciferase reporter assay, RIP and ChIP assay, we investigated the potential mechanisms of FOXQ1 in breast cancer ferroptosis and progression. We found that FOXQ1 was overexpressed in breast cancer and associated with worse survival. Additionally, inhibition of FOXQ1 suppressed breast cancer ferroptosis and progression. Mechanically, we confirmed that FOXQ1 could bind to the promoter of circ_0000643 host gene to increase the levels of circ_0000643, which could sponge miR-153 and enhance the expression of SLC7A11, leading to reduced cell ferroptosis in breast cancer cells. Targeting the FOXQ1/circ_0000643/miR-153/SLC7A11 axis could be a promising strategy in breast cancer treatment.

Clinical analysis of 2790 children with retinoblastoma: a single-center experience in China.

BACKGROUND: In this study, we aimed to analyze the clinical characteristics and prognosis of children with retinoblastoma (RB) in a single center in China with a large sample collection spanning 17 years. METHODS: The clinical data of 2790 children with RB treated in Beijing Tongren Hospital from 2005 to 2021 were collected, and a retrospective analysis was conducted. RESULTS: The median age of the participants was 28.3 months. There were 3624 affected eyes, 12.4% of which were in groups A-C, 67.1% in groups D-E and 16.2% were not specified. The primary symptom observed in most cases was a white pupil, accounting for 66.5%, followed by strabismus (12.8%). The median follow-up time was 59.7 months. The enucleation rate was 71.3% (703/986) in a single left eye and 72.5% (702/968) in a single right eye. The overall survival (OS) rate was 95.8% (2444/2552) because 237 patients dropped out, and 109 died. Kaplan‒Meier survival analysis showed that the median survival time (MST) was 125.92 months [95% confidence interval (CI) = 124.83-127.01]. Cox multivariate survival analysis showed that trilateral RB (P = 0.017), metastasis site (P = 0.001), and combined distant tissue metastasis (P = 0.001) were independent prognostic factors for RB. The OS of 44 cases of familial RB was 93.2% (41/44), with an MST of 80.62 months (95% CI = 67.70-93.54). CONCLUSIONS: The timing of eye protection treatment and enucleation should be comprehensively judged to avoid worsening prognosis due to operation time delay. More importantly, the promotion and popularization of diagnosis and treatment technologies are necessary to further improve RB prognosis.

Clinical characteristics, treatment and prognosis of infants with retinoblastoma: a multicenter, 10-year retrospective analysis.

BACKGROUND: To summarize the characteristics and treatment, and analyze the prognosis of large number of infants with retinoblastoma (RB) in China through a multicenter, 10-year retrospective analysis. METHODS: The data of RB infants were collected from multiple centers. The characteristics and survival prognosis were analyzed. The overall survival (OS) rate was estimated by the Kaplan-Meier method. Multivariate Cox survival analysis was to evaluate the independent risk factors affecting the prognosis of RB infants. RESULTS: A total of 373 RB infants (202 boys and 171 girls) were included, the median age was 6.22 months (10 days to 11.93 months). The median follow-up time of RB infants was 18.4 (1.02-122.81 months). After excluding the lost to follow-up cases, the OS rate was 97.7% (345/353). Kaplan-Meier survival analysis indicated that 9 cases died and the median survival time was not reached. Univariate analysis of prognostic factors revealed eye affected, presenting signs, left eye stage and recurrence to be poor prognostic factors for OS rate in RB infants (all P < 0.05). Multivariate Cox regression analyses for OS showed recurrence (HR = 1.376, 95% CI: 0.878-2.156, P = 0.048) was an independent factor for prognosis of infants with RB. The median survival time of infants underwent chemotherapy + intra-arterial chemotherapy (IAC) + enucleation + vitrectomy was the longest than other treatments (n = 9, 47.64 months, OS = 100%, all P < 0.05). There was a history of RB in 17 infants' lineal relatives. Kaplan-merier survival analysis indicated 1 case died and the median survival time was not reached. CONCLUSION: Recurrence is an independent factor for prognosis of RB infants, which still needs attention after treatment. Early screening, comprehensive treatments and follow-up of patients may lead to improvements of prognosis of RB infants.

Pegfilgrastim on febrile neutropenia in pediatric and adolescent cancer patients: a systematic review and meta-analysis.

OBJECTIVES: There is no meta-analysis about the effects of pegfilgrastim on the occurrence of febrile neutropenia (FN) in pediatric/adolescent cancer patients. The study explored the efficacy of prophylactic pegfilgrastim in preventing FN in children/adolescents with cancer. METHODS: PubMed, Embase, and the Cochrane Library were searched for studies published before April 7, 2020. The primary outcome was the rate of FN. Effect size (ES) and odds ratio (OR) with 95% confidence intervals (CIs) were used to evaluate the outcome. The ES represented the rate of FN, and the STATA 'metaprop' command was used to synthesize the rate. RESULTS: Eight studies were included, comprising 167 patients and 550 courses of treatment. There was no difference between pegfilgrastim and filgrastim for the rate of FN in children receiving chemotherapy (OR = 0.68, 95% CI: 0.20-2.23, P = 0.520). In patients receiving pegfilgrastim, the rate of FN was 25.6% (95% CI: 14.9%-36.3%), the rate of grade 4 FN was 38.3% (95% CI: 19.2%-59.5%), the rate of severe neutropenia (SN) was 40.5% (95% CI: 35.1%-46.1%), and the rate of treatment delays due to FN was 4.8% (95% CI: 0.8%-11.3%). DISCUSSION: The number of studies that could be included was small; therefore, a specific type of cancer or a specific treatment could be studied. Heterogeneity was high. CONCLUSION: There was no difference between pegfilgrastim and filgrastim for the rate of FN. The use of pegfilgrastim was still associated with rates of FN, grade 4 FN, severe neutropenia, and treatment delays due to FN in pediatric cancer patients.

HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages.

The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response. Lipopolysaccharide (LPS) and soluble signals indicating distal or far-away danger trigger HDAC7-dependent glycolysis and proinflammatory IL-1ß production. In contrast, HDAC7 initiates the pentose phosphate pathway (PPP) for NADPH and reactive oxygen species (ROS) production in response to the more proximal threat of nearby bacteria, as exemplified by studies on uropathogenic Escherichia coli (UPEC). HDAC7-mediated PPP engagement via 6-phosphogluconate dehydrogenase (6PGD) generates NADPH for antimicrobial ROS production, as well as D-ribulose-5-phosphate (RL5P) that both synergizes with ROS for UPEC killing and suppresses selective inflammatory responses. This dual functionality of the HDAC7-6PGD-RL5P axis prioritizes responses to proximal threats. Our findings thus reveal that the PPP metabolite RL5P has both antimicrobial and immunomodulatory activities and that engagement of enzymes in catabolic versus anabolic metabolic pathways triages responses to different types of danger for generation of inflammatory versus antimicrobial responses, respectively.

Histone deacetylase 7: a signalling hub controlling development, inflammation, metabolism and disease.

Histone deacetylases (HDACs) catalyse removal of acetyl groups from lysine residues on both histone and non-histone proteins to control numerous cellular processes. Of the 11 zinc-dependent classical HDACs, HDAC4, 5, 7 and 9 are class IIa HDAC enzymes that regulate cellular and developmental processes through both enzymatic and non-enzymatic mechanisms. Over the last two decades, HDAC7 has been associated with key roles in numerous physiological and pathological processes. Molecular, cellular, in vivo and disease association studies have revealed that HDAC7 acts through multiple mechanisms to control biological processes in immune cells, osteoclasts, muscle, the endothelium and epithelium. This HDAC protein regulates gene expression, cell proliferation, cell differentiation and cell survival and consequently controls development, angiogenesis, immune functions, inflammation and metabolism. This review focuses on the cell biology of HDAC7, including the regulation of its cellular localisation and molecular mechanisms of action, as well as its associative and causal links with cancer and inflammatory, metabolic and fibrotic diseases. We also review the development status of small molecule inhibitors targeting HDAC7 and their potential for intervention in different disease contexts.