Formation of chronic morphine withdrawal memories requires C1QL3-mediated regulation of PSD95 in the mouse basolateral amygdala.

Chronic morphine withdrawal memory formation is a complex process influenced by various molecular mechanisms. In this study, we aimed to investigate the contributions of the basolateral amygdala (BLA) and complement component 1, q subcomponent-like 3 (C1QL3), a secreted and presynaptically targeted protein, to the formation of chronic morphine (repeat dosing of morphine) withdrawal memory using conditioned place aversion (CPA) and chemogenetic methods. We conducted experiments involving the inhibition of the BLA during naloxone-induced withdrawal to assess its impact on CPA scores, providing insights into the significance of the BLA in the chronic morphine memory formation process. We also examined changes in C1ql3/C1QL3 expression within the BLA following conditioning. Immunofluorescence analysis revealed the colocalization of C1QL3 and the G protein-coupled receptor, brain-specific angiogenesis inhibitor 3 (BAI3) in the BLA, supporting their involvement in synaptic development. Moreover, we downregulated C1QL3 expression in the BLA to investigate its role in chronic morphine withdrawal memory formation. Our findings revealed that BLA inhibition during naloxone-induced withdrawal led to a significant reduction in CPA scores, confirming the critical role of the BLA in this memory process. Additionally, the upregulation of C1ql3 expression within the BLA postconditioning suggested its participation in withdrawal memory formation. The colocalization of C1QL3 and BAI3 in the BLA further supported their involvement in synaptic development. Furthermore, downregulation of C1QL3 in the BLA effectively hindered chronic morphine withdrawal memory formation, emphasizing its pivotal role in this process. Notably, we identified postsynaptic density protein 95 (PSD95) as a potential downstream effector of C1QL3 during chronic morphine withdrawal memory formation. Blocking PSD95 led to a significant reduction in the CPA score, and it appeared that C1QL3 modulated the ubiquitination-mediated degradation of PSD95, resulting in decreased PSD95 protein levels. This study underscores the importance of the BLA, C1QL3 and PSD95 in chronic morphine withdrawal memory formation. It provides valuable insights into the underlying molecular mechanisms, emphasizing their significance in this intricate process.

Validity and reliability test of the Indonesian version of the PedHALshort questionnaire.

INTRODUCTION: The PedHAL questionnaire is employed in measuring the activities of haemophilia children. The PedHALshort was developed in 2022 to determine the most relevant item for the assessment. Haemo-QoL questionnaire assesses the quality of life of haemophilia children. AIM: Determine the validity and reliability of the PedHALshort Indonesia language version compared to the Haemo-QoL in the Indonesian population. METHODS: A cross-sectional study was conducted in Jakarta, Indonesia. The subjects were children (4-16 years old) with moderate or severe haemophilia A or B with repeated joint bleeding. The daily activity was assessed using the PedHALshorts and Haemo-QoL. The validity and reliability were tested. The validity was determined with Pearson correlation test, construct validity was assessed using convergent and discriminant validity. The Spearman correlation was used to determine which domains of Haemo-QoL correlated with PedHALshort. The reliability was analyzed using test-retest reliability. Cronbach's α was used to determined internal consistency. RESULTS: Fifty children were included in the study (78% haemophilia A, 70% severe group). All domains were valid (r > .284). The convergent validity test showed PedHALshort had a moderate negative correlation with physical health and sports school domain of Haemo-QoL (r = -.479, p < .001). The discriminant validity test showed the PedHALshort demonstrated a moderate negative correlation with physical health (r = -.585), view (r = -.590), sport school domain (r = -.430) in severe haemophilia subjects. The internal consistency of the PedHALshort questionnaire was high (Cronbach's α of .85 (.74-.92)). CONCLUSION: The PedHALshort is valid and reliable, hence, it can be used to measure the functional physical activity of children with haemophilia.

Methane Quantification Performance of the Quantitative Optical Gas Imaging (QOGI) System Using Single-Blind Controlled Release Assessment.

Quantitative optical gas imaging (QOGI) system can rapidly quantify leaks detected by optical gas imaging (OGI) cameras across the oil and gas supply chain. A comprehensive evaluation of the QOGI system's quantification capability is needed for the successful adoption of the technology. This study conducted single-blind experiments to examine the quantification performance of the FLIR QL320 QOGI system under near-field conditions at a pseudo-realistic, outdoor, controlled testing facility that mimics upstream and midstream natural gas operations. The study completed 357 individual measurements across 26 controlled releases and 71 camera positions for release rates between 0.1 kg Ch4/h and 2.9 kg Ch4/h of compressed natural gas (which accounts for more than 90% of typical component-level leaks in several production facilities). The majority (75%) of measurements were within a quantification factor of 3 (quantification error of -67% to 200%) with individual errors between -90% and 831%, which reduced to -79% to +297% when the mean of estimates of the same controlled release from multiple camera positions was considered. Performance improved with increasing release rate, using clear sky as plume background, and at wind speeds ≤1 mph relative to other measurement conditions.

Aesthetic Outcomes and Patient Satisfaction in Laparoscopic vs. Open Incisional Hernia Repair: Have We Asked the Patients?

Background: Incisional hernias are predominantly treated through open or laparoscopic surgery, with each method influencing recovery and patient-reported outcomes. This underscores the need for reliable assessment tools such as the EuraHS-QoL questionnaire to evaluate quality of life after surgery. Methods: This prospective single-center study was aimed at evaluating aestethic outcomes and patient satisfaction following laparoscopic versus open hernia repair. It involved 222 patients categorized by type of approach. The EuraHS-QoL questionnaire was used preoperatively and at 1- and 3-months post-surgery, with data analysis performed using Origin Pro 2018 and SPSS software version 28.0. Results: Among the participants, 152 were females and 70 males, with 78% undergoing open surgery and 22% laparoscopic. Findings revealed superior patient outcomes with laparoscopic repair in terms of pain management, daily activities, and aesthetic satisfaction. Patients reported significantly lower pain levels and fewer restrictions in daily activities post-laparoscopic surgery. While initial postoperative cosmetic results favored laparoscopic methods, the perceived differences in abdominal shape diminished over time. Conclusions: Laparoscopic repair significantly improves quality of life compared to open surgery, as shown by EuraHS-QoL scores. These results support the use of laparoscopic techniques in appropriate cases due to their benefits in pain reduction and faster functional recovery.

Comparison of analgesic efficacy of ultrasound-guided quadratus lumborum block versus erector spinae plane block in children undergoing elective open pyeloplasty - A randomized, double-blinded, controlled study.

Background and Aims: Comparison of analgesic efficacy of ultrasound-guided transmuscular quadratus lumborum block (QL-3) and erector spinae block (ESP) in children undergoing open pyeloplasty was done in this study. Material and Methods: This was a randomized, double-blinded, controlled study conducted in a tertiary care center, operating rooms, post-anesthesia care unit (PACU), and paediatric surgical ward. Sixty children of age 1-6 years, with American Society of Anesthesiologists (ASA) status I or II, undergoing elective open pyeloplasty were included in the study. Patients were randomized into two groups: group I (QL block-3) and group II (ESP). Both blocks were performed under USG guidance using 0.5 ml/kg of 0.25% ropivacaine after induction of general anesthesia. Postoperative Modified Objective Pain Score (MOPS), perioperative hemodynamic parameters, perioperative time for first rescue analgesia, total rescue analgesia, and incidence of complications were recorded. Statistical tests were applied as follows: (i) quantitative variables were compared using independent t-test/Mann-Whitney test (when the data sets were not normally distributed) between the two groups, and repeated measure analysis of variance (ANOVA)/Friedman test was used for comparison between different time intervals within the same group and (ii) qualitative variables were correlated using the Chi-square test/Fisher's exact test. A P value of <0.05 was considered statistically significant. Results: Pain was assessed using MOPS in the postoperative period at 0, 30 min, 1, 2, 4, 6, 12, and 24 h. Overall, the pain scores were low and showed a decreasing trend toward baseline as time progressed. Group I showed lower score, but was statistically significant only at the sixth hour. Highest mean score was 2.4 ± 2.01 in group I and 2.67 ± 2.32 in group II. Perioperative hemodynamic parameters were comparable. Total rescue analgesia during the perioperative period was not statistically significant (intraoperative P = 0.075 and postoperative P = 0.928). Also, 63.33% patients in group I and 63% patients in group II required rescue analgesia in the postoperative period and were comparable. Mean ± standard deviation (SD) for first rescue analgesia time was 6.32 ± 12.57 in group I and 16.67 ± 31.25 in group II, but not significant. The distribution in group II was skewed, hence the larger value for group II, but when compared to group I, this was statistically not significant. Conclusion: Both ultrasound-guided ESP block and QL block using 0.25% ropivacaine 0.5 ml/kg provided adequate analgesia during the first 24 h post-surgery in children undergoing open pyeloplasty. The fentanyl requirement during the first 24-h postoperative period was also decreased.

Pleiotropy of C1QL proteins across physiological systems and their emerging role in synapse homeostasis.

The C1q/TNF superfamily of proteins engages in a pleiotropy of physiological functions associated with various diseases. C1QL proteins demonstrate important protective and regulatory roles in the endocrine, immune, cardiovascular, and nervous systems in both human and rodent studies. Studies in the central nervous system (CNS), adipose, and muscle tissue reveal several C1QL protein and receptor pathways altering multiple cellular responses, including cell fusion, morphology, and adhesion. This review examines C1QL proteins across these systems, summarizing functional and disease associations and highlighting cellular responses based on in vitro and in vivo data, receptor interaction partners, and C1QL-associated protein signaling pathways. We highlight the functions of C1QL proteins in organizing CNS synapses, regulating synapse homeostasis, maintaining excitatory synapses, and mediating signaling and trans-synaptic connections. Yet, while these associations are known, present studies provide insufficient insight into the underlying molecular mechanism of their pleiotropy, including specific protein interactions and functional pathways. Thus, we suggest several areas for more in-depth and interdisciplinary hypothesis testing.

CTRP11 contributes modestly to systemic metabolism and energy balance.

C1q/TNF-related proteins (CTRP1-15) constitute a conserved group of secreted proteins of the C1q family with diverse functions. In vitro studies have shown that CTRP11/C1QL4 can inhibit adipogenesis, antagonize myoblast fusion, and promote testosterone synthesis and secretion. Whether CTRP11 is required for these processes in vivo remains unknown. Here, we show that knockout (KO) mice lacking CTRP11 have normal skeletal muscle mass and function, and testosterone level, suggesting that CTRP11 is dispensable for skeletal muscle development and testosterone production. We focused our analysis on whether this nutrient-responsive secreted protein plays a role in controlling sugar and fat metabolism. At baseline when mice are fed a standard chow, CTRP11 deficiency affects metabolic parameters in a sexually dimorphic manner. Only Ctrp11-KO female mice have significantly higher fasting serum ketones and reduced physical activity. In the refeeding phase following food withdrawal, Ctrp11-KO female mice have reduced food intake and increased metabolic rate and energy expenditure, highlighting CTRP11's role in fasting-refeeding response. When challenged with a high-fat diet to induce obesity and metabolic dysfunction, CTRP11 deficiency modestly exacerbates obesity-induced glucose intolerance, with more pronounced effects seen in Ctrp11-KO male mice. Switching to a low-fat diet after obesity induction results in greater fat loss in wild type relative to KO male mice, suggesting impaired response to obesity reversal and reduced metabolic flexibility in the absence of CTRP11. Collectively, our data provide genetic evidence for novel sex-dependent metabolic regulation by CTRP11, but note the overall modest contribution of CTRP11 to systemic energy homeostasis.

Comparison of recombinant human FSH biosimilar QL1012 with Gonal-f® for ovarian stimulation: a phase-three trial.

RESEARCH QUESTION: Are QL1012 and Gonal-f® equivalent in women undergoing ovarian stimulation for assisted reproductive technology (ART)? DESIGN: This multicentre, randomized, assessor-blinded, phase-three trial was conducted at 13 centres in China. Eligible patients were infertile women; age 20-39 years; body mass index 18-30 kg/m2; regular menstrual cycles; and indication for ART. After successful pituitary downregulation, patients were randomly assigned (1:1) to receive QL1012 or Gonal-f®, stratified by age (initial dose of 75-150 IU for women younger than 30 years, 150-225 IU for women aged 30-34 years and 225-300 IU for women aged ≥35 years, subcutaneously, once daily). The primary end point was the number of oocytes retrieved. RESULTS: Between October 2018, and June 2019, 341 patients were included in the per-protocol set. The mean numbers of oocytes retrieved were 14.7 ± 7.0 in the QL1012 group (n = 169) and 13.4 ± 6.1 in the Gonal-f® group (n = 172). Adjusted by analysis of covariance model, the least-squares mean difference was 1.3 oocytes (95% CI -0.1 to 2.7; P = 0.0650), within the pre-defined equivalence margins of ±3.0. Similar results were observed in the full analysis set. Additionally, no statistical differences were found in secondary end points except oestradiol concentration (median 3948.0 pg/ml versus 3545.3 pg/ml; P = 0.0015). Ovarian hyperstimulation syndrome (12.4% versus 13.1 %) and other adverse events were similar between the two groups. CONCLUSIONS: Therapeutic equivalence and similar safety profiles were demonstrated between QL1012 and Gonal-f® in women undergoing ovarian stimulation for ART.

Translation and validation of the speech, spatial, and qualities of hearing scale (SSQ) and the hearing environments and reflection on quality of life (HEAR-QL) questionnaire for children and adolescents in Dutch.

OBJECTIVE: To date, no hearing-specific self-report tool is available in Dutch to give insight into how deficits in auditory skills are experienced by a child in daily life or to examine the impact of hearing loss on children's quality of life. Therefore, we aimed to translate and validate the Speech, Spatial, and Qualities of Hearing Scale (SSQ) and the Hearing Environments and Reflection on Quality of Life (HEAR-QL) Questionnaire for children and adolescents into Dutch. DESIGN: Translation of the questionnaires into Dutch was conducted by means of the forward-backward procedure. Participants were invited to complete the questionnaires digitally. We examined discriminant validity, internal consistency, and test-retest reliability. STUDY SAMPLE: A total of 121 subjects between 7 and 18 years old were included, of which 54 normal hearing and 67 bilaterally hearing-impaired subjects. Hearing-impaired subjects were fitted with hearing aids, bone conductive devices and/or cochlear implants. RESULTS: All questionnaires were shown to significantly discriminate between the normal hearing and the hearing-impaired group. Satisfying internal consistency and good test-retest reliability were found. CONCLUSIONS: The Dutch SSQ and HEAR-QL questionnaires for children and adolescents appear to be valid and reliable self-report tools for management and follow-up of those with hearing loss.

Determining photosynthetic control, a probe for the balance between electron transport and Calvin-Benson cycle activity, with the DUAL-KLAS-NIR.

Photosynthetic Control is defined as the control imposed on photosynthetic electron transport by the lumen-pH-sensitive re-oxidation of plastoquinol (PQH2) by cytochrome b6f. Photosynthetic Control leads at higher actinic light intensities to an electron transport chain with a (relatively) reduced photosystem (PS) II and PQ pool and a (relatively) oxidized PS I. Making Light Curves of more than 33 plant species with the recently introduced DUAL-KLAS-NIR (Chl a fluorescence + the redox states of plastocyanin (PC), P700, and ferredoxin (Fd)) the light intensity-dependent induction of Photosynthetic Control was probed and characterized. It was observed that PC became completely oxidized at light intensities ≤ 400 µmol photons m-2 s-1 (at lower light intensities in shade than in sun leaves). The relationship between qP and P700(red) was used to determine the extent of Photosynthetic Control. Instead of measuring the whole Light Curve, it was shown that a single moderate light intensity can be used to characterize the status of a leaf relative to that of other leaves. It was further found that in some shade-acclimated leaves Fd becomes again more oxidized at high light intensities indicating that electron transfer from the PQ pool to P700 cannot keep up with the outflow of electrons on the acceptor side of PS I. It was observed as well that for NPQ-induction a lower light intensity (less acidified lumen) was needed than for the induction of Photosynthetic Control. The measurements were also used to make a comparison between the parameters qP and qL, a comparison suggesting that qP was the more relevant parameter.

Equivalent efficacy assessment of QL1101 and bevacizumab in nonsquamous non-small cell lung cancer patients: A two-year follow-up data update.

Objective: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies are an effective means of treating non-small cell lung cancer (NSCLC). Here, we aim to update the equivalent efficacy assessment between QL1101 and bevacizumab based on two-year follow-up data. Methods: In total, 535 eligible NSCLC patients were enrolled in this randomized controlled trial. Patients were randomly assigned 1:1 to the QL1101 group and the bevacizumab group. The full end time of this study was defined as 24 months after the last enrolled patient was randomized. The primary endpoint was the objective response rate (ORR); equivalence was confirmed if the two-sided 90% confidence interval (90% CI) of the relative risk was within the range of 0.75-1.33. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: The two-year updated data showed similar ORR (QL1101 vs. bevacizumab: 53.1% vs. 54.3%; relative risk=0.977; 90% CI: 0.838-1.144), PFS (235 d vs. 254 d, log-rank P=0.311), and OS (577 d vs. 641 d, log-rank P=0.099) results between the QL1101 group and the bevacizumab group. The mean shrinkage ratio of targeted lesions was also similar between the QL1101 group and the bevacizumab group (22.5% vs. 23.5%). For patients who received QL1101 maintenance therapy, similar results were shown between the QL1101 group (n=157) and the bevacizumab group (n=148) (PFS: 253 d vs. 272 d, log-rank P=0.387; OS: 673 d vs. 790 d, log-rank P=0.101; mean tumor shrinkage rate: 26.6% vs. 27.5%). Conclusions: This study reported that QL1101 had similar efficacy in treating nonsquamous NSCLC in terms of ORR, PFS and OS based on two-year updated data, providing a basis for the clinical application of QL1101.

Azithromycin-Resistant Salmonella enterica Serovar Typhi AcrB-R717Q/L, Singapore.

Global travel has led to intermittent importation of multidrug-resistant Salmonella enterica serovar Typhi into industrialized countries. We detected azithromycin-resistant Salmonella Typhi in Singapore, of which 2 isolates were likely locally acquired. Ongoing vigilance and surveillance to minimize the public health risk for this serious pathogen is needed.

The contribution of neurocognitive situation, physical capacity and daily life activities to quality of life in childhood acute lymphoblastic leukemia survivors

Background/aim: There are no extensive studies on the QL in children who completed acute lymphoblastic leukemia (ALL) treatment and currently living without any disease in Turkey. Our study aimed to analyze both the QL and the effects of physical, neurocognitive capacities on QL in childhood ALL survivors aged 7­12 years at the time of recruitment. Materials and methods: PedsQL cancer module 3.0 child and proxy report, for ages 5­7 and 8­12 years, WeeFIM scale, BOTMP Short Form, RPM, reading, writing, and mathematics assessment tools, sociodemographic information form were carried out to the children and their family. Results: There was no effect of the months since the completion of therapy on pain, anxiety, cognitive problems, perceived physical appearance, and the total QL scores of children and proxy reports (p > 0.05). Children's physical capacities were significantly worse than healthy controls and have not reached the level of healthy children even after a long time since completion of ALL therapy. There was a significant association between physical capacity and daily independent living status (p < 0.001). Reading, writing, and mathematical skills were significantly associated with the mean time off-treatment (p < 0.001), and the total score of RPM and PedsQL of those with mathematical difficulties were significantly lower than those without any difficulty (p < 0.05). Conclusion: The months after the treatment (off-treatment time) have not affected total and subunit QL scores. As motor skills difficulties will lead to low academic achievement, early recognition direct the parents for immediate intervention. lead to low academic achievement, early recognition could direct the parents for immediate intervention. Planning psychosocial support programs for physical activity and age-appropriate development of patients from the initiation of treatment will increase the QL in childhood ALL with a survival rate of 80% or more.

Effects of quadratus lumborum block regional anesthesia on postoperative pain after colorectal resection: a randomized controlled trial.

INTRODUCTION: Postoperative pain following colorectal surgery is associated with a significant use of opioids. Recently, regional anesthesia, such as the posterior quadratus lumborum block (QL2), has been proposed to improve pain relief and reduce opioid use. However, the benefit of the QL2 on postoperative pain control remains controversial. METHODS: We conducted a randomized controlled trial of patients undergoing colorectal surgery at the CHU de Québec-Université Laval. Patients were randomized to regional QL2 anesthesia with 150 mg of ropivacaine combined with standard analgesia or to QL2 with a sham intervention and standard analgesia. Our primary outcome was postoperative opioid administration at 24 h. Secondary outcomes included opioid administration in the post-anesthesia care unit (PACU), at 48 h and at hospital discharge, postoperative pain scores, delay in resumption of intestinal transit, nausea and vomiting, and hospital length of stay. RESULTS: A total of 62 patients were enrolled from November 2017 to February 2018. QL2 regional anesthesia compared with a sham intervention was not associated with a reduction in postoperative morphine dose equivalent (100.2 mg, 95% CI 68.9-131.5 versus 88.7 mg, 95% CI 59.3-118.0, p = 0.81, respectively). Compared to QL2 regional anesthesia, postoperative pain scores in the control group were lower although statistical significance was not consistent for all postoperative time points. Other secondary outcomes were comparable between both groups. CONCLUSION: We did not observe a reduction in postoperative opioid administration at 24 h with a posterior quadratus lumborum block regional anesthesia in patients undergoing elective colorectal surgery.

Quadratus lumborum block versus transversus abdominis plane block for postoperative analgesia in patients undergoing abdominal surgeries: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Abdominal surgery is common and is associated with severe postoperative pain. The transverse abdominal plane (TAP) block is considered an effective means for pain control in such cases. The quadratus lumborum (QL) block is another option for the management of postoperative pain. The aim of this study was to conduct a meta-analysis and thereby evaluate the efficacy and safety of QL blocks and TAP blocks for pain management after abdominal surgery. METHODS: We comprehensively searched PubMed, EMBASE, EBSCO, the Cochrane Library, Web of Science and CNKI for randomized controlled trials (RCTs) that compared QL blocks and TAP blocks for pain management in patients undergoing abdominal surgery. All of the data were screened and evaluated by two researchers. RevMan5.3 was adopted for the meta-analysis. RESULTS: A total of 8 RCTs involving 564 patients were included. The meta-analysis showed statistically significant differences between the two groups with respect to postoperative pain scores at 2 h (standardized mean difference [Std.MD] = - 1.76; 95% confidence interval [CI] = - 2.63 to - 0.89; p < .001), 4 h (Std.MD = -0.77; 95% CI = -1.36 to - 0.18; p = .01),6 h (Std.MD = -1.24; 95% CI = -2.31 to - 0.17; p = .02),12 h (Std.MD = -0.70; 95% CI = -1.27 to - 0.13; p = .02) and 24 h (Std.MD = -0.65; 95% CI = -1.29 to - 0.02; p = .04); postoperative morphine consumption at 24 h (Std.MD = -1.39; 95% CI = -1.83 to - 0.95; p < .001); and duration of postoperative analgesia (Std.MD = 2.30; 95% CI = 1.85 to 2.75; p < .001). There was no statistically significant difference between the two groups with regard to the incidence of postoperative nausea and vomiting (PONV) (RR = 0.55;95% CI = 0.27 to 1.14;p = 0.11). CONCLUSION: The QL block provides better pain management with less opioid consumption than the TAP block after abdominal surgery. In addition, there are no differences between the TAP block and QL block with respect to PONV.

CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension.

BACKGROUND: The prognostic variability of thyroid carcinomas has led to the search for accurate biomarkers at the molecular level. Follicular thyroid carcinoma (FTC) is a typical example of differentiated thyroid carcinomas (DTC) in which challenges are faced in the differential diagnosis. METHODS: We used high-throughput paired-end RNA sequencing technology to study four cases of FTC with different degree of capsular invasion: two minimally invasive (mFTC) and two widely invasive FTC (wFTC). We searched by genes differentially expressed between mFTC and wFTC, in an attempt to find biomarkers of thyroid cancer diagnosis and/or progression. Selected biomarkers were validated by real-time quantitative PCR in 137 frozen thyroid samples and in an independent dataset (TCGA), evaluating the diagnostic and the prognostic performance of the candidate biomarkers. RESULTS: We identified 17 genes significantly differentially expressed between mFTC and wFTC. C1QL1, LCN2, CRABP1 and CILP were differentially expressed in DTC in comparison with normal thyroid tissues. LCN2 and CRABP1 were also differentially expressed in DTC when compared with follicular thyroid adenoma. Additionally, overexpression of LCN2 and C1QL1 were found to be independent predictors of extrathyroidal extension in DTC. CONCLUSIONS: We conclude that the underexpression of CRABP1 and the overexpression of LCN2 may be useful diagnostic biomarkers in thyroid tumours with questionable malignity, and the overexpression of LCN2 and C1QL1 may be useful for prognostic purposes.

C1ql1/Ctrp14 and C1ql4/Ctrp11 promote angiogenesis of endothelial cells through activation of ERK1/2 signal pathway.

C1ql-like (C1QL)-1 and -4 proteins are encoded by homologous genes that are highly expressed in brain and adipose tissues. However, functional properties of C1QL proteins outside of the brain and adipocytes remain unknown. Here, we report that the globular domain of C1ql1/Ctrp14 and C1ql4/Ctrp11 proteins directly stimulate the angiogenesis of endothelial cells. In this study, soluble C1ql1/CTRP14 and C1ql4/Ctrp11 proteins, produced in prokaryote expression system, are co-cultured with human umbilical vein endothelium cells (HUVECs), which phenotype is identified with von Willebrand factor antibody. C1ql1/Ctrp14 and C1ql4/Ctrp11 promote the migration and capillary tube formation of HUVECs in a dose-dependent manner. During this process, phosphorylation of c-Raf, MEK1/2, ERK1/2, and p90RSK are activated by C1ql1/Ctrp14 and C1ql4/Ctrp11. MEK1/2 inhibitor, U0126, blocks C1ql1/Ctrp14-, and C1ql4/Ctrp11-induced capillary tube formation and cell migration. Moreover, the immunoreactivity of the receptor of C1QL1-C1QL4, brain-specific angiogenesis inhibitor 3 (BAI3), is detected in HUVECs, suggesting that BAI3 may mediate C1QL1/CTRP14- and C1QL4/CTRP11-induced angiogenesis. Meanwhile, C1ql1/Ctrp14 and C1ql4/Ctrp11 exposure also causes a stimulatory response of angiogenesis in chick yolk sac membrane. These data demonstrate that C1ql1/Ctrp14 and C1ql4/Ctrp11 stimulate the new blood vessel growth by activation of ERK1/2 signal pathway. The proangiogenic activity of C1ql1/Ctrp14 and C1ql4/Ctrp11 provides novel insights into the new opportunities for therapeutic intervention by targeting C1QLs in tumorigenesis, tissue regeneration, and recovery of ischemic heart disease.

Efficacy and Safety of Biosimilar QL1207 vs. the Reference Aflibercept for Patients with Neovascular Age-Related Macular Degeneration: A Randomized Phase 3 Trial.

INTRODUCTION: This trial aimed to compare the efficacy and safety between biosimilar QL1207 and the reference aflibercept for the treatment of neovascular age-related macular degeneration (nAMD). METHODS: This randomized, double-blind, phase 3 trial was conducted at 35 centers in China. Patients aged ≥ 50 years old with untreated subfoveal choroidal neovascularization secondary to nAMD and best-corrected visual acuity (BCVA) letter score of 73-34 were eligible. Patients were randomly assigned to receive intravitreous injections of QL1207 or aflibercept 2 mg (0.05 ml) in the study eye every 4 weeks for the first 3 months, followed by 2 mg every 8 weeks until week 48, stratified by baseline BCVA ≥ or < 45 letters. The primary endpoint was BCVA change from baseline at week 12. The equivalence margin was ± 5 letters. The safety, immunogenicity, pharmacokinetics (PK), and plasma vascular endothelial growth factor (VEGF) concentration were also evaluated. RESULTS: A total of 366 patients were enrolled (QL1207 group, n = 185; aflibercept group, n = 181) from Aug 2019 to Jan 2022 with comparable baseline characteristics. The least-squares mean difference in BCVA changes was - 1.1 letters (95% confidence interval - 3.0 to 0.7; P = 0.2275) between the two groups, within the equivalence margin. The incidences of treatment-emergent adverse events (TEAE; QL1207: 71.4% [132/185] vs. aflibercept: 71.8% [130/181]) and serious TEAE (QL1207: 14.1% [26] vs. aflibercept: 12.7% [23]) appeared comparable between treatment groups, and no new safety signal was found. Anti-drug antibody, PK profiles, and VEGF concentration were similar between the two groups. CONCLUSIONS: QL1207 has equivalent efficacy to aflibercept for nAMD with similar safety profiles. It could be used as an alternative anti-VEGF agent for clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05345236 (retrospectively registered on April 25, 2022); National Medical Products Administration of China: CTR20190937 (May 20, 2019).

C1ql3 knockout affects microglia activation, neuronal integrity, and spontaneous behavior in Wistar rats.

BACKGROUND: C1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons. However, its function is still not clear. We established C1ql3-deficient rats to investigate the role of C1QL3 in the brain. METHODS: C1ql3 knockout (KO) rats were generated using CRISPR/Cas9. C1ql3 KO was determined by polymerase chain reaction (PCR), DNA sequencing, and western blotting. Microglia morphology and cytokine expression with or without lipopolysaccharide (LPS) stimulus were analyzed using immunohistochemistry and real-time PCR. The brain structure changes in KO rats were examined using magnetic resonance imaging. Neuronal architecture alteration was analyzed by performing Golgi staining. Behavior was evaluated using the open field test, Morris water maze test, and Y maze test. RESULTS: C1ql3 KO significantly increased the number of ramified microglia and decreased the number of hypertrophic microglia, whereas C1ql3 KO did not influence the expression of pro-inflammatory factors and anti-inflammatory factors except IL-10. C1ql3 KO brains had more amoeboid microglia types and higher Arg-1 expression compared with the WT rats after LPS stimulation. The brain weights and HPC sizes of C1ql3 KO rats did not differ from WT rats. C1ql3 KO damaged neuronal integrity including neuron dendritic arbors and spine density. C1ql3 KO rats demonstrated an increase in spontaneous activity and an impairment in short working memory. CONCLUSIONS: C1ql3 KO not only interrupts the neuronal integrity but also affects the microglial activation, resulting in hyperactive behavior and impaired short memory in rats, which highlights the role of C1QL3 in the regulation of structure and function of both neuronal and microglial cells.

QL1604 combined with bevacizumab as an innovative first-line treatment for HCC patient with extensive metastasis who showed remarkable effect: a case report.

Hepatocellular carcinoma (HCC) is a common and highly malignant tumor with poor outcomes, especially when it metastasizes. In this report, we present the case of a 64-year-old male patient diagnosed with recurrence and multiple metastases of HCC 7 years after surgery. As the tumor invaded the spinal canal and pressed on the spinal cord, the patient experienced paralysis in the lower limbs. After undergoing surgical resection for spinal decompression, the patient chose an innovative regimen: QL1604 200 mg every 3 weeks plus bevacizumab 675 mg every 3 weeks as first-line treatment. From July 2022 to February 2024, the patient has regularly received the treatment. During the treatment, the paralysis symptoms of the patient gradually improved, and the motor function of the lower limbs completely returned to normal. When re-evaluated his spinal cord injury, the Frankel grade of the patient was downgraded from C to E. The tumor shrank to reach a state of PR and lasted for one and a half years. QL1604 combined with bevacizumab demonstrated excellent efficacy and minimal side effects in this patient. This new combined therapy holds potential as a first-line treatment strategy.