HPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling and as such is an attractive target for cancer immunotherapy. Although the role of the HPK1 kinase domain (KD) has been extensively characterized, the function of its citron homology domain (CHD) remains elusive. Through a combination of structural, biochemical, and mechanistic studies, we characterize the structure-function of CHD in relationship to KD. Crystallography and hydrogen-deuterium exchange mass spectrometry reveal that CHD adopts a seven-bladed ß-propellor fold that binds to KD. Mutagenesis associated with binding and functional studies show a direct correlation between domain-domain interaction and negative regulation of kinase activity. We further demonstrate that the CHD provides stability to HPK1 protein in cells as well as contributes to the docking of its substrate SLP76. Altogether, this study highlights the importance of the CHD in the direct and indirect regulation of HPK1 function.

A case report of multicentric carpotarsal osteolysis syndrome: Depiction of a debilitating disease course.

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by progressive osteolysis involving the carpal and tarsal bones, and often associated with nephropathy. It is caused by heterozygous mutation in the MAF bZIP transcription factor B (MAFB) gene. Heterogeneous clinical manifestation and wide spectrum of disease severity have been observed in patients with MCTO. Here, we report a case of a male patient who presented with kidney failure in childhood with progressive disabling skeletal deformity. He was diagnosed with MCTO at 31-years-old, where a de novo pathogenic heterozygous variant in NM_005461.5:c.212C>A: p.(Pro71His) of the MAFB gene was identified. While there has been little data on the long-term prognosis and life expectancy of this disease, this case report sheds light on the debilitating disease course with multiple significant morbidities of a patient with MCTO throughout his lifetime of 33 years.

Safety and feasibility of transbronchial microwave ablation for subpleural lung nodules.

BACKGROUND: Transbronchial microwave ablation in treating lung nodules is gaining popularity. However, microwave ablation in subpleural lung nodules raised concerns about pleural-based complications due to the proximity between the pleura and the ablation zone. METHODS: Patients who underwent transbronchial microwave ablation between March 2019 and November 2022 were included in this analysis. The lung nodules were categorized into the subpleural group-less than 5 mm distance to the nearest pleural surface; the deep nodule group-larger or equal to 5 mm distance to the nearest pleural surface. A review of the safety profile of subpleural lung nodule ablation was conducted. RESULTS: Eighty-two lung nodules (n = 82) from 77 patients were treated. The mean nodule size was 14.2 ± 5.50 mm. The technical success rate was 100%. The mean procedural time was 133 min. No statistically significant differences were detected in the complication rate and the length of stay between the subpleural and deep nodule groups. Complications occured in 21 nodules (25.6%). No minor pneumothorax was reported. Total five cases of pneumothorax required drainage were observed (6.06% in subpleural nodules [n = 2] vs. 6.12% in deep nodules [n = 3], p = 0.991). Total seven cases of pleuritic chest pain were observed (12.1% in subpleural nodules [n = 4] vs. 6.12% in deep nodules [n = 3], p = 0.340). CONCLUSIONS: This single-center retrospective analysis found no significant difference in the safety outcomes between subpleural and nonsubpleural lung nodule ablation. The overall rate of complications was low in the cohort. This demonstrated that transbronchial microwave was feasible and safe for most lung nodules.

Computerized cognitive training for memory functions in mild cognitive impairment or dementia: a systematic review and meta-analysis.

Dementia is a common medical condition in the ageing population, and cognitive intervention is a non-pharmacologic strategy to improve cognitive functions. This meta-analysis evaluated the benefits of computerized cognitive training (CCT) on memory functions in individuals with MCI or dementia. The study was registered prospectively with PROSPERO under CRD42022363715 and received no funding. The search was conducted on MEDLINE, Embase, and PsycINFO on Sept 19, 2022, and Google Scholar on May 9, 2023, to identify randomized controlled trials that examined the effects of CCT on memory outcomes in individuals with MCI or dementia. Mean differences and standard deviations of neuropsychological assessment scores were extracted to derive standardized mean differences. Our search identified 10,678 studies, of which 35 studies were included. Among 1489 participants with MCI, CCT showed improvements in verbal memory (SMD (95%CI) = 0.55 (0.35-0.74)), visual memory (0.36 (0.12-0.60)), and working memory (0.37 (0.10-0.64)). Supervised CCT showed improvements in verbal memory (0.72 (0.45-0.98)), visual memory (0.51 (0.22-0.79)), and working memory (0.33 (0.01-0.66)). Unsupervised CCT showed improvement in verbal memory (0.21 (0.04-0.38)) only. Among 371 participants with dementia, CCT showed improvement in verbal memory (0.64 (0.02-1.27)) only. Inconsistency due to heterogeneity (as indicated by I2 values) is observed, which reduces our confidence in MCI outcomes to a moderate level and dementia outcomes to a low level. The results suggest that CCT is efficacious on various memory domains in individuals with MCI. Although the supervised approach showed greater effects, the unsupervised approach can improve verbal memory while allowing users to receive CCT at home without engaging as many healthcare resources.

Concomitant electromagnetic navigation transbronchial microwave ablation of multiple lung nodules is safe, time-saving, and cost-effective.

Objectives: Transbronchial microwave ablation of lung nodules using electromagnetic navigation bronchoscopy is an emerging local therapy for lung oligometastases and multifocal lung cancers as part of a lung-preserving strategy. Concomitant ablation of multiple lung nodules in a single operating session may provide a one-stop solution. Methods: Between April 2019 and April 2023, 25 patients had 2 or more lung nodules ablated concomitantly in our hybrid operating room. Nodules were proven or highly suspicious of malignancies or metastases. Feasibility and safety were retrospectively reviewed. Results: A total of 56 nodules in 25 patients received concomitant multi-nodular ablation. The mean age of patients was 60 years, and the reasons for the lung-preserving strategy were multifocal lung cancers (80%) and lung oligometastases (20%). Among those with multifocal disease, 65% had previous major lung resection for lung cancer. Two to 4 nodules were ablated in each session. The mean nodule size was 9.9 mm (range, 5-20 mm), and the mean minimal margin was 5.9 mm. When comparing concomitant nodule ablation with the 103 single-nodule ablations performed in our institute, a mean of 86 minutes of operative time and 131 minutes of anesthetic time were saved. There were no increased complications despite overlapping ablation zones, and the mean hospital stay was 1.23 days. The rate of pneumothorax was 8%, and that of pleural effusion, pain, and fever was 4% respectively. Conclusions: Concomitant transbronchial microwave ablation of multiple lung nodules is feasible, safe, and associated with reduction in overall anesthetic and operative time. It is an important armamentarium in the contemporary lung-preserving strategy for battling multifocal lung cancers or lung oligometastases.

N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model.

Epalrestat, an aldose reductase inhibitor (ARI), has been clinically adopted in treating diabetic neuropathy in China and Japan. Apart from the involvement in diabetic complications, AR has been implicated in inflammation. Here, we seek to investigate the feasibility of clinically approved ARI, epalrestat, for the treatment of rheumatoid arthritis (RA). The mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression. Epalrestat significantly suppressed lipopolysaccharide (LPS) induced TNF-α, IL-1ß, and IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly, epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Interestingly, the combined treatment of epalrestat with N-Acetylcysteine (NAC), an anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory cytokines, and significantly improved the arthritic condition. Taken together, the anti-arthritic effect of epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of epalrestat, suggesting that the combined therapy of epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need epalrestat for the treatment of diabetic complications.

Relative Validity of a Short Food Frequency Questionnaire for Disadvantaged Families in Hong Kong.

Individuals with lower socioeconomic status are more vulnerable in securing good nutritional quality. It was also found that people who had received a lower education level had greater difficulty in completing the conventional dietary assessment such as a food frequency questionnaire (FFQ). Previous studies have demonstrated the validity of a short FFQ in Hong Kong's pregnant women, but its validity among a wider community was still unknown. For the present study, we aimed to validate a short FFQ among disadvantaged communities in Hong Kong. Amongst 103 individuals participating in a dietary intervention programme, their dietary data were collected by FFQs and three-day dietary records. Relative validity was assessed by correlation analysis, cross-tabulation, one-sample t-test, and linear regression. In general, water and total energy intake had significant correlations (0.77 for crude water intake and 0.87 for crude total energy intake) between values reported by FFQ and dietary records, good agreement (both with over 50% of observations falling into the same quartile), and insignificant differences between assessment methods reported by one-sample t-test and linear regression. Meanwhile, several nutrients had good agreement in terms of the values reported by FFQ and dietary records, such as energy from total fat, carbohydrates, total fat, cholesterol, phosphorus, and potassium. The results of this study demonstrated that the short version FFQ could be a convenient assessment tool of multiple dietary behaviors, especially in total energy and water intakes.

Electromagnetic navigation bronchoscopy transbronchial lung nodule ablation with IllumisiteTM platform corrects CT-to-body divergence with tomosynthesis and improves ablation workflow: a case report.

Background: Transbronchial ablation of lung nodules is gaining popularity as part of lung-preserving strategy for patients with multifocal lung cancers or multiple lung oligometastases. Accuracy in placement of ablation catheter is of utmost importance in order to achieve adequate ablation margin. However, older systems are not precise enough for confident placement of ablation catheter and often require multiple cone-beam CT (CBCT) to confirm and readjust its position. The following case is the first microwave lung ablation utilizing the novel IllumisiteTM platform (Medtronic, Minneapolis, MN, USA) in the hybrid operating room (HOR), with enhanced accuracy and workflow. Case Description: A 66-year-old lady had multiple resected adenocarcinomas in bilateral lungs. Upon CT monitoring a right middle lobe (RML) ground glass opacity with solid centre was found to be suspicious due to increasing size and density. Transbronchial electromagnetic navigation bronchoscopy (ENB) microwave ablation of the lesion was performed as part of lung-conserving strategy. After initial navigation, the adjusted nodule position provided by the IllumisiteTM platform after correcting the CT-to-body divergence prompted operators to renavigate and readjust the position of the locatable guide (LG) swiftly to gain accurate access to the nodule, which was confirmed by CBCT. Positional data at the tip of extended working channel (EWC) also allowed precise placement of needle for subsequent ablation. Conclusions: IllumisiteTM is a novel electromagnetic navigational platform that corrects for CT-to-body divergence and ensures continuous locational information by an additional positional coil in the tip of EWC. This precision is especially important for the placement of ablation catheter, as slight deviation would lead to insufficient ablation margin and future recurrence. Workflow is improved by reducing the number of CBCT required for instrument position adjustment.

Fibrodysplasia ossificans progressiva in Hong Kong-A case report series.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare condition. The diagnosis could be challenging due to its rarity and non-specific presenting symptoms. However, early diagnosis and appropriate management help in preserving patients' function and quality of life. Herein, we report the diagnostic journeys and clinical courses of 8 patients with FOP in Hong Kong and illustrate the challenges involved.

Statins to prevent early cardiac dysfunction in cancer patients at increased cardiotoxicity risk receiving anthracyclines.

BACKGROUND AND AIMS: Anthracyclines can cause cancer therapy-related cardiac dysfunction (CTRCD). We aimed to assess whether statins prevent decline in left ventricular ejection fraction (LVEF) in anthracycline-treated patients at increased risk for CTRCD. METHODS: In this multicenter double-blinded, placebo-controlled trial, patients with cancer at increased risk of anthracycline-related CTRCD (per ASCO guidelines) were randomly assigned to atorvastatin 40 mg or placebo once-daily. Cardiovascular magnetic resonance (CMR) imaging was performed before and within 4 weeks after anthracyclines. Blood biomarkers were measured at every cycle. The primary outcome was post-anthracycline LVEF, adjusted for baseline. CTRCD was defined as a fall in LVEF by >10% to <53%. Secondary endpoints included left ventricular (LV) volumes, CTRCD, CMR tissue characterization, high sensitivity troponin I (hsTnI), and B-type natriuretic peptide (BNP). RESULTS: We randomized 112 patients (56.9 ± 13.6 years, 87 female, and 73 with breast cancer): 54 to atorvastatin and 58 to placebo. Post-anthracycline CMR was performed 22 (13-27) days from last anthracycline dose. Post-anthracycline LVEF did not differ between the atorvastatin and placebo groups (57.3 ± 5.8% and 55.9 ± 7.4%, respectively) when adjusted for baseline LVEF (P = 0.34). There were no significant between-group differences in post-anthracycline LV end-diastolic (P = 0.20) or end-systolic volume (P = 0.12), CMR myocardial edema and/or fibrosis (P = 0.06-0.47), or peak hsTnI (P ≥ 0.99) and BNP (P = 0.23). CTRCD incidence was similar (4% versus 4%, P ≥ 0.99). There was no difference in adverse events. CONCLUSIONS: In patients at increased risk of CTRCD, primary prevention with atorvastatin during anthracycline therapy did not ameliorate early LVEF decline, LV remodeling, CTRCD, change in serum cardiac biomarkers, or CMR myocardial tissue changes. TRIAL REGISTRATION: NCT03186404.

The incidence, risk factors, and outcomes of symptomatic avascular necrosis of bone among Chinese pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: Avascular necrosis (AVN) of bone is a debilitating complication of pediatric patients with acute lymphoblastic leukemia (ALL). While it is extensively studied and reported in Western population, studies focused on Orientals are limited. This study aims to evaluate the incidence, risk factors, and clinical outcomes of AVN among Chinese children with ALL. METHODS: This study is a retrospective, territory-wide population-based cohort study of pediatric patients with ALL enrolled on one of the three consecutive ALL study protocols (ALL-IC-BFM 2002, CCLG-ALL 2008, and CCCG-ALL 2015). RESULTS: A total of 24 out of 533 pediatric subjects with ALL (4.5%) had symptomatic AVN. Age was the single most important risk factor associated with the development of AVN. Only three patients were below age of 10 at the time of diagnosis of ALL. The incidences of AVN in patients aged above and below 10 years were 18.2% ± 3.6% and 0.8% ± 0.5%, respectively, and were significantly different (p < 0.005). Treatment protocol, immunophenotype, and gender were not predictive of AVN. Among the 24 patients, five required orthopedic interventions in view of progressive and severe disease. For subjects with hip joints involvement, follow-up assessments showed 12 of 22 hip joints had radiological progression over a median duration of 3.63 years. Seventeen of them did not have pain at the latest follow-up and among patients with pain (n = 7), five did not experience any limitation on activities of daily living while two required use of walking aids or wheelchair. CONCLUSION: The incidence of symptomatic AVN in Chinese ALL patients was comparable to other studies in Western population. Adolescent age more than 10 years old was recognized to be the most important factor for development of AVN. Significant proportion of patients had radiological progression over time with a small percentage of subjects had daily activities affected.

Use of a paediatric advice line for parents of infants recruited to a randomised controlled trial.

BACKGROUND: This study aims to describe the use of a paediatric advice line (PAL) provided to parents whose infants were recruited to a large randomised controlled trial (RCT), including the number and types of medical concerns addressed, seasonal variability and call outcomes. Additionally, sociodemographic characteristics of the parents and children of those parents who used the PAL are compared with those who did not. METHODS: Prospective cohort of 1246 children nested in the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) RCT. All MIS BAIR participants were offered access to the PAL. Data were collected over the initial 2 years of a 5-year follow-up. Data were analysed using χ2 tests, and ORs were calculated using multiple logistic regression. RESULTS: The PAL was used by 230 (18.5%) participants, who made a total of 586 calls during the 2-year study period. The reasons for calling the PAL were dermatological (24%); gastrointestinal (18%); disturbances in feeding, sleeping and crying (14%); respiratory (7%); and developmental/neurological (6%). Analysis revealed that those who used the PAL were more likely to be first-time parents (OR 1.4, 95% CI 1.1 to 1.9) and mothers who hold a university degree (OR 3.3, 95% CI 1.3 to 8.4). PAL costs were minimal and comprised 15 clinicians with paediatric experience. CONCLUSIONS: A cost-effective PAL service for clinical trial participants was used appropriately by parents for relatively minor concerns and may have a role in trials to promote participant engagement and reduce demand for other health services.

Transbronchial Techniques for Lung Cancer Treatment: Where Are We Now?

The demand for parenchyma-sparing local therapies for lung cancer is rising owing to an increasing incidence of multifocal lung cancers and patients who are unfit for surgery. With the latest evidence of the efficacy of lung cancer screening, more premalignant or early-stage lung cancers are being discovered and the paradigm has shifted from treatment to prevention. Transbronchial therapy is an important armamentarium in the local treatment of lung cancers, with microwave ablation being the most promising based on early to midterm results. Adjuncts to improve transbronchial ablation efficiency and accuracy include mobile C-arm platforms, software to correct for the CT-to-body divergence, metal-containing nanoparticles, and robotic bronchoscopy. Other forms of energy including steam vapor therapy and pulse electric field are under intensive investigation.

Hyperoside alleviates toxicity of ß-amyloid via endoplasmic reticulum-mitochondrial calcium signal transduction cascade in APP/PS1 double transgenic Alzheimer's disease mice.

Alzheimer's disease is a neurodegenerative disorder characterized by a decline in cognitive function. The ß-amyloid (Aß) hypothesis suggests that Aß peptides can spontaneously aggregate into ß-fragment-containing oligomers and protofibrils, and this activation of the amyloid pathway alters Ca2+ signaling in neurons, leading to neurotoxicity and thus apoptosis of neuronal cells. In our study, a blood-brain barrier crossing flavonol glycoside hyperoside was identified with anti-Aß aggregation, BACE inhibitory, and neuroprotective effect in cellular or APP/PSEN1 double transgenic Alzheimer's disease mice model. While our pharmacokinetic data confirmed that intranasal administration of hyperoside resulted in a higher bio-availability in mice brain, further in vivo studies revealed that it improved motor deficit, spatial memory and learning ability of APP/PSEN1 mice with reducing level of Aß plaques and GFAP in the cortex and hippocampus. Bioinformatics, computational docking and in vitro assay results suggested that hyperoside bind to Aß and interacted with ryanodine receptors, then regulated cellular apoptosis via endoplasmic reticulum-mitochondrial calcium (Ca2+) signaling pathway. Consistently, it was confirmed that hyperoside increased Bcl2, decreased Bax and cyto-c protein levels, and ameliorated neuronal cell death in both in vitro and in vivo model. By regulating Aß-induced cell death via regulation on Ca2+ signaling cascade and mitochondrial membrane potential, our study suggested that hyperoside may work as a potential therapeutic agent or preventive remedy for Alzheimer's disease.

Vascular smooth muscle cells in low SYNTAX scores coronary artery disease exhibit proinflammatory transcripts and proteins correlated with IL1B activation.

BACKGROUND AND AIMS: The SYNTAX score is clinically validated to stratify number of lesions and pattern of CAD. A better understanding of the underlying molecular mechanisms influencing the pattern and complexity of coronary arteries lesions among CAD patients is needed. METHODS: Human arterial biopsies from 49 patients (16 low-SYNTAX-score (LSS, <23), 16 intermediate-SYNTAX-score (ISS, 23 to 32) and 17 high-SYNTAX-score (HSS, >32)) were evaluated using Affymetrix GeneChip® Human Genome U133 Plus 2.0 microarray. The data were validated by Next-Generation Sequencing (NGS). Primary VSMC from patients with low and high SYNTAX scores were isolated and compared using immunohistochemistry, qPCR and immunoblotting to confirm mRNA and proteomic results. RESULTS: The IL1B was verified as the top upstream regulator of 47 inflammatory DEGs in LSS patients and validated by another sets of patient samples using NGS analysis. The upregulated expression of IL1B was translated to increased level of IL1ß protein in the LSS tissue based on immunohistochemical quantitative analysis. Plausibility of idea that IL1B in the arterial wall could be originated from VSMC was checked by exposing culture to proinflammatory conditions where IL1B came out as the top DEG (logFC = 7.083, FDR = 1.38 × 10-114). The LSS patient-derived primary VSMCs confirmed higher levels of IL1B mRNA and protein. CONCLUSIONS: LSS patients could represent a group of patients where IL1B could play a substantial role in disease pathogenesis. The LSS group could represent a plausible cohort of patients for whom anti-inflammatory therapy could be considered.

Study protocol of ConquerFear-HK: a randomised controlled trial of a metacognition-based, manualised intervention for fear of cancer recurrence among Chinese cancer survivors.

INTRODUCTION: Fear of cancer recurrence (FCR) is a prevalent and frequently debilitating response to a cancer diagnosis, affecting a substantial proportion of cancer survivors. Approximately 30% of local Hong Kong Chinese cancer survivors in a recent survey reportedly experienced persistent high FCR over the first-year post-surgery. This was associated with lower levels of psychological well-being and quality of life. A manualised intervention (ConquerFear) developed primarily based on the Self-Regulatory Executive Function Model and the Rational Frame Theory, has been found to reduce FCR effectively among Caucasian cancer survivors. The intervention now has been adapted to a Chinese context; ConquerFear-HK. The primary aim of this study is to evaluate its efficacy vs a standard-survivorship-care control (BasicCancerCare) in FCR improvement in a randomised control trial (RCT). METHODS AND ANALYSIS: In this RCT, using the sealed envelope method, 174 eligible Chinese cancer survivors will be randomised to either the ConquerFear-HK or BasicCancerCare intervention. Both interventions include six sessions over 10 weeks, which will be delivered via face to face or online by trained therapists. The ConquerFear-HK intervention incorporates value classification, metacognitive therapy, attentional training, detached mindfulness and psychoeducation; BasicCancerCare includes relaxation training, dietary and physical activity consultations. Participants will be assessed at prior randomisation (baseline; T0), immediately postintervention (T1), 3 months (T2) and 6 months postintervention (T3) on the measures of FCR (Fear of Cancer Recurrence Inventory) as a primary outcome; metacognition (30-item Metacognitions Quesionnaire) and cognitive attentional syndrome (Cognitive-attentional Syndrome Questionnaire) as process outcomes; psychological distress (Hospital Anxiety and Depression Scale), cancer-related distress (Chinese Impact of Events Scale), quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire) and treatment satisfaction are secondary outcomes. ETHICS AND DISSEMINATION: Ethics approval has been obtained from HKU/HA HKW Institutional Review Board (ref: UW19-183). The patients/participants provide their written informed consent to participate in this study. The study results will be disseminated through international peer-review publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04568226.

Systematic pharmacological analysis of agonistic and antagonistic fibroblast growth factor receptor 1 MAbs reveals a similar unique mode of action.

Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase that plays a major role in developmental processes and metabolism. The dysregulation of FGFR1 through genetic aberrations leads to skeletal and metabolic diseases as well as cancer. For this reason, FGFR1 is a promising therapeutic target, yet a very challenging one due to potential on-target toxicity. More puzzling is that both agonistic and antagonistic FGFR1 antibodies are reported to exhibit similar toxicity profiles in vivo, namely weight loss. In this study, we aimed to assess and compare the mechanism of action of these molecules to better understand this apparent contradiction. By systematically comparing the binding of these antibodies and the activation or the inhibition of the major FGFR1 signaling events, we demonstrated that the molecules displayed similar properties and can behave either as an agonist or antagonist depending on the presence or the absence of the endogenous ligand. We further demonstrated that these findings translated in xenografts mice models. In addition, using time-resolved FRET and mass spectrometry analysis, we showed a functionally distinct FGFR1 active conformation in the presence of an antibody that preferentially activates the FGFR substrate 2 (FRS2)-dependent signaling pathway, demonstrating that modulating the geometry of a FGFR1 dimer can effectively change the signaling outputs and ultimately the activity of the molecule in preclinical studies. Altogether, our results highlighted how bivalent antibodies can exhibit both agonistic and antagonistic activities and have implications for targeting other receptor tyrosine kinases with antibodies.

Clinical outcomes and complications of laparoscopic sacrocolpopexy with versus without concomitant hysterectomy for pelvic organ prolapse in Hong Kong Chinese patients after median follow-up of 7 years.

INTRODUCTION AND HYPOTHESIS: This retrospective cohort study is aimed at comparing outcomes and complications of laparoscopic sacrocolpopexy (LSC) with or without concomitant hysterectomy in the Hong Kong Chinese population. METHODS: Women with stage II or above uterine or apical vault prolapse who underwent LSC with or without concomitant hysterectomy in a regional referral unit from 2007 to 2019 were included. The primary objectives were to compare the anatomical outcomes by pelvic organ prolapse quantification system (POP-Q) and recurrence of apical vault prolapse (≥stage II). The secondary objective was to compare the functional outcomes and complications. Anatomical recurrence and incidence of mesh exposure were analyzed using the Kaplan-Meier method. Cox proportional hazard regression was performed to identify risk factors of anatomical recurrence. RESULTS: Seventy-six women were included for analysis. The recurrence rate of apical vault prolapse was 3.9% after a median follow-up time of 83 months (20-190 months). A significant reduction of POP-Q scores of three compartments in both groups of women were demonstrated (p<0.001). There was no difference between the two groups in terms of functional outcomes and complications. 6.6% of women developed mesh exposure. The time to recurrence of apical vault prolapse was shorter in women who had LSC with prior hysterectomy (p =0.019). No risk factors were identified for recurrence of apical vault prolapse. CONCLUSIONS: Laparoscopic sacrocolpopexy with concomitant hysterectomy is comparable with LSC alone. The recurrence and complication rates are low. We suggest that LSC with concomitant hysterectomy might be offered to women with pelvic organ prolapse, with women's preference taken into account.

Kaposiform haemangioendothelioma of the spine associated with fixed hyperlordotic deformity and Kasabach-Merritt Syndrome: a case report and literature review.

Kaposiform haemangioendothelioma (KHE) is a rare childhood disease classified by the International Society for the Study of Vascular Anomalies (ISSVA) as a locally aggressive vascular tumor. It has been reported to affect any site, with a predilection for the extremities and trunk. Although it typically manifests as an enlarging cutaneous or soft tissue lesion, less than 10% of cases have no skin involvement, with the retroperitoneum being the most frequently involved extracutaneous site. Approximately twenty cases of KHE with bony involvement have been reported in the literature to date, with only five of those cases involving the spine specifically.We present a, rare case of KHE who presented with progressive fixed hyperlordotic deformity, multiple non-specific spinal lesions, and abnormal blood tests, posing a clinical and radiological diagnostic challenge. Additionally, we conducted a thorough review of the literature to compare and contrast the various multimodality imaging manifestations of KHE involving the spine.