Cancer immunity by tissue-resident type 1 innate lymphoid cells and killer innate-like T cells.

Cancer progression can be restrained by tumor-infiltrating lymphocytes in a process termed cancer immunosurveillance. Based on how lymphocytes are activated and recruited to the tumor tissue, cancer immunity is either pre-wired, in which innate lymphocytes and innate-like T cells are directly recruited to and activated in tumors following their differentiation in primary lymphoid organs; or priming-dependent, in which conventional adaptive T cells are first primed by cognate antigens in secondary lymphoid organs before homing to and reactivated in tumors. While priming-dependent cancer immunity has been a focus of cancer immunology research for decades, in part due to historical preconception of cancer theory and tumor model choice as well as clinical success of conventional adaptive T cell-directed therapeutic programs, recent studies have revealed that pre-wired cancer immunity mediated by tissue-resident type 1 innate lymphoid cells (ILC1s) and killer innate-like T cells (ILTCKs) is an integral component of the cancer immunosurveillance process. Herein we review the distinct ontogenies and cancer-sensing mechanisms of ILC1s and ILTCKs in murine genetic cancer models as well as the conspicuously conserved responses in human malignancies. How ILC1s and ILTCKs may be targeted to broaden the scope of cancer immunotherapy beyond conventional adaptive T cells is also discussed.

Serine starvation silences estrogen receptor signaling through histone hypoacetylation.

Loss of estrogen receptor (ER) pathway activity promotes breast cancer progression, yet how this occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in breast cancer, represses estrogen receptor alpha (ERα) signaling by reprogramming glucose metabolism and epigenetics. Using isotope tracing and time-resolved metabolomic analyses, we demonstrate that serine is required to maintain glucose flux through glycolysis and the TCA cycle to support acetyl-CoA generation for histone acetylation. Consequently, limiting serine depletes histone H3 lysine 27 acetylation (H3K27ac), particularly at the promoter region of ER pathway genes including the gene encoding ERα, ESR1. Mechanistically, serine starvation impairs acetyl-CoA-dependent gene expression by inhibiting the entry of glycolytic carbon into the TCA cycle and down-regulating the mitochondrial citrate exporter SLC25A1, a critical enzyme in the production of nucleocytosolic acetyl-CoA from glucose. Consistent with this model, total H3K27ac and ERα expression are suppressed by SLC25A1 inhibition and restored by acetate, an alternate source of acetyl-CoA, in serine-free conditions. We thus uncover an unexpected role for serine in sustaining ER signaling through the regulation of acetyl-CoA metabolism.

Objective monitoring tools for improved management of childhood asthma.

Asthma is a common chronic disease amongst children. Epidemiological studies showed that the mortality rate of asthma in children is still high worldwide. Asthma control is therefore essential to minimize asthma exacerbations, which can be fatal if the condition is poorly controlled. Frequent monitoring could help to detect asthma progression and ensure treatment effectiveness. Although subjective asthma monitoring tools are available, the results vary as they rely on patients' self-perception. Emerging evidence suggests several objective tools could have the potential for monitoring purposes. However, there is no consensus to standardise the use of objective monitoring tools. In this review, we start with the prevalence and severity of childhood asthma worldwide. Then, we detail the latest available objective monitoring tools, focusing on their effectiveness in paediatric asthma management. Publications of spirometry, fractional exhaled nitric oxide (FeNO), hyperresponsiveness tests and electronic monitoring devices (EMDs) between 2016 and 2023 were included. The potential advantages and limitations of each tool were also discussed. Overall, this review provides a summary for researchers dedicated to further improving objective paediatric asthma monitoring and provides insights for clinicians to incorporate different objective monitoring tools in clinical practices.

Airway inflammation in severe asthmatics with acid gastro-oesophageal reflux.

The relationship between childhood asthma and gastro-oesophageal reflux (GOR) is contentious. Recent studies in adult asthmatics suggest that GOR is associated with worse control and differences in sputum proteomics related to epithelial integrity, systemic inflammation and host defence. We assessed 127 children with severe asthma undergoing bronchoscopy and pH study. There were no differences in asthma control or measures of airway inflammation or remodelling when those with acid GOR were compared with those without. These results suggest that acid GOR is not an important comorbidity in paediatric severe asthma.

Iron status of full-term infants in early infancy is not associated with maternal ferritin levels nor infant feeding practice.

Iron deficiency (ID) in early life is associated with morbidities. Most fetal iron required for infant growth is acquired in the third trimester from maternal iron store. However, how prenatal iron level affects ferritin level in early infancy remains controversial. This study aimed to examine the associations between maternal ferritin levels and cord blood serum ferritin (CBSF) and to compare the ferritin levels between different feeding practices in early infancy. Healthy Chinese mothers with uncomplicated pregnancy and their infants were followed up at 3 months post-delivery for questionnaire completion and infant blood collection. Infants who were predominantly breastfed and those who were predominantly formula fed were included in this analysis. Serum ferritin levels were measured in maternal blood samples collected upon delivery, cord blood and infant blood samples at 3 months of age. Ninety-seven mother-baby dyads were included. Maternal ID is common (56 %) while the CBSF levels were significantly higher than maternal ferritin levels. Only three infants (3 %) had ID at 3 months of age. There were no significant correlations between maternal ferritin levels with CBSF (r 0·168, P = 0·108) nor with infant ferritin levels at 3 months of age (r 0·023, P = 0·828). Infant ferritin levels at 3 months were significantly and independently associated with CBSF (P = 0·007) and birth weight (P < 0·001) after adjusting for maternal age, parity, maternal education, infant sex and feeding practice. In conclusion, maternal ID was common upon delivery. However, maternal ferritin levels were not significantly associated with CBSF concentrations nor infant ferritin concentrations at 3 months of age.

Effect of surgical intervention for mild childhood obstructive sleep apnoea on attention and behavioural outcomes: A randomized controlled study.

BACKGROUND AND OBJECTIVE: We evaluated inattention and behavioural outcomes following surgery versus watchful waiting (WW) in school-aged children with mild obstructive sleep apnoea (OSA). METHODS: A prospective randomized controlled study was performed in pre-pubertal children aged 6-11 years with polysomnography (PSG)-confirmed mild OSA. They were assigned randomly to early surgical intervention (ES) or WW. The surgical intervention consisting of tonsillectomy with or without adenoidectomy and turbinate reduction was carried out within 4-6 weeks after randomization. Both groups underwent PSG, attention and behavioural assessment and review by an otorhinolaryngologist at baseline and 9-month follow-up. The primary outcome was omission T score from Conners' continuous performance test (CPT). Secondary outcomes were parent-reported behaviours, quality of life, symptoms and PSG parameters. RESULTS: A total of 114 participants were randomized. Data of 35 subjects from the ES and 36 from the WW group were available for final analysis. No significant treatment effect could be found in all CPT parameters and behavioural outcomes. Nevertheless, significantly greater reductions were seen in PSG parameters (obstructive apnoea-hypopnoea index [-1.4 ± 2.0 cf. +0.3 ± 4.1/h, p = 0.038] and arousal index [-1.3 ± 4.4 cf. +1.4 ± 4.5/h, p = 0.013]) and OSA-18 total symptom score (-17.3 ± 19.7 cf. -3.6 ± 14.1, p = 0.001) in the ES group. Subjects who underwent surgery also had significantly greater weight gain (+3.3 ± 2.1 cf. +2.2 ± 1.5 kg, p = 0.014) and increase in systolic blood pressure (+5.1 ± 12.4 cf. -1.2 ± 8.7 mm Hg, p = 0.016). CONCLUSION: Despite improvements in PSG parameters and parent-reported symptoms, surgical treatment did not lead to parallel improvements in objective attention measures in school-aged children with mild OSA.

Age- and gender-specific trends in respiratory outpatient visits and diagnoses at a tertiary pediatric hospital in China: a 10-year retrospective study.

BACKGROUND: Respiratory infections are one of three leading causes of childhood mortality, and worldwide increase and recent plateau in childhood asthma has been reported. However, data on trends of respiratory diseases over long period of time is limited. This study aimed to determine the trends of respiratory disease outpatient visits (ROVs) and diagnoses (RODs) in one of the largest children's teaching hospitals in China between 2009 and 2018. METHODS: A retrospective study based on routine administrative data was designed and implemented according to the RECORD statement. Demographic details and diagnoses of the outpatients < 18 years visiting the respiratory department of the hospital were extracted from the Hospital Information System. Age- and gender-specific trends were illustrated by calculating average annual growth rate (AAGR) for ROVs and comparing change of proportion for different RODs over time. RESULTS: There were 698,054 ROVs from 285,574 children (40.4% female). AAGR of ROVs was 15.2%. Children aged 4 to < 7 years had a faster increase than other age groups. Bronchitis (27.6%), pneumonia (18.5%), pneumonia affecting other systems (18.4%), asthma and status asthmaticus (10.7%), and vasomotor and allergic rhinitis (9.2%) accounted for 84.4% of all RODs. The proportion of bronchitis decreased across years, with the concomitant increasing trend in the proportion of pneumonia. Age-specific trend in diagnoses showed greater proportion of asthma in all visits for the children aged 7 to < 18 years than younger children. Gender-specific trend in diagnoses showed the proportion of asthma was greater for males but the AAGR was greater for females. CONCLUSION: The persistent upward trend in ROVs was observed among children at different ages and a gender difference was also seen. In contrast to what has been reported, burden of asthma and allergies diseases continues to increase locally.

Early sleep deprivation and attention-deficit/hyperactivity disorder.

BACKGROUND: This study aims to study prospectively specific sleep patterns and risk of ADHD after adjusting for potential confounders such as obstructive sleep apnoea (OSA) and methylphenidate use. METHODS: A population-representative sample of 514 Chinese preschool children was recruited when in kindergarten (K3). Parents reported on their socioeconomic status and children's sleep duration. The cohort was reassessed 3 years later when the children were in Grade 3 (P3). Parents reported on children's sleep patterns and ADHD symptoms. Information on OSA diagnosis and methylphenidate use was retrieved from health records. RESULTS: Among the 514 parent-child dyads (mean [SD] age, 5.52 [0.33] years), 411 were reassessed (80.0% retention; 9.35 [0.33] years) at follow-up. There were no significant baseline differences between follow-up and drop-out groups. A gradient relationship was observed between probable ADHD in P3 and sleep duration in K3. The risk of probable ADHD was 15.5 per 100 for children with <8 h of sleep in K3, whereas it was 1.1 per 100 for children with 11-12 h of sleep in K3. The adjusted risk ratio was 14.19 (p = 0.02). CONCLUSIONS: Sleep deprivation in early childhood is associated with higher risk of ADHD in middle childhood.

Nocturnal Oximetry-based Evaluation of Habitually Snoring Children.

RATIONALE: The vast majority of children around the world undergoing adenotonsillectomy for obstructive sleep apnea-hypopnea syndrome (OSA) are not objectively diagnosed by nocturnal polysomnography because of access availability and cost issues. Automated analysis of nocturnal oximetry (nSpO2), which is readily and globally available, could potentially provide a reliable and convenient diagnostic approach for pediatric OSA. METHODS: Deidentified nSpO2 recordings from a total of 4,191 children originating from 13 pediatric sleep laboratories around the world were prospectively evaluated after developing and validating an automated neural network algorithm using an initial set of single-channel nSpO2 recordings from 589 patients referred for suspected OSA. MEASUREMENTS AND MAIN RESULTS: The automatically estimated apnea-hypopnea index (AHI) showed high agreement with AHI from conventional polysomnography (intraclass correlation coefficient, 0.785) when tested in 3,602 additional subjects. Further assessment on the widely used AHI cutoff points of 1, 5, and 10 events/h revealed an incremental diagnostic ability (75.2, 81.7, and 90.2% accuracy; 0.788, 0.854, and 0.913 area under the receiver operating characteristic curve, respectively). CONCLUSIONS: Neural network-based automated analyses of nSpO2 recordings provide accurate identification of OSA severity among habitually snoring children with a high pretest probability of OSA. Thus, nocturnal oximetry may enable a simple and effective diagnostic alternative to nocturnal polysomnography, leading to more timely interventions and potentially improved outcomes.

Association between waist circumference and childhood-masked hypertension: A community-based study.

AIM: The aim of this study is to determine the association between waist circumference (WC) and childhood-masked hypertension. METHODS: A territory-wide, school-based cohort of 1385 Hong Kong students (672 boys and 713 girls) aged 8-17 years was analysed. The ambulatory blood pressure-monitoring assessment was performed using validated oscillometric recorders (A&D TM-2430 (A&D Inc., Tokyo, Japan)) following American Heart Association's recommendations. Subjects were considered normotensive if their casual blood pressure, 24-h daytime and night-time average systolic blood pressure and diastolic blood pressure (DBP) were <95th percentile. If one or more of the ambulatory blood pressure parameters was ≥95th percentile, subjects would be considered suffering from masked hypertension (MH). Subjects who had three successive casual blood pressure measurements above the 95th percentile were excluded. RESULTS: By body mass index, 148 (10.7%) subjects were obese, 182 (13.1%) overweight and 359 (25.9%) having larger WC (≥85th percentiles). MH was diagnosed in 217 subjects (15.7%). Subjects with larger WC or obesity were significantly associated with higher 24-h daytime and night-time systolic blood pressure (≥95th percentile) (odds ratios from 1.84 to 2.09 and from 2.07 to 3.54 for larger WC and obese respectively, all P < 0.05) as well as 24-h DBP for larger WC (odds ratio = 2, P = 0.015) than normal subjects adjusted by sex, age and height. CONCLUSION: Waist circumference and body mass index are independent risk factors of childhood and adolescent MH. WC appears a significant associated factor of elevated 24-h DBP in children aged 8-17 years.

A randomized controlled trial to investigate the impact of a low glycemic index (GI) diet on body mass index in obese adolescents.

BACKGROUND: The role of a low glycemic index (GI) diet in the management of adolescent obesity remains controversial. In this study, we aim to evaluate the impact of low GI diet versus a conventional Chinese diet on the body mass index (BMI) and other obesity indices of obese adolescents. METHODS: Obese adolescents aged 15-18 years were identified from population-recruited, territory-wide surveys. Obesity was defined as BMI ≥95th percentile of Hong Kong local age- and sex-specific references. Eligible subjects were randomized to either an intervention with low GI diet (consisting of 45-50% carbohydrate, 30-35% fat and 15-20% protein) or conventional Chinese diet as control (consisting of 55-60% carbohydrate, 25-30% fat and 10-15% protein). We used random intercept mixed effects model to compare the differential changes across the time points from baseline to month 6 between the 2 groups. RESULTS: 104 obese adolescents were recruited (52 in low GI group and 52 in control group; 43.3% boys). Mean age was 16.7 ± 1.0 years and 16.8 ±1.0 years in low GI and control group respectively. 58.7% subjects completed the study at 6 months (65.4% in low GI group and 51.9% in control group). After adjustment for age and sex, subjects in the low GI group had a significantly greater reduction in obesity indices including BMI, body weight and waist circumference (WC) compared to subjects in the control group (all p <0.05). After further adjustment for physical activity levels, WC was found to be significantly lower in the low GI group compared to the conventional group (p = 0.018). CONCLUSION: Low GI diet in the context of a comprehensive lifestyle modification program may be an alternative to conventional diet in the management of obese adolescents. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Ref. No: NCT01278563.

Epigenetic priming targets tumor heterogeneity to shift transcriptomic phenotype of pancreatic ductal adenocarcinoma towards a Vitamin D susceptible state.

As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2'-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC.

Mitochondrial Raf1 Regulates Glutamine Catabolism.

Raf kinases play vital roles in normal mitogenic signaling and cancer, however, the identities of functionally important Raf-proximal proteins throughout the cell are not fully known. Raf1 proximity proteomics/BioID in Raf1-dependent cancer cells unexpectedly identified Raf1-adjacent proteins known to reside in the mitochondrial matrix. Inner-mitochondrial localization of Raf1 was confirmed by mitochondrial purification and super-resolution microscopy. Inside mitochondria, Raf1 associated with glutaminase (GLS) in diverse human cancers and enabled glutaminolysis, an important source of biosynthetic precursors in cancer. These impacts required Raf1 kinase activity and were independent of canonical MAP kinase pathway signaling. Kinase-dead mitochondrial matrix-localized Raf1 impaired glutaminolysis and tumorigenesis in vivo. These data indicate that Raf1 localizes inside mitochondria where it interacts with GLS to engage glutamine catabolism and support tumorigenesis.

Mitochondrial uncoupler and retinoic acid synergistically induce differentiation and inhibit proliferation in neuroblastoma.

Neuroblastoma is a leading cause of death in childhood cancer cases. Unlike adult malignancies, which typically develop from aged cells through accumulated damage and mutagenesis, neuroblastoma originates from neural crest cells with disrupted differentiation. This distinct feature provides novel therapeutic opportunities beyond conventional cytotoxic methods. Previously, we reported that the mitochondrial uncoupler NEN (niclosamide ethanolamine) activated mitochondria respiration to reprogram the epigenome, promoting neuronal differentiation. In the current study, we further combine NEN with retinoic acid (RA) to promote neural differentiation both in vitro and in vivo. The treatment increased the expression of RA signaling and neuron differentiation-related genes, resulting in a global shift in the transcriptome towards a more favorable prognosis. Overall, these results suggest that the combination of a mitochondrial uncoupler and the differentiation agent RA is a promising therapeutic strategy for neuroblastoma.

Prevalence of habitual snoring and its correlates in young children across the Asia Pacific.

AIMS: To evaluate: (i) the prevalence of habitual snoring (HS) in a large sample of children aged from birth to 36 months in 14 countries across Asia Pacific; and (ii) the different correlates associated with HS in Caucasians, Chinese and non-Chinese, non-Caucasian Asians. METHODS: This was a multi-centre, cross-sectional survey conducted across Asia Pacific. Parents/caregivers of 23,481 infants and toddlers completed an expanded version of the Brief Infant Sleep Questionnaire. We defined HS as snoring more than three nights per week. RESULTS: Chinese and non-Caucasian non-Chinese (NCNC) children had a lower prevalence of HS across the age range from birth to 3 years than their Caucasian counterparts (6.2% and 5.1% vs. 11%, P < 0.01). Boys had a higher prevalence of HS compared to girls (χ(2) = 98.5, P < 0.0001). History of prematurity (OR = 1.37-1.56, CI (1.1-2.17), P < 0.01) and gender (OR = 1.53-1.54, CI (1.26-1.85), P < 0.0001) were found to be significant predictors for HS. Current breastfeeding (OR = 0.69, CI (0.54-0.88), P < 0.005) and greater parental age (OR = 0.86, CI (0.78-0.96), P < 0.01) were protective against HS among NCNC children. HS was less prevalent in younger Chinese subjects (OR = 0.88, CI (0.84-0.93), P < 0.0001). In Caucasians, parents' education (OR = 0.78, CI (0.67-0.91), P < 0.005) and their not sleeping in the same room as their child (OR = 0.62, CI (0.45-0.86), P < 0.005) were negatively associated with parental report of HS. CONCLUSIONS: Prevalence of HS shows racial differences among countries across Asia Pacific. Future studies should assess craniofacial structure and body fat distribution as contributory factors for this differential prevalence.

Orlistat improves endothelial function in obese adolescents: a randomised trial.

AIM: To investigate the effect of orlistat on endothelial function in obese adolescents. METHODS: Single-blind 10-week controlled trial of 67 normolipidaemic obese adolescents randomised into three groups. Group 1 (diet alone), Group 2 (diet and orlistat), Group 3 (diet, orlistat and exercise). Endothelial function measured by flow-mediated dilatation (FMD) of the brachial artery, anthropometric parameters, blood pressure, fasting blood lipids, insulin and glucose levels were recorded at baseline and at 10 weeks. RESULTS: Sixty four subjects completed the study. Groups were comparable at baseline. FMD increased significantly with orlistat (Groups 2 and 3) but not in Group 1. Orlistat treatment resulted in significantly reduced bodyweight, body mass index (BMI), waist circumference, total and low-density lipoprotein (LDL) cholesterol levels. High-density lipoprotein cholesterol levels were unchanged. Triglyceride and insulin levels were significantly reduced in all three groups. The reduction in cholesterols did not correlate with reductions in weight and BMI. A slight reduction of body fat, both with and without orlistat treatment, correlated with reduction in BMI after adjustment for baseline values. Blood pressure was unaltered by orlistat. Calorie intake was reduced with orlistat, and the decrease noted in % fat and increase in % carbohydrate was significant only in those taking orlistat. The addition of exercise (Group 3 compared with Group 2) altered no parameter. CONCLUSIONS: Orlistat improves endothelial function and reduces bodyweight, BMI, fasting total and LDL-cholesterol in obese adolescents when combined with dietary control. Improvement in endothelial function if maintained could reflect long-term cardiovascular benefit.

Fever as a predictor of doctor shopping in the paediatric population.

OBJECTIVES: To estimate prevalence and assess factors associated with doctor shopping among caregivers of children acutely admitted to a hospital in Hong Kong, and examine the reasons for such behaviour and caregivers' awareness of its possible dangers. DESIGN: Cross-sectional study with face-to-face surveys. SETTING: A paediatric unit in a teaching hospital in Hong Kong. PARTICIPANTS: Caregivers of children admitted to acute paediatric wards between April and July 2011. MAIN OUTCOME MEASURES; Socio-demographic characteristics of the interviewee, personal history and clinical data of the patient, presence of doctor shopping (consulting more than one doctor for medical advice without referral) for each episode, the reasons behind such behaviour, and awareness of potential dangers. Data retrieved were analysed to estimate the prevalence and logistic regression was used to assess factors associated with doctor shopping. RESULTS: In all, 649 such patients were admitted into hospital during the study period, of which 336 were recruited, with about a half being absent or given home leave. Thirty-four patients were excluded due to absent caregivers or refusal, and 302 were included in the study. More than half (79.5%) were female and the caregivers' monthly household incomes were between HK$10 001 and HK$15 000 (21.2%), similar to the median household income in Hong Kong. The prevalence of doctor shopping was 53%. The only significant clinical parameter associated with doctor shopping was presence of fever (odds ratio=2.4; 95% confidence interval, 1.4-3.9). Persistence of symptoms was the commonest reason given by interviewees for doctor shopping, and the majority (75.5%) were unaware of the possible dangers of this behaviour. CONCLUSION: Doctor shopping is highly prevalent among caregivers of children with acute paediatric conditions. Most caregivers do not know the potential complications of this behaviour. Further measures should be taken to educate subjects on the associated dangers of this behaviour and the natural course of acute illnesses with fever.

Rare but life-threatening cause of massive haemoptysis in an adolscent with tuberculosis: Rasmussen's aneurysm.

Rasmussen's aneurysm is a rare yet fatal cause of massive haemoptysis in pulmonary tuberculosis. Early identification and timely intervention are of utmost importance to reduce the associated mortality. A girl in early adolescence presented with persistent fever and massive haemoptysis who required intubation and was subsequently confirmed to have tuberculosis. CT pulmonary angiogram showed the presence of pseudoaneurysms in the left upper and lower lobes. The haemoptysis resolved following the embolisation of the culprit's vessel. Residual lung destruction was evident on CT after a 12-month course of antituberculosis therapy. Rasmussen's aneurysm is a significant vascular complication of cavitary tuberculosis and needs to be considered in patients presenting with massive haemoptysis.

Association of growth patterns during infancy and puberty with lung function, wheezing and asthma in adolescents aged 17.5 years: evidence from 'Children of 1997' Hong Kong Chinese Birth Cohort.

BACKGROUND: Rapid growth is related to adverse respiratory outcomes although possibly confounded or limited by growth modelling methods. We investigated the association of infant and pubertal growth with lung function, wheezing and asthma in a non-Western setting. METHODS: In Hong Kong's 'Children of 1997' Chinese birth cohort (n = 8327), weight during infancy and weight, height and body mass index (BMI) during puberty were modelled using a super-imposition by translation and rotation model to identify (larger or smaller) size, (earlier or later) tempo and (slower or faster) velocity. Sex-specific associations with forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC (Global Lung function Initiative z-score) and self-reported wheezing and asthma at ∼17.5 years were assessed. RESULTS: For each fraction higher than average weight growth velocity during infancy, FVC was higher in boys (0.90 SD, 95% CI 0.35; 1.44) and girls (0.77 SD, 95% CI 0.24; 1.30), FEV1/FVC was lower (-0.74 SD, 95% CI -1.38; -0.10) and wheezing was higher (odds ratio 6.92, 95% CI 1.60; 29.99) in boys and an inverse association with FVC was observed for tempo but not for size. Associations for weight growth velocity in puberty were similar but weaker. Greater size and higher velocity of BMI growth was associated with higher FVC, lower FEV1/FVC and higher asthma and wheezing risk. CONCLUSION: Accelerated infant and pubertal weight growth were associated with disproportionate lung size and airway growth, and higher risk of asthma; optimizing early-life growth patterns could be important.

Mitochondrial Uncoupling Inhibits Reductive Carboxylation in Cancer Cells.

When the electron transport chain (ETC) function is impaired, cancer cells rely on reductive carboxylation (RC) to convert α-ketoglutarate (αKG) to citrate for macromolecular synthesis, thereby promoting tumor growth. Currently, there is no viable therapy to inhibit RC for cancer treatment. In this study, we demonstrate that the mitochondrial uncoupler treatment effectively inhibits RC in cancer cells. Mitochondrial uncoupler treatment activates the ETC and increases the NAD+/NADH ratio. Using U-13C-glutamine and 1-13C-glutamine tracers, we show that mitochondrial uncoupling accelerates the oxidative tricarboxylic acid (TCA) cycle and blocks RC under hypoxia, in von Hippel-Lindau (VHL) tumor suppressor-deficient kidney cancer cells, or under anchorage-independent growth condition. Together, these data demonstrate that mitochondrial uncoupling redirects α-KG from RC back to the oxidative TCA cycle, highlighting that the NAD+/NADH ratio is one key switch that determines the metabolic fate of α-KG. Inhibiting RC could be a key mechanism by which mitochondrial uncouplers inhibit tumor growth. IMPLICATIONS: Mitochondrial uncoupling is a novel strategy to target RC in cancer.