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Laura J Hartley,1 Scott Evans,2 Mark A Davies,2 Suzanne Kelly,2 Jonathan J Gregory2 1University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 2The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UKCorrespondence: Laura J HartleyUniversity Hospitals Birmingham NHS Foundation Trust, Birmingham, UKTel +44 121 424 0000Email l.hartley2@nhs.netBackground and Objectives: Cancer services are under increasing pressure to deliver waiting time targets. Our service has seen referral numbers increase to over 3000 per annum, with more than 80% coming from secondary care. In order to deliver a responsive service, the department has introduced a daily diagnostic multidisciplinary meeting (DMDT) with the aim being stratification of resources by directing rapid access to clinics and diagnostics to those felt to be at greatest risk of malignancy at the start of the pathway. It also aimed to improve communication with patients and referrers, consistency in decision making and deliver improved diagnostic turn-around times in a sustainable manner. An evaluation was undertaken to assess whether the introduction of the DMDT has improved the pathway, the primary endpoint being a reduction in time to definitive diagnosis (TTDD). Secondary endpoints included measurements of efficiency and whether there has been a reduction in variation in practice.Methods: Retrospective access to a prospective database over a 1-month period before (2015) and after (2018) the intervention.Results: The introduction of the DMDT has led to a reduction in TTDD (7 days). The service also has an added benefit in reducing average total patient miles travelled over the course of diagnosis by 22.68 miles.Conclusion: The introduction of a diagnostic MDT at the start of the pathway does lead to an improvement in service efficiency and a reduction in TTDD.Keywords: multidisciplinary, cancer, oncology, diagnosis, waiting times, sarcoma

BackgroundPrevious analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients.Patients and methodsThis double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.ResultsBetween 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and

5-Fluorouracil (5-FU) serves as a first-line therapeutic agent for colorectal cancer, however, its utility is limited by a short half-life and significant cytotoxicity. This study focused on the construction of 5-Fluorouracil-β-Cyclodextrin polymers (5-FUSA-β-CD and 5-FUBA-β-CD) by covalent conjugation using linker strategies to address limitations. The cytotoxicity assays on human colon cancer cell lines HT-29 and normal colon epithelial cells NCM-460 demonstrated that the IC50 value of the 5-FUBA-β-CD conjugate for the HT-29 cells was 38.72 ± 0.13 μM, indicating superior antitumor activity compared to both 5-FUBA-β-CD and 5-FU. Additionally, the conjugate exhibited reduced cytotoxicity towards normal colon epithelial cells. Pharmacokinetic analyses revealed that 5-FUSA-β-CD and 5-FUBA-β-CD were eliminated slowly and their half-lives were longer than that of free 5-FU. Distinct linkers were meticulously designed and synthesized to generate 5-Fluorouracil-β-Cyclodextrin conjugates that exhibit differential anti-colon cancer activity and half-lives. These findings not only demonstrated that 5-Fluorouracil-β-Cyclodextrin conjugates exhibits superior antitumor activity and reduced toxicity but also suggest that the linker plays a crucial role in determining both the efficacy of drug conjugates as an anticancer agent and its associated adverse effects. Future designs of linker can be optimized for greater efficiency.

Matrine is a quinoline alkaloid extracted and separated from the dried root, fruit, and other parts of the plant Sophora flavescens using an organic solvent. Matrine exhibits a variety of biological activities and is widely used in pharmacy, agronomy, and other fields. Due to its low bioavailability, poor chemical stability, and toxicity to the central nervous system, a large number of researchers have searched for matrine derivatives with higher biological activity and safety by modifying its structure. In this review article, the research progress of matrine derivatives obtained using two methods (extraction from Sophora flavescens and structural modifications) from 2018 to 2022 in terms of pharmacological activity, mechanism of action, and structure–activity relationship are presented. The modification of matrine over the past five years has been mainly on the D-ring. Many new matrine alkaloids have been extracted from natural products, some of which have good pharmacological activity, which broadens the strategy for matrine structural modification in the future.

Effective therapies for the long-term care of individuals with bipolar disorder feature medication management and an interactional component between patients and care providers. In this paper, we discuss the effectiveness of applying a collaborative practice model to the long-term care of individuals with bipolar disorder who receive outpatient treatment. The model emphasizes that patients are co-managers of their illness and successful outcomes are enhanced within a supportive social environment. Key elements include joint patient-provider treatment planning and decision making. Several controlled trials have demonstrated that when the model is adopted, significant improvements in clinical and functional outcomes can be achieved. The paper concludes with a case study, which illustrates that the model can be successfully implemented in a clinical setting. Given that the clinical and research evidence demonstrates the effectiveness of the model, we suggest that advanced practice psychiatric nurses apply key elements of the collaborative practice model in their work with clients with bipolar disorder. [ABSTRACT FROM AUTHOR]

Abstract Background Individuals with Autism Spectrum Disorders (ASD) typically show impaired eye contact during social interactions. From a young age, they look less at faces than typically developing (TD) children and tend to avoid direct gaze. However, the reason for this behavior remains controversial; ASD children might avoid eye contact because they perceive the eyes as aversive or because they do not find social engagement through mutual gaze rewarding. Methods We monitored pupillary diameter as a measure of autonomic response in children with ASD (n = 20, mean age = 12.4) and TD controls (n = 18, mean age = 13.7) while they looked at faces displaying different emotions. Each face displayed happy, fearful, angry or neutral emotions with the gaze either directed to or averted from the subjects. Results Overall, children with ASD and TD controls showed similar pupillary responses; however, they differed significantly in their sensitivity to gaze direction for happy faces. Specifically, pupillary diameter increased among TD children when viewing happy faces with direct gaze as compared to those with averted gaze, whereas children with ASD did not show such sensitivity to gaze direction. We found no group differences in fixation that could explain the differential pupillary responses. There was no effect of gaze direction on pupil diameter for negative affect or neutral faces among either the TD or ASD group. Conclusions We interpret the increased pupillary diameter to happy faces with direct gaze in TD children to reflect the intrinsic reward value of a smiling face looking directly at an individual. The lack of this effect in children with ASD is consistent with the hypothesis that individuals with ASD may have reduced sensitivity to the reward value of social stimuli.

Abstract Background Clinical activities that trainees can be trusted to perform with minimal or no supervision have been labelled as Entrustable Professional Activities (EPAs). We sought to examine what activities could be entrusted to psychiatry trainees in their first year of specialist training. Methods We conducted an online survey of Fellows of the Royal Australian and New Zealand College of Psychiatrists (RANZCP). Results The majority of respondents considered initiating patients with the common medications, discharging patient suffering from schizophrenia, bipolar disorder or following a crisis admission, conducting risk assessments and managing psychiatric emergencies were activities that trainees could be entrusted with by the end of the first stage of training. Conclusions Four activities were identified that trainees should be entrusted with by the end of their first year of training. Each of these activities comprises a set of competencies in each of the CanMEDS roles. When a trainee is unable to satisfactorily perform an EPA, deficits in the underpinning competencies can be a focus for remediation. Further EPAs are being identified in areas of more specialised practice for use within more advanced training.

Abstract Background Recent interest has focused on the potential use of serial interferon gamma (IFN-γ) release assay (IGRA) measurements to assess the response to anti-tuberculous (TB) treatment. The kinetics of IFN-γ responses to Mycobacterium tuberculosis (MTB) antigens in HIV-infected children during treatment have not however been previously investigated. Methods IFN-γ responses to the MTB antigens, ESAT-6, CFP-10 and PPD were measured by an enzyme-linked immunospot assay (IFN-γ ELISpot) at presentation and at one, two and six months after starting anti-tuberculous treatment in HIV-infected children with definite or probable TB. Responses at different time points were compared using a Mann-Whitney U test with paired data analysed using the Wilcoxon signed rank test. A Fisher's exact or Chi-squared test was used to compare proportions when test results were analysed as dichotomous outcomes. Results Of 102 children with suspected TB, 22 (21%) had definite TB and 24 (23%) probable TB. At least one follow up IFN-γ ELISpot assay result was available for 31 (67%) of the 46 children. In children with definite or probable TB in whom the IFN-γ ELISpot assay result was positive at presentation, anti-tuberculous treatment was accompanied by a significant decrease in both the magnitude of the IFN-γ response to individual or combined MTB-specific antigens (ESAT-6 median 110 SFCs/106 PBMC (IQR 65-305) at presentation vs. 15 (10-115) at six months, p = 0.04; CFP-10 177 (48-508) vs. 20 (5-165), p = 0.004, ESAT-6 or CFP-10 median 250 SFCs/106 PBMC (IQR 94-508) vs. 25 (10-165), p = 0.004) and in the proportion of children with a positive IFN-γ ELISpot assay (Fisher's exact test: ESAT-6 15/0 vs 5/11, p = 0.0002, CFP-10 22/0 vs 8/17, p = 0.0001, ESAT-6 or CFP-10 22/0 vs. 9/17, p= 0.002). However almost half of the children had a positive IFN-γ ELISpot assay after six months of anti-tuberculous treatment. In addition, there was conversion of the IFN-γ ELISpot assay result during anti-tuberculous therapy in six of 12 children in whom the initial IFN-γ ELISpot assay was negative. Conclusions In HIV-infected children with definite or probable TB, anti-tuberculosis treatment is accompanied by a reduction in the magnitude of the IFN-γ ELISpot response to MTB-antigens. However, serial IFN-γ ELISpot measurements appear to have limited clinical utility in assessing a successful response to anti-tuberculous treatment in HIV infected children.

Abstract Background Antiretroviral therapy (ART) dramatically improves outcomes for children in Africa; however excellent adherence is required for treatment success. This study describes the utility of different measures of adherence in detecting lapses in infants and young children in Cape Town, South Africa. Methods In a prospective cohort of 122 HIV-infected children commenced on ART, adherence was measured monthly during the first year of treatment by medication return (MR) for both syrups and tablets/capsules. A questionnaire was administered to caregivers after 3 months of treatment to assess experience with giving medication and self-reported adherence. Viral and immune response to treatment were assessed at the end of one year and associations with measured adherence determined. Results Medication was returned for 115/122 (94%) children with median age (IQR) of 37 (16 – 61) months. Ninety-one (79%) children achieved annual average MR adherence ≥ 90%. This was an important covariate associated with viral suppression after adjustment for disease severity (OR = 5.5 [95%CI: 0.8–35.6], p = 0.075), however was not associated with immunological response to ART. By 3 months on ART, 13 (10%) children had deceased and 11 (10%) were lost to follow-up. Questionnaires were completed by 87/98 (90%) of caregivers of those who remained in care. Sensitivity of poor reported adherence (missing ≥ 1 dose in the previous 3 days) for MR adherence Conclusion Excellent adherence to ART is possible in African infants and young children and the relatively simple low technology measure of adherence by MR strongly predicts viral response. Better socio-economic status and more palatable regimens are associated with better adherence.

Abstract Background G protein-coupled receptors (GPCRs) play important physiological roles transducing extracellular signals into intracellular responses. Approximately 50% of all marketed drugs target a GPCR. There remains considerable interest in effectively predicting the function of a GPCR from its primary sequence. Findings Using techniques drawn from data mining and proteochemometrics, an alignment-free approach to GPCR classification has been devised. It uses a simple representation of a protein's physical properties. GPCRTree, a publicly-available internet server, implements an algorithm that classifies GPCRs at the class, sub-family and sub-subfamily level. Conclusion A selective top-down classifier was developed which assigns sequences within a GPCR hierarchy. Compared to other publicly available GPCR prediction servers, GPCRTree is considerably more accurate at every level of classification. The server has been available online since March 2008 at URL: http://igrid-ext.cryst.bbk.ac.uk/gpcrtree/.

Abstract Background Debate regarding the benefit of radiotherapy after local excision of ductal carcinoma in situ (DCIS) continues. The Van Nuys Prognostic Index (VNPI) is thought to be a useful aid in deciding which patients are at increased risk of local recurrence and who may benefit from adjuvant radiotherapy (RT). Recently published interim data from the Sloane project has showed that the VNPI score did significantly affect the chances of getting planned radiotherapy in the UK, suggesting that British clinicians may already be using this scoring system to assist in decision making. This paper independently assesses the prognostic validity of the VNPI in a British population. Patients and methods A retrospective review was conducted of all patients (n = 215) who underwent breast conserving surgery for DCIS at a single institution between 1997 – 2006. No patients included in the study received additional radiotherapy or hormonal treatment. Kaplan Meier survival curves were calculated, to determine disease free survival, for the total sample and a series of univariate analyses were performed to examine the value of various prognostic factors including the VNPI. The log-rank test was used to determine statistical significance of differential survival rates. Multivariate Cox regression analysis was performed to analyze the significance of the individual components of the VNPI. All analyses were conducted using SPSS software, version 14.5. Results The mean follow-up period was 53 months (range 12–97, SD19.9). Ninety five tumours were high grade (44%) and 84 tumours exhibited comedo necrosis (39%). The closest mean initial excision margin was 2.4 mm (range 0–22 mm, standard deviation 2.8) and a total of 72 tumours (33%) underwent further re-excision. The observed and the actuarial 8 year disease-free survival rates in this study were 91% and 83% respectively. The VNPI score and the presence of comedo necrosis were the only statistically significant prognostic indicators (P < 0.05). Conclusion This follow-up study of 215 patients with DCIS treated with local excision and observation alone is one of the largest series in which rates of recurrence are unaffected by radiation therapy, hormone manipulation or chemotherapy. It has afforded us the opportunity to assess the prognostic impact of patient and tumour characteristics free of any potentially confounding treatment related influences. The results suggest that the VNPI can be used to identify a subset of patients who are at risk of local recurrence and who may potentially benefit from RT.

Abstract Introduction The insertion of percutaneous central venous catheters is a common procedure in neonatal intensive care nurseries. Placement of the catheter tip in a large central vein is most desirable. Occasionally, due to difficult venous access, catheter tips are left in places that are less than ideal. Case presentation A female infant with a complicated gastroschisis developed signs of short bowel syndrome post surgery. She was treated with a combination of parenteral nutrition and enteral feeds. A central venous line was inserted through a scalp vein. The tip was noted to be in a vessel at the level of the mandible. She subsequently became unwell with large milky pharyngeal aspirates and episodes of bradycardia. Chest radiography revealed aspiration. The central venous line was removed because of presumed extravasation. This is the first reported case of parenteral nutrition extravasation into the pharynx causing aspiration in an infant. Conclusion This complication may have been prevented by recognising that the tip of the catheter was not correctly placed. When catheters are in unusual positions it may be useful to obtain a second radiograph from a different angle or an ultrasound scan to confirm the positioning of the catheter tip.

Abstract Background Perfluorocarbon (PFC) vapour in the expired gases during partial liquid ventilation should be prevented from entering the atmosphere and recovered for potential reuse. This study aimed to determine how much PFC liquid could be recovered using a conventional humidified neonatal ventilator with chilled condensers in place of the usual expiratory ventilator circuit and whether PFC liquid could be recovered when using the chilled condensers at the ventilator exhaust outlet. Methods Using a model lung, perfluorocarbon vapour loss during humidified partial liquid ventilation of a 3.5 kg infant was approximated. For each test 30 mL of FC-77 was infused into the model lung. Condensers were placed in the expiratory limb of the ventilator circuit and the amounts of PFC (FC-77) and water recovered were measured five times. This was repeated with the condensers placed at the ventilator exhaust outlet. Results When the condensers were used as the expiratory limb, the mean (± SD) volume of FC77 recovered was 16.4 mL (± 0.18 mL). When the condensers were connected to the ventilator exhaust outlet the mean (± SD) volume of FC-77 recovered was 7.6 mL (± 1.14 mL). The volume of FC-77 recovered was significantly higher when the condenser was used as an expiratory limb. Conclusion Using two series connected condensers in the ventilator expiratory line 55% of PFC liquid (FC-77) can be recovered during partial liquid ventilation without altering the function of the of the ventilator circuit. This volume of PFC recovered was just over twice that recovered with the condensers connected to the ventilator exhaust outlet.

Abstract Background The loss of perfluorocarbon (PFC) vapour in the expired gases during partial liquid ventilation should be minimized both to prevent perfluorocarbon vapour entering the atmosphere and to re-use the recovered PFC liquid. Using a substantially modified design of our previously described condenser, we aimed to determine how much perfluorocarbon liquid could be recovered from gases containing PFC and water vapour, at concentrations found during partial liquid ventilation, and to determine if the amount recovered differed with background flow rate (at flow rates suitable for use in neonates). Methods The expiratory line of a standard ventilator circuit set-up was mimicked, with the addition of two condensers. Perfluorocarbon (30 mL of FC-77) and water vapour, at concentrations found during partial liquid ventilation, were passed through the circuit at a number of flow rates and the percentage recovery of the liquids measured. Results From 14.2 mL (47%) to 27.3 mL (91%) of the infused 30 mL of FC-77 was recovered at the flow rates studied. Significantly higher FC-77 recovery was obtained at lower flow rates (ANOVA with Bonferroni's multiple comparison test, p < 0.0001). As a percentage of the theoretical maximum recovery, 64 to 95% of the FC-77 was recovered. Statistically significantly less FC-77 was recovered at 5 Lmin-1 (ANOVA with Bonferroni's multiple comparison test, p < 0.0001). Amounts of perfluorocarbon vapour recovered were 47%, 50%, 81% and 91% at flow rates of 10, 5, 2 and 1 Lmin-1, respectively. Conclusion Using two condensers in series 47% to 91% of perfluorocarbon liquid can be recovered, from gases containing perfluorocarbon and water vapour, at concentrations found during partial liquid ventilation.

Abstract Background Nurr1 is an orphan member of the nuclear receptor superfamily; these orphan receptors are a group for which a ligand has yet to be identified. Nurr1 has been shown to regulate the expression of a small number of genes as a monomeric, constitutively active receptor. These Nurr1 regulated genes are primarily associated with dopamine cell maturation and survival. However, previous reports have shown an increased expression of Nurr1 in the synovium of patients with rheumatoid arthritis (RA) suggesting a pro-inflammatory role for Nurr1 in RA. In this study we investigate the potential pro-inflammatory role of Nurr1 by monitoring Nurr1 dependent gene expression in an immortalised synoviocyte cell line, K4IM. Methods We overexpressed the wild type and a dominant negative form of the orphan nuclear receptor Nurr1, in a model synoviocyte cell line. Using the Affymetrix HG-U133 Genechips we demonstrate the effects on the transcriptome by the receptor. Further evidence of gene expression change was demonstrated using quantitative RT-PCR and ELISA analysis. Results We show that Nurr1 regulates transcription of a small number of genes for pro-inflammatory modulators of which the most significant is interleukin-8 (IL-8). We also demonstrate increased synthesis and secretion of IL-8 further supporting a role for Nurr1 in inflammatory signalling pathways. Conclusion Using microarray analysis we show that elevated levels of Nurr1 leads to increased gene expression of pro-inflammatory genes: IL-8, Amphiregulin and Kit ligand in a model cell line. This data provides further evidence for an additional role for Nurr1 in inflammation and may play a role in the pathogenesis of rheumatoid arthritis.

Abstract Background In a previous study it has been shown that mean population perception of air pollution correlates well with physical measures of actual air pollution and could be used as a measure of exposure to air pollution, at least for those forms of pollution perceptible to humans. However, for such a measure to be valid researchers would need to be confident that it was not strongly biased by possible confounding variables. This study reports the association between perception of above average levels of air pollution compared with others in the neighbourhood and a number of factors that may influence reporting. Methods This was a postal cross-sectional study of 3402 households in England in a mixed rural and urban area adjacent to a large industrial complex. Respondents were asked about their social and demographic characteristics, the presence of respiratory symptoms and frequency of exposure to a range of pollution types. Results and discussion There were strong associations (p < 0.01) with the presence of a person in the home with respiratory symptoms, the belief that industrial pollution was harming their health, social class, living in rented accommodation and reporting noise from neighbours and other people's smoke. Smoking behaviour did not affect reporting. Conclusions We did not find any evidence of bias that would substantially invalidate mean population reporting of air pollution severity as a measure of exposure in epidemiological studies, though care may be needed in interpreting results where those factors found to be significant in this study vary substantially between areas.

Background: Recent interest has focused on the potential use of serial interferon gamma (IFN-gamma) release assay (IGRA) measurements to assess the response to anti-tuberculous (TB) treatment. The kinetics of IFN-gamma responses to Mycobacterium tuberculosis (MTB) antigens in HIV-infected children during treatment have not however been previously investigated.Methods: IFN-gamma responses to the MTB antigens, ESAT-6, CFP-10 and PPD were measured by an enzyme-linked immunospot assay (IFN-gamma ELISpot) at presentation and at one, two and six months after starting anti-tuberculous treatment in HIV-infected children with definite or probable TB. Responses at different time points were compared using a Mann-Whitney U test with paired data analysed using the Wilcoxon signed rank test. A Fisher's exact or Chi-squared test was used to compare proportions when test results were analysed as dichotomous outcomes.Results: Of 102 children with suspected TB, 22 (21%) had definite TB and 24 (23%) probable TB. At least one follow up IFN-gamma ELISpot assay result was available for 31 (67%) of the 46 children. In children with definite or probable TB in whom the IFN-gamma ELISpot assay result was positive at presentation, anti-tuberculous treatment was accompanied by a significant decrease in both the magnitude of the IFN-gamma response to individual or combined MTB-specific antigens (ESAT-6 median 110 SFCs/106 PBMC (IQR 65-305) at presentation vs. 15 (10-115) at six months, p = 0.04; CFP-10 177 (48-508) vs. 20 (5-165), p = 0.004, ESAT-6 or CFP-10 median 250 SFCs/106 PBMC (IQR 94-508) vs. 25 (10-165), p = 0.004) and in the proportion of children with a positive IFN-gamma ELISpot assay (Fisher's exact test: ESAT-6 15/0 vs 5/11, p = 0.0002, CFP-10 22/0 vs 8/17, p = 0.0001, ESAT-6 or CFP-10 22/0 vs. 9/17, p= 0.002). However almost half of the children had a positive IFN-gamma ELISpot assay after six months of anti-tuberculous treatment. In addition, there was conversion of the IFN-gamma ELISpot assay result during anti-tuberculous therapy in six of 12 children in whom the initial IFN-gamma ELISpot assay was negative.Conclusions: In HIV-infected children with definite or probable TB, anti-tuberculosis treatment is accompanied by a reduction in the magnitude of the IFN-gamma ELISpot response to MTB-antigens. However, serial IFN-gamma ELISpot measurements appear to have limited clinical utility in assessing a successful response to anti-tuberculous treatment in HIV infected children. [ABSTRACT FROM AUTHOR]

Background: Cancer creates an immunosuppressive environment that hampers immune responses, allowing tumors to grow and resist therapy. One way the immune system fights back is by inducing ferroptosis, a type of cell death, in tumor cells through CD8  +  T cells. This involves lipid peroxidation and enzymes like lysophosphatidylcholine acyltransferase 3 (Lpcat3), which makes cells more prone to ferroptosis. However, the mechanisms by which cancer cells avoid immunotherapy-mediated ferroptosis are unclear. Our study reveals how cancer cells evade ferroptosis and anti-tumor immunity through the upregulation of fatty acid-binding protein 7 (Fabp7)., Methods: To explore how cancer cells resist immune cell-mediated ferroptosis, we used a comprehensive range of techniques. We worked with cell lines including PD1-sensitive, PD1-resistant, B16F10, and QPP7 glioblastoma cells, and conducted in vivo studies in syngeneic 129 Sv/Ev, C57BL/6, and conditional knockout mice with Rora deletion specifically in CD8 + T cells, Cd8 cre;Rora fl mice. Methods included mass spectrometry-based lipidomics, targeted lipidomics, Oil Red O staining, Seahorse analysis, quantitative PCR, immunohistochemistry, PPARγ transcription factor assays, ChIP-seq, untargeted lipidomic analysis, ROS assay, ex vivo co-culture of CD8 + T cells with cancer cells, ATAC-seq, RNA-seq, Western blotting, co-immunoprecipitation assay, flow cytometry and Imaging Mass Cytometry., Results: PD1-resistant tumors upregulate Fabp7, driving protective metabolic changes that shield cells from ferroptosis and evade anti-tumor immunity. Fabp7 decreases the transcription of ferroptosis-inducing genes like Lpcat3 and increases the transcription of ferroptosis-protective genes such as Bmal1 through epigenetic reprogramming. Lipidomic profiling revealed that Fabp7 increases triglycerides and monounsaturated fatty acids (MUFAs), which impede lipid peroxidation and ROS generation. Fabp7 also improves mitochondrial function and fatty acid oxidation (FAO), enhancing cancer cell survival. Furthermore, cancer cells increase Fabp7 expression in CD8 + T cells, disrupting circadian clock gene expression and triggering apoptosis through p53 stabilization. Clinical trial data revealed that higher FABP7 expression correlates with poorer overall survival and progression-free survival in patients undergoing immunotherapy., Conclusions: Our study uncovers a novel mechanism by which cancer cells evade immune-mediated ferroptosis through Fabp7 upregulation. This protein reprograms lipid metabolism and disrupts circadian regulation in immune cells, promoting tumor survival and resistance to immunotherapy. Targeting Fabp7 could enhance immunotherapy effectiveness by re-sensitizing resistant tumors to ferroptosis., Competing Interests: Declarations. Competing interests: M.A.F.C. and J.W.W. has pending patent on a small molecule targeting Fabp7. J.W.W. is supported by Alkermes (Research grant), Nanobiotix (Research grant, Travel expenses, SAB), GSK (Research grant), BMS (Research grant), Merck (Research grant), Varian (Research grant, Travel expenses, clinical sponsored research), Checkmate Pharmaceuticals (Research grant, SAB), Reflexion (Research grant, Travel expenses, Stock options, SAB), Artidis (research grants, clinical sponsored research), Takeda (Research grant), Hotspot Therapeutics (Research grant), Gilead (Research grant), Kiromic (Research grant), Bayer Health (Research grant), Agenus (SAB), Novocure (SAB), Alpine Immune Science (SAB, stock options), Oncoresponse (SAB, stock options), Astra Zeneca (consultant), Nanorobotix (stock options), GI innovation (consultant), Molecular Match (Stock options, consultant), Kezar Life Science (SAB). M.A.D. has been a consultant to Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, Iovance, Merck, and ABM Therapeutics, and he has been the PI of research grants to MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, Oncothyreon, Pfizer, ABM Therapeutics, and LEAD Pharma. All other authors have no conflict of interest to declare., (© 2025. The Author(s).)

Purpose: Copanlisib, a pan-class phosphatidylinositol 3-kinase (PI3K) inhibitor with activity predominantly against the PI3K-delta and PI3K-alpha isoforms, has shown promising results in preclinical cancer models with PTEN loss. Herein, we report the activity and safety data from the Z1G and Z1H subprotocols, which included patients with PTEN loss, of the National Cancer Institute Molecular Analysis for Therapy Choice trial., Methods: Patients with complete loss of cytoplasmic and nuclear PTEN as determined by immunohistochemistry regardless of PTEN mutation or deletion status were included in subprotocol Z1G, and patients with a deleterious mutation in the PTEN gene and retained expression of PTEN were included in subprotocol Z1H. Copanlisib was given intravenously over 1 hour at a dose of 60 mg on days 1, 8, and 15 in a 21-day-on and 7-day-off schedule in 28-day cycles. Patients continued treatment until disease progression or unacceptable toxicity., Results: Overall, 49 patients (20 patients in Z1G and 29 in Z1H) were included in the primary efficacy analyses. The objective response rates in both cohorts were 0% (Z1G; 90% CI, 0 to 13.9) and 3.4% (Z1H; 90% CI, 0.2 to 15.3), respectively. The median progression-free and overall survival durations were 1.8 months (90% CI, 1.4 to 3.9 months) and 13.7 months (90% CI, 6.8 to 18.3 months) for the Z1G cohort and 1.8 months (90% CI, 1.8 to 2.1 months) and 9.0 months (90% CI, 5.4 to 13.3 months) for the Z1H cohort, respectively., Conclusion: Our results do not support the antitumor activity of single-agent copanlisib in tumors with PTEN loss regardless of mutation or deletion status or PTEN deleterious mutations with PTEN expression.

Introduction: Globally, children living with HIV continue to lag behind UNAIDS targets for viral suppression (VS). Because studies with linked mother-child data are limited, we describe VS and associated factors among young children in a setting with early infant HIV testing (at birth, age 10 weeks and 6 months) and early protease inhibitor-based first-line antiretroviral therapy (ART)., Methods: We analysed routinely collected mother-child data for children living with HIV born 2018-2022 in Western Cape province, South Africa (followed through mid-2023). We assessed associations between child and maternal viral load (VL) results at 12 and 24 months after child ART start using logistic regression, adjusted for child sex, birthyear, severity of child immunodeficiency at ART start, maternal age and timing of maternal HIV diagnosis., Results: Among 2219 children living with HIV; 30% were diagnosed at birth (≤7 days), 41% before age 1 year (8-365 days) and 29% at age >1 year. Overall, 5% (n = 112/2219) of children died, a third of whom had not started ART; 90% of children (n = 1990) started ART, at median age 5 months (IQR 1-16). Median follow-up from ART start was 26 months (IQR 14-40). Among children with available VL at 12 months (n = 853/1582), 24 months (n = 614/1129) and 36 months (n = 350/658) after ART start, 36%, 43% and 48% were virally suppressed, respectively (VL<100 copies/ml). VS among children at 12 and 24 months was more likely if maternal VL was <100 versus ≥100 copies/ml at 12 months (adjusted odds ratio [aOR] = 3.5; 95% CI 1.9-6.5) and 24 months (aOR = 6.1; 95% CI 2.8-13.1) after child ART start. Children with no/mild versus advanced/severe immunodeficiency at ART start were more likely to achieve VS at 12 months (aOR = 2.3; 95% CI 1.3-4.2) but not at 24 months. Eligible children with missing VL at 24 months (39%) were more likely to have gaps in care of >6 months than those with VL≥100 or VL<100 copies/ml (84% vs. 28% vs. 14%, respectively; p<0.001)., Conclusions: Less than half of children on ART achieved VS, and children were more likely to achieve VS if their mothers were also virally suppressed. Significant efforts are needed to support mother-child dyads to achieve optimal VS., (© 2025 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Melanoma mortality is driven by the formation and growth of distant metastases. Here, we interrogated the role of tumor oxidative phosphorylation (OXPHOS) in the formation of distant metastases in melanoma. OXPHOS was the most upregulated metabolic pathway in primary tumors that formed distant metastases in the RCAS-TVA mouse model of spontaneous lung and brain metastases, and in melanoma patients that developed brain or other distant metastases. Knockout of PGC1α in melanocytes in the RCAS-TVA melanoma mouse model had no impact on primary tumor formation, but markedly reduced the incidence of lung and brain metastases. Genetic knockout of a component of electron transport chain complex I, NDUFS4, in B16-F10 and D4M-UV2 murine melanoma cell lines did not impact tumor incidence following subcutaneous, intravenous, or intracranial injection, but decreased tumor burden specifically in the lungs and brain. Together, these data demonstrate that OXPHOS is critical for the formation of metastases in melanoma., Structured Abstract: Purpose: Melanoma mortality is driven by the formation and growth of distant metastases. However, the process and pathogenesis of melanoma metastasis remain poorly understood. Here, we interrogate the role of tumor oxidative phosphorylation (OXPHOS) in the formation of distant metastases in melanoma. Experimental Design: This study includes (1) new RNA-seq analysis of primary melanomas from patients characterized for distant metastasis events; (2) RNA-seq analysis and functional testing of genetic OXPHOS inhibition (PGC1α KO) the RCAS-TVA model, which is the only existing immunocompetent murine model of autochthonous lung and brain metastasis formation from primary melanoma tumors; and (3) functional experiments of genetic OXPHOS inhibition (NDUFS4 KO) in the B16-F10 and D4M-UV2 murine melanoma cell lines, including evaluation of subcutaneous, lung, and brain metastatic site dependencies. Results: OXPHOS was the most upregulated metabolic pathway in primary tumors that formed distant metastases in the RCAS-TVA mouse model of spontaneous lung and brain metastases, and in melanoma patients that developed brain or other distant metastases. Knockout of PGC1a in melanocytes in the RCAS-TVA melanoma mouse model had no impact on primary tumor formation, but markedly reduced the incidence of lung and brain metastases. Genetic knockout of a component of electron transport chain complex I, NDUFS4, in B16-F10 and D4M-UV2 murine melanoma cell lines did not impact tumor incidence following subcutaneous, intravenous, or intracranial injection, but decreased tumor burden specifically in the lungs and brain. Conclusions: Together, these data demonstrate that OXPHOS is critical for the formation of metastases in melanoma., Translational Relevance: Melanoma is the most aggressive form of skin cancer. One hallmark of this disease is a high risk of distant metastasis formation. The process and pathogenesis of metastasis in this disease remain poorly understood and there is controversy regarding the role of oxidative phosphorylation (OXPHOS) in melanoma metastasis. This study incorporates RNAseq analysis of primary melanoma tumors from patients characterized for distant metastasis events, RNAseq analysis of the only existing immunocompetent murine model of autochthonous lung and brain metastasis formation from primary melanoma tumors, and functional testing in multiple syngeneic models of melanoma at different tissue sites. This integrated analysis consistently demonstrates that melanoma OXPHOS promotes distant metastasis to the lungs and brain, two of the most common and clinically relevant sites of melanoma metastasis. This improved understanding of tumor OXPHOS may represent novel vulnerabilities for therapeutics development and surveillance/preventative strategies for melanoma metastasis.

Background: Data on tuberculosis (TB) incidence and risk factors among children living with HIV (CLHIV) in the universal ART era are limited., Methods: We analysed routinely-collected data on TB diagnoses for CLHIV age ≤5 years, born 2018-2022, in the Westen Cape, South Africa. We examined factors associated with TB diagnosis, with death and loss to follow-up as competing events., Results: Among 2,219 CLHIV, 30% were diagnosed with HIV at birth. Median follow-up from birth was 38 months (IQR 24-50); 90% started antiretroviral therapy (ART). TB was diagnosed in 28% of CLHIV (n=626/2219); 62% were first diagnosed before/within 3 months of ART start ('TB before ART') and 38% >3 months after ART start ('TB after ART'). Of those with 'TB before ART' (n=390), median age at HIV diagnosis was 13 months (IQR:6-22); median time between HIV and TB diagnoses was 5 days (IQR:0-31). 'TB before ART' was associated with older age at HIV diagnosis and advanced/severe immunodeficiency. Of those with 'TB after ART' (n=258), median age at HIV diagnosis was 2 months (IQR 0-8) and median time from ART start to TB diagnosis was 12 months (IQR:7-21). 'TB after ART' was associated with increased viral load and advanced/severe immunosuppression (time-updated). Overall, 5% (n=112/2219) of CLHIV died, 36% of whom were diagnosed with TB (median time from TB diagnosis to death: 58 days; IQR:17-191)., Conclusions: Young CLHIV in this setting have high TB-associated morbidity and mortality. Efforts to improve early HIV and TB diagnosis, viral suppression and TB preventive therapy are needed., Competing Interests: Conflicts of Interest and Source of Funding: The Western Cape Provincial Health Data Centre was supported by Grant Number U01AI069924 from the National Institutes of Health (NIH) (NIAID, NICHD, NCI, NIDA, NIMH) – PI: M. Egger and M-A. Davies. AB, MAD and EK were supported by Grant Number R01HD080465 (NICHD) and U01TW012626 (Fogarty International Centre) from the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. KA, MAD and EK received funding from ViiV Healthcare for a separate but related project. The other authors have no conflicts of interest to declare., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Data to Care (D2C) strategies - using routine data to facilitate identification and linkage back to care of people living with HIV who are not in care - have shown promise in high-income settings but received little attention in lower resourced or vertical HIV transmission prevention (VTP) contexts. In this proof-of-concept study, we monitored existing linked electronic medical records in near real-time to identify key gaps in postpartum VTP steps among 336 mothers living with HIV and their infants in Cape Town, South Africa (recruited March 2021 - April 2022). We attempted to confirm observed gaps through source data systems and telephonic tracing, and facilitated re-engagement in care where needed. There were 302 gaps observed in the routine data; 123 (41%) were false gaps and 179 (59%) were considered probable gaps (133 mother-infant pairs). Overall, 54 mothers (16%) did not link to HIV care within 12 weeks of delivery, 43 mothers (13%) linked to care but had a gap in ART dispensing by nine months postpartum, 25 infants (10%) did not have an HIV test around 10 weeks and 57 (17%) had no HIV test around 6 months of age. Only 100 of the probable gaps (56%) could be confirmed through telephonic tracing and, of those, only 47 were successfully re-linked to care. Mobility and clinic transfer, fear of stigma and employment-related challenges were commonly reported reasons for gaps in VTP steps. This study highlights that linked routine data sources linking mother-infant pairs across health facilities has the potential to streamline tracing efforts; however, implementation is challenging and, even when gaps are identified, re-engagement in care may be difficult. Further research is needed to combine D2C strategies with interventions addressing broader social and structural determinants of health, and to tailor D2C strategies to fit available resources and data sources in low-resource settings.

Background: For children with HIV on antiretroviral therapy (ART), transitioning to dolutegravir-containing regimens is recommended. The aim of this study was to assess whether introducing viral load testing to inform new nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) for children with HIV and viraemia alongside dolutegravir-based ART is beneficial and of good economic value., Methods: We used the Cost-Effectiveness of Preventing AIDS Complications-Pediatric model to project clinical and cost implications of three strategies among a simulated cohort of South African children aged 8 years with HIV receiving abacavir-lamivudine-efavirenz: (1) continue current ART (no dolutegravir; abacavir-lamivudine-efavirenz); (2) transition all children with HIV to dolutegravir, keeping current NRTIs (dolutegravir; abacavir-lamivudine-dolutegravir); or (3) transition to dolutegravir based on viral load testing (viral load plus dolutegravir), keeping current NRTIs if virologically suppressed (abacavir-lamivudine-dolutegravir, 70% of cohort) or switching abacavir to zidovudine (zidovudine) if viraemic (zidovudine-lamivudine-dolutegravir, 30%). We assumed 50% of children who had viraemia after abacavir-lamivudine exposure had NRTI resistance; with resistance, we assumed zidovudine-lamivudine-dolutegravir was more effective than abacavir-lamivudine-dolutegravir. We designated a strategy as preferred if it was most effective and least costly or had an incremental cost-effectiveness ratio less than half the South African 2020 gross domestic product per capita., Findings: Under base-case assumptions, the viral load plus dolutegravir strategy would be the most effective (projected undiscounted life expectancy of 39·72 life-years) and least costly strategy (US$24 600 per person); the no dolutegravir strategy was the least effective (34·49 life-years) and most expensive ($26 480 per person). In sensitivity analyses, the 24-week virological suppression probability and subsequent monthly virological failure risks (ie, late failure) were most influential on cost-effectiveness. Only with a high late-failure risk for zidovudine-lamivudine-dolutegravir (ie, ≥0·3% per month in the base case or >0·5% per month if abacavir also confers low virological suppression probability in the presence of NRTI resistance [65%]) would the dolutegravir strategy become preferred above the viral load plus dolutegravir strategy., Interpretation: For programmes transitioning to dolutegravir-based regimens, our model predicted that doing so would be more effective and less costly than continuing current ART regimens, regardless of NRTI choice. Whether viral load testing for children with HIV is necessary to inform NRTI choice depends substantially on the comparative outcomes of abacavir and zidovudine after switching to dolutegravir-containing ART., Funding: The Eunice Kennedy Shriver Institute for Child Health and Human Development, the National Institute of Allergy and Infectious Diseases, the Massachusetts General Hospital Executive Committee on Research, the Massachusetts General Hospital, and the Medical Research Council., Competing Interests: Declaration of interests IJC and SC received funding via their institution from ViiV Healthcare and Gilead Sciences, outside of the submitted work. M-AD received funding to her institution from ViiV Healthcare. ALC, EA, EPH, and KAF received funding to their respective institutions from the National Institutes of Health. ALC and EPH received funding from the Massachusetts General Hospital. EPH received royalties from UpToDate. All other authors declare no competing interests., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd. This is an Open Access article published under the CC BY NC ND 3.0 IGO license which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is properly cited. This article shall not be used or reproduced in association with the promotion of commercial products, services or any entity. There should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients., Methods: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models., Results: CLPP expression was detected in primary and mUM patient samples. ONC201 and 212 decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis in human UM cell lines in vitro. ONC212 inhibited OXPHOS, increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models., Conclusions: Imipridones are a promising strategy for further testing and development in mUM., Competing Interests: Competing interests: VVP is an employee and stockholder of Chimerix/Oncoceutics. MAD has been a consultant to Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, Iovance, Merck, and ABM Therapeutics, and he has been the PI of research grants to The University of Texas MD Anderson Cancer Center by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, Oncothyreon, Pfizer, ABM Therapeutics, and LEAD Pharma. Ethics approval and consent to participate: All procedures performed in obtaining tissues from human participants were in accordance with the ethical standards of The University of Texas MD Anderson Cancer Center and ethical tenets in the Declaration of Helsinki. All the human tissues were obtained and banked under The University of Texas MD Anderson Cancer Center approved IRB protocol. We attest that all human tissues were obtained with informed consent from subjects involved. All animal studies and procedures were performed in accordance with The University of Texas at MD Anderson Cancer Center’s approved IACUC protocol following relevant guidelines and regulations. Consent for publication: All authors have been provided with a copy of the manuscript and have reviewed prior to submission and have provided consent to publication., (© 2024. The Author(s).)

Using the Data Evaluation and Preparation for HIV-Exposed Uninfected Child Cohorts project's standardized child HIV exposure definitions, 64%, 64% and 90% of children exposed to HIV in utero could be classified as HIV-uninfected with moderate or high certainty at the ages of 1 and 3 years and at the time of first infectious disease hospitalization, respectively. These definitions can be applied retrospectively to routine datasets with linked mother-child data., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Since 2022, many countries have reported an upsurge in invasive group A streptococcal (iGAS) infections. We explored whether changes in Streptococcus pyogenes carriage rates or emergence of strains with potentially altered virulence, such as emm 1 variants M1 UK and M1 DK , contributed to the 2022/2023 surge in the Netherlands. We determined emm (sub)type distribution for 2,698 invasive and 351 S . pyogenes carriage isolates collected between January 2009 and March 2023. Genetic evolution of emm 1 was analyzed by whole-genome sequencing of 497 emm 1 isolates. The nationwide iGAS upsurge coincided with a sharp increase of emm 1.0 from 18% (18/100) of invasive isolates in Q1 2022 to 58% (388/670) in Q1 2023 (Fisher's exact test, P < 0.0001). M1 UK became dominant among invasive emm 1 isolates in 2016 and further expanded from 72% in Q1 2022 to 96% in Q1 2023. Phylogenetic comparison revealed evolution and clonal expansion of four new M1 UK clades in 2022/2023. DNase Spd1 and superantigen SpeC were acquired in 9% (46/497) of emm 1 isolates. S. pyogenes carriage rates and emm 1 proportions in carriage isolates remained stable during this surge, and the expansion of M1 UK in iGAS was not reflected in carriage isolates. During the 2022/2023 iGAS surge in the Netherlands, expansion of four new M1 UK clades was observed among invasive isolates, but not carriage isolates, suggesting increased virulence and fitness of M1 UK compared to contemporary M1 strains. The emergence of more virulent clades has important implications for public health strategies such as antibiotic prophylaxis for close contacts of iGAS patients.IMPORTANCEThis study describes the molecular epidemiology of invasive group A streptococcal (iGAS) infections in the Netherlands based on >3,000 Streptococcus pyogenes isolates from both asymptomatic carriers and iGAS patients collected before, during, and after the COVID-19 pandemic period (2009-2023) and is the first to assess whether changes in carriage rates or carried emm types contributed to the alarming post-COVID-19 upsurge in iGAS infections. We show that the 2022/2023 iGAS surge coincided with a sharp increase of emm 1, particularly the toxicogenic M1 UK variant, in invasive isolates, but not in carriage isolates. These findings suggest that increased virulence and fitness of M1 UK likely contributes to an increased dissemination between hosts. The emergence of a more virulent and fit lineage has important implications for iGAS control interventions such as antibiotic prophylaxis for close contacts of iGAS patients and calls for a reappraisal of iGAS control interventions and guidelines., Competing Interests: N.M.V.S. reports fee for service and presentations from MSD and GSK, grants from the Dutch Health Council (ZonMW; all directly paid to the institution), contract research with Argenx (unrelated to this work), a patent on vaccine development against S. pyogenes (licensee: University of California San Diego, inventors Nina van Sorge and Victor Nizet; licensed by Vaxcyte; personal revenue), and participation in the science advisory board of the ItsME foundation (no honorarium; https://itsme-foundation.com/en/) and Rapua te me ngaro ka tau, a project facilitating Strep A vaccine development for Aotearoa New Zealand (honorarium paid directly to the institution). M.A.V.H. reports grants or contracts with Pfizer (RSV prevention uptake study) and consulting fee from Pfizer on RSV vaccination (both unrelated to this work). Other authors have nothing to disclose.

Background: Pretreatment of HIV drug resistance among children living with HIV (CLHIV) can compromise antiretroviral therapy (ART) effectiveness. Resistance may be transmitted directly from mothers or acquired following exposure to antiretrovirals consumed through breastfeeding or administered as prophylaxis., Methods: We performed resistance testing in children aged <3 years, newly diagnosed with HIV in Western Cape, South Africa (2021-2022), who either (1) acquired HIV via possible breastfeeding transmission from mothers who received ART (any regimen) during pregnancy/postpartum and/or (2) were exposed to protease inhibitors or integrase strand transfer inhibitors (INSTIs) in utero. Possible breastfeeding transmission was defined as testing HIV-polymerase chain reaction positive at age >28 days, after previously testing negative. We used surveillance drug-resistance mutation lists to define mutations., Results: We included 135 CLHIV. Most mothers started ART prepregnancy (73%). Overall, 57% (77/135) of children had resistance mutations detected. Nonnucleoside reverse transcriptase inhibitor-associated, nucleoside reverse transcriptase inhibitor-associated, protease inhibitor-associated and INSTI-associated mutations were found in 55% (74/135), 10% (13/135), <1% (1/135) and <1% (1/122) of children tested, respectively. One child with breastfeeding transmission had high-level INSTI resistance detected at HIV diagnosis, aged 18 months (E138K and G118R mutations)., Conclusions: Although not clinically relevant, nonnucleoside reverse transcriptase inhibitor-associated mutations were common. Dolutegravir is currently the preferred first-line treatment for adults and CLHIV age ≥4 weeks, and although very low INSTI resistance levels have been observed in adults, limited data exist on genotyping the integrase region in children. Pretreatment INSTI resistance in children is likely to be unusual, but future surveillance, including longitudinal studies with paired mother-child resistance testing, is needed., Competing Interests: K.A., E.K. and M.-A.D. received funding from ViiV Healthcare for this project. The Provincial Health Data Centre was supported by grant U01AI069924 from National Institutes of Health (National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Cancer Institute, National Institute on Drug Abuse and National Institute of Mental Health)—Principal Investigator: M. Egger and M.-A.D. E.K., A.B. and M.-A.D. were supported by grant R01HD080465 from National Institutes of Health (National Institute of Child Health and Human Development). The other authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) are foundational resources in cancer research, providing extensive molecular and phenotypic data. However, large-scale proteomic data across various cancer types for these cohorts remain limited. Here, we expand upon our previous work to generate high-quality protein expression data for approximately 8,000 TCGA patient samples and around 900 CCLE cell line samples, covering 447 clinically relevant proteins, using reverse-phase protein arrays. These protein expression profiles offer profound insights into intertumor heterogeneity and cancer dependency and serve as sensitive functional readouts for somatic alterations. We develop a systematic protein-centered strategy for identifying synthetic lethality pairs and experimentally validate an interaction between protein kinase A subunit α and epidermal growth factor receptor. We also identify metastasis-related protein markers with clinical relevance. This dataset represents a valuable resource for advancing our understanding of cancer mechanisms, discovering protein biomarkers and developing innovative therapeutic strategies., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)