Site-specific therapy guided by a 90-gene expression assay versus empirical chemotherapy in patients with cancer of unknown primary (Fudan CUP-001): a randomised controlled trial.

BACKGROUND: Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP. METHODS: This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m2 by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m2 by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600). FINDINGS: Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequent of these in the site-specific therapy and empirical chemotherapy groups were decreased neutrophil count (36 [44%] vs 42 [49%]), decreased white blood cell count (17 [21%] vs 26 [31%]), and anaemia (ten [12%] vs nine [11%]). Treatment-related serious adverse events were reported in five (6%) patients in the site-specific therapy group and two (2%) in the empirical chemotherapy group. No treatment-related deaths were observed. INTERPRETATION: This single-centre randomised trial showed that site-specific therapy guided by the 90-gene expression assay could improve progression-free survival compared with empirical chemotherapy among patients with previously untreated CUP. Site-specific prediction by the 90-gene expression assay might provide more disease information and expand the therapeutic armamentarium in these patients. FUNDING: Clinical Research Plan of Shanghai Hospital Development Center, Program for Shanghai Outstanding Academic Leader, and Shanghai Anticancer Association SOAR PROJECT. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Differences in the incidence and mortality of digestive cancer between Global Cancer Observatory 2020 and Global Burden of Disease 2019.

The burden of digestive cancers is increasing worldwide. The Global Cancer Observatory (GLOBOCAN) 2020 and the Global Burden of Disease (GBD) 2019 are two primary cancer databases, which have a significant impact on policy formulation and resource allocation. We aim to compare the incidence and mortality of digestive cancers between them. Digestive cancer (esophageal, stomach, colorectal, liver, gallbladder and pancreatic cancer) incidence was obtained from the Cancer Today and GBD 2019 result tool. The top five countries with the most or minor difference between GLOBOCAN 2020 and GBD 2019 in age-standardized incidence rates (ASIRs) of digestive cancers were identified. A systematic search on the incidence of specific digestive cancer in selected countries from PubMed and Embase was conducted, and 20 of 281 publications were included. The most significant differences in digestive cancers incidence were commonly found in Asian countries (70%), particularly Indonesia, Vietnam and Myanmar, located in Southeast Asia. The ASIRs for most digestive cancers, except liver cancer, in GLOBOCAN 2020 were higher than those in GBD 2019. Gallbladder cancer had the highest average ratio, followed by liver cancer. The most commonly used standard population was Segi's standard population, followed by the World Health Organization standard population. The data sources nor the processing methods of GLOBOCAN 2020 and GBD 2019 were not similar. Low- and middle-income countries without population-based cancer registries were more likely to have selection bias in data collection and amplify regional variations of etiological factors. Better judgments on the quality of cancer data can be made.

Biosynthesis of Halogenated Tryptophans for Protein Engineering Using Genetic Code Expansion.

Genetic Code Expansion technology offers significant potential in incorporating noncanonical amino acids into proteins at precise locations, allowing for the modulation of protein structures and functions. However, this technology is often limited by the need for costly and challenging-to-synthesize external noncanonical amino acid sources. In this study, we address this limitation by developing autonomous cells capable of biosynthesizing halogenated tryptophan derivatives and introducing them into proteins using Genetic Code Expansion technology. By utilizing inexpensive halide salts and different halogenases, we successfully achieve the selective biosynthesis of 6-chloro-tryptophan, 7-chloro-tryptophan, 6-bromo-tryptophan, and 7-bromo-tryptophan. These derivatives are introduced at specific positions with corresponding bioorthogonal aminoacyl-tRNA synthetase/tRNA pairs in response to the amber codon. Following optimization, we demonstrate the robust expression of proteins containing halogenated tryptophan residues in cells with the ability to biosynthesize these tryptophan derivatives. This study establishes a versatile platform for engineering proteins with various halogenated tryptophans.

Multifaceted anomaly detection framework for leachate monitoring in landfills.

The imperative to preserve environmental resources has transcended traditional conservation efforts, becoming a crucial element for sustaining life. Our deep interconnectedness with the natural environment, which directly impacts our well-being, emphasizes this urgency. Contaminants such as leachate from landfills are increasingly threatening groundwater, a vital resource that provides drinking water for nearly half of the global population. This critical environmental threat requires advanced detection and monitoring solutions to effectively safeguard our groundwater resources. To address this pressing need, we introduce the Multifaceted Anomaly Detection Framework (MADF), which integrates Electrical Resistivity Tomography (ERT) with advanced machine learning models-Isolation Forest (IF), One-Class Support Vector Machines (OC-SVM), and Local Outlier Factor (LOF). MADF processes and analyzes ERT data, employing these hybrid machine learning models to identify and quantify anomaly signals accurately via the majority vote strategy. Applied to the Chaling landfill site in Zhuzhou, China, MADF demonstrated significant improvements in detection capability. The framework enhanced the precision of anomaly detection, evidenced by higher Youden Index values (≈ 6.216%), with a 30% increase in sensitivity and a 25% reduction in false positives compared to traditional ERT inversion methods. Indeed, these enhancements are crucial for effective environmental monitoring, where the cost of missing a leak could be catastrophic, and for reducing unnecessary interventions that can be resource-intensive. These results underscore MADF's potential as a robust tool for proactive environmental management, offering a scalable and adaptable solution for comprehensive landfill monitoring and pollution prevention across varied environmental settings.

Three-dimensional (3-D) fluoride molecular glue to improve the SnO2/perovskite interface for efficient perovskite solar cells.

Aiming at numerous defects at SnO2/perovskite interface and lattice mismatch in perovskite solar cells (PSCs), we design a kind of three-dimensional (3D) molecular glue (KBF4-TFMSA), which is derived from strong intramolecular hydrogen bonding interaction between potassium tetrafluoroborate (KBF4) and trifluoromethanesulfonamide (TFMSA). A remarkable efficiency of 25.8% with negligible hysteresis and a stabilized power output of 25.0% have been achieved, in addition, 24.57% certified efficiency of 1 cm2 device is also obtained. Further investigation reveals that this KBF4-TFMSA can interact with oxygen vacancies and under-coordinated Sn(IV) from the SnO2, in the meantime, FA+ (NH2-C=NH) and K+ cations can be well fixed by hydrogen bonding interaction between FA+  and BF4-, and electrostatic attraction between sulfonyl oxygen and K+ ions, respectively. Thereby, FAPbI3 crystal grain sizes are increased, interfacial defects are significantly reduced and carrier extraction/transport is facilitated, leading to better cell performance and excellent stabilities. Non-encapsulated devices can maintain 91% of their initial efficiency under maximum-power-point (MPP) tracking while continuous illumination (~100 mW cm-2) for 1000 h, and retain 91% of the initial efficiency after 1000 h "double 60" damp-heat stability testing (60°C and 60%RH (RH, relatively humidity)).

CircAGO2 promotes colorectal cancer progression by inhibiting heat shock protein family B (small) member 8 via miR-1-3p/retinoblastoma binding protein 4 axis.

This paper was to uncover the mechanism of circular RNA Argonaute 2 (circAGO2) in colorectal cancer (CRC) progression. The expression of circAGO2 was detected in CRC cells and tissues, and the relationship between clinicopathological features of CRC and circAGO2 level was evaluated. The growth and invasion of CRC cells and subcutaneous xenograft of nude mice were measured to evaluate the effect of circAGO2 on CRC development. Bioinformatics databases were applied to analyze levels of retinoblastoma binding protein 4 (RBBP4) and heat shock protein family B 8 (HSPB8) in cancer tissues. The relevance of circAGO2 and RBBP4 expression and the relationship between RBBP4 and HSPB8 during histone acetylation were assessed. The targeting relationship between miR-1-3p and circAGO2 or RBBP4 was predicted and confirmed. The effects of miR-1-3p and RBBP4 on biological functions of CRC cells were also verified. CircAGO2 was upregulated in CRC. CircAGO2 promoted the growth and invasion of CRC cells. CircAGO2 competitively bound to miR-1-3p and regulated RBBP4 expression, thus inhibiting HSPB8 transcription by promoting histone deacetylation. Silencing circAGO2 enhanced miR-1-3p expression and reduced RBBP4 expression, while suppression of miR-1-3p downgraded levels of miR-1-3p, up-regulated RBBP4, and facilitated cell proliferation and invasion in the presence of silencing circAGO2. RBBP4 silencing decreased RBBP4 expression and reduced proliferation and invasion of cells where circAGO2 and miR-1-3p were silenced. CircAGO2 overexpression decoyed miR-1-3p to increase RBBP4 expression, which inhibited HSPB8 transcription via histone deacetylation in HSPB8 promoter region, promoting proliferation and invasion of CRC cells.

HNOXPred: a web tool for the prediction of gas-sensing H-NOX proteins from amino acid sequence.

SUMMARY: HNOXPred is a webserver for the prediction of gas-sensing heme-nitric oxide/oxygen (H-NOX) proteins from amino acid sequence. H-NOX proteins are gas-sensing hemoproteins found in diverse organisms ranging from bacteria to eukaryotes. Recently, gas-sensing complex multi-functional proteins containing only the conserved amino acids at the heme centers of H-NOX proteins, have been identified through a motif-based approach. Based on experimental data and H-NOX candidates reported in the literature, HNOXPred is created to automate and facilitate the identification of similar H-NOX centers across systems. The server features HNOXSCORES scaled from 0 to 1 that consider in its calculation, the physicochemical properties of amino acids constituting the heme center in H-NOX in addition to the conserved amino acids within the center. From user input amino acid sequence, the server returns positive hits and their calculated HNOXSCORES ordered from high to low confidence which are accompanied by interpretation guides and recommendations. The utility of this server is demonstrated using the human proteome as an example. AVAILABILITY AND IMPLEMENTATION: The HNOXPred server is available at https://www.hnoxpred.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Plasmonic fiber-optic sensing system for in situ monitoring the capacitance and temperature of supercapacitors.

Compared with ex situ measurement, the in situ measurement is more suitable for inspecting complex electrochemical reactions and improving the intelligent energy storage management. However, most of the in situ investigation instruments are bulky and expensive. Here we demonstrate a miniaturized, portable, and low-cost fiber-optic sensing system for in situ monitoring the capacitance and temperature. It can help evaluate the self-discharge rate in supercapacitors (SCs). The fiber-optic sensing system with two probes are implanted inside the SCs to monitor the capacitance and temperature, respectively. The dual fiber-optic probes can work independently and avoid cross-interference through structure design. The fiber-optic localized surface plasmon resonance (LSPR) probe near the electrode surface can detect the capacitance in real-time by monitoring ion aggregation on the opposite electrode. The fiber-optic surface plasmon resonance (SPR) probe encapsulated in the thermosensitive liquid can independently detect the temperature change. The measurement uncertainties of the two sensing probes are 5.6 mF and 0.08 ℃, respectively. The proposed tiny and flexible fiber-optic sensing system provides a promising method for in situ monitoring the critical parameters. It is also a powerful tool for investigating electrochemical reactions in various energy storage devices.

Rh-endostatin combined with chemotherapy in patients with advanced or recurrent mucosal melanoma: retrospective analysis of real-world data.

BACKGROUND: Mucosal melanoma is rare and has distinct clinical and genetic features. Even with advances in targeted and immune therapies, the survival of patients with advanced or recurrent mucosal melanomas remains poor. The standard treatment remains controversial and we conducted this real-world study aimed to explore continuous intravenous recombinant human endostatin (Rh-endostatin) infusion plus chemotherapy in this population in the first-line setting. METHODS: Overall, 43 patients with advanced or recurrent mucosal melanoma treated at Fudan University Shanghai Cancer Center between April 2017 and August 2020 were retrospectively included. Patients received dacarbazine plus cisplatin or temozolomide plus cisplatin per the investigators' preference. Rh-endostatin (105 mg/m2) was administered with continuous infusion for 168 h (Civ 168 h). RESULTS: Of the 43 patients, 72.1% had metastatic disease, and the most common primary site was the gastrointestinal tract (51.2%). The most commonly observed mutations were NRAS (23.1%), BRAF (7.7%) and CKIT mutations (5.1%). An objective response was observed in 12 (30.0%) of the 40 evaluable patients, and disease control was achieved in 31 (77.5%) patients. With a median follow-up of 17.6 months, the median progression-free survival (PFS) and overall survival (OS) were 4.9 and 15.3 months, respectively. Additionally, high lymphocyte-to-monocyte ratio (LMR) (p = 0.023, HR 0.29, 95% CI: 0.10-0.84) and BRAF/KIT/RAS mutation (p = 0.028, HR 0.24, 95% CI: 0.07-0.86) were independently correlated with prolonged OS. Toxicity was manageable overall. CONCLUSION: Continuous Rh-endostatin infusion plus chemotherapy was effective and safe for the treatment of advanced or recurrent mucosal melanoma. High LMR was correlated with favorable PFS and OS in this patient population.

Prognostic significance of baseline neutrophil-lymphocyte ratio in patients with non-small-cell lung cancer: a pooled analysis of open phase III clinical trial data.

Aim: This study aimed to assess survival and hematological prognostic indicators of patients with non-small-cell lung cancer (NSCLC). Material & methods: Through the Project Data Sphere portal, two phase III clinical trial datasets were downloaded to analyze survival outcomes and related risk factors. Results: The median progression-free survival and overall survival of 756 patients with stage III-IV NSCLC were 6.2 and 14.2 months, respectively. In multivariate Cox analysis, high baseline neutrophil-lymphocyte ratio (NLR; ≥3.8) was associated with worse progression-free survival (hazard ratio: 1.37; p = 0.0004) and overall survival (hazard ratio: 1.65; p < 0.0001). In addition, it exerted an unfavorable impact on survival across multiple subgroups. Conclusions: NLR, a powerful inflammatory and immunologic indicator, is an independent prognostic indicator in patients with advanced NSCLC.

Control of wakefulness by lateral hypothalamic glutamatergic neurons in male mice.

The lateral hypothalamus (LH) plays a key role in the maintenance of cortical activation and wakefulness. In the LH, the two main neuronal cell populations consist of excitatory glutamatergic neurons and inhibitory GABAergic neurons. Recent studies have shown that inhibitory LH GABAergic neurons are wake-promoting. However, the mechanism by which excitatory LH glutamatergic neurons contribute to sleep-wake regulation remains unclear. Using fiber photometry in male mice, we demonstrated that LH glutamatergic neurons exhibited high activities during both wakefulness and rapid eye movement sleep. Chemogenetic activation of LH glutamatergic neurons induced an increase in wakefulness that lasted for 6 hr, whereas suppression of LH glutamatergic neuronal activity caused a reduction in wakefulness. Brief optogenetic activation of LH glutamatergic neurons induced an immediate transition from slow-wave sleep to wakefulness, and long-lasting optogenetic stimulation of these neurons maintained wakefulness. Moreover, we found that LH-locus coeruleus/parabrachial nucleus and LH-basal forebrain projections mediated the wake-promoting effects of LH glutamatergic neurons. Taken together, our data indicate that LH glutamatergic neurons are essential for the induction and maintenance of wakefulness. The results presented here may advance our understanding of the role of LH in the control of wakefulness.

Carboplatin versus cisplatin in combination with etoposide in the first-line treatment of small cell lung cancer: a pooled analysis.

BACKGROUND: Extensive-stage small cell lung cancer (ES-SCLC) is an aggressive disease with poor survival, and platinum-etoposide chemotherapy is indicated as the mainstay of treatment. In this study, we compared the efficacy and safety between the cisplatin plus etoposide (EP) and carboplatin plus etoposide (EC) regimens. METHODS: A total of 1305 patients with previously untreated ES-SCLC were included in this study. Data from five trials were collected from the public database Project Data Sphere. Survival analysis and adverse events (AEs) analysis were conducted. RESULTS: Of the 1305 patients, 800 received the EC regimen whereas 505 received the EP regimen as their front-line treatment. Overall, the median progression-free survival (PFS) and the median overall survival (OS) were 172 and 289 days, respectively. The EP and EC treatment groups did not have significantly different PFS or OS. After adjusting for age, sex, body mass index (BMI) and Eastern Cooperative Oncology Group (ECOG) performance status (PS), the EP regimen was independently associated with better PFS (hazard ratio [HR] = 0.76, 95% CI = 0.63-0.92, p = 0.0041) and OS (HR = 0.79, 95% CI = 0.64-0.97, p = 0.0220) among patients who were overweight and obese (BMI ≥ 25 kg/m2). In the safety analysis, patients who received the EC treatment experienced significantly more grade ≥ 3 AEs (n = 599, 74.9%) than those who received the EP treatment (n = 337, 66.7%; p = 0.002). Furthermore, the EC regimen was associated with a higher risk of grade 3-4 neutropaenia (p = 0.001), thrombocytopaenia (p < 0.001) and hyponatraemia (p = 0.036), whereas the EP regimen was associated with a higher risk of grade 3-4 vomiting (p = 0.021). CONCLUSIONS: In summary, this study presented the efficacy and safety of the EC and EP regimens in patients with ES-SCLC in the first-line setting. Patients who are overweight and obese benefit more from the EP regimen than EC regimen. Approaches to define the optimal chemotherapy regimen in different BMI subgroups are needed.

De novo assembly of Auricularia polytricha transcriptome and discovery of genes involved in the degradation of lignocellulose.

Auricularia polytricha belonging to Basidiomycota has the ability to degrade lignocellulose. However, there has been no resource in public databases examining the transcriptome of A. polytricha. In this study, high-throughput sequencing platform BGISEQ-500 was used to generate large amount of transcript sequences from A. polytricha for gene discovery and molecular marker development. A total of 28,102 unigenes were discovered from the assembly of clean reads. In addition, functional categorization of the gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) metabolic pathways revealed several important biological processes. GO annotation analysis presented 47 categories, with the major subcategories being catalytic activity, binding, cellular process, metabolic process, and cell. Among the five functional categories and 21 subcategories of processes discovered from KEGG, global and overview maps, carbohydrate metabolism, transport, and catabolism are the main subcategories. Furthermore, among the unigenes related to lignocellulosic degradation discovered by KEGG pathway enrichment analysis, 2, 5, and 16 unigenes in de novo assembly of A. polytricha transcriptome were found to relate to cellulose, hemicellulose, and lignin degradation, respectively. The study provided valuable information on the degradation of lignocellulose to facilitate research on the degradation mechanism, molecular marker, functional research, gene mapping, and other multigenomic studies of species containing lignocellulose.

Chidamide combined with cyclophosphamide, doxorubicin, vincristine and prednisone in previously untreated patients with peripheral T-cell lymphoma.

OBJECTIVE: Chidamide is an oral histone deacetylase subtype-selective inhibitor approved for relapsed or refractory peripheral T-cell lymphoma (PTCL). This phase 1b study evaluated the safety, pharmacokinetics, and preliminary efficacy of chidamide in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) for treatment-naïve PTCL patients. METHODS: This study was an open-label, multicenter trial composed of dose escalation and dose expansion. Patients received CHOP for six 21-d cycles and chidamide on d 1, 4, 8 and 11 in each cycle. Four dose levels of chidamide (20, 25, 30 and 35 mg) were evaluated. The primary objective was to evaluate the safety and tolerability of the combination regimen. RESULTS: A total of 30 patients were evaluated in this study: 15 in the dose-escalation part and 15 in the dose-expansion part. In the dose-escalation study, three patients were enrolled in the 35 mg chidamide cohort. One had dose-limiting toxicity with grade 3 vascular access complications, and one had grade 2 neutropenia with a sustained temperature >38 °C. Dose escalation was stopped at this chidamide dose level. The most common (≥10%) grade 3 or 4 adverse events (AEs) were leukopenia (90.0%), neutropenia (83.3%), vomiting (13.3%), thrombocytopenia (10.0%) and febrile neutropenia (10.0%). No significant changes in chidamide pharmacokinetic properties were observed before and after combination treatment. The objective response rate for the 28 patients evaluable for preliminary efficacy was 89.3% (25/28), with 16 (57.1%) achieving complete response or unconfirmed complete response. The estimated median progression-free survival was 14.0 months. In summary, we chose chidamide 30 mg as the recommended dose for phase 2. CONCLUSIONS: The addition of chidamide to standard CHOP chemotherapy was tolerable with promising preliminary efficacy in previously untreated PTCL patients, which supports further clinical studies with this combination regimen for the frontline treatment of PTCL.

Clinical features and prognostic factors for extracranial oligometastatic breast cancer in China.

Evidence of an oligometastatic state in metastatic breast cancer (MBC) is relatively limited. The aim of our study was to investigate the clinical features and prognostic factors for extracranial oligometastatic breast cancer and to identify the best treatment approaches in this select population. Fifty postoperative inpatients diagnosed with extracranial oligometastatic breast cancer at the National Cancer Center in China between 2009 and 2014 were consecutively enrolled. Oligometastatic breast cancer was defined as MBC with three or fewer metastatic lesions confined to one organ; de novo Stage IV disease and local-regional recurrence were excluded. The median progression-free survival (PFS) and overall survival (OS) times were 15.2 and 78.9 months, respectively, and the 2-year PFS and 5-year OS rates were 40% and 58%, respectively. First-line treatment approach with standard systemic treatment + surgical resection for all metastatic lesions was an independent prognostic factor for prolonged PFS (hazard ratio = 0.32; 95% confidence interval [CI], 0.14-0.73; P = .006) and OS (hazard ratio = 0.35; 95% CI, 0.14-0.86; P = .022). Subgroup analysis showed that patients with a disease-free interval (DFI) ≥24 months, one metastatic lesion or the hormone receptor (HR) + subtype were more likely to get benefit from resection. Patients with oligometastatic breast cancer have a relatively good prognosis. Surgical resection for metastatic lesions could significantly improve PFS and OS. Further prospective research is warranted to confirm the results and to develop biomarkers for better patient selection.

Molecular profiling of Chinese R-CHOP treated DLBCL patients: Identifying a high-risk subgroup.

Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive and heterogenous disease. Although most patients can be cured by immunochemotherapy, 30% to 40% patient will ultimately develop relapsed or refractory disease. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP. We performed capture-based targeted sequencing on baseline samples of 105 DLBCL patients using a panel consisting of 112 lymphoma-related genes. Subsequently, 81 treatment-naïve patients with measurable disease and followed for over 1 year were included for survival analysis. Collectively, the most commonly seen mutations included IGH fusion (69%), PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (87.0% vs 50.0%, P = .009). For those with TP53 disruptive mutations, 91.7% patients were in the primary refractory group. Interestingly, BCL-2 somatic hypermutation was only seen in patients without primary refractory disease (P = .014). In multivariate analysis, BCL-2 amplification (hazard ratio [HR] = 2.94, P = .022), B2M mutation (HR = 2.99, P = .017) and TP53 mutation (HR = 3.19, P < .001) were independently associated with shorter time to progression (TTP). Furthermore, TP53 mutations was correlated with worse overall survival (P = .049). Next, we investigated mutation landscape in patients with wild-type (WT) TP53 (n = 58) and found that patients harboring MYD88 L265P had significantly inferior TTP than those with WT or non-265P (P = .046). Our study reveals the mutation spectrum of treatment-naive Chinese DLBCL patients. It also confirms the clinical significance of TP53 mutations and indicates the prognostic value of MYD88 L265P in TP53 WT patients.

The short-term health and psychosocial impacts of domestic energy efficiency investments in low-income areas: a controlled before and after study.

BACKGROUND: Research suggests that living in fuel poverty and cold homes contributes to poor physical and mental health, and that interventions targeted at those living in poor quality housing may lead to health improvements. However, little is known about the socio-economic intermediaries and processes that contribute to better health. This study examined the relationship between energy efficiency investments to homes in low-income areas and mental and physical health of residents, as well as a number of psychosocial outcomes likely to be part of the complex relationship between energy efficiency measures and health outcomes. METHODS: A quasi-experimental field study with a controlled pretest-posttest design was conducted (intervention n = 364; control n = 418) to investigate the short-term health and psychosocial impacts of a domestic energy efficiency programme that took place across Wales between 2013 and 2015. Survey data were collected in the winters before and after installation of energy efficiency measures, including external wall insulation. The study used a multilevel modelling repeated measures approach to analyse the data. RESULTS: The energy efficiency programme was not associated with improvements in physical and mental health (using the SF-12v2 physical and mental health composite scales) or reductions in self-reported respiratory and asthma symptoms. However, the programme was associated with improved subjective wellbeing (B = 0.38, 95% CI 0.12 to 0.65), as well as improvements in a number of psychosocial outcomes, including increased thermal satisfaction (OR = 3.83, 95% CI 2.40 to 5.90), reduced reports of putting up with feeling cold to save heating costs (OR = 0.49, CI = 0.25 to 0.94), fewer financial difficulties (B = -0.15, 95% CI -0.25 to -0.05), and reduced social isolation (OR = 0.32, 95% CI 0.13 to 0.77). CONCLUSION: The study showed that investing in energy efficiency in low-income communities does not lead to self-reported health improvements in the short term. However, investments increased subjective wellbeing and were linked to a number of psychosocial intermediaries that are conducive to better health. It is likely that better living conditions contribute to improvements in health outcomes in the longer term. Better understanding of the impacts on recipients of energy efficiency schemes, could improve targeting of future fuel poverty policies.

Cold homes, fuel poverty and energy efficiency improvements: A longitudinal focus group approach.

Cold homes and fuel poverty have been identified as factors in health and social inequalities that could be alleviated through energy efficiency interventions. Research on fuel poverty and the health impacts of affordable warmth initiatives have to date primarily been conducted using quantitative and statistical methods, limiting the way how fuel poverty is understood. This study took a longitudinal focus group approach that allowed exploration of lived experiences of fuel poverty before and after an energy efficiency intervention. Focus group discussions were held with residents from three low-income communities before (n = 28) and after (n = 22) they received energy efficiency measures funded through a government-led scheme. The results show that improving the energy efficiency of homes at risk of fuel poverty has a profound impact on wellbeing and quality of life, financial stress, thermal comfort, social interactions and indoor space use. However, the process of receiving the intervention was experienced by some as stressful. There is a need for better community engagement and communication to improve the benefits delivered by fuel poverty programmes, as well as further qualitative exploration to better understand the wider impacts of fuel poverty and policy-led intervention schemes.

Ethanol inhibits histaminergic neurons in mouse tuberomammillary nucleus slices via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites.

AIM: Ethanol, one of the most frequently used and abused substances in our society, has a profound impact on sedation. However, the neuronal mechanisms underlying its sedative effect remain unclear. In this study, we investigated the effects of ethanol on histaminergic neurons in the tuberomammillary nucleus (TMN), a brain region thought to be critical for wakefulness. METHODS: Coronal brain slices (250 µm thick) containing the TMN were prepared from GAD67-GFP knock-in mice. GAD67-GFP was used to identify histaminergic neurons in the TMN. The spontaneous firing and membrane potential of histaminergic neurons, and GABAergic transmission onto these neurons were recorded using whole-cell patch-clamp recordings. Drugs were applied through superfusion. RESULTS: Histaminergic and GAD67-expressing neurons in the TMN of GAD67-GFP mice were highly co-localized. TMN GFP-positive neurons exhibited a regular spontaneous discharge at a rate of 2-4 Hz without burst firing. Brief superfusion of ethanol (64, 190, and 560 mmol/L) dose-dependently and reversibly suppressed the spontaneous firing of the neurons in the TMN; when synaptic transmission was blocked by tetrodotoxin (1 µmol/L), ethanol caused hyperpolarization of the membrane potential. Furthermore, superfusion of ethanol markedly increased the frequency and amplitude of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs), which were abolished in the presence of the GABAA receptor antagonist bicuculline (20 µmol/L). Finally, ethanol-mediated enhancement of sIPSCs and mIPSCs was significantly attenuated when the slices were pretreated with the GABAB agonist baclofen (30 µmol/L). CONCLUSION: Ethanol inhibits the excitability of histaminergic neurons in mouse TMN slices, possibly via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites.