Mutual regulation between deubiquitinase CYLD and retroviral oncoprotein Tax

<p>Abstract</p> <p>Background</p> <p>Oncoprotein Tax, encoded by the human T-cell leukemia virus type 1 (HTLV1), persistently induces NF-κB activation, which contributes to HTLV1-mediated T-cell transformation. Recent studies suggest that the signaling function of Tax requires its ubiquitination, although how the Tax ubiquitination is regulated remains unclear.</p> <p>Results</p> <p>We show here that the deubiquitinase CYLD physically interacts with Tax and negatively regulates the ubiquitination of this viral protein. This function of CYLD is associated with inhibition of Tax-mediated activation of IKK although not that of Tak1. Interestingly, CYLD undergoes constitutive phosphorylation in HTLV1-transformed T cells, a mechanism known to inactivate the catalytic activity of CYLD. Consistently, a phospho-mimetic CYLD mutant fails to inhibit Tax ubiquitination.</p> <p>Conclusion</p> <p>These findings suggest that CYLD negatively regulates the signaling function of Tax through inhibition of Tax ubiquitination. Conversely, induction of CYLD phosphorylation may serve as a mechanism by which HTLV1 overrides the inhibitory function of CYLD, leading to the persistent activation of NF-κB.</p

T cell receptor engineering targeting FOXM1 for the treatment of lung cancer

https://openworks.mdanderson.org/sumexp23/1069/thumbnail.jp

Handwriting velcro: Endowing AR glasses with personalized and posture-adaptive text input using flexible touch sensor

Text input is a desired feature for AR glasses. While there already exist various input modalities (e.g., voice, mid-air gesture), the diverse demands required by different input scenarios can hardly be met by the small number of fixed input postures offered by existing solutions. In this paper, we present Handwriting Velcro, a novel text input solution for AR glasses based on flexible touch sensors. The distinct advantage of our system is that it can easily stick to different body parts, thus endowing AR glasses with posture-adaptive handwriting input. We explored the design space of on-body device positions and identified the best interaction positions for various user postures. To flatten users' learning curves, we adapt our device to the established writing habits of different users by training a 36-character (i.e., A-Z, 0-9) recognition neural network in a human-in-the-loop manner. Such a personalization attempt ultimately achieves a low error rate of 0.005 on average for users with different writing styles. Subjective feedback shows that our solution has a good performance in system practicability and social acceptance. Empirically, we conducted a heuristic study to explore and identify the best interaction Position-Posture Correlation. Experimental results show that our Handwriting Velcro excels similar work [6] and commercial product in both practicality (12.3 WPM) and user-friendliness in different contexts

Fibroblast growth factor 3 promotes spontaneous mammary tumorigenesis in Tientsin albino 2 mice via the FGF3/FGFR1/STAT3 pathway

IntroductionTientsin albino 2 (TA2) mice can develop spontaneous breast cancer (SBC), which is associated with multiple pregnancies and infection with the mouse mammary tumor virus (MMTV). In this study, we sought to elucidate the molecular mechanisms underlying the development of SBC in TA2 mice induced by MMTV.MethodsThe integration site of MMTV in TA2 SBC was identified using whole-genome sequencing. The expression of fibroblast growth factor 3 (FGF3) in SBCs and normal breast tissues was compared. The primary cell line, TA-1106, derived from SBC, was cultured. The proliferation, cell cycle, migration, invasion, and tumorigenicity abilities, as well as the expression of epithelial-mesenchymal transition-related proteins, phosphorylated STAT3, and phosphorylated Akt, were assessed in MA-891cell line from TA2 and TA-1106 cells after FGF3 knockdown. The binding of FGF3 to FGF receptor 1 (FGFR1) was determined by co-immunoprecipitation. Additionally, the relationship between STAT3 and Akt phosphorylation was investigated using a small molecule inhibitor and STAT3 knockdown.ResultsMMTV integrated upstream of the FGF3 gene, and the FGF3 protein was highly expressed in TA2 SBCs. FGF3 knockdown in MA-891 and TA-1106 decreased their proliferation, migration, and invasion abilities, affected the cell cycle and expression of epithelial-mesenchymal transition-related proteins, and inhibited the growth of animal xenografts. FGF3 binds to FGFR1, and either FGF3 or FGFR1 knockdown decreases STAT3 and Akt phosphorylation levels. Inhibition of phosphorylation or expression of STAT3 resulted in decreased Akt phosphorylation levels. Inhibition of Akt phosphorylation also resulted in decreased STAT3 phosphorylation levels. Furthermore, treatment of MA-891 and TA-1106 cells with Wortmannin or Stattic caused FGFR1 upregulation in addition to inhibiting Akt or STAT3 phosphorylation.ConclusionThe results of this study demonstrate that FGF3 plays a significant role in the development of SBC through the FGF3/FGFR1/STAT3 signaling pathway. There is a reciprocal activation between STAT3 and Akt. Inhibition of STAT3 or Akt phosphorylation promoted the expression of FGFR1. Validating the conclusions obtained in this study in human breast cancer (HBC) may contribute to targeted therapy and it is worth exploring whether the homologous sequences of MMTV in HBC have a similar oncogenic effect

Habitual night sleep duration is associated with general obesity and visceral obesity among Chinese women, independent of sleep quality

PurposeResearch on the relationship between sleep duration and obesity defined using multiple anthropometric and bioelectrical indices in women remains scarce. We aimed to explore the association between sleep duration and body mass index (BMI), waist-hip ratio (WHR), body fat percentage (PBF) and visceral fat area (VFA) among females.MethodsWe recruited women for medical examination using multistage cluster sampling. Sleep was assessed using Pittsburgh Sleep Quality Index (PSQI) and sleep duration was categorized into short (&lt;7 h), optimal (7 &lt;9 h) and long sleep (≥ 9 h). Weight and height were measured using a calibrated stadiometer. Waist circumference was manually measured. PBF, and VFA were estimated by bioelectrical impedance analysis. Data on sociodemographic characteristics and lifestyle factors were also collected and included in the logistic regression models to explore the independent association between sleep duration and obesity defined by different indices.ResultsA total of 7,763 women with a mean age of 42.6 ± 13.5 years were included. The percentage of women reporting short and long sleep was 10.3 and 13.4% respectively. The mean BMI, WHR, PBF and VFA were 23.07 ± 3.30 kg/m2, 0.78 ± 0.06, 32.23 ± 6.08% and 91.64 ± 35.97cm2, respectively. Short sleep was independently associated with 35% (95% CI: 1.05–1.75) increased odds of general obesity (BMI ≥ 28 kg/cm2), and long sleep was associated with 18% (95% CI: 1.01–1.37) increased odds of visceral obesity (VFA &gt; 100 cm2). No association was observed between sleep deprivation or excessive sleep and high WHR or high PBF.ConclusionIn women, short sleep was associated with an increased odds of general obesity, whereas long sleep was associated with an increased odds of visceral obesity. Longitudinal observations are needed to confirm this cross-sectional relationship

Case report: Clinical complete response in advanced ALK-positive lung squamous cell carcinoma: a case study of successful anti-PD-1 immunotherapy post ALK-TKIs failure

In patients with advanced lung adenocarcinoma (LADC) harboring the echinoderm microtubule-associated protein-like 4 (EML4) -anaplastic lymphoma kinase (ALK) rearrangement, targeted therapy typically demonstrates superior efficacy as an initial treatment compared to chemotherapy. Following resistance to ALK-tyrosine kinase inhibitors (TKIs), regimens incorporating platinum-based dual agents or combined with bevacizumab often show effectiveness. However, therapeutic alternatives become constrained after resistance develops to both TKIs and platinum-based therapies. Given that the majority of ALK-positive non-small cell lung carcinomas (NSCLC) are LADC, the benefits of TKIs for patients with ALK-positive lung squamous cell carcinoma (LSCC) and the optimal treatment strategy for these patients remain a subject of debate. In this case study, we report on a patient with advanced LSCC, in whom the EML4-ALK rearrangement was identified via ARMS-PCR (Amplification Refractory Mutation System-Polymerase Chain Reaction). The patient underwent oral treatment with crizotinib and alectinib, showing effectiveness in both first-line and second-line ALK-TKI therapies, albeit with limited progression-free survival (PFS). Subsequent resistance to second-generation TKI was followed by the detection of tumors in the left neck region via computed tomography (CT). Biopsy pathology revealed non-squamous cell carcinoma, and subsequent treatment with platinum-based double-drug therapy proved ineffective. Further analysis through next-generation sequencing (NGS) indicated ALK negativity but a high expression of programmed death-ligand 1 (PD-L1). Immunotherapy was then initiated, resulting in a PFS of over 29 months and clinical complete remission (cCR). This case underscores the potential benefit of ALK-TKIs in patients with ALK-positive LSCC. Resistance to second-generation TKIs may lead to ALK negativity and histological transformation, highlighting the necessity of repeated biopsies post-TKI resistance for informed treatment decision-making. As of November 2023, imaging studies continue to indicate cCR in the patient, with a survival time exceeding 47 months

Multifaceted role of BTLA in the control of CD8+ T cell fate after antigen encounter

Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40%–50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte associated) expression on transferred CD8+ TILs was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8+BTLA+TIL subset and define the contribution of the Grb2 motif of BTLA in T-cell costimulation. Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8+ TILs and mouse CD8+ T cells. Functional assays were used including single-cell analysis, reverse-phase protein array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as patient-derived xenograft (PDX) model using immunodeficient NOD-scid IL2Rgammanull (NSG) tumor-bearing mice treated with autologous TILs. Results: CD8+BTLA? TILs could not control tumor growth in vivo as well as their BTLA+ counterpart and antigen-specific CD8+BTLA? T cells had impaired recall response to a vaccine. However, CD8+BTLA+ TILs displayed improved survival following the killing of a tumor target and heightened “serial killing” capacity. Using mutants of BTLA signaling motifs, we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. Conclusions: Our data portrays BTLA as a molecule with the singular ability to provide both costimulatory and coinhibitory signals to activated CD8+ T cells, resulting in extended survival, improved tumor control, and the development of a functional recall response. Clin Cancer Res; 23(20); 6151–64. ©2017 AACR

Prevalence of hyperuricemia and the population attributable fraction of modifiable risk factors: Evidence from a general population cohort in China

Data on updated hyperuricemia prevalence in Beijing-Tianjin-Hebei (BTH) region in China, which is one of the world-class urban agglomerations, is sparse. Overweight/obesity, alcohol consumption, smoking and sedentary behavior are modifiable risk factors (MRFs) for elevated serum uric acid (SUA), but their population attributable fractions (PAFs) for hyperuricemia is still unclear. Using baseline data from the BTH Physical Examination General Population Cohort, we calculated the crude- and adjusted-prevalence of hyperuricemia based on the 30,158 participants aged 18–80 years. Hyperuricemia was defined as SUA &gt;420 μmol/L in men and &gt;360 μmol/L in women, or currently use of uric acid lowering drugs. Overweight/obesity, alcohol consumption, smoking and sedentary behavior were considered as MRFs and their adjusted PAFs were estimated. The prevalence of hyperuricemia was 19.37%, 27.72% in men and 10.69% in women. The PAFs and 95% confidence intervals for overweight, obesity were 16.25% (14.26–18.25%) and 12.08% (11.40–12.77%) in men, 13.95% (12.31–15.59%) and 6.35% (5.97–6.74%) in women, respectively. Alcohol consumption can explain 4.64% (2.72–6.56%) hyperuricemia cases in men, but with no statistical significance in women. Cigarette smoking contributed to 3.15% (1.09–5.21%) cases in men, but a much lower fraction in women (0.85%, 0.49–1.22%). Compared with sedentary time &lt;2 h per day, the PAFs of 2–4 h, 4–6 h, and more than 6 h per day were 3.14% (1.34–4.93%), 6.72% (4.44–8.99%) and 8.04% (4.95–11.13%) in men, respectively. Sedentary time was not found to be associated with hyperuricemia in women. These findings concluded that hyperuricemia is prevalent in this representative Chinese adult general population with substantial sex difference. Four MRFs (overweight/obesity, alcohol consumption, cigarette smoking and sedentary behavior) accounted for a notable proportion of hyperuricemia cases. The PAF estimations enable the exploration of the expected proportion of hyperuricemia cases that could be prevented if the MRFs were removed, which warrants the public health significance of life-style intervention

Natural Splice Variant of MHC Class I Cytoplasmic Tail Enhances Dendritic Cell-Induced CD8+ T-Cell Responses and Boosts Anti-Tumor Immunity

Dendritic cell (DC)-mediated presentation of MHC class I (MHC-I)/peptide complexes is a crucial first step in the priming of CTL responses, and the cytoplasmic tail of MHC-I plays an important role in modulating this process. Several species express a splice variant of the MHC-I tail that deletes exon 7-encoding amino acids (Δ7), including a conserved serine phosphorylation site. Previously, it has been shown that Δ7 MHC-I molecules demonstrate extended DC surface half-lives, and that mice expressing Δ7-Kb generate significantly augmented CTL responses to viral challenge. Herein, we show that Δ7-Db-expressing DCs stimulated significantly more proliferation and much higher cytokine secretion by melanoma antigen-specific (Pmel-1) T cells. Moreover, in combination with adoptive Pmel-1 T-cell transfer, Δ7-Db DCs were superior to WT-Db DCs at stimulating anti-tumor responses against established B16 melanoma tumors, significantly extending mouse survival. Human DCs engineered to express Δ7-HLA-A*0201 showed similarly enhanced CTL stimulatory capacity. Further studies demonstrated impaired lateral membrane movement and clustering of human Δ7-MHC-I/peptide complexes, resulting in significantly increased bioavailability of MHC-I/peptide complexes for specific CD8+ T cells. Collectively, these data suggest that targeting exon 7-encoded MHC-I cytoplasmic determinants in DC vaccines has the potential to increase CD8+ T-cell stimulatory capacity and substantially improve their clinical efficacy