BASP1 is a prognostic biomarker associated with immunotherapeutic response in head and neck squamous cell carcinoma

BackgroundsImmunotherapy is effective in a subset of head and neck squamous cell carcinoma (HNSCC). However, the unfavorable response rate and inadequate biomarkers for stratifying patients have primarily limited its clinical application. Considering transcriptional factors (TFs) play essential roles in regulating immune activity during HNSCC progression, we comprehensively analyzed the expression alterations of TFs and their prognostic values.MethodsGene expression datasets and clinical information of HNSCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repository. Then, Brain abundant membrane attached signal protein 1 (BASP1) was screened out of differentially expressed TFs by univariate and multivariate survival analysis. Tumor immune dysfunction and exclusion (TIDE) was applied to analyze the response to immunotherapy of BASP1high/low patients. Meanwhile, GO, KEGG and GSEA analyses were used to enrich the pathways between the BASP1high and BASP1low groups. Single-sample gene set enrichment analysis (ssGSEA), CIBERSORT, EPIC and quanTiseq algorithms were applied to explore immune infiltrations. Also, immune cycle analysis was conducted by ssGSEA. Additionally, lipid peroxidation, glutathione and reactive oxygen species were performed to detect the ferroptosis alternations.ResultsBASP1 was upregulated and associated with poor survival in HNSCC patients. BASP1high patients exhibited better response rates to anti-PD-1 immunotherapy and higher expressions of immune checkpoint inhibitors. GO, KEGG and GSEA analyses indicated that the expression of BASP1 was related to several immune-related pathways and immunogenic ferroptosis signature. The infiltration of activated CD8+ T cells was authenticated to be decreased in BASP1high patients. Furthermore, BASP1 was identified to be positively correlated with T cell dysfunction and immune escape. Moreover, silencing BASP1 triggered ferroptosis in HNSCC cells, representing as increased LDH, lipid peroxidation and ROS levels, and reduced glutathione synthesisConclusionsWe demonstrated that BASP1 suppressed immunogenic ferroptosis to induce immunosuppressive tumor microenvironment. BASP1 plays a critical role in immune response, and might be a promising classifier for selecting HNSCC patients who benefit from current immunotherapy

Physical activity levels associated with insomnia and depressive symptoms in middle-aged and elderly patients with chronic schizophrenia

BackgroundPrevious evidence suggested that physical activity had beneficial effects on psychopathological symptoms, insomnia, or depressive symptoms in people with schizophrenia. This study investigated the association between physical activity levels and insomnia and depressive symptoms in middle-aged and elderly hospitalized patients with chronic schizophrenia (CS).Methods179 participants were enrolled. We used the 30-item Positive and Negative Syndrome Scale (PANSS–30) to assess the psychopathological symptoms. We used the Insomnia Severity Index scale (ISI) and 17-item Hamilton Depression Scale (HAMD-17) to evaluate insomnia and depressive symptoms. Daily physical activity time less than 30 min, within 30–60 min, and more than 60 min were defined as physical inactivity, moderate physical activity, and vigorous physical activity, respectively. The Chi-square test, analysis of variance (ANOVA), and Mann–Whitney U-test were applied for categorical, continuous, and non-normal distribution variables, respectively. The Pearson or Spearman’s correlation analyses were utilized to examine the association between physical activity levels, ISI total scores, HAMD total scores, and socio-demographic and clinical variables. Finally, socio-demographic variables with a P-value < 0.05 in the comparison between insomnia/depressive group and non-insomnia/depressive group were considered for inclusion in binary logistic regression analysis to determine the relationship between physical activity levels and insomnia or depressive symptoms.ResultsThe ISI total scores (r = –0.247, P = 0.001) and HAMD total scores (r = –0.312, P < 0.001) were negatively correlated with physical activity levels. Logistic regression analysis revealed that older age, higher depressive factor scores, and lower physical activity level were influential factors of insomnia symptoms in CS patients (P < 0.05). In addition, vigorous physical activity (compared with physical inactivity) and higher negative and depressive factor scores were independently associated with depressive symptoms in CS patients (P < 0.05).ConclusionPhysical activity levels were influential factors in comorbid insomnia and depressive symptoms in CS patients. Given the benefits of physical activity, it should be strengthened as a routine adjunct to clinical treatment or psychiatric care so as to improve the physical and mental health of patients with psychiatric symptoms

Maximizing the scattering of multiwavelength phonons in novel biphasic high-entropy ZrCoSb-based half-Heusler alloys

The thermoelectric (TE) performance of p-type ZrCoSb-based half-Heusler (HH) alloys has been improved tremendously in recent years; however, it remains challenging to find suitable n-type ZrCoSb-based HH alloys due to their high lattice thermal conductivity (κL). In this work, n-type Zr1−xTaxCo1−xNixSb HH alloys were firstly designed by multisite alloying. The evolution of the Raman peak proved that alloy scattering, phonon softening, anharmonicity, entropy-driven disorder, and precipitates had a combined effect on decreasing κL by 46.7% compared to that of pristine ZrCoSb. Subsequently, Hf0.75Zr0.25NiSn0.99Sb0.01 was introduced into Zr0.88Ta0.12Co0.88Ni0.12Sb to further suppress κL. Remarkably, the grain size of the biphasic HH alloys was refined by at least one order of magnitude. A biphasic high-entropy HH alloy with y = 0.2 exhibited the minimum κL of ∼2.44 W/(m·K) at 923 K, reducing by 67.7% compared to that of ZrCoSb. Consequently, (Zr0.88Ta0.12Co0.88Ni0.12Sb)0.9(Hf0.75Zr0.25NiSn0.99Sb0.01)0.1 exhibited the highest TE figure of merit (∼0.38) at 923 K. The cooperation between the entropy and biphasic microstructure resulted in multiscale defects, refined grains, and biphasic interfaces, which maximized the scattering of the multiwavelength phonons in HH alloys. This work provides a new strategy for further reducing the grain size and κL of medium- and high-entropy HH alloys

ZrNiSn-based compounds with high thermoelectric performance and ultralow lattice thermal conductivity via introduction of multiscale scattering centers

The high lattice thermal conductivity of half-Heuslers (HHs) restricts the further enhancement of their thermoelectric figure-of-merit (ZT). In this study, multiscale scattering centers, such as point defects, dislocations, and nanoprecipitates, are synchronously introduced in a n-type ZrNiSn-based HH matrix through Nb doping and Hf substitution. The lattice thermal conductivity is substantially decreased from 4.55 (for the pristine ZrNiSn) to 1.8 W·m−1·K−1 at 1 123 K via phonon scattering over a broad wavelength range through the adjustment of multiscale defects. This value is close to the theoretically estimated lowest thermal conductivity. The power factor (PF) is enhanced from 3.25 (for the pristine ZrNiSn) to 5.01 mW·m−1·K−2 for Zr0.66Hf0.30Nb0.04NiSn at 1 123 K owing to the donor doping and band regulation via Nb doping and Hf substitution. This can be ascribed to the synergistic interaction between the lowering of the lattice thermal conductivity and retention of the high PF. Consequently, a ZT value of as high as 1.06 is achieved for Zr0.66Hf0.30Nb0.04NiSn at 1 123 K. This work demonstrates that these actions are effective in jointly manipulating the transport of electrons and phonons, thereby improving the thermoelectric performance through defect engineering

TIPE3 represses head and neck squamous cell carcinoma progression via triggering PGAM5 mediated mitochondria dysfunction

Abstract Mitochondria are essential organelles in balancing oxidative stress and cell death during cancer cell proliferation. Rapid tumor growth induces tremendous stress on mitochondria. The mammalian tumor necrosis factor-α-induced protein 8-likes (TIPEs) family plays critical roles in balancing cancer cell death and survival. Yet, the roles of TIPEs in HNSCC tumorigenesis and mitochondria stress maintenance is unclear. Based on an integrative analysis of public HNSCC datasets, we identified that the downregulation of TIPE3 via its promoter hypermethylation modification is the major event of TIPEs alterations during HNSCC tumorigenesis. Low expression levels of TIPE3 were correlated with high malignancy and poor clinical outcomes of HNSCC patients. Restoring TIPE3 represses HNSCC proliferation, migration, and invasion in vitro and in vivo, while silencing TIPE3 acted on an opposite way. Mechanistically, TIPE3 band to the PGAM5 and electron transport chain (ETC) complex. Restoring TIPE3 promoted PGAM5 recruiting BAX and dephosphorylating p-DRP1(Ser637), which triggered mitochondrial outer membrane permeabilization and fragmentation. Ultimately, TIPE3 induced ETC damage and oxygen consumption rate decrease, ROS accumulation, mitochondrial membrane potential depolarization, and cell apoptosis. Collectively, our work reveals that TIPE3 plays critical role in maintaining mitochondrial stress and cancer cell progression in HNSCC, which might be a potential therapeutic target for HNSCC patients

Integrative single-cell and bulk transcriptomes analyses reveals heterogeneity of serine-glycine-one-carbon metabolism with distinct prognoses and therapeutic vulnerabilities in HNSCC

Abstract Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine–glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8+ T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment