Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

The Application of High-Intensity Ultrasound on Wet-Dry Combined Aged Pork Loin Induces Physicochemical and Oxidative Alterations.

This research investigated the synergic outcome of high intensity ultrasound (HIU) treatment and wet-dry combined aging (WDCA) on physiochemical characteristics and lipid oxidation during refrigerated storage to ameliorate pork meat's quality and shelf life. The CIE b* values, cooking loss (CL %), and pH of the HIU treated samples were higher than those of the control over the aging period. They were significantly (p<0.05) modified by the aging period and ultrasound (US) treatment. However, the released water (RW %) and moisture were not significantly influenced by US treatment (p>0.05). The Warner-Bratzler shear force of HIU-treated samples was lower over control values except in 7-14 d, and it showed a significant difference between control and US treatment according to the significance of HIU (p<0.05). The thiobarbituric acid reactive substance of HIU-treated samples was significantly higher (p<0.05) than control values over the aging period. These results suggested that HIU treatment and WDCA showed a synergistic effect of maximizing the tenderness, but lipid oxidation was higher than before ultrasonic treatment. In agreement with this, the most favorable approach would involve implementing wet aging for a period of two weeks followed by dry aging for a period not exceeding one week after the application of HIU.

NSUN6-mediated 5-methylcytosine modification of NDRG1 mRNA promotes radioresistance in cervical cancer.

BACKGROUND: Radioresistance is the leading cause of death in advanced cervical cancer (CC). Dysregulation of RNA modification has recently emerged as a regulatory mechanism in radiation and drug resistance. We aimed to explore the biological function and clinical significance of 5-methylcytosine (m5C) in cervical cancer radiosensitivity. METHODS: The abundance of RNA modification in radiotherapy-resistant and sensitive CC specimens was quantified by liquid chromatography-tandem mass spectrometry. The essential RNA modification-related genes involved in CC radiosensitivity were screened via RNA sequencing. The effect of NSUN6 on radiosensitivity was verified in CC cell lines, cell-derived xenograft (CDX), and 3D bioprinted patient-derived organoid (PDO). The mechanisms of NSUN6 in regulating CC radiosensitivity were investigated by integrative m5C sequencing, mRNA sequencing, and RNA immunoprecipitation. RESULTS: We found a higher abundance of m5C modification in resistant CC samples, and NSUN6 was the essential m5C-regulating gene concerning radiosensitivity. NSUN6 overexpression was clinically correlated with radioresistance and poor prognosis in cervical cancer. Functionally, higher NSUN6 expression was associated with radioresistance in the 3D PDO model of cervical cancer. Moreover, silencing NSUN6 increased CC radiosensitivity in vivo and in vitro. Mechanistically, NDRG1 was one of the downstream target genes of NSUN6 identified by integrated m5C-seq, mRNA-seq, and functional validation. NSUN6 promoted the m5C modification of NDRG1 mRNA, and the m5C reader ALYREF bound explicitly to the m5C-labeled NDRG1 mRNA and enhanced NDRG1 mRNA stability. NDRG1 overexpression promoted homologous recombination-mediated DNA repair, which in turn led to radioresistance in cervical cancer. CONCLUSIONS: Aberrant m5C hypermethylation and NSUN6 overexpression drive resistance to radiotherapy in cervical cancer. Elevated NSUN6 expression promotes radioresistance in cervical cancer by activating the NSUN6/ALYREF-m5C-NDRG1 pathway. The low expression of NSUN6 in cervical cancer indicates sensitivity to radiotherapy and a better prognosis.

Linggui Zhugan Decoction Improves High Glucose-Induced Autophagy in Podocytes.

Objective To explore the influence of Linggui Zhugan Decoction (LGZGD) on high glucose induced podocyte autophagy Methods LGZGD containing serum were prepared by intragastric administation of 4.2 g·kg-1 (low dose), 8.4 g·kg-1 (medium dose), and 12.6 g·kg-1 (high dose) LGZGD into SD rats respectively. MPC5 and AB8/13 cells were treated with 60 mmol/L glucose to establish diabetic nephropathy podocyte model in vitro. Podocytes, MPC5 and AB8.13, were divided into control group, high glucose group, low dose LGZGD group, medium dose LGZGD group, and high dose LGZGD group, respectively. For the three LGZGD groups, before LGZGD intervention, podocytes were treated with 60 mmol/L glucose for 3 days. After treated with LGZGD containing serum, cells were collected to analyze cell migration using Transwell assay, proliferation using CCK8, apoptosis and cell cycle using flow cytometry,, autophagosome formation using transmission electron microscopy, and expression levels of Beclin-1, Atg5, LC3II/I, and P62 proteins using western blot.Results Compared with the control group, the proliferation and migration of MPC5 and AB8.13 cells in high glucose group showed slightly decreased, whereas these parameters restored after intervention with low and medium concentrations of LGZGD, with the medium dose LGZGD having the best effect. Flow cytometry analysis showed that the medium dose LGZGD group had a lower apoptosis rate (P < 0.05) and higher survival rate (P > 0.05) compared to the high dose group. High glucose arrested podocytes in G1 phase, whereas LGZGD shifted podocytes from being predominant in G1 phase to increasing into G2. High dose LGZGD significanly reduced increased autophagosome formation due to high glucose in both podocytes (P < 0.05). Western blot analysis showed that Beclin-1, Atg5, LC3Ⅱ/Ⅰ, and P62 expressions were increased in MPC5 cells treated with high glucose, and reversed after adminstration of low and medium doses of LGZGD (P < 0.05). Conclusion LGZGD reduced apoptosis and enhanced autophagy in high glucose treated podocytes via regulating Beclin-1/LC3II/I/Atg5 expression.

Five years of change in adult twins: longitudinal changes of genetic and environmental influence on epigenetic clocks.

BACKGROUND: Epigenetic clocks were known as promising biomarkers of aging, including original clocks trained by individual CpG sites and principal component (PC) clocks trained by PCs of CpG sites. The effects of genetic and environmental factors on epigenetic clocks are still unclear, especially for PC clocks. METHODS: We constructed univariate twin models in 477 same-sex twin pairs from the Chinese National Twin Registry (CNTR) to estimate the heritability of five epigenetic clocks (GrimAge, PhenoAge, DunedinPACE, PCGrimAge, and PCPhenoAge). Besides, we investigated the longitudinal changes of genetic and environmental influences on epigenetic clocks across 5 years in 134 same-sex twin pairs. RESULTS: Heritability of epigenetic clocks ranged from 0.45 to 0.70, and those for PC clocks were higher than those for original clocks. For five epigenetic clocks, the longitudinal stability was moderate to high and was largely due to genetic effects. The genetic correlations between baseline and follow-up epigenetic clocks were moderate to high. Special unique environmental factors emerged both at baseline and at follow-up. PC clocks showed higher longitudinal stability and unique environmental correlations than original clocks. CONCLUSIONS: For five epigenetic clocks, they have the potential to identify aging interventions. High longitudinal stability is mainly due to genetic factors, and changes of epigenetic clocks over time are primarily due to changes in unique environmental factors. Given the disparities in genetic and environmental factors as well as longitudinal stability between PC and original clocks, the results of studies with original clocks need to be further verified with PC clocks.

Involvement of long non-coding RNA LOXL1-AS1 in the tumourigenesis and development of malignant tumours: a narrative review.

Background and Objective: Long noncoding RNAs (lncRNAs) are involved in a wide variety of physiological and pathological processes in organisms. LncRNAs play a significant role as oncogenic or tumour-suppressing factors in various biological processes associated with malignant tumours and are closely linked to the occurrence and development of malignancies. Lysyl oxidase like 1 antisense RNA 1 (LOXL1-AS1) is a recently discovered lncRNA. It is upregulated in various malignant tumours and is associated with pathological characteristics such as tumour size, tumour node metastasis (TNM) staging, lymph node metastasis, and tumour prognosis. LOXL1-AS1 exerts its oncogenic role by competitively binding with multiple microRNAs (miRs), thereby regulating the expression of downstream target genes and controlling relevant signalling pathways. This article aims to explore the structure and the function of LOXL1-AS1, and the relationship between LOXL1-AS1 and the occurrence and development of human malignant tumours to provide a reference for further clinical research. Methods: English literature on LOXL1-AS1 in the occurrence and development of various malignant tumours was searched in PubMed. The main search terms were "LOXL1-AS1", "tumour". Key Content and Findings: This article mainly summarizes the biological processes in which LOXL1-AS1 is involved in various human malignant tumours and the ways in which this lncRNA affects malignant biological behaviours such as proliferation, metastasis, invasion, and apoptosis of tumour cells through different molecular regulatory mechanisms. This article also explores the potential clinical significance and application prospects of LOXL1-AS1, aiming to provide a theoretical basis and reference for the clinical diagnosis, treatment, and screening of prognostic markers for malignant tumours. Conclusions: LOXL1-AS1 acts as a competing endogenous RNA (ceRNA), binding to miRs to regulate downstream target genes and exert its oncogenic effects. LOXL1-AS1 may become a novel molecular biomarker for cancer diagnosis and treatment in humans, and it may also serve as an independent prognostic indicator.

Biofunctionalized hydrogel composed of genipin-crosslinked gelatin/hyaluronic acid incorporated with lyophilized platelet-rich fibrin for segmental bone defect repair.

Segmental bone defects can arise from trauma, infection, metabolic bone disorders, or tumor removal. Hydrogels have gained attention in the field of bone regeneration due to their unique hydrophilic properties and the ability to customize their physical and chemical characteristics to serve as scaffolds and carriers for growth factors. However, the limited mechanical strength of hydrogels and the rapid release of active substances have hindered their clinical utility and therapeutic effectiveness. With ongoing advancements in material science, the development of injectable and biofunctionalized hydrogels holds great promise for addressing the challenges associated with segmental bone defects. In this study, we incorporated lyophilized platelet-rich fibrin (LPRF), which contains a multitude of growth factors, into a genipin-crosslinked gelatin/hyaluronic acid (GLT/HA-0.5 % GP) hydrogel to create an injectable and biofunctionalized composite material. Our findings demonstrate that this biofunctionalized hydrogel possesses optimal attributes for bone tissue engineering. Furthermore, results obtained from rabbit model with segmental tibial bone defects, indicate that the treatment with this biofunctionalized hydrogel resulted in increased new bone formation, as confirmed by imaging and histological analysis. From a translational perspective, this biofunctionalized hydrogel provides innovative and bioinspired capabilities that have the potential to enhance bone repair and regeneration in future clinical applications.

Combined dynamic transcriptome and flavonoid metabolome reveal the role of Mo nanoparticles in the nodulation process in soybean.

Symbiotic nitrogen fixation can reduce the impact of agriculture on the environment by reducing fertilizer input. The rapid development of nanomaterials in agriculture provides a new prospect for us to improve the biological nitrogen fixation ability of leguminous crops. Molybdenum is an important component of nitrogenase, and the potential application of MoO3NPs in agriculture is largely unexplored. In this study, on the basis of verifying that MoO3NPs can improve the nitrogen fixation ability of soybean, the effects of MoO3NPs on the symbiotic nitrogen fixation process of soybean were investigated by using dynamic transcriptome and targeted metabolome techniques. Here we showed that compared with conventional molybdenum fertilizer, minute concentrations of MoO3NPs (0.01-0.1 mg kg-1) could promote soybean growth and nitrogen fixation efficiency. The nodules number, fresh nodule weight and nitrogenase activity of 0.1 mg kg-1 were increased by 17 %, 14 % and 27 %, and plant nitrogen accumulation increased by 17 %. Compared with conventional molybdenum fertilizer, MoO3NPs had a greater effect on apigenin, kaempferol and other flavonoid, and the expression of nodulation related genes such as ENOD93, F3'H. Based on WGCNA analysis, we identified a core gene GmCHS9 that was positively responsive to molybdenum and was highly expressed during MoO3NPs induced nodulation. MoO3NPs could improve the nitrogen fixation ability of soybean by promoting the secretion of flavonoids and the expression of key genes. This study provided a new perspective for the nano-strengthening strategy of nodules development and flavonoid biosynthesis by molybdenum.

Clinical significance of LINC02532 in hepatitis B virus-associated hepatocellular carcinoma and its regulatory effect on tumor progression.

BACKGROUND AND AIM: Long non-coding RNAs (lncRNAs) play an important role in tumor progression, including in hepatocellular carcinoma (HCC) induced by hepatitis B virus (HBV). Therefore, the aim of this study was to investigate the role of LINC02532 in HCC, mainly for diagnostic prognostic value and cellular function, as well as mechanistic aspects. METHODS: Initially, GEO and VirBase databases were used to screen for aberrant lncRNAs in HBV-HCC.Then, HBV-HCC persons followed up in our center were retrospectively studied to investigate the diagnostic, prognostic value of LINC02532 in HBV-HCC. Subsequently, the role of LINC02532 in HBV-HCC was measured using cellular function assay methods and possible mechanisms were analyzed in conjunction with bioinformatic predictive science. RESULTS: LINC02532 was a lncRNA abnormally expressed in HBV-HCC. LINC02532 was significantly up-regulated in the expression level in HBV-HCC tissues compared with normal tissues from patients. Moreover, LINC02532 could distinguish HBV-HCC and predict the prognosis of HBV-HCC. In vitro experiments showed that LINC02532 could regulate miR-455-3p and promote the malignant characterization of HBV-HCC cells. CHEK2 was a target gene of miR-455-3p. CONCLUSIONS: The prognosis and diagnosis of HBV-HCC can rely on the expression of LINC02532. LINC02532 was important for further progression of HBV-HCC, by moderating miR-455-3p/CHEK2.

A Finite Element Model for Simulating Stress Responses of Permeable Road Pavement.

Permeable road pavements, due to their open-graded design, suffer from low structural strength, restricting their use in areas with light traffic volume and low bearing capacity. To expand application of permeable road pavements, accurate simulation of stress parameters used in pavement design is essential. A 3D finite element (3D FE) model was developed using ABAQUS/CAE 2021 to simulate pavement stress responses. Utilizing a 53 cm thick permeable road pavement and a 315/80 R22.5 wheel as prototypes, the model was calibrated and validated, with its accuracy confirmed through t-test statistical analysis. Simulations of wheel speeds at 11, 15, and 22 m/s revealed significant impact on pavement depths of 3 cm and 8 cm, while minimal effects were observed at depths of 13 cm and 33 cm. Notably, stress values at a depth of 3 cm with 15 m/s speed in the open-graded asphalt concrete (OGFC) surface layer exceeded those at the speed of 11 m/s, while at a depth of 8 cm in the porous asphalt concrete (PAC) base layer, an opposite performance was observed. This may be attributed to the higher elastic modulus of the OGFC surface layer, which results in different response trends to velocity changes. Overall, lower speeds increase stress responses and prolong action times for both layers, negatively affecting pavement performance. Increasing the moduli of layers is recommended for new permeable road pavements for low-speed traffic. Furthermore, considering the effects of heavy loads and changes in wheel speed, the recommended design depth for permeable road pavement is 30 cm. These conclusions provide a reference for the design of permeable road pavements to address climate change and improve performance.

Facile Preparation Method of TiO2/Activated Carbon for Photocatalytic Degradation of Methylene Blue.

The development of nanocomposite photocatalysts with high photocatalytic activity, cost-effectiveness, a simple preparation process, and scalability for practical applications is of great interest. In this study, nanocomposites of TiO2 Degussa P25 nanoparticles/activated carbon (TiO2/AC) were prepared at various mass ratios of (4:1), (3:2), (2:3), and (1:4) by a facile process involving manual mechanical pounding, ultrasonic-assisted mixing in an ethanol solution, paper filtration, and mild thermal annealing. The characterization methods included XRD, SEM-EDS, Raman, FTIR, XPS, and UV-Vis spectroscopies. The effects of TiO2/AC mass ratios on the structural, morphological, and photocatalytic properties were systematically studied in comparison with bare TiO2 and bare AC. TiO2 nanoparticles exhibited dominant anatase and minor rutile phases and a crystallite size of approximately 21 nm, while AC had XRD peaks of graphite and carbon and a crystallite size of 49 nm. The composites exhibited tight decoration of TiO2 nanoparticles on micron-/submicron AC particles, and uniform TiO2/AC composites were obtained, as evidenced by the uniform distribution of Ti, O, and C in an EDS mapping. Moreover, Raman spectra show the typical vibration modes of anatase TiO2 (e.g., E1g(1), B1g(1), Eg(3)) and carbon materials with D and G bands. The TiO2/AC with (4:1), (3:2), and (2:3) possessed higher reaction rate constants (k) in photocatalytic degradation of methylene blue (MB) than that of either TiO2 or AC. Among the investigated materials, TiO2/AC = 4:1 achieved the highest photocatalytic activity with a high k of 55.2 × 10-3 min-1 and an MB removal efficiency of 96.6% after 30 min of treatment under UV-Vis irradiation (120 mW/cm2). The enhanced photocatalytic activity for TiO2/AC is due to the synergistic effect of the high adsorption capability of AC and the high photocatalytic activity of TiO2. Furthermore, TiO2/AC promotes the separation of photoexcited electron/hole (e-/h+) pairs to reduce their recombination rate and thus enhance photocatalytic activity. The optimal TiO2/AC composite with a mass ratio of 4/1 is suggested for treating industrial or household wastewater with organic pollutants.

Time-Dependent Effect of Eggshell Membrane on Monosodium-Iodoacetate-Induced Osteoarthritis: Early-Stage Inflammation Control and Late-Stage Cartilage Protection.

Osteoarthritis (OA) is a chronic degenerative joint disease that causes chronic pain, swelling, stiffness, disability, and significantly reduces the quality of life. Typically, OA is treated using painkillers and non-steroidal anti-inflammatory drugs (NSAIDs). While current pharmacologic treatments are common, their potential side effects have prompted exploration into functional dietary supplements. Recently, eggshell membrane (ESM) has emerged as a potential functional ingredient for joint and connective tissue disorders due to its clinical efficacy in relieving joint pain and stiffness. Despite promising clinical evidence, the effects of ESM on OA progression and its mechanism of action remain poorly understood. This study evaluated the efficacy of Ovomet®, a powdered natural ESM, against joint pain and disease progression in a monosodium iodoacetate (MIA)-induced rodent model of OA in mice and rats. The results demonstrate that ESM significantly alleviates joint pain and attenuates articular cartilage destruction in both mice and rats that received oral supplementation for 5 days prior to OA induction and for 28 days thereafter. Interestingly, ESM significantly inhibited mRNA expression levels of pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), as well as inflammatory mediators, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase in the knee joint cartilage at the early stage of OA, within 7 days after OA induction. However, this effect was not observed in the late stage at 28 days after OA induction. ESM further attenuates the induction of protein expression for cartilage-degrading enzymes like matrix metalloproteinase (MMPs) 3 and 13, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), in the late-stage. In addition, MIA-induced reduction of the protein expression levels of cartilage components, cartilage oligomeric matrix protein (COMP), aggrecan (ACAN) and collagen type II α-1 chain (COL2α1), and cartilage extracellular matrix (ECM) synthesis promoting transcriptional factor SRY-Box 9 (SOX-9) were increased via ESM treatment in the cartilage tissue. Our findings suggest that Ovomet®, a natural ESM powder, is a promising dietary functional ingredient that can alleviate pain, inflammatory response, and cartilage degradation associated with the progression of OA.

Role of Flavohemoglobins in the Development and Aflatoxin Biosynthesis of Aspergillus flavus.

Aspergillus flavus is notorious for contaminating food with its secondary metabolite-highly carcinogenic aflatoxins. In this study, we found that exogenous nitric oxide (NO) donor could influence aflatoxin production in A. flavus. Flavohemoglobins (FHbs) are vital functional units in maintaining nitric oxide (NO) homeostasis and are crucial for normal cell function. To investigate whether endogenous NO changes affect aflatoxin biosynthesis, two FHbs, FHbA and FHbB, were identified in this study. FHbA was confirmed as the main protein to maintain NO homeostasis, as its absence led to a significant increase in intracellular NO levels and heightened sensitivity to SNP stress. Dramatically, FHbA deletion retarded aflatoxin production. In addition, FHbA played important roles in mycelial growth, conidial germination, and sclerotial development, and response to oxidative stress and high-temperature stress. Although FHbB did not significantly impact the cellular NO level, it was also involved in sclerotial development, aflatoxin synthesis, and stress response. Our findings provide a new perspective for studying the regulatory mechanism of the development and secondary mechanism in A. flavus.

A novel endocardial activation-derived predictor for focal paraseptal atrial tachycardias: evidence from a multicenter cohort study.

BACKGROUND: The electrocardiogram-based algorithm for predicting para-septal atrial tachycardia (PSAT) is limited by the significant overlaps in the P-wave morphology originating from various para-septal sites. OBJECTIVE: The aim of this study was to investigate the endocardial activation characteristics of PSAT and to seek an endocardial activation-derived predictor for the ablation site. METHODS: Forty-four patients (11 males, average 62.6±14.7 years) with PSAT ablation in four tertiary medical centers were assigned into three groups according to the ablation site: right atrial (RA) para-Hisian region (Group 1, n=10), the noncoronary cusp (NCC) (Group 2, n=13) and left atrial (LA) para-septal areas (Group 3, n=21). Multiple-chamber activation mapping was performed guided by a 3D navigation system. The discrepancies in the earliest activation time between two of three chambers (ΔRA-LA, ΔRA-NCC and ΔLA-NCC) were calculated in each group and used for pairwise comparisons. RESULTS: There was significant difference in ΔRA-LA, ΔRA-NCC, and ΔLA-NCC compared among three groups. ΔRA-LA was the only parameter which could consistently predict the ablation site of PSAT with good accuracy (AUC 1.000, sensitivity 100%/ specificity 100%, and cut-off value 7ms for predicting right para-Hisian or NCC ablation; AUC 0.974, sensitivity 92.3%/specificity 95.2%, and cut-off value -4 ms for predicting NCC or left para-septal ablation). Based on two cut-off values, A two-step algorithm was developed to predict the ablation site of PSAT with positive predictive value of 95.4% and negative predictive value of 97.0%. CONCLUSIONS: ΔRA-LA is a useful endocardial activation-derived parameter for predicting the successful ablation site of PSAT.

Association of night-time sleep and daytime napping with painful temporomandibular disorder.

BACKGROUND: Painful temporomandibular disorder (TMD) is the common cause of chronic oro-facial pain, which may interfere with sleep. Previous studies have documented an association between sleep and TMD. OBJECTIVES: This study aimed to further explore the association of night-time sleep and daytime napping with painful TMD. METHODS: A total of 419 patients (aged 31.88 ± 11.54 years with women forming 85.4%) from a TMD/Orofacial Pain center were enrolled. Patients' sleep conditions were evaluated with the Pittsburgh Sleep Quality Index (PSQI) questionnaire, and information on night-time sleep duration, napping duration and napping frequency was interviewed. TMD was diagnosed according to the Diagnostic Criteria for TMD protocol and stratified into myalgia (muscle pain), arthralgia (joint pain) and combined (muscle and joint pain) subgroups. The severity of TMD was measured with the Fonseca Anamnestic Index (FAI) questionnaire. Restricted cubic spline (RCS) regression models were established to explore relationships between sleep and painful TMD subgroups. RESULTS: Patients with poor sleep quality (PSQI≥6) had higher FAI scores (median 60, p < .001) and higher proportions of painful TMDs. The myalgia subgroup had higher PSQI scores (median 8, p < .001) than the arthralgia subgroup. The RCS models indicated a non-linear relationship between night-time sleep duration and myalgia (p < .001), which was not observed in arthralgia. However, there were no significant findings concerning napping and painful TMD subgroups. CONCLUSION: This study found that the association between sleep and TMD is mainly related to painful TMD conditions, which are associated with night-time sleep duration.

An atlas of human vector-borne microbe interactions reveals pathogenicity mechanisms.

Vector-borne diseases are a leading cause of death worldwide and pose a substantial unmet medical need. Pathogens binding to host extracellular proteins (the "exoproteome") represents a crucial interface in the etiology of vector-borne disease. Here, we used bacterial selection to elucidate host-microbe interactions in high throughput (BASEHIT)-a technique enabling interrogation of microbial interactions with 3,324 human exoproteins-to profile the interactomes of 82 human-pathogen samples, including 30 strains of arthropod-borne pathogens and 8 strains of related non-vector-borne pathogens. The resulting atlas revealed 1,303 putative interactions, including hundreds of pairings with potential roles in pathogenesis, including cell invasion, tissue colonization, immune evasion, and host sensing. Subsequent functional investigations uncovered that Lyme disease spirochetes recognize epidermal growth factor as an environmental cue of transcriptional regulation and that conserved interactions between intracellular pathogens and thioredoxins facilitate cell invasion. In summary, this interactome atlas provides molecular-level insights into microbial pathogenesis and reveals potential host-directed targets for next-generation therapeutics.

Differences in Polysomnographic and Craniofacial Characteristics of Catathrenia Phenotypes: A Cluster Analysis.

Purpose: Catathrenia is a rare sleeping disorder characterized by repetitive nocturnal groaning during prolonged expirations. Patients with catathrenia had heterogeneous polysomnographic, comorbidity, craniofacial characteristics, and responses to treatment. Identifying phenotypes of catathrenia might benefit the exploration of etiology and personalized therapy. Patients and Methods: Sixty-six patients diagnosed with catathrenia by full-night audio/video polysomnography seeking treatment with mandibular advancement devices (MAD) or continuous positive airway pressure (CPAP) were included in the cohort. Polysomnographic characteristics including sleep architecture, respiratory, groaning, and arousal events were analyzed. Three-dimensional (3D) and 2D craniofacial hard tissue and upper airway structures were evaluated with cone-beam computed tomography and lateral cephalometry. Phenotypes of catathrenia were identified by K-mean cluster analysis, and inter-group comparisons were assessed. Results: Two distinct clusters of catathrenia were identified: cluster 1 (n=17) was characterized to have more males (71%), a longer average duration of groaning events (18.5±4.8 and 12.8±5.7s, p=0.005), and broader upper airway (volume 41,386±10,543 and 26,661±6700 mm3, p<0.001); cluster 2 (n=49) was characterized to have more females (73%), higher respiratory disturbance index (RDI) (median 1.0 [0.3, 2.0] and 5.2 [1.2, 13.3]/h, p=0.009), more respiratory effort-related arousals (RERA)(1 [1, 109] and 32 [13, 57)], p=0.005), smaller upper airway (cross-sectional area of velopharynx 512±87 and 339±84 mm2, p<0.001) and better response to treatment (41.2% and 82.6%, p=0.004). Conclusion: Two distinct phenotypes were identified in patients with catathrenia, primary catathrenia, and catathrenia associated with upper airway obstruction, suggesting respiratory events and upper airway structures might be related to the etiology of catathrenia, with implications for its treatment.

Plasma EBV quantification is associated with the efficacy of immune checkpoint blockade and disease monitoring in patients with primary pulmonary lymphoepithelioma-like carcinoma.

Objectives: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein-Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation. Methods: We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral EBNA-1 and BamHI-W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction. Results: Progression-free survival (PFS) was significantly longer in EBNA-1 high or BamHI-W high groups. A longer PFS was also observed in patients with both high plasma EBNA-1 or BamHI-W and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA-1 and BamHI-W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months. Conclusions: Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.