Host-virus coevolution drives soil microbial function succession along a millennium land reclamation chronosequence.

INTRODUCTION: Gene exchange between viruses and hosts plays an important role in driving virus-host coevolution, enabling adaptation of both viruses and hosts to environmental changes. However, the mechanisms and functional significance of virus-host gene exchanges over long-term scales remain largely unexplored. OBJECTIVE: The present study aimed to gain insights into the role of viruses in virus-host interactions and coevolution by monitoring virome dynamics along a millennium-long land reclamation chronosequence. METHODS: We collected 24 soil samples from 8 stages of a millennium-long land reclamation chronosequence, including non-reclamation, and reclamation periods of 10, 50, 100, 300, 500, 700, and 1000 years. We characterized their metagenomes, and identified DNA viruses within these metagenomes. RESULTS: Our findings reveal a significant shift in viral community composition after 50 years of land reclamation, but soil viral diversity reached a stable phase approximately 300 years after the initial reclamation. Analysis of the virus-host network showed a scale-free degree distribution and a reduction in complexity over time, with generalist viruses emerging as key facilitators of horizontal gene transfer. CONCLUSION: These findings highlight the integral role of viruses, especially generalist types, in mediating gene exchanges between viruses and hosts, thereby influencing the coevolutionary dynamics in soil ecosystems over significant timescales. This study offers novel insights into long-term virus-host interactions, showing how the virome responds to environmental changes, driving shifts in various microbial functions in reclaimed land.

Non-complete recovery of temporal lobe white matter diffusion metrics at one year Post-Radiotherapy: Implications for Radiation-Induced necrosis risk.

BACKGROUND: Temporal lobe (TL) white matter (WM) injuries are often seen early after radiotherapy (RT) in nasopharyngeal carcinoma patients (NPCs), which fail to fully recover in later stages, exhibiting a "non-complete recovery pattern". Herein, we explored the correlation between non-complete recovery WM injuries and TL necrosis (TLN), identifying dosimetric predictors for TLN-related high-risk WM injuries. METHODS: We longitudinally examined 161 NPCs and 19 healthy controls employing multi-shell diffusion MRI. Automated fiber-tract quantification quantified diffusion metrics within TL WM tracts segments. ANOVA identified non-complete recovery WM tract segments one-year post-RT. Cox regression models discerned TLN risk factors utilizing non-complete recovery diffusion metrics. Normal tissue complication probability (NTCP) models and dose-response analysis further scrutinized RT-related toxicity to high-risk WM tract segments. RESULTS: Seven TL WM tract segments exhibited a " non-complete recovery pattern ". Cox regression analysis identified mean diffusivity of left uncinate fasciculus segment 1, neurite density index (NDI) of the left cingulum hippocampus segment 1, and NDI of the right inferior longitudinal fasciculus segment 1 as TLN risk predictors (hazard ratios [HRs] with confidence interval [CIs] 1.45 [1.17-1.81], 1.07 [1.00-1.15], 1.15 [1.03-1.30], respectively; all P-values < 0.05). In NTCP models, D10cc.L, D20cc.L and D10cc.R demonstrated superior performance, with TD50 of 37.22 Gy, 24.96 Gy and 37.28 Gy, respectively. CONCLUSIONS: Our findings underscore the significance of the "non-complete recovery pattern" in TL WM tract segment injuries during TLN development. Understanding TLN-related high-risk WM tract segments and their tolerance doses could facilitate early intervention in TLN and improve RT protocols.

Loss of Smooth Muscle Tenascin-X Inhibits Vascular Remodeling Through Increased TGF-ß Signaling.

BACKGROUND: Vascular smooth muscle cells (VSMCs) are highly plastic. Vessel injury induces a phenotypic transformation from differentiated to dedifferentiated VSMCs, which involves reduced expression of contractile proteins and increased production of extracellular matrix and inflammatory cytokines. This transition plays an important role in several cardiovascular diseases such as atherosclerosis, hypertension, and aortic aneurysm. TGF-ß (transforming growth factor-ß) is critical for VSMC differentiation and to counterbalance the effect of dedifferentiating factors. However, the mechanisms controlling TGF-ß activity and VSMC phenotypic regulation under in vivo conditions are poorly understood. The extracellular matrix protein TN-X (tenascin-X) has recently been shown to bind TGF-ß and to prevent it from activating its receptor. METHODS: We studied the role of TN-X in VSMCs in various murine disease models using tamoxifen-inducible SMC-specific knockout and adeno-associated virus-mediated knockdown. RESULTS: In hypertensive and high-fat diet-fed mice, after carotid artery ligation as well as in human aneurysmal aortae, expression of Tnxb, the gene encoding TN-X, was increased in VSMCs. Mice with smooth muscle cell-specific loss of TN-X (SMC-Tnxb-KO) showed increased TGF-ß signaling in VSMCs, as well as upregulated expression of VSMC differentiation marker genes during vascular remodeling compared with controls. SMC-specific TN-X deficiency decreased neointima formation after carotid artery ligation and reduced vessel wall thickening during Ang II (angiotensin II)-induced hypertension. SMC-Tnxb-KO mice lacking ApoE showed reduced atherosclerosis and Ang II-induced aneurysm formation under high-fat diet. Adeno-associated virus-mediated SMC-specific expression of short hairpin RNA against Tnxb showed similar beneficial effects. Treatment with an anti-TGF-ß antibody or additional SMC-specific loss of the TGF-ß receptor reverted the effects of SMC-specific TN-X deficiency. CONCLUSIONS: In summary, TN-X critically regulates VSMC plasticity during vascular injury by inhibiting TGF-ß signaling. Our data indicate that inhibition of vascular smooth muscle TN-X may represent a strategy to prevent and treat pathological vascular remodeling.

Rho GTPase-activating protein 4 is upregulated in Kidney Renal Clear Cell Carcinoma and associated with poor prognosis and immune infiltration.

BACKGROUND: Kidney Renal Clear Cell Carcinoma (KIRC) is a malignant tumor that seriously threatens human health. Rho GTPase-activating protein 4 (ARHGAP4) plays an important role in the occurrence and development of tumors. OBJECTIVE: The purpose of this study was to explore the role of ARHGAP4 in the progression of KIRC and its diagnostic and prognostic value. METHODS: Multiple analytical methods and in vitro cell assays were used to explore the expression of ARHGAP4 and its value in the progression, diagnosis and prognosis of KIRC. The biological function of ARHGAP4 was studied by GO analysis and KEGG pathway analysis, and then the relationship between ARHGAP4 and immune infiltration was analyzed. RESULTS: The expression of ARHGAP4 was significantly up-regulated in KIRC. We found that the high expression of ARHGAP4 was related to the progression of KIRC and suggested a poor prognosis. Compared with normal tissues, ARHGAP4 had a better diagnostic value in KIRC. The biological function of ARHGAP4 was related to immunity, and its expression was also closely related to tumor immune infiltration and immune checkpoints. CONCLUSIONS: Our study demonstrated that ARHGAP4 may be a biomarker, which is related to the progression, diagnosis and prognosis of KIRC. Its biological functions are related to tumor immune infiltration.

Radiomics Analysis of Quantitative Maps from Synthetic MRI for Predicting Grades and Molecular Subtypes of Diffuse Gliomas.

PURPOSE: To investigate the feasibility of using radiomics analysis of quantitative maps from synthetic MRI to preoperatively predict diffuse glioma grades, isocitrate dehydrogenase (IDH) subtypes, and 1p/19q codeletion status. METHODS: Data from 124 patients with diffuse glioma were used for analysis (n = 87 for training, n = 37 for testing). Quantitative T1, T2, and proton density (PD) maps were obtained using synthetic MRI. Enhancing tumour (ET), non-enhancing tumour and necrosis (NET), and peritumoral edema (PE) regions were segmented followed by manual fine-tuning. Features were extracted using PyRadiomics and then selected using Levene/T, BorutaShap and maximum relevance minimum redundancy algorithms. A support vector machine was adopted for classification. Receiver operating characteristic curve analysis and integrated discrimination improvement analysis were implemented to compare the performance of different radiomics models. RESULTS: Radiomics models constructed using features from multiple tumour subregions (ET + NET + PE) in the combined maps (T1 + T2 + PD) achieved the highest AUC in all three prediction tasks, among which the AUC for differentiating lower-grade and high-grade diffuse gliomas, predicting IDH mutation status and predicting 1p/19q codeletion status were 0.92, 0.95 and 0.86 respectively. Compared with those constructed on individual T1, T2, and PD maps, the discriminant ability of radiomics models constructed on the combined maps separately increased by 11, 17 and 10% in predicting glioma grades, 35, 52 and 19% in predicting IDH mutation status, and 16, 15 and 14% in predicting 1p/19q codeletion status (p < 0.05). CONCLUSION: Radiomics analysis of quantitative maps from synthetic MRI provides a new quantitative imaging tool for the preoperative prediction of grades and molecular subtypes in diffuse gliomas.

Vascular smooth muscle-specific LRRC8A knockout ameliorates angiotensin II-induced cerebrovascular remodeling by inhibiting the WNK1/FOXO3a/MMP signaling pathway.

Hypertensive cerebrovascular remodeling involves the enlargement of vascular smooth muscle cells (VSMCs), which activates volume-regulated Cl- channels (VRCCs). The leucine-rich repeat-containing family 8 A (LRRC8A) has been shown to be the molecular identity of VRCCs. However, its role in vascular remodeling during hypertension is unclear. In this study, we used vascular smooth muscle-specific LRRC8A knockout (CKO) mice and an angiotensin II (Ang II)-induced hypertension model. The results showed that cerebrovascular remodeling during hypertension was ameliorated in CKO mice, and extracellular matrix (ECM) deposition was reduced. Based on the RNA-sequencing analysis of aortic tissues, the level of matrix metalloproteinases (MMPs), such as MMP-9 and MMP-14, were reduced in CKO mice with hypertension, which was further verified in vivo by qPCR and immunofluorescence analysis. Knockdown of LRRC8A in VSMCs inhibited the Ang II-induced upregulation of collagen I, fibronectin, and matrix metalloproteinases (MMPs), and overexpression of LRRC8A had the opposite effect. Further experiments revealed an interaction between with-no-lysine (K)-1 (WNK1), which is a "Cl--sensitive kinase", and Forkhead transcription factor O3a (FOXO3a), which is a transcription factor that regulates MMP expression. Ang II induced the phosphorylation of WNK1 and downstream FOXO3a, which then increased the expression of MMP-2 and MMP-9. This process was inhibited or potentiated when LRRC8A was knocked down or overexpressed, respectively. Overall, these results demonstrate that LRRC8A knockout in vascular smooth muscle protects against cerebrovascular remodeling during hypertension by reducing ECM deposition and inhibiting the WNK1/FOXO3a/MMP signaling pathway, demonstrating that LRRC8A is a potential therapeutic target for vascular remodeling-associated diseases such as stroke.

Radiomic signatures associated with tumor immune heterogeneity predict survival in locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The prognostic value of traditional clinical indicators for locally recurrent nasopharyngeal carcinoma (lrNPC) is limited due to their inability to reflect intratumor heterogeneity. We aimed to develop a radiomic signature to reveal tumor immune heterogeneity and predict survival in lrNPC. METHODS: This multicenter, retrospective study included 921 patients with lrNPC. A machine learning signature and nomogram based on pretreatment MRI features were developed for predicting overall survival (OS) in a training cohort and validated in two independent cohorts. A clinical nomogram and an integrated nomogram were constructed for comparison. Nomogram performance was evaluated by concordance index (C-index) and receiver operating characteristic curve analysis. Accordingly, patients were classified into risk groups. The biological characteristics and immune infiltration of the signature were explored by RNA sequencing (RNA-seq) analysis. RESULTS: The machine learning signature and nomogram demonstrated comparable prognostic ability to a clinical nomogram, achieving C-indexes of 0.729, 0.718, and 0.731 in the training, internal, and external validation cohorts, respectively. Integration of the signature and clinical variables significantly improved the predictive performance. The proposed signature effectively distinguished patients between risk groups with significantly distinct OS rates. Subgroup analysis indicated the recommendation of local salvage treatments for low-risk patients. Exploratory RNA-seq analysis revealed differences in interferon response and lymphocyte infiltration between risk groups. CONCLUSIONS: An MRI-based radiomic signature predicted OS more accurately. The proposed signature associated with tumor immune heterogeneity may serve as a valuable tool to facilitate prognostic stratification and guide individualized management for lrNPC patients.

Biogeographic patterns and drivers of soil viromes.

Viruses are crucial in shaping soil microbial functions and ecosystems. However, studies on soil viromes have been limited in both spatial scale and biome coverage. Here we present a comprehensive synthesis of soil virome biogeographic patterns using the Global Soil Virome dataset (GSV) wherein we analysed 1,824 soil metagenomes worldwide, uncovering 80,750 partial genomes of DNA viruses, 96.7% of which are taxonomically unassigned. The biogeography of soil viral diversity and community structure varies across different biomes. Interestingly, the diversity of viruses does not align with microbial diversity and contrasts with it by showing low diversity in forest and shrubland soils. Soil texture and moisture conditions are further corroborated as key factors affecting diversity by our predicted soil viral diversity atlas, revealing higher diversity in humid and subhumid regions. In addition, the binomial degree distribution pattern suggests a random co-occurrence pattern of soil viruses. These findings are essential for elucidating soil viral ecology and for the comprehensive incorporation of viruses into soil ecosystem models.

Combined magnetic biochar and ryegrass enhanced the remediation effect of soils contaminated with multiple heavy metals.

Biochar is a very promising material for soil remediation. However, most studies mainly focus on the adsorption ability of biochar on one heavy metal, which is difficult to evaluate the actual remediation effect since soils were contaminated with multiple heavy metals. In order to improve the soil remediation efficiency, we used the joint remediation method of magnetically modified biochar and ryegrass to remediate the soil polluted by compound heavy metals (chromium, nickel, copper, zinc, arsenic and cadmium), and evaluate the effect on the process of organic carbon mineralization in polluted soils. It was found that magnetic biochar and ryegrass together decreased the concentrations of Cr, Ni, Cu, Zn, As, and Cd in soils by 24.12 %, 23.30 %, 22.01 %, 9.98 %, 14.83 %, and 15.08 %, respectively, and reduced the available fractions. Ryegrass roots were the main accumulation part of heavy metals, and the order of enrichment effect was ranked as Zn > As > Cr > Cu > Ni > Cd. In addition, magnetic biochar can maintained the stability of the organic carbon pool, and inhibited the emission of volatile organic compounds from ryegrass. Overall, this study indicates that magnetic biochar spheres combined with ryegrass is an effective method for heavy metals co-contaminated soils, and has the excellent remediation ability for actual co-contaminated soils.

Nuclear miR-204-3p mitigates metabolic dysfunction-associated steatotic liver disease in mice.

BACKGROUND & AIMS: Accumulating evidence has indicated the presence of mature microRNAs (miR) in the nucleus, but their effects on steatohepatitis remain elusive. We have previously demonstrated that the intranuclear miR-204-3p in macrophages protects against atherosclerosis, which shares multiple risk factors with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we aimed to explore the functional significance of miR-204-3p in steatohepatitis. METHODS: miR-204-3p levels and subcellular localization were assessed in the livers and peripheral blood mononuclear cells of patients with MASLD. Wild-type mice fed high-fat or methionine- and choline-deficient diets were injected with an adeno-associated virus system containing miR-204-3p to determine the effect of miR-204-3p on steatohepatitis. Co-culture systems were applied to investigate the crosstalk between macrophages and hepatocytes or hepatic stellate cells (HSCs). Multiple high-throughput epigenomic sequencings were performed to explore miR-204-3p targets. RESULTS: miR-204-3p expression decreased in livers and macrophages in mice and patients with fatty liver. In patients with MASLD, miR-204-3p levels in peripheral blood mononuclear cells were inversely related to the severity of hepatic inflammation and damage. Macrophage-specific miR-204-3p overexpression reduced steatohepatitis in high-fat or methionine- and choline-deficient diet-fed mice. miR-204-3p-overexpressing macrophages inhibited TLR4/JNK signaling and pro-inflammatory cytokine release, thereby limiting fat deposition and inflammation in hepatocytes and fibrogenic activation in HSCs. Epigenomic profiling identified miR-204-3p as a specific regulator of ULK1 expression. ULK1 transcription and VPS34 complex activation by intranuclear miR-204-3p improved autophagic flux, promoting the anti-inflammatory effects of miR-204-3p in macrophages. CONCLUSIONS: miR-204-3p inhibits macrophage inflammation, coordinating macrophage actions on hepatocytes and HSCs to ameliorate steatohepatitis. Macrophage miR-204-3p may be a therapeutic target for MASLD. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic inflammatory disease ranging from simple steatosis to steatohepatitis. However, the molecular mechanisms underlying the progression of MASLD remain incompletely understood. Here, we demonstrate that miR-204-3p levels in circulating peripheral blood mononuclear cells are negatively correlated with disease severity in patients with MASLD. Nuclear miR-204-3p activates ULK1 transcription and improves autophagic flux, limiting macrophage activation and hepatic steatosis. Our study provides a novel understanding of the mechanism of macrophage autophagy and inflammation in steatohepatitis and suggests that miR-204-3p may act as a potential therapeutic target for MASLD.

Metabolome regulation and restoration mechanism of different varieties of rice (Oryza sativa L.) after lindane stress.

There is a lack of studies on the ability of plants to metabolize chlorinated organic pollutants (COPs) and the dynamic expression changes of metabolic molecules during degradation. In this study, hybrid rice Chunyou 927 (CY) and Zhongzheyou 8 (ZZY), traditional rice subsp. Indica Baohan 1 (BH) and Xiangzaoxian 45 (XZX), and subsp. Japonica Yangjing 687 (YJ) and Longjing 31 (LJ) were stressed by a typical COPs of lindane and then transferred to a lindane-free culture to incubate for 9 days. The cumulative concentrations in the roots of BH, XZX, CY, ZZY, YJ and LJ were 71.46, 65.42, 82.06, 80.11, 47.59 and 56.10 mg·kg-1, respectively. And the degradation ratios on day 9 were 87.89 %, 86.92 %, 94.63 %, 95.49 %, 72.04 % and 82.79 %, respectively. On the 0 day after the release of lindane stress, the accumulated lindane inhibited the normal physiological activities of rice by affecting lipid metabolism in subsp. Indica BH, amino acid metabolism and synthesis and nucleotide metabolism in hybrid CY. Carbohydrate metabolism of subsp. Japonica YJ also was inhibited, but with low accumulation of lindane, YJ regulated amino acid metabolism to resist stress. With the degradation of lindane in rice, the amino acid metabolism of BH and CY, which had high degradation ratios on day 9, was activated to compound biomolecules required for the organism to recover from the damage. Amino acid metabolism and carbohydrate metabolism were disturbed and inhibited mainly in YJ with low degradation ratios. This study provides the difference of the metabolic capacity of the metabolic capacity of different rice varieties to lindane, and changes at the molecular level and metabolic response mechanism of rice during the metabolism of lindane.

Modulation Effects of the CEP128 Gene on Radiotherapy-Related Brain Injury: A Longitudinal Structural Study Using Multi-Parametric Brain MR Images.

BACKGROUND: The promoter variant rs17111237 in the CEP128 closely relates to radiotherapy (RT)-related brain necrosis in nasopharyngeal carcinoma (NPC) patients. PURPOSE: To explore RT-related dynamic alterations in brain morphology and their potential genetic mechanism, and to explore the modulatory effects of CEP128 genetic variants on RT-related brain morphological alterations in NPC patients. STUDY TYPE: Prospective, longitudinal. POPULATION: One hundred one patients with histopathologic ally-proven NPC (age 41.64 ± 9.63, 46 male), analyzed at baseline (pre-RT), 3-months post-RT and 6 months post-RT, and 19 sex-, age- and education-matched healthy controls. FIELD STRENGTH/SEQUENCE: 3D gradient echo brain volume (3D-BRAVO) and diffusion-weighted single-shot spin-echo echo-planar sequences at 3.0 T. ASSESSMENT: rs17111237 in CEP128 was detected by Sanger sequencing. Structural and diffusion images were processed with FreeSurfer and FSL. Morphometric similarity network (MSN) was constructed with nine cortical indices derived from structural and diffusion images. STATISTICAL TESTS: One-way ANOVA, chi-square test. Pearson's correlation analysis was conducted to measure the relationship between CEP128 gene-expression level in human brain and MSN alterations. Repeated analysis of variance performed to assess group differences in MSN and the modulatory effects of the CEP128 gene within patients. Significance level: P < 0.05, false-discovery rate correction. RESULTS: RT-related significant widespread MSN alterations were observed in the cortices of NPC patients. Notably, regional MSN alterations had a weak but significant negative correlation with the cortical pattern of CEP128 gene expression (r = -0.152). Furthermore, rs17111237 in the CEP128 had significant modulatory effects on the observed MSN alterations in NPC patients, with the modulatory effects being most obvious at 3 months post-RT. CONCLUSIONS: MSN has potential to serve as a sensitive biomarker to detect RT-related brain injury. Inter-brain regional and inter-patient variability of RT-related brain injuries may be attributed to the cortical expression of the CEP128 gene and the modulatory effects of the promoter variant rs17111237 in CEP128. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Disparate Radiation-Induced Microstructural Injuries in Whole-Brain White Matter of Patients With Nasopharyngeal Carcinoma: A Longitudinal Study Using Multishell Diffusion MRI.

BACKGROUND: Evidence for prevention strategies of radiotherapy (RT)-related injury in patients with nasopharyngeal carcinoma (NPC) was lacking. Understanding the dynamic alterations in the cerebral white matter (WM) microstructure after RT may be helpful. PURPOSE: To investigate the dynamic alterations in the whole brain WM microstructure in patients with NPC in the 12 months after RT using multishell diffusion MRI (MS-dMRI). STUDY TYPE: Single-center longitudinal study. POPULATION: A total of 28 treatment-naïve patients with pathologically confirmed NPC (age: 39.68 ± 8.93 years, 11 female) and 20 healthy controls (age: 40.65 ± 9.76 years, 7 female). FIELD STRENGTH/SEQUENCES: A 3 T, MS-dMRI using a single-shot echo planar imaging sequence. ASSESSMENT: MS-dMRI was acquired at baseline for the NPC patients and healthy controls, at 0-3 (acute, AC), 6 (early delayed, ED) and 12 months (late delayed, LD) after RT for the NPC patients. The mean and maximum radiation doses to the temporal lobe were acquired. The quality of images was reviewed. MS-dMRI was analyzed using tract-based spatial statistics (TBSS). The presentations of injury were defined by the findings of TBSS. STATISTICAL TESTS: Chi-square, t tests, repeated ANOVA, and Spearman-rank correlation analysis were used. P < 0.05 was considered to be statistically significant. RESULTS: TBSS showed two WM injuries (injuries 1 and 2). Injury 1 emerged in the ED phase in the bilateral temporal poles and persisted throughout the ED and LD phases. Injury 2 developed from the AC to ED phase in the bilateral hemisphere and partially recovered in the LD phase. In the ED and LD phases, the multiple diffusion metrics were well correlated (r > 0.5 or <-0.5) with the RT dose, especially in the WM tracts in the temporal lobes. DATA CONCLUSION: Disparate WM injuries were observed in NPC patients after RT. The injuries may be primarily or secondarily induced by radiation. Injury 1 may be irreversible, while injury 2 seems to partially recover. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 4.

A genomic catalogue of soil microbiomes boosts mining of biodiversity and genetic resources.

Soil harbors a vast expanse of unidentified microbes, termed as microbial dark matter, presenting an untapped reservo)ir of microbial biodiversity and genetic resources, but has yet to be fully explored. In this study, we conduct a large-scale excavation of soil microbial dark matter by reconstructing 40,039 metagenome-assembled genome bins (the SMAG catalogue) from 3304 soil metagenomes. We identify 16,530 of 21,077 species-level genome bins (SGBs) as unknown SGBs (uSGBs), which expand archaeal and bacterial diversity across the tree of life. We also illustrate the pivotal role of uSGBs in augmenting soil microbiome's functional landscape and intra-species genome diversity, providing large proportions of the 43,169 biosynthetic gene clusters and 8545 CRISPR-Cas genes. Additionally, we determine that uSGBs contributed 84.6% of previously unexplored viral-host associations from the SMAG catalogue. The SMAG catalogue provides an useful genomic resource for further studies investigating soil microbial biodiversity and genetic resources.

Reduced-dose radiotherapy for Epstein-Barr virus DNA selected staged III nasopharyngeal carcinoma: A single-arm, phase 2 trial.

BACKGROUND: Radiotherapy-related toxicities of nasopharyngeal carcinoma (NPC) caused by a standard dose of 70 Gy remain a critical issue. Therefore, we assessed whether a radiotherapy dose of 60 Gy was non-inferior to the standard dose in patients with low-risk stage III NPC with a favourable response to induction chemotherapy (IC). PATIENTS AND METHODS: We did a single-arm, single-centre, phase II clinical trial in China. Patients with low-risk (Epstein-Barr virus [EBV] DNA level <4000 copies/ml) stage III NPC were treated with two cycles IC. Patients with complete/partial response and undetectable EBV DNA level were assigned 60 Gy intensity-modulated radiotherapy concurrently with three cycles of cisplatin. The primary end-point was 2-year progression-free survival (PFS). This trial is registered with ClinicalTrials.gov, number NCT03668730. RESULTS: One patient quit because of withdrawal of informed consent after IC. In total, 215 patients completed two cycles of IC, after which 116 (54.0%) and 99 (46.0%) patients were assigned 60 and 70 Gy radiotherapy, respectively. For 215 patients, the 2-year PFS was 90.7% (95% CI, 86.8%-94.6%) with a median follow-up of 43.9 months (interquartile range [IQR], 39.8-46.2). For patients treated with 60 Gy radiotherapy, the 2-year PFS rate was 94.8% (95%CI 90.7%-98.9%) with a median follow-up of 43.9 months (IQR 40.2-46.2). The most common late toxicity was grade 1-2 dry mouth (incidence rate: 54.3%). No grade 3+ long-term adverse event was observed, and most quality-of-life items, domains, and symptom scores returned to baseline by 6 months. CONCLUSION: Reduced-dose radiation (60 Gy) is associated with favourable survival outcomes and limited treatment-related toxicities in patients with low-risk stage III NPC sensitive to IC.

Paclitaxel liposome, cisplatin and 5-fluorouracil-based induction chemotherapy followed by de-escalated intensity-modulated radiotherapy with concurrent cisplatin in stage IVA-IVB childhood nasopharyngeal carcinoma in endemic area: a phase II, single-arm trial.

Background: Previous studies demonstrated that induction chemotherapy (IC) followed by de-escalated chemoradiotherapy adapted to tumor response was effective in treating childhood nasopharyngeal carcinoma (NPC), but the toxicity profile of this treatment strategy, and whether childhood patients with advanced stages can obtain enough benefits from it requires further investigation. Methods: We conducted a single-center phase II trial (NCT03020329). All participants received 3 cycles of paclitaxel liposome, cisplatin and 5-fluorouracil (TPF)-based IC. Patients who showed complete or partial response received de-escalated radiotherapy of 60 Gy with 3 cycles of concurrent cisplatin, and those who showed stable or progressive disease received standard-dose radiotherapy of 70 Gy with concurrent cisplatin. The primary endpoint was the complete response (CR) rate at the end of concurrent chemoradiotherapy (CCRT). Findings: From November 2016 to March 2021, 44 patients were recruited in the cohort. The CR rate was 80% (35/44, 95% CI, 65-90) of the whole cohort. All patients achieved CR 3 months after CCRT. By the last follow-up, the 3-year progression-free survival and overall survival were 91% (95% CI, 82-99) and 100% respectively. Dry mouth was the most common late toxicity, with an incidence of 41% (18/44), followed by skin fibrosis and hearing impairment. No patient suffered from severe late toxicity and growth retardation. Interpretation: Our results proved the efficacy and safety of TPF regimen followed by de-escalated radiotherapy with concurrent cisplatin in treating stage IVa-b childhood NPC patients. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Association between serum vitamin D levels and sensitivity to thyroid hormone indices: a cross-sectional observational study in NHANES 2007-2012.

Objective: We designed this study to determine whether there is a link between vitamin D levels and sensitivity to thyroid hormone and to provide a new perspective for studying the relationship between vitamin D and thyroid disease. Methods: Our study included 8,126 participators from the National Health and Nutrition Examination Survey (NHANES) database between 2007 and 2012. We used weighted multiple linear regression models to enquire the connection between serum vitamin D levels and thyroid hormone sensitivity indicators, including the following: Thyroid-stimulating hormone index (TSHI), Free Triiodothyronine/Free thyroxine (FT3/FT4), Thyroid Feedback Quantile-based Index (TFQI), and Thyrotroph Thyroxine Resistance Index (TT4RI). Finally, we used constrained cubic splines to explore possible nonlinear relationships. All data cleaning and statistical analyses were performed using R software. Results: The final Results were reached after adjusting for various confounding factors. We found a U-shaped relationship between TFQI and serum vitamin D, and the lowest TFQI appeared when the serum vitamin D concentration was 25.77ng/ml. However, an inverse U-shaped relationship was found between FT3/FT4 and vitamin D levels. When the serum vitamin D concentration was 25.43ng/ml, the ratio of FT3/FT4 was the highest. Conclusion: In the US population, our study concluded that FTQI and FT3/FT4 were U-shaped or inverse-U-shaped with serum vitamin D levels respectively after several adjustments. Therefore, FTQI and FT3/FT4 are considered indicators of the complex relationship between thyroid hormone resistance and vitamin D metabolism. In the future, more complex prospective investigations are needed to confirm these findings and find a causal link between them.

Erratum: Author correction to 'TMEM16A inhibits angiotensin II-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner' [Acta Pharmaceutica Sinica B 11 (2021) 3994-4007].

[This corrects the article DOI: 10.1016/j.apsb.2021.04.013.].

Camrelizumab combined with apatinib in patients with first-line platinum-resistant or PD-1 inhibitor resistant recurrent/metastatic nasopharyngeal carcinoma: a single-arm, phase 2 trial.

Immunotherapy combined with antiangiogenic targeted therapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for refractory recurrent/metastatic nasopharyngeal carcinoma (RM-NPC). We conducted a phase 2 trial to evaluate the safety and activity of camrelizumab plus apatinib in platinum-resistant (cohort 1, NCT04547088) and PD-1 inhibitor resistant NPC (cohort 2, NCT04548271). Here we report on the primary outcome of objective response rate (ORR) and secondary endpoints of safety, duration of response, disease control rate, progression-free survival, and overall survival. The primary endpoint of ORR was met for cohort 1 (65%, 95% CI, 49.6-80.4, n = 40) and cohort 2 (34.3%; 95% CI, 17.0-51.8, n = 32). Grade ≥ 3 treatment-related adverse events (TRAE) were reported in 47 (65.3%) of 72 patients. Results of our predefined exploratory investigation of predictive biomarkers show: B cell markers are the most differentially expressed genes in the tumors of responders versus non-responders in cohort 1 and that tertiary lymphoid structure is associated with higher ORR; Angiogenesis gene expression signatures are strongly associated with ORR in cohort 2. Camrelizumab plus apatinib combination effectiveness is associated with high expression of PD-L1, VEGF Receptor 2 and B-cell-related genes signatures. Camrelizumab plus apatinib shows promising efficacy with a measurable safety profile in RM-NPC patients.