Can the radiation dose be safely reduced in the treatment of nk/T cell lymphoma?

The aim of this study is to investigate the feasibility and safety of dose reduction in the radiotherapy of NK/T-cell lymphoma. A retrospective collection of clinical and treatment data was conducted on 41 patients. The analysis aimed to assess whether the reduction in radiation therapy dosage affected patients' local control and survival. Among the 41 patients, all achieved complete remission after the initial treatment. With a median follow-up of 28.4 months, all except one patient demonstrated good control within the irradiated area. In the entire cohort, a total of 6 patients died and none of the deaths were caused by local tumor failure. The 3-year overall survival rate and progression-free survival rate was 83.8%, 94.4%, respectively. The incidence of long-term toxicity was low. It seems safe to reduce the prophylactic radiation dose to 45 Gy and the preliminary treatment results are satisfactory, with further reduction in side effects.

Maize residue retention shapes soil microbial communities and co-occurrence networks upon freeze-thawing cycles.

Maize residue retention is an effective agricultural practice for improving soil fertility in black soil region, where suffered from long freezing-thawing periods and intense freeze-thawing (FT) cycles. However, very few studies have examined the influence of maize residue retention on soil microbial communities under FT cycles. We investigated the response of soil microbial communities and co-occurrence networks to maize residue retention at different FT intensities over 12 cycles using a microcosm experiment conditioned in a temperature incubator. Our results indicated that maize residue retention induced dramatic shifts in soil archaeal, bacterial and fungal communities towards copiotroph-dominated communities. Maize residue retention consistently reduced soil fungal richness across all cycles, but this effect was weaker for archaea and bacteria. Normalized stochastic ratio analysis revealed that maize residue retention significantly enhanced the deterministic process of archaeal, bacterial and fungal communities. Although FT intensity significantly impacted soil respiration, it did not induce profound changes in soil microbial diversity and community composition. Co-occurrence network analysis revealed that maize residue retention simplified prokaryotic network, while did not impact fungal network complexity. The network robustness index suggested that maize residue retention enhanced the fungal network stability, but reduced prokaryotic network stability. Moreover, the fungal network in severe FT treatment harbored the most abundant keystone taxa, mainly being cold-adapted fungi. By identifying modules in networks, we observed that prokaryotic Module #1 and fungal Module #3 were enhanced by maize residue retention and contributed greatly to soil quality. Together, our results showed that maize residue retention exerted stronger influence on soil microbial communities and co-occurrence network patterns than FT intensity and highlighted the potential of microbial interactions in improving soil functionality.

[Research progress in chemical constituents and pigment extraction process of Carthami Flos].

Carthami Flos(flowers of Carthamus tinctorius) with the effects of activating blood, dredging meridians, dissipating stasis, and relieving pain is one of the commonly used traditional Chinese medicines for promoting blood circulation and resolving stasis in clinical practice. So far, more than 210 compounds in Carthami Flos have been isolated and reported, including quinochalcones(safflower yellow pigments and red pigments), flavonoids, spermidines, alkaloids, polyacetylenes, and organic acids. Safflower yellow pigments, as the main water-soluble active components of Carthami Flos, is commonly obtained by the water extraction method, while red pigments are commonly obtained by the alkali extraction and acid precipitation method. In recent years, natural deep eutectic solvents as green solvents have demonstrated promising application prospects in the extraction and separation of pigments from Carthami Flos. This review systematically summarizes the chemical constituents of Carthami Flos and analyzes the extraction process of pigment components from Carthami Flos, aiming to provide a reference for further utilization of Carthami Flos resources.

Knockdown H19 Accelerated iPSCs Reprogramming through Epigenetic Modifications and Mesenchymal-to-Epithelial Transition.

H19 is an essential imprinted gene that is expressed to govern normal embryonic development. During reprogramming, the parental pronuclei have asymmetric reprogramming capacities and the critical reprogramming factors predominantly reside in the male pronucleus. After inhibiting the expression of H19 and Gtl2, androgenetic haploid ESCs (AG-haESCs) can efficiently and stably support the generation of healthy SC pups at a rate of ~20%, and double-knockout parthenogenetic haESCs can also produce efficiently. Induced pluripotent stem (iPS) cell reprogramming is thought to have a characteristic epigenetic pattern that is the reverse of its developmental potential; however, it is unclear how H19 participates in iPS cell reprogramming. Here, we showed that the expression of H19 was transiently increased during iPSC reprogramming. H19 knockdown resulted in greater reprogramming efficiency. The genes associated with pluripotency showed enhanced expression during the early reprogramming process, and the Oct4 promoter was demethylated by bisulfite genomic sequencing analysis. Moreover, expression analysis revealed that the mesenchymal master regulators associated with epithelial-to-mesenchymal transition (EMT) were downregulated during reprogramming in H19 knockdown. These findings provide functional insight into the role of H19 as a barrier to the early reprogramming process.

Source-free active domain adaptation for diabetic retinopathy grading based on ultra-wide-field fundus images.

Domain adaptation (DA) is commonly employed in diabetic retinopathy (DR) grading using unannotated fundus images, allowing knowledge transfer from labeled color fundus images. Existing DAs often struggle with domain disparities, hindering DR grading performance compared to clinical diagnosis. A source-free active domain adaptation method (SFADA), which generates features of color fundus images by noise, selects valuable ultra-wide-field (UWF) fundus images through local representation matching, and adapts models using DR lesion prototypes, is proposed to upgrade DR diagnostic accuracy. Importantly, SFADA enhances data security and patient privacy by excluding source domain data. It reduces image resolution and boosts model training speed by modeling DR grade relationships directly. Experiments show SFADA significantly improves DR grading performance, increasing accuracy by 20.90% and quadratic weighted kappa by 18.63% over baseline, reaching 85.36% and 92.38%, respectively. This suggests SFADA's promise for real clinical applications.

Disparities in mortality risk after diagnosis of hematological malignancies in 185 countries: A global data analysis.

This study was to report proxy measures for mortality risk in patients with hematological malignancies across 185 countries globally and explore its association with their socioeconomic status and treatment. The incidence, mortality, and 5-year prevalence data were extracted from the GLOBOCAN database. The data regarding the human development index (HDI), gross national income (GNI), vulnerability index, and concordance with cancer Essential Medicines List (EML) were obtained from open-source reports. The ratio of mortality to 5-year-prevalence (MPR) and that of mortality to incidence (MIR) were calculated and age-standardized using Segi's world standard population. Finally, the possible associations were assessed using Pearson correlation analyses. In 2020, the global incidence, mortality, and 5-year prevalence of HMs were 1,278,362, 711,840, and 3,616,685, respectively. Global age-standardized MPR and MIR were 0.15 and 0.44, respectively; they varied significantly among 6 regions, 185 countries, 4 HM types, and 4 HDI groups worldwide. Older populations always had higher ratios. The correlation of MPRs and MIRs with HDI, GNI, and concordance with cancer EML was negative, whereas it was positive with the vulnerability index (lower was better). Increasing access to cancer drugs in resource-limited regions with a focus on vulnerable children may aid in reducing HM-related mortality risk.

Efficacy and Safety of Nimotuzumab in Combination with Radiotherapy or Chemoradiotherapy for Local Advanced Head and Neck Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: The present meta-analysis aimed to evaluate the efficacy and safety of adding nimotuzumab to radiotherapy (RT) or chemoradiotherapy (CRT). METHODS: Prospective randomized controlled studies at EMBASE, PubMed, and the Cochrane Library from January 1, 2010, to October 1, 2022, were searched. Data on the overall survival (OS), progress-free survival (PFS), disease-free survival (DFS), complete response rate (CRR), objective response rate (ORR), and all grade adverse events were collected from the enrolled publications. OS was the primary measurement indicator. Pooled analysis was performed with relative risks (RRs), hazard risks (HRs), and their corresponding 95% confidence intervals (CIs) in the software Stata SE 16.0. RESULTS: Six randomized controlled studies were included in the analysis of the overall pooled effect. As compared to the control group, the nimotuzumab intervention group exhibited improved OS by 21% (pooled HR=0.79,95% CI: 0.64-0.98, P=0.028), along with PFS up to 31% (HR=0.69, 95% CI: 0.55-0.86, P=0.001) and DFS up to 29% (HR=0.71, 95% CI: 0.56-0.91, P=0.006), increased CRR as 50% (RR=1.50, 95%CI:1.09-2.04; P=0.012), and ORR as 35% (RR=1.35, 95%- CI:1.04-1.73; P=0.022). Regarding safety, nimotuzumab in combination with RT or CRT did not increase the incidence of all grade adverse events (pooled-RD=-1.27, 95%CI:-2.78-0.23, P=0.099). CONCLUSION: The present meta-analysis has demonstrated that nimotuzumab, in combination with RT or CRT, could provide survival benefits and increase response rates. Its safety profile has been found to be controllable.

Core bacteria and fungi in response to residue retention and their contribution to soil multifunctionality in maize agroecosystem.

Core microbiome has been proven to play crucial roles in soil function. However, we still lack knowledge on how core microbiome responds to crop residue retention, and whether they contribute to this process. Consequently, we examined the effect of residue retention on soil core and non-core microbial communities in maize seedling, mature stage and freezing period based on a multi-site field experiment in Sanjiang Plain, Northeast China. Totally, 247 bacterial amplicon sequence variants (ASVs) and 109 fungal ASVs were identified as core microbiota. Both core and non-core bacterial/fungal community composition were significantly influenced by residue retention across all study sites. Especially, the core fungal community shifted towards a saprotroph-dominated community. Normalized stochastic ratio pattern revealed that that deterministic process dominated both core and non-core microbial community assembly processes. Residue retention enhanced the deterministic process of core microbial community assembly, while exhibited opposite effect on non-core microbial community. This study also revealed that soil fungi were more sensitive to residue retention than bacteria, with a larger proportion of core fungi were enriched or depleted by residue retention. In addition, residue retention complicated core bacterial co-occurrence network, while simplified fungal network. Our results pointed out both no reduction in microbial diversity or collapse in microbial network structure after repeated freezing-thawing cycles. The potential function of core microbiome was evaluated through random forest analysis and structural equation model, the results indicated core microbiome contributed more to multifunctionality than non-core microbiome. Overall, this study strengthened our understanding of soil core microbiome in response to residue retention, and highlighted their importance in maintaining soil multifunctionality.

Nitrogen deposition mediates more stochastic processes in structuring plant community than soil microbial community in the Eurasian steppe.

Anthropogenic environmental changes may affect community assembly through mediating both deterministic (e.g., competitive exclusion and environmental filtering) and stochastic processes (e.g., birth/death and dispersal/colonization). It is traditionally thought that environmental changes have a larger mediation effect on stochastic processes in structuring soil microbial community than aboveground plant community; however, this hypothesis remains largely untested. Here we report an unexpected pattern that nitrogen (N) deposition has a larger mediation effect on stochastic processes in structuring plant community than soil microbial community (those <2 mm in diameter, including archaea, bacteria, fungi, and protists) in the Eurasian steppe. We performed a ten-year nitrogen deposition experiment in a semiarid grassland ecosystem in Inner Mongolia, manipulating nine rates (0-50 g N m-2 per year) at two frequencies (nitrogen added twice or 12 times per year) under two grassland management strategies (fencing or mowing). We separated the compositional variation of plant and soil microbial communities caused by each treatment into the deterministic and stochastic components with a recently-developed method. As nitrogen addition rate increased, the relative importance of stochastic component of plant community first increased and then decreased, while that of soil microbial community first decreased and then increased. On the whole, the relative importance of stochastic component was significantly larger in plant community (0.552±0.035; mean±standard error) than in microbial community (0.427±0.035). Consistently, the proportion of compositional variation explained by the deterministic soil and community indices was smaller for plant community (0.172-0.186) than microbial community (0.240-0.767). Meanwhile, as nitrogen addition rate increased, the linkage between plant and microbial community composition first became weaker and then became stronger. The larger stochasticity in plant community relative to microbial community assembly suggested that more stochastic strategies (e.g., seeds addition) should be adopted to maintain above- than below-ground biodiversity under the pressure of nitrogen deposition.

Cholesterol-induced HRD1 reduction accelerates vascular smooth muscle cell senescence via stimulation of endoplasmic reticulum stress-induced reactive oxygen species.

Senescence of vascular smooth muscle cells (VSMCs) is a key contributor to plaque vulnerability in atherosclerosis (AS), which is affected by endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production. However, the crosstalk between ER stress and ROS production in the pathogenesis of VSMC senescence remains to be elucidated. ER-associated degradation (ERAD) is a complex process that clears unfolded or misfolded proteins to maintain ER homeostasis. HRD1 is the major E3 ligase in mammalian ERAD machineries that catalyzes ubiquitin conjugation to the unfolded or misfolded proteins for degradation. Our results showed that HRD1 protein levels were reduced in human AS plaques and aortic roots from ApoE-/- mice fed with high-fat diet (HFD), along with the increased ER stress response. Exposure to cholesterol in VSMCs activated inflammatory signaling and induced senescence, while reduced HRD1 protein expression. CRISPR Cas9-mediated HRD1 knockout (KO) exacerbated cholesterol- and thapsigargin-induced cell senescence. Inhibiting ER stress with 4-PBA (4-Phenylbutyric acid) partially reversed the ROS production and cell senescence induced by HRD1 deficiency in VSMCs, suggesting that ER stress alone could be sufficient to induce ROS production and senescence in VSMCs. Besides, HRD1 deficiency led to mitochondrial dysfunction, and reducing ROS production from impaired mitochondria partly reversed HRD1 deficiency-induced cell senescence. Finally, we showed that the overexpression of HDR1 reversed cholesterol-induced ER stress, ROS production, and cellular senescence in VSMCs. Our findings indicate that HRD1 protects against senescence by maintaining ER homeostasis and mitochondrial functionality. Thus, targeting HRD1 function may help to mitigate VSMC senescence and prevent vascular aging related diseases. TRIAL REGISTRATION: A real-world study based on the discussion of primary and secondary prevention strategies for coronary heart disease, URL:https://www.clinicaltrials.gov, the trial registration number is [2022]-02-121-01.

m6A-modified circ_0124554 promotes colorectal cancer progression and radioresistance through the miR-1184/LASP1 pathway.

BACKGROUND: Circular RNAs (circRNAs) are believed to regulate the progression of various cancers including colorectal cancer (CRC). However, the role and mechanism of circ_0124554 in regulating the sensitivity of CRC to radiation remain unknown. METHODS: The RNA levels of circ_0124554, LIM and SH3 protein 1 (LASP1), and methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3) were detected by quantitative real-time polymerase chain reaction. Protein expression was checked by western blot. Cell proliferation, apoptosis, migration, and invasion were investigated by 5-Ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry analysis, and transwell assay, respectively. The sensitivity of CRC cells to radiation was analyzed by cell colony formation assay. Xenograft mouse model assay was conducted to disclose the role of circ_0001023 in the sensitivity of tumors to radiation in vivo. The binding relationships among circ_0124554, miR-1184 and LASP1 were confirmed by a dual-luciferase reporter assay. m6A RNA immunoprecipitation assay was performed to identify the association of METTL3 with circ_0124554. RESULTS: Circ_0124554 expression was upregulated in CRC tissues and cells in comparison with normal colorectal tissues and cells. Circ_0124554 knockdown inhibited proliferation, migration and invasion and promoted apoptosis and radiosensitivity of CRC cells. Moreover, circ_0124554 depletion inhibited tumor formation and improved radiosensitivity in vivo. MiR-1184 was identified as a target miRNA of circ_0124554 and targeted LASP1. Additionally, LASP1 overexpression rescued circ_0124554 knockdown-mediated effects in CRC cells. METTL3 mediated m6A methylation of circ_0124554. Further, circ_0124554 overexpression attenuated METTL3 depletion-induced effects in CRC cells. CONCLUSION: m6A-modified circ_0124554 promoted CRC progression and radioresistance by inducing LASP1 expression through interaction with miR-1184.

The inhibition of VDAC1 oligomerization promotes pigmentation through the CaMK-CRTCs/CREB-MITF pathway.

The voltage-dependent anion channel 1 (VDAC1) forms an oligomeric structure on the mitochondrial outer membrane, which plays critical roles in many physiological processes. Research studies have demonstrated that the knockout of VDAC1 increases pigment content and up-regulates the expression of melanogenic genes. Due to its involvement in various physiological processes, the depletion of VDAC1 has significant detrimental effects on cellular functions and the inhibition of VDAC1 oligomerization has recently emerged as a promising strategy for the treatment of several diseases. In this study, we found that VDAC1 oligomerization inhibitors, VBIT-12 and NSC-15364, promote melanogenesis, dendrite formation and melanosome transport in human epidermal melanocytes (HEMCs). Mechanistically, treatment of HEMCs with an oligomerization inhibitor increased the level of cytoplasmic calcium ions, which activated calcium-calmodulin dependent protein kinase (CaMK) and led to the phosphorylation of CREB and the nuclear translocation of CREB-regulated transcription coactivators (CRTCs). Subsequently, CRTCs, p-CREB and CREB-binding protein (CBP) in the nucleus cooperatively recruit the transcription machinery to initiate the transcription of MITF thus promoting pigmentation. Importantly, our study also demonstrates that VDAC1 oligomerization inhibitors increase pigmentation in zebrafish and in human skin explants, highlighting their potential as a therapeutic strategy for skin pigmentation disorders.

A soil fumigant increases American ginseng (Panax quinquefolius L.) survival and growth under continuous cropping by affecting soil microbiome assembly: a 4-year in situ field experiment.

IMPORTANCE: Numerous reports of soil fumigants and fungicides on annual crops exist; however, it is unclear whether the single application to perennial plants persistently improves plant growth and controls disease or whether it has a long-lasting impact on soil microbes. We found that soil fumigation enhances ginseng growth and suppresses root rot disease by reshaping the soil microbial community. Our findings benefit the agricultural development of ginseng and provide a theoretical basis for the prevention of ginseng diseases.

Real-world data of immunotherapy from China in recurrent or metastatic head and neck squamous cell carcinoma.

PURPOSE: Immune checkpoint inhibitors (ICIs) have become a standard therapy for recurrent or metastatic head and neck squamous cell carcinoma (R/MHNSCC), however, there are still unanswered questions about immunotherapy. Furthermore, immunotherapy for R/MHNSCC of the mainland Chinese population are lacking. The aim of this study is to evaluate the efficacy and safety of ICIs in real-world settings in China. MATERIALS AND METHODS: We retrospectively reviewed 59 patients with R/MHNSCC who received immunotherapy between May 2019 and December 2021. We assessed demographics, efficacy, survival and safety. RESULTS: Fifty-nine patients were included in the study, all of whom had R/MHNSCC affecting the oral cavity, oropharynx, hypopharynx, larynx, nasal cavity, paranasal sinuses and metastatic cancer in the neck with an unknown primary. The objective response rate (ORR) for all patients was found to be 40.6 %. Out of these patients, 11 patients achieved a complete response and 13 achieved a partial response. The median progression-free survival (PFS) was calculated to be 10.64 months (range: 1.15-29.24 months), while the median overall survival (OS) was 21.75 months (range 2.0-37.55 months). The addition of local radiotherapy resulted in higher ORR and PFS compared to previous reports. Notably, patients with R/MHNSCC in the paranasal sinuses and nasal cavity also showed benefits from immunotherapy. Additionally, patients who achieved stable disease (SD) had similar survival rates to those who achieved partial response (PR), indicating that SD is also an indicator of clinical benefit from immunotherapy. The overall incidence of immune-related adverse reactions in this study was low, with fatigue and rash being the most common side effects. CONCLUSION: These findings highlight the effectiveness and safety of immunotherapy for R/MHNSCC in a real-world setting in China. Further investigation is warranted to explore the potential benefits of incorporating local radiotherapy into the treatment of R/MHNSCC.

HRD1 reduction promotes cholesterol-induced vascular smooth muscle cell phenotypic change via endoplasmic reticulum stress.

Phenotypic change of vascular smooth muscle cells (VSMCs) is the main contributor of vascular pathological remodeling in atherosclerosis. The endoplasmic reticulum (ER) is critical for maintaining VSMC function through elimination of misfolded proteins that impair VSMC cellular function. ER-associated degradation (ERAD) is an ER-mediated process that controls protein quality by clearing misfolded proteins. One of the critical regulators of ERAD is HRD1, which also plays a vital role in lipid metabolism. However, the function of HRD1 in VSMCs of atherosclerotic vessels remains poorly understood. The level of HRD1 expression was analyzed in aortic tissues of mice fed with a high-fat diet (HFD). The H&E and EVG (VERHOEFF'S VAN GIESON) staining were used to demonstrate pathological vascular changes. IF (immunofluorescence) and WB (western blot) were used to explore the signaling pathways in vivo and in vitro. The wound closure and transwell assays were also used to test the migration rate of VSMCs. CRISPR gene editing and transcriptomic analysis were applied in vitro to explore the cellular mechanism. Our data showed significant reduction of HRD1 in aortic tissues of mice under HFD feeding. VSMC phenotypic change and HRD1 downregulation were detected by cholesterol supplement. Transcriptomic and further analysis of HRD1-KO VSMCs showed that HRD1 deficiency induced the expression of genes related to ER stress response, proliferation and migration, but reduced the contractile-related genes in VSMCs. HRD1 deficiency also exacerbated the proliferation, migration and ROS production of VSMCs induced by cholesterol, which promoted the VSMC dedifferentiation. Our results showed that HRD1 played an essential role in the contractile homeostasis of VSMCs by negatively regulating ER stress response. Thus, HRD1 in VSMCs could serve as a potential therapeutic target in metabolic disorder-induced vascular remodeling.

Characteristics of fundus autofluorescence imaging at 795 nm and its correlations with postoperative outcomes for idiopathic macular hole.

BACKGROUND: Vitrectomy combined with internal limiting membrane (ILM) peeling or ILM inverted flap greatly improves hole closure and vision prognosis for idiopathic macular holes (IMH). The application of indocyanine green (ICG) in MH surgery increases the visibility of ILM and the safety of surgery. However, the area of ILM peeling and the state of the flap and a closed hole has not been well observed. AIM: Fundus autofluorescence at 7935nm can show the range of ILM peeling and the state of the hole site and ILM flap by monitoring residual ICG postoperatively. However, the characteristics of fundus autofluorescence especially the site of the closed hole, and its relationship with vision prognosis have not been explored. The aim of this project was to find the autofluorescence features of the closed hole and their relation with vision. OBJECTIVE: To investigate the characteristics of fundus autofluorescence imaging after ICG-assisted vitrectomy for IMH and to evaluate the correlations of fluorescence patterns at the MH site with visual acuity and macular anatomic outcomes. METHODS: We retrospectively evaluated 33 IMH patients (33 eyes) who underwent a 25G pars plana vitrectomy (follow-up, 6-14.5 months). ICG staining (2.5 mg/mL) was either used to remove the internal limiting membrane (ILM) or the inverted ILM flap was overlaid on the hole. After surgery, fluorescence imaging of the fundus was obtained using a scanning laser ophthalmoscope at 795 nm. RESULTS: On fluorescence imaging, the area of ILM peeling in all eyes showed hypofluorescence with no changes over time. The inverted ILM flap (performed in 18 eyes) was positioned on the inferior retina and exhibited early mild hyperfluorescence with blurred edges. This was gradually enhanced up to 3-6 months postoperatively and was then attenuated. MHs showed two distinct patterns on optical coherence tomography: granular (21 eyes) and patchy hyperfluorescence (12 eyes). Best-corrected visual acuity improved postoperatively in all cases (p<0.001, Z=-4.744). VA was worse in the patchy (vs. granular) hyperfluorescence cases (p=0.011, Z=-2.548). CONCLUSION: The status of the ILM peeling area, ILM flap, and closed MH can be clearly observed using autofluorescence imaging at 795 nm. Fluorescence may be due to ICG staining of the ILM and accumulation in retinal pigment epithelium cells during ICG-assisted surgery. Granular hyperfluorescence at the MH site may indicate good anatomic and visual prognoses.

Camrelizumab plus famitinib in patients with recurrent or metastatic nasopharyngeal carcinoma treated with PD-1 blockade: data from a multicohort phase 2 study.

Background: Treatment options for patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) are not clear after progression on previous treatment with PD-(L)1 inhibitor; critical gaps in evidence remain for such cases. Immunotherapy combined with antiangiogenic therapy has been reported to have synergistic antitumor activity. Therefore, we evaluated the efficacy and safety of camrelizumab plus famitinib in patients with RM-NPC who failed treatment with PD-1 inhibitor-containing regimens. Methods: This multicenter, adaptive Simon minimax two-stage, phase II study enrolled patients with RM-NPC refractory to at least one line of systemic platinum-containing chemotherapy and anti-PD-(L)1 immunotherapy. The patient received camrelizumab 200 mg every 3 weeks and famitinib 20 mg once per day. The primary endpoint was objective response rate (ORR), and the study could be stopped early as criterion for efficacy was met (>5 responses). Key secondary endpoints included time to response (TTR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. This trial was registered with ClinicalTrials.gov, NCT04346381. Findings: Between October 12, 2020, and December 6, 2021, a total of 18 patients were enrolled since six responses were observed. The ORR was 33.3% (90% CI, 15.6-55.4) and the DCR was 77.8% (90% CI, 56.1-92.0). The median TTR was 2.1 months, the median DoR was 4.2 months (90% CI, 3.0-not reach), and the median PFS was 7.2 months (90% CI, 4.4-13.3), with a median follow-up duration of 16.7 months. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in eight (44.4%) patients, with the most common being decreased platelet count and/or neutropenia (n = 4, 22.2%). Treatment-related serious AEs occurred in six (33.3%) patients, and no deaths occurred due to TRAEs. Four patients developed grade ≥3 nasopharyngeal necrosis; two of them developed grade 3-4 major epistaxis, and they were cured by nasal packing and vascular embolization. Interpretation: Camrelizumab plus famitinib exhibited encouraging efficacy and tolerable safety profiles in patients with RM-NPC who failed frontline immunotherapy. Further studies are needed to confirm and expand these findings. Funding: Jiangsu Hengrui Pharmaceutical Co., Ltd.

Outcome and risk prediction of early progression in patients with extranodal natural killer/T cell lymphoma from the CLCG study.

Recently, progression-free survival at 24 months (PFS24) was defined as clinically relevant for patients with extranodal NK/T cell lymphoma. Herein, the clinical data from two independent random cohorts (696 patients each in the primary and validation datasets) were used to develop and validate a risk index for PFS24 (PFS24-RI), and evaluate its ability to predict early progression. Patients achieving PFS24 had a 5-year overall survival (OS) of 95.8%, whereas OS was only 21.2% in those failing PFS24 (P<0.001). PFS24 was an important predictor of subsequent OS, independent of risk stratification. The proportion of patients achieving PFS24 and 5-year OS rates correlated linearly among risk-stratified groups. Based on multivariate analysis of the primary dataset, the PFS24-RI included five risk factors: stage II or III/IV, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group score ≥2, primary tumor invasion, and extra-upper aerodigestive tract. PFS24-RI stratified the patients into low-risk (0), intermediate-risk (1-2), high-risk (≥3) groups with different prognoses. Harrell's C-index of PFS24-RI for PFS24 prediction was 0.667 in the validation dataset, indicating a good discriminative ability. PFS24-RI calibration indicated that the actual observed and predicted probability of failing PFS24 agreed well. PFS24-RI provided the probability of achieving PFS24 at an individual patient level.

The two sides of resistance-resilience relationship in both aboveground and belowground communities in the Eurasian steppe.

The ongoing nitrogen (N) deposition has led to profound changes in aboveground and belowground ecosystems. However, the stability of plant and soil microbial community toward N addition in terms of resistance and resilience is less understood. We established a long-running field trial (2008-2018) in a series of N applications in combination with a mowing and fencing (unmown) treatment in a semiarid steppe. We assessed the resistance via ongoing N treatment of one subplot and the resilience via discontinuing N treatment in another to promote natural recovery since 2014. Plant resistance was negatively correlated with N application rate, while microbial resistance was independent of N rate. Mowing significantly reduced plant resistance and resilience, reduced soil microbial resistance but improved its resilience. Generally, plants are more resilient but less resistant to N than soil microbes. The two sides of resistance-resilience relationship were revealed: trade-offs exist between resistance and resilience for both plants and microbes at the community level; and trade-offs between resistance and resilience cannot be scaled down to species/group level. This study provided an important theoretical basis for the recovery and conservation of semiarid steppe and new insight into resistance-resilience relationship.