Exploring Mechanical Forces Shaping Self-Organization and Morphogenesis During Early Embryo Development.

Embryonic development is a dynamic process orchestrated by a delicate interplay of biochemical and biophysical factors. While the role of genetics and biochemistry in embryogenesis has been extensively studied, recent research has highlighted the significance of mechanical regulation in shaping and guiding this intricate process. Here, we provide an overview of the current understanding of the mechanical regulation of embryo development. We explore how mechanical forces generated by cells and tissues play a crucial role in driving the development of different stages. We examine key morphogenetic processes such as compaction, blastocyst formation, implantation, and egg cylinder formation, and discuss the mechanical mechanisms and cues involved. By synthesizing the current body of literature, we highlight the emerging concepts and open questions in the field of mechanical regulation. We aim to provide an overview of the field, inspiring future investigations and fostering a deeper understanding of the mechanical aspects of embryo development.

Modulated Cell Internalization Behavior of Icosahedral DNA Framework with Programmable Surface Modification.

Surface modification could enhance the cell internalization efficiency of nanovehicles for targeted gene or drug delivery. However, the influence of surface modification parameters, including recognition manners, valences, and patterns, is often clouded, especially for the endocytosis of DNA nanostructures in customized shapes. Focusing on an icosahedral DNA framework, we systematically programmed three distinct types of ligands with diverse valence and spatial distribution on their outer surface to study the internalization efficiency, endocytic pathways, and postinternalization fate. The comparison in different aspects of parameters deepens our understanding of the intricate relationship between surface modification and cell entry behavior, offering insights crucial for designing and optimizing DNA framework nanostructures for potent cell-targeted purposes.

Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia.

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. METHODS: In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. RESULTS: Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, -1.0; 95% CI, -2.5 to 0; P = 0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points; 95% CI, -7.6 to 8.2; nominal P = 0.94). CONCLUSIONS: In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann-La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615.).

A new framework for drug-disease association prediction combing light-gated message passing neural network and gated fusion mechanism.

With the development of research on the complex aetiology of many diseases, computational drug repositioning methodology has proven to be a shortcut to costly and inefficient traditional methods. Therefore, developing more promising computational methods is indispensable for finding new candidate diseases to treat with existing drugs. In this paper, a model integrating a new variant of message passing neural network and a novel-gated fusion mechanism called GLGMPNN is proposed for drug-disease association prediction. First, a light-gated message passing neural network (LGMPNN), including message passing, aggregation and updating, is proposed to separately extract multiple pieces of information from the similarity networks and the association network. Then, a gated fusion mechanism consisting of a forget gate and an output gate is applied to integrate the multiple pieces of information to extent. The forget gate calculated by the multiple embeddings is built to integrate the association information into the similarity information. Furthermore, the final node representations are controlled by the output gate, which fuses the topology information of the networks and the initial similarity information. Finally, a bilinear decoder is adopted to reconstruct an adjacency matrix for drug-disease associations. Evaluated by 10-fold cross-validations, GLGMPNN achieves excellent performance compared with the current models. The following studies show that our model can effectively discover novel drug-disease associations.

Clinical features, prognostic stratification, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma: a multi-institutional real-world study.

The present study aimed to investigate the clinical features, prognosis, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma (ENKTCL). This real-world study retrospectively reviewed 56 newly diagnosed advanced-stage non-nasal type ENKTCL patients from two large-scale Chinese cancer centers in the last 10-15 years and screened 139 newly diagnosed advanced-stage nasal type ENKTCLs admitted during the same period for comparison. The non-nasal type ENKTCLs exhibited significantly higher Ki-67 expression levels compared to nasal type disease (P = 0.011). With a median follow-up duration of 75.03 months, the non-nasal group showed slightly inferior survival outcomes without statistically significant differences compared to the nasal group (median overall survival (OS): 14.57 vs. 21.53 months, 5-year OS: 28.0% vs. 38.5%, P = 0.120). Eastern Cooperative Oncology Group (ECOG) score ≥ 2 (hazard ratio (HR) = 2.18, P = 0.039) and lactic dehydrogenase (LDH) elevation (HR = 2.44, P = 0.012) were significantly correlated with worse OS in the non-nasal group. First-line gemcitabine-based chemotherapy regimens showed a trend toward slightly improved efficacy and survival outcomes compared to non-gemcitabine-based ones in the present cohort of non-nasal ENKTCLs (objective response rate: 91.7% vs. 63.6%, P = 0.144; complete response rate: 50.0% vs. 33.3%, P = 0.502; median progression-free survival: 10.43 vs. 3.40 months, P = 0.106; median OS: 25.13 vs. 9.30 months, P = 0.125), which requires further validation in larger sample size studies. Advanced-stage non-nasal type patients could achieve comparable prognosis with nasal cases after rational therapy. The modified nomogram-revised index (including age, ECOG score, and LDH) and modified international prognostic index (including age, ECOG score, LDH, and number of extranodal involvement) functioned effectively for prognostic stratification in non-nasal type ENKTCLs.

The role of eye-specific attention in ocular dominance plasticity.

It is well known how selective attention biases information processing in real time, but few work investigates the aftereffects of prolonged attention, let alone the underlying neural mechanisms. To examine perceptual aftereffect after prolonged attention to a monocular pathway, movie images played normally were presented to normal adult's one eye (attended eye), while movie images of the same episode but played backwards were presented to the opposite eye (unattended eye). One hour of watching this dichoptic movie caused a shift of perceptual ocular dominance towards the unattended eye. Interestingly, the aftereffect positively correlated with the advantage of neural activity for the attended-eye over unattended-eye signals at the frontal electrodes measured with steady-state visual evoked potentials. Moreover, the aftereffect disappeared when interocular competition was minimized during adaptation. These results suggest that top-down eye-specific attention can induce ocular dominance plasticity through binocular rivalry mechanisms. The present study opens the route to explain at least part of short-term ocular dominance plasticity with the ocular-opponency-neuron model, which may be an interesting complement to the homeostatic compensation theory.

Research on the supply and demand of elderly care service resources in China.

PURPOSE: This study aims to assess the current status and spatial distribution differences of elderly care service resources supply and demand in China. METHODS: Semi-structured qualitative interviews were utilized to gather participants' insights into the current demands for elderly care services, the status of resource allocation, and related indicators. The entropy weight method was employed to determine indicator weights, yielding objective demand and allocation indices for elderly care service resources. Kernel density estimation was used to illustrate the distribution characteristics of the demand and allocation indices. The coupling coordination degree model was applied to measure the coupling coordination level of China's elderly care service resource supply and demand system in 2020. RESULTS: The demand index ranks highest in Beijing (0.3291), Shanghai (0.2941), and Tianjin (0.2563), while the lowest are found in Tibet (0.1673), Guangxi (0.1727), and Guizhou (0.1737). Kernel density estimation shows that the demand index is concentrated in the range of 0.1800 to 0.2000. The top three regions for allocation index are Shanghai (184.0007), Qinghai (129.8177), and Beijing (109.5941), with the lowest in Liaoning (34.8558), Hainan (35.3168), and Yunnan (36.6366). Kernel density estimation indicates that the allocation index is concentrated in the range of 25-75. Calculations of coupling coordination degree show that Shanghai has high coordination quality (0.9368), Beijing has good coordination (0.8392), while Hainan and Yunnan experience severe imbalances (0.1990, 0.1831). CONCLUSIONS: There is a significant lack of coordination between the demand for elderly care services and the allocation of resources in Hainan and Yunnan provinces in China. Most provinces, with the exception of Beijing and Shanghai, exhibit some degree of misalignment. The Chinese government should address the varying needs of the elderly population in different regions, pay timely attention to regional disparities, enhance regional cooperation, and dynamically allocate elderly care resources in a rational manner.

Intensive therapy can improve long-term survival in newly diagnosed, advanced-stage extranodal NK/T-cell lymphoma: A multi-institutional, real-world study.

The study investigated the treatment and prognosis of advanced-stage extranodal natural killer/T-cell lymphoma (ENKTL). With a median follow-up of 75.03 months, the median overall survival (mOS) for the 195 newly diagnosed stage III/IV ENKTL patients was 19.43 months, and estimated 1-, 2-, 3- and 5-year OS were 59.5%, 46.3%, 41.8% and 35.1%, respectively. Chemotherapy (CT) + radiotherapy (RT) compared to CT alone (P = .007), and hematopoietic stem cell transplantation (HSCT) compared to non-HSCT (P < .001), both improved OS. For patients ≤60 years and ineligible for HSCT, other therapies with complete remission led to comparable OS (P = .141). Nine patients ever treated with chidamide achieved a median progression-free survival (mPFS) and mOS of 53.63 (range, 3.47-92.33) and 54.80 (range, 5.50-95.70) months, and four with chidamide maintenance therapy (MT) achieved a mPFS and mOS of 55.83 (range, 53.27-92.33) and 60.65 (range, 53.70-95.70) months, possibly providing an alternative option for non-HSCT patients. Non-anthracycline (ANT)- compared to ANT-, asparaginase (Aspa)- compared to non-Aspa- and gemcitabine (Gem)- compared to non-Gem-based regimens, prolonged PFS (P = .031; P = .005; P = .009) and OS (P = .010; P = .086; P = .003), respectively. Multivariate analysis demonstrated that Gem-based regimens improved PFS (HR = 0.691, P = .061) and OS (HR = 0.624, P = .037). Gem + Aspa combinations slightly improved PFS and OS compared to regimens containing Gem or Aspa alone (P > 0.05). First-line "intensive therapy," including CT (particularly Gem + Aspa regimens), RT, HSCT and alternative chidamide MT, was proposed and could improve long-term survival for advanced-stage ENKTLs. Ongoing prospective clinical studies may shed further light on the value of chidamide MT.

Treating amblyopia using altered reality enhances the fine-scale functional correlations in early visual areas.

Amblyopia is a developmental visual disorder that causes substantial visual deficits. Studies using resting-state functional magnetic resonance imaging have disclosed abnormal brain functional connectivity (FC) both across long-range cortical sites and within the visual cortex in amblyopes, which is considered to be related to impaired visual functions. However, little work has examined whether restoring the vision of amblyopes accompanies with an improvement of FC. Here in adult amblyopes and healthy participants, we compared their brain FC before and after an altered-reality adaptation training. Before the training, the voxel-wise FCs of amblyopia patients were substantially weaker than those of healthy control participants both within and across the early visual areas. After the training, visual acuities improved in amblyopes but not in the control participants. The effect kept strengthening in the subsequent month without further adaptation. Importantly, we observed enhanced voxel-wise FC both within and across the early visual areas of amblyopes. Moreover, the enhancement continued for at least 1 month. These results suggest that the effective treatment can improve both the amblyopes' vision and functional connections in the visual cortex.

Identification of acid phosphatase (ShACP) from the freshwater crab Sinopotamon henanense and its expression pattern changes in response to cadmium.

Acid phosphatase(ACP) is an important immune enzyme in crustacean humoral immunity. At present, the research on ACP mainly focuses on the biochemical properties of the enzyme, while few studies on gene expression. In this study, ShACP was cloned and the effect of cadmium stress on the expression and function of ShACP in the freshwater crab Sinopotamon henanense was studied. Analysis of the ShACP sequence and tissue distribution results showed that the cDNA sequence of ShACP was 1629 bp, including 48 bp 5' untranslated region, 1209 bp open reading frame region, and 372 bp 3' untranslated region, encoding 402 amino acids. ShACP contained multiple phosphorylation sites and mainly played a role in the hemolymph. Under low-concentration cadmium stress, the body improved immunity by enhancing the expression of ShACP, while high-concentration cadmium stress inhibited the expression of ShACP. ShACP can promote the phagocytosis of hemocytes, while cadmium stress reduced the phagocytosis of hemocytes. This study provides a theoretical basis for further research on the immune system of crabs and is of great significance for the study of crustacean immune responses under heavy metal stress.

Comparison Between the Efficacy of Spinal Cord Stimulation and of Endovascular Revascularization in the Treatment of Diabetic Foot Ulcers: A Retrospective Observational Study.

OBJECTIVE: We aimed to compare the effects of spinal cord stimulation (SCS) with those of endovascular revascularization on the treatment of diabetic foot ulcers. MATERIALS AND METHODS: A total of 104 patients with diabetic foot ulcers who met the inclusion criteria were retrospectively analyzed and classified to the SCS treatment group (n = 46) and endovascular revascularization treatment group (n = 46). The quality-of-life scores (Quality of Life Scale for Patients with Liver Cancer v2.0), visual pain analog scale score, lower limb skin temperature, lower limb arterial ultrasound results, and lower extremity electromyography results were analyzed to compare the efficacy of the two treatments for diabetic foot ulcers in the two groups before surgery and six months after surgery. RESULTS: A total of 92 patients (men: 73.9%, mean age: 66.51 ± 11.67 years) completed the six-month postoperative follow-up period. The patients in the SCS treatment group had a higher quality-of-life score (25.54% vs 13.77%, p < 0.05), a larger reduction in pain scores (69.18% vs 37.21%, p < 0.05), and a larger reduction in foot temperature (18.56% vs 7.24%, p < 0.05) than those of the endovascular revascularization treatment group at six months after surgery. The degree of vasodilation in the lower limbs on color Doppler arterial ultrasound and the nerve conduction velocity were higher in the SCS treatment group than in the endovascular revascularization treatment group at six months after surgery (p < 0.05). CONCLUSION: SCS was more effective than endovascular revascularization in improving quality of life, relieving pain, improving lower limb skin temperature, increasing lower limb blood flow, and improving nerve conduction in patients with diabetic foot ulcers at six months after surgery.

Clinical Effect Analysis of Spinal Cord Electrical Stimulator Implantation for Diabetic Foot.

OBJECTIVE: To investigate the clinical effect of spinal cord electrical stimulator implantation in the treatment of a diabetic foot (DF). MATERIALS AND METHODS: We recruited 19 patients with DF who were admitted to Shengjing Hospital of China Medical University between January 2018 and May 2020. All the patients were treated with spinal cord electrical stimulator implantation. Skin temperature, degree of pain, quality of life (QOL) score, limb (toe) preservation, and nerve conduction velocity of the patients were compared pre- and postoperatively. RESULTS: The diameter and peak velocity of multisegment arteries in the lower limbs had significantly increased post surgery. Foot skin temperature significantly increased in patients with good effect. The postoperative visual analog scale score of the patients was significantly lower than that noted preoperatively (p < 0.05). The conduction velocities of the lower limb sensory nerves (eg, superficial peroneal nerve and sural nerve) and motor nerves (eg, common peroneal nerve and tibial nerve) had improved post surgery. Moreover, patients' QOL score had significantly improved postoperatively (p < 0.05). The limb (toe) salvage rate was 94.74%. CONCLUSION: The implantation of a spinal cord electrical stimulator for treating DF can effectively relieve pain and other associated symptoms. Additionally, this device can promote nerve function recovery and lower limb blood supply and reduce the risk of toe amputation; therefore, it is clinically effective and should be considered in the treatment of DF.

The association between the Short Physical Performance Battery and longitudinal trajectories of depressive symptoms among Chinese older adults.

BACKGROUND: In this study, the long-term trajectories of depressive symptoms in a 7-year prospective survey cohort of Chinese older adults were explored. Additionally, the study examined whether there was an independent association between scores on the Short Physical Performance Battery (SPPB) and the different trajectories of depressive symptoms. METHODS: A total of 2177 elderly individuals had their depressive symptoms assessed based on the Center for Epidemiological Studies-Depression (CES-D) scale in the years 2011, 2013, 2015, and 2018. In addition, their demographic characteristics, chronic diseases, and lifestyle factors were also assessed. The trajectories of depressive symptoms were analysed using the group-based trajectories analysis model. Furthermore, the relationship between the objectively measured SPPB scores and the long-term trajectory of depressive symptoms was explored using multinomial logistic regression. RESULTS: The group-based trajectory analysis model categorized the trajectories of depressive symptoms across four waves into four groups: persistent low depressive symptoms, increasing depressive symptoms, decreased depressive symptoms, and persistent high depressive symptoms. After controlling for confounding factors, it was observed that a higher baseline SPPB score was associated with an increased likelihood of persistent high depressive symptoms, OR (95% CI) = 0.724 (0.644, 0.814), for the persistent high depressive symptoms versus the persistent low depressive symptoms. CONCLUSIONS: Low levels of SPPB score are associated with persistent high depressive symptoms in older adults. Conversely, improving physical performance as measured by the SPPB can help reduce the risk of major depressive disorder and persistent depressive disorder in the elderly.

Defective autophagy triggered by arterial cyclic stretch promotes neointimal hyperplasia in vein grafts via the p62/nrf2/slc7a11 signaling pathway.

Autophagy is an adaptation mechanism to keep cellular homeostasis, and its deregulation is implicated in various cardiovascular diseases. After vein grafting, hemodynamic factors play crucial roles in neointimal hyperplasia, but the mechanisms are poorly understood. Here, we investigated the impacts of arterial cyclic stretch on autophagy of venous smooth muscle cells (SMCs) and its role in neointima formation after vein grafting. Rat jugular vein graft were generated via the 'cuff' technique. Autophagic flux in venous SMCs is impaired in 3-day, 1-week and 2-week grafted veins. 10%-1.25 Hz cyclic stretch (arterial stretch) loaded with FX5000 stretch system on venous SMCs blocks cellular autophagic flux in vitro and shows no significant impact on activity of mTORC1 and AMPK. Microtubule depolymerization but not lysosome dysfunction nor autophagosome/amphisome-lysosomal membrane fusion blockade is involved in the impairment of autophagic flux. Microtubule stabilization, induced by paclitaxel treatment and external stents intervention respectively, restores venous SMC autophagy and ameliorates neointimal hyperplasia in vivo. Moreover, autophagy impairment causes accumulation of the cargo receptor p62, which sequesters keap1 to p62 aggregates and results in the stabilization and nuclear translocation of nrf2 to modulate its target antioxidative gene SLC7A11. p62 silencing abrogates the increases of nrf2 and slc7a11 protein expression, glutathione level and venous SMC proliferation triggered by arterial cyclic stretch in vitro, and further hinders nrf2 nuclear translocation, reduces neointimal thickness after vein grafting in vivo. p62 (T349A) mutation also inhibited venous SMC proliferation and alleviated neointimal formation in vivo. These findings suggest that stabilization of microtubules to rescue autophagic flux or direct silencing of p62 are potential therapeutic strategies for neointimal hyperplasia.

Extracellular matrix stiffness controls VEGF165 secretion and neuroblastoma angiogenesis via the YAP/RUNX2/SRSF1 axis.

Aberrant variations in angiogenesis have been observed in tumor tissues with abnormal stiffness of extracellular matrix (ECM). However, it remains largely unclear how ECM stiffness influences tumor angiogenesis. Numerous studies have reported that vascular endothelial growth factor-A (VEGF-A) released from tumor cells plays crucial roles in angiogenesis. Hence, we demonstrated the role of ECM stiffness in VEGF-A release from neuroblastoma (NB) cells and the underlying mechanisms. Based on 17 NB clinical samples, a negative correlation was observed between the length of blood vessels and stiffness of NB tissues. In vitro, an ECM stiffness of 30 kPa repressed the secretion of VEGF165 from NB cells which subsequently inhibited the tube formation of human umbilical vein endothelial cells (HUVECs). Knocked down VEGF165 in NB cells or blocked VEGF165 with neutralizing antibodies both repressed the tube formation of HUVECs. Specifically, 30 kPa ECM stiffness repressed the expression and nuclear accumulation of Yes-associated protein (YAP) to regulate the expression of Serine/Arginine Splicing Factor 1 (SRSF1) via Runt-related transcription factor 2 (RUNX2), which may then subsequently induce the expression and secretion of VEGF165 in NB tumor cells. Through implantation of 3D col-Tgels with different stiffness into nude mice, the inhibitory effect of 30 kPa on NB angiogenesis was confirmed in vivo. Furthermore, we found that the inhibitory effect of 30 kPa stiffness on NB angiogenesis was reversed by YAP overexpression, suggesting the important role of YAP in NB angiogenesis regulated by ECM stiffness. Overall, our work not only showed a regulatory effect of ECM stiffness on NB angiogenesis, but also revealed a new signaling axis, YAP-RUNX2-SRSF1, that mediates angiogenesis by regulating the expression and secretion of VEGF165 from NB cells. ECM stiffness and the potential molecules revealed in the present study may be new therapeutic targets for NB angiogenesis.

Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma.

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial.

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.

New-onset versus relapsing giant cell arteritis treated with tocilizumab: 3-year results from a randomized controlled trial and extension.

OBJECTIVE: Tocilizumab plus prednisone induces sustained glucocorticoid-free remission in patients with GCA. However, its long-term benefits in new-onset vs relapsing disease are uncertain, and the value of weekly vs every-other-week dosing has not been evaluated. METHODS: In Giant-Cell Arteritis Actemra (GiACTA) part 1, patients with new-onset or relapsing GCA received blinded tocilizumab weekly (TCZ QW), tocilizumab every-other-week (TCZ Q2W) or placebo for 52 weeks, with a prednisone taper. In part 2 (open-label), patients were treated at investigator discretion for 104 weeks. In this analysis, patients were evaluated according to their original treatment assignments, and outcomes beyond 52 weeks were assessed. Outcomes of interest included time to first flare and cumulative glucocorticoid exposure over 3 years according to baseline disease status. RESULTS: Part 1 enrolled 250 patients; 215 entered part 2. At baseline, 48% had new-onset disease and 52% had relapsing disease. In patients with new-onset and relapsing disease, the median time to first flare in the TCZ QW group was 577 and 575 days, respectively, vs 479 and 428 days with TCZ Q2W and 179 and 224 days with placebo; the median cumulative glucocorticoid dose was 3068 mg and 2191 mg with TCZ QW, 4080 mg and 2353 mg with TCZ Q2W, and 4639 mg and 6178 mg with placebo. CONCLUSION: TCZ QW delayed the time to flare and reduced the cumulative glucocorticoid dose in patients with relapsing GCA and new-onset GCA. These data support initiating TCZ QW as part of first-line therapy in all patients with active GCA. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01791153.

Insight into the shaping of microbial communities in element sulfur-based denitrification at different temperatures.

Nitrate pollution is an important cause of eutrophication and ecological disruption. Recently, element sulfur-based denitrification (ESDeN) has attracted increasing attention because of its non-carbon source dependence, low sludge yield, and cost-effectiveness. Although the denitrification performance of sulfur autotrophic denitrifying bacteria at different temperatures has been widely studied, there are still many unknown factors about the adaptability and the shaping of microbial community. In this study, we comprehensively understood the shaping of ESDeN microbial communities under different temperature conditions. Results revealed that microbial communities cultivated at temperatures ranging from 10 °C to 35 °C could be classified as high-temperature (35 °C), middle-temperature (30, 25 and 20 °C), and low-temperature (15 and 10 °C) communities. Dissolved oxygen in water was an important factor that, in combination with temperature, shaped microbial community structure. According to network analysis, the composition of keystone taxa was different for the three groups of communities. Some bacteria that did not have sulfur compound oxidation function were identified as the "keystone species". The abundances of carbon, nitrogen, and sulfur metabolism of the three microbial communities were significantly changed, which was reflected in that the high-temperature and middle-temperature communities were dominated by dark oxidation of sulfur compounds and dark sulfide oxidation, while the low-temperature community was dominated by chemoheterotrophy and aerobic chemoheterotrophy. The fact that the number of microorganisms with dark oxidation of sulfur compounds capacity was quite higher than that of microorganisms with dark sulfur oxidation capacity suggested that the sulfur bioavailability at different temperatures, especially low temperature, was the main challenge for the development of efficient ESDeN process. This study provided a biological basis for developing a high-efficiency ESDeN process to cope with temperature changes in different seasons or regions.