Purpose: Metastatic rectal cancer (mRC) is a highly lethal and complex disease that demands a multidisciplinary treatment approach. However, the clinical effectiveness of radiotherapy (RT) for de novo mRC remains controversial and uncertain. Methods: This retrospective cohort study examined medical records from Kaohsiung Chang Gung Memorial Hospital for patients with histologically confirmed de novo mRC diagnosed between January 2015 and December 2020. All patients received standard systemic therapy and radical surgery when feasible. The primary outcome, overall survival (OS), was assessed using the Kaplan-Meier method. Multivariable analysis was performed using a Cox regression model. Results: Among 271 patients included in the analysis, 117 received RT and 154 did not. The median OS was significantly longer in the RT group compared with the non-RT group (27.8 months vs. 21.9 months; P=0.046). Multivariate analysis identified several independent predictors of OS: age ≥65 years (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.26–2.27; P=0.001), primary tumor resection (HR, 2.62; 95% CI, 1.90–3.61; P<0.001), M1b or M1c disease (HR, 1.97; 95% CI, 1.44–2.69; P<0.001), and receipt of RT (HR, 1.41; 95% CI, 1.02–1.94; P=0.036). Conclusion RT significantly improves OS in patients with mRC, underscoring its role in treatment strategies. These findings support its inclusion in therapeutic protocols and highlight the need for larger, multicenter trials to confirm and extend these results.

The drug resistance in the treatment of solid tumors is closely related to abnormalities in the tumor vascular microenvironment (TVM). The TVM is dynamically composed of multiple stromal, vascular, and immune cell populations together with extracellular matrix. Its structural disorder and functional imbalance can lead to abnormal angiogenesis, perfusion disorders, limited drug delivery, and insufficient immune cell infiltration, thereby creating a microenvironment conducive to tumor progression and treatment resistance. Therefore, the coordinated regulation of TVM through vascular normalization and immune remodeling has become an important research direction for improving the treatment effect of solid tumors. Tumor necrosis factor superfamily member 14 (TNFSF14), also known as LIGHT (homologous to lymphotoxin, inducible, competes with herpes simplex virus (HSV) glycoprotein D for herpesvirus entry mediator (HVEM), expressed by T lymphocyte), is an important molecule connecting tumor vascular remodeling and immune regulation. LIGHT can bind to the lymphotoxin β receptor (LTβR) to activate the NF-κB (nuclear factor kappa B)-related signaling pathway, regulate the functions of vascular endothelial cells and stromal cells, and induce the expression of adhesion molecules and chemokines such as VCAM-1(vascular cell adhesion molecule 1), ICAM-1(intercellular adhesion molecule 1), CCL19 (C-C motif chemokine ligand 19), CCL21 (C-C motif chemokine ligand 21), and CXCL13 (C-X-C motif chemokine ligand 13), promoting the formation of high endothelial venules (HEVs). HEVs can improve the vascular access of immune cells into tumor tissues and further promote the formation of tertiary lymphoid structures (TLS), providing a structural basis for the recruitment of effector T cells and sustained anti-tumor immune responses. At the same time, LIGHT interacts with HVEM to provide costimulatory signals to T cells, enhancing their activation, proliferation, and cytotoxic function. Thus, LIGHT can link tumor vascular normalization, immune cell recruitment, and T cell activation through the dual actions mediated by LTβR and HVEM, forming a coordinated regulation model of “vascular remodeling-immune infiltration-immune activation”, providing new molecular targets for the treatment of solid tumors. Despite LIGHT’s good anti-tumor potential, its therapeutic application is still limited by factors such as insufficient stability in vivo, short half-life, and potential off-target effects due to systemic exposure. In recent years, researchers have developed various strategies for the precise delivery of LIGHT, including fusion proteins, bacterial vectors, viral vectors, nanoparticles, chimeric antigen receptor T cells (CAR-T), and mesenchymal stem cells (MSCs), to enhance the enrichment, expression, or sustained release of LIGHT in tumor sites through different approaches, thereby improving its therapeutic efficacy and safety. This article systematically reviews the structural characteristics, biological functions, and molecular mechanisms mediating TVM remodeling by LIGHT, with a focus on the signal transduction mediated by LTβR and HVEM and their roles in tumor immune regulation. Subsequently, it systematically outlines the molecular mechanisms by which LIGHT regulates the tumor vascular microenvironment and its intrinsic connection with immune cell recruitment and activation, from the perspectives of TVM abnormalities, vascular normalization, HEV formation, and TLS induction. Furthermore, it categorizes and summarizes precise delivery strategies such as LIGHT fusion proteins, bacterial vectors, viral vectors, nanoparticles, CAR-T cells, and MSCs according to delivery vectors and modes of action, and compares their functional characteristics, antitumor effects, and potential advantages and limitations. On this basis, the article further discusses the key issues that LIGHT therapeutic strategies still face in terms of targeting, controllability,in vivo stability, safety, and clinical translation, and anticipates the potential value of its combination with immune checkpoint inhibitors, anti-angiogenic therapy, and other tumor treatment methods. This article aims to deepen the understanding of the antitumor mechanism of LIGHT from the perspective of synergistic regulation of tumor vascular microenvironment remodeling and immune activation, providing theoretical basis and new research ideas for the design of solid tumor treatment strategies based on precise regulation of TVM and the clinical translation of LIGHT-related treatment systems.

Electroencephalogram (EEG) is a non-invasive, high temporal-resolution technique for monitoring brain activity. However, affected by the volume conduction effect, EEG has a low spatial resolution and is difficult to locate brain neuronal activity precisely. The surface Laplacian (SL) technique obtains the Laplacian EEG (LEEG) by estimating the second-order spatial derivative of the scalp potential. LEEG can reflect the radial current activity under the scalp, with positive values indicating current flow from the brain to the scalp (“source”) and negative values indicating current flow from the scalp to the brain (“sink”). It attenuates signals from volume conduction, effectively improving the spatial resolution of EEG, and is expected to contribute to breakthroughs in neural engineering. This paper provides a systematic overview of the principles and development of SL technology. Currently, there are two implementation paths for SL technology: current source density algorithms (CSD) and concentric ring electrodes (CRE). CSD performs the Laplace transform of the EEG signals acquired by conventional disc electrodes to indirectly estimate the LEEG. It can be mainly classified into local methods, global methods, and realistic Laplacian methods. The global method is the most commonly used approach in CSD, which can achieve more accurate estimation compared with the local method, and it does not require additional imaging equipment compared with the realistic Laplacian method. CRE employs new concentric ring electrodes instead of the traditional disc electrodes, and measures the LEEG directly by differential acquisition of the multi-ring signals. Depending on the structure, it can be divided into bipolar CRE, quasi-bipolar CRE, tripolar CRE, and multi-pole CRE. The tripolar CRE is widely used due to its optimal detection performance. While ensuring the quality of signal acquisition, the complexity of its preamplifier is relatively acceptable. Here, this paper introduces the study of the SL technique in resting rhythms, visual-related potentials, movement-related potentials, and sensorimotor rhythms. These studies demonstrate that SL technology can improve signal quality and enhance signal characteristics, confirming its potential applications in neuroscientific research, disease diagnosis, visual pathway detection, and brain-computer interfaces. CSD is frequently utilized in applications such as neuroscientific research and disease detection, where high-precision estimation of LEEG is required. And CRE tends to be used in brain-computer interfaces, that have stringent requirements for real-time data processing. Finally, this paper summarizes the strengths and weaknesses of SL technology and envisages its future development. SL technology boasts advantages such as reference independence, high spatial resolution, high temporal resolution, enhanced source connectivity analysis, and noise suppression. However, it also has shortcomings that can be further improved. Theoretically, simulation experiments should be conducted to investigate the theoretical characteristics of SL technology. For CSD methods, the algorithm needs to be optimized to improve the precision of LEEG estimation, reduce dependence on the number of channels, and decrease computational complexity and time consumption. For CRE methods, the electrodes need to be designed with appropriate structures and sizes, and the low-noise, high common-mode rejection ratio preamplifier should be developed. We hope that this paper can promote the in-depth research and wide application of SL technology.

This study identified 8 members including NjBIN2 of the GSK3 family in Nardostachys jatamansi by bioinformatics analysis. Moreover, the phylogenetic tree revealed that the GKS3 family members of N. jatamansi had a close relationship with those of Arabidopsis. RT-qPCR results showed that NjBIN2 presented a tissue-specific expression pattern with the highest expression in roots, suggesting that NjBIN2 played a role in root growth and development. In addition, the application of epibrassinolide or the brassinosteroid(BR) synthesis inhibitor(brassinazole) altered the expression pattern of NjBIN2 and influenced the photomorphogenesis(cotyledon opening) and root development of N. jatamansi, which provided direct evidence about the functions of NjBIN2. In conclusion, this study highlights the roles of BIN2 in regulating the growth and development of N. jatamansi by analyzing the expression pattern and biological function of NjBIN2. It not only enriches the understanding about the regulatory mechanism of the growth and development of N. jatamansi but also provides a theoretical basis and potential gene targets for molecular breeding of N. jatamansi with improved quality in the future.
Brassinosteroids/metabolism* ; Steroids, Heterocyclic/metabolism* ; Gene Expression Regulation, Plant/drug effects* ; Plant Proteins/metabolism* ; Phylogeny ; Nardostachys/metabolism* ; Plant Growth Regulators/pharmacology* ; Plant Roots/drug effects*

Aromatic traditional Chinese medicine(TCM) has played an important role against epidemics and viruses, and volatile components are the main components that exert the pharmacological effects of aromatic TCM. By screening the related monomer components in aromatic TCM against epidemic and viruses and analyzing and endowing TCM with medicinal properties based on its clinical application and pharmacological research according to the theoretical thinking of TCM, the key technical issues of compatibility of TCM monomer components were solved from a theoretical perspective, providing new ideas and methods for screening raw materials and formulas for the development of new TCM drugs. Based on the conditions of antiviral activity, clinical application foundation, definite therapeutic effect, and high safety, a gradient screening of aromatic TCM was carried out. Firstly, 30 aromatic TCM were screened from anti-epidemic literature and clinical trial formulas, and seven volatile monomers were further screened from them. Then, four monomer components with significant effects, namely patchouli alcohol, carvacrol, p-cymene, and eucalyptol were screened. By adopting the "four-step method for a systematic study of TCM properties", the four monomer components were endowed with medicinal properties, and compatibility and combination studies were conducted to explore the theoretical basis of monomer formulas and form monomer formulas guided by TCM theory. The screening results of volatile monomers in aromatic TCM against viral pneumonia included patchouli alcohol, carvacrol, p-cymene, and eucalyptol. The medicinal properties and compatibility theory of volatile monomer components in TCM were explored. Patchouli alcohol was the main herb, with a cool and pungent nature. It entered the lung meridian to dispel evil Qi and has the effects of aromatization, detoxification, and epidemic prevention. Carvacrol was a minister drug with a cool and pungent taste. It had the effects of aromatizing, moistening, and dissolving the exterior, as well as strengthening the spleen and stomach. p-Cymene was an adjunctive medicine with a mild and pungent nature. It entered the lungs and kidneys and had the effects of aromatic purification, cough relief, and asthma relief. Eucalyptol was also an adjunctive medicine with a pungent and warm taste. It had the functions of aromatic purification, cough relief, phlegm reduction, and pain relief. The combination of the four medicines had the effects of aromatizing, moistening, detoxifying, and epidemic prevention, as well as relieving cough and asthma and strengthening the spleen and stomach. They were used to treat viral pneumonia caused by upper respiratory tract viral infections, with symptoms such as chest tightness, cough, wheezing, fatigue, nasal congestion, runny nose, nausea, and vomiting. This study has laid a literature and theoretical foundation for further drug efficacy verification experiments, compatibility efficacy experiments, and subsequent product development and clinical applications, and it serves as an innovative practice that combines literature research, theoretical research, experimental research, and clinical practice to develop new products.
Drugs, Chinese Herbal/therapeutic use* ; Antiviral Agents/pharmacology* ; Humans ; Pneumonia, Viral/virology* ; Medicine, Chinese Traditional ; Volatile Organic Compounds/pharmacology* ; Animals

This paper aims to investigate the influence of eucalyptol on the biological effects of spleen cold and spleen heat syndromes in rats and its regulation of transient receptor potential vanilloid 1(TRPV1), transient receptor potential melastatin 8(TRPM8), and uncoupling protein 1(UCP1), so as to explore the cold-heat properties of eucalyptol. Rats were randomly divided into groups as follows: blank group, spleen cold syndrome model group, spleen cold syndrome+Atractylodis Rhizoma group, spleen cold syndrome + low-dose eucalyptol group, and spleen cold syndrome+high-dose eucalyptol group, as well as blank group, spleen heat syndrome model group, spleen heat syndrome+Coptidis Rhizoma group, spleen heat syndrome + low-dose eucalyptol group, and spleen heat syndrome + high-dose eucalyptol group. Spleen cold and spleen heat syndromes were induced by disorders of hunger and satiety combined with bitter cold drugs, as well as a high-fat diet combined with liquor. Except for the blank and model groups, the other groups were administered once a day during the modeling process for 14 consecutive days. The general condition and body weight of rats in each group were observed, and the histopathological morphology of the gastric antrum and small intestine was observed by hematoxylin-eosin(HE) staining. The contents of cyclic adenosine monophosphate(cAMP), cyclic guanosine monophosphate(cGMP), triiodothyronine(T3), thyroxine(T4), Na~+-K~+-ATPase, total cholesterol(TC), triglyceride(TG), gastrin(GAS), motilin(MTL), D-xylose, and other related indices were detected in rats. The expression levels of TRPV1, TRPM8, and UCP1 in small intestine tissue of rats with spleen cold syndrome were detected. The results showed that eucalyptol had a certain degree of improvement in the overall state and body weight of rats with spleen cold syndrome. Compared with the spleen cold syndrome model group, high-dose eucalyptol significantly increased the levels of serum cAMP, cAMP/cGMP, TG, and TC in rats with spleen cold syndrome(P<0.05, P<0.01), decreased the content of cGMP, and significantly elevated the levels of gastrointestinal function-related indicators GAS, MTL, and D-xylose(P<0.05, P<0.01). Low-dose eucalyptol significantly increased the level of cAMP/cGMP in the serum and Na~+-K~+-ATPase levels in hepatic tissue(P<0.05, P<0.01), and significantly increased the levels of GAS and D-xylose(P<0.01). Eucalyptol showed similar effects to Atractylodis Rhizoma with a warm nature on rats with spleen cold syndrome. Compared with the spleen heat syndrome model group, the high-dose and low-dose eucalyptol groups showed a trend of increase in gastrointestinal indicators, with no significant changes in other indicators. In addition, high-dose eucalyptol increased the expression of TRPV1 and UCP1 and decreased the expression of TRPM8 in the small intestine tissue of rats with spleen cold syndrome. Eucalyptol could affect the cyclic nucleotide and material energy metabolism levels of rats with spleen cold syndrome and had a certain improvement effect on their gastrointestinal digestion and absorption function, thereby improving spleen cold syndrome. Eucalyptol had no significant improvement effect on rats with spleen heat syndrome, suggesting that eucalyptol may have a warm nature and regulate spleen meridians. It is speculated that eucalyptol may exhibit its medicinal properties by activating the TRPV1 pathway, promoting the expression of UCP1, and inhibiting the TRPM8 channel.
Animals ; Rats ; Spleen/metabolism* ; Male ; TRPV Cation Channels/genetics* ; Rats, Sprague-Dawley ; Eucalyptol/administration & dosage* ; TRPM Cation Channels/genetics* ; Uncoupling Protein 1/genetics* ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Cold Temperature ; Cyclic GMP/metabolism*

This paper aims to study the effect of p-cymene on mice with deficiency-cold syndrome induced by hydrocortisone and deficiency-heat syndrome induced by dexamethasone and explore the medicinal properties and mechanism of p-cymene with mild and warm nature based on the dominant characteristics of the two-way applicable conditions of mild drugs. A total of 80 KM mice were randomly divided into blank group, deficiency-cold syndrome model group, deficiency-cold syndrome + ginseng group, and deficiency-cold syndrome + low-dose and high-dose p-cymene groups, as well as blank group, deficiency-heat syndrome model group, deficiency-heat syndrome + American ginseng group, and deficiency-heat syndrome + low-dose and high-dose p-cymene groups. Hydrocortisone and dexamethasone solution were intragastrically administered for 14 consecutive days to prepare deficiency-cold syndrome and deficiency-heat syndrome models. Except for the blank group and the model group intragastrically administered with normal saline, the other groups were intragastrically administrated with drugs for 14 days. The levels of cyclic adenosine monophosphate(cAMP), cyclic guanosine monophosphate(cGMP), triiodothyronine(T3), thyroxine(T4), total cholesterol(TC), triglyceride(TG), immunoglobin G(IgG), and immunoglobin M(IgM) in serum, as well as the activity of Na~+-K~+-ATPase in liver tissue were detected. The expression of transient receptor potential melastatin 8(TRPM8), transient receptor potential vanilloid 1(TRPV1), and uncoupling protein 1(UCP1) in brown adipose tissue of deficiency-cold syndrome model after intervention with p-cymene was studied. The results showed that p-cymene could effectively improve the levels of cAMP, cAMP/cGMP, TC, IgM, and IgG in serum and the activity of Na~+-K~+-ATPase in liver tissue of mice with deficiency-cold syndrome and reduce the content of cGMP. The effects on T3, T4, and TG were not statistically significant. At the same time, p-cymene could reduce the levels of cAMP, cAMP/cGMP, and T4 in serum and the activity of Na~+-K~+-ATPase in liver tissue of mice with deficiency-cold syndrome and increase the levels of cGMP, IgM, and IgG, and it had no effect on T3, TC, and TG. In addition, p-cymene could up-regulate the expression of TRPV1 and UCP1 in brown fat of mice with deficiency-cold syndrome and down-regulate the expression of TRPM8. In summary, p-cymene could significantly regulate the syndrome indexes of mice with deficiency-cold syndrome, and some indexes of mice with deficiency-heat syndrome could be improved, but the effects on lipid metabolism and energy metabolism indexes were not obvious, indicating that the regulation effect of p-cymene on deficiency-cold syndrome model was more prominent and that the medicinal properties of p-cymene were mild and warm. The regulation of TRPV1/TRPM8/UCP1 channel expression may be the molecular biological mechanism of p-cymene with mild and warm nature affecting the energy metabolism of the body.
Animals ; Cymenes ; Mice ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Disease Models, Animal ; Humans ; Cyclic AMP/metabolism* ; Monoterpenes/administration & dosage* ; Liver/metabolism* ; Cyclic GMP/metabolism* ; TRPV Cation Channels/genetics* ; Uncoupling Protein 1/genetics*

Non-steroidal anti-inflammatory drugs(NSAIDs),commonly utilized analgesics,are extensively employed for managing pain associated with musculoskeletal disorders or injuries.Recent clinical studies have demonstrated a heightened risk of bone stress injuries(BSI)in soldiers and athletes,particularly during high-intensity training,due to NSAID usage.Furthermore,the impact of NSAIDs on fracture healing is well-documented;however,the precise mechanism by which their use during training contributes to an increased incidence of stress bone injuries remains unclear.This article aims to summarize potential mechanisms through an extensive review of domestic and international literature in order to standardize the utilization and clinical management of NSAIDs,optimize pain management strategies,and prevent stress bone injuries or fractures in specific populations such as soldiers and elite athletes.

Objective To observe the therapeutic effects of different doses of methylprednisolone(MP)on smoke inhalation-induced acute lung injury(SI-ALI)in rats,and to explore the changes in the expression of aquaporins(AQPs)and the underlying mechanisms for alleviating lung injury.Methods A total of 86 healthy adult male Sprague-Dawley(SD)rats were randomly divided into five groups:control group(n=6),smoke inhalation injury(SI)group(n=20),low-dose MP group(LMP,SI+0.4 mg/kg MP,n=20),medium-dose MP group(MMP,SI+4 mg/kg MP,n=20),and high-dose MP group(HMP,SI+40 mg/kg MP,n=20).A model of smoke inhalation-induced lung injury was established.The survival status of the rats in each group was monitored.Lung tissues were collected 24 hours after injury to determine the wet-to-dry(W/D)ratio of the lung tissues,arterial oxygen partial pressure(PaO2),and the expression levels of inflammatory cytokines TNF-α and IL-6.The degree of lung injury was evaluated using HE staining,and the mRNA and protein expression levels of AQP1 and AQP5 in the lung tissues were detected.Results Compared with control group,the survival rate of the rats in SI group was significantly decreased(P<0.05);compared with SI group,the survival rates of the rats in MMP and HMP groups were significantly increased(P<0.05).Compared with control group,the PaO2 of the Rats in SI group was significantly decreased(P<0.05),and the wet-to-dry(W/D)ratio and lung injury scores were significantly increased(P<0.05).Compared with SI group,the PaO2 of the rats in LMP,MMP,and HMP groups(P<0.05)was significantly increased(P<0.05),and the lung W/D ratio and injury scores in MMP and HMP groups were significantly decreased(P<0.05).ELISA results showed that compared with control group,the serum concentrations of TNF-α and IL-6 in SI group were significantly increased(P<0.05);compared with SI group,the concentrations of TNF-α and IL-6 in MMP and HMP groups were significantly decreased(P<0.05).HE staining revealed that the alveolar structure of the rats in SI group was severely damaged;compared with SI group,the damage to the alveolar structure in MMP and HMP groups was alleviated.Real-time PCR and Western blotting analysis results showed that compared with control group,the mRNA and protein expression levels of AQP1 and AQP5 in lung tissues in SI group were significantly decreased(P<0.05);however,compared with SI group,these levels in LMP,MMP,and HMP groups were significantly increased(P<0.05).Conclusions Smoke inhalation can induce acute lung injury in rats and down-regulate the expression levels of AQP1 and AQP5 in the lung tissues.Methylprednisolone can alleviate pulmonary edema and tissue damage in rats caused by smoke inhalation,and induce the up-regulation of the expression of AQP1 and AQP5.

BACKGROUND: Severe stroke has high rates of mortality and morbidity. This study aimed to investigate the clinical course, causes of worsening, and outcomes of severe ischemic stroke. METHODS: This prospective, multicenter cohort study enrolled adult patients admitted ≤30 days after ischemic stroke from nine hospitals in China between September 2017 and December 2019. Severe stroke was defined as a score of ≥15 on the National Institutes of Health Stroke Scale (NIHSS). Clinical worsening was defined as an increase of 4 in the NIHSS score from baseline. Unfavorable functional outcome was defined as a modified Rankin scale score ≥3 at 3 months and 1 year after stroke onset, respectively. We performed Logistic regression to explore baseline features and reperfusion therapies associated with clinical worsening and functional outcomes. RESULTS: Among 4201 patients enrolled, 854 patients (20.33%) had severe stroke on admission. Of 3347 patients without severe stroke on admission, 142 (4.24%) patients developed severe stroke in hospital. Of 854 patients with severe stroke on admission, 33.95% (290/854) experienced clinical worsening (median time from stroke onset: 43 h, Q1-Q3: 20-88 h), with brain edema (54.83% [159/290]) as the leading cause; 24.59% (210/854) of these patients died by 30 days, and 81.47% (677/831) and 78.44% (633/807) had unfavorable functional outcomes at 3 months and 1 year respectively. Reperfusion reduced the risk of worsening (adjusted odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.12-0.49, P  <0.01), 30-day death (adjusted OR: 0.22, 95% CI: 0.11-0.41, P  <0.01), and unfavorable functional outcomes at 3 months (adjusted OR: 0.24, 95% CI: 0.08-0.68, P <0.01) and 1 year (adjusted OR: 0.17, 95% CI: 0.06-0.50, P  <0.01). CONCLUSIONS: Approximately one-fifth of patients with ischemic stroke had severe neurological deficits on admission. Clinical worsening mainly occurred in the first 3 to 4 days after stroke onset, with brain edema as the leading cause of worsening. Reperfusion reduced the risk of clinical worsening and improved functional outcomes. REGISTRATION ClinicalTrials.gov , NCT03222024.
Humans ; Male ; Female ; Prospective Studies ; Ischemic Stroke/mortality* ; Aged ; Middle Aged ; Aged, 80 and over ; Stroke ; Brain Ischemia