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Engineered T cell therapies, mainly chimeric antigen receptor (CAR)-T and T cell receptor (TCR)-T, have become the new frontier of cancer treatment. CAR-T and TCR-T therapies differ in many aspects, including cell persistence and toxicity, leading to different therapeutic outcomes. Both TCR and CAR recognize antigens and trigger T cell mediated antitumor response, but they have distinct molecular structures and signaling properties. TCR represents one of the most complex receptors, while CAR is a single-chain chimera integrating modules from multiple immune receptors. Understanding the mechanisms underlying the strengths and limitations of both systems can pave the way for the development of next-generation T cell therapy. This review synthesizes recent findings on TCR and CAR signaling and highlights the potential strategies of T cell engineering by signaling refinement.

CD19-targeting chimeric antigen receptor (CAR) T cells have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, a significant portion of patients still do not benefit from the therapy owing to various resistance mechanisms, including high expression of multiple inhibitory immune checkpoint receptors. Here, we report a lentiviral two-in-one CAR T approach in which two checkpoint receptors are downregulated simultaneously by a dual short hairpin RNA cassette integrated into a CAR vector. Using this system, we evaluated CD19-targeting CAR T cells in the context of four different checkpoint combinations—PD-1/TIM-3, PD-1/LAG-3, PD-1/CTLA-4, and PD-1/TIGIT—and found that CAR T cells with PD-1/TIGIT downregulation uniquely exerted synergistic antitumor effects. Importantly, functional and phenotypic analyses suggested that downregulation of PD-1 enhances short-term effector function, whereas downregulation of TIGIT is primarily responsible for maintaining a less differentiated/exhausted state, providing a potential mechanism for the observed synergy. The PD-1/TIGIT-downregulated CAR T cells generated from diffuse large B cell lymphoma patient-derived T cells also showed robust antitumor activity and significantly improved persistence in vivo. The efficacy and safety of PD-1/TIGIT-downregulated CD19-targeting CAR T cells are currently being evaluated in adult patients with relapsed or refractory large B cell lymphoma (ClinicalTrials.gov: NCT04836507 ).

Gastric cancer (GC) has a dismal prognosis and is also one of the most commonly diagnosed malignancies worldwide. circRNAs are covalently closed circular RNA molecules without 5'-cap and a 3'-tail, currently listed among the broad noncoding RNA family. circRNAs participate in a variety of pathophysiological processes relevant to human diseases, especially malignancies, including GC. Compelling evidence has shown that circRNAs can function by sponging miRNAs, interacting with RNA binding proteins, and encoding proteins or peptides. Yet, our current understanding of these RNA circles remains very limited. Here, we overview the biogenesis, characteristics, functions, and degradation of circRNAs. Moreover, we give an account of the circRNAs that have been linked with GC, describing their functions and mechanisms of action in the context of GC. Next, we discuss the potential value of circRNAs as diagnostic or prognostic GC biomarkers and summarize future prospects, important questions, and challenges of circRNA-based therapeutics.

Traumatic brain injury (TBI) is a common neurotrauma leading to brain dysfunction and death. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold promise in the treatment of TBI. However, their efficacy is modest due to low survival and differentiation under the harsh microenvironment of the injured brain. MG53, a member of TRIM family protein, plays a vital role in cell and tissue damage repair. The present study aims to test whether MG53 preserves hUC-MSCs against oxidative stress and enhances stem cell survival and efficacy in TBI treatment.In this study, we performed a series of in vitro and in vivo experiments in hUC-MSCs and mice to define the function of MG53 enhancing survival, neurogenesis, and therapeutic efficacy of stem cells in murine traumatic brain injury.We found that recombinant human MG53 (rhMG53) protein protected hUC-MSCs against HMG53 enhances the efficacy of hUC-MSCs in the recovery of TBI, indicating that such adjunctive therapy may provide a novel strategy to lessen damage and optimize recovery for brain injury.

The chaperone-assisted soluble expression and characterization of high molecular weight chitinase chiZJ408 in Escherichia coli BL21 were investigated. Chitin degradation products by chitinase chiZJ408 were analyzed. The results indicated that the introduction of the chaperone GroELS promoted the correct folding of chitinase chiZJ408 and increased its soluble expression by 14.9% (p < 0.05) in E. coli BL21. The optimal pH and temperature of chitinase chiZJ408 were respectively 6.0 and 50 °C. Chitinase chiZJ408 was stable at pHs of 4.0 ∼ 7.0 and at below 40 °C. Mg2+and Ca2+ had a significant impact on improving the activity of chitinase chiZJ408. Chitinase chiZJ408 was demonstrated to be exochitinase that cleaved the β-1,4-glycosidic bond of the chitin chain to generate only N,N'-diacetylchitobiose. This study broadens our understanding of chitinase and provides a basis for solving the problem of inclusion body formed by long fragment gene expression in E. coli.

To develop anti-ischemic stroke drugs with higher blood-brain barrier (BBB) penetrating capability and neuroprotective activity, a series of hybrid compounds containing edaravone analogue and 3-n-butylphthalide (NBP) ring-opened derivatives were synthesized and biologically evaluated. Among them, compound 10a displayed the highest protective activity in SH-SY5Y cells against oxygen and glucose deprivation (OGD) and H2O2 insults. Experiment results indicated that 10a could inhibit platelet aggregation via the synergistic action of the edaravone analogue and NBP, and its oral administration protected the rats against ischemia/reperfusion-induced brain injury. Moreover, 10a effectively inhibited apoptosis and reduced oxidative stress in OGD-exposed cells. Further analysis suggested that 10a might alleviate oxidative damage in SH-SY5Y cells via the modulation of the Nrf2 pathway. Collectively, these findings demonstrate that 10a can emerge as a potential candidate drug for the treatment of ischemic stroke.

Purpose To investigate and compare the CT and MRI features of hepatic sclerosed hemangioma (HSH) and sclerosing cavernous hemangioma (SCH). Materials and methods Twelve HSH cases and 36 SCH cases were included, the imaging findings on CT (9 HSH and 34 SCH) and MRI (8 HSH and 10 SCH) were analyzed. Qualitative image analysis included the location, size, shape, capsular retraction, density, calcification, signal intensity on T1-weighted image (T1WI) and T2-weighted image (T2WI), presence of diffusion restriction, apparent diffusion coefficient (ADC) map, transient hepatic attenuation difference around the lesion, and the dynamic enhancement patterns. Results The presence of liver cirrhosis in patients with HSH (3/12) was higher than SCH (1/36) (P = 0.043). The morphology appearance before enhancement showed no significant difference between HSH and SCH. Moreover, SCH had a stronger trend of centripetal enhancement patterns of cavernous hemangiomas (83.3%) compared to HSH (25%) (P P P = 0.009, P = 0.002); however, there was no significant difference in ADC values between themselves (P = 0.613). Conclusion SCH showed the same trend of centripetal enhancement characteristics as typical hemangioma, while HSH exhibited atypical enhancement features due to complete sclerosis. Higher ADC values might contribute to the identification of atypical HSH and SCH from malignancies.

As the potential risk of radiation exposure is increasing, radioprotectors studies are gaining importance. In this study, novel hybrid compounds containing edaravone analogue and 3‐n‐butylphthalide ring‐opening derivatives were synthesized, and their radioprotective effects were evaluated. Among these, compound 10a displayed the highest radioprotective activity in IEC‐6 and HFL‐1 cells. Its oral administration increased the survival rates of irradiated mice and alleviated total body irradiation (TBI)‐induced hematopoietic damage by mitigating myelosuppression and improving hematopoietic stem/progenitor cell frequencies. Furthermore, 10a treatment prevented abdominal irradiation (ABI)‐induced structural damage to the small intestine. Experiment results demonstrated that 10a increased the number of Lgr5+ intestinal stem cells, lysozyme+ Paneth cells and Ki67+ transient amplifying cells, and reduced apoptosis of the intestinal epithelium cells in irradiated mice. Moreover, in vitro and in vivo studies demonstrated that the radioprotective activity of 10a is associated to the reduction of oxidative stress and the inhibition of DNA damage. Furthermore, compound 10a downregulated the expressions of p53, Bax, caspase‐9 and caspase‐3, and upregulated the expression of Bcl‐2, suggesting that it could prevent irradiation‐induced intestinal damage through the p53‐dependent apoptotic pathway. Collectively, these findings demonstrate that 10a is beneficial for the prevention of radiation damage and has the potential to be a radioprotector.

Protecting the body from radiation damage is a huge medical challenge. Amifostine and curcumin are both effective radioprotectants, but their use has been greatly restricted due to various reasons including low bioavailability. Nanoscale drug delivery systems of poly(ethylene glycol)-poly(ε-caprolactone) copolymers can improve the bioavailability of drugs due to excellent biocompatibility, biodegradability, and long circulation characteristics. In this study, a new reactive oxygen species-sensitive nanocarrier fabricated by linking curcumin and thioketal to poly(ethylene glycol)-poly(ε-caprolactone) polymer was used for delivery of WR-1065 (the active ingredient of amifostine). The content of curcumin in this polymer was about 7.6%, and the drug loading of WR-1065 was 44%. The WR-1065-loaded nanoparticles (NPs) had an average size of 128.6 nm and uniform spherical morphology. These WR-1065-loaded NPs reduced the metabolism of curcumin and WR-1065 in the gastrointestinal tract and could be well absorbed by cells and distributed to multiple organs. Compared with a single drug, oral administration of WR-1065-loaded NPs demonstrated obvious radioprotective effects on the hematopoietic system and prevented intestinal injury. The 30-day survival rate after half-lethal dose (7.2 Gy) of total body irradiation was 100%. In general, WR-1065-loaded NPs improved the oral bioavailability of WR-1065 and curcumin. This multifunctional nanocarrier provides a possibility for combination therapy in treating ionizing radiation damage.

Jin Li,1,* Yang Zhou,1,2,* Xinxin Wang,2 Yanyan Yu,2 Xueyan Zhou,3 Kuan Luan1 1College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, 150001, Heilongjiang Province, People’s Republic of China; 2Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, 150001, Heilongjiang Province, People’s Republic of China; 3School of Technology, Harbin University, Harbin, 150001, Heilongjiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kuan LuanCollege of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, 150001, Heilongjiang Province, People’s Republic of ChinaEmail luankuan@hrbeu.edu.cnPurpose: This study investigated the predictive value of apparent diffusion coefficient (ADC) histogram parameters of the primary tumor for regional lymph node metastasis (LNM) in pathological T3 stage rectal cancer.Patients and Methods: We retrospectively studied 175 patients with T3 stage rectal cancer who underwent preoperative MRI, including diffusion-weighted imaging, between January 2015 and October 2017. Based on pathological analysis of surgical specimens, 113 patients were classified into the LN− group and 62 in the LN+ group. We analyzed clinical data, radiological characteristics and histogram parameters derived from ADC maps. Then, receiver operating characteristic curve (ROC) analyses were generated to determine the best diagnostic performance.Results: The mean (p=0.002, cutoff=1.08× 10– 3 s/mm2), coefficient of variation (CV) (p=0.040, cutoff=0.249) of the ADC map, carbohydrate antigen 199, and N stage with magnetic resonance (mrN stage) were independent factors for LNM. Combining these factors yielded the best diagnostic performance, with the area under the ROC curve of 0.838, 72.9% sensitivity, 79.1% specificity, 65.2% positive predictive value, and 84.5% negative predictive value.Conclusion: With the mean > 1.08× 10– 3 s/mm2 and CV < 0.249, the ADC improved the diagnostic performance of LNM in T3 stage rectal cancer, which could assist surgeons with neoadjuvant chemoradiotherapy.Keywords: diffusion-weighted magnetic resonance imaging, rectal cancer, lymph node metastasis, histogram analysis

PM2.5 and its main chemical components have been investigated during six air pollution periods across four seasons from Jun. 16, 2016 to Jun. 15, 2017 at a suburban site in Beijing, China. Daily PM2.5 mass concentrations were measured with associated ions, OC, EC, 16 PAHs and seven heavy metals. Mass closure analyses were conducted using measured and reconstructed chemical components. Chemical ratios were used to identify possible pollution sources, while principal component analysis (PCA) coupled with multiple linear regression (MLR) method was used to estimate the source contribution to PM2.5 mass. The annual mean PM2.5 concentration (96.7 μg m−3) is about 2.8 times the national level-2 standard limit, with apparent seasonal variation of daily exceedances as winter > spring > autumn > summer. Generally, higher levels are observed in winter and autumn than in spring and summer for NO3−, SO42−, NH4+, Cl−, K+, OC, EC, PAHs and metals Zn, As, Cu, Pb, along with higher concentrations of NOx, CO and SO2. Secondary ions and carbon fractions are most abundant over all seasons, except levels of dust related species Ca2+, Mg2+, Ca, Fe and Mn are also high in spring. The reconstructed results show that PM2.5 consists of mostly organic compounds (26–38%) and ammonium salts (NH4NO3 + (NH4)2SO4) (43–53%) in winter and autumn, while summer is dominated mainly by ammonium salts (81%). In spring, very high PM2.5 episodes are occasionally composed of large amount of soil/road dust and gypsum particles (23–55%) due to floating dust events with drier weather conditions and human activities. Fuel combustions and secondary sources are responsible for ~70% of PM2.5 mass while mobile source is mostly a regional origin.

BACKGROUND: Only a fraction of patients with advanced non-small cell lung cancer (NSCLC) respond well to immune checkpoint blockade (ICB) therapy. Here, we investigated whether Titin (TTN) mutation, which has been demonstrated to be a predictive biomarker in tissue-based analysis, can identify patients with a greater likelihood in response to ICB based on circulatory tumor DNA (ctDNA) sequencing. METHODS: In this retrospective analysis, 92 patients with advanced NSCLC from two independent cohorts who received ICB treatment were included. A probe panel covering all exons of TTN was developed and validated to detect TTN mutation in ctDNA. Baseline plasma samples were collected and subjected to ctDNA sequencing with the TTN probe panel. RESULTS: Of the 92 patients, 28.3% harbored TTN mutation in their baseline ctDNA. Progression-free survival was significantly improved in patients with the mutated TTN (212 days and 334.5 days for cohort 1 and 2) compared to those without the mutation (113 days and 147 days for cohort 1 and 2). Objective response to ICB treatment (40% for TTN(mut) and 15.8% for TTN(wt) in cohort 1; 50% for TTN(mut) and 23.4% for TTN(wt) in cohort 2) was common in patients with mutated TTN. Stratified analysis showed a generally predictive potential of TTN mutation in patients with advanced NSCLC. CONCLUSIONS: The presence of mutated TTN in pre-treatment peripheral blood was associated with favorable objective response and survival with ICB administration. Therefore, circulatory TTN mutation may be applicable for guiding ICB immunotherapy in patients with NSCLC.

DNA methylation is a prevalent epigenetic modification in vertebrates, and it has been shown to be involved the regulation of gene expression and embryo development. However, it remains unclear how DNA methylation regulates sexual development, especially in species without sex chromosomes. To determine this, we utilized zebrafish to investigate DNA methylation reprogramming during juvenile germ cell development and adult female-to-male sex transition. We reveal that primordial germ cells (PGCs) undergo significant DNA methylation reprogramming during germ cell development, and the methylome of PGCs is reset to an oocyte/ovary-like pattern at 9 days post fertilization (9 dpf). When DNA methyltransferase (DNMT) activity in juveniles was blocked after 9 dpf, the zebrafish developed into females. We also show that Tet3 is involved in PGC development. Notably, we find that DNA methylome reprogramming during adult zebrafish sex transition is similar to the reprogramming during the sex differentiation from 9 dpf PGCs to sperm. Furthermore, inhibiting DNMT activity can prevent the female-to-male sex transition, suggesting that methylation reprogramming is required for zebrafish sex transition. In summary, DNA methylation plays important roles in zebrafish germ cell development and sexual plasticity.

Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). However, there is no direct evidence in humans to support this role1-5. In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD.

Low-dimensional metal halides have attracted much attention because of their excellent physical properties and potential application in optoelectronic field. Herein, we developed a novel facile method based on mechanochemical synthesis to prepare one-dimensional (1D) C4H14N2PbBr4 (C4H14N22+: N,N′-dimethylethylenediamine cation) micro-crystals on a large scale. This 1D structure enables the formation of self-trapped excited states that exhibit bluish white-light emission, and the photoluminescence quantum yield (PLQY) is about 18.4% under excitation of a 365 nm ultraviolet (UV) lamp. Interestingly, C4H14N2PbBr4 exhibits an unusual bistable emission, i.e., when excited by a 365 nm beam from a UV lamp, its emission occurs at about 461 nm, while excited by a 365 nm laser pulse, its emission maximum is located at 546 nm. The formation of self-trapped exciton (STE) pairs (bipolaron) via coupling of two adjacent PbBr42− clusters by di-amine groups results in the bistable emission in the 1D chain. It is worth mentioning that the as-synthesized C4H14N2PbBr4 has the advantages of high chemical, thermal and photostability, and large-scale manufacture along with remarkable photophysical properties, which provide a broad prospect for optoelectronic applications.

Glioblastoma is a central nervous malignancy with a very poor prognosis. This study attempted to explore the role of exosomes induced by low-dose radiation-induced (ldrEXOs) and ldrEXOs-derived circ-METRN in glioblastoma progression and radioresistance at the molecular, cellular, animal, and clinical levels. Results in the present study revealed that low-dose radiation stimulated the secretion of ldrEXOs which delivered high levels of circ-METRN. And circ-METRN-abundant ldrEXOs increased the expression of γ-H2AX, indicating an efficient DNA damage-repair process in glioblastoma cells. The ldrEXOs-derived circ-METRN enhanced the glioblastoma progression and radioresistance via miR-4709-3p/GRB14/PDGFRα pathway. Up-regulating PDGFRα can rescue the tumor-promoting function of ldrEXOs in groups previously treated with inhibition of GRB14. Additionally, in-vivo experiments revealed that treatments with ldrEXOs promoted the growth of xenografted tumors and shortened the survival period. Furthermore, clinical researches indicated that circ-METRN may be transported into the bloodstream by exosomes in the early stages of fractionated radiotherapy. It has important clinical values to detect the serum exosomal circ-METRN in the early stage of radiotherapy, which is not only conducive to predict radioresistance and prognosis but also to assist MRI diagnosis in detecting the very early recurrence of glioblastoma. In summary, this study reveals for the first time that low-dose radiation-induced exosomal circ-METRN plays an oncogenic role in glioblastoma progression and radioresistance through miR-4709-3p/GRB14/PDGFRα pathway, providing mechanistic insights into the roles of circRNAs and a valuable marker for therapeutic targets in glioblastoma.

Background: The current model for predicting prognosis and chemotherapy response of patients with gastric adenocarcinoma is the TNM staging system, which may lack adequate accuracy and evaluations of molecular features at the individual level. We aimed to develop a prediction model to assess the individualized prognosis and responsiveness to fluorouracil-based adjuvant chemotherapy. Method: This retrospective study concluded 2 independent cohorts of patients with GAC. The expression of dysbindin was quantified and evaluated the association with the overall survival for GAC patients. A prediction model for postoperative overall survival was generated and internally and externally validated. The interaction between dysbindin expression and PACT was detected in advanced GAC patients. Results: Of the 637 patients enrolled in the study, 425 were men (66.7%) with a mean (SD) age of 59.79 (9.81) years. High levels of dysbindin expression predicted a poor prognosis in patients with GAC. Multivariate analysis demonstrated dysbindin expression was an independent prognostic predictor of overall survival in the test, validation and combined cohorts. A prognostic predictive model incorporating age, dysbindin expression, pathological differentiation, Lauren's classification and the TNM staging system was established. This model had better predictive accuracy for overall survival than the traditional TNM staging system and was internally and externally validated. More importantly, advanced GAC patients with low dysbindin expression were likely to benefit from fluorouracil-based PACT. Conclusion: The risk stratification model incorporating dysbindin expression and TNM staging system showed better predictive accuracy. Advanced GAC patients with low dysbindin expression revealed better response of fluorouracil-based adjuvant chemotherapy.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, characterized by phosphorylated TDP-43 (pTDP-43)-positive inclusions in neurons and glial cells. However, the pathogenic mechanism that underlies ALS remains largely unknown. To investigate the effects of autophagy deficiency in the formation and spreading of pathological TDP-43 along corticospinal tract axons, TDP-43 preformed fibrils (PFFs) were prepared and unilaterally injected into the fifth layer of the left primary motor cortex (M1) or the left anterior horn of the seventh cervical spinal cord segment (C7) of Atg5+/- mice. After the injection of TDP-43 PFFs, the elevated levels of pTDP-43 were present in several pyramidal tract-associated regions of Atg5+/- mice. Additionally, the occurrence of spontaneous potentials detected by electromyography demonstrates evidence of lower motor neuron dysfunction in M1-TDP-43 PFFs-injected Atg5+/- mice, and prolonged central motor conduction time detected by motor evoked potentials provides evidence of upper motor neuron dysfunction in C7-TDP-43 PFFs-injected Atg5+/- mice. These results show that injection of TDP-43 PFFs into the M1 or C7 of Atg5+/- mice induces the spreading of pathological TDP-43 along corticospinal tract axons in both an anterograde and retrograde manner. Importantly, TDP-43 PFFs-injected Atg5+/- mice also display ALS-like motor dysfunction. Taken together, our findings provide direct evidence that TDP-43 PFFs-injected Atg5+/- mice exhibited ALS-like neuropathology and motor phenotypes, suggesting that autophagy deficiency promotes the formation and spreading of pathological TDP-43 in vivo.

To apply a multi-objective radiomics model based on pre-operative magnetic resonance imaging (MRI) for improving diagnostic accuracy of LN metastasis in rectal cancer patients. This study consisted of 91 patients diagnosed with rectal cancer from April 2018 to March 2019. All patients underwent rectal MRI before surgery without any other treatment. Clinical data, subjective radiologist assessments, and radiomic features of LNs were obtained. A total of 1409 radiomic features were extracted from T2WI LN images. Multi-objective optimization with the iterative multi-objective immune algorithm (IMIA) was used to select radiomic features to build prediction models. Predictive performances of radiomic, radiologist, and combined radiomic and radiologist models were assessed for accuracy by receiver operating characteristics (ROC) curves. For the radiologist analysis, heterogeneity was the only significant independent predictor of LN status. The sensitivity, specificity, and accuracy of the subjective radiologist analysis were 72.09%, 73.81%, and 78.12%, respectively. The sensitivity, specificity, and accuracy of the solitary radiomic model consisting of 10 features were 89.81%, 82.57%, and 87.77%, respectively. The sensitivity, specificity, and accuracy of the combined model, which consisted of 12 radiomic and radiologist features, were 92.23%, 84.69%, and 89.88%, respectively. The combined model had the best prediction performance with an AUC of 0.94. The multi-objective radiomics model based on T2WI images was very useful in predicting pre-operative LN status in rectal cancer patients.

Background Severe acute respiratory syndrome coronavirus 2 has been confirmed to be a newly discovered zoonotic pathogen that causes highly contagious viral pneumonia, which the World Health Organization has named novel coronavirus pneumonia. Since its outbreak, it has become a global pandemic. During the outbreak of coronavirus disease 2019 (COVID-19), however, there is no mature experience or guidance on how to carry out emergency surgery for suspected cases requiring emergency surgical intervention and perioperative safety protection against virus. Case summary A 41-year-old man was admitted to the hospital for emergency treatment due to "3-d abdominal pain aggravated with cessation of exhaust and defecation". After improving inspections and laboratory tests, the patient was assessed and diagnosed by the multiple discipline team as "strangulation obstruction, pulmonary infection". His body temperature was 38.8 °C, and the chest computed tomography showed pulmonary infection. Given fever and pneumonia, we could not rule out COVID-19 after consultation by fever clinicians and respiratory experts. Hence, we performed emergency surgery under three-level protection for the suspected case. After surgery, his nucleic acid test for COVID-19 was negative, meaning COVID-19 was excluded, and routine postoperative treatment and nursing was followed. The patient was treated with symptomatic support after the operation. The stomach tube and urinary tube were removed on the 1st d after the operation. The clearing diet was started on the 3rd d after the operation, and the body temperature returned to normal. Flatus and bowel movements were noted on 5th postoperative day. He was discharged after 8 d of hospitalization. The patient was followed up for 4 mo after discharge, no serious complications occurred. A 71-year-old woman was admitted to our emergency room due to "abdominal distention, fatigue for 6 d and fever for 13 h". After the multiple discipline team evaluation, the patient was diagnosed as "intestinal obstruction, abdominal mass, peritonitis and pulmonary infection". At that time, the patient's body temperature was 39.6 °C, and chest computed tomography indicated pulmonary infection. COVID-19 could not be completely excluded after consultation in the fever outpatient department and respiratory department. Therefore, the patient was treated as a suspected case, and an urgent operation was performed under three-level medical protection. Postoperative nucleic acid test was negative, COVID-19 was excluded, and routine postoperative treatment and nursing were followed. After the operation, the patient received symptomatic and supportive treatment. The gastric tube was removed on the 1st d after the operation, and the urinary tube was removed on the 3rd d after the operation. Enteral nutrition began on the 3rd d after the operation. To date, no serious complications have been found during follow-up after discharge. Conclusion Based on the previous treatment experience, we reviewed the procedures of two cases of suspected COVID-19 emergency surgery and extracted the perioperative protection experience. By referring to the literature and following the regulations on prevention and management of infectious diseases, we have developed a relatively mature and complete emergency surgical workflow for suspected COVID-19 cases and shared perioperative protection and management experience and measures.

Background Circadian differences in the induction, maintenance, or emergence from volatile anaesthesia have not been well studied. Methods The minimal alveolar concentration (MAC) for preventing movement in response to a painful stimulus, MAC for loss of righting reflex (MACLORR), and MAC for recovery of righting reflex (MACRORR) in C57BL/6J male mice with isoflurane or sevoflurane exposure were measured during either the light or dark phase. Time to onset of loss of righting reflex (TimeLORR) and recovery of righting reflex (TimeRORR) upon exposure to 1 MAC of isoflurane or sevoflurane were determined. EEG was also monitored in the light and dark phase under isoflurane or sevoflurane exposure. The noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was used to deplete noradrenergic neurones in the locus coeruleus to explore the impact of norepinephrine on these measurements. Results MACLORR, TimeLORR, and MAC did not show light- or dark-phase-dependent variations for either isoflurane or sevoflurane exposure. However, MACRORR was higher and TimeRORR was shorter in the dark phase than in the light phase for both isoflurane and sevoflurane exposure. The EEG delta wave power was higher but theta wave power was lower in the light phase than that in the dark phase during the rest state and emergence of anaesthesia. These light- and dark-phase-dependent changes in emergence were abolished in DSP-4-treated mice. Conclusion Our data show that circadian differences exist during emergence but not during induction or maintenance of sevoflurane or isoflurane anaesthesia. The locus coeruleus noradrenergic system may contribute to these differences.

BACKGROUND Gastric cancer is the second most common malignant tumor in China, ranking third among all malignant tumor mortality rates. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to increase significantly the effectiveness of intraperitoneal chemotherapeutic drugs, prolong the action time of these drugs on intraperitoneal tumor cells, and enhance their diffusion in tumor tissues. HIPEC may be one of the best choices for the eradication of residual cancer cells in the abdominal cavity. AIM The aim of this study was to study the role of preventive HIPEC after radical gastrectomy. METHODS A prospective analysis was performed with patients with cT4N0-3M0 gastric cancer to compare the effects of postoperative prophylactic HIPEC plus intravenous chemotherapy with those of routine adjuvant chemotherapy. Patients’ medical records were analyzed, and differences in the peritoneal recurrence rate, disease-free survival time, and total survival time between groups were examined. RESULTS The first site of tumor recurrence was the peritoneum in 11 cases in the conventional adjuvant chemotherapy group and in 2 cases in the HIPEC group (P = 0.020). The 1-year and 3-year disease-free survival rates were 91.9% and 60.4%, respectively, in the conventional adjuvant chemotherapy group and 92.1% and 63.0%, respectively, in the HIPEC group. The 1-year and 3-year overall survival rates were 95.2% and 66.3%, respectively, in the conventional adjuvant chemotherapy group and 96.1% and 68.6%, respectively, in the HIPEC group. No significant difference in postoperative or chemotherapy complications was observed between groups. CONCLUSION In patients with cT4N0-3M0 gastric cancer, prophylactic HIPEC after radical tumor surgery is beneficial to reduce peritoneal tumor recurrence and prolong survival.

The bed nucleus of the stria terminalis (BNST) plays a critical role in regulating anxiety, yet the involved specific cell types and their connections functioning in anxiety-related behaviors remains elusive. Here we identified two cell subpopulations—corticotropin-releasing hormone-positive (CRH+) and protein kinase C-δ-positive (PKC-δ+) neurons—each displayed discrete emotionally valenced behaviors in the anterior-dorsal BNST (adBNST). Using whole-cell patch-clamp recordings and virus-assisted circuit tracing techniques, we delineated the local and long-range connectivity networks in a cell-type-specific manner. The results show that the CRH+ and PKC-δ+ neurons received inputs from similar brain regions and exhibited significant differences in the downstream projection density. In addition, in vivo calcium imaging as well as gain- and loss-of-function studies characterized the physiological response properties and the functional heterogeneities in modulating anxiety, further suggesting the similarity and individuality between the two adBNST cell types. These results provide novel insights into the circuit architecture of adBNST neurons underlying the functionally specific neural pathways that relate to anxiety disorders.

Introduction Long non-coding RNA (lncRNA) DSCAM-AS1 was reported to be aberrantly expressed and play pivotal roles in various human cancers. The aim of the present study was to investigate the expression and roles of DSCAM-AS1 in colon cancer (CC). Methods Quantitative real-time PCR (qRT-PCR) was used to detect the expression of DSCAM-AS1, miR-204 and the mRNA level of SOX4. Cell proliferation and cell cycle were analyzed by MTT assay and flow cytometry, respectively. Transwell assay was used for migration capacity detection. Luciferase activity assay was conducted to verify the direct binding of DSCAM-AS1 and miR-204 or miR-204 and SOX4. The protein expression of SOX4 was determined by Western blot. Kaplan-Meier curves were calculated and the Log rank test was performed for the survival data analysis. Results DSCAM-AS1 was significantly upregulated in CC and high expression of DSCAM-AS1 was associated with poor prognosis in patients with colon cancer. Knockdown of DSCAM-AS1 significantly suppressed CC cells proliferation and migration. In addition, DSCAM-AS acted as a molecular sponge for miR-204 and SOX4 was identified as a direct target of miR-204 in CC. Moreover, the rescue assay revealed that miR-204 inhibition partly abolished the effects of DSCAM-AS1 knockdown on CC cells proliferation, migration and SOX4 expression. Discussion The present study demonstrated that DSCAM-AS1 acted as an oncogenic lncRNA in CC progression by regulating miR-204/SOX4 axis and DSCAM-AS1 may serve as a novel therapeutic target in the treatment of colon cancer.

Background The dysregulation of microRNA (miRNAs) is broadly participated in cancer progression, resulting in sustained cell proliferation by directly targeting various targets. This study investigated the expression of miR-582 in GC and its association with liver metastasis. Methods Firstly, differentially expressed miRNAs in gastric cancer (GC) tissues were predicted by microarray. Then, the relationship between miR-582 and clinical characteristics of GC patients was analyzed. By silencing of miR-582 in GC cells, the change in malignant biological behaviors of GC cells was detected. The upstream lncRNA, downstream targeting genes of miR-582 and the corresponding signaling pathway were predicted by online databases and verified by luciferase reporter assays, RT-qPCR and Western blot analysis. Finally, the effects of miR-582 on the growth and metastasis of GC cells were detected by in vivo tumorigenesis and metastasis tests. Results MiR-582 was highly expressed in GC tissues and related to the metastasis of patients with GC. Silencing of miR-582 expression blocked malignant biological behaviors of GC cells in vitro and in vivo. MiR-582 inhibited forkhead box protein O3 (FOXO3) to upregulate the PI3K/AKT/Snail signaling pathway in GC cells. Besides, GATA6-AS1 was found as an upstream lncRNA to modulate the expression of miR-582. Conclusion MiR-582 induced by GATA6-AS1 silencing promotes the growth and metastasis of GC cells by targeting FOXO3 to induce the activation of the PI3K/AKT/Snail signaling pathway. MiR-582 could be a potential molecular therapy target for patients with GC.

Oral lichen planus (OLP) is an inflammatory disease. It is believed that infection and immune dysfunction play a key role in its pathogenesis, but the specific mechanism of action remains unclear. The 16s rRNA high-throughput sequencing technique was used to analyze the microbial flora structure in the saliva of OLP patients and healthy controls. The relative abundance of Derxia, Haemophilus, and Pseudomonas in the saliva of the OLP group was lower than that of the healthy control group, but there was no significant difference in the overall structure of the microbial population. In addition, we measured the protein expression levels of toll-like receptor 4 (TLR4) and nuclear factor-kappab p65 (NF-κB p65) in the tissues of OLP patients, and found that there was a significant increase and positive correlation between them (r = 0.907, P = 0.034). The expression levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the OLP group were consistent with those of NF-κB p65. Therefore, we believe that changes in the composition ratio of microbialflora break the original balance state of flora, promote the occurrence of immune inflammatory reaction, and then lead to the generation or aggravation of OLP disease. This discovery provides new ideas for further research on OLP initiation and immune regulation mechanism.

Objective The aim of this study was to determine the role of contrast-enhanced computed tomography (CE-CT) parameters in predicting the expression status of HER2 in gastric adenocarcinoma (GAC) patients before radical gastrectomy. Materials and Methods A total of 460 GAC patients who underwent non-contrast CT (NC-CT) and CE-CT examinations before radical resection were enrolled in this retrospective study. The radiologists reviewed their CT scans and recorded parameters, including CT attenuate value (CAV) and corrected CAV (cCAV). The pathologist identified the postoperative HER2 expression status, and HER2 expression status was evaluated by immunohistochemical staining (IHC). The association between CE-CT parameters and HER2 expression status was analyzed. Results Among the 460 patients, 84 patients had HER2 over-expression status, at a prevalence of 18.3%. The CAVs were significantly different between the 2 different HER2 expression groups in the non-contrast and arterial phases (non-contrast phase: p = 0.005; arterial phase: p < 0.001). Besides, there was a significant difference in the cCAVs between the 2 groups in the arterial phase (arterial phase: p = 0.003). Univariate and multivariate logistic regression analyses identified that the maximum diameter of tumor, differentiation degree, CAV in non-contrast, arterial, and portal phases, and cCAV in the arterial phase were predictive factors of HER2 expression status. Conclusion Our analyses showed that the CE-CT parameters were significantly different between different HER2 expression groups. CE-CT parameters could serve as simple, objective predictive factors of HER2 expression status of GAC patients.

The viral capsid protein p24 of human immunodeficiency virus is expressed at different level during viral invasion. Detection of p24 is of great importance in acquired immunodeficiency syndrome monitoring and therapy. A ratiometric probe that is easily-synthesized was constructed based on self-assembled fluorescent Ce(Ⅲ) and fluorescein. Fluorescein was used as reference. Hydrogen peroxide quenches the fluorescence of the Ce(III) easily but does not quench the fluorescence of fluorescein. The mechanism of reaction was discussed. Benefiting from the sensitive response to hydrogen peroxide, this probe was applied for p24 detection in enzyme linked immunoassay. The fluorescence ratio was in a good linear relationship with the concentration of p24, and the detection limit was 1.1 pg mL−1. This proposed method has shown potential in virus detection with easy operation.