Multifunctional Nanoassembly for MRI-Trackable Dendritic Cell Dependent and Independent Photoimmunotherapy.

Immunotherapy has emerged as a triumph in the treatment of malignant cancers. Nevertheless, current immunotherapeutics are insufficient in addressing tumors characterized by tumor cells' inadequate antigenicity and the tumor microenvironment's low immunogenicity (TME). Herein, we developed a novel multifunctional nanoassembly termed FMMC through the self-assembly of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-methyl-tryptophan prodrug (FM), Ce6, and ionic manganese (Mn2+) via noncovalent interactions. The laser-ignited FMMC treatment could induce effective immunogenic cell death and activate the STING/MHC-I signaling pathway, thus deeply sculpting the tumor-intrinsic antigenicity to achieve dendritic cell (DC)-dependent and -independent T cell responses against tumors. Meanwhile, by inhibiting IDO-1, FMMC could lead to immunosuppressive TME reversion to an immunoactivated one. FMMC-based phototherapy led to the up-regulation of programmed death-ligand 1 (PD-L1), enhancing the sensitivity of tumors to anti-PD-1 therapy. Furthermore, the incorporation of Mn2+ into FMMC resulted in an augmented longitudinal relaxivity and enhanced the MRI for monitoring the growth of primary tumors and lung metastases. Collectively, the superior reprogramming performance of immunosuppressive tumor cells and TME, combined with excellent anticancer efficacy and MRI capability, made FMMC a promising immune nanosculptor for cancer theranostics.

[A case of COVID-19 associated ischemic colitis].

Ischemic colitis is a disease in which local tissue in the intestinal wall dies to varying degrees due to insufficient blood supply to the colon. Risk factors include cardiovascular disease, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, etc. Typical clinical manifestations of the disease are abdominal pain and hematochezia. The most common locations are the watershed areas of splenic flexure and rectosigmoid junction. The lesions are segmental and clearly demarcated from normal mucosa under endoscopy. The digestive tract is a common extra-pulmonary organ affected by the novel coronavirus, which can be directly damaged by the virus or indirectly caused by virus-mediated inflammation and hypercoagulability. The corona virus disease 2019 (COVID-19) associated intestinal injury can be characterized by malabsorption, malnutrition, intestinal flora shift, etc. CT can show intestinal ischemia, intestinal wall thickening, intestinal wall cystoid gas, intestinal obstruction, ascites, intussusception and other signs. In this study, we reported a case of ischemic colitis in a moderate COVID-19 patient. The affected area was atypical and the endoscope showed diffuse lesions from the cecum to the rectosigmoid junction. No signs of intestinal ischemia were found on imaging and clear thrombosis in small interstitial vessels was found in pathological tissue. Combined with the fact that the patient had no special risk factors in his past history, the laboratory tests indicated elevated ferritin and D-dimer, while the autoantibodies and fecal etiology results were negative, we speculated that the hypercoagulability caused by novel coronavirus infection was involved in the occurrence and development of the disease in this patient. After prolonged infusion support and prophylactic anti-infection therapy, the patient slowly resumed diet and eventually went into remission. Finally, we hoped to attract clinical attention with the help of this case of moderate COVID-19 complicated with ischemic colitis which had a wide range of lesions and a slow reco-very. For patients with abdominal pain and blood in the stool after being diagnosed as COVID-19, even if they are not severe COVID-19, they should be alert to the possibility of ischemic colitis, so as not to be mistaken for gastrointestinal reactions related to COVID-19.

Endovascular Treatment Versus Best Medical Management in Acute Basilar Artery Occlusion Strokes: Results From the ATTENTION Multicenter Registry.

BACKGROUND: The authors compare the effectiveness and safety of endovascular treatment (EVT) versus best medical management (BMM) in strokes attributable to acute basilar artery occlusion (BAO). METHODS: The present analysis was based on the ongoing, prospective, multicenter ATTENTION (Endovascular Treatment for Acute Basilar Artery Occlusion) trial registry in China. Our analytic sample comprised 2134 patients recruited at 48 sites between 2017 and 2021 and included 462 patients who received BMM and 1672 patients who received EVT. We performed an inversed probability of treatment weighting analysis. Qualifying patients had to present within 24 hours of estimated BAO. The primary clinical outcome was favorable functional outcome (modified Rankin Scale score, 0-3) at 90 days. We also performed a sensitivity analysis with the propensity score matching-based and the instrumental variable-based analysis. RESULTS: In our primary analysis using the inversed probability of treatment weighting-based analysis, there was a significantly higher rate of favorable outcome at 90 days among EVT patients compared with BMM-treated patients (adjusted relative risk, 1.42 [95% CI, 1.19-1.65]; absolute risk difference, 11.8% [95% CI, 6.9-16.7]). The mortality was significantly lower (adjusted relative risk, 0.78 [95% CI, 0.69-0.88]; absolute risk difference, -10.3% [95% CI, -15.8 to -4.9]) in patients undergoing EVT. Results were generally consistent across the secondary end points. Similar associations were seen in the propensity score matching-based and instrumental variable-based analysis. CONCLUSIONS: In this real-world study, EVT was associated with significantly better functional outcomes and survival at 90 days. Well-designed randomized studies comparing EVT with BMM in the acute BAO are needed. REGISTRATION: URL: www.chictr.org.cn; Unique identifier: ChiCTR2000041117.

A prospective prognostic signature for pancreatic adenocarcinoma based on ubiquitination-related mRNA-lncRNA with experimental validation in vitro and vivo.

Ubiquitination-related genes (URGs) exerted a crucial part in a variety of human disease disorders; however, their association with pancreatic adenocarcinoma (PAAD) had yet to be clearly described. We aimed to comprehensively characterize the contributions of URGs in PAAD through in silico analysis and experimental validation, and then identified a robust mRNA-lncRNA-based molecular prognostic panel for patients with PAAD using bulk RNA-sequencing and single-cell RNA-sequencing data. Initially, we collected the multi-omics data from TCGA platform to depict a comprehensive landscape of URGs in pan-cancer. Furthermore, we were accurate to PAAD for in-depth analysis. Significant differences of the activation of ubiquitination pathways and the expression of URGs were detected between normal and malignant cells. Unsupervised hierarchical clustering determined two PAAD subtypes with distinct clinical outcomes, ubiquitination pathway activities, immune microenvironment, and functional annotation characteristics. The expression profiles of ubiquitination-associated mRNAs and lncRNAs in the training and validation datasets were utilized to develop and verify a novel ubiquitination-related mRNA-lncRNA prognostic panel, which had a satisfied prediction efficiency. Our ubiquitination-associated model could function as an effective prognostic index and outperformed four other recognized panels in evaluating PAAD patients' survival status. Tumor immune microenvironment, mutation burden, and chemotherapy response were intensively explored to demonstrate the underlying mechanism of prognostic difference according to our panel. Our findings also revealed that FTI-277, a farnesyltransferase inhibitor, had a better curative effect in high-risk patients, while MK-2206, an Akt allosteric inhibitor, had a superior therapeutic effect in low-risk patients. The real-time PCR results uncovered the RNA expression of AC005062.1 in all the three PAAD cell lines was elevated several thousandfold. In conclusion, our URGs-based classification panel could be triumphantly served as a prediction tool for survival evaluation in patients with PAAD, and the genes in this panel could be developed as a potential target in PAAD therapy.

Influences of Rapamycin on Retinal Ganglion Cells in Rats with Acute High Intraocular Pressure Through Regulating COX-2.

The study aimed to explore the influences of rapamycin on the retinal ganglion cells in rats with acute high intraocular pressure through regulating cyclooxygenase-2 (COX-2). 36 Sprague-Dawley rats were randomly assigned to the normal group (n=12), model group (n=12) and rapamycin group (n=12). The rats in the normal group were normally fed, those in the model group were prepared the model of acute high intraocular pressure and injected with normal saline, and those in the rapamycin group were given rapamycin. At 7 d after the operation, sampling was performed. The expressions of COX-2 and Caspase-3 were detected via immunohistochemistry, and their protein expressions were determined using Western blotting (WB). Quantitative polymerase chain reaction (qPCR) was conducted to measure the messenger ribonucleic acid (mRNA) expression levels, and cell apoptosis was evaluated using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay. The content of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) was determined via enzyme-linked immunosorbent assay (ELISA). Compared with those in the normal group, the positive expression levels rose substantially in the other two groups, and those in the rapamycin group were notably lower (p<0.05). The relative protein expression levels in the model group and rapamycin group were higher, and the rapamycin group exhibited remarkable decreases (p<0.05). In comparison with the normal group, the other two groups had considerably raised relative mRNA expression levels and those in the rapamycin group were lower (p<0.05). The cells in the model and rapamycin groups had a higher apoptosis rate, and the apoptosis rate of cells in the rapamycin group was lower (p<0.05). Compared with that in the normal group, the content of IL-6 and TNF-α was elevated in the other two groups and their content in the rapamycin group was lower. Rapamycin inhibits COX-2 to repress inflammation and apoptosis, thereby exerting a protective effect on the retinal ganglion cells in rats with acute high intraocular pressure.

Idebenone relieves the damage of heat stress on the maturation and developmental competence of porcine oocytes.

The reproductive function of animals is often affected by climatic conditions. High-temperature conditions can cause damage to oocyte maturation and embryonic development in a variety of ways. The purpose of this study was to prove that supplementation idebenone (IDB) to the maturation medium can improve the maturation and development of porcine oocytes after heat stress (HS). Porcine cumulus-oocyte complexes (COCs) were cultured in the maturation medium with different concentrations of IDB (0, 0.1, 1 and 10 µM) for 44 hr at either 38.5°C or under the HS conditions. The cumulus oophorus expansion, nuclear maturation and blastocyst rate after parthenogenetic activation (PA) were measured. We found that HS (in vitro maturation 20-24 hr, 42°C) exposure significantly reduced cumulus expansion index and maturation rate of oocytes and the blastocyst rate of PA embryos, while IDB supplementation significantly improved oocyte maturation and development to the blastocysts stage after PA. Moreover, the addition of IDB decreased the intracellular level of ROS and increased GSH content, hence enhancing the antioxidant capacity of oocytes under HS. Meanwhile, IDB treatment also obviously improved the mitochondrial membrane potential and ATP synthesis of oocytes under HS conditions. Furthermore, IDB treatment increased the expression of GDF9 and BMP15 in IVM oocytes which attribute to improve the quality and outcome of IVM oocytes and the development competence of PA embryos in pigs. In summary, we demonstrated that IDB supplementation into the maturation medium exerted protective effects and improved the ability of maturation and developmental competence of porcine oocytes exposed to HS.

The effect of hemodialysis on ocular changes in patients with the end-stage renal disease.

Background: Numerous metabolic parameters can be changed during hemodialysis in the end-stage renal disease (ESRD) caused by systemic diseases, such as diabetes mellitus, hypertension. Some ocular parameters also can be variable due to the changes after hemodialysis. This study evaluates the effects of ocular parameters, including best-corrected visual acuity (BCVA), intraocular pressure (IOP), central macular thickness (CMT), subfoveal choroidal thickness (SFCT), retinal arteriolar caliber (RAC), retinal venular calibre (RVC), in ESRD patients following hemodialysis. Materials and methods: Two-hundred and two ESRD patients were recruited resulting in 404 eyes evaluations. All patients underwent hemodialysis in the Dialysis Unit of the Second Hospital of Tianjin Medical University. BCVA, CMT, IOP, SFCT, RAC and RVC were evaluated before and after hemodialysis. Systemic parameters were collected such as age, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), duration of hemodialysis, body weight changes, high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), very low density lipoprotein cholesterol (VLDLC), glycosylated hemoglobin (HbA1c). Results: The causes of ESRD patients included chronic glomerulonephritis (n = 65), diabetes mellitus (n = 60), hypertensive nephrosclerosis (n = 37), and other causes (n = 40). In our study, BCVA (p = .817), CMT (p = .252) and IOP (p = .978) did not significantly change after hemodialysis. SFCT significantly decreased from 254.29 ± 69.36 µm to 235.54 ± 659.90 µm (p = .002) following hemodialysis. SFCT changes were significantly correlated with SBP (p = .042) and body weight changes (p = .044). The RAC and RVC were dilated significantly (p = .033, p = .007). RVC changes were correlated with baseline DBP (p = .003), HDLC (p = .009), LDLC (p = .004) and changes in DBP (p = .037) and body weight (p = .001). Conclusion: Hemodialysis can affect various ocular parameters including SFCT, RAC and RVC, which changed significantly following hemodialysis. Whereas BCVA, IOP and CMT did not change after hemodialysis in ESRD patients. The systemic compensatory mechanisms of the changes in SBP, DBP, body weight following hemodialysis need further study.

The efficacy of conbercept or ranibizumab intravitreal injection combined with laser therapy for Coats' disease.

PURPOSE: The current treatment approaches for Coats' disease by intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents (ranibizumab or conbercept) combined with laser therapy were evaluated for the efficacy during the treatment. METHODS: The medical records of 28 patients diagnosed with Coats' disease followed by the treatment with intravitreal injection of anti-VEGF agents and laser therapies at Tianjin Medical University Eye Hospital and Hebei Eye Hospital during July 2012 and October 2017 were reviewed retrospectively. Clinical outcomes were recorded with a minimum follow-up of 6 months. The patients were divided into ranibizumab- and conbercept-treated groups, as well as based on age: pediatric and adult groups. RESULT: Twenty-eight patients were involved in this study. The average number of the injections was 2.82 ± 0.98. Laser photocoagulation was conducted in all patients, and the average number of lasers was 2.63 ± 0.74. The average follow-up period was 24.29 ± 9.85 months. Fourteen patients (50%) were stable, 12 (43%) patients were improved, and 2 patients (7%) showed recurred subretinal fluid and exudation. The final best corrected visual acuity (BCVA) increased markedly after intravitreal injection of ranibizumab or conbercept combined with laser therapy (p = 0.029, p = 0.009, respectively). The number of injections and lasers between conbercept and ranibizumab groups did not vary significantly (p = 0.160, p = 0.573, respectively). Nine patients (60%) in the ranibizumab-treated group and five (38%) in the conbercept-treated group reached a stable phase, and five (33%) and seven (54%) patients got the vision improved after treated with ranibizumab or conbercept, respectively. In pediatric and adult groups, the initial and final BCVA differed significantly (p = 0.03, p = 0.008, respectively). However, the injection number was remarkably different (p = 0.02), while the laser numbers did not have any markedly difference (p = 0.38). CONCLUSION: Intravitreal injection of ranibizumab or conbercept combined with laser therapy is an effective therapeutic option in Coats' disease. Moreover, the intravitreal injection of ranibizumab or conbercept had no significant adverse effects and appeared to offer visual improvement in Coats' disease.

Insulin-like growth factors I and II in starry flounder (Platichthys stellatus): molecular cloning and differential expression during embryonic development.

In order to elucidate the possible roles of insulin-like growth factors I and II (IGF-I and IGF-II) in the embryonic development of Platichthys stellatus, their cDNAs were isolated and their spatial expression pattern in adult organs and temporal expression pattern throughout embryonic development were examined by quantitative real-time PCR assay. The IGF-I cDNA sequence was 1,268 bp in length and contained an open reading frame (ORF) of 558 bp, which encoded 185 amino acid residues. With respect to IGF-II, the full-length cDNA was 899 bp in length and contained a 648-bp ORF, which encoded 215 amino acid residues. The amino acid sequences of IGF-I and IGF-II exhibited high identities with their fish counterparts. The highest IGF-I mRNA level was found in the liver for both sexes, whereas the IGF-II gene was most abundantly expressed in female liver and male liver, gill, and brain. The sex-specific and spatial expression patterns of IGF-I and IGF-II mRNAs are thought to be related to the sexually dimorphic growth and development of starry flounder. Both IGF-I and IGF-II mRNAs were detected in unfertilized eggs, which indicated that IGF-I and IGF-II were parentally transmitted. Nineteen embryonic development stages were tested. IGF-I mRNA level remained high from unfertilized eggs to low blastula followed by a significant decrease at early gastrula and then maintained a lower level. In contrast, IGF-II mRNA level was low from unfertilized eggs to high blastula and peaked at low blastula followed by a gradual decrease. Moreover, higher levels of IGF-I mRNA than that of IGF-II were found from unfertilized eggs to high blastula, vice versa from low blastula to newly hatched larva, and the different expression pattern verified the differential roles of IGF-I and IGF-II in starry flounder embryonic development. These results could help in understanding the endocrine mechanism involved in the early development and growth of starry flounder.

[Adult-onset generalized autoimmune enteropathy involving small intestine and colon: report of a case and review of literature].

OBJECTIVE: To investigate the clinicopathologic features of adult-onset autoimmune enteropathy (AIE). METHODS: A case of adult-onset AIE was described along with a literature review. RESULTS: A 41-year-old male patient was admitted for intractable diarrhea for more than three months despite of any dietary restriction or anti-inflammatory therapy. Fat globule was observed by stool examination and Sudan III staining of the stool was positive. Enteroclysis showed weak movement and few plica of small intestine, while colonoscopy appeared normal. Small bowel biopsies revealed villus atrophy and increased crypt apoptotic bodies and lymphocytic infiltration in deep crypt. Although without significant surface intro-epithelial lymphocytosis, there were a large number of monocytes, lymphocytes, plasmacytes and neutrophilic granulocytes infiltrating in the lamina propria. Morphologically, the colonic mucous was similar to the small intestine although cryptitis and crypt abscess were significant in the former. Serum IgG anti-goblet cell antibody was demonstrated by indirect immunofluorescence. Other causes of diarrhea were excluded on the base of medical history, histopathology and other accessory examinations before the diagnosis of AIE was made. The patient had a complete remission after steroid treatment without recurrence for eight months during the follow-up even after steroid withdrawal for five months. CONCLUSIONS: AIE is exceedingly rare and timely diagnosis is important for successful therapy. Histological differential diagnoses should include ulcerative colitis, celiac disease, lymphocytic colitis, etc. The final diagnosis should be based on histological examination combined with the patient history, clinical manifestation, endoscopy finding and serological testing.

[Value of detection of DNA mismatch repair proteins deficiency by immunohistochemistry in predicting tumor microsatellite status].

OBJECTIVE: To evaluate the sensitivity and specificity of immunohistochemical (IHC) staining of DNA mismatch repair (MMR) protein for the screening of microsatellite instability (MSI) colorectal cancer (CRC). METHODS: A total of 255 CRC cases were studied, including 140 cases of routine paraffin-embedded tissue samples and 115 cases constructed on tissue microarray. Expressions of 4 MMR proteins including MHL1, MSH2, MSH6 and PMS2 were investigated by IHC. Negative protein expression was defined as complete absence of nuclear staining within tumor cells in the presence of positively labeled internal non-neoplastic cells. Focal staining was defined as the presence of staining in < 5% of the tumor cells. CRCs showing negative staining for any MMR proteins were interpreted as MMR deficient tumors. PCR-genescan MSI analysis was performed in each case by a five marker panel including Bat26, Bat25, NR-21, NR-24 and MONO-27. RESULTS: Among the 140 CRCs with routine formalin-fixed paraffin embedded tissue sections, concordance rate between IHC and PCR-genescan was 98.6% (138/140), the sensitivity and specificity of IHC in detecting MSI tumors were 94.9% (37/39) and 100.0% (101/101), respectively. The 2 disconcordant cases showed focal staining in at least one of the MMR proteins but were confirmed to be MSI-H CRCs by PCR-genescan assay. On tissue microarray, 91.3% (105/115) of the cases had informative results. The concordance rate between IHC and PCR-genescan was 100.0% (105/105). Both the specificity and sensitivity of IHC in detecting MSI tumors on available tissue microarray samples were 100.0%. Ten cases were inclusive due to the presence of negative stains of MMR proteins in both the tumor and internal control cells. CONCLUSIONS: Detection of 4 MMR proteins expression by IHC is reliable for identifying MSI CRCs and is recommended for routine practice. Tumors with focal MMR protein staining are highly suspected for the presence of MSI-H and PCR-genescan based MSI analysis should be performed to confirm.

Two three-dimensional lanthanide frameworks exhibiting luminescence increases upon dehydration and novel water layer involving in situ decarboxylation.

Two three-dimensional polymeric Tb(III) and Yb(III) frameworks, namely, {[Tb3(Hptc)(ptc)(pdc)(H2O)6]·2H2O}n (1) and {[Yb2(ptc)(ox)(H2O)5]·7H2O}n (2) (H4ptc = pyridine-2,3,5,6-tetracarboxylic acid, H2pdc = pyridine-3,5-dicarboxylic acid, ox = oxalate), have been synthesized by a hydrothermal method and characterized by infrared spectra, elemental analysis, powder X-ray diffraction, thermogravimetric analysis, and single-crystal X-ray diffraction. Framework 1 shows an interesting three-dimensional (8,8)-connected net with a Schläfli symbol of (3(3)·4(18)·5(5)·6(2))2(3(6)·4(14)·5(7)·6), while 2 exhibits an unusual (4,8)-connected sqc21 net with a Schläfli symbol of (3(2)·4(2)·5(2))(3(4)·4(8)·5(12)·6(4)). Luminescence studies of 1 reveal that the luminescence intensity increases when the framework is dehydrated.

[A clinical study about applying different R1 criteria to evaluate pancreatic head ductal adenocarcinoma specimens].

OBJECTIVE: To analyze the R1 rate of the pancreatic head carcinoma resection specimens which delt with a unified protocol by two different R1 criteria. METHODS: Between November 2011 and October 2013, a unified pathological protocol was prospectively used to handle 70 consecutive pancreatioduodenectomy specimens for pancreatic ductal adenocarcinoma. Apart from the pancreatic transection margin, the bile duct and stomach/jejunum margins, different colors were used to stain the anterior surface, the superior mesenteric vein (SMV) groove margin, the superior mesenteric artery (SMA) margin, and the posterior surface. Axial slicing technique was used to dissect the pancreatioduodenectomy specimens. RESULTS: Among the 70 patients, 3, 30 and 37 patients were classified as well, moderately and poorly differentiated respectively;7, 15 and 48 patients were classified as pT1, pT2 and pT3 respectively.Forty patients (57.1%) had metastases in regional lymph nodes (pN1) , and 16 patients (22.9%) had metastases in para-aortic nodes.Resection of the portal vein and/or the superior mesenteric vein was performed in 13 patients (18.6%) .When applying the UICC criteria, 26 cancer resections were classified R1 (37.1%) , 33 margins were turned out to be R1. The SMV groove margin and SMA margin were infiltrated in 13 specimens (13/33, 39.4%) respectively.When applying the Royal College of Pathologist's criteria, 39 cancer resections were classified R1 (55.7%) , 51 margins were turned out to be R1. The SMV groove margin and SMA margin were infiltrated in 18 (18/51, 35.3%) and 19 (19/51, 37.3%) specimen respectively.Until April 2014, the median follow-up was 18(range 6-42) months. CONCLUSIONS: Applying the unified protocol for pancreatic head ductal adenocarcinoma specimens results in an significant R1 rate of the resection margins, and the R1 rate is related to the R1 criterion. The SMV groove margin and SMA margin are the two most frequent sites of R1.

Improvement effects of cyclic peptides from Annona squamosa on cognitive decline in neuroinflammatory mice.

Cyclic peptides can resist enzymatic hydrolysis to pass through the intestine barrier, which may reduce the risk of mild cognition decline. But evidence is lacking on whether they work by alleviating neuroinflammation. A cylic peptide from Annona squamosa, Cylic(PIYAG), was biologically evaluated in vivo and in vitro. Cylic(PIYAG) enhanced the spatial memory ability of LPS-induced mice. And treatment with Cylic(PIYAG) markedly reduced the iNOS, MCP-1, TNF-α, and gp91phox expression induced by LPS. Cylic(PIYAG, 0.01, 0.05 and 0.2 µM) could significantly reduce the protein expression level of COX-2 and iNOS (P < 0.05) in BV2 cells. The concentration of Cylic(PIYAG) in blood reached a peak of 3.64 ± 1.22 µg/ml after intragastric administration in 1 h. And fluorescence microscope shows that Cylic(PIYAG) mainly locates and may play an anti-inflammatory role in the cytoplasm of microglia. This study demonstrates that the peptidic can prevent microglia activation, decrease the inflammatory reaction, improve the cognition of LPS-induced mice. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01441-8.

Multiplexed detection of eight respiratory viruses based on nanozyme colorimetric microfluidic immunoassay.

Pandemics caused by respiratory viruses, such as the SARS-CoV-1/2, influenza virus, and respiratory syncytial virus, have resulted in serious consequences to humans and a large number of deaths. The detection of such respiratory viruses in the early stages of infection can help control diseases by preventing the spread of viruses. However, the diversity of respiratory virus species and subtypes, their rapid antigenic mutations, and the limited viral release during the early stages of infection pose challenges to their detection. This work reports a multiplexed microfluidic immunoassay chip for simultaneous detection of eight respiratory viruses with noticeable infection population, namely, influenza A virus, influenza B virus, respiratory syncytial virus, SARS-CoV-2, human bocavirus, human metapneumovirus, adenovirus, and human parainfluenza viruses. The nanomaterial of the nanozyme (Au@Pt nanoparticles) was optimized to improve labeling efficiency and enhance the detection sensitivity significantly. Nanozyme-binding antibodies were used to detect viral proteins with a limit of detection of 0.1 pg/mL with the naked eye and a microplate reader within 40 min. Furthermore, specific antibodies were screened against the conserved proteins of each virus in the immunoassay, and the clinical sample detection showed high specificity without cross reactivity among the eight pathogens. In addition, the microfluidic chip immunoassay showed high accuracy, as compared with the RT-PCR assay for clinical sample detection, with 97.2%/94.3% positive/negative coincidence rates. This proposed approach thus provides a convenient, rapid, and sensitive method for simultaneous detection of eight respiratory viruses, which is meaningful for the early diagnosis of viral infections. Significantly, it can be widely used to detect pathogens and biomarkers by replacing only the antigen-specific antibodies.

Acid-triggered rattan ball-like ß-glucan carrier embedding doxorubicin to synergistically alleviate precancerous lesions of gastric cancer via p53 and PI3K pathways.

The early intervention of precancerous lesions of gastric cancer (PLGC) is crucial for improving the survival of patients with gastric cancer. Traditional pharmaceuticals for the treatment of PLGC are limited by side effects, thus developing innovative drug carrier that are more efficient but without the undesirable side effects is required. Here, we proposed an acid-triggered mushroom-derived ß-glucan carrier embedding doxorubicin (DOX) to circumvent drug cytotoxicity and synergistically alleviate PLGC based on the controlled conformational transformation. The triple helix ß-glucan extracted from Dictyophora rubrovolvata (DRP) loaded doxorubicin driven by pH and DMSO regulation, forming two rattan ball-like nanoparticles (DRP-DOX(pH) and DRP-DOX(DMSO)) via its collapse and recombination of triple-helix conformation. The findings revealed that DRP-DOXs achieved acid-triggerable and sustained drug delivery with an average particle size of 500 nm and 550 nm. In vitro evaluation of GES-1 cells showed DRP-DOXs reduced reactive oxygen species (ROS) production and altered mitochondrial membrane potential. Compared to DRP-DOX(DMSO) and DRP, DRP-DOX(pH) could more effectively downregulate cellular oxidative stress and inflammation to eventually alleviate PLGC, by regulating the p53 and PI3K pathways to mitigate gastric mucosa damage. Consequently, the nature-derived ß-glucan delivery nanovesicle holds great promising applications in reducing drug toxicity and suppressing the development of PLGC.

Comparative Analysis of Physiological Responses and Intestinal Microbiota in Juvenile Soft-Shelled Turtle (Pelodiscus sinensis) Fed Four Types of Dietary Carbohydrates.

A 60 day feeding trial was conducted to evaluate the impacts of dietary carbohydrates with different complexities and configurations on the growth, plasma parameters, apparent digestibility, intestinal microbiota, glucose, and lipid metabolism of soft-shelled turtles (Pelodiscus sinensis). Four experimental diets were formulated by adding 170 g/kg glucose, fructose, α-starch, or cellulose, respectively. A total of 280 turtles (initial body weight 5.11 ± 0.21 g) were distributed into 28 tanks and were fed twice daily. The results showed that the best growth performance and apparent digestibility was observed in the α-starch group, followed by the glucose, fructose, and cellulose groups (p < 0.05). Monosaccharides (glucose and fructose) significantly enhanced the postprandial plasma glucose levels and hepatosomatic index compared to polysaccharides, due to the un-inhibited gluconeogenesis (p < 0.05). Starch significantly up-regulated the expression of the genes involved in glycolysis, pentose phosphate pathway, lipid anabolism and catabolism, and the transcriptional regulation factors of glycolipid metabolism (srebp and chrebp) (p < 0.05), resulting in higher plasma triglyceride levels and lipid contents in the liver and the whole body. The fructose group exhibited a lower lipid deposition compared with the glucose group, mainly by inhibiting the expression of srebp and chrebp. Cellulose enhanced the proportion of opportunistic pathogenic bacteria. In conclusion, P. sinensis utilized α-starch better than glucose, fructose, and cellulose.

In situ formed reactive oxygen species-responsive dipyridamole prodrug hydrogel: Spatiotemporal drug delivery for chemoimmunotherapy.

In the realm of combined cancer immunotherapy, the strategic combination of therapeutics targeting both cancer cells and macrophages holds immense potential. However, the major challenges remain on how to achieve facile spatiotemporal delivery of these therapies, allowing ease of manipulation and ensuring differential drug release for enhanced synergistic therapeutic effects. In the present study, we introduced a tumor microenvironment (TME)-adapted hydrogel with the phenylboronic acid-modified dipyridamole prodrug (DIPP) as a crosslinker. This prodrug hydrogel scaffold, 3BP@DIPPGel, could be formed in situ by a simple mixture of DIPP and poly(vinyl alcohol) (PVA), and loaded with a high ratio of 3-bromopyruvic acid (3BP). The 3BP@DIPPGel enables spatiotemporal localized delivery of dipyridamole (DIP) and 3BP with distinct release kinetics that effectively reshape the immunosuppressive TME. Upon reactive oxygen species (ROS) stimulation, 3BP@DIPPGel preferentially released 3BP, inducing tumor-specific pyroptosis via the ROS/BAX/caspase-3/GSDME signaling pathway and decreasing the secretion of chemokines such as CCL8 to counteract macrophage recruitment. Subsequently, the crosslinked DIP is released, triggering the tumor-associated macrophages (TAMs) polarization towards the immunostimulatory M1 phenotype via the CCR2/JAK2/STAT3 cascade signaling pathway. This dual action from 3BP@DIPPGel leads to the restoration of tumor cell immunogenicity with high efficacy and activation of immune cells. Furthermore, the 3BP@DIPPGel-based chemoimmunotherapy upregulates the expression of sialic-acid-binding Ig-like lectin 10 and hence sensitizing tumors to anti-CD24 therapy in the tumor-bearing mice. Therefore, this strategy can have significant potential in the prevention of tumor metastases and recurrence. To the best of our understanding, this study represents a pioneering showcase of tumor pyroptosis, induced by glycolytic inhibitors, which can be effectively coordinated with DIP-mediated TAM polarization for immune activation, offering a new paradigm for differentially sustained drug delivery to foster cancer immunotherapy.

Sublingual Edaravone Dexborneol for the Treatment of Acute Ischemic Stroke: The TASTE-SL Randomized Clinical Trial.

Importance: Sublingual edaravone dexborneol, which can rapidly diffuse and be absorbed through the oral mucosa after sublingual exposure, is a multitarget brain cytoprotection composed of antioxidant and anti-inflammatory ingredients edaravone and dexborneol. Objective: To investigate the efficacy and safety of sublingual edaravone dexborneol on 90-day functional outcome in patients with acute ischemic stroke (AIS). Design, Setting, and Participants: This was a double-blind, placebo-controlled, multicenter, parallel-group, phase 3 randomized clinical trial conducted from June 28, 2021, to August 10, 2022, with 90-day follow-up. Participants were recruited from 33 centers in China. Patients randomly assigned to treatment groups were aged 18 to 80 years and had a National Institutes of Health Stroke Scale score between 6 and 20, a total motor deficit score of the upper and lower limbs of 2 or greater, a clinically diagnosed AIS symptom within 48 hours, and a modified Rankin Scale (mRS) score of 1 or less before stroke. Patients who did not meet the eligibility criteria or declined to participate were excluded. Intervention: Patients were assigned, in a 1:1 ratio, to receive sublingual edaravone dexborneol (edaravone, 30 mg; dexborneol, 6 mg) or placebo (edaravone, 0 mg; dexborneol, 60 µg) twice daily for 14 days and were followed up until 90 days. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with mRS score of 1 or less on day 90 after randomization. Results: Of 956 patients, 42 were excluded. A total of 914 patients (median [IQR] age, 64.0 [56.0-70.0] years; 608 male [66.5%]) were randomly allocated to the edaravone dexborneol group (450 [49.2%]) or placebo group (464 [50.8%]). The edaravone dexborneol group showed a significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization compared with the placebo group (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P = .003). The rate of adverse events was similar between the 2 groups (89.8% [405 of 450] vs 90.1% [418 of 464]). Conclusion and Relevance: Among patients with AIS within 48 hours, sublingual edaravone dexborneol could improve the proportion of those achieving a favorable functional outcome at 90 days compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04950920.

Indolent T-cell lymphoproliferative disorder of gastrointestinal tract with unusual clinical courses: report of 6 cases and literature review.

Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (iTLPD-GI) is a rare neoplasm usually having an indolent clinical course and easily misdiagnosed as inflammatory bowel disease or other T-cell lymphomas. A subset of the disorders that progressed to overt peripheral T-cell lymphoma have been reported, and the etiology and pathogenesis are poorly understood. The current study retrospectively examined the pathological, molecular, and clinical features of 6 cases of iTLPD-GI. Hematoxylin and eosin staining, immunohistochemistry, in situ hybridization, T-cell receptor gene rearrangement, and next-generation sequencing (NGS) were performed with the diseased tissues. All the 6 patients were immunocompetent Chinese men, who presented with recurrent abdominal pain and diarrhea for 4 to 13 years. Histologically, the intestinal tissue was expanded by lymphoid infiltration, composed of small-to-medium-sized lymphocytes with gland intact. The neoplastic cells were CD4 - /CD8 + with expression of TIA1 and variable granzyme B in five cases, and the other one was CD4 + /CD8 - . Two of the 5 patients progressed to more aggressive T-cell lymphoma and died of disease with complications. NGS identified TET2 and DDX3X mutations in patient 1, and BIRC6 and REV3L mutations in patient 2. Literature review indicated that iTLPD-GI with CD4 - /CD8 + immunophenotype was more commonly reported in Chinese cases. Our limited data indicated CD4-/CD8 + iTLPD-GI have similar potential to progress to more aggressive T-cell lymphoma as that of CD4 + /CD8 - , and gradually increased expression of granzyme B and Ki-67 may be early signs of the disease progression. Gain of novel gene mutations may be indicators of the pathogenesis.