Targeting Neuronal GPR65 With Delayed BTB09089 Treatment Improves Neurorehabilitation Following Ischemic Stroke.

BACKGROUND: GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089 has been proven to produce neuroprotection in acute ischemic stroke. However, whether delayed BTB09089 treatment and neuronal GPR65 activation promote neurorestoration remains unknown. METHODS: Ischemic stroke was induced in wild-type (WT) or GPR65 knockout (GPR65-/-) mice by photothrombotic ischemia. Male mice were injected intraperitoneally with BTB09089 every other day at days 3, 7, or 14 poststroke. AAV-Syn-GPR65 (adenoassociated virus-synapsin-GPR65) was utilized to overexpress GPR65 in the peri-infarct cortical neurons of GPR65-/- and WT mice. Motor function was monitored by grid-walk and cylinder tests. The neurorestorative effects of BTB09089 were observed by immunohistochemistry, Golgi-Cox staining, and Western blotting. RESULTS: BTB09089 significantly promoted motor outcomes in WT but not in GPR65-/- mice, even when BTB09089 was delayed for 3 to 7 days. BTB09089 inhibited the activation of microglia and glial scar progression in WT but not in GPR65-/- mice. Meanwhile, BTB09089 reduced the decrease in neuronal density in WT mice, but this benefit was abolished in GPR65-/- mice and reemerged by overexpressing GPR65 in peri-infarct cortical neurons. Furthermore, BTB09089 increased the GAP43 (growth-associated protein-43) and synaptophysin puncta density, dendritic spine density, dendritic branch length, and dendritic complexity by overexpressing GPR65 in the peri-infarct cortical neurons of GPR65-/- mice, which was accompanied by increased levels of p-CREB (phosphorylated cAMP-responsive element-binding protein). In addition, the therapeutic window of BTB09089 was extended to day 14 by overexpressing GPR65 in the peri-infarct cortical neurons of WT mice. CONCLUSIONS: Our findings indicated that delayed BTB09089 treatment improved neurological functional recovery and brain tissue repair poststroke through activating neuronal GRP65. GPR65 overexpression may be a potential strategy to expand the therapeutic time window of GPR65 agonists for neurorehabilitation after ischemic stroke.

Association of the Controlling Nutritional Status (CONUT) score with all-cause and cause-specific mortality in patients with diabetic kidney disease: evidence from the NHANES 2009-2018.

OBJECTIVE: To investigate the association between the Controlling Nutritional Status (CONUT) score and all-cause and cause-specific mortality in patients with diabetic kidney disease (DKD). DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Data on patients with DKD from the National Health and Nutrition Examination Survey 2009-2018. PRIMARY AND SECONDARY OUTCOME MEASURES: All-cause mortality, cardiovascular disease (CVD)-related mortality, diabetes-related mortality and nephropathy-related mortality. RESULTS: A total of 1714 patients were included, with 1119 (65.29%) in normal nutrition group (a score of 0-1), 553 (32.26%) in mild malnutrition group (a score of 2-4) and 42 (2.45%) in moderate and severe malnutrition group (a score of 5-12), according to the CONUT score. After controlling for age, race, marital status, smoking, hypertension, CVD, diabetic retinopathy, poverty income ratio, antidiabetics, diuretics, urinary albumin to creatinine ratio, uric acid, energy, protein, total fat, sodium and estimated glomerular filtration rate, a higher CONUT score was associated with a significantly greater risk of all-cause death (HR 1.30, 95% CI 1.15 to 1.46, p<0.001). In contrast to patients with a CONUT score of 0-1, those who scored 5-12 had significantly increased risks of all-cause death (HR 2.80, 95% CI 1.42 to 5.51, p=0.003), diabetes-related death (HR 1.78, 95% CI 1.02 to 3.11, p=0.041) and nephropathy-related death (HR 1.84, 95% CI 1.04 to 3.24, p=0.036). CONCLUSION: Moderate and severe malnutrition was associated with greater risks of all-cause death, diabetes-related death and nephropathy-related death than normal nutritional status in DKD. Close monitoring of immuno-nutritional status in patients with DKD may help prognosis management and improvement.

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study.

BACKGROUND: Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. PRIMARY OBJECTIVE: To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. STUDY HYPOTHESIS: A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. TRIAL DESIGN: The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. PRIMARY ENDPOINT: Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. SAMPLE SIZE: 160 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment is estimated to be completed by 2024 and results may be published by 2027. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05044871.

Multibarrier-penetrating drug delivery systems for deep tumor therapy based on synergistic penetration strategy.

Nanotherapies, valued for their high efficacy and low toxicity, frequently serve as antitumor treatments, but do not readily penetrate deep into tumor tissues and cells. Here we developed an improved tumor-penetrating peptide (TPP)-based drug delivery system. Briefly, the established TPP iNGR was modified to generate a linear NGR peptide capable of transporting nanotherapeutic drugs into tumors through a CendR pathway-dependent, neuropilin-1 receptor-mediated process. Although TPPs have been reported to reach intended tumor targets, they often fail to penetrate cell membranes to deliver tumoricidal drugs to intracellular targets. We addressed this issue by harnessing cell penetrating peptide technology to develop a liposome-based multibarrier-penetrating delivery system (mbPDS) with improved synergistic drug penetration into deep tumor tissues and cells. The system incorporated doxorubicin-loaded liposomes coated with nona-arginine (R9) CPP and cyclic iNGR (CRNGRGPDC) molecules, yielding Lip-mbPDS. Lip-mbPDS tumor-targeting, tumor cell/tissue-penetrating and antitumor capabilities were assessed using CD13-positive human fibrosarcoma-derived cell (HT1080)-based in vitro and in vivo tumor models. Lip-mbPDS evaluation included three-dimensional layer-by-layer confocal laser scanning microscopy, cell internalization/toxicity assays, three-dimensional tumor spheroid-based penetration assays and antitumor efficacy assays conducted in an animal model. Lip-mbPDS provided enhanced synergistic drug penetration of multiple biointerfaces for potentially deep tumor therapeutic outcomes.

Macrophages regulate healing-associated fibroblasts in diabetic wound.

BACKGROUND: Recovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages. METHODS AND RESULTS: We used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1ß (IL1ß), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice. CONCLUSIONS: Macrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.

Multimodal Imaging-Guided Photoimmunotherapy of Pancreatic Cancer by Organosilica Nanomedicine.

Immune checkpoint blockade (ICB) treatments have contributed to substantial clinical progress. However, challenges persist, including inefficient drug delivery and penetration into deep tumor areas, inadequate response to ICB treatments, and potential risk of inflammation due to over-activation of immune cells and uncontrolled release of cytokines following immunotherapy. In response, this study, for the first time, presents a multimodal imaging-guided organosilica nanomedicine (DCCGP) for photoimmunotherapy of pancreatic cancer. The novel DCCGP nanoplatform integrates fluorescence, magnetic resonance, and real-time infrared photothermal imaging, thereby enhancing diagnostic precision and treatment efficacy for pancreatic cancer. In addition, the incorporated copper sulfide nanoparticles (CuS NPs) lead to improved tumor penetration and provide external regulation of immunotherapy via photothermal stimulation. The synergistic immunotherapy effect is realized through the photothermal behavior of CuS NPs, inducing immunogenic cell death and relieving the immunosuppressive tumor microenvironment. Coupling photothermal stimulation with αPD-L1-induced ICB, the platform amplifies the clearance efficiency of tumor cells, achieving an optimized synergistic photoimmunotherapy effect. This study offers a promising strategy for the clinical application of ICB-based combined immunotherapy and presents valuable insights for applications of organosilica in precise tumor immunotherapy and theranostics.

A midterm follow-up study of the application of a confluent aortic valve neocuspidization technique with pericardium in children.

Background: The treatment of aortic valve diseases in children remains a great challenge. We aim to report outcomes and midterm follow-up data of our confluent neocuspidization technique with pericardium for aortic valve replacement (AVR) in children. Methods: A retrospective analysis was performed on all 20 children who underwent the confluent neocuspidization technique with pericardium at Children's Hospital of Fudan University from March 2017 to May 2022. Outcome measures included echocardiographic measurements, surgical intervention, and mortality. Results: A total of 20 patients (17 males vs. 3 females), with a median age of 7.5 years [min-max, 0.3-12 years; interquartile range (IQR), 4.4-9.7 years], a median body weight of 24.0 kg (min-max, 6.0-52.3 kg; IQR, 15.6-31.0 kg), and median aortic valve annulus size before surgery of 19.0 mm (min-max, 11.0-25.0 mm; IQR, 17.1-21.5 mm), underwent the neocuspidization technique with pericardium (17 autologous pericardia and 3 bovine patch). With 50% of bicuspid aortic valve and 50% of tricuspid, they were respectively diagnosed as aortic stenosis (AS) (7/20, 35%), aortic regurgitation (AR) (8/20, 40%) and mixed AS and AR (AS & AR) (5/20, 25%). The median postoperative follow-up time was 19 months (min-max, 5-61 months; IQR, 16.3-35 months). The peak pressure gradient across the aortic valve decreased from 81.0±37.0 mmHg in AS group and AS & AR group before surgery to 25.9±15.8 mmHg within 24 hours after surgery (P<0.001) and was mostly around 25 mmHg during follow-up. All patients presented mild or less than mild regurgitation within 24 hours after surgery. There were no hospital mortalities. Three patients needed reintervention during follow-up. There was one late death related to mitral valve stenosis. Conclusions: Though the confluent neocuspidization technique with pericardium provided immediate relief of significant AS or regurgitation, the midterm outcome was suboptimal. More research is needed to find the optimal material for AVR.

Clinical features and treatment outcomes of Castleman disease in children: a retrospective cohort in China.

Castleman disease (CD) is a rare lymphoproliferative disorder of undetermined etiology. Unicentric CD (UCD) and multicentric CD (MCD) are two phenotypes of CD diagnosed by the histopathology of lymph nodes. We attempted to describe a pediatric CD cohort to optimize the management of this disease. We reviewed the medical records of pediatric patients diagnosed with CD between April, 2004, and October, 2022, at the Children's Hospital of Fudan University. Prognosis information was collected in January, 2023, by telephone inquiry. Twenty-two patients with UCD and 2 patients with MCD were identified, all with hyaline vascular (HV) type. The median ages at diagnosis were 10.75 years (IQR 8, 12.81) for UCD and 14.42 years (IQR 13.42, 15.42) for MCD. The most common lesion location of UCD was the neck (9/22, 40.91%) and abdomen (9/22, 40.91%). Systematic symptoms occurred on 10/22 (45.45%) patients with UCD and 1/2 (50%) patients with MCD, and abnormal laboratory indexes were detected in both. Resection and biopsy were performed on all patients. One out of two patients with MCD also received rituximab for upfront therapy. After a median of 4 years (IQR 1.5, 6) of follow-up time, the overall survival was 100% and the complete remission rate in UCD was 63%. There was no relapse or progression. CONCLUSIONS: Our series demonstrated that HV-UCD was the most common type in children. Resection and biopsy were used for both deterministic diagnoses and treatments. Despite the high possibility to develop systematic inflammation, children with CD showed promising outcomes. WHAT IS KNOWN: • Castleman disease is a rare lymphoproliferative disorder with limited cohort studies, especially in pediatrics. • The ubiquity of delayed confirmations and misdiagnoses points to a lack of knowledge about etiology and characteristics, which is a prerequisite for novel therapeutics. WHAT IS NEW: • We retrospectively reviewed and analyzed the clinical and pathological symptoms, laboratory and imaging features, and treatment outcomes of a Chinese pediatric cohort with Castleman disease. • Our work may improve the recognition and optimize the management of this rare disease in children.

SGCE promotes breast cancer stemness by promoting the transcription of FGF-BP1 by Sp1.

Breast cancer stem cells are mainly responsible for poor prognosis, especially in triple-negative breast cancer (TNBC). In a previous study, we demonstrated that ε-Sarcoglycan (SGCE), a type Ⅰ single-transmembrane protein, is a potential oncogene that promotes TNBC stemness by stabilizing EGFR. Here, we further found that SGCE depletion reduces breast cancer stem cells, partially through inhibiting the transcription of FGF-BP1, a secreted oncoprotein. Mechanistically, we demonstrate that SGCE could interact with the specific protein 1 transcription factor and translocate into the nucleus, which leads to an increase in the transcription of FGF-BP1, and the secreted FBF-BP1 activates FGF-FGFR signaling to promote cancer cell stemness. The novel SGCE-Sp1-FGF-BP1 axis provides novel potential candidate diagnostic markers and therapeutic targets for TNBC.

The changes of Treg and Th17 cells relate to serum 25(OH)D in patients with initial-onset childhood systemic lupus erythematosus.

Background: T helper 17 (Th17) cells and regulatory T cells (Treg) are known to play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). Improving the balance between Treg and Th17 cells can be a promising new therapeutic target in SLE patients. Vitamin D has a significant impact on the immune inflammatory process and the immune cells involved in this process. The purpose of this study is to investigate the relationship between Th17, Treg, cytokines, and serum 25 hydroxyvitamin D [25(OH)D] in patients with initial-onset childhood SLE. Methods: A total of 82 children aged <18 years with initial-onset SLE were included, as well as 60 healthy subjects during the same period at the Pediatrics Department of the Second Hospital of Hebei Medical University. The chemiluminescence method was performed to detect serum 25(OH)D levels. Flow cytometry was used to evaluate Treg and Th17 cells. An enzyme-linked immunosorbent assay kit was used to evaluate plasma interleukin (IL)-23, IL-17, IL-10, IL-6, and tumor necrosis factor alpha (TNF-α) concentrations. Result: The serum 25(OH)D levels in patients with initial-onset childhood SLE were significantly lower than those in the healthy controls. The proportion of lupus nephritis (LN) was higher in the vitamin D insufficiency group (71.4%) compared with the vitamin D sufficiency group (30.3%) (p < 0.05). The SLE disease activity index (SLEDAI) was higher in the vitamin D insufficiency group (median = 14) than that in the vitamin D sufficiency group (median = 9) (p < 0.05).The 25(OH)D level was positively correlated with the Treg ratio (r = 0.337, p = 0.002), and it was negatively correlated with the Th17 cell ratio (r = -0.370, p = 0.001). The serum 25(OH)D level had a negative correlation with IL-23 (r = -0.589, p < 0.001), IL-17(r = -0.351, p = 0.001), TNF-α (r = -0.283, p = 0.01), IL-6 (r = -0.392, p < 0.001), and IL-10 (r = -0.313, p = 0.004) levels. Conclusion: The serum 25(OH)D levels decreased in patients with initial-onset childhood SLE. There was a negative correlation between the serum 25(OH)D levels and SLEDAI. The serum 25(OH)D levels in patients with initial-onset childhood SLE were negatively correlated with the Th17 ratio and related cytokines, while positively correlated with the Treg ratio.

Risk factors for mitral valve dysfunction, reoperation and death following repair of the primary mitral valve disease in children.

Background: After primary mitral valve (MV) repair, residual mitral valve regurgitation (MR) and recurred mitral valve stenosis (MS) are the principal occurrences. This study's purpose is to identify the risk factors of MV dysfunction, reoperation and death following repair of primary MV diseases. Methods: We retrospectively reviewed 98 patients (47 males and 51 females) with primary MV diseases between January 2013 and December 2021. The median age was 34 months [interquartile range (IQR), 11.4-59] for male and 24 months (IQR, 7.35-72) for female. The left ventricular ejection fraction (LVEF), the left ventricular end-diastolic volume index (LVEDVI) and left ventricular end-systolic volume index (LVESVI) were assessed to evaluate patient's left ventricular function. Risk factors that increased the likelihood of MV dysfunction, reoperation and death after surgery were investigated. Results: During the 23.5 months (IQR, 9-44.5) of follow-up, 5 (5.1%) patients died, including one early death and two late deaths (n=3; 3.9%) in the MR group and one early death and one late death (n=2; 9.1%) in the MS group. Seven (9.2%) patients in the primary MR disease group and 2 (9.1%) patients in the primary MS disease group required a second MV operation for a total reoperation rate of 9.2% (9/98). As of the most recent follow-up, 34 patients experienced MV dysfunction. No significant difference was recorded between primary MR and MS disease groups in Kaplan-Meier freedom from MV dysfunction and reoperation. Mixed MV pathology (P=0.014) acted as an independent risk factor for MV dysfunction, and ≥ moderate MR at 24 h after first surgery (P=0.014) an independent risk factor for MV reoperation. Double-orifice MV technique (P=0.002), MV reoperation (P=0.023) and severe MR at 24 h after first surgery (P=0.028) were independent risk factors for death. Conclusions: The Kaplan-Meier freedom from MV dysfunction and reoperation were comparable between primary MR and MS disease groups. A high probability of MV dysfunction was predicted due to the mixed MV pathology. Patients with ≥ moderate MR at 24 h after first surgery had a higher risk of MV reoperation. Double-orifice MV technique, MV reoperation and severe MR at 24 h after first surgery had a higher risk for death.

Aging under endocrine hormone regulation.

Aging is a biological process in which the environment interacts with the body to cause a progressive decline in effective physiological function. Aging in the human body can lead to a dysfunction of the vital organ systems, resulting in the onset of age-related diseases, such as neurodegenerative and cardiovascular diseases, which can seriously affect an individual's quality of life. The endocrine system acts on specific targets through hormones and related major functional factors in its pathways, which play biological roles in coordinating cellular interactions, metabolism, growth, and aging. Aging is the result of a combination of many pathological, physiological, and psychological processes, among which the endocrine system can achieve a bidirectional effect on the aging process by regulating the hormone levels in the body. In this paper, we explored the mechanisms of growth hormone, thyroid hormone, and estrogen in the aging process to provide a reference for the exploration of endocrine mechanisms related to aging.

Concordance of bone culture and deep tissue culture during the operation of diabetic foot osteomyelitis and clinical characteristics of patients.

PURPOSE: To retrospectively analyze the concordance of bacterial culture between bone tissue and deep soft tissue in diabetic foot osteomyelitis (DFO) patients and clinical characteristics of patients. METHODS: This study collected samples from 155 patients with suspected DFO (who required amputation after clinical evaluation). Bacterial culture and drug susceptibility tests were performed on the patients' deep soft tissue and bone tissue, and the consistency between the two was compared. In addition, the differences among DFO patients with different degrees of infection were compared classified by the PEDIS classifications. RESULTS: Among the 155 patients diagnosed with DFO, the positive rate of bone culture was 78.7% (122/155). This study cultured 162 strains, including 73 Gram-positive bacteria, 83 Gram-negative bacteria, and 6 fungi. Staphylococcus aureus (33 strains) was the most common bacteria. The overall agreement between bone culture and tissue culture was 42.8%, with Staphylococcus aureus and Enterobacteria having the best (64.3%) and least agreements (27.3%), respectively. The drug sensitivity results in bone culture showed that Staphylococcus aureus was the main Gram-positive bacteria. The bacteria were sensitive to linezolid and vancomycin. Proteus mirabilis was the main Gram-negative bacteria. These were more sensitive than biapenem and piperacillin/tazobactam. Fungi were more sensitive to voriconazole and itraconazole. CONCLUSION: The culture results of deep soft tissues near the bone cannot accurately represent the true pathogen of DFO. For DFO patients, bone culture should be taken as much as possible, and appropriate antibiotics should be selected according to the drug susceptibility results.

Biomimetic Gold Nanorods Modified with Erythrocyte Membranes for Imaging-Guided Photothermal/Gene Synergistic Therapy.

Pancreatic cancer (PC) is one of the most malignant cancers that develops rapidly and carries a poor prognosis. Synergistic cancer therapy strategy could enhance the clinical efficacy compared to either treatment alone. In this study, gold nanorods (AuNRs) were used as siRNA delivery vehicles to interfere with the oncogenes of KRAS. In addition, AuNRs were one of anisotropic nanomaterials that can absorb near-infrared (NIR) laser and achieve rapid photothermal therapy for malignant cancer cells. Modification of the erythrocyte membrane and antibody Plectin-1 occurred on the surface of the AuNRs, making them a promising target nanocarrier for enhancing antitumor effects. As a result, biomimetic nanoprobes presented advantages in biocompatibility, targeting capability, and drug-loading efficiency. Moreover, excellent antitumor effects have been achieved by synergistic photothermal/gene treatment. Therefore, our study would provide a general strategy to construct a multifunctional biomimetic theranostic multifunctional nanoplatform for preclinical studies of PC.

Delayed CO2 postconditioning promotes neurological recovery after cryogenic traumatic brain injury by downregulating IRF7 expression.

AIMS: Few treatments are available in the subacute phase of traumatic brain injury (TBI) except rehabilitation training. We previously reported that transient CO2 inhalation applied within minutes after reperfusion has neuroprotective effects against cerebral ischemia/reperfusion injury. In this study, it was hypothesized that delayed CO2 postconditioning (DCPC) starting at the subacute phase may promote neurological recovery of TBI. METHODS: Using a cryogenic TBI (cTBI) model, mice received DCPC daily by inhaling 5%/10%/20% CO2 for various time-courses (one/two/three cycles of 10-min inhalation/10-min break) at Days 3-7, 3-14 or 7-18 after cTBI. Beam walking and gait tests were used to assess the effect of DCPC. Lesion size, expression of GAP-43 and synaptophysin, amoeboid microglia number and glia scar area were detected. Transcriptome and recombinant interferon regulatory factor 7 (Irf7) adeno-associated virus were applied to investigate the molecular mechanisms. RESULTS: DCPC significantly promoted recovery of motor function in a concentration and time-course dependent manner with a wide therapeutic time window of at least 7 days after cTBI. The beneficial effects of DCPC were blocked by intracerebroventricular injection of NaHCO3 . DCPC also increased puncta density of GAP-43 and synaptophysin, and reduced amoeboid microglia number and glial scar formation in the cortex surrounding the lesion. Transcriptome analysis showed many inflammation-related genes and pathways were altered by DCPC, and Irf7 was a hub gene, while overexpression of IRF7 blocked the motor function improvement of DCPC. CONCLUSIONS: We first showed that DCPC promoted functional recovery and brain tissue repair, which opens a new therapeutic time window of postconditioning for TBI. Inhibition of IRF7 is a key molecular mechanism for the beneficial effects of DCPC, and IRF7 may be a potential therapeutic target for rehabilitation after TBI.

Threshold of Main Pancreatic Duct Diameter in Identifying Malignant Intraductal Papillary Mucinous Neoplasm by Magnetic Resonance Imaging.

Objective: Intraductal papillary mucinous neoplasm (IPMN) is a rare pancreatic lesion. The identification of malignancy is critical for the establishment of treatment strategies. Main pancreatic duct (MPD) diameter is one critical feature for malignant IPMNs. However, the threshold of 1.0 cm is challenged. In this study, we explored independent risk factors and further calculated the threshold of MPD in identifying malignant IPMNs. Method: A total of 151 IPMN patients were included in this retrospective study. Demographic information, clinicopathological features, laboratory testing, and preoperative radiological characteristics by magnetic resonance imaging were collected. The receiver operating characteristic (ROC) curves were performed to determine the MPD diameter's cutoff levels and evaluate the predicted factors' diagnostic ability. Results: A cutoff value of 0.77 cm MPD (an area under the curve (AUC) = 0.746) in all IPMNs and 0.82 cm (AUC = 0.742) in the main duct involved IPMNs was obtained. MPD diameter (odds ratio (OR), 12.67; 95% confidence interval (CI), 4.80-33.48) and the mural nodule (OR, 12.98; 95% CI, 3.18-52.97) were the independent associated factors with high-risk IPMNs. The combined model with MPD and mural nodule showed a better predictive performance than mural nodule or MPD diameter alone (AUC = 0.803 vs 0.619, 0.746). A nomogram was developed and showed good performance (C index = 0.803). Conclusion: Our data show that mural nodule and MPD diameter are independent risk factors in identifying malignant intraductal papillary mucinous neoplasms. A cutoff value of 0.77 cm of MPD diameter may be a threshold value in identifying malignant intraductal papillary mucinous neoplasms or undergoing surgical resection.

Diagnosis and intervention of severe tricuspid regurgitation secondary to rupture of the chordae tendineae: A case report and literature review.

Unguarded severe tricuspid regurgitation caused by rupture of papillary muscle or chordae tendineae is rare but fatal in neonates. The experience in the management of these patients is still limited. A newborn presenting severe cyanosis after delivery was diagnosed with severe tricuspid regurgitation secondary to rupture of chordae tendineae by echocardiography (Echo), then treated by surgical reconstruction of chordae/papillary muscle connection without artificial materials. A takeaway lesson from this case is that Echo is an important method to diagnose a rupture of chordae tendineae or papillary muscle and that prompt diagnosis and timely surgery can be life-saving.

Association of the KISS1, LIN28B, VDR and ERα gene polymorphisms with early and fast puberty in Chinese girls.

OBJECTIVES: To explore the association of KISS1, LIN28B, vitamin D receptor (VDR), and estrogen receptor α (ERα) gene polymorphisms and the risk of early with fast puberty (EFP) risk, and with hormone levels in EFP cases, in Chinese girls. METHODS: The analysis was based on the data of 141 girls with EFP and 152 girls without EFP. Clinical features were documented, and all SNP genotyping was conducted using SNaPshot method. Statistical analysis was performed to assess the association of the SNPs with EFP risk, and with hormone levels in EFP cases. RESULTS: There was a significant association between rs7759938-C polymorphism in the LIN28B gene and the risk for EFP in the recessive (TT + CT vs. CC) model (p = 0.040). Remarkably, rs5780218-delA polymorphism in the KISS1 gene and rs2234693-C polymorphism in the ERα gene were significantly associated with peak LH (luteinizing hormone) levels (p = 0.008, 0.045) and peak LH/FSH (follicle-stimulating hormone) ratio (p = 0.007, 0.006). Additionally, on 7 of the 8 variant loci the alleles associated with increased levels of both peak LH levels and peak LH/FSH ratio in EFP cases were also associated with increased CPP risk. CONCLUSIONS: Our findings indicate that rs7759938-C polymorphism in the LIN28B gene might have a protective effect on EFP susceptibility. The most striking findings of this study is that, rs5780218-delA polymorphism in the KISS1 gene and rs2234693-C polymorphism in the ERα gene influenced levels of GnRH-stimulated peak LH and LH/FSH ratio, and in general CPP risk genes might also contributes to the abnormality of hormonal levels in EFP.

Terbium-triggered aggregation-induced emission of bimetallic nanoclusters for anticancer drugs sensing via the inner filter effect.

The development of accurate and sensitive detection methods of anticancer drugs is of significant importance because they play vital roles in biological systems. In recent years, bimetallic nanoclusters (BMNCs) incorporating the advantages of two metals have gained more and more attention, and can be widely applied in sensing applications. In this work, for the first time, we designed a sensing platform based on terbium ion (Tb3+) triggered aggregation-induced emission (AIE) of BMNCs. Tb3+ hybrid glutathione (GS) protected Ag/Cu nanoclusters (Tb3+@GS-AgCuNCs) were facilely fabricated according to the complexation reaction between Tb3+ and the carboxyl group of GS. Due to the inner filter effect (IFE), the fluorescence of Tb3+@GS-AgCuNCs decreased significantly in the presence of anticancer drugs with 6-thioguanine and methotrexate as representatives. In addition, the sensing platform was applied to monitor 6-thioguanine and methotrexate in real serum samples, indicating that it has great potential in anticancer drugs related applications.

Morphology Optimization of Leaflet for Surgical Reconstruction of the Aortic Valve: In Vitro Test and Simulation-Based DOE Study.

This study was to evaluate the impact of leaflet trimming strategy on the hemodynamic behaviors of the aortic valve after reconstructive surgery, and give recommendations based on design of experiment (DOE) and in vitro studies. An in vitro hemodynamic test was performed on the simulated surgical model to quantify the efficacy of conventional reconstructive surgery. The very same computational model was built and verified, on which the full factorial DOE was carried out to summarize the correlations between leaflet trimming parameters and valve hemodynamic characteristics. Hemodynamic characteristics of the valve substitute were significantly associated with leaflet trimming parameters. The total regurgitant and transvalvular regurgitant of the valve substitute were reduced by 27.44% and 13.61% after optimization of the leaflet design. Synthetic use of in vitro tests and DOE study based on computational models helped improve outcomes of the reconstruction of aortic valve by reducing free edge length and increasing commissure height and leaflet height.