Neurons upregulate PD-L1 via IFN/STAT1/IRF1 to alleviate damage by CD8+ T cells in cerebral malaria.

BACKGROUND: Cerebral malaria (CM) is the most lethal complication of malaria, and survivors usually endure neurological sequelae. Notably, the cytotoxic effect of infiltrating Plasmodium-activated CD8+ T cells on cerebral microvasculature endothelial cells is a prominent feature of the experimental CM (ECM) model with blood-brain barrier disruption. However, the damage effect of CD8+ T cells infiltrating the brain parenchyma on neurons remains unclear. Based on the immunosuppressive effect of the PD-1/PD-L1 pathway on T cells, our previous study demonstrated that the systemic upregulation of PD-L1 to inhibit CD8+ T cell function could effectively alleviate the symptoms of ECM mice. However, it has not been reported whether neurons can suppress the pathogenic effect of CD8+ T cells through the PD-1/PD-L1 negative immunomodulatory pathway. As the important inflammatory factor of CM, interferons can induce the expression of PD-L1 via different molecular mechanisms according to the neuro-immune microenvironment. Therefore, this study aimed to investigate the direct interaction between CD8+ T cells and neurons, as well as the mechanism of neurons to alleviate the pathogenic effect of CD8+ T cells through up-regulating PD-L1 induced by IFNs. METHODS: Using the ECM model of C57BL/6J mice infected with Plasmodium berghei ANKA (PbA), morphological observations were conducted in vivo by electron microscope and IF staining. The interaction between the ECM CD8+ T cells (immune magnetic bead sorting from spleen of ECM mice) and primary cultured cortical neurons in vitro was observed by IF staining and time-lapse photography. RNA-seq was performed to analyze the signaling pathway of PD-L1 upregulation in neurons induced by IFNß or IFNγ, and verified through q-PCR, WB, IF staining, and flow cytometry both in vitro and in vivo using IFNAR or IFNGR gene knockout mice. The protective effect of adenovirus-mediated PD-L1 IgGFc fusion protein expression was verified in ECM mice with brain stereotaxic injection in vivo and in primary cultured neurons via viral infection in vitro. RESULTS: In vivo, ECM mice showed infiltration of activated CD8+ T cells and neuronal injury in the brain parenchyma. In vitro, ECM CD8+ T cells were in direct contact with neurons and induced axonal damage, as an active behavior. The PD-L1 protein level was elevated in neurons of ECM mice and in primary cultured neurons induced by IFNß, IFNγ, or ECM CD8+ T cells in vitro. Furthermore, the IFNß or IFNγ induced neuronal expression of PD-L1 was mediated by increasing STAT1/IRF1 pathway via IFN receptors. The increase of PD-L1 expression in neurons during PbA infection was weakened after deleting the IFNAR or IFNGR. Increased PD-L1 expression by adenovirus partially protected neurons from CD8+ T cell-mediated damage both in vitro and in vivo. CONCLUSION: Our study demonstrates that both type I and type II IFNs can induce neurons to upregulate PD-L1 via the STAT1/IRF1 pathway mediated by IFN receptors to protect against activated CD8+ T cell-mediated damage, providing a targeted pathway to alleviate neuroinflammation during ECM.

Efficacy of neoadjuvant chemo-immunotherapy in non-small cell lung cancer: a real-world, multicenter, retrospective study.

Background: Resectable non-small cell lung cancer (NSCLC) patients have a high risk of recurrence. Multiple randomized controlled trials (RCTs) have shown that neoadjuvant chemo-immunotherapy brings new hope for these patients. The study aims to evaluate the safety, surgery-related outcomes and oncological outcomes for neoadjuvant chemo-immunotherapy in real-world setting with a large sample size and long-term follow-up. Methods: Patients with clinical stage IB-IIIB NSCLC who received neoadjuvant chemo-immunotherapy at two Chinese institutions were included in this retrospective cohort study. Surgical and oncological outcomes of the enrolled NSCLC patients were collected and analyzed. Results: There were 158 patients identified, of which 124 (78.5%) were at stage IIIA-IIIB and the remaining 34 (21.5%) were at stage IB-IIB. Forty-one patients (25.9%) received two cycles of neoadjuvant treatment, 80 (50.6%) had three cycles, and 37 (23.4%) had four cycles. Twenty-four patients (15.2%) experienced grade 3 or worse immune-related adverse events. The median interval time between the last neoadjuvant therapy and surgery was 37 [interquartile range (IQR), 31-43] days. Fifty-eight out of 96 (60.4%) central NSCLC patients who were expected to undergo complex surgery had the scope or the difficulty of operation reduced. Ninety-five (60.1%) patients achieved major pathologic response (MPR), including 62 (39.2%) patients with pathologic complete response (pCR). Multivariate regression analysis showed that no clinical factor other than programmed death-ligand 1 (PD-L1) expression was predictive of the pathological response. The median follow-up time from diagnosis was 27.1 months. MPR and pCR were significantly associated with improved progression-free survival (PFS) and overall survival (OS). Neither stage nor PD-L1 expression was significantly associated with long-term survival. Conclusions: The neoadjuvant chemo-immunotherapy is a feasible strategy for NSCLC with a favorable rate of pCR/MPR, modified resection and 2-year survival. No clinical factor other than PD-L1 expression was predictive of the pathological response. pCR/MPR may be effective surrogate endpoint for survival in NSCLC patients who received neoadjuvant chemo-immunotherapy.

Prognostic impact of spread through air spaces in patients with ≤2 cm stage IA lung adenocarcinoma.

Background: In 2015, the World Health Organization (WHO) included spread through air space (STAS) as a new invasive mode of lung cancer. As a new mode of lung cancer dissemination, STAS has a significant and negative impact on patient prognosis. The surgical approach as well as lymph node dissection (LND) for STAS-positive patients is currently unclear. The aim of this study was to investigate the impact of different surgical approaches to STAS and LND on the prognosis of patients with ≤2 cm stage IA lung adenocarcinoma (LUAD). This study also investigated the possible relationship between STAS and the micropapillary histological subtype and its impact on patient prognosis. Methods: A total of 212 patients with LUAD were included in this study from January 2016 to December 2017, and the overall survival (OS) of the patients was compared. The chi-square test and t-test were applied to compare the clinicopathological data of the patients, and the Cox model was used for the multivariate survival analysis. Results: Of the 212 patients, 93 (43.9%) were STAS positive. The univariate analysis showed that the surgical approach, LND type, micropapillary pattern (MP), solid pattern, and STAS were risk factors for OS. The multivariate analysis showed that the surgical approach, MP, and STAS were risk factors for OS. The STAS-positive patients who underwent lobectomy had a better prognosis than those who underwent sublobar resection; however, there was no significant difference between the two surgical procedures in the STAS-negative group. Additionally, the STAS-positive patients who underwent systematic lymph node dissection (SLND) had a better prognosis than those who underwent limited lymph node dissection (LLND); however, there was no significant difference between the two LNDs in the STAS-negative group. Conclusions: STAS plays an important role in patient prognosis and is an independent risk factor for OS of patients with ≤2 cm stage IA LUAD. When STAS is positive, the choice of lobectomy with SLND may result in a better long-term prognosis for patients.

Clinico-pathological study of esophageal mucoepidermoid carcinoma: a 10-year survival from a single center.

BACKGROUND: Mucoepidermoid Carcinoma of the Esophagus (MECE) is a relatively rare tumor type, with most of the current data derived from case reports or small sample studies. This retrospective study reports on the 10-year survival data and detailed clinicopathological characteristics of 48 patients with esophageal MEC. METHODS: Data were collected from 48 patients who underwent curative surgery for esophageal MEC at the Fourth Hospital of Hebei Medical University between January 1, 2004, and December 31, 2020. These were compared with contemporaneous cases of Esophageal Squamous Cell Carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC). Using the Kaplan-Meier method and multivariate Cox regression analysis, we investigated the clinicopathological factors affecting the survival of patients with MEC. RESULTS: The incidence of MECE was predominantly higher in males, with a male-to-female ratio of approximately 7:1. The mid-thoracic segment emerged as the most common site of occurrence. A mere 6.3% of cases were correctly diagnosed preoperatively. The lymph node metastasis rate stood at 35.4%. The overall 1-year, 3-year, 5-year, and 10-year survival rates for all patients were 85.4%, 52.1%, 37.0%, and 31.0%, respectively. Post 1:1 propensity score matching, no significant statistical difference was observed in the Overall Survival (OS) between MEC patients and those with Esophageal Squamous Cell Carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC) (P = 0.119, P = 0.669). Univariate analysis indicated that T staging and N staging were the primary factors influencing the prognosis of esophageal MEC. CONCLUSIONS: MECE occurs more frequently in males than females, with the mid-thoracic segment being the most common site of occurrence. The rate of accurate preoperative endoscopic diagnosis is low. The characteristic of having a short lesion length yet exhibiting significant extramural invasion may be a crucial clinicopathological feature of MECE. The OS of patients with MEC does not appear to significantly differ from those with esophageal squamous carcinoma and adenocarcinoma.

N6-methyladenosine modification of KLF2 may contribute to endothelial-to-mesenchymal transition in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disease characterized by pulmonary vascular remodeling. Increasing evidence indicates that endothelial-to-mesenchymal transition (EndMT) in pulmonary artery endothelial cells (PAECs) is a pivotal trigger initiating this remodeling. However, the regulatory mechanisms underlying EndMT in PH are still not fully understood. METHODS: Cytokine-induced hPAECs were assessed using RNA methylation quantification, qRT-PCR, and western blotting to determine the involvement of N6-methyladenosine (m6A) methylation in EndMT. Lentivirus-mediated silencing, overexpression, tube formation, and wound healing assays were utilized to investigate the function of METTL3 in EndMT. Endothelial-specific gene knockout, hemodynamic measurement, and immunostaining were performed to explore the roles of METTL3 in pulmonary vascular remodeling and PH. RNA-seq, RNA Immunoprecipitation-based qPCR, mRNA stability assay, m6A mutation, and dual-luciferase assays were employed to elucidate the mechanisms of RNA methylation in EndMT. RESULTS: The global levels of m6A and METTL3 expression were found to decrease in TNF-α- and TGF-ß1-induced EndMT in human PAECs (hPAECs). METTL3 inhibition led to reduced endothelial markers (CD31 and VE-cadherin) and increased mesenchymal markers (SM22 and N-cadherin) as well as EndMT-related transcription factors (Snail, Zeb1, Zeb2, and Slug). The endothelial-specific knockout of Mettl3 promoted EndMT and exacerbated pulmonary vascular remodeling and hypoxia-induced PH (HPH) in mice. Mechanistically, METTL3-mediated m6A modification of kruppel-like factor 2 (KLF2) plays a crucial role in the EndMT process. KLF2 overexpression increased CD31 and VE-cadherin levels while decreasing SM22, N-cadherin, and EndMT-related transcription factors, thereby mitigating EndMT in PH. Mutations in the m6A site of KLF2 mRNA compromise KLF2 expression, subsequently diminishing its protective effect against EndMT. Furthermore, KLF2 modulates SM22 expression through direct binding to its promoter. CONCLUSIONS: Our findings unveil a novel METTL3/KLF2 pathway critical for protecting hPAECs against EndMT, highlighting a promising avenue for therapeutic investigation in PH.

The Scheduling Mode of Anesthesia Nurses Affects Postanesthesia Care Unit Efficiency: A Single-Center Retrospective Study From China.

PURPOSE: Anesthesia nurses play an important postsurgical role during the anesthesia recovery period, which is characterized by a high incidence of complications related to anesthesia and surgery. Strengthening staff allocation and skill management in the postanesthesia care unit (PACU) is therefore particularly important in managing length of stay. We aimed to investigate the effect of two schedule modes for anesthesia nurses on PACU efficiency. DESIGN: A retrospective observational cohort study. METHODS: We conducted a retrospective study in a large tertiary academic medical center. In 2018, the PACU operated with traditional scheduling and the nurse-to-patient ratio was 1.2:1. The PACU implemented intensive scheduling and this ratio was adjusted to 1:1 in 2019 by adjusting the anesthesia nurse allocation scheme. We compared the number of admitted patients, length of PACU stay, the incidence of anesthesia-related complications, and nurse satisfaction with the two modes. FINDINGS: The total number of admitted patients was 10,531 in 2018 and 10,914 in 2019. PACU admitted 401 more patients in 2019 than in 2018, even with two fewer nurses per day. Nevertheless, the median length of PACU stay in 2019 was statistically significantly shorter than in 2018 (29 [22-40] vs 28 [21-39], P < .001], while the incidence of anesthesia-related complications including postoperative pain, nausea and vomiting, hypertension, and shivering were comparable in the 2 years (P > .091). The intensive scheduling implemented in 2019 received more satisfaction from nurses than the traditional scheduling applied in 2018 (P < .01). CONCLUSIONS: The scheduling of anesthesia nurses affects PACU efficiency. The intensive scheduling mode implemented in 2019 resulted in a comparable number of admitted patients, a better quality of care, and higher nurse satisfaction than those under the traditional scheduling mode.

Generation of Slco1a4-CreERT2-tdTomato Knock-in Mice for Specific Cerebrovascular Endothelial Cell Targeting.

The cerebrovascular endothelial cells with distinct characteristics line cerebrovascular blood vessels and are the fundamental structure of the blood-brain barrier, which is important for the development and homeostatic maintenance of the central nervous system. Cre-LoxP system-based spatial gene manipulation in mice is critical for investigating the physiological functions of key factors or signaling pathways in cerebrovascular endothelial cells. However, there is a lack of Cre recombinase mouse lines that specifically target cerebrovascular endothelial cells. Here, using a publicly available single-cell RNAseq database, we screened the solute carrier organic anion transporter family member 1a4 (Slco1a4) as a candidate marker of cerebrovascular endothelial cells. Then, we generated an inducible Cre mouse line in which a CreERT2-T2A-tdTomato cassette was placed after the initiation codon ATG of the Slco1a4 locus. We found that tdTomato, which can indicate the endogenous Slco1a4 expression, was expressed in almost all cerebrovascular endothelial cells but not in any other non-endothelial cell types in the brain, including neurons, astrocytes, oligodendrocytes, pericytes, smooth muscle cells, and microglial cells, as well as in other organs. Consistently, when crossing the ROSA26LSL-EYFP Cre reporter mouse, EYFP also specifically labeled almost all cerebrovascular endothelial cells upon tamoxifen induction. Overall, we generated a new inducible Cre line that specifically targets cerebrovascular endothelial cells.

Chemoradiotherapy versus surgery after neoadjuvant chemoimmunotherapy in patients with stage III NSCLC: a real-world multicenter retrospective study.

PURPOSE: The optimal treatment after neoadjuvant chemoimmunotherapy for patients with stage III non-small cell lung cancer (NSCLC) is unclear. This study aimed at comparing the efficacy and safety of chemoradiotherapy and surgery after neoadjuvant chemoimmunotherapy in stage III NSCLC. MATERIALS AND METHODS: We conducted a real-world multicenter retrospective study on patients with stage III NSCLC who received surgery or chemoradiotherapy after neoadjuvant chemoimmunotherapy between October 2018 and December 2022. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of neoadjuvant treatment and estimated by the Kaplan‒Meier method. Univariate and multivariate Cox regression models were used to examine potential prognostic factors. One-to-one propensity score matching (PSM) was used to further minimize confounding. RESULTS: A total of 239 eligible patients were enrolled, with 104 (43.5%) receiving surgery and 135 (56.5%) receiving CRT. After 1:1 PSM, 1- and 2-year PFS rates in patients receiving radical surgery (rSurgery group) vs. patients receiving definitive cCRT (dCCRT group) were 80.0% vs. 79.2% and 67.2% vs. 53.1%, respectively (P = 0.774). One- and 2-year OS rates were 97.5% vs. 97.4% and 87.3% vs. 89.9%, respectively (P = 0.558). Patients in the dCCRT group had a numerically lower incidence of distant metastases compared to those in the rSurgery group (42.9% vs. 70.6%, P = 0.119). The incidence of treatment-related adverse events was similar in both groups, except that the incidence of grade 3/4 hematological toxicity was significantly higher in the dCCRT group (30.0% vs. 10.0%, P = 0.025). CONCLUSION: Following neoadjuvant chemoimmunotherapy, definitive concurrent chemoradiotherapy may achieve noninferior outcomes to radical surgery in stage III NSCLC.

Immunomodulation of adipose-derived mesenchymal stem cells on peripheral blood mononuclear cells in colorectal cancer patients with COVID-19.

BACKGROUND: Accumulating evidence has shown that adipose tissue-derived mesenchymal stem cells (ADSCs) are an effective therapeutic approach for managing coronavirus disease 2019 (COVID-19); however, further elucidation is required to determine their underlying immunomodulatory effect on the mRNA expression of T helper cell-related transcription factors (TFs) and cytokine release in peripheral blood mononuclear cells (PBMCs). AIM: To investigate the impact of ADSCs on the mRNA expression of TFs and cytokine release in PBMCs from colorectal cancer (CRC) patients with severe COVID-19 (CRC+ patients). METHODS: PBMCs from CRC+ patients (PBMCs-C+) and age-matched CRC patients (PBMCs-C) were stimulated and cultured in the presence/absence of ADSCs. The mRNA levels of T-box TF TBX21 (T-bet), GATA binding protein 3 (GATA-3), RAR-related orphan receptor C (RORC), and forkhead box P3 (FoxP3) in the PBMCs were determined by reverse transcriptase-polymerase chain reaction. Culture supernatants were evaluated for levels of interferon gamma (IFN-γ), interleukin 4 (IL-4), IL-17A, and transforming growth factor beta 1 (TGF-ß1) using an enzyme-linked immunosorbent assay. RESULTS: Compared with PBMCs-C, PBMCs-C+ exhibited higher mRNA levels of T-bet and RORC, and increased levels of IFN-γ and IL-17A. Additionally, a significant decrease in FoxP3 mRNA and TGF-ß1, as well as an increase in T-bet/GATA-3, RORC/FoxP3, IFN-γ/IL-4, and IL-17A/TGF-ß1 ratios were observed in PBMCs-C+. Furthermore, ADSCs significantly induced a functional regulatory T cell (Treg) subset, as evidenced by an increase in FoxP3 mRNA and TGF-ß1 release levels. This was accompanied by a significant decrease in the mRNA levels of T-bet and RORC, release of IFN-γ and IL-17A, and T-bet/GATA-3, RORC/FoxP3, IFN-γ/IL-4, and IL-17A/TGF-ß1 ratios, compared with the PBMCs-C+alone. CONCLUSION: The present in vitro studies showed that ADSCs contributed to the immunosuppressive effects on PBMCs-C+, favoring Treg responses. Thus, ADSC-based cell therapy could be a beneficial approach for patients with severe COVID-19 who fail to respond to conventional therapies.

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Multiarmed DNA jumper and metal-organic frameworks-functionalized paper-based bioplatform for small extracellular vesicle-derived miRNAs assay.

Small extracellular vesicle-derived microRNAs (sEV-miRNAs) have emerged as promising noninvasive biomarkers for early cancer diagnosis. Herein, we developed a molecular probe based on three-dimensional (3D) multiarmed DNA tetrahedral jumpers (mDNA-Js)-assisted DNAzyme activated by Na+, combined with a disposable paper-based electrode modified with a Zr-MOF-rGO-Au NP nanocomplex (ZrGA) to fabricate a novel biosensor for sEV-miRNAs Assay. Zr-MOF tightly wrapped by rGO was prepared via a one-step method, and it effectively aids electron transfer and maximizes the effective reaction area. In addition, the mechanically rigid, and nanoscale-addressable mDNA-Js assembled from the bottom up ensure the distance and orientation between fixed biological probes as well as avoid probe entanglement, considerably improving the efficiency of molecular hybridization. The fabricated bioplatform achieved the sensitive detection of sEV-miR-21 with a detection limit of 34.6 aM and a dynamic range from100 aM to 0.2 µM. In clinical blood sample tests, the proposed bioplatform showed results highly consistent with those of qRT-PCRs and the signal increased proportionally with the NSCLC staging. The proposed biosensor with a portable wireless USB-type analyzer is promising for the fast, easy, low-cost, and highly sensitive detection of various nucleic acids and their mutation derivatives, making it ideal for POC biosensing.

Effects of Apatinib combined with Temozolomide on levels of sPD-1 and sPD-L1 in patients with drug-resistant recurrent glioblastoma.

OBJECTIVE: This study aimed to explore the effects of Apatinib combined with Temozolomide (TMZ) on the levels of Soluble PD-1 (sPD-1) and Soluble Programmed Death-1 Ligand (sPD-L1) in patients with drug-resistant recurrent Glioblastoma (GB). STUDY DESIGN: A total of 69 patients with recurrent GB from September 2020 to March 2022 were recruited and assigned to the control group (n = 34) and observation group (n = 35) according to different treatment options after tumor recurrence. The control group was treated with TMZ, and the observation group was treated with Apatinib combined with TMZ. Levels of sPD-1 and spd-l1, clinical efficacy, survival time and adverse reactions were observed and compared between the two groups. RESULTS: General data including gender, age, body mass index, and combined diseases indicated no statistical significance between groups (p > 0.05). Before the intervention, sPD-1 and sPD-L1 levels were not significantly different in the two groups (p > 0.05). After interventions, levels of PD-1 and sPD-L1 levels decreased significantly (p < 0.05). The objective remission rate and clinical benefit rate of the observation group were higher and overall survival and progression-free survival were longer than those of the control group (p < 0.05). No significant difference was observed in major adverse reactions among patients (p > 0.05). CONCLUSIONS: Apatinib combined with TMZ is safe and effective in the treatment of recurrent GB. The combined application of the two can reduce the levels of sPD-1 and sPD-L1, which has important clinical application value.

Biomechanical study of 3D-printed titanium alloy pad for repairing glenoid bone defect.

Background: The purpose of this study was to investigate the effect of 3D-printed technology to repair glenoid bone defect on shoulder joint stability. Methods: The shoulder joints of 25 male cadavers were tested. The 3D-printed glenoid pad was designed and fabricated. The specimens were divided into 5 groups. Group A: no bone defect and the structure of the glenoid labrum and joint capsule was intact; Group B: Anterior inferior bone defect of the shoulder glenoid; Group C: a pad with a width of 2 mm was installed; Group D: a pad with a width of 4 mm was installed; Group E: a pad with a width of 6 mm was installed. This study measured the distance the humeral head moved forward at the time of glenohumeral dislocation and the maximum load required to dislocate the shoulder. Results: The shoulder joint stability and humerus displacement was significantly lower in groups B and C compared with group A (p < .05). Compared with group A, the stability of the shoulder joint of group D was significantly improved (p < .05). However, there was no significant difference in humerus displacement between groups D and A (p > .05). In addition, compared with group A, shoulder joint stability was significantly increased and humerus displacement was significantly decreased in group E (p < .05). Conclusion: The 3D-printed technology can be used to make the shoulder glenoid pad to perfectly restore the geometric shape of the shoulder glenoid articular surface. Moreover, the 3D-printed pad is 2 mm larger than the normal glenoid width to restore the initial stability of the shoulder joint.

Inflammation-based lung adenocarcinoma molecular subtype identification and construction of an inflammation-related signature with bulk and single-cell RNA-seq data.

The role of inflammation is increasingly understood to have a central influence on therapeutic outcomes and prognosis in lung adenocarcinoma (LUAD). However, the detailed molecular divisions involved in inflammatory responses are yet to be fully elucidated. Our study identified two main inflammation-oriented LUAD grades: the inflammation-low (INF-low) and the inflammation-high (INF-high) subtypes. Both presented with unique clinicopathological features, implications for prognosis, and distinctive tumor microenvironment profiles. Broadly, the INF-low grade, marked by its dominant immunosuppressive tumor microenvironment, was accompanied by less favorable prognostic outcomes and a heightened prevalence of oncogenic mutations. In contrast, the INF-high grade exhibited more optimistic clinical trajectories, underscored by its immune-active environment. In addition, our efforts led to the conceptualization and empirical validation of an inflammation-centric predictive model with considerable predictive potency. Our study paves the way for a refined inflammation-centric LUAD classification and fosters a deeper understanding of tumor microenvironment intricacies.

Three-Dimensional-Printed Template-Guided Radioactive Seed Brachytherapy via a Submental Approach for Recurrent Base of Tongue and Floor of Mouth Cancer.

Background: This study assessed clinical outcomes of three-dimensional-printed template (3DPT)-guided radioactive seed brachytherapy (RSBT) via a submental approach for recurrent base of tongue and floor of mouth cancer. Methods: Thirty-one patients with recurrent lingual and floor of mouth squamous cell carcinoma after surgery and radiotherapy were treated with 3DPT-guided RSBT from 2015 to 2022. Seeds were implanted through a submental approach guided by 3DPTs. Local control (LC), overall survival (OS), disease control (DC) and quality of life (QOL) were evaluated. Results: The median follow-up was 13.7 months. The 1-, 3- and 5-year LC rates were 66.1%, 66.1%, and 55.1% respectively. The 1-, 3- and 5-year OS rates were 63.4%, 33.4%, and 8.3%. The 1-, 3- and 5-year DC rates were 37.8%, 26.5%, and 21.2%. Univariate analysis showed tumor size significantly affected LC (P = 0.031). The presence of extraterritorial lesions affected DC and OS on multivariate analysis (P < 0.01). QOL improved significantly in domains of pain, swallowing, chewing, taste, and emotion after treatment compared to baseline. Four patients (13%) developed necrosis and osteoradionecrosis. Conclusions: 3DPT-guided submental RSBT provided favorable LC and QOL for recurrent tongue/floor of mouth cancer with minimal toxicity; moreover, severe toxicity should be noted.

Interfacial effects of perfluorooctanoic acid and its alternative hexafluoropropylene oxide dimer acid with polystyrene nanoplastics on oxidative stress, histopathology and gut microbiota in Crassostrea hongkongensis oysters.

The increasing interfacial impacts of polystyrene nanoplastics (PS) and per- and polyfluoroalkyl substances (PFAS) complex aquatic environments are becoming more evident, drawing attention to the potential risks to aquatic animal health and human seafood safety. This study aims to investigate the relative impacts following exposure (7 days) of Crassostrea hongkongensis oysters to the traditional PFAS congener, perfluorooctanoic acid (PFOA) at 50 µg/L, and its novel alternative, hexafluoropropylene oxide dimer acid (HFPO-DA), also known as GenX at 50 µg/L, in conjunction with fluorescent polystyrene nanoplastics (PS, 80 nm) at 1 mg/L. The research focuses on assessing the effects of combined exposure on oxidative stress responses and gut microbiota in the C. hongkongensis. Comparing the final results of PS + GenX (PG) and PS + PFOA (PF) groups, we observed bioaccumulation of PS in both groups, with the former causing more pronounced histopathological damage to the gills and intestines. Furthermore, the content of antioxidant enzymes induced by PG was higher than that of PF, including Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Reductase (GR) and Glutathione Peroxidase (GSH). Additionally, in both PG and PF groups, the expression levels of several immune-related genes were significantly upregulated, including tnfα, cat, stat, tlr-4, sod, and ß-gbp, with no significant difference between these two groups (p > 0.05). Combined exposure induced significant changes in the gut microbiota of C. hongkongensis at its genus level, with a significant increase in Legionella and a notable decrease in Endozoicomonas and Lactococcus caused by PG. These shifts led to beneficial bacteria declining and pathogenic microbes increasing. Consequently, the microbial community structure might be disrupted. In summary, our findings contribute to a deeper understanding of the comparative toxicities of marine bivalves under combined exposure of traditional and alternative PFAS.

Active Oxygenated Structure-Intensified CO2 Capture Enables Efficient Electrochemical Ethylene Production Over Carbon Nanofibers.

The pursuit of high efficacy C-C coupling during the electrochemical CO2 reduction reaction remains a tremendous challenge owing to the high energy barrier of CO2 activation and insufficient coverage of the desired intermediates on catalytic sites. Inspired by the concept of capture-coupled CO2 activation, we fabricated quinone-grafted carbon nanofibers via an in situ oxidative carbonylation strategy. The quinone functionality of carbon nanofibers promotes the capture of CO2 followed by activation. At a current density of 400 mA cm-2, the Faradaic efficiency of ethylene reached 62.9%, and a partial current density of 295 mA cm-2 was achieved on the quinone-rich carbon nanofibers. The results of in situ spectroscopy and theoretical calculations indicated that the remarkable selectivity enhancement in ethylene originates from the quinone structure, rather than the electronic properties of Cu particles. The interaction of quinone with CO2 increases the local *CO coverage and simultaneously hinders the co-adsorption of *H on Cu sites, which greatly reduces the energy barrier for C-C coupling and restrains subsequent *CO protonation. The modulation strategy involving specific oxygenated structure, as an independent degree of freedom, guides the design of functionalized carbon materials for tailoring the selectivity of desired products during the CO2 capture and reduction.

NIR-II light in clinical oncology: opportunities and challenges.

Novel strategies utilizing light in the second near-infrared region (NIR-II; 900-1,880 nm wavelengths) offer the potential to visualize and treat solid tumours with enhanced precision. Over the past few decades, numerous techniques leveraging NIR-II light have been developed with the aim of precisely eliminating tumours while maximally preserving organ function. During cancer surgery, NIR-II optical imaging enables the visualization of clinically occult lesions and surrounding vital structures with increased sensitivity and resolution, thereby enhancing surgical quality and improving patient prognosis. Furthermore, the use of NIR-II light promises to improve cancer phototherapy by enabling the selective delivery of increased therapeutic energy to tissues at greater depths. Initial clinical studies of NIR-II-based imaging and phototherapy have indicated impressive potential to decrease cancer recurrence, reduce complications and prolong survival. Despite the encouraging results achieved, clinical translation of innovative NIR-II techniques remains challenging and inefficient; multidisciplinary cooperation is necessary to bridge the gap between preclinical research and clinical practice, and thus accelerate the translation of technical advances into clinical benefits. In this Review, we summarize the available clinical data on NIR-II-based imaging and phototherapy, demonstrating the feasibility and utility of integrating these technologies into the treatment of cancer. We also introduce emerging NIR-II-based approaches with substantial potential to further enhance patient outcomes, while also highlighting the challenges associated with imminent clinical studies of these modalities.

Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS: To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS: Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS: This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.