Clinical study of chemotherapy-related cognitive impairment in patients with non-Hodgkin lymphoma.

BACKGROUND: Chemotherapy for malignant tumors can cause brain changes and cognitive impairment, leading to chemotherapy-induced cognitive impairment (CICI). Current research on CICI has focused on breast cancer and Hodgkin's lymphoma. Whether patients with non-Hodgkin's lymphoma (NHL) undergoing chemotherapy have cognitive impairment has not been fully investigated. AIM: To investigate whether NHL patients undergoing chemotherapy had cognitive impairments. METHODS: The study included 100 NHL patients who were required to complete a comprehensive psychological scale including the Brief Psychiatric Examination Scale (MMSE) at two time points: before chemotherapy and within 2 wk of two chemotherapy courses. A language proficiency test (VFT), Symbol Number Pattern Test (SDMT), Clock Drawing Test (CDT), Abbreviated Daily Cognition Scale (ECog-12), Prospective and Retrospective Memory Questionnaire, and Karnofsky Performance Status were used to assess cognitive changes before and after chemotherapy. RESULTS: The VFT scores for before treatment (BT) and after treatment (AT) groups were 45.20 ± 15.62, and 42.30 ± 17.53, respectively (t -2.16, P < 0.05). The CDT scores were 8 (3.5-9.25) for BT and 7 (2.5-9) for AT groups (Z -2.1, P < 0.05). Retrospective memory scores were 13.5 (9-17) for BT and 15 (13-18) for AT (Z -3.7, P < 0.01). The prospective memory scores were 12.63 ± 3.61 for BT and 14.43 ± 4.32 for AT groups (t -4.97, P < 0.01). The ECog-12 scores were 1.71 (1.25-2.08) for BT and 1.79 (1.42-2.08) for AT groups (Z -2.84, P < 0.01). The SDMT and MMSE values did not show a significant difference between BT and AT groups. CONCLUSION: Compared to the AT group, the BT group showed impaired language, memory, and subjective cognition, but objective cognition and execution were not significantly affected.

Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Pedicled flap versus skin graft for great toe defect repair after wrap-around flap transfer.

This study compared the clinical outcomes of tibial-sided digital artery pedicled flap from the second toe versus full-thickness skin grafting to repair great toe defects after wrap-around flap transfers. The pedicled flap resulted in better pain scores and aesthetic outcomes.

Antioxidant and anti-inflammatory function of Eupatorium adenophora Spreng leaves (EASL) on human intestinal Caco-2 cells treated with tert-butyl hydroperoxide.

Chronic non-communicable diseases (CNCDs) pose a significant public health challenge. Addressing this issue, there has been a notable breakthrough in the prevention and mitigation of NCDs through the use of antioxidants and anti-inflammatory agents. In this study, we aim to explore the effectiveness of Eupatorium adenophora Spreng leaves (EASL) as an antioxidant and anti-inflammatory agent, and its potential applications. To construct a cellular model of oxidative damage and inflammation, Caco-2 cells were treated with tert-butyl hydroperoxide (t-BHP). The biocompatibility of EASL-AE with Caco-2 cells was assessed using the MTT assay, while compatibility was further verified by measuring LDH release and the protective effect against oxidative damage was also assessed using the MTT assay. Additionally, we measured intracellular oxidative stress indicators such as ROS and 8-OHdG, as well as inflammatory pathway signalling protein NFκB and inflammatory factors TNF-α and IL-1ß using ELISA, to evaluate the antioxidant and anti-inflammatory capacity of EASL-AE. The scavenging capacity of EASL-AE against free radicals was determined through the DPPH Assay and ABTS Assay. Furthermore, we measured the total phenolic, total flavonoid, and total polysaccharide contents using common chemical methods. The chemical composition of EASL-AE was analyzed using the LC-MS/MS technique. Our findings demonstrate that EASL-AE is biocompatible with Caco-2 cells and non-toxic at experimental levels. Moreover, EASL-AE exhibits a significant protective effect on Caco-2 cells subjected to oxidative damage. The antioxidant effect of EASL-AE involves the scavenging of intracellular ROS, while its anti-inflammatory effect is achieved by down-regulation of the NFκB pathway. Which in turn reduces the release of inflammatory factors TNF-α and IL-1ß. Through LC-MS/MS analysis, we identified 222 compounds in EASL-AE, among which gentianic acid, procaine and L-tyrosine were the compounds with high antioxidant capacity and may be the effective constituent for EASL-AE with antioxidant activity. These results suggest that EASL-AE is a natural and high-quality antioxidant and anti-inflammatory biomaterial that warrants further investigation. It holds great potential for applications in healthcare and other related fields.

Small molecule conjugates with selective estrogen receptor ß agonism promote anti-aging benefits in metabolism and skin recovery.

Estrogen is imperative to mammalian reproductivity, metabolism, and aging. However, the hormone activating estrogen receptor (ERs) α can cause major safety concerns due to the enrichment of ERα in female tissues and certain malignancies. In contrast, ERß is more broadly expressed in metabolic tissues and the skin. Thus, it is desirable to generate selective ERß agonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERα activation. Here, we report the design and production of small molecule conjugates containing selective non-steroid ERß agonists Gtx878 or genistein. Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity, visceral adipose integrity, skeletal muscle function, and skin health, with validation in vitro. We further uncovered the benefits of ERß conjugates in the skin using two inducible skin injury mouse models, showing increased skin basal cell proliferation, epidermal thickness, and wound healing. Therefore, our ERß-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.

Intratumoral delivery of a Tim-3 antibody-encoding oncolytic adenovirus engages an effective antitumor immune response in liver cancer.

BACKGROUND AND PURPOSE: The use of oncolytic viruses as a gene therapy vector is an area of active biomedical research, particularly in the context of cancer treatment. However, the actual therapeutic success of this approach to tumor elimination remains limited. As such, the present study was developed with the goal of simultaneously enhancing the antitumor efficacy of oncolytic viruses and the local immune response by combining the Ad-GD55 oncolytic adenovirus and an antibody specific for the TIM-3 immune checkpoint molecule (α-TIM-3). APPROACH AND KEY RESULTS: The results of Virus and cell-mediated cytotoxicity assay, qPCR, and Western immunoblotting showed that Ad-GD55-α-Tim-3 oncolytic adenovirus is capable of inducing α-TIM-3 expression within hepatoma cells upon infection, and Ad-GD55-α-TIM-3 exhibited inhibitory efficacy superior to that of Ad-GD55 when used to treat these tumor cells together with the induction of enhanced intracellular immunity. In vivo experiments revealed that Ad-GD55-α-TIM-3 administration was sufficient to inhibit tumor growth and engage in a more robust local immune response within the simulated tumor immune microenvironment. CONCLUSION AND IMPLICATIONS: These results highlighted the promising therapeutic effects of Ad-GD55-α-TIM-3 oncolytic adenovirus against HCC in vitro and in vivo. As such, this Ad-GD55-α-TIM-3 oncolytic adenovirus may represent a viable approach to the treatment of hepatocellular carcinoma.

A glimpse of the connection between PPARγ and macrophage.

Nuclear receptors are ligand-regulated transcription factors that regulate vast cellular activities and serve as an important class of drug targets. Among them, peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family and have been extensively studied for their roles in metabolism, differentiation, development, and cancer, among others. Recently, there has been considerable interest in understanding and defining the function of PPARs and their agonists in regulating innate and adaptive immune responses and their pharmacological potential in combating chronic inflammatory diseases. In this review, we focus on emerging evidence for the potential role of PPARγ in macrophage biology, which is the prior innate immune executive in metabolic and tissue homeostasis. We also discuss the role of PPARγ as a regulator of macrophage function in inflammatory diseases. Lastly, we discuss the possible application of PPARγ antagonists in metabolic pathologies.

Correlation between the setting of gating window width and setup accuracy in left breast cancer radiotherapy based on deep inspiration breath hold.

Personalized precision irradiation of patients with left-sided breast cancer is possible by examining the setup errors of 3- and 4-mm gated window widths for those treated with deep inspiration breath-hold (DIBH) treatment. An observational study was performed via a retrospective analysis of 250 cone-beam computed tomography (CBCT) images of 60 left-breast cancer patients who underwent whole-breast radiotherapy with the DIBH technique between January 2021 and 2022 at our hospital. Among them, 30 patients had a gated window width of 3 mm, while the remaining 30 had a gated window width of 4 mm; both groups received radiotherapy using DIBH technology. All patients underwent CBCT scans once a week, and the setup errors in the left-right (x-axis), inferior-superior (y-axis), and anterior-posterior (z-axis) directions were recorded. The clinical-to-planning target volume (CTV-PTV) margins of the two gating windows were calculated using established methods. The setup error in the Y direction was 1.69 ± 1.33 mm for the 3-mm - wide gated window and 2.42 ± 3.02 mm for the 4-mm - wide gated window. The two groups had statistically significant differences in the overall mean setup error (Dif 0.7, 95% CI 0.15-1.31, t = 2.48, p= 0.014). The Z-direction setup error was 2.32 ± 2.12 mm for the 3-mm - wide gated window and 3.15 ± 3.34 mm for the 4-mm - wide gated window. The overall mean setup error was statistically significant between the two groups (Dif 0.8, 95% CI 0.13-1.53, t= 2.34, p = 0.020). There was no significant difference in the X-direction setup error (p > 0.05). Therefore, the CTV-PTV margin values for a 3-mm gated window width in the X, Y, and Z directions are 5.51, 5.15, and 7.28 mm, respectively; those for a 4-mm gated window width in the X, Y, and Z directions are 5.52, 8.16, and 10.21 mm, respectively. The setup errors of the 3-mm - wide gating window are smaller than those of the 4-mm - wide gating window in the three dimensions. Therefore, when the patient's respiratory gating window width is reduced, the margin values of CTV-PTV can be reduced to increase the distance between the PTV and the organs at risk (OARs), which ensures adequate space for the dose to decrease, resulting in lower dose exposure to the OARs (heart, lungs, etc.), thus sparing the OARs from further damage. However, some patients with poor pulmonary function or unstable breathing amplitudes must be treated with a slightly larger gating window. Therefore, this study lays a theoretical basis for personalized precision radiotherapy, which can save time and reduce manpower in the delivery of clinical treatment to a certain extent. Another potential benefit of this work is to bring awareness to the potential implications of a slightly larger gating window during treatment without considering the resulting dosimetric impact.

Functional and aesthetic recovery of the second toe defect using a wrap-around pedicled flap from the great toe.

We report the results of using a fibula-sided digital artery pedicled flap from the great toe to cover the second toe free flap donor site, which avoids delayed wound healing, and prevents pain and skin ulceration. This study included 15 patients who had second toe wrap-around free flaps to reconstruct thumb and finger defects. All 15 pedicled flaps used to cover the defect healed uneventfully. All patients were able to stand and walk and were satisfied with the postoperative aesthetic outcome at the 6-month follow-up. We conclude that this an effective procedure for preventing donor site defects after second toe wrap-around free flap transfer.Level of evidence: IV.

Establishment and validation of a nomogram based on coagulation parameters to predict the prognosis of pancreatic cancer.

BACKGROUND: In recent years, multiple coagulation and fibrinolysis (CF) indexes have been reported to be significantly related to the progression and prognosis of some cancers. OBJECTIVE: The purpose of this study was to comprehensively analyze the value of CF parameters in prognosis prediction of pancreatic cancer (PC). METHODS: The preoperative coagulation related data, clinicopathological information, and survival data of patients with pancreatic tumor were collected retrospectively. Mann Whitney U test, Kaplan-Meier analysis, and Cox proportional hazards regression model were applied to analyze the differences of coagulation indexes between benign and malignant tumors, as well as the roles of these indexes in PC prognosis prediction. RESULTS: Compared with benign tumors, the preoperative levels of some traditional coagulation and fibrinolysis (TCF) indexes (such as TT, Fibrinogen, APTT, and D-dimer) were abnormally increased or decreased in patients with pancreatic cancer, as well as Thromboelastography (TEG) parameters (such as R, K, α Angle, MA, and CI). Kaplan Meier survival analysis based on resectable PC patients showed that the overall survival (OS) of patients with elevated α angle, MA, CI, PT, D-dimer, or decreased PDW was markedly shorter than other patients; moreover, patients with lower CI or PT have longer disease-free survival. Further univariate and multivariate analysis revealed that PT, D-dimer, PDW, vascular invasion (VI), and tumor size (TS) were independent risk factors for poor prognosis of PC. According to the results of modeling group and validation group, the nomogram model based on independent risk factors could effectively predict the postoperative survival of PC patients. CONCLUSION: Many abnormal CF parameters were remarkably correlated with PC prognosis, including α Angle, MA, CI, PT, D-dimer, and PDW. Furthermore, only PT, D-dimer, and PDW were independent prognostic indicators for poor prognosis of PC, and the prognosis prediction model based on these indicators was an effective tool to predict the postoperative survival of PC.

Transforming Growth Factor-ß Blockade in Pancreatic Cancer Enhances Sensitivity to Combination Chemotherapy.

BACKGROUND & AIMS: Transforming growth factor-b (TGFb) plays pleiotropic roles in pancreatic cancer, including promoting metastasis, attenuating CD8 T-cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent TGFb inhibition has shown limited efficacy against pancreatic cancer in mice or humans. METHODS: We evaluated the TGFß-blocking antibody NIS793 in combination with gemcitabine/nanoparticle (albumin-bound)-paclitaxel or FOLFIRINOX (folinic acid [FOL], 5-fluorouracil [F], irinotecan [IRI] and oxaliplatin [OX]) in orthotopic pancreatic cancer models. Single-cell RNA sequencing and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment. RESULTS: Blockade of TGFß with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, because response to TGFß blockade was preserved in CD8-depleted or recombination activating gene 2 (RAG2-/-) mice. TGFß blockade decreased total α-smooth muscle actin-positive fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA sequencing on tumor cells sorted ex vivo revealed that tumor cells treated with TGFß blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that TGFß blockade increased chemotherapy-induced cell death in vivo. CONCLUSIONS: TGFß regulates pancreatic cancer cell plasticity between classical and basal cell states. TGFß blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with FOLFIRINOX or gemcitabine/nanoparticle (albumin-bound) paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.

Delayed surgery is associated with adverse outcomes in patients with hip fracture undergoing hip arthroplasty.

BACKGROUND: Hip arthroplasty (HA) is one of the most effective procedures for patients with hip fractures. The timing of surgery played a significant role in the short-term outcome for these patients, but conflicting evidence has been found. METHODS: The Nationwide Inpatient Sample database was investigated from 2002 to 2014 and identified 247,377 patients with hip fractures undergoing HA. The sample was stratified into ultra-early (0 day), early (1-2 days) and delayed (3-14 days) groups based on time to surgery. Yearly trends, postoperative surgical and medical complications, postoperative length of hospital stay (POS) and total costs were compared after propensity scores were matched between groups by demographics and comorbidity. RESULTS: From 2002 to 2014, the percentage of hip fracture patients who underwent HA increased from 30.61 to 31.98%. Early surgery groups showed fewer medical complications but higher surgical complications. However, specific complication evaluation showed both ultra-early and early groups decreased most of the surgery and medical complications with increasing post hemorrhagic anemia and fever. Medical complications were also reduced in the ultra-early group, but surgical complications increased. Early surgery groups reduced the POS by 0.90 to 1.05 days and total hospital charges by 32.6 to 44.9 percent than delayed surgery groups. Ultra-early surgery showed no benefit from POS than early group, but reduced total hospital charges by 12.2 percent. CONCLUSION: HA surgery performed within 2 days showed more beneficial effects on adverse events than delayed surgery. But surgeons should be cognizant of the potential increased risks of mechanical complications and post-hemorrhagic anemia.

In vitro flow cytometry assay to assess primary human and mouse macrophage phagocytosis of live cells.

Although tumor-associated macrophages are generally immunosuppressive, macrophages may also promote tumor clearance via phagocytosis of live tumor cells. Here, we present a protocol for assessing macrophage engulfment of tumor cells in vitro using flow cytometry. We describe steps for cell preparation, reseeding macrophages, and setting up phagocytosis. We then detail procedures for collecting samples, staining macrophages, and flow cytometry. The protocol is applicable to both mouse bone-marrow-derived macrophages and human monocyte-derived macrophages. For complete details on the use and execution of this protocol, please refer to Roehle et al. (2021).1.

cIAP1/2 Antagonism Induces Antigen-Specific T Cell-Dependent Immunity.

Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types in part due to inadequate T cell priming. Naive T cells can receive costimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-κB. Antagonists of the ubiquitin ligases cellular inhibitor of apoptosis protein (cIAP)1/2, also called second mitochondria-derived activator of caspases (SMAC) mimetics, induce degradation of cIAP1/2 proteins, allowing for the accumulation of NIK and constitutive, ligand-independent activation of alternate NF-κB signaling that mimics costimulation in T cells. In tumor cells, cIAP1/2 antagonists can increase TNF production and TNF-mediated apoptosis; however, pancreatic cancer cells are resistant to cytokine-mediated apoptosis, even in the presence of cIAP1/2 antagonism. Dendritic cell activation is enhanced by cIAP1/2 antagonism in vitro, and intratumoral dendritic cells show higher expression of MHC class II in tumors from cIAP1/2 antagonism-treated mice. In this study, we use in vivo mouse models of syngeneic pancreatic cancer that generate endogenous T cell responses ranging from moderate to poor. Across multiple models, cIAP1/2 antagonism has pleiotropic beneficial effects on antitumor immunity, including direct effects on tumor-specific T cells leading to overall increased activation, increased control of tumor growth in vivo, synergy with multiple immunotherapy modalities, and immunologic memory. In contrast to checkpoint blockade, cIAP1/2 antagonism does not increase intratumoral T cell frequencies. Furthermore, we confirm our previous findings that even poorly immunogenic tumors with a paucity of T cells can experience T cell-dependent antitumor immunity, and we provide transcriptional clues into how these rare T cells coordinate downstream immune responses.

Retinoic acid released from self-assembling peptide activates cardiomyocyte proliferation and enhances repair of infarcted myocardium.

The limited cardiomyocyte proliferation is insufficient for repair of the myocardium. Therefore, activating cardiomyocyte proliferation might be a reasonable option for myocardial regeneration. Here, we investigated effect of retinoic acid (RA) on inducing adult cardiomyocyte proliferation and assessed efficacy of self-assembling peptide (SAP)-released RA in activating regeneration of the infarcted myocardium. Effect of RA on inducing cardiomyocyte proliferation was examined with the isolated cardiomyocytes. Expression of the cell cycle-associated genes and paracrine factors in the infarcted myocardium was examined at one week after treatment with SAP-carried RA. Cardiomyocyte proliferation, myocardial regeneration and improvement of cardiac function were assessed at four weeks after treatment. In the adult rat myocardium, expression of RA synthetase gene Raldh2 and RA concentration were decreased significantly. After treatment with RA, the proliferated cardiomyocytes were increased. The formulated SAP could sustainedly release RA. After treatment with SAP-carried RA, expression of the pro-proliferative genes in cell cycle and paracrine factors in the infarcted myocardium were up-regulated. Myocardial regeneration was enhanced, and cardiac function was improved significantly. These results demonstrate that RA can induce adult cardiomyocytes to proliferate effectively. The sustained release of RA with SAP is a promise strategy to enhance repair of the infarcted myocardium.

[Treatment of acute unstable proximal clavicular fracture with hook plate of sternoclavicular joint].

OBJECTIVE: To investigate clinical effect of sternoclavicular hook plate in treating acute proximal clavicle fracture. METHODS: The clinical of 12 patients with acute unstable proximal clavicle fracture from June 2016 to June 2019 were retrospectively analyzed. There were 8 males and 4 females, aged from 46 to 63 years old. Ten patients caused by car accident and 2 patients caused by high falling. All patients had multiple injuries;the time from injury to surgery ranged from 2 to 14 d. All patients were treated with domestic sternoclavicular joint hook plate. The operative time ranged from 40 to 115 min. The intraoperative bleeding volume ranged from 30 to 110 ml, follow-up time ranged from 10 to 36 months, the fracture healing time ranged from 8 to 18 weeks. At the latest follow-up, the efficacy was evaluated by using shoulder joint function score (Rockwood score). RESULTS: All 12 patients were followed up, with no obvious pain at the latest follow-up. The rockwood scores of the affected shoulder ranged from 13 to 14, and the healthy shoulder ranged from 14 to 15. CONCLUSION: The sternocleidoclavicular joint plate is fixed with preformed plate. The cantilever is designed to retain the motion of the sternoclavicular joint. It's safe and simple, avoid, the injury of important organs during operation, and has a good prognosis. It is an ideal fixation method for the treatment of proximal clavicle fracture.

Human differentiated eosinophils release IL-13 in response to IL-33 stimulation.

Objective: Eosinophils are hallmarks in allergic type 2 inflammation and are known to release cytotoxic granule proteins that contribute to inflammation. Eosinophils develop in the bone marrow from hematopoietic stem cells and once mature, have a limited lifespan in culture, making them difficult to study ex vivo. IL-33 has increasingly been shown as a key regulator of type 2 inflammation via signaling through its receptor, ST2. The present study was conducted to detail a method of eosinophil differentiation from hematopoietic stem cells and determine the response to IL-33. Methods: CD34+ and CD14+ cells were isolated from donor apheresis cones and differentiated into eosinophils or macrophage controls, respectively. Morphologic, transcriptional and protein analyses were performed to validate this method of eosinophil differentiation. The effect of IL-33 on differentiated eosinophils was assessed using qPCR, immunofluorescence, and multiplex cytokine array. Results: CD34 differentiated eosinophils appear morphologically similar by H&E and express eosinophil peroxidase (EPX) protein as well as the conventional eosinophil transcripts EPX, CLC, and MBP. In addition, differentiated eosinophils expressed both isoforms of the IL-33 receptor, ST2L and sST2 throughout the differentiation process. Transcript levels of both IL-33 receptors were up-regulated by treatment with IL-33 at earlier timepoints in the differentiation. These cells also expressed IL-4 and IL-13 mRNA which were up-regulated by IL-33 as well. Notably, IL-13 expression was significantly higher with IL-33 treatment compared to media control at every timepoint measured. IL-33 significantly increased cellular secretion of IL-13 protein at most timepoints throughout differentiation. IL-8, LIF, CCL1, CCL5, CCL7, and CCL8 were also significantly secreted after IL-33 stimulation. Conclusions: Our findings suggest that CD34 differentiated eosinophils are morphologically and phenotypically similar to peripheral eosinophils. The release of specific cytokines in direct response to IL-33 may contribute to the pathogenesis of type 2 inflammation and facilitates new avenues for studying eosinophils as effector cells in vitro.

Contribution of Trp63CreERT2-labeled cells to alveolar regeneration is independent of tuft cells.

Viral infection often causes severe damage to the lungs, leading to the appearance of ectopic basal cells (EBCs) and tuft cells in the lung parenchyma. Thus far, the roles of these ectopic epithelial cells in alveolar regeneration remain controversial. Here, we confirm that the ectopic tuft cells are originated from EBCs in mouse models and COVID-19 lungs. The differentiation of tuft cells from EBCs is promoted by Wnt inhibition while suppressed by Notch inhibition. Although progenitor functions have been suggested in other organs, pulmonary tuft cells don't proliferate or give rise to other cell lineages. Consistent with previous reports, Trp63CreERT2 and KRT5-CreERT2-labeled ectopic EBCs do not exhibit alveolar regeneration potential. Intriguingly, when tamoxifen was administrated post-viral infection, Trp63CreERT2 but not KRT5-CreERT2 labels islands of alveolar epithelial cells that are negative for EBC biomarkers. Furthermore, germline deletion of Trpm5 significantly increases the contribution of Trp63CreERT2-labeled cells to the alveolar epithelium. Although Trpm5 is known to regulate tuft cell development, complete ablation of tuft cell production fails to improve alveolar regeneration in Pou2f3-/- mice, implying that Trpm5 promotes alveolar epithelial regeneration through a mechanism independent of tuft cells.

Complex Evaluation of Surfactant Protein A and D as Biomarkers for the Severity of COPD.

Purpose: Pulmonary surfactant proteins A (SP-A) and D (SP-D) are lectins, involved in host defense and regulation of pulmonary inflammatory response. However, studies on the assessment of COPD progress are limited. Patients and Methods: Pulmonary surfactant proteins were obtained from the COPD mouse model induced by cigarette and lipopolysaccharide, and the specimens of peripheral blood and bronchoalveolar lavage (BALF) in COPD populations. H&E staining and RT-PCR were performed to demonstrate the successfully established of the mouse model. The expression of SP-A and SP-D in mice was detected by Western Blot and immunohistochemistry, while the proteins in human samples were measured by ELISA. Pulmonary function test, inflammatory factors (CRP, WBC, NLR, PCT, EOS, PLT), dyspnea index score (mMRC and CAT), length of hospital stay, incidence of complications and ventilator use were collected to assess airway remodeling and progression of COPD. Results: COPD model mice with emphysema and airway wall thickening were more prone to have decreased SP-A, SP-D and increased TNF-α, TGF-ß, and NF-kb in lung tissue. In humans, SP-A and SP-D decreased in BALF, but increased in serum. The serum SP-A and SP-D were negatively correlated with FVC, FEV1, FEV1/FVC, and positively correlated with CRP, WBC, NLR, mMRC and CAT scores (P < 0.05, respectively). The lower the SP-A and SP-D in BALF, the worse the lung function and the increased probability of complications and ventilator use. Moreover, the same trend emerged in COPD patients grouped according to GOLD severity grade (Gold 1-2 group vs Gold 3-4 group). The worse the patient's condition, the more pronounced the change. Conclusion: This study suggests that SP-A and SP-D may be related to the progression and prognostic evaluation of COPD in terms of airway remodeling, inflammatory response and clinical symptoms, and emphasizes the necessity of future studies of surfactant protein markers in COPD.