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Abstract Objective With advancements in respiratory interventional techniques, bronchoscopic intervention technology has emerged as a viable approach for managing postintubation tracheal stenosis (PITS). However, there was a paucity of research investigating the potential impact of stenosis characteristics and morphology (such as stenosis degree, length, type, and morphology) on bronchoscopic intervention treatment prognosis for PITS patients. This study was to assess the impact of various preoperative stenosis characteristic factors on the bronchoscopic cure rate among patients. Methods This is a retrospective study analyzing the medical records of patients with PITS who received bronchoscopic intervention at the tertiary interventional pulmonology center. Results Among the cases, 115 individuals achieved a in a success rate of 79.86% for bronchoscopic intervention therapy and were assigned to Group S. On the other hand, 29 cases required surgical intervention, accounting for a surgical treatment rate of 20.14% and were assigned to Group F. The stenosis in the Group F predominantly exhibited irregular shapes with scar granulation accompanied by tracheal chondromalacia collapse. Patients in group S experienced fewer total procedures, rigid bronchoscopy treatment, intraoperative hypoxemia, needed emergency re‐bronchoscopy in 24 h and transferred to ICU postoperatively. Patients with pure scar and granuloma, the rate of bronchoscopic success cure was higher than patients with scar granulation accompanied by tracheal chondromalacia (odds ratio: 8.208; 95% confidence interval: 2.755–24.459), and regular stenosis morphology was associated with a higher bronchoscopic success cure rate (odds ratio: 9.463; 95% confidence interval: 3.128–28.623). Conclusion Irregular airway stenosis, chondromalacia or airway collapse are key factors affecting the success rate of bronchoscopic treatment for post‐intubation tracheal stenosis. Level of evidence: 4 (historically controlled studies).

Abstract Purpose Hypoxia is one of the most frequent adverse events under deep sedation in the semiprone position. We hypothesized that supraglottic jet oxygenation and ventilation (SJOV) via Wei nasal jet tube (WNJ) can reduce the incidence of hypoxia in patients under deep sedation during endoscopic retrograde cholangiopancreatography (ERCP). Methods A total of 171 patients were divided into three groups: N group, supplementary oxygen via a nasopharyngeal airway (4–6 L/min); W group, supplementary oxygen via WNJ (4–6 L/min); WS group, SJOV via WNJ. The primary outcome was the incidence of adverse events, including sedation-related adverse events [SRAEs, hypoxemia (SpO2 = 75–89% lasted less than 60 s); severe hypoxemia (SpO2

Abstract Supraglottic jet oxygenation/ventilation (SJOV) can reduce hypoxemia in sedated endoscopy but may increase minor side effects like pharyngalgia and xerostomia. This study aimed to identify risk factors for pharyngalgia/xerostomia with SJOV during gastrointestinal endoscopy. From January 1 to December 31, 2021, 5313 patients with propofol sedation and SJOV underwent gastrointestinal endoscopy or removal of gastrointestinal polyps was analyzed retrospectively. Data included patient characteristics, operation details, postoperative adverse events, and potential risk factors for postoperative adverse events. Parameters considered as potential risk factors were identified based on study results published previously and based on the researcher’s idea and clinical experience. The patient factors and the incidence of pharyngalgia/xerostomia at 30 min post-procedure were assessed. Descriptive statistics were calculated using SPSS software. Evaluation potential risk factors using univariate and multivariate logistic regression. Pharyngalgia/xerostomia occurred in 18.7% of patients at 30 min after procedure. A multivariable analysis showed that procedure time and pharyngalgia/xerostomia within 2 weeks were independent risk factors. Procedure time had the strongest association with postoperative pharyngalgia/xerostomia (OR, 8.09 [95% CI, 4.197–6.312]). No factors were significantly associated with hypoxemia risk (1.7% incidence). There were no barotrauma or other serious morbidity or mortality. Procedure duration and recent pharyngalgia/xerostomia increased risk of pharyngalgia/xerostomia with SJOV during endoscopy. Limiting SJOV duration may reduce side effects in susceptible patients. No predictors of hypoxemia were identified.

Abstract Background The current concept of bronchoscopy-associated massive airway hemorrhage is not accurate enough, and the amount of bleeding as the only evaluation criterion cannot comprehensively evaluate magnitude of the effects and the severity. Objective To propose the concept of bronchoscopy-associated acute massive airway hemorrhage, analyze its impact on patients and highlight the treatment approach of acute massive airway hemorrhage without ECMO support. Designs A retrospective cohort study. Setting Include all patients who received bronchoscopy intervention therapy at Interventional Pulmonology Center of Emergency General Hospital from 2004 to December 2021. Patients 223 patients met the inclusion criteria. Intervention Patients were divided into two groups: acute massive airway hemorrhage group (n = 29) and non-acute massive airway hemorrhage group (n = 194). Main outcome measures Perioperative adverse events between two groups were the main outcome. Secondary outcome was the impact of lung isolation on patient in group Acute. Results The incidence of acute massive airway hemorrhage was 0.11%, and the incidence of non-acute massive airway hemorrhage was 0.76% in this study. There were significant differences in the incidence of intraoperative hypoxemia, lowest SpO2, hemorrhagic shock, cardiopulmonary resuscitation, intraoperative mortality, and transfer to ICU between acute group and non-acute group (P

Pin-fin and flat-tube heat exchangers (PFFTHXs) offer a promising alternative to traditional louvered-fin and flat-tube heat exchangers (LFFTHXs), especially when used as evaporators. The streamlined structure of pin fins helps to effectively remove condensate and defrost water. In this study, we conducted a numerical analysis of 60 different pin-fin configurations across three pin diameters to enhance heat transfer in PFFTHXs. Our investigation focused on how pin pitch affects both airflow and heat transfer efficiency. The results show that a closer pin pitch increases both the heat transfer rate per unit area and the pressure drop for a given airflow velocity. We evaluated the overall performance of these configurations using the heat transfer rate per unit frontal area obtained at equivalent fan power levels. The analysis identified optimal configurations for each pin diameter, with the 0.2 mm diameter configuration demonstrating the highest heat transfer efficiency—this was on par with louvered fins but used fewer resources. This makes it an ideal choice for evaporative applications in PFFTHXs.

Claudin 18.2 (CLDN18.2)-targeting chimeric antigen receptor (CAR)-modified T cells are one of the few cell therapies currently producing an impressive therapeutic effect in treating solid tumors; however, their long-term therapeutic efficacy is not satisfactory with a short duration of response. Transgenic expression of interleukin (IL)-15 has been reported to promote T-cell expansion, survival, and function and enhance the antitumor activity of engineered T cells in vitro and in vivo. Therefore, this study aimed to explore whether IL-15 modification would increase the antitumor activity of CLDN18.2-targeting CAR-modified T (CAR-T) cells in immunocompetent murine tumor models. CLDN18.2-specific CAR-T cells with (H9 CAR-IL15) or without transgenic IL-15 expression (H9 CAR) were generated by retroviral transduction of mouse splenic T cells. In vitro, compared with H9 CAR T cells, H9 CAR-IL15 T cells exhibited better expansion and viability in the absence of antigen stimulation, with a less differentiated and T-cell exhausted phenotype; although IL-15 modification did not affect the production of effector cytokines and cytotoxic activity in the short-term killing assay, it moderately improved the in vitro recursive killing activity of CAR-T cells against CLDN18.2-expressing tumor cells. In vivo, H9 CAR T cells showed no antitumor activity against CLDN18.2-expressing pancreatic tumors in immunocompetent mice without lymphodepleting pretreatment; however, H9 CAR-IL15 T cells produced significant tumor-suppressive effects. Furthermore, H9 CAR-IL15 T cells exhibited greater in vivo expansion and tumor infiltration when combined with lymphodepleting preconditioning, resulting in superior antitumor activity in two murine tumor models and a survival advantage in one tumor model. We further demonstrated that recurrent tumors following H9 CAR-IL15 T-cell therapy downregulated CLDN18.2 expression, suggesting immune escape through the selection of antigen-negative cells under persistent CAR-T-cell immune pressure. In conclusion, our findings provide preclinical evidence supporting the clinical evaluation of IL-15-expressing CLDN18.2 CAR-T cells in patients with CLDN18.2-positive tumors.

Abstract Background Some retrospective and in vitro studies suggest that general anesthetics influence breast cancer recurrence and metastasis. We compared the effects of general anesthetics sevoflurane versus propofol on breast cancer cell survival, proliferation and invasion in vitro. The investigation focused on effects in intracellular Ca2+ homeostasis as a mechanism for general anesthetic-mediated effects on breast cancer cell survival and metastasis. Methods Estrogen receptor-positive (MCF7) and estrogen receptor-negative (MDA-MB-436) human breast cancer cell lines along with normal breast tissue (MCF10A) were used. Cells were exposed to sevoflurane or propofol at clinically relevant and extreme doses and durations for dose- and time-dependence studies. Cell survival, proliferation and migration following anesthetic exposure were assessed. Intracellular and extracellular Ca2+ concentrations were modulated using Ca2+ chelation and a TRPV1 Ca2+ channel antagonist to examine the role of Ca2+ in mediating anesthetic effects. Results Sevoflurane affected breast cancer cell survival in dose-, time- and cell type-dependent manners. Sevoflurane, but not propofol, at equipotent and clinically relevant doses (2% vs. 2 μM) for 6 h significantly promoted breast cell survival in all three types of cells. Paradoxically, extreme exposure to sevoflurane (4%, 24 h) decreased survival in all three cell lines. Chelation of cytosolic Ca2+ dramatically decreased cell survival in both breast cancer lines but not control cells. Inhibition of TRPV1 receptors significantly reduced cell survival in all cell types, an effect that was partially reversed by equipotent sevoflurane but not propofol. Six-hour exposure to sevoflurane or propofol did not affect cell proliferation, metastasis or TRPV1 protein expression in any type of cell. Conclusion Sevoflurane, but not propofol, at clinically relevant concentrations and durations, increased survival of breast cancer cells in vitro but had no effect on cell proliferation, migration or TRPV1 expression. Breast cancer cells require higher cytoplasmic Ca2+ levels for survival than normal breast tissue. Sevoflurane affects breast cancer cell survival via modulation of intracellular Ca2+ homeostasis.

In spite of impressive success in treating hematologic malignancies, adoptive therapy with chimeric antigen receptor modified T cells (CAR T) has not yet been effective in solid tumors, where identification of suitable tumor-specific antigens remains a major obstacle for CAR T-cell therapy due to the “on target off tumor” toxicity. Protein tyrosine kinase 7 (PTK7) is a member of the Wnt-related pseudokinases and identified as a highly expressed antigen enriched in cancer stem cells (CSCs) from multiple solid tumors, including but not limited to triple-negative breast cancer, non-small-cell lung cancer, and ovarian cancer, suggesting it may serve as a promising tumor-specific target for CAR T-cell therapy. In this study, we constructed three different PTK7-specific CAR (PTK7-CAR1/2/3), each comprising a humanized PTK7-specific single-chain variable fragment (scFv), hinge and transmembrane (TM) regions of the human CD8α molecule, 4-1BB intracellular co-stimulatory domain (BB-ICD), and CD3ζ intracellular domain (CD3ζ-ICD) sequence, and then prepared the CAR T cells by lentivirus-mediated transduction of human activated T cells accordingly, and we sequentially evaluated their antigen-specific recognition and killing activity in vitro and in vivo. T cells transduced with all three PTK7-CAR candidates exhibited antigen-specific cytokine production and potent cytotoxicity against naturally expressing PTK7-positive tumor cells of multiple cancer types without mediating cytotoxicity of a panel of normal primary human cells; meanwhile, in vitro recursive cytotoxicity assays demonstrated that only PTK7-CAR2 modified T cells retained effective through multiple rounds of tumor challenge. Using in vivo xenograft models of lung cancers with different expression levels of PTK7, systemic delivery of PTK7-CAR2 modified T cells significantly prevented tumor growth and prolonged overall survival of mice. Altogether, our results support PTK7 as a therapeutic target suitable for CAR T-cell therapy that could be applied for lung cancers and many other solid cancers with PTK7 overexpression.

Abstract Background Supraglottic jet oxygenation and ventilation (SJOV) can effectively maintain adequate oxygenation in patients with respiratory depression, even in apnea patients. However, there have been no randomized controlled clinical trials of SJOV in obese patients. This study investigated the efficacy and safety of SJOV using WEI Nasal Jet tube (WNJ) for obese patients who underwent hysteroscopy under intravenous anesthesia without endotracheal intubation. Methods A single-center, prospective, randomized controlled study was conducted. The obese patients receiving hysteroscopy under intravenous anesthesia were randomly divided into three groups: Control group maintaining oxygen supply via face masks (100% oxygen, flow at 6 L/min), the WNJ Oxygen Group with WNJ (100% oxygen, flow: 6 L/min) and the WNJ SJOV Group with SJOV via WNJ [Jet ventilator working parameters:100% oxygen supply, driving pressure (DP) 0.1 MPa, respiratory rate; (RR): 15 bpm, I/E; ratio 1:1.5]. SpO2, PETCO2, BP, HR, ECG and BIS were continuously monitored during anesthesia. Two-Diameter Method was deployed to measure cross sectional area of the gastric antrum (CSA-GA) by ultrasound before and after SJOV in the WNJ SJOV Group. Episodes of SpO2 less than 95%, PETCO2 less than 10 mmHg, depth of WNJ placement and measured CSA-GA before and after jet ventilation in the WNJ SJOV Group during the operation were recorded. The other adverse events were collected as well. Results A total of 102 patients were enrolled, with two patients excluded. Demographic characteristics were similar among the three groups. Compared with the Control Group, the incidence of PETCO2

Abstract Background Hypoxia is a major concern and cause of morbidity or mortality during tracheal intubation after anesthesia induction in a pathological obese patient with obstructive sleep apnea (OSA). We introduce a case using Supraglottic jet oxygenation and ventilation (SJOV) to promote oxygenation/ventilation during fiberoptic intubation in a paralyzed patient with morbid obesity and OSA. Case presentation A 46-year-old man weighting 176 kg with BMI 53.7 kg/m2 was scheduled for gastric volume reduction surgery to reduce body weight under general anesthesia. SpO2 decreased during induction, and two hand pressured mask ventilation partial failed. We then placed WEI Nasal Jet Tube (WNJ) in the patient’s right nostril to provide SJOV. Then fiberoptic bronchoscopy guided endotracheal intubation was performed via mouth approach, and vital signs were stable. The operation was successfully completed after 3 h. Patient recovered smoothly in hospital for 8 days and did not have any recall inside the operating room. Conclusion SJOV via WNJ could effectively maintain adequate oxygenation/ventilation during long time fiberoptic intubation in an apnea patient with morbid obesity and OSA after partial failure of two hand pressured mask ventilation, without obvious complications. This may provide a new effective approach for difficult airway management in these patients.

Antibodies against checkpoint inhibitors such as anti-programmed cell death protein 1 (PD-1) and its ligand anti-programmed death ligand 1 (PD-L1) have shown clinical efficacy in the treatment of multiple cancers. However, there are only a few studies on biomarkers for these targeted immunotherapies, especially in peripheral blood. We first studied the role of interferon-induced protein-10 (IP10) combined with interleukin-8 (IL-8) in peripheral blood as a biomarker of immune-combined chemotherapy for lung cancer and multiple cancers. We used the high-throughput cytokine detection platform and performed bioinformatics analysis of blood samples from 67 patients with lung cancer and 24 with multiple cancers. We selected the ratio of IP-10 to IL-8 (S2/S0, ratio of changes at 10–12 weeks after treatment to baseline) to predict the response to immunotherapy combined with chemotherapy and evaluate the survival of lung cancer patients and mixed cancer patients. In patients treated with the combination therapy, the specificity and sensitivity of IL-8 and IP10 together as predictors were improved compared with those of IL-8 and IP10 alone. Our conclusion was verified in not only lung cancer but also multiple cancer research cohorts. We then further validated the predictive effect of biomarkers in different histologic types of NSCLC and chemotherapy combined with different PD-1 drug groups. Subsequent validation should be conducted with a larger number of patients. The proposed marker IP10 (S2/S0)/IL-8 (S2/S0), as a predictive immunotherapy biomarker, has broad prospects for future clinical applications in treating patients with multiple intractable neoplasms.

Dantrolene has been demonstrated to be neuroprotective for multiple neurodegenerative diseases. However, dantrolene's limited penetration into the CNS hampers its effectiveness as a neuroprotective agent. Here, we studied whether the intranasal administration of dantrolene provided better penetration into the brain than the commonly used oral approach. C57BL/6 mice, aged 2-4 months, received a single dose of either intranasal or oral dantrolene (5mg/kg). Inhibition of dantrolene clearance from the brain was examined by co-administration with P-gp/BCRP inhibitors, nimodipine or elacridar. The concentration of dantrolene in the brain and plasma was measured at 10, 20, 30, 50, 70, 120, 150 and 180 minutes after administration. Separate cohorts of mice were given intranasal dantrolene (5mg/kg) or vehicle, 3 times/ week, for either 3 weeks or 4 months, to examine potential adverse side effects on olfaction and motor coordination, respectively. We found that Dantrolene concentrations were sustained in the brain after intranasal administration for 180 min, while concentrations fell to zero at 120 min for oral administration. Chronic use of intranasal dantrolene did not impair olfaction or motor function in these mice. Blood brain barrier pump inhibitors did not further increase dantrolene peak concentrations in the brain. Our results suggested that Intranasal administration of dantrolene is an effective route to increase its concentration and duration in the brain compared to the oral approach, without any obvious side effects on olfaction or motor function.

This manuscript reports a case of foreign body removal surgery and anaesthesia of an elderly patient with a challenging airway and fragile cardiopulmonary function. WEI Nasal Jet Tube (WNJ) was used to sustain sufficient oxygenation without interfering with the gastroscopy operation. Because the device could be well tolerated by the patient, it was beneficial to maintain circulation stability as well. This case was a considerable anaesthetic challenge, as the anaesthesia depth for the patient was difficult to manage.

Many in vivo studies suggest that inhalational anesthetics can accelerate or prevent the progression of neuropathology and cognitive impairments in Alzheimer Disease (AD), but the synaptic mechanisms mediating these ambiguous effects are unclear. Here, we show that repeated exposures of neonatal and old triple transgenic AD (3xTg) and non-transgenic (NonTg) mice to isoflurane (Iso) distinctly increased neurodegeneration as measured by S100β levels, intracellular Aβ, Tau oligomerization, and apoptotic markers. Spatial cognition measured by reference and working memory testing in the Morris Water Maze (MWM) were altered in young NonTg and 3xTg. Field recordings in the cornu ammonis 1 (CA1) hippocampus showed that neonatal control 3xTg mice exhibited hypo-excitable synaptic transmission, reduced paired-pulse facilitation (PPF), and normal long-term potentiation (LTP) compared to NonTg controls. By contrast, the old control 3xTg mice exhibited hyper-excitable synaptic transmission, enhanced PPF, and unstable LTP compared to NonTg controls. Repeated Iso exposures reduced synaptic transmission and PPF in neonatal NonTg and old 3xTg mice. LTP was normalized in old 3xTg mice, but reduced in neonates. By contrast, LTP was reduced in old but not neonatal NonTg mice. Our results indicate that Iso-mediated neuropathologic and cognitive defects in AD mice are associated with synaptic pathologies in an age-dependent manner. Based on these findings, the extent of this association with age and, possibly, treatment paradigms warrant further study.

Obesity is a major risk factor for many chronic diseases, including diabetes, fatty livers, and cancer. Expansion of the adipose mass has been shown to be related to adipogenic differentiation of adipose-derived mesenchymal stem cells (ASCs). However, the underlying mechanism of this effect has yet to be elucidated. We found that osteopontin (OPN) is downregulated in ASCs and adipose tissues of obese mice and overweight human beings because of methylation on its promoter, indicating that OPN may affect the development of obesity. Silencing of OPN in wild-type ASCs promotes adipogenic differentiation, while reexpression of OPN reduced adipogenic differentiation in OPN−/− ASCs. The role of extracellular OPN in ASC differentiation was further demonstrated by supplementation and neutralization of OPN. Additionally, OPN suppresses adipogenic differentiation in ASCs through the C/EBP pathways. Consistent with these in vitro results, by intravenous injection of OPN-expressing adenovirus to the mice, we found OPN can delay the development of obesity and improve insulin sensitivity. Therefore, our study demonstrates an important role of OPN in regulating the development of obesity, indicating OPN might be a novel target to attenuate obesity and its complications.

BACKGROUND:While previous studies have demonstrated neuronal apoptosis and associated cognitive impairment after isoflurane or propofol exposure in neonatal rodents, the effects of these two anesthetics have not been directly compared. Here, we compare and contrast the effectiveness of isoflurane and propofol to cause neurodegeneration in the developing brain and associated cognitive dysfunction. METHODS:Seven-day-old mice were used. Mice in the isoflurane treatment group received 6 h of 1.5% isoflurane, while mice in propofol treatment group received one peritoneal injection (150 mg/kg), which produced persistent anesthesia with loss of righting for at least 6 h. Mice in control groups received carrying gas or a peritoneal injection of vehicle (intralipid). At 6 h after anesthetic treatment, a subset of each group was sacrificed and examined for evidence of neurodegeneration, using plasma levels of S100β, and apoptosis using caspase-3 immunohistochemistry in the cerebral cortex and hippocampus and Western blot assays of the cortex. In addition, biomarkers for inflammation (interleukin-1, interleukin-6, and tumor necrosis factor alpha) were examined with Western blot analyses of the cortex. In another subset of mice, learning and memory were assessed 32 days after the anesthetic exposures using the Morris water maze. RESULTS:Isoflurane significantly increased plasma S100β levels compared to controls and propofol. Both isoflurane and propofol significantly increased caspase-3 levels in the cortex and hippocampus, though isoflurane was significantly more potent than propofol. However, there were no significant differences in the inflammatory biomarkers in the cortex or in subsequent learning and memory between the experimental groups. CONCLUSION:Both isoflurane and propofol caused significant apoptosis in the mouse developing brain, with isoflurane being more potent. Isoflurane significantly increased levels of the plasma neurodegenerative biomarker, S100β. However, these neurodegenerative effects of isoflurane and propofol in the developing brain were not associated with effects on inflammation or with cognitive dysfunction in later life.

There is an urgent need for improved therapy for advanced ovarian carcinoma, which may be met by administering immune-modulatory monoclonal antibodies (mAbs) to generate a tumor-destructive immune response. Using the ID8 mouse ovarian cancer model, we investigated the therapeutic efficacy of various mAb combinations in mice with intraperitoneal (i.p.) tumor established by transplanting 3 × 10(6) ID8 cells 10 days previously. While most of the tested mAbs were ineffective when given individually or together, the data confirm our previous finding that 2 i.p. injections of a combination of anti-CD137 with anti-PD-1 mAbs doubles overall survival. Mice treated with this mAb combination have a significantly increased frequency and total number of CD8(+) T cells both in the peritoneal lavage and spleens, and these cells are functional as demonstrated by antigen-specific cytolytic activity and IFN-γ production. While administration of anti-CD137 mAb as a single agent similarly increases CD8(+) T cells, these have no functional activity, which may be attributed to up-regulation of co-inhibitory PD-1 and TIM-3 molecules induced by CD137. Addition of the anti-cancer drug cisplatin to the 2 mAb combination increased overall survival >90 days (and was probably curative) by a mechanism which included a systemic CD8(+) T cell response with tumor specificity and immunological memory. Strikingly, combined treatment of cisplatin and CD137/PD-1 mAb also gave rise to the long-term survival of mice with established TC1 lung tumors. A similar combination of the 2 mAbs and cisplatin should be considered for clinical 'translation'.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T cell immunity in tumor-bearing hosts. In patients with colon cancer, MDSCs have recently been described as Lin(-/low)HLA-DR(-)CD11b(+)CD33(+) cells correlating with cancer stage, metastasis and chemotherapy response. To learn in more detail the dynamic change and clinical relevance of circulating and tumor-infiltrating Lin(-/low)HLA-DR(-)CD11b(+)CD33(+) MDSC in colorectal cancer, we harvested the blood from 64 patients with varying stage of colorectal cancer and tumor and matched paraneoplastic tissues from 5 patients with advanced colorectal cancer, subjected them to multicolor flow cytometric analysis of percentage, absolute number and phenotype of MDSC and finally characterized their immunosuppressive functions. Our results demonstrate that peripheral blood from colorectal cancer patients contains markedly increased percentage and absolute number of Lin(-/low)HLA-DR(-)CD11b(+)CD33(+) MDSCs compared with healthy individuals, and this increase is closely correlated with clinical cancer stage and tumor metastasis but not primary tumor size and serum concentrations of cancer biomarker. A similar increase of MDSCs was also observed in the tumor tissues. Phenotyping MDSCs shows that they express high CD13 and CD39, low CD115, CD117, CD124 and PD-L1, and devoid of CD14, CD15 and CD66b, reminiscent of precursor myeloid cells. MDSCs from cancer patients but not healthy donors have the immunosuppressive activity and were able to inhibit in vitro autologous T-cell proliferation. Collectively, this study substantiates the presence of increased immunosuppressive circulating and tumor-resident Lin(-/low)HLA-DR(-)CD11b(+)CD33(+) MDSCs in patients with colorectal cancers correlating with cancer stage and metastasis, and suggests that pharmacologic blockade of MDSCs should be considered in future clinical trials.

Carbon monoxide (CO) exposure at high concentrations results in overt neurotoxicity. Exposure to low CO concentrations occurs commonly yet is usually sub-clinical. Infants are uniquely vulnerable to a variety of toxins, however, the effects of postnatal sub-clinical CO exposure on the developing brain are unknown. Apoptosis occurs normally within the brain during development and is critical for synaptogenesis. Here we demonstrate that brief, postnatal sub-clinical CO exposure inhibits developmental neuroapoptosis resulting in impaired learning, memory, and social behavior. Three hour exposure to 5 ppm or 100 ppm CO impaired cytochrome c release, caspase-3 activation, and apoptosis in neocortex and hippocampus of 10 day old CD-1 mice. CO increased NeuN protein, neuronal numbers, and resulted in megalencephaly. CO-exposed mice demonstrated impaired memory and learning and reduced socialization following exposure. Thus, CO-mediated inhibition of neuroapoptosis might represent an important etiology of acquired neurocognitive impairment and behavioral disorders in children.