Increased circulating LOX-1+ neutrophils activate T cells and demonstrate a pro-inflammatory role in allergic rhinitis.

Background: Low-density neutrophils are heterogeneous immune cells with immunosuppressive (such as polymorphonuclear myeloid-derived suppressor cells [PMN-MDSC]) or pro-inflammatory (such as low-density granulocytes [LDG]) properties that have been well described in multiple cancers and immune diseases. However, its role in allergic rhinitis (AR) is still unclear. Methods: In the present study, we defined low-density neutrophils as CD14-CD11B+CD15+LOX-1+ (LOX-1+ neutrophils), and their levels in the peripheral blood (PB) were evaluated and compared between patients with AR and healthy donors using flow cytometric analysis. LOX-1 expression on polymorphonuclear neutrophils was identified. Carboxyfluorescein succinimidyl ester (CFSE)-stained CD3+ T cells were cultured alone or with LOX-1+ neutrophils, T cell proliferation was assessed using flow cytometry, and pro-inflammatory cytokines in the supernatants were detected using enzyme-linked immunosorbent assay (ELISA). Clinicopathological analyses were performed to gain a thorough understanding of LOX-1+ neutrophils. Results: We determined that LOX-1+ neutrophils were significantly increased in the PB of patients with AR, and LOX-1 expression in neutrophils from patients with AR was elevated. Interestingly, LOX-1+ neutrophils derived from patients with AR, unlike PMN-MDSC, promoted T cell proliferation and pro-inflammatory cytokine production. Moreover, clinicopathological analysis revealed that there was no any relation between circulating LOX-1+ neutrophil levels and the levels of IgE, age and sex. Conclusion: These findings indicate that elevated circulating LOX-1+ neutrophils play a pro-inflammatory role in AR.

Serum amyloid A1 induced dysfunction of airway macrophages via CD36 pathway in allergic airway inflammation.

Previous studies showed that serum amyloid A (SAA) and macrophages were associated with allergic airway inflammation. However, the interaction between SAA1 and macrophages in allergic airway inflammation remains to be further elucidated. In this study, the levels of SAA1 were measured in nasal tissues from patients with eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), house dust mite (HDM)-treated BEAS-2B cells and the tissues of mice of HDM-induced allergic airway inflammation. Human monocytes-derived macrophages and mouse bone marrow-derived macrophages (BMDMs) were exposed to SAA1, and CCL17 and the other M1/M2-related factors were evaluated using RT-PCR and/or ELISA. To test the effects of SAA1-treated BMDMs on chemotaxis and differentiation of CD4+ T cells, number of migrated cells and the levels of Th1 and Th2 were measured using flow cytometry. SAA1 receptors were examined in BMDMs and lung macrophages of model mice. CD36 neutralizing antibody was applied to explore the mechanisms of SAA1 in regulating BMDMs using RT-PCR and/or ELISA. We found that SAA1 was expressed in epithelial cells, and was increased in the nasal tissues of patients with eosinophilic CRSwNP and HDM-treated BEAS-2B- cells as well as the bronchoalveolar lavage fluid and lung tissues of mice exposed to HDM. We also found that the level of CCL17 was increased in M2 macrophages, more CD4+ T cells were recruited and proportion of Th2 was increased after the treatment of SAA1. The treatment of CD36 neutralizing antibody decreased CCL17 level in SAA1-treated M2 BMDMs. In summary, our results showed that SAA1 was increased in allergic airway inflammation, and the administration of SAA1 upregulated the expression of CCL17 in M2 macrophages via CD36 and promoted the chemotaxis of CD4+ T cells and differentiation of Th2. It may provide a new therapeutic strategy that could mediate allergic airway inflammation via suppressing SAA1 to reduce recruitment of CD4+ T cells and activation of Th2.

Clinical and pathogen features of COVID-19-associated infections during an Omicron strain outbreak in Guangzhou, China.

Although the Omicron variant has been associated with greater transmissibility and tropism of the upper respiratory tract, the clinical and pathogenic features of patients infected with the Omicron variant during an outbreak in China have been unclear. Adults with COVID-19 were retrospectively enrolled from seven medical centers in Guangzhou, China, and clinical information and specimens ( BALF, sputum, and throat swabs) from participants were collected. Conventional detection methods, metagenomics next-generation sequencing (mNGS), and other methods were used to detect pathogens in lower respiratory tract samples. From December 2022 to January 2023, we enrolled 836 patients with COVID-19, among which 56.7% patients had severe/critical illness. About 91.4% of patients were infected with the Omicron strain (BA.5.2). The detection rate of possible co-infection pathogens was 53.4% by mNGS, including Klebsiella pneumoniae (16.3%), Aspergillus fumigatus (12.2%), and Pseudomonas aeruginosa (11.8%). The co-infection rate was 19.5%, with common pathogens being Streptococcus pneumoniae (11.5%), Haemophilus influenzae (9.2%), and Adenovirus (6.9%). The superinfection rate was 75.4%, with common pathogens such as Klebsiella pneumoniae (26.1%) and Pseudomonas aeruginosa (19.4%). Klebsiella pneumoniae (27.1%% vs 6.1%, P < 0.001), Aspergillus fumigatus (19.6% vs 5.3%, P = 0.001), Acinetobacter baumannii (18.7% vs 4.4%, P = 0.001), Pseudomonas aeruginosa (16.8% vs 7.0%, P = 0.024), Staphylococcus aureus (14.0% vs 5.3%, P = 0.027), and Streptococcus pneumoniae (0.9% vs 10.5%, P = 0.002) were more common in severe cases. Co-infection and superinfection of bacteria and fungi are common in patients with severe pneumonia associated with Omicron variant infection. Sequencing methods may aid in the diagnosis and differential diagnosis of pathogens. IMPORTANCE: Our study has analyzed the clinical characteristics and pathogen spectrum of the lower respiratory tract associated with co-infection or superinfection in Guangzhou during the outbreak of the Omicron strain, particularly after the relaxation of the epidemic prevention and control strategy in China. This study will likely prompt further research into the specific issue, which will benefit clinical practice.

Survival-Related Genes on Chromosomes 6 and 17 in Medulloblastoma.

Survival of Medulloblastoma (MB) depends on various factors, including the gene expression profiles of MB tumor tissues. In this study, we identified 967 MB survival-related genes (SRGs) using a gene expression dataset and the Cox proportional hazards regression model. Notably, the SRGs were over-represented on chromosomes 6 and 17, known for the abnormalities monosomy 6 and isochromosome 17 in MB. The most significant SRG was HMGA1 (high mobility group AT-hook 1) on chromosome 6, which is a known oncogene and a histone H1 competitor. High expression of HMGA1 was associated with worse survival, primarily in the Group 3γ subtype. The high expression of HMGA1 was unrelated to any known somatic copy number alteration. Most SRGs on chromosome 17p were associated with low expression in Group 4ß, the MB subtype, with 93% deletion of 17p and 98% copy gain of 17q. GO enrichment analysis showed that both chromosomes 6 and 17 included SRGs related to telomere maintenance and provided a rationale for testing telomerase inhibitors in Group 3 MBs. We conclude that HMGA1, along with other SRGs on chromosomes 6 and 17, warrant further investigation as potential therapeutic targets in selected subgroups or subtypes of MB.

Synthesis of Indole-Fused Pyrazino[1,2-a]quinazolinones by Copper(I)-Catalyzed Selective Hydroamination-Cyclization of Alkynyl-tethered Quinazolinones.

We described a copper(I)-catalyzed atom economic and selective hydroamination-cyclization of alkynyl-tethered quinazolinones to prepare a variety of indole-fused pyrazino[1,2-a]quinazolinones in good to excellent yields ranging from 39 %-99 % under mild reaction conditions. Control experiments revealed that coordination-directed method of quinazolinone moiety with copper(I) was important for the selective hydroamination-cyclization of alkynes at the N1-atom instead of N3-atom of quinazolinone. The reaction could be easily performed at gram scales and some prepared indole-fused pyrazino[1,2-a]quinazolinones with donating groups on the indole moiety showed a distinct fluorescence emission wavelength with blue shift under the acid conditions.

Small extracellular vesicles derived from human mesenchymal stem cells prevent Th17-dominant neutrophilic airway inflammation via immunoregulation on Th17 cells.

Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation is critical in the pathogenesis of steroid-resistant airway inflammation such as severe asthma. Small extracellular vesicles (sEV) derived from human mesenchymal stem cells (MSCs) display extensive therapeutic effects and advantages in many diseases. However, the role of MSC-sEV in Th17-dominant neutrophilic airway inflammation and the related mechanisms are still poorly studied. Here we found that MSC-sEV significantly alleviated the infiltration of inflammatory cells in peribronchial interstitial tissues and reduced levels of inflammatory cells, especially neutrophils, in bronchoalveolar lavage fluids (BALF) of mice with neutrophilic airway inflammation. Consistently, MSC-sEV significantly decreased levels of IL-17A in BALF and Th17 in lung tissues. Furthermore, we found that labelled MSC-sEV were taken up by human CD4+ T cells most obviously at 12 h after incubation, and distributed mostly in mouse lungs. More importantly, potential signaling pathways involved in the MSC-sEV mediated inhibition of Th17 polarization were found using RNA sequencing. Using Western blot, JAK2-STAT3 pathway was identified as an important role in the inhibition of Th17 polarization by MSC-sEV. We found that proteins in MSC-sEV were mostly involved in the therapeutic effects of MSC-sEV. In total, our study suggested that MSC-sEV could be a potential therapeutic strategy for the treatment of neutrophilic airway inflammation.

Retrospective Cohort Study of Syphilis-Related Stillbirths in Winnipeg, Manitoba From 2017-2020.

OBJECTIVE: Syphilis-related stillbirths (SRSBs) disproportionately affect marginalized women with 11% of all local stillbirths having maternal syphilis as a contributory factor in 2020. This study describes the incidence and perinatal factors associated with SRSB. METHODS: This was a retrospective cohort study of all stillbirths occurring from 1 January 2017 to 31 December 2020, at a single tertiary-level referral hospital in Winnipeg, Manitoba. Cases that met criteria for SRSB were identified from hospital records and included in the final analysis. Maternal demographics, comorbidities, prenatal care attendance, sexually transmitted infection testing, treatment, and diagnostic investigations at time of stillbirth were collected from hospital charts using a standardized data collection form. Descriptive statistics were performed to present the results. RESULTS: The proportion of SRSB increased over the period of study from 0%-11%. Eleven cases were identified as SRSB, with diagnosis occurring intrapartum in 7 cases and antenatally in 4 cases. Of the 4 antenatal cases, only 2 had identifiable treatment responses indicated by microbiological and pathology workup. Commonly identified risk factors for SRSB were homelessness, mental illness, substance use, sexually transmitted co-infections, and lack of prenatal care. CONCLUSIONS: Cases of SRSB are rising in Winnipeg with 11% of all stillbirths having maternal syphilis as a contributory factor by 2020. SRSBs disproportionately affect marginalized women. The dramatic and rapid changes in the epidemiology of syphilis in Winnipeg are likely shared by other Canadian regions and warrant increased prevention strategies to improve outcomes.

Mesenchymal stem cells overexpressing interleukin-10 prevent allergic airway inflammation.

BACKGROUNDS: Allergic airway inflammation is prevalent worldwide and imposes a considerable burden on both society and affected individuals. This study aimed to investigate the therapeutic advantages of mesenchymal stem cells (MSCs) overexpressed interleukin-10 (IL-10) for the treatment of allergic airway inflammation, as both IL-10 and MSCs possess immunosuppressive properties. METHODS: Induced pluripotent stem cell (iPSC)-derived MSCs were engineered to overexpress IL-10 via lentiviral transfection (designated as IL-10-MSCs). MSCs and IL-10-MSCs were administered intravenously to mice with allergic inflammation induced by ovalbumin (OVA), and the features of allergic inflammation including inflammatory cell infiltration, Th cells in the lungs, and T helper 2 cell (Th2) cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. MSCs and IL-10-MSCs were co-cultured with CD4+ T cells from patients with allergic rhinitis (AR), and the levels of Th2 cells and corresponding type 2 cytokines were studied. RNA-sequence was performed to further investigate the potential effects of MSCs and IL-10-MSCs on CD4+ T cells. RESULTS: Stable IL-10-MSCs were established and characterised by high IL-10 expression. IL-10-MSCs significantly reduced inflammatory cell infiltration and epithelial goblet cell numbers in the lung tissues of mice with allergic airway inflammation. Inflammatory cell and cytokine levels in BALF also decreased after the administration of IL-10-MSCs. Moreover, IL-10-MSCs showed a stronger capacity to inhibit the levels of Th2 after co-cultured with CD4+ T cells from patients with AR. Furthermore, we elucidated lower levels of IL-5 and IL-13 in IL-10-MSCs treated CD4+ T cells, and blockade of IL-10 significantly reversed the inhibitory effects of IL-10-MSCs. We also reported the mRNA profiles of CD4+ T cells treated with IL-10-MSCs and MSCs, in which IL-10 played an important role. CONCLUSION: IL-10-MSCs showed positive effects in the treatment of allergic airway inflammation, providing solid support for the use of genetically engineered MSCs as a potential novel therapy for allergic airway inflammation.

Lifestyle improvement and the reduced risk of cardiovascular disease: the China-PAR project.

BACKGROUND: The benefits of healthy lifestyles are well recognized. However, the extent to which improving unhealthy lifestyles reduces cardiovascular disease (CVD) risk needs to be discussed. We evaluated the impact of lifestyle improvement on CVD incidence using data from the China-PAR project (Prediction for Atherosclerotic Cardiovascular Disease Risk in China). METHODS: A total of 12,588 participants free of CVD were followed up for three visits after the baseline examination. Changes in four lifestyle factors (LFs) (smoking, diet, physical activity, and alcohol consumption) were assessed through questionnaires from the baseline to the first follow-up visit. Cox proportional hazard models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). The risk advancement periods (RAPs: the age difference between exposed and unexposed participants reaching the same incident CVD risk) and population-attributable risk percentage (PAR%) were also calculated. RESULTS: A total of 909 incident CVD cases occurred over a median follow-up of 11.14 years. Compared with maintaining 0-1 healthy LFs, maintaining 3-4 healthy LFs was associated with a 40% risk reduction of incident CVD (HR = 0.60, 95% CI: 0.45-0.79) and delayed CVD risk by 6.31 years (RAP: -6.31 [-9.92, -2.70] years). The PAR% of maintaining 3-4 unhealthy LFs was 22.0% compared to maintaining 0-1 unhealthy LFs. Besides, compared with maintaining two healthy LFs, improving healthy LFs from 2 to 3-4 was associated with a 23% lower risk of CVD (HR = 0.77, 95% CI: 0.60-0.98). CONCLUSIONS: Long-term sustenance of healthy lifestyles or improving unhealthy lifestyles can reduce and delay CVD risk.

Circulating inflammatory cytokines and psoriasis risk: A systematic review and meta-analysis.

BACKGROUND: Psoriasis is a systemic immune-mediated chronic inflammatory skin disease; its systemic manifestations and periodic recurrence negatively affect a patient's quality of life. Inflammatory cytokines are known to have an important role in the onset and progression of psoriasis, however, data on the association between circulating inflammatory cytokines and psoriasis risk is inconclusive. Here, we explore the relevance of circulating proinflammatory factors to the pathogenesis of psoriasis using a meta-analysis. OBJECTIVE: To explore the association between circulating levels of inflammatory factors and psoriasis to elucidate the mechanisms underlying psoriasis and improve clinical diagnosis and treatment. METHODS: We systematically retrieved articles published in PubMed, EMBASE, the Cochrane Library and the Web of Science from the establishment of each database to January 2023. The standard mean difference (SMD) in cytokine levels of individuals with psoriasis and healthy controls was used to check for correlations between circulating inflammatory factor levels and psoriasis. RESULTS: Fifty-seven studies, with data from 2838 patients, were retrieved and included in the meta-analysis. Eleven inflammatory factors were studied (circulating interleukin-2 (IL-2), IL-4, IL-12, IL-17, IL-18, IL-22, IL-23, IL-35, IL-36, transforming growth factor-beta (TGF-ß) and gamma-interferon (IFN-γ)). Of these, IL-2 [SMD = 1.29 (95% CI: 0.61-1.97; P <0.001)], IL-17 [SMD = 0.71 (95% CI: 0.12-1.30; P = 0.018)], IL-18 [SMD = 1.27 (95% CI: 0.64-1.90; P <0.001)], and IFN-γ [SMD = 1.90 (95% CI: 1.27-2.52; P <0.001)] levels had significant correlations with psoriasis. CONCLUSION: Increased serum concentrations of the circulating inflammatory cytokines IL-2, IL-17, IL-18 and IFN-γ were significantly correlated with psoriasis.

The thalamic reticular nucleus-lateral habenula circuit regulates depressive-like behaviors in chronic stress and chronic pain.

Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in the pathophysiology of depression. However, the contribution of inhibitory transmission remains unclear. Here, we dissect an inhibitory projection from the sensory thalamic reticular nucleus (sTRN) to the LHb, which is activated by acute aversive stimuli. However, chronic restraint stress (CRS) weakens sTRN-LHb synaptic strength, and this synaptic attenuation is indispensable for CRS-induced LHb neural hyperactivity and depression onset. Moreover, artificially inhibiting the sTRN-LHb circuit induces depressive-like behaviors in healthy mice, while enhancing this circuit relieves depression induced by both chronic stress and chronic pain. Intriguingly, neither neuropathic pain nor comorbid mechanical hypersensitivity in chronic stress is affected by this pathway. Altogether, our study demonstrates an sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.

Facile Fabrication of Dual-Activatable Gastrointestinal-Based Nanocarriers for Safe Delivery and Controlled Release of Methotrexate.

Colon cancer is emerging as one of the most common cancers worldwide, ranking in the top three in morbidity and mortality. Oral methotrexate (MTX) has been employed as a first-line treatment for various cancers, such as colon, breast, and lung cancer. However, the complexity and particularity of the gastrointestinal microenvironment and the limitations of MTX itself, including severe adverse effects and instability, are the main obstacles to the safe delivery of MTX to colon tumor sites. Herein, an innovative oral administrated anticancer therapeutic MTX@Am7CD/SDS NPs equipped with both pH and temperature sensitivity, which could effectively prevent MTX@Am7CD/SDS NPs from being degraded in the acidic environment mimicking the stomach and small intestine, thus harboring the potential to accumulate at the site of colon lesions and further release intestinal drug under mild conditions. In cellular assays, compared with free MTX, MTX@Am7CD/SDS NPs showed a favorable tumor inhibition effect on three tumor cell lines, as well as excellent cell uptake and apoptosis-inducing effect on SW480 cells. Therefore, this work provides a feasible solution for the safe use of MTX in the treatment of colon cancer and even other intestinal diseases.

Orthohantavirus infections in humans and rodents in the Yichun region, China, from 2016 to 2021.

BACKGROUND: Rodents are the predominant natural hosts of orthohantavirus and the source of human infection, hemorrhagic fever with renal syndrome (HFRS) caused by orthohantavirus is a severe public health problem in the Yichun region, Jiangxi Province, China. However, little information is known about the infection of orthohantavirus in humans and rodents, and the genetic characteristics of the epidemic orthohantavirus in the region. METHODS: The clinical data of HFRS cases in 2016-2021 was analyzed. Virus infection in rodents was analyzed by orthohantavirus antigen detection using immunofluorescent assay, and the species of orthohantaviruses in rodents and patients were identified by real-time RT-PCR and gene sequencing. The S and M segments of orthohantaviruses from rodents and patients were recovered and analyzed. RESULTS: A total of 1,573 HFRS cases were reported in the Yichun region from 2016 to 2021, including 11 death cases. HFRS cases peaked twice each year: in winter from November to January and early summer from May to June. Farmers constituted the predominant population suffering from HFRS. The orthohantavirus antigen was identified in five species of rodents: Apodemus agrarius (A. agrarius), Rattus norvegicus (R. norvegicus), Sorex araneus, Rattus losea (R. losea), and Niviventer confucianus (N. confucianus). The real-time RT-PCR test and genetic analysis results showed that Hantaan orthohantavirus (HTNV), Seoul orthohantavirus (SEOV), and Dabieshan orthohantavirus (DBSV) were circulated in the rodents. HTNV, SEOV, and DBSV from the rodents were distantly related to other known orthohantaviruses and belonged to novel genetic lineages. SEOV and HTNV were found in HFRS patients, but 97.8% (90/92) of the infections were caused by HTNV. Winter and early summer peaks were both caused by HTNV. The HTNV sequences recovered from HFRS cases were closely related to those from A. agrarius. CONCLUSIONS: In the Yichun region, the orthohantaviruses transmitted in rodents include HTNV, SEOV, and DBSV, which have obvious genetic characteristics and high genetic diversity. At the same time, this region is an HFRS mixed epidemic area dominated by HTNV, with two peaks every year, which deserves our high attention.

A glutamatergic DRN-VTA pathway modulates neuropathic pain and comorbid anhedonia-like behavior in mice.

Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here using a mouse model, we report a pathway from vesicular glutamate transporter 3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRN→DAVTA) wherein population-level activity in response to innocuous mechanical stimuli and sucrose consumption is inhibited by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN → DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN → DAVTA activation alleviates neuropathic pain and comorbid anhedonia-like behavior (CAB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesic and anti-anhedonia effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN → DAVTA inhibition produces pain-like reflexive hypersensitivity and anhedonia-like behavior in intact mice. These findings reveal a crucial role for VGluT3DRN → DAVTA → D2/D1NAcMed pathway in establishing and modulating chronic pain and CAB.

Dendritic cells mediated by small extracellular vesicles derived from MSCs attenuated the ILC2 activity via PGE2 in patients with allergic rhinitis.

BACKGROUND: Mesenchymal stromal cells-derived small extracellular vesicles (MSC-sEVs) have recently attracted considerable attention because of their therapeutic potential in various immune diseases. We previously reported that MSC-sEVs could exert immunomodulatory roles in allergic airway inflammation by regulating group 2 innate lymphoid cell (ILC2) and dendritic cell (DC) functions. Therefore, this study aimed to investigate the indirect effects of MSC-sEVs on ILC2s from patients with allergic rhinitis (AR) via DCs. METHODS: Here, we isolated sEVs from induced pluripotent stem cells-MSCs using anion-exchange chromatography and mature DCs (mDCs) were treated with MSC-sEVs. sEV-mDCs were co-cultured with peripheral blood mononuclear cells from patients with AR or purified ILC2s. The levels of IL-13 and GATA3 in ILC2s were examined by flow cytometry. Bulk RNA sequence for mDCs and sEV-mDCs was employed to further probe the potential mechanisms, which were then validated in the co-culture systems. RESULTS: sEV-mDCs showed impaired capacity in priming the levels of IL-13 and GATA3 in ILC2s when compared with mDCs. Furthermore, there was higher PGE2 and IL-10 production from sEV-mDCs, and the blockade of them especially the former one reversed the inhibitory effects of sEV-mDCs. CONCLUSIONS: We demonstrated that MSC-sEVs were able to dampen the activating effects of mDCs on ILC2s in patients with AR. Mechanismly, the PGE2-EP2/4 axis played an essential role in the immunomodulatory effects of sEV-mDCs on ILC2s. Herein, we provided new insights into the mechanism underlying the therapeutic effects of MSC-sEVs in allergic airway inflammation.

Nomogram Predicting the Prognosis of Patients with Surgically Resected Stage IA Non-small Cell Lung Cancer.

The American Joint Committee on Cancer (AJCC) 8th stage system was limited in accuracy for predicting prognosis of stage IA non-small cell lung cancer (NSCLC) patients. This study aimed to establish and validate two nomograms that predict overall survival (OS) and lung cancer-specific survival (LCSS) in surgically resected stage IA NSCLC patients. Postoperative patients with stage IA NSCLC in SEER database between 2004 and 2015 were examined. Survival and clinical information according to the inclusion and exclusion criteria were collected. All patients were randomly divided into the training cohort and validation cohort with a ratio of 7:3. Independent prognosis factors were evaluated using univariate and multivariate Cox regression analyses, and predictive nomogram was established based on these factors. Nomogram performance was measured using the C-index, calibration plots, and DCA. Patients were grouped by quartiles of nomogram scores and survival curves were plotted by Kaplan-Meier analysis. In total, 33,533 patients were included in the study. The nomogram contained 12 prognostic factors in OS and 10 prognostic factors in LCSS. In the validation set, the C-index was 0.652 for predicting OS and 0.651 for predicting LCSS. The calibration curves for the nomogram-predicted probability of OS and LCSS showed good agreement between the actual observation and nomogram prediction. DCA indicated that the clinical value of the nomograms were higher than AJCC 8th stage for predicting OS and LCSS. Nomogram scores related risk stratification revealed statistically significant difference which have better discrimination than AJCC 8th stage. The nomogram can accurately predict OS and LCSS in surgically resected patients with stage IA NSCLC. Supplementary Information: The online version contains supplementary material available at 10.1007/s13193-022-01700-w.

The lateral habenula nucleus regulates pruritic sensation and emotion.

Itch is a complex aversive sensory and emotional experience. As a most upsetting symptom in many dermatological and systemic diseases, it lacks efficient treatments. The lateral habenula nucleus (LHb) encodes negative emotions in the epithalamus and has been implicated in pain and analgesia. Nevertheless, the role of the lateral habenula nucleus in the pruritic sensation and emotion remains elusive. Here we defined the crucial role of glutamatergic neurons within the lateral habenula nucleus (GluLHb) in itch modulation in mice. We established histamine-dependent and histamine-independent models of acute pruritus, as well as the acetone-ether-water (AEW) model of chronic pruritus. We first assessed the effects of pruritogen injection on neural activation in both medial and lateral divisions of LHb in vitro. We then demonstrated that the population activity of GluLHb neurons was increased during the acute itch and chronic itch-induced scratching behaviors in vivo. In addition, electrophysiological data showed that the excitability of GluLHb neurons was enhanced by chronic itch. Chemogenetic suppression of GluLHb neurons disrupted both acute and chronic itch-evoked scratching behaviors. Furthermore, itch-induced conditioned place aversion (CPA) was abolished by GluLHb neuronal inhibition. Finally, we dissected the LHb upstream brain regions. Together, these findings reveal the involvement of LHb in processing both the sensational and emotional components of pruritus and may shed new insights into itch therapy.

Circulating tumor cells dynamics during chemotherapy predict survival and response in advanced non-small-cell lung cancer patients.

Background: Circulating tumor cells (CTCs) are prognostic biomarker in non-small-cell lung cancer (NSCLC). CTCs could also be used as predictor of efficacy of systemic treatments in advanced NSCLC. Objectives: We described the dynamic changes of CTCs during first-line platinum-based chemotherapy in advanced NSCLC and clarified the correlation between CTC counts and efficacy of chemotherapy. Design: Chemotherapy is administered and blood specimens are collected at four time points from baseline to disease progression for CTC detection. Methods: This multicenter prospective study enrolled patients with previously untreated stage III or IV NSCLC fit for standard platinum-based chemotherapy. Bloods were sampled as per standard operating procedures at baseline, cycle 1 and cycle 4 of chemotherapy, and at disease progression for CTC analysis using the CellSearch system. Results: Among 150 patients enrolled, median overall survival (OS) was 13.8, 8.4, and 7.9 months in patients with CTC-, KIT-CTC, and KIT+CTC at baseline (p = 0.002). Patients with persistent negative CTC (46.0%) had longer progression-free survival [5.7 months, 95% confidence interval (CI): 5.0-6.5 versus 3.0 months, 0.6-5.4; hazard ratio (HR): 0.34, 95% CI: 0.18-0.67) and OS (13.1 months, 10.9-15.3 versus 5.6 months, 4.1-7.1; HR: 0.17, 0.08-0.36) compared with patients with persistent positive CTC (10.7%), which was not impacted by chemotherapy. Chemotherapy decreased CTC from 36.0% (54/150) to 13.7% (13/95). Conclusions: CTC persistent presence during treatment represents poor prognosis and resistance to chemotherapy in advanced NSCLC. Chemotherapy could effectively eliminate CTCs. Molecular characterization and the functionalization of CTC will be warranted for further intensive investigation. Trial registration: NCT01740804.