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Background: Resolvin D2 (RvD2), with an anti-inflammatory activity, harbors a neuroprotective property. Here, serum RvD2 levels were detected with an attempt to explore its prognostic implication in human acute intracerebral hemorrhage (ICH)., Methods: In this prospective cohort study, serum RvD2 levels of 301 ICH patients, coupled with 100 heathy individuals, were gauged. All patients were randomly divided to two groups (200 patients in the study group and 101 in the validation group) in a 2:1 ratio. Change of serum RvD2 levels after ICH was investigated, and its correlations with National Institutes of Health Stroke Scale (NIHSS) scores, hematoma volume and poststroke six-month modified Rankin Scale (mRS) scores were determined using multivariate analysis. Its independent association with poor prognosis (mRS scores of 3-6) was uncovered in the study group and its prognostic predictive value was verified in the validation group., Results: The serum levels of RvD2 in patients displayed a notable decline upon admission, as compared to controls. The levels exhibited independent correlations with NIHSS scores, hematoma size and mRS scores. Alternatively, RvD2 levels had independent relation to a poor prognosis after ICH. Within the framework of restricted cubic spline analysis, RvD2 levels were linearly correlated with the likelihood of poor prognosis, even adjusting for NIHSS scores and hematoma size. In the context of receiver operating characteristic (ROC) curve analysis, serum RvD2 dramatically distinguished risk of poor prognosis, with similar predictive ability to NIHSS scores and hematoma volume. By employing subgroup analysis, the relationship between RvD2 levels and poor prognosis was not obviously influenced by other parameters, such as age, sex, hypertension, and more. The integrated model containing serum RvD2, NIHSS scores and hematoma volume was visualized on a nomogram and showed high predictive performance and clinical effectiveness for poor prognosis via multiple evaluation metrics, including the Hosmer-Lemeshow test, ROC curve analysis, calibration curve analysis and decision curve analysis. Clinical usefulness of serum RvD2 was verified in the validation group., Conclusion: Serum RvD2 levels exhibit an immediate decrease post-ICH, which could be able to accurately reflect ICH severity and efficiently prognosticate poor neurological outcomes, signifying that serum RvD2 may represent an encouraging prognostic indicator in ICH., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The unmet needs of managing patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer who progress after cyclin-dependent kinase (CDK)4/6 inhibitor (CDK4/6i) treatment remain unclarified., Methods: This was a phase 1b/2, single-arm, open-label study that enrolled 29 patients with HR+/HER2- breast cancer who experienced first-line palbociclib treatment failure. The primary endpoint was the incidence of dose-limiting toxicity (DLT). The secondary endpoints were the objective response rate (ORR) and progression-free survival (PFS). The clinical trial registration number is ClinicalTrials.gov: NCT05953350., Findings: The phase 1b study demonstrated no DLT in patients treated with hydroxychloroquine (HCQ; 600 mg, bis in die [bid]) plus increasing doses of palbociclib (100, 150, or 200 mg, quaque die [qd]). The plasma pharmacokinetics of palbociclib were not significantly affected by HCQ. The recommended phase 2 dose (RP2D) was HCQ (600 mg, bid) plus palbociclib (200 mg, qd). The dose-expansion cohort demonstrated that HCQ plus palbociclib (200 mg, qd) treatment was tolerable. Grade 3 treatment-emergent adverse events (TEAEs) with an incidence higher than 15.0% included neutropenia (25.0%), leukopenia (25.0%), fatigue (20.0%), and back pain (15.0%). The ORR of all enrolled patients in our present trial was 41.4% (12/29). In the dose-expansion cohort, with the last enrolled patient having a follow-up duration of 32.3 weeks, the median PFS was not reached. The clinical benefit rate (CBR) at 6 months was 90.0% (95% confidence interval [CI]: 68.3%-98.8%). These findings were supported by preclinical data., Conclusions: Combined HCQ with high-dose CDK4/6i palbociclib (200 mg, qd) showed tolerable toxicity and promising efficacy for patients with advanced HR+/HER2- breast cancer after CDK4/6i failure., Funding: This work was funded by the National Natural Science Foundation of China., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The prognosis of patients with luminal/human epidermal growth factor receptor 2 (HER2)-low early breast cancer (EBC) needs to be improved. This preclinical study and phase 2 trial (ChiCTR2100047233) aims to explore the efficacy and safety of pyrotinib (a pan-HER tyrosine kinase inhibitor) plus chemotherapy in this population. Our preclinical experiments indicate a synergistic anti-tumor effect of pyrotinib plus chemotherapy in luminal/HER2-low (immunochemistry [IHC] 2+/fluorescent in situ hybridization [FISH]-negative) breast cancer models. Furthermore, 48 women with luminal/HER2-low (IHC 2+/FISH-negative) high-risk EBC are enrolled to receive neoadjuvant pyrotinib plus chemotherapy (epirubicin-cyclophosphamide followed by docetaxel). Ultimately, 26 (54.2%; 95% confidence interval [CI] 39.2%-68.6%) patients achieve the primary endpoint (residual cancer burden [RCB] 0/I). Treatment-related adverse events of grade ≥3 occur in 21 (43.8%) patients, with the most prevalent being diarrhea (10 [20.8%]). In conclusion, neoadjuvant pyrotinib plus chemotherapy has encouraging efficacy and manageable toxicity in women with luminal/HER2-low (IHC 2+/FISH-negative) high-risk EBC. This regimen warrants to be further validated., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Toremifene, a selective estrogen receptor modulator, is commonly used in China for premenopausal breast cancer patients. This real-world study aimed to compare patient-reported outcome (PRO) and survival between toremifene and aromatase inhibitor (AI) plus ovarian function suppression (OFS) in patients with moderate-/high-risk premenopausal hormone receptor (HR)-positive breast cancer. The primary endpoint was PROs, assessed using SF-36 and EQ-5D-5L questionnaires between January and March 2023. A total of 392 patients were included, with 171 receiving toremifene and 221 receiving AI. The toremifene group showed significantly higher scores in the role physical ( p  = 0.034) and mental health ( p  = 0.009) dimensions of SF-36 and lower anxiety/depression (AD) scores ( p  = 0.038) in EQ-5D-5L compared to AI group. The estimated 5- and 8-year disease-free survival (DFS) rates were similar in toremifene and AI groups: 96.5% versus 91.9%, and 87.4% versus 87.8% ( p  = 0.39), respectively. Adverse event rates were similar in two groups, except for a greater risk of endometrial thickening ( p  < 0.001) and a lower occurrence of morning stiffness ( p  < 0.001) in the toremifene compared to the AI group. Premenopausal HR-positive breast cancer patients receiving toremifene plus OFS had better role physical and mental health outcomes and lower AD dimensions than those receiving AI plus OFS. Both treatments had comparable DFS and favorable tolerability profiles., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Background and Aims: Guillain-Barré syndrome (GBS) is an acute, self-limited, immune-mediated peripheral neuropathy. Current treatments for GBS include intravenous immunoglobulin (IVIg) and plasma exchange, which may not sufficiently benefit severely affected patients. This study evaluated the efficacy and safety of eculizumab add-on therapy to IVIg (standard-of-care treatment) in patients with severe GBS., Methods: This phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial (NCT04752566), enrolled Japanese adults (age ≥ 18 years) with severe GBS (Hughes functional grade [FG] score FG3 or FG4/FG5 within 2 weeks of onset of GBS). Participants were randomized 2:1 to receive intravenous infusion of eculizumab or placebo (once weekly for 4 weeks) with IVIg treatment with 20 weeks of follow-up. Primary efficacy endpoint was the time to first reach FG score ≤1 (able to run). Key secondary endpoints were proportion of participants achieving FG ≤1 at weeks 8 and 24 and FG improvement ≥3 at week 24. Pharmacodynamic analysis of serum free C5 concentration over time was performed. Safety was evaluated., Results: The analysis included 57 participants (eculizumab, n = 37; placebo, n = 20). Primary endpoint was not achieved (hazard ratio, 0.9; 95% CI, 0.45-1.97; p = .89). Key secondary endpoints did not reach statistical significance. Serum C5 concentration was reduced by 99.99% at 1 h postdose and sustained to week 5 but returned to baseline at the end of follow-up period. No new safety signals for eculizumab were identified., Interpretation: Although well tolerated, eculizumab treatment did not show significant effects on motor function recovery compared to placebo in patients with GBS., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

The discovery of novel antitumor agents derived from natural plants is a principal objective of anticancer drug research. Frankincense, a widely recognized natural antitumor medicine, has undergone a systematic review encompassing its species, chemical constituents, and diverse pharmacological activities and mechanisms. The different species of frankincense include Boswellia serrata, Somali frankincense, Boswellia frereana, and Boswellia arabica. Various frankincense extracts and compounds exhibit antitumor, anti-inflammatory, and hepatoprotective properties and antioxidation, memory enhancement, and immunological regulation capabilities. They also have comprehensive effects on regulating flora. Frankincense and its principal chemical constituents have demonstrated promising chemoprophylactic and therapeutic abilities against tumors. This review provides a systematic summary of the mechanism of action underlying the antitumor effects of frankincense and its major constituents, thus laying the foundations for developing effective tumor-combating targets., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: As a newly identified subtype of HER2-negative tumors associated with a less favorable prognosis, it remains crucial to evaluate potential prognostic and predictive factors, particularly non-invasive biomarkers, for individuals with human epidermal growth factor 2 (HER2) low early-stage breast cancer (EBC). Multiple investigations have highlighted that HER2-negative patients with EBC exhibiting high homologous recombination deficiency (HRD) scores display lower rates of pathological complete response (PCR) to neoadjuvant chemotherapy (NAC). Nevertheless, no study to date has explored the correlation between HRD and the long-term prognosis in HER2-low patients with EBC., Patients and Methods: This retrospective observational study focuses on primary EBC sourced from The Cancer Genome Atlas dataset (TCGA). It reveals the gene mutation landscape in EBC with low HER2 expression and elucidates the tumor immune landscape across different HRD states. Utilizing bioinformatics analysis and Cox proportional models, along with the Kaplan-Meier method, the study assesses the correlation between HRD status and disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Subgroup analyses were conducted to identify potential variations in the association between HRD and prognosis., Results: In the patients with HER2-low breast cancer, patients with homologous recombination related genes (HRRGs) defects had an HRD score about twice that of those without related genes mutations, and were at higher risk of acquiring ARID1A, ATM, and BRCA2 mutations. We also found that most immune cell abundances were significantly higher in EBC tumors with high HRD than in EBC tumors with low HRD or HRD-medium, particularly plasma B-cell abundance, CD8 T-cell abundance, and M1 macrophages. In addition, these tumors with HRD-high also appear to have significantly higher tumor immune scores and lower interstitial scores. Then, we analyzed the relationship between different HRD status and prognosis. There was statistical significance (P = .036 and P = .046, respectively) in DSS and PFI between the HRD-low and HRD-high groups, and patients with HRD-high EBC showed relatively poor survival outcomes. A medium HRD score (hazard ratio, HR = 2.15, 95% CI: 1.04-4.41, P = .038) was a significant risk factor for PFI. Hormone receptor positivity is an important factor in obtaining medium-high HRD score and poor prognosis., Conclusion: Higher HRD scores were associated with poorer PFI outcomes, particularly in people with HR+/HER2-low. Varied HRD states exhibited distinctions in HRRGs and the tumor immune landscape. These insights have the potential to assist clinicians in promptly identifying high-risk groups and tailoring personalized treatments for patients with HER2-low EBC, aiming to enhance long-term outcomes., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The effect of two lung ventilation (TLV) with carbon dioxide artificial pneumothorax on cerebral desaturation and postoperative neurocognitive changes in elderly patients undergoing elective minimally invasive esophagectomy (MIE) is unclear., Objectives: The first aim of this study was to compare the effect of TLV and one lung ventilation (OLV) on cerebral desaturation. The second aim was to assess changes in early postoperative cognitive outcomes of two ventilation methods., Methods: This prospective, randomized, controlled trial enrolled patients 65 and older scheduled for MIE. Patients were randomly assigned (1:1) to TLV group or OLV group. The primary outcome was the incidence of cerebral desaturation events (CDE). Secondary outcomes were the cumulative area under the curve of desaturation for decreases in regional cerebral oxygen saturation (rSO 2 ) values below 20% relative to the baseline value (AUC.20) and the incidence of delayed neurocognitive recovery., Results: Fifty-six patients were recruited between November 2019 and August 2020. TLV group had a lower incidence of CDE than OLV group [3 (10.71%) vs. 13 (48.14%), P = 0.002]. TLV group had a lower AUC.20 [0 (0-35.86) % min vs. 0 (0-0) % min, P = 0.007], and the incidence of delayed neurocognitive recovery [2 (7.4%) vs. 11 (40.7%), P = 0.009] than OLV group. Predictors of delayed neurocognitive recovery on postoperative day 7 were age (OR 1.676, 95% CI 1.122 to 2.505, P = 0.006) and AUC.20 (OR 1.059, 95% CI 1.025 to 1.094, P < 0.001)., Conclusion: Compared to OLV, TLV had a lower incidence of CDE and delayed neurocognitive recovery in elderly patients undergoing MIE. The method of TLV combined with carbon dioxide artificial pneumothorax may be an option for these elderly patients. Chinese Clinical Trial Registry (identifier: ChiCTR1900027454)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ischemia-reperfusion (IR) induces a wide range of irreversible injuries. Cerebral IR injury (IRI) refers to additional brain tissue damage that occurs after blood flow is restored following cerebral ischemia. Currently, no established methods exist for treating IRI. Oxidative stress is recognized as a primary mechanism initiating IRI and a crucial focal target for its treatment. Urolithin B, a metabolite derived from ellagitannins, antioxidant polyphenols, has demonstrated protective effects against oxidative stress in various disease conditions. However, the precise mechanism underlying UB's effect on IRI remains unclear. In our current investigation, we assessed UB's ability to mitigate neurological functional impairment induced by IR using a neurological deficit score. Additionally, we examined cerebral infarction following UB administration through TTC staining and neuron Nissl staining. UB's inhibition of neuronal apoptosis was demonstrated through the TUNEL assay and Caspase-3 measurement. Additionally, we examined UB's effect on oxidative stress levels by analyzing malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity, and immunohistochemistry analysis of inducible nitric oxide synthase (iNOS) and 8-hydroxyl-2'-deoxyguanosine (8-OHdG). Notably, UB demonstrated a reduction in oxidative stress levels. Mechanistically, UB was found to stimulate the Nrf2/HO-1 signaling pathway, as evidenced by the significant reduction in UB's neuroprotective effects upon administration of ATRA, an Nrf2 inhibitor. In summary, UB effectively inhibits oxidative stress induced by IR through the activation of the Nrf2/HO-1 signaling pathway. These findings suggest that UB holds promise as a therapeutic agent for the treatment of IRI., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To explore the predictive value of nutritional risk for all-cause death and functional outcomes among elderly acute stroke patients., Patients and Methods: A total of 479 elderly acute stroke patients were enrolled in this study. The nutritional risk of patients was screened by the GNRI and NRS-2002. The primary outcome was all-cause death, and the secondary outcome was poor prognosis defined as a modified Rankin Scale (mRS) score ≥3., Results: Based on the NRS-2002, patients with nutritional risk had a higher risk of all-cause death at 3 months (adjusted OR: 3.642, 95% CI 1.046~12.689) and at 3 years (adjusted OR: 2.266, 95% CI 1.259~4.076) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 2.748, 95% CI 1.518~4.972. Based on the GNRI, compared to those without nutritional risk, patients with mild malnutrition also had a higher risk of all-cause death at 3 months (adjusted OR: 7.186, 95% CI 1.550~33.315) and at 3 years (adjusted OR: 2.255, 95% CI 1.211~4.199) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 1.947, 95% CI 1.030~3.680), so patients with moderate and severe malnutrition had a higher risk of all-cause death at 3 months (adjusted OR: 6.535, 95% CI 1.380~30.945) and at 3 years (adjusted OR: 2.498, 95% CI 1.301~4.799) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 2.213, 95% CI 1.144~4.279)., Conclusion: Nutritional risk increases the risk of poor short-term and long-term outcomes in elderly patients with acute stroke. For elderly stroke patients, we should pay attention to early nutritional risk screening, and effective intervention should be provided to improve the prognosis of such patients., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Cong et al.)

Background: The association between different phenotypes and genotypes of circulating tumor cells (CTCs) and efficacy of neoadjuvant chemotherapy (NAC) remains uncertain. This study was conducted to evaluate the relationship of FTH1 gene-associated CTCs (F-CTC) with/without epithelial-mesenchymal transition (EMT) markers, or their dynamic changes with the efficacy of NAC in patients with non-metastatic breast cancer., Patients and Methods: This study enrolled 120 patients with non-metastatic breast cancer who planned to undergo NAC. The FTH1 gene and EMT markers in CTCs were detected before NAC (T0), after 2 cycles of chemotherapy (T1), and before surgery (T2). The associations of these different types of CTCs with rates of pathological complete response (pCR) and breast-conserving surgery (BCS) were evaluated using the binary logistic regression analysis., Results: F-CTC in peripheral blood ≥1 at T0 was an independent factor for pCR rate in patients with HER2-positive (odds ratio [OR]=0.08, 95% confidence interval [CI], 0.01-0.98, P = .048). The reduction in the number of F-CTC at T2 was an independent factor for BCS rate (OR = 4.54, 95% CI, 1.14-18.08, P = .03)., Conclusions: The number of F-CTC prior to NAC was related to poor response to NAC. Monitoring of F-CTC may help clinicians formulate personalized NAC regimens and implement BCS for patients with non-metastatic breast cancer., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Dural mater is punctured by using a spinal needle without drugs administrated into intrathecal space directly in dural puncture epidural (DPE) analgesia., Objective: This study aimed to summarize the evidence of benefits and risks of DPE analgesia with 25-G spinal needles for labor pain relief., Methods: DPE analgesia with EP analgesia for labor pain relief were systematically searched. The Embase, MEDLINE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science databases were systematically searched till 6th November 2022 to find out randomized controlled trials (RCTs) comparing DPE (using 25-G spinal needles) with conventional epidural (EP) analgesia. The risk of bias was assessed with the Cochrane tool. Risk ratio, mean difference, and 95% confidence intervals were calculated., Results: Seven RCTs with 761 parturients were identified. Pool data showed that DPE technique was associated with shorter time to pain score ⩽ 3/10, higher percentage with pain score ⩽ 3/10 at 10 min and 20 min, lower incidence of epidural top-up bolus and no S2 block, higher incidence of bilateral S2 blockade at 10 min and during labor, lower incidence of epidural top-up bolus and incidence of asymmetric block. No statistical difference in side effect and parturient satisfaction between DPE and EP technique., Conclusion: DPE technique with 25-G spinal needles was associated with faster analgesia onset and sacral coverage, greater sacral spread, lesser requirement of epidural top-up and lower incidence of asymmetric block. DPE technique with 25-G spinal needles showed a greater benefit to parturients.

Multivalent ligands hold promise for enhancing avidity and selectivity to simultaneously target multimeric proteins, as well as potentially modulating receptor signaling in pharmaceutical applications. Essential for these manipulations are nanosized scaffolds that precisely control ligand display patterns, which can be achieved by using polyproline oligo-helix macrocyclic nanoscaffolds via selective binding to protein oligomers and cell surface receptors. This work focuses on synthesis and structural characterization of different-sized polyproline tri-helix macrocyclic (PP3M) scaffolds. Through combined analysis of circular dichroism (CD), small- and wide-angle X-ray scattering (SWAXS), electron spin resonance (ESR) spectroscopy, and molecular modeling, a non-coplanar tri-helix loop structure with partially crossover helix ends is elucidated. This structural model aligns well with scanning tunneling microscopy (STM) imaging. The present work enhances the precision of nanoscale organic synthesis, offering prospects for controlled ligand positioning on scaffolds. This advancement paves the way for further applications in nanomedicine through selective protein interaction, manipulation of cell surface receptor functions, and developments of more complex polyproline-based nanostructures., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: To compare the effect of Dural puncture epidural (DPE) and conventional epidural (EP), in conjunction with programmed intermittent epidural bolus (PIEB) and low-concentration ropivacaine strategy., Methods: After written informed consent was obtained, healthy nulliparous women with singleton pregnancies, vertex presentation at 38-42 weeks' gestation, cervical dilation of 3-5 cm, and a desire for pain relief were randomly assigned to DPE or EP group. Dural matter was puncture with 25G Whitacre needle in DPE group. Analgesia was initiated with 15 mL of 0.1% ropivacaine over 5 minutes and was maintained by PIEB (8 mL of 0.08% ropivacaine with 2 μg/mL fentanyl every 40 min). Primary outcome was the percentage of adequate analgesia, defined as NRPS ≤1, at 30 minutes after the initiation of the epidural bolus., Results: Out of 130 enrolled parturients, 127 were included in final analysis (64 in DPE group, 63 in EP group). No significant difference was found in percentage of adequate analgesia at 30 minutes (risk ratio: 1.09; 95% confidence interval: 0.90-1.31; P = 0.366). At 8, 12, 14, and 16 minutes, percentage of adequate analgesia was higher in DPE group ( P = 0.023, 0.027, 0.016 and 0.033, respectively). NPRS scores in DPE group decreased more dramatically within the first 30 min. The incidence of S2 sensory blocks at 20 and 30 min in DPE group was higher ( P = 0.010 and 0.006, respectively). There were no differences in patient satisfaction, delivery mode, adverse effects, fetal bradycardia, and Apgar scores at 1 and 5 minutes., Conclusion: The combination of the use of DPE technique with 25G spinal needle and PIEB technique for labor analgesia appears to enhance the quality of labor analgesia by accelerating onset and providing improved sacral blockade, without increasing adverse effects., Competing Interests: The authors declare that they have no conflict of interest., (© 2023 Lin et al.)

Importance: Additional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression., Objective: To evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS., Design, Setting, and Participants: This double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of -0.3 points per month., Interventions: Study treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment., Main Outcomes and Measures: The primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS)., Results: A total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n = 255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n = 127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was -14.67 points (SE, 0.89 points; 95% CI, -16.42 to -12.91 points) for ravulizumab and -13.33 points (SE, 1.22 points; 95% CI, -15.72 to -10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, -1.34 [1.46] points; 95% CI, -4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, -15.7 to 26.6 points; P = .61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%])., Conclusions and Relevance: This trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS., Trial Registration: ClinicalTrials.gov Identifier: NCT04248465.

2A peptides are widely used for polycistronic gene expression from vectors. In contrast, the separation of endogenous genes via 2A peptides has been largely unexplored. We show that in fission yeast Schizosaccharomyces pombe , the "cleaving" efficiency of the 2A peptide from ERBV-1 (Equine rhinitis B virus 1) range from ~70% to ~99% for End4 at different insertion sites. Our results suggest a high "cleaving" efficiency as well as considerable variation for using 2A peptide to separate endogenous protein domains in fission yeast. Verification of the "cleaving" efficiency of 2A peptides is advised for its application., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2023 by the authors.)

Apelin-13 may have neuroprotective effects. We aimed to determine whether serum apelin-13 could serve as a potential biomarker for severity, delayed cerebral ischemia (DCI), and prognosis after human aneurysmal subarachnoid hemorrhage (aSAH). In this prospective, observational, cohort, single-center study of 139 patients with aSAH and 139 healthy individuals, serum apelin-13 levels were determined. The indicators of stroke severity were the Hunt-Hess scale and the modified Fisher grading scale. The prognostic parameters were DCI and 6-month worse prognosis (Extended Glasgow Outcome Scale scores of 1-4). Using binary logistic regression analysis, the relationship between serum apelin-13 levels and prognosis was reported as odds ratios (ORs) with 95% confidence intervals (CIs). Under the receiver operating characteristic curve, prognostic abilities were shown as areas under the curve (AUCs) with 95% CIs. Serum apelin-13 levels were substantially lower in patients than in controls (median, 28.8 versus 48.6 ng/ml; P < 0.001), in patients with DCI than in non-DCI patients (median, 14.9 versus 31.6 ng/ml; P < 0.001), and in patients with worse prognosis than in those with good prognosis (median, 16.3 versus 33.7 ng/ml; P < 0.001). Serum apelin-13 levels were independently correlated with Hunt-Hess scores (beta, -6.836; 95% CI, -8.963-4.708; VIF, 2.219; P = 0.001) and modified Fisher scores (beta, -3.350; 95% CI, -6.151-0.549; VIF, 1.562; P = 0.019). Serum apelin-13 levels were an independent predictor of DCI (OR, 0.951; 95% CI, 0.914-0.990; P = 0.022) and worse prognosis (OR, 0.954; 95% CI, 0.916-0.993; P = 0.013). Serum apelin-13 levels significantly differentiated DCI and poor prognosis, with AUCs of 0.753 (95% CI, 0.656-0.850) and 0.791 (95% CI, 0.713-0.868) respectively. Using the Youden method, serum apelin-13 levels < 19.3 ng/ml distinguished the risk of DCI with 64.7% sensitivity and 77.1% specificity, and serum apelin-13 levels < 30.2 ng/ml discriminated the development of worse prognosis with 89.1% sensitivity and 63.4% specificity. Serum apelin-13 levels combined with Hunt-Hess scores and modified Fisher scores displayed a significantly higher AUC than any one of them for prognostic prediction (all P < 0.05). Decreased serum apelin-13 levels, which are strongly correlated with disease severity, independently predicted poor outcomes following aSAH, substantializing serum apelin-13 as a useful prognostic biomarker of aSAH., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Breast cancer (BC) is a heterogeneous disease characterized by significant differences in prognosis and therapy response. Numerous prognostic tools have been developed for breast cancer. Usually these tools are based on bulk RNA-sequencing (RNA-Seq) and ignore tumor heterogeneity. Consequently, the goal of this study was to construct a single-cell level tool for predicting the prognosis of BC patients. In this study, we constructed a stemness-risk gene score (SGS) model based on single-sample gene set enrichment analysis (ssGSEA). Patients were divided into two groups based on the median SGS. Patients with a high SGS scores had a significantly worse prognosis than those with a low SGS, and these groups exhibited differences in several tumor characteristics, such as immune infiltration, gene mutations, and copy number variants. Our results indicate that the SGS is a reliable tool for predicting prognosis and response to immunotherapy in BC patients.

Marine algicidal bacteria and their metabolites are considered to be one of the most effective strategies to mitigate the harmful algal blooms (HABs). The bacterium Hahella sp. KA22 has previously been confirmed to have strong algicidal activity against the HABs causing microalgae, Heterosigma akashiwo. In this study, the molecular mechanism of microalgae cell death was detected. The results showed that the cell growth rate and photosynthetic efficiency were inhibited with addition of algicidal strain KA22, while the accumulation of reactive oxygen species (ROS) and oxidative damage in H. akashiwo cells increased. A total of 2056 unigenes were recognized to be differentially expressed in transcriptome sequences. In particular, the transcriptional levels of light-harvesting pigments and structural proteins in the oxygen-evolving-complex were continuously down-regulated, corresponding to the significant reduction of photosynthetic efficiency and the accumulation of ROS. Furthermore, glutamate dehydrogenase was significantly up-regulated in abundance. Meanwhile, calcium-dependent protein kinases were also detected with significant changes. Collectively, algicidal stress caused the suppressed electron transfer in chloroplast and impaired detoxification of intracellular oxidants by glutathione, which may subsequently result in multiple cell regulation and metabolic responses and ultimately lead to the ROS-dependent cell death of H. akashiwo., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests to declare that are relevant to the content of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Therapy resistance remains a huge challenge for current breast cancer treatments. Exploring molecular mechanisms of therapy resistance might provide therapeutic targets for patients with advanced breast cancer and improve their prognosis. RNA-binding proteins (RBPs) play an important role in regulating therapy resistance. Here we summarize the functions of RBPs, highlight their tremendously important roles in regulating therapy sensitivity and resistance and we also reveal current therapeutic approaches reversing abnormal functions of RBPs in breast cancer., (© 2023. The Author(s).)

Background: Whole genome bisulfite sequencing (WGBS), possesses the aptitude to dissect methylation status at the nucleotide-level resolution of 5-methylcytosine (5-mC) on a genome-wide scale. It is a powerful technique for epigenome in various cell types, and tissues. As a recently established next-generation sequencing (NGS) platform, GenoLab M is a promising alternative platform. However, its comprehensive evaluation for WGBS has not been reported. We sequenced two bisulfite-converted mammal DNA in this research using our GenoLab M and NovaSeq 6000, respectively. Then, we systematically compared those data via four widely used WGBS tools (BSMAP, Bismark, BatMeth2, BS-Seeker2) and a new bisulfite-seq tool (BSBolt). We interrogated their computational time, genome depth and coverage, and evaluated their percentage of methylated Cs., Result: Here, benchmarking a combination of pre- and post-processing methods, we found that trimming improved the performance of mapping efficiency in eight datasets. The data from two platforms uncovered ~ 80% of CpG sites genome-wide in the human cell line. Those data sequenced by GenoLab M achieved a far lower proportion of duplicates (~ 5.5%). Among pipelines, BSMAP provided an intriguing representation of 5-mC distribution at CpG sites with 5-mC levels > ~ 78% in datasets from human cell lines, especially in the GenoLab M. BSMAP performed more advantages in running time, uniquely mapped reads percentages, genomic coverage, and quantitative accuracy. Finally, compared with the previous methylation pattern of human cell line and mouse tissue, we confirmed that the data from GenoLab M performed similar consistency and accuracy in methylation levels of CpG sites with that from NovaSeq 6000., Conclusion: Together we confirmed that GenoLab M was a qualified NGS platform for WGBS with high performance. Our results showed that BSMAP was the suitable pipeline that allowed for WGBS studies on the GenoLab M platform., (© 2023. The Author(s).)

Introduction: Adverse impacts of soil microplastics (MPs, diameter<5 mm) on vegetative growth and crop production have been widely reported, however, the single and composite damage mechanisms of polyethylene (PE) /polyvinyl chloride (PVC) microplastics (MPs) induced photosynthesis inhibition are still rarely known., Methods: In this study, two widely distributed MPs, PE and PVC, were added to soils at a dose of 7% (dry soil) to examine the single and composite effects of PE-MPs and PVC-MPs on the photosynthetic performance of soybean., Results: Results showed PE-MPs, PVC-MPs and the combination of these two contaminants increased malondialdehyde (MDA) content by 21.8-97.9%, while decreased net photosynthesis rate (Pn) by 11.5-22.4% compared to those in non-stressed plants, PVC MPs caused the most severe oxidative stress, while MPs stress resulted in Pn reduction caused by non-stomatal restriction. The reason for this is the single and composite MPs stress resulted in a 6% to 23% reduction in soybean PSII activity RCs reaction centers, along with negative effects on soybean PSII energy uptake, capture, transport, and dissipation. The presence of K-band and L-band also represents an imbalance in the number of electrons on the donor and acceptor side of PSII and a decrease in PSII energy transfer. Similarly, PVC single stress caused greater effects on soybean chloroplast PSII than PE single stress and combined stresses., Discussion: PE and PVC microplastic stress led to oxidative stress in soybean, which affected the structure and function of photosynthetic PSII in soybean, ultimately leading to a decrease in net photosynthetic rate in soybean., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Song, Song, Zhu, Lin, Zhang and Ning.)

Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here we show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM). Single-cell RNA-seq analyses indicate that retinal ECs from the three mutant mice have increased TGFβ signaling and altered gene expressions associated with vascular maturation and extracellular matrix, correlating with vascular malformation and increased basement membrane thickening in microvesels of mutant retinas. Mechanistic studies suggest that mitochondrial dysfunction from Tfam, Cox10, or Trx2 depletion induces a mitochondrial localization and MAPKs-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling. Importantly, pharmacological blockade of ALK5 signaling or genetic deficiency of SMAD2 prevented retinal vessel growth retardation and AVM in all three mutant mice. Our studies uncover a novel mechanism whereby mitochondrial dysfunction via the ALK5-SMAD2 signaling induces retinal vascular malformations, and have therapeutic values for the alleviation of angiogenesis-associated human retinal diseases., (© 2022. The Author(s).)

Osteoarthritis (OA) is primarily characterized by progressive degeneration and destruction of articular cartilage. Currently, there is no effective method to treat OA. The metabolic disturbance of cartilage extracellular matrix (ECM) and oxidative stress are critical to promote OA progression. Galangin (Gal) is a small molecule compound that pertains to flavonoids. To determine the protective effect and mechanism of Gal against OA progression, various experiments were performed in vitro and in vivo. In vitro, Gal promoted ECM production and attenuated ECM degradation in human OA chondrocytes. The expression of ECM components from human OA cartilage explants was also stimulated by Gal treatment. As demonstrated from the in vivo study, the intra-articular injection of Gal delayed OA progression in rat models. Moreover, RNA sequencing analysis showed that proline/arginine-rich end leucine repeat protein (PRELP) was a molecular target of Gal activity. Gal inhibited oxidative stress and attenuated ECM degradation by activating PRELP expression. The study demonstrated that Gal could attenuate ECM degradation and ameliorate OA progression, and PRELP may be a potential candidate drug of Gal for treating OA., Competing Interests: Declaration of competing interest The authors disclose no potential conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Most cancer-related deaths are a result of metastasis. The development of small molecular inhibitors reversing cancer metastasis represents a promising therapeutic opportunity for cancer patients. This pan-cancer analysis identifies oncogenic roles of membrane-associated phosphatidylinositol transfer protein 3 (PITPNM3), which is crucial for cancer metastasis. Small molecules targeting PITPNM3 must be explored further. Here, PITPNM3-selective small molecular inhibitors are reported. These compounds exhibit target-specific inhibition of PITPNM3 signaling, thereby reducing metastasis of breast cancer cells. Besides, by using nanoparticle-based delivery systems, these PITPNM3-selective compounds loaded nanoparticles significantly repress metastasis of breast cancer in mouse xenograft models and organoid models. Notably, the results establish an important metastatic-promoting role for PITPNM3 and offer PITPNM3 inhibition as a therapeutic strategy in metastatic breast cancer., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Context: Chlorogenic acid (CGA) has good antioxidant effects, but its explicit mechanism in cerebral ischaemia-reperfusion injury is still uncertain., Objective: We studied the effect of CGA in human brain microvascular endothelial cells (HBMECs) under OGD/R damage., Materials and Methods: HBMECs in 4 groups were treated with oxygen-glucose deprivation/re-oxygenation (OGD/R) (4   + 24 h), normal no CGA treatment and different concentrations (20, 40 or 80 μM) of CGA. Male C57BL/6J mice were classified as sham, middle cerebral artery occlusion (MCAO), and MCAO + CGA (30 mg/kg/day) groups. Mice in the sham group were not subjected to MCAO. Cell viability, apoptosis, angiogenesis and related protein levels were investigated by CCK-8, flow cytometry, TUNEL staining, tube formation and western blot assays. Infarct volume of brain tissues was analyzed by TTC staining., Results: CGA curbed apoptosis (from 32.87% to 13.12% in flow cytometry; from 34.46% to 17.8% in TUNEL assay) but accelerated cell angiogenesis of HBMECs with OGD/R treatment. Moreover, CGA augmented activation of the PI3K-Akt signalling (p-PI3K/PI3K level, from 0.39 to 0.49; p-Akt/Akt level, from 0.52 to 0.81), and the effect of CGA on apoptosis and angiogenesis was abolished by an inhibitor of PI3K-Akt signalling. Furthermore, CGA attenuated infarct (from 41.26% to 22.21%) and apoptosis and promoted angiogenesis and activation of the PI3K/Akt signalling in MCAO-induced mice., Conclusions: CGA effectively repressed apoptosis and promoted angiogenesis in OGD/R-treated HBMECs and MCAO-treated mice by modulating PI3K-Akt signalling. Our research provides a theoretical basis for the use of CGA in the treatment of ischaemic stroke.

Objective: To investigate the epidemiological and clinicopathological characteristics of PCa and provide some strategies for the clinical prevention and treatment of the malignancy., Methods: This study included 1 594 cases of pathologically diagnosed PCa after radical prostatectomy in Xiangya Hospital of Central South University from January 1, 2010 to December 31, 2020. We collected the basic information about the patients, their main complaints and clinicopathological results, and analyzed the epidemiological and clinicopathological data., Results: The patients were aged from 28 to 93 years, and the number of PCa cases showed an overall upward trend from 2010 to 2020. Urinary system symptoms were most common (62.53%) as initial symptoms, followed by increased PSA (17.82%), PCa, prostate nodule, prostate mass (8.43%) and bone metastasis (2.94%) found at physical examinations, and the cases of PSA elevation among the clinic visitors increased year by year from 2010 to 2020. Gleason score 7 was found in a largest proportion of the PCa patients, and adenocarcinoma was the main pathological type (78.6%). Logistic regression analysis showed that high Gleason score, instead of age and expressions of Ki67, AR and ERG, was an independent risk factor for intraductal carcinoma., Conclusion: The incidence of PCa shows an increasing trend, and is more common in those over 50 years old. PSA screening is gradually popularized in China. Intraductal carcinoma, as a major risk factor for aggressive PCa and poor prognosis of the malignancy, is significantly correlated with high Gleason scores.

Linezolid is an oxazolidinone antibacterial drug, and its therapeutic drug monitoring and individualized treatment have been challenged since its approval. With the in-depth clinical research of linezolid, we have changed our attitude toward its therapeutic drug monitoring and our view of individualized treatment. On the basis of summarizing the existing clinical studies, and based on the practical experience of each expert in their respective professional fields, we have formed this expert consensus. Our team of specialists is a multidisciplinary team that includes pharmacotherapists, clinical pharmacology specialists, critical care medicine specialists, respiratory specialists, infectious disease specialists, emergency medicine specialists and more. We are committed to the safe and effective use of linezolid in patients in need, and the promotion of its therapeutic drug monitoring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Hu, Xu, Xu, Chen, He, Zhou, Chen, Zhang, Yu, Fang, Zhu, Ji, Lin, Cao, Dai, Lu, Shi, Li, Wang, Li, Fang, Miao, Zhu, Lin, Zhan, Lv, Zhu, Cai, Ying, Chen, Xu, Zhang, Xu, Federico, Jiang and Dai.)

The role of CD39 pathway in Th1 cell function in tuberculosis (TB) is rarely elucidated. The present study aims to investigate the modulating mechanism of CD39 pathway during Mycobacterium tuberculosis (MTB) infection. CD39 expression was examined on host immune cells among patients with TB. The relationship between CD39 expression and Th1 cell function was analysed. Patients with TB displayed dramatically higher CD39 expression on Th1 cells than healthy controls, and a significantly increased expression of surface markers, including activation, exhaustion and apoptosis markers, were noted in CD39 + Th1 cells in comparison with CD39 - Th1 cells. Conversely, CD39 expression on Th1 cells was associated with diminished number of polyfunctional cells producing Th1-type cytokines, and CD39 + Th1 cells showed obviously lower proliferation potential. Notably, tetramer analysis demonstrated a predominant CD39 expression on TB-specific CD4 + cells, which was associated with higher apoptosis and lower cytokine-producing ability. Transcriptome sequencing identified 27 genes that were differentially expressed between CD39 + and CD39 - Th1 cells, such as IL32, DUSP4 and RGS1. Inhibition of CD39 pathway could enhance the activation, proliferation and cytokine-producing ability of Th1 cells. Furthermore, there was a significantly negative correlation between CD39 expression on Th1 cells and nutritional status indicators such as lymphocyte count and albumin levels, and we observed a significant decline in CD39 expression on Th1 cells after anti-TB treatment. CD39 is predominantly expressed on TB-specific Th1 cells and correlated with their exhausted function, which suggests that CD39 could serve as a prominent target for TB therapy., (© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.)

Autophagy, a lysosome-mediated cellular degradation pathway, recycles intracellular components to maintain metabolic balance and survival. Autophagy plays an important role in tumor immunotherapy as a "double-edged sword" that can both promote and inhibit tumor progression. Autophagy acts on innate and adaptive immunity and interacts with immune cells to modulate tumor immunotherapy. The discovery of autophagy inducers and autophagy inhibitors also provides new insights for clinical anti-tumor therapy. However, there are also difficulties in the application of autophagy-related regulators, such as low bioavailability and the lack of efficient selectivity. This review focuses on autophagy-related immunogenic regulation and its application in cancer therapy.

Nutritional Risk Screening index is a standard tool to assess nutritional risk, but epidemiological data are scarce on controlling nutritional status (CONUT) as a prognostic marker in acute haemorrhagic stroke (AHS). We aimed to explore whether the CONUT may predict a 3-month functional outcome in AHS. In total, 349 Chinese patients with incident AHS were consecutively recruited, and their malnutrition risks were determined using a high CONUT score of ≥ 2. The cohort patients were divided into high-CONUT (≥ 2) and low-CONUT (< 2) groups, and primary outcomes were a poor functional prognosis defined as the modified Rankin Scale (mRS) score of ≥ 3 at post-discharge for 3 months. Odds ratios (OR) with 95 % confidence intervals (CI) for the poor functional prognosis at post-discharge were estimated by using a logistic analysis with additional adjustments for unbalanced variables between the high-CONUT and low-CONUT groups. A total of 328 patients (60·38 ± 12·83 years; 66·77 % male) completed the mRS assessment at post-discharge for 3 months, with 172 patients at malnutrition risk at admission and 104 patients with a poor prognosis. The levels of total cholesterol and total lymphocyte counts were significantly lower in high-CONUT patients than low-CONUT patients ( P = 0·012 and < 0·001, respectively). At 3-month post discharge, there was a greater risk for the poor outcome in the high-CONUT compared with the low-CONUT patients at admission (OR: 2·32, 95 % CI: 1·28, 4·17). High-CONUT scores independently predict a 3-month poor prognosis in AHS, which helps to identify those who need additional nutritional managements.

Osteoarthritis (OA) has been reported as a progressive disease in the elderly, primarily characterized by degenerated articular cartilage. There has been no satisfactory drug for the treatment of OA. DL-3-n-butylphthalide (NBP), a small molecule compound extracted from celery seeds, may have antiapoptotic, antioxidant, and anti-inflammatory activities in numerous studies. However, the effects of NBP on OA and its mechanisms have been rarely reported. In this study, the effect of NBP on OA in vitro and in vivo and its possible mechanism were investigated. The results showed that NBP injection into the knee joint inhibited osteoarthritis development in a rat model of osteoarthritis induced by DMM+ACLT. NBP could increase the expressions of extracellular matrix-related components (such as type II collagen, aggrecan, proteoglycan 4, and SRY-box 9) in human osteoarthritic chondrocytes and cartilage explants. Moreover, NBP promoted the expressions of SOD and CAT. NBP upregulated the expression of FoxO3a by inhibiting the PI3K/AKT pathway, which subsequently inhibited the apoptosis of human OA chondrocytes. In conclusion, NBP promotes cartilage extracellular matrix synthesis and inhibits osteoarthritis development and the underlying mechanism related to the activation of FoxO3a., Competing Interests: The authors declare no conflict of interest regarding the publication of this paper., (Copyright © 2022 Yaxin Zhang et al.)

Objective: Growth arrest-specific protein 6 (Gas6) may harbor protective effects in acute brain injury. This study was designed to determine the relation of serum Gas6 levels to severity and prognosis after traumatic brain injury (TBI)., Methods: In this prospective cohort study of 114 controls and 114 patients with severe TBI, multivariate analysis was used to assess relationships between serum Gas6 levels, Glasgow coma scale (GCS) score, Rotterdam computed tomography (CT) score, postinjury 180-day mortality, overall survival and poor prognosis (Extended Glasgow outcome scale score 1-4)., Results: Significantly increased serum Gas6 levels of patients (median, 10.3 ng/mL versus 32.5 ng/mL; P < 0.001), as compared with controls, were independently correlated with Rotterdam CT score (t = 3.629, P < 0.001) and GCS score (t=-3.393, P = 0.001), and independently predicted 180-day mortality (odds ratio, 1.078; 95% confidence interval (CI), 1.007-1.154), overall survival (hazard ratio, 1.074; 95% CI, 1.012-1.139) and poor prognosis (odds ratio, 1.129; 95% CI, 1.059-1.205). Areas under receiver operating characteristic curve (AUCs) of serum Gas6 levels for discriminating risks of 180-day mortality and poor prognosis were 0.785 (95% CI, 0.699-0.857) and 0.793 (95% CI, 0.707-0.863), respectively; and serum Gas6 levels above 30.9 ng/mL and 28.3 ng/mL predicted 180-day mortality and poor prognosis with maximum Youden indices of 0.451 and 0.468, respectively. The predictive ability of serum Gas6 levels for mortality was similar to those of GCS score (AUC, 0.833; 95% CI, 0.751-0.896; P = 0.286) and Rotterdam CT score (AUC, 0.823; 95% CI, 0.740-0.888; P = 0.432). The discriminatory capability of serum Gas6 levels for the risk of poor prognosis was in the range of GCS score (AUC, 0.846; 95% CI, 0.766-0.906; P = 0.178) and Rotterdam CT score (AUC, 0.831; 95% CI, 0.750-0.895; P = 0.368)., Conclusion: Serum Gas6 may appear as a promising biochemical parameter for aiding in the assessment of trauma severity and prediction of prognosis among patients with severe TBI., Competing Interests: The authors have no conflicts of interest in this work., (© 2022 Ni et al.)

Background: Stroke is a leading cause of death and functional impairment in older people. To assess the prospective association between fasting blood glucose-to-glycated hemoglobin ratio and all-cause mortality and poor prognosis in stroke patients., Methods: A total of 971 Chinese inpatients with acute stroke (mean age of 65.7) were consecutively enrolled in the prospective clinical study and followed up for 12 months after discharge. Stress hyperglycemia was measured using the ratio of fasting blood glucose (FBG, mmol/L)/glycated hemoglobin (HbA1c, %). The primary outcome was all-cause mortality, and secondary outcomes were poor prognosis defined as infectious complications, a National Institutes of Health Stroke Scale (NIHSS) score ≥ 6, a Barthel Index score ≤ 60, or a modified Rankin Scale (mRS) score of 3-6, presented as multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) across the quartiles of the FBG/HbA1c ratio., Results: There were 35 (4.1%) all-cause deaths at 3 months and 85 (11.4%) at 12 months. The inpatients with the highest quartile of the FBG/HbA1c ratio had a higher risk of all-cause death at 3 months (adjusted OR: 5.16, 95% CI: 1.03-25.74) and at 12 months (adjusted OR: 2.59, 95% CI: 1.14-5.89)) and a higher risk of infectious complications (adjusted OR 2.37, 95% CI 1.27-4.43) and dysfunction (adjusted OR 1.79, 95% CI 1.06-3.01) during hospitalization than inpatients with the lowest quartile., Conclusions: Stress hyperglycemia, measured by the FBG/HbA1c ratio, was associated with an increased risk of adverse outcomes, including all-cause death, infectious complications, and dysfunction after stroke., (© 2022. The Author(s).)

Background: Hyperbilirubinemia is the most common cause of neonatal hospitalization and, although it generally has a good prognosis, a significant percentage of neonatal patients maintain a high bilirubin level, which can lead to severe complications, including lifelong disability such as growth retardation, encephalopathy, autism and hearing impairment. The study of risk factors for neonatal hyperbilirubinemia has been controversial. Therefore, we evaluated the risk factors of neonatal hyperbilirubinemia using a meta-analysis., Methods: Relevant English and Chinese studies that discussed risk factors for neonatal hyperbilirubinemia were retrieved from the PubMed, EMBASE, Medline, Central, China National Knowledge Infrastructure (CNKI), Wanfang and China Science Digital Library (CSDL). The literature took newborns as the research object, set up a control group, and observed the relationship between exposure factors and neonatal hyperbilirubinemia. The combined effect size was expressed by odds ratio (OR) and 95% confidence interval (CI). The Chi-square test was used to test heterogeneity of the studies, and if it existed, subgroup analyses were used to explore the source of heterogeneity, and the random-effects model was selected for the combined analysis. The fixed-effects model was chosen for the combined analysis if there was no heterogeneity. Publication bias was assessed using Egger's test and funnel plot., Results: Risk factors for neonatal hyperbilirubinemia were exclusive breastfeeding (BF: OR =1.74, 95% CI: 1.42, 2.12, Z=5.43, P<0.00001); glucose-6-phosphate dehydrogenase deficiency (G6PD: OR =1.62, 95% CI: 1.44, 1.81, Z=8.39, P<0.00001); maternal-fetal ABO blood group incompatibility (OR =1.64, 95% CI: 1.42, 1.89, Z=6.75, P<0.00001); and preterm birth (PTB: OR =1.31, 95% CI: 1.17, 1.47, Z=4.60, P<0.00001); there was no heterogeneity or publication bias among the studies (BF: χ 2 =5.34, P=0.25, I 2 =25%; G6PD: χ 2 =4.40, P=0.49, I 2 =0%; ABO: χ 2 =1.91, P=0.75, I 2 =0%; PTB: χ 2 =0.81, P=0.67, I 2 =0%)., Conclusions: Exclusive breastfeeding, G6PD deficiency, ABO incompatibility and premature birth were confirmed as risk factors for neonatal hyperbilirubinemia. Pregnant women with risk factors should be monitored more closely and clinical intervention should be given in a timely manner., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-229/coif). The authors have no conflicts of interest to declare., (2022 Translational Pediatrics. All rights reserved.)

Background: Chlorogenic acid (CGA) is a polyphenolic compound with antioxidant and anti-inflammatory properties. CGA has been shown to improve neuroinflammation. This study is aimed at elucidating the exact mechanism by which CGA reduces neuroinflammation., Methods: Oxygen and glucose deprivation (OGD) was utilized to treat BV2 microglia and HT-22 hippocampal neurons to engineer an in vitro model of hypoxic ischemia reperfusion. The levels of inflammatory factors (IL-1 β , IL-6, TNF- α , IL-4, and IL-10) and oxidative stress factors (MDA, SOD, and GSH-PX) in microglia were determined by ELISA kits. The neuron proliferation was assessed by CCK-8 assay, and LDH kit was used to determine LDH release in neurons. The fluorescent dye DCF-DA was employed to measure ROS levels in neurons. Correlation of MIR497HG, miR-29b-3p, and SIRT1/NF- κ B in neurons and microglia was determined by qRT-PCR. Expressions of inflammatory proteins (COX2, iNOS), oxidative stress pathways (Nrf2, HO-1), and apoptosis-related proteins (Bcl-2, Bax, caspase3, caspase8, and caspase9) in microglia or neurons were determined by western blot. The interactions between MIR497HG and miR-29b-3p, as well as between miR-29b-3p and SIRT1, were determined by dual luciferase assay and RIP assay., Results: CGA attenuated OGD-mediated inflammation and oxidative stress in microglia and inhibited microglia-mediated neuronal apoptosis. CGA increased the levels of MIR497HG and SIRT1 and suppressed the levels of miR-29b-3p in BV2 and HT-22 cells. MIR497HG knockdown, miR-29b-3p upregulation, and SIRT1 inhibition inhibited CGA-mediated anti-inflammatory and neuronal protective functions. There is a targeting correlation between MIR497HG, miR-29b-3p, and Sirt1. MIR497HG sponges miR-29b-3p to regulate SIRT1 expression in an indirect manner., Conclusion: CGA upregulates MIR497HG to curb miR-29b-3p expression, hence initiating the SIRT1/NF- κ B signaling pathway and repressing OGD-elicited inflammation, oxidative stress, and neuron apoptosis., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yong Fan et al.)

Purpose: To investigate the risk factors of increased hidden blood loss (HBL) after total hip arthroplasty (THA) for femoral neck fracture in elderly women and establish the nomogram prediction model for the guidance to reduce HBL in clinic., Patients and Methods: A total of 206 elderly female patients with femoral neck fracture who underwent THA in Northern Jiangsu People's Hospital from January 2019 to November 2021 were included. The demographic and relevant clinical information of the patients were collected. Pearson, independent sample t -test, multiple linear regression and other statistical methods were used for correlation analysis by SPSS 22.0 statistical software. Moreover, the risk factors of postoperative HBL increase in THA patients were obtained and the nomogram prediction model for the guidance to reduce HBL in clinic was established., Results: HBL was 626 ± 400 mL, accounting for 72.8% ± 18.4% of the perioperative total blood loss (TBL) (799 ± 411 mL), while blood loss of HGB was 15.1±10.4 g/L. Multiple linear regression analysis showed that HBL was associated with lower age (regression coefficient = -9.271, P = 0.010), operative time (regression coefficient = 2.653, P = 0.004), preoperative blood calcium (<2.25 mmol/L) (regression coefficient = 232.492, P < 0.001), hypertension (regression coefficient = 150.352, P = 0.002) and osteoporosis (regression coefficient = 276.072, P < 0.001). R software was used to construct the nomogram prediction model and draw the ROC curve and calibration curve. The area under the curve (AUC) is 0.92 and the slope of calibration curve is close to 1., Conclusion: Based on the five independent risk factors including age, operative time, preoperative blood calcium, hypertension and osteoporosis, the nomogram can predict the risk of HBL after THA for femoral neck fracture in elderly women with favorable differentiation and accuracy., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Hong et al.)

Background and Objective: Persistent infection of hepatitis B virus (HBV) and liver damage in immune active chronic hepatitis B (CHB) could be partly due to the overreaction of natural killer (NK) cells, including pro-inflammatory cytokine secretion and cytotoxicity. An immunosuppressive receptor, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is specifically expressed in NK cells. This study aims to investigate the role of the TIGIT signaling pathway in regulating NK cell functions in patients with CHB., Method: We comparatively assessed the expression of TIGIT in NK cells of patients with immune active CHB (CHB-IA), carriers of immune control chronic HBV (CHB-IC), and healthy controls (HCs), and then explored mechanisms of the TIGIT signaling pathway in regulating NK cell-mediated liver injury by different molecular assessments., Result: The expression of TIGIT in NK cells was enhanced in CHB-IC but was reduced in CHB-IA compared with the HC group. In patients with CHB-IA, the expression of TIGIT was inversely correlated with intensity of the liver damage. Moreover, TIGIT-NK cells show higher IFN-γ secretion capability, degranulation activity, and cytotoxicity but lower apoptosis than TIGIT+ NK cells. Blockade of the TIGIT pathway with anti-TIGIT antibody increased NK cell function, while activation of the TIGIT pathway with TIGIT Fc and CD155 Fc chimera protein down-regulated NK cell function., Conclusion: Our data showed that the TIGIT signaling pathway participates in NK cell impairment, which could be used as a new therapeutic target to protect patients with chronic HBV infection from severe liver injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Hou, Mao, Wang, Yu, Luo, Lin and Sun.)

Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer's disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors., Objective: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans., Methods: The effect of LY3202626 versus vehicle on amyloid-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aβ levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey's post hoc test and clinical data used summary statistics., Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC 50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC 50 of 0.275±0.176 nM for lowering Aβ 1-40 and 0.228±0.244 nM for Aβ 1-42 in PDAPP neuronal cultures. In dogs, CSF Aβ 1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ 1-42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans., Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development., Competing Interests: BAW, SLL, SAM, PJC, CDA, LNB, ARB, RAB, RAD, SJG, DEJ, QL, ACL, PCM, BMW, LLW, ZY, JAZ, DLM, DJM are all employed by and minor stockholders in Eli Lilly and Company or were at the time these studies were conducted., (© 2022 – The authors. Published by IOS Press.)

Background: Approximate 25% HER2-positive (HER2 + ) breast cancer (BC) patients treated with trastuzumab recurred rapidly. However, the mechanisms underlying trastuzumab resistance remained largely unclear., Methods: Trastuzumab-resistant associated circRNAs were identified by circRNAs high-throughput screen and qRT-PCR in HER2 + breast cancer tissues with different trastuzumab response. The biological roles of trastuzumab-resistant associated circRNAs were detected by cell vitality assay, colony formation assay, Edu assay, patient-derived xenograft (PDX) models and orthotopic animal models. For mechanisms research, the co-immunoprecipitation, Western blot, immunofluorescence, and pull down assays confirmed the relevant mechanisms of circRNA and binding proteins., Results: We identified a circRNA circCDYL2, which was overexpressed in trastuzumab-resistant patients, which conferred trastuzumab resistance in breast cancer cells in vitro and in vivo. Mechanically, circCDYL2 stabilized GRB7 by preventing its ubiquitination degradation and enhanced its interaction with FAK, which thus sustained the activities of downstream AKT and ERK1/2. Trastuzumab-resistance of HER2 + BC cells with high circCDYL2 could be reversed by FAK or GRB7 inhibitor. Clinically, HER2 + BC patients with high levels of circCDYL2 developed rapid recurrence and had shorter disease-free survival (DFS) and overall survival (OS) following anti-HER2 therapy compared to those with low circCDYL2., Conclusions: circCDYL2-GRB7-FAK complex plays a critical role in maintaining HER2 signaling, which contributes to trastuzumab resistance and circCDYL2 is a potential biomarker for trastuzumab-resistance in HER2 + BC patients., (© 2021. The Author(s).)

Recent advances highlight that non-coding RNAs (ncRNAs) are emerging as fundamental regulators in various physiological as well as pathological processes by regulating macro-autophagy. Studies have disclosed that macro-autophagy, which is a highly conserved process involving cellular nutrients, components, and recycling of organelles, can be either selective or non-selective and ncRNAs show their regulation on selective autophagy as well as non-selective autophagy. The abnormal expression of ncRNAs will result in the impairment of autophagy and contribute to carcinogenesis and cancer progression by regulating both selective autophagy as well as non-selective autophagy. This review focuses on the regulatory roles of ncRNAs in autophagy and their involvement in cancer which may provide valuable therapeutic targets for cancer management., (Copyright © 2021. Published by Elsevier B.V.)

Bone metastasis from triple-negative breast cancer (TNBC) frequently results in poorer prognosis than other types of breast cancer due to the delay in diagnosis and intervention, lack of effective treatments and more skeletal-related complications. In the present study, we identified CTNND1 as a most reduced molecule in metastatic bone lesion from TNBC by way of high throughput sequencing of TNBC samples. In vivo experiments revealed that knockdown of CTNND1 enhanced tumor cells metastasis to bones and also increased neutrophils infiltration in bones. In vitro, we demonstrated that knockdown of CTNND1 accelerated epithelial-mesenchymal transformation (EMT) of tumor cells and their recruitment to bones. The involvement by CTNND1 in EMT and bone homing was achieved by upregulating CXCR4 via activating the PI3K/AKT/HIF-1αpathway. Moreover, TNBC cells with reduced expression of CTNND1 elicited cytotoxic T-cells responses through accelerating neutrophils infiltration by secreting more GM-CSF and IL-8. Clinically, patients with triple-negative breast cancer and lower level of CTNND1 had shorter overall survival (OS) and distant metastasis-free survival (DMFS). It was concluded that downregulation of CTNND1 played a critical role in facilitating bone metastasis of TNBC and that CTNND1 might be a potential biomarker for predicting the risk of bone metastases in TNBC.

Background: The differential diagnosis between tuberculous meningitis (TBM) and bacterial meningitis (BM) remains challenging in clinical practice. This study aimed to establish a diagnostic model that could accurately distinguish TBM from BM., Methods: Patients with TBM or BM were recruited between January 2017 and January 2021 at Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort). The detection for indicators involved in cerebrospinal fluid (CSF) and T-SPOT assay were performed simultaneously. Multivariate logistic regression was used to create a diagnostic model., Results: A total of 174 patients (76 TBM and 98 BM) and another 105 cases (39 TBM and 66 BM) were enrolled from Qiaokou cohort and Caidian cohort, respectively. Significantly higher level of CSF lymphocyte proportion while significantly lower levels of CSF chlorine, nucleated cell count, and neutrophil proportion were observed in TBM group when comparing with those in BM group. However, receiver operating characteristic (ROC) curve analysis showed that the areas under the ROC curve (AUCs) produced by these indicators were all under 0.8. Meanwhile, tuberculosis-specific antigen/phytohemagglutinin (TBAg/PHA) ratio yielded an AUC of 0.889 (95% CI, 0.840-0.938) in distinguishing TBM from BM, with a sensitivity of 68.42% (95% CI, 57.30%-77.77%) and a specificity of 92.86% (95% CI, 85.98%-96.50%) when a cutoff value of 0.163 was used. Consequently, we successfully established a diagnostic model based on the combination of TBAg/PHA ratio, CSF chlorine, CSF nucleated cell count, and CSF lymphocyte proportion for discrimination between TBM and BM. The established model showed good performance in differentiating TBM from BM (AUC: 0.949; 95% CI, 0.921-0.978), with 81.58% (95% CI, 71.42%-88.70%) sensitivity and 91.84% (95% CI, 84.71%-95.81%) specificity. The performance of the diagnostic model obtained in Qiaokou cohort was further validated in Caidian cohort. The diagnostic model in Caidian cohort produced an AUC of 0.923 (95% CI, 0.867-0.980) with 79.49% (95% CI, 64.47%-89.22%) sensitivity and 90.91% (95% CI, 81.55%-95.77%) specificity., Conclusions: The diagnostic model established based on the combination of four indicators had excellent utility in the discrimination between TBM and BM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Luo, Xue, Lin, Mao, Tang, Song, Liu, Wu, Liu, Zhou, Xu, Xiong, Wang, Yuan, Gan, Sun and Wang.)

Background: Novel approaches for tuberculosis (TB) diagnosis, especially for distinguishing active TB (ATB) from latent TB infection (LTBI), are urgently warranted. The present study aims to determine whether the combination of HLA-DR on Mycobacterium tuberculosis (MTB)-specific cells and TB antigen/phytohemagglutinin (TBAg/PHA) ratio could facilitate MTB infection status discrimination., Methods: Between June 2020 and June 2021, participants with ATB and LTBI were recruited from Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort), respectively. The detection of HLA-DR on MTB-specific cells upon TB antigen stimulation and T-SPOT assay were simultaneously performed on all subjects., Results: A total of 116 (54 ATB and 62 LTBI) and another 84 (43 ATB and 41 LTBI) cases were respectively enrolled from Qiaokou cohort and Caidian cohort. Both HLA-DR on IFN-γ + TNF-α + cells and TBAg/PHA ratio showed discriminatory value in distinguishing between ATB and LTBI. Receiver operator characteristic (ROC) curve analysis showed that HLA-DR on IFN-γ + TNF-α + cells produced an area under the ROC curve (AUC) of 0.886. Besides, TBAg/PHA ratio yield an AUC of 0.736. Furthermore, the combination of these two indicators resulted in the accurate discrimination with an AUC of 0.937. When the threshold was set as 0.36, the diagnostic model could differentiate ATB from LTBI with a sensitivity of 92.00% and a specificity of 81.82%. The performance obtained in Qiaokou cohort was further validated in Caidian cohort., Conclusions: The combination of HLA-DR on MTB-specific cells and TBAg/PHA ratio could serve as a robust tool to determine TB disease states., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Luo, Xue, Tang, Lin, Song, Liu, Yin, Huang, Wei, Mao, Wang and Sun.)

Objectives: The longitudinal and systematic evaluation of immunity in coronavirus disease 2019 (COVID-19) patients is rarely reported., Methods: Parameters involved in innate, adaptive, and humoral immunity were continuously monitored in COVID-19 patients from onset of illness until 45 days after symptom onset., Results: This study enrolled 27 mild, 47 severe, and 46 deceased COVID-19 patients. Generally, deceased patients demonstrated a gradual increase of neutrophils and IL-6 but a decrease of lymphocytes and platelets after the onset of illness. Specifically, sustained low numbers of CD8 + T cells, NK cells, and dendritic cells were noted in deceased patients, while these cells gradually restored in mild and severe patients. Furthermore, deceased patients displayed a rapid increase of HLA-DR expression on CD4 + T cells in the early phase, but with a low level of overall CD45RO and HLA-DR expressions on CD4 + and CD8 + T cells, respectively. Notably, in the early phase, deceased patients showed a lower level of plasma cells and antigen-specific IgG, but higher expansion of CD16 + CD14 + proinflammatory monocytes and HLA-DR - CD14 + monocytic-myeloid-derived suppressor cells (M-MDSCs) than mild or severe patients. Among these immunological parameters, M-MDSCs showed the best performance in predicting COVID-19 mortality, when using a cutoff value of ≥10%. Cluster analysis found a typical immunological pattern in deceased patients on day 9 after onset, which was characterized as the increase of inflammatory markers (M-MDSCs, neutrophils, CD16 + CD14 + monocytes, and IL-6) but a decrease of host immunity markers., Conclusions: This study systemically characterizes the kinetics of immunity of COVID-19, highlighting the importance of immunity in patient prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tang, Huang, Luo, Liu, Lin, Mao, Wu, Xiong, Hou, Sun and Wang.)

Knee osteoarthritis (KOA) refers to a common disease in orthopaedics, whereas effective treatments have been rarely developed. As indicated from existing studies, chondrocyte death, extracellular matrix degradation and subchondral bone injury are recognized as the pathological basis of KOA. The present study aimed to determine the therapeutic effect of decellularized extracellular matrix-chitosan (dECM-CS) compound on KOA. In this study, rat knee cartilage was decellularized, and a satisfactory decellularized extracellular matrix was developed. As suggested from the in vitro experiments, the rat chondrocytes co-cultured with allogeneic dECM grew effectively. According to the results of the alamar blue detection, dECM did not adversely affect the viability of rat chondrocytes, and dECM could up-regulate the genes related to the cartilage synthesis and metabolism. As reported from the animal experiments, dECM-CS compound could protect cartilage, alleviate knee joint pain in rats, significantly delay the progress of KOA in rats, and achieve high drug safety. In brief, dECM-CS compound shows a good therapeutic effect on KOA., Competing Interests: The authors declare that they have no competing interests., (© 2021 Chen et al.)

Background: Rapid and effective discrimination between active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains a challenge. There is an urgent need for developing practical and affordable approaches targeting this issue., Methods: Participants with ATB and LTBI were recruited at Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort) based on positive T-SPOT results from June 2020 to January 2021. The expression of activation markers including HLA-DR, CD38, CD69, and CD25 was examined on Mycobacterium tuberculosis (MTB)-specific CD4 + T cells defined by IFN-γ, TNF-α, and IL-2 expression upon MTB antigen stimulation., Results: A total of 90 (40 ATB and 50 LTBI) and another 64 (29 ATB and 35 LTBI) subjects were recruited from the Qiaokou cohort and Caidian cohort, respectively. The expression patterns of Th1 cytokines including IFN-γ, TNF-α, and IL-2 upon MTB antigen stimulation could not differentiate ATB patients from LTBI individuals well. However, both HLA-DR and CD38 on MTB-specific cells showed discriminatory value in distinguishing between ATB patients and LTBI individuals. As for developing a single candidate biomarker, HLA-DR had the advantage over CD38. Moreover, HLA-DR on TNF-α + or IL-2 + cells had superiority over that on IFN-γ + cells in differentiating ATB patients from LTBI individuals. Besides, HLA-DR on MTB-specific cells defined by multiple cytokine co-expression had a higher ability to discriminate patients with ATB from LTBI individuals than that of MTB-specific cells defined by one kind of cytokine expression. Specially, HLA-DR on TNF-α + IL-2 + cells produced an AUC of 0.901 (95% CI, 0.833-0.969), with a sensitivity of 93.75% (95% CI, 79.85-98.27%) and specificity of 72.97% (95% CI, 57.02-84.60%) as a threshold of 44% was used. Furthermore, the performance of HLA-DR on TNF-α + IL-2 + cells for differential diagnosis was obtained with validation cohort data: 90.91% (95% CI, 72.19-97.47%) sensitivity and 68.97% (95% CI, 50.77-82.73%) specificity., Conclusions: We demonstrated that HLA-DR on MTB-specific cells was a potentially useful biomarker for accurate discrimination between ATB and LTBI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Luo, Xue, Mao, Lin, Tang, Song, Liu, Tong, Hou, Huang, Ouyang, Wang and Sun.)

Phosphatidylinositol transfer protein membrane-associated 1 (PITPNM1) contains a highly conserved phosphatidylinositol transfer domain which is involved in phosphoinositide trafficking and signaling transduction under physiological conditions. However, the functional role of PITPNM1 in cancer progression remains unknown. Here, by integrating datasets of The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer (METABRIC), we found that the expression of PITPNM1 is much higher in breast cancer tissues than in normal breast tissues, and a high expression of PITPNM1 predicts a poor prognosis for breast cancer patients. Through gene set variation analysis (GSEA) and gene ontology (GO) analysis, we found PITPNM1 is mainly associated with carcinogenesis and cell-to-cell signaling ontology. Silencing of PITPNM1, in vitro, significantly abrogates proliferation and colony formation of breast cancer cells. Collectively, PITPNM1 is an important prognostic indicator and a potential therapeutic target for breast cancer.

Since the discovery of the first microRNA (miRNA), the exploration of miRNA biology has come to a new era in recent decades. Monumental studies have proven that miRNAs can be dysregulated in different types of cancers and the roles of miRNAs turn out to function to either tumor promoters or tumor suppressors. The interplay between miRNAs and the development of cancers has grabbed attention of miRNAs as novel tools and targets for therapeutic attempts. Moreover, the development of miRNA delivery system accelerates miRNA preclinical implications. In this review, we depict recent advances of miRNAs in cancer and discuss the potential diagnostic or therapeutic approaches of miRNAs.