Impact of obesity on sentinel lymph node biopsy outcomes and survival in breast cancer patients: A single-center retrospective study.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a common choice for axillary surgery in patients with early-stage breast cancer (BC) who have clinically negative lymph nodes. Most research indicates that obesity is a prognostic factor for BC patients, but studies assessing its association with the rate of positive sentinel lymph nodes (SLN) and the prognosis of patients with early BC undergoing SLNB are limited. METHODS: Between 2013 and 2016, 7062 early-stage BC patients from the Shanghai Cancer Center of Fudan University were included. Based on the Chinese Body Mass Index (BMI) classification standards, the patients were divided into three groups as follows: normal weight, overweight, and obese. Propensity score matching analysis was used to balance the baseline characteristics of the participants. Logistic regression analysis was used to determine the association between obesity and positive SLN rate. Cox regression analysis was used to investigate whether obesity was an independent prognostic factor for early-stage BC patients who had undergone SLNB. RESULTS: No significant association was observed between obesity and positive SLN rate in early-stage BC patients who had undergone SLNB. However, multivariate analysis revealed that compared to patients with normal BMI, the overall survival (hazard ratio (HR) 2.240, 95% confidence interval (CI) 1.27-3.95, p = 0.005) and disease-free survival (HR 1.750, 95% CI 1.16-2.62, p = 0.007) were poorer in patients with high BMI. CONCLUSION: Obesity is an independent prognostic factor for early-stage BC patients who undergo SLNB; however, it does not affect the positive SLN rate.

CRTAM promotes antitumor immune response in triple negative breast cancer by enhancing CD8+ T cell infiltration.

The immunomodulatory (IM) subtype of triple negative breast cancer (TNBC) exhibits high expression of immune cell signaling genes and is more responsive to immunotherapy. However, the specific mechanism underlying this phenomenon remains unclear. One of the potential key genes appears to be the cytotoxic and regulatory T cell molecule (CRTAM). A cohort of 360 previously untreated TNBC patients from Fudan University Shanghai Cancer Center (FUSCC) underwent RNA sequencing analysis of their primary tumor tissue. Combined with three RNA-seq datasets obtained from the GEO database, a LASSO regression analysis was conducted to identify genes specific to the IM type of TNBC. Our findings revealed elevated CRTAM expression in the IM-type TNBC, which correlated with a favorable overall survival and recurrence-free survival in TNBC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated a strong association between CRTAM and immune responses as well as immune system processes. Notably, CRTAM overexpression induced STAT1 phosphorylation and upregulation of interferon-stimulated genes. We also found that CRTAM enhanced tumor-associated immune cell infiltration, especially CD8+ T cells, which may be related to the increased expression of MHC class I molecules caused by CRTAM overexpression. These results suggest that CRTAM may serve as a potential biomarker for predicting the efficacy of immunotherapy in TNBC.

Paeoniflorin improves ulcerative colitis via regulation of PI3K­AKT based on network pharmacology analysis.

Paeoniflorin (PF) is the primary component derived from Paeonia lactiflora and white peony root and has been used widely for the treatment of ulcerative colitis (UC) in China. UC primarily manifests as a chronic inflammatory response in the intestine. In the present study, a network pharmacology approach was used to explore the specific effects and underlying mechanisms of action of PF in the treatment of UC. A research strategy based on network pharmacology, combining target prediction, network construction, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and molecular docking simulation was used to predict the targets of PF. A total of 288 potential targets of PF and 599 UC-related targets were identified. A total of 60 therapeutic targets of PF against UC were identified. Of these, 20 core targets were obtained by protein-protein interaction network construction. GO and KEGG pathway analyses showed that PF alleviated UC through EGFR tyrosine kinase inhibitor resistance, the IL-17 signaling pathway, and the PI3K/AKT signaling pathway. Molecular docking simulation showed that AKT1 and EGFR had good binding energy with PF. Animal-based experiments revealed that the administration of PF ameliorated the colonic pathological damage in a dextran sulfate sodium-induced mouse model, resulting in lower levels of proinflammatory cytokines including IL-1ß, IL-6, and TNF-α, and higher levels of IL-10 and TGF-ß. PF decreased the mRNA and protein expression levels of AKT1, EGFR, mTOR, and PI3K. These findings suggested that PF plays a therapeutic protective role in the treatment of UC by regulating the PI3K/AKT signaling pathway.

Latissimus dorsi flap - the main force in breast reconstruction for breast tumor in Chinese population.

Background: The latissimus dorsi flap (LDF) is the most commonly used autologous flap for breast reconstruction (BR) in China. We conducted this study to explore the current status of BR using LDF with/without implants. Methods: This study was a single-center retrospective study that included breast tumor patients who underwent LDF breast reconstruction at Fudan University Shanghai Cancer Center (FUSCC) between 2000 and 2021. Results: We analyzed 4918 patients who underwent postmastectomy BR, including 1730 patients (35.2%) with autologous flaps. LDF was used for BR in 1093 (22.2%) patients, and an abdominal flap was used in 637 (13.0%) patients. The proportion of LDFs used in autologous BR patients decreased each year and dropped to approximately 65.0% after 2013 due to the increased use of abdominal flaps. Among these patients, 609 underwent extended LDF (ELDF) BR, 455 underwent LDF BR with implants, and 30 received a LDF as a salvage flap due to previous flap or implant failure. Patients who underwent ELDF reconstruction were older and had a higher BMI than those who received a LDF with implants. There was no significant difference in the mean postoperative hospital stay, neoadjuvant chemotherapy rates, or adjuvant radiotherapy rates between the two groups. Major complications requiring surgical intervention occurred in 25 patients (2.29%). There was no significant difference in the incidence of major complications between the two groups (P=0.542). Conclusions: LDF breast reconstruction is a well-developed and safe procedure. The duration of postoperative hospitalization nor the incidence of major complications was affected by implant use.

Development of Sustainable Engineered Cementitious Composites by Incorporating Local Recycled Fine Aggregate.

In this study, sustainable engineered cementitious composites (ECC) exhibiting high tensile strength as well as high tensile strain capacity were successfully developed by incorporating polyethylene (PE) fiber, local recycled fine aggregate (RFA), and limestone calcined clay cement (LC3). The improvement in tensile strength and tensile ductility was attributed to the self-cementing properties of RFA as well as the pozzolanic reaction between calcined clay and cement. Carbonate aluminates were also generated owing to the reaction between calcium carbonate in limestone and the aluminates in both calcined clay and cement. The bond strength between fiber and matrix was also enhanced. At the age of 150 days, the tensile stress-strain curves of ECC containing LC3 and RFA shifted from a bilinear model to a trilinear model, and the hydrophobic PE fiber exhibited hydrophilic bonding performance when embedded in RFA-LC3-ECC matrix, which could be explained by the densified cementitious matrix as well as the refined pore structure of ECC. Moreover, the substitution of ordinary Portland cement (OPC) by LC3 resulted in energy consumption and equivalent CO2 emission reduction ratios of 13.61% and 30.34%, respectively, when the replacement ratio of LC3 is 35%. Therefore, PE fiber-reinforced RFA-LC3-ECC demonstrates excellent mechanical performance as well as considerable environmental benefits.

NPAS4 Exacerbates Pyroptosis via Transcriptionally Regulating NLRP6 in the Acute Phase of Intracerebral Hemorrhage in Mice.

Intracerebral hemorrhage (ICH) is a severe cerebrovascular disease with a high disability rate and high mortality, and pyroptosis is a type of programmed cell death in the acute phase of ICH. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is a specific transcription factor highly expressed in the nervous system, yet the role of NPAS4 in ICH-induced pyroptosis is not fully understood. NLR family Pyrin-domain-containing 6 (NLRP6), a new member of the Nod-like receptor family, aggravates pyroptosis via activating cysteine protease-1 (Caspase-1) and Caspase-11. In this study, we found that NPAS4 was upregulated in human and mouse peri-hematoma brain tissues and peaked at approximately 24 h after ICH modeling. Additionally, NPAS4 knockdown improved neurologic dysfunction and brain damage induced by ICH in mice after 24 h. Meanwhile, inhibiting NPAS4 expression reduced the levels of myeloperoxidase (MPO)-positive cells and Caspase-1/TUNEL-double-positive cells and decreased cleaved Caspase-1, cleaved Caspase-11, and N-terminal GSDMD levels. Consistently, NPAS4 overexpression reversed the above alternations after ICH in the mice. Moreover, NPAS4 could interact with the Nlrp6 promoter region (-400--391 bp and -33--24 bp) and activate the transcription of Nlrp6. Altogether, our study demonstrated that NPAS4, as a transcription factor, can exacerbate pyroptosis and transcriptionally activate NLRP6 in the acute phase of intracerebral hemorrhage in mice.

Ferroptosis: Promising approach for cancer and cancer immunotherapy.

Ferroptosis is the cell death induced by ferrous ions and lipid peroxidation accumulation in tumor cells. Targeting ferroptosis, which is regulated by various metabolic and immune elements, might become a novel strategy for anti-tumor therapy. In this review, we will focus on the mechanism of ferroptosis and its interaction with cancer and tumor immune microenvironment, especially for the relationship between immune cells and ferroptosis. Also, we will discuss the latest preclinical progress of the collaboration between the ferroptosis-targeted drugs and immunotherapy, and the best potential conditions for their combined use. It will present a future insight on the possible value of ferroptosis in cancer immunotherapy.

Tracking of Mutational Signature of SARS-CoV-2 Omicron on Distinct Continents and Little Difference was Found.

The Omicron variant is currently ravaging the world, raising serious concern globally. Monitoring genomic variations and determining their influence on biological features are critical for tracing its ongoing transmission and facilitating effective measures. Based on large-scale sequences from different continents, this study found that: (i) The genetic diversity of Omicron is much lower than that of the Delta variant. Still, eight deletions (Del 1-8) and 1 insertion, as well as 130 SNPs, were detected on the Omicron genomes, with two deletions (Del 3 and 4) and 38 SNPs commonly detected on all continents and exhibiting high-occurring frequencies. (ii) Four groups of tightly linked SNPs (linkage I-IV) were detected, among which linkage I, containing 38 SNPs, with 6 located in the RBD, increased its occurring frequency remarkably over time. (iii) The third codons of the Omicron shouldered the most mutation pressures, while the second codons presented the least flexibility. (iv) Four major mutants with amino acid substitutions in the RBD were detected, and further structural analysis suggested that the substitutions did not alter the viral receptor binding ability greatly. It was inferred that though the Omicron genome harbored great changes in antigenicity and remarkable ability to evade immunity, it was immune-pressure selected. This study tracked mutational signatures of Omicron variant and the potential biological significance of the SNPs, and the linkages await further functional verification.

Ultrasound-guided Versus Computed Tomography Fluoroscopy-assisted Cervical Transforaminal Steroid Injection for the Treatment of Radicular Pain in the Lower Cervical Spine: A Randomized Single-blind Controlled Noninferiority Study.

OBJECT: To estimate the contrast dispersion short-term clinical efficacy and safety of ultrasound (US)-guided transforaminal steroid injection (TFSI) compared with computed tomography (CT) guidance for the treatment of cervical radicular pain. METHOD: A total of 430 patients with cervical radicular pain from cervical herniated disk or cervical spondylosis were recruited in the randomized, single-blind, controlled, noninferiority trial. The patients were randomly assigned to receive either the US-guided or CT-guided TFSI for 1 affected cervical nerve. The dispersion pattern of contrast was monitored at the time of TFSI in both groups, using CT. Patients were assessed for pain intensity by numeric rating scale (NrS) and functional disability by Neck Disability Index (NDI) at baseline, 1 and 3 months after the intervention. Complications were also recorded. RESULTS: The satisfactory rate of contrast distribution was respectively 92.1% in US group and 95.8% in CT group. Pain reduction and functional improvement were showed in both groups during follow-up. Statistical difference was not observed in the decrease in NRS pain scores and NDI scores between 2 groups with F =1.050, P =0.306 at 1 month and F =0.103, P =0.749 at 3 months after intervention. No permanent and severe complications were observed. CONCLUSIONS: This study demonstrated that US provided a noninferior injectate spread pattern and similar improvement of radicular pain and functional status when compared with CT-guided TFSI. US may be advantageous during this procedure because it allows visualization of critical vessels and avoids radiation exposure.

The Prognostic Values of Androgen Receptor in Breast Cancer.

CONTEXT.­: Whether androgen receptor (AR) expression can predict prognosis in breast cancer is under debate. OBJECTIVE.­: To analyze, retrospectively, the prognostic and treatment-predictive ability of AR status in breast cancer. DESIGN.­: A total of 5765 patients diagnosed with primary invasive breast cancer without distant metastasis in the adjuvant setting were analyzed. The propensity score-matching method was used to develop a new cohort of 3978 patients (1989 patients each) in which important prognostic factors were balanced. RESULTS.­: Positive AR expression is an independent prognostic factor for disease-free survival and overall survival. Estrogen receptor (ER)+ and progesterone receptor (PR)+ AR+ breast cancer patients had the longest survival, whereas ER-PR-AR- breast cancer patients had the shortest survival. The ER/PR/AR combinations could not predict the treatment effects for adjuvant trastuzumab but could be used for adjuvant chemotherapy and endocrine therapy selection. The worst survival was found in ER+PR-AR- patients receiving toremifene, ER+PR-AR+ patients receiving exemestane, ER+PR+AR- patients receiving anthracycline, and ER-PR-AR+ patients receiving taxanes. ER+PR-AR-, ER-PR-AR+, and ER-PR-AR- patients were associated with the worst survival among those who received radiotherapy and anthracycline plus taxanes. CONCLUSIONS.­: AR in combination with ER and PR could predict the prognosis and treatment effects of chemotherapy, endocrine therapy, and radiotherapy in the adjuvant setting.

MNX1 Promotes Anti-HER2 Therapy Sensitivity via Transcriptional Regulation of CD-M6PR in HER2-Positive Breast Cancer.

Although targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer has significantly prolonged survival time and improved patients' quality of life, drug resistance has gradually emerged. This study explored the mechanisms underlying the effect of the motor neuron and pancreatic homeobox 1 (MNX1) genes on drug sensitivity in HER2-positive breast cancer. From July 2017 to 2018, core needle biopsies of HER2-positive breast cancer were collected from patients who received paclitaxel, carboplatin, and trastuzumab neoadjuvant therapy at our center. Based on treatment efficacy, 81 patients were divided into pathological complete response (pCR) and non-pCR groups. High-throughput RNA sequencing results were analyzed along with the GSE181574 dataset. MNX1 was significantly upregulated in the pCR group compared with the non-pCR group in both sequencing datasets, suggesting that MNX1 might be correlated with drug sensitivity in HER2-positive breast cancer. Meanwhile, tissue array results revealed that high MNX1 expression corresponded to a good prognosis. In vitro functional tests showed that upregulation of MNX1 significantly increased the sensitivity of HER2-positive breast cancer cells to lapatinib and pyrotinib. In conclusion, MNX1 may serve as a prognostic marker for patients with HER2-positive breast cancer, and its expression may facilitate clinical screening of patients sensitive to anti-HER2-targeted therapy.

The Role of Tumor Microenvironment in Invasion and Metastasis of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in the world, with a high rate of morbidity. The invasion and metastasis of ESCC is the main reason for high mortality. More and more evidence suggests that metastasized cancer cells require cellular elements that contribute to ESCC tumor microenvironment (TME) formation. TME contains many immune cells and stromal components, which are critical to epithelial-mesenchymal transition, immune escape, angiogenesis/lymphangiogenesis, metastasis niche formation, and invasion/metastasis. In this review, we will focus on the mechanism of different microenvironment cellular elements in ESCC invasion and metastasis and discuss recent therapeutic attempts to restore the tumor-suppressing function of cells within the TME. It will represent the whole picture of TME in the metastasis and invasion process of ESCC.

Neoadjuvant Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer.

Lung cancer is the leading cause of cancer-related death worldwide. A meta-analysis was conducted to assess the benefits and risks of neoadjuvant immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Online databases, including PubMed, Embase, Web of Science, Cochrane Library, and clinicaltrials.gov, were retrospectively and systematically searched for eligible trials from database inception to May 2021. A total of 792 patients from 21 clinical trials were included. For surgical data, the pooled operation rate and R0 resection rate were 92% (95% CI 87-96%) and 97% (95% CI 94-99%). Additionally, neoadjuvant ICIs achieved a major pathological response (MPR) of 39% (95% CI 25-53%), including 25% (95% CI 16-36%) pathological complete response (pCR). With radiological response assessment, the pooled objective response rate (ORR) and disease control rate (DCR) were 44% (95% CI 21-68%) and 88% (95% CI 75-98%), respectively. In terms of safety, the pooled rate of any-grade and grade 3-5 treatment-related adverse effects (TRAEs) were 57% (95% CI 38-76%) and 15% (95% CI 6-28%). Eventually, the study concludes that neoadjuvant ICIs are effective and safe for patients with early-stage NSCLC. Key Words: Neoadjuvant therapy, Immune checkpoint inhibitors, Non-small cell lung cancer, Meta-analysis.

Long-term recurrence-free survival and complications of percutaneous balloon compression and radiofrequency thermocoagulation of Gasserian ganglion for trigeminal neuralgia: A retrospective study of 1313 cases.

OBJECTIVE: To estimate long-term recurrence, complications after percutaneous balloon compression (PBC) and radiofrequency thermocoagulation (RFT) of gasserian ganglion among a large sample of patients with trigeminal neuralgia (TN) during a long-term follow-up. METHODS: A retrospective analysis of 1313 patients undergoing PBC or RFT for the treatment of TN was conducted from 2006 to 2020. Recurrence-free survival (RFS) was assessed by the Kaplan-Meier method. Complications including facial numbness, corneal reflex decrease and masseter weakness were also estimated. RESULTS: For patients who received first initial PBC and RFT, the median RFS was 130.1 months (95% CI: 124.4, 135.9) and 123.3 months (95% CI: 117.6, 128.9) in PBC and RFT group with log-rank p = 0.108. The RFS rate was, respectively, 90.6% (95% CI: 88.1%-93.3%) and 91.4% (95% CI: 89.1%-93.7%) at 1 year, 84.6% (95% CI: 81.4%-87.8%) and 83.3% (95% CI: 80.3%-86.3%) at 3 years, 81.5% (95% CI: 78.1%-85.0%), and 78.6% (95% CI: 75.2%-81.9%) at 5 years, 71.5% (95% CI: 67.5%-75.5%), and 64.8% (95% CI: 61.0%-68.7%) at 10 years in two groups. No significant difference was observed in facial numbness degree between two groups after procedure. Compared with PBC group, ophthalmic complication prevalence was higher in RFT group (9.6%) (p = 0.001). However, masseter weakness incidence was lower (10.7%) than that in PBC group (24.0%) with p < 0.001. CONCLUSIONS: Patients with TN seemed to attain similar long-term benefit from PBC and RFT, especially in elderly. However, in order to reduce postoperative complications, PBC provided a safer and alternative for treating TN involving ophthalmic division, whereas RFT could be employed as a preferred regimen for maxillary and mandibular TN.

Benefits of neoadjuvant therapy compared with adjuvant chemotherapy for the survival of patients with HER2-positive breast cancer: A retrospective cohort study at FUSCC.

PURPOSE: Neoadjuvant therapy (NAT) is considered the standard of care for patients with HER2-positive breast cancer (BC). However, there is no proven survival benefit of NAT compared to adjuvant therapy for the survival of patients with early-stage HER2-positive BC. This study aimed to compare the prognosis of HER2-positive BC patients treated with NAT to that of patients treated with adjuvant therapy. METHODS: This was a single-center real-world retrospective study. This study analyzed the disease-free survival (DFS) and overall survival (OS) of 538 HER2-positive BC patients treated with neoadjuvant therapy and 2684 patients treated with adjuvant therapy at Fudan University Shanghai Cancer Center (FUSCC) between 2012 and 2016. Patients with a clinical tumor size (cT) ≤5 cm or >5 cm were matched using the propensity score matching (PSM) method to prevent selection bias. RESULTS: After PSM, among patients with cT ≤ 5 cm, there was no significant difference in DFS (P = 0.08) or OS (P = 0.11) between the two groups. The analysis of survival outcomes of patients treated with neoadjuvant and adjuvant therapy in the different chemotherapy subgroups yielded consistent results. According to multivariate analysis, lymph node status and response to NAT showed independent prognostic value for OS and DFS. Among patients with cT > 5 cm, the DFS (P = 0.25) and OS (P = 0.57) of patients treated with NAT were similar to those of patients treated with adjuvant therapy after PSM. CONCLUSION: We confirmed the equivalent effects of adjuvant therapy and NAT in HER2-positive BC patients. Neoadjuvant therapy should be used for patients with HER2-positive BC.

Multiscale Investigation on the Performance of Engineered Cementitious Composites Incorporating PE Fiber and Limstone Calcined Clay Cement (LC3).

Limestone calcined clay cement (LC3) is successfully used to fabricate engineered cementitious composites (ECC) exhibiting tensile strength σtu of 9.55 ± 0.59 MPa or tensile strain capacity εtu of 8.53 ± 0.30%. The high tensile strength of the composites is closely related to the improvement of fiber/matrix interfacial bond strength, and the high ductility is attributed to the enhancement of fiber dispersion homogeneity. For the case of ECC incorporating 50% LC3, the reduction of initial cracking stress σtc that favors the growth of the crack in a controlled manner also contributes to the improvement of strain hardening behavior. The composition analysis indicates that carboaluminates and additional hydration products including C-(A)-S-H and ettringite are generated, which contributes to the densification of the microstructure of the ECC matrix. The pore structure is thus remarkably refined. Besides, when ordinary Portland cement (OPC) is partly replaced by LC3, the consumed energy and equivalent CO2 emission decrease, especially the equivalent CO2 emission with the reduction ratio attaining 40.31%. It is found that ECC using 35% LC3 exhibits the highest mechanical resistance and ECC incorporating 50% LC3 shows the highest ductility from the environmental point of view.

High-Performance Wearable Sensor Inspired by the Neuron Conduction Mechanism through Gold-Induced Sulfur Vacancies.

Practical application of wearable gas-sensing devices has been greatly inhibited by the poorly sensitive and specific recognition of target gases. Rapid charge transfer caused by rich sensory neurons in the biological olfactory system has inspired the construction of a highly sensitive sensor network with abundant defect sites for adsorption. Herein, for the first time, we demonstrate an in situ formed neuron-mimic gas sensor in a single gas-sensing channel, which is derived from lattice deviation of S atoms in Bi2S3 nanosheets induced by gold quantum dots. Due to the favorable gas adsorption and charge transfer properties arising from S vacancies, the fabricated sensor exhibits a significantly enhanced response value of 5.6-5 ppm NO2, ultrafast response/recovery performance (18 and 338 s), and excellent selectivity. Furthermore, real-time visual detection of target gases has been accomplished by integrating the flexible sensor into a wearable device.

The pivotal role of the NLRC4 inflammasome in neuroinflammation after intracerebral hemorrhage in rats.

The NLRC4 inflammasome, a member of the nucleotide-binding and oligomerization domain-like receptor (NLR) family, amplifies inflammation by facilitating the processing of caspase-1, interleukin (IL)-1ß, and IL-18. We explored whether NLRC4 knockdown alleviated inflammatory injury following intracerebral hemorrhage (ICH). Furthermore, we investigated whether NLRC4 inflammasome activation can be adjusted by the regulator of G protein signaling 2/leucine-rich repeat kinase-2 pathway. Fifty microliters of arterial blood was drawn and injected into the basal ganglion to simulate the ICH model. NLRC4 small interfering RNAs (siRNAs) were utilized to knockdown NLRC4. An LRRK2 inhibitor (GNE7915) was injected into the abdominal cavity. Short hairpin (sh) RNA lentiviruses and lentiviruses containing RGS2 were designed and applied to knockdown and promote RGS2 expression. Neurological functions, brain edema, Western blot, enzyme-linked immunosorbent, hematoxylin and eosin staining, Nissl staining, immunoprecipitation, immunofluorescence assay and Evans blue dye extravasation and autofluorescence assay were evaluated. It was shown that the NLRC4 inflammasome was activated following ICH injury. NLRC4 knockdown extenuated neuronal death, damage to the blood-brain barrier, brain edema and neurological deficiency 3 days after ICH. NLRC4 knockdown reduced myeloperoxidase (MPO) cells as well as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß and IL-18 following ICH. GNE7915 reduced pNLRC4 and NLRC4 inflammasome activation. RGS2 suppressed the interaction of LRRK2 and NLRC4 and NLRC4 inflammasome activation by regulating pLRRK2. Our study demonstrated that the NLRC4 inflammasome may aggravate the inflammatory injury induced by ICH and that RGS2/LRRK2 may relieve inflammatory injury by restraining NLRC4 inflammasome activation.

Association Between Efficacy of Immune Checkpoint Inhibitors and Sex: An Updated Meta-Analysis on 21 Trials and 12,675 Non-Small Cell Lung Cancer Patients.

BACKGROUND: Mounting randomized clinical trials have proved that immune checkpoint inhibitors (ICIs) achieved better overall survival (OS) and progression-free survival (PFS) than chemotherapy drugs for advanced non-small cell lung cancer (NSCLC) patients. However, some literatures have indicated that different sexes might not have equal immune response. Also, no agreement reached on the issue whether therapeutic benefit of ICIs is related to sex. OBJECTIVES: To explore the association between efficacy of ICIs for NSCLC patients and their sexes and summarize overall treatment-related adverse events (TRAEs) in an exploratory manner. METHODS: We performed this systematic review and meta-analysis of all potentially relevant studies retrieved from PubMed, EMBASE, and the Cochrane Library until June 2021, for eligible randomized controlled trials (RCTs) comparing immunotherapy with chemotherapy in advanced NSCLC patients. Literature screening, summary data extraction was performed independently and in duplicate. The pooled hazard ratio (HR) and 95% confidence interval (CI) of OS, PFS and TRAEs were calculated, applying STATA software and random-effects models. This study was registered in international prospective register of systematic reviews (PROSPERO), number CRD42020210797. RESULTS: Twenty-one trials involving 12,675 NSCLC patients were included. For patients with advanced NSCLC, ICIs significantly prolonged the OS (males: HR 0.73, 95%CI 0.67-0.79; females: HR 0.73, 95%CI 0.61-0.85) and PFS (males: HR 0.62, 95%CI 0.55-0.70; females: HR 0.68, 95%CI 0.55-0.81) versus chemotherapy. Overall, there was no statistical difference between their sexes (OS: P = 0.97; PFS: P = 0.43), respectively. Owing to insufficient TRAEs data of different sexes, we only found immunotherapy for NSCLC patients had more all-grades (RR 0.88; 95%CI 0.82-0.95) and 3-5 grades (RR 0.60; 95%CI 0.47-0.75) AEs compared with chemotherapy. CONCLUSION: Our findings indicated that the interaction between immunotherapy efficacy and different sexes was equally evident. Overall, patients with NSCLC could obtain more benefits from ICIs than chemotherapy regimen regardless of their sexes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (https://www.crd.york.ac.uk/prospero/), identifier CRD42020210797.

Clinical and Genetic Predictive Models for the Prediction of Pathological Complete Response to Optimize the Effectiveness for Trastuzumab Based Chemotherapy.

BACKGROUND: Trastuzumab shows excellent benefits for HER2+ breast cancer patients, although 20% treated remain unresponsive. We conducted a retrospective cohort study to optimize neoadjuvant chemotherapy and trastuzumab treatment in HER2+ breast cancer patients. METHODS: Six hundred patients were analyzed to identify clinical characteristics of those not achieving a pathological complete response (pCR) to develop a clinical predictive model. Available RNA sequence data was also reviewed to develop a genetic model for pCR. RESULTS: The pCR rate was 39.8% and pCR was associated with superior disease free survival and overall survival. ER negativity and PR negativity, higher HER2 IHC scores, higher Ki-67, and trastuzumab use were associated with improved pCR. Weekly paclitaxel and carboplatin had the highest pCR rate (46.70%) and the anthracycline+taxanes regimen had the lowest rate (11.11%). Four published GEO datasets were analyzed and a 10-gene model and immune signature for pCR were developed. Non-pCR patients were ER+PR+ and had a lower immune signature and gene model score. Hormone receptor status and immune signatures were independent predictive factors of pCR. CONCLUSION: Hormone receptor status and a 10-gene model could predict pCR independently and may be applied for patient selection and drug effectiveness optimization.