Anlotinib enhanced CD8+ T cell infiltration via induction of CCL5 improves the efficacy of PD-1/PD-L1 blockade therapy in lung cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of mortality worldwide and requires effective treatment strategies. Recently, the development of a novel multiple-target tyrosine kinase inhibitor, anlotinib, has drawn increasing attention, especially it shows advantages when combined with PD-1/PD-L1 blockade. However, the mechanism by which anlotinib improves immunotherapy and remodeling of the tumor microenvironment remains unclear. In this study, we found that anlotinib combined with PD-1 blockade significantly inhibited tumor growth and reduced tumor weight in a lung cancer xenograft model compared to any single treatment. Both immunofluorescence and flow cytometry analyses revealed that anlotinib induced a CD8+ T cell dominated tumor microenvironment, which might account for its improved role in immunotherapy. Further investigations showed that CCL5-mediated CD8+ T cell recruitment plays a critical role in anlotinib and PD-1 blockade strategies. The depletion of CD8+ T cells abrogated this process. In conclusion, our findings showed that the combination of anlotinib and PD-1 blockade produced promising effects in the treatment of lung cancer, and that the induction of CCL5-mediced CD8+ T cell recruitment by anlotinib provided a novel mechanism of action.

Hypoxia-Derived Exosomes Promote Lung Adenocarcinoma by Regulating HS3ST1-GPC4-Mediated Glycolysis.

OBJECTIVE: The diagnosis of lung adenocarcinoma (LUAD) is often delayed due to the typically asymptomatic nature of the early-stage disease, causing advanced-stage LUAD diagnosis in most patients. Hypoxia is widely recognized as a driving force in cancer progression. Exosomes originating from hypoxic tumor cells promote tumorigenesis by influencing glycolysis, migration, invasion, and immune infiltration. Given these insights, our study aimed to explore the role of hypoxia-derived exosomal long non-coding RNA (lncRNA) OIP5-AS1 in LUAD cell lines and mouse models. MATERIALS AND METHODS: Exosomes were meticulously isolated and authenticated based on their morphology and biomarkers. The interaction between heparan sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1) and Glypican 4 (GPC4) was examined using immunoprecipitation. The influence of the hypoxia-derived exosomal lncRNA OIP5-AS1 on glycolysis was assessed in LUAD cell lines. The effect of the hypoxia-derived exosomal lncRNA OIP5-AS1 on cell proliferation and metastasis was evaluated using colony formation, cell viability, cell cycle, and apoptosis analyses. Its effects on tumor size were confirmed in xenograft animal models. RESULTS: Our study revealed the mechanism of the hypoxia-derived exosomal lncRNA OIP5-AS1 in LUAD progression. We discovered that GPC4 promotes HS3ST1-mediated glycolysis and that the hypoxia-derived exosomal lncRNA OIP5-AS1 enhances glycolysis by regulating miR-200c-3p in LUAD cells. Notably, this lncRNA stimulates LUAD cell proliferation and metastasis and fosters LUAD tumor size via miR-200c-3p. Our findings underscore the potential role of the hypoxia-derived exosomal lncRNA OIP5-AS1 in LUAD progression. CONCLUSIONS: The hypoxia-derived exosomal lncRNA OIP5-AS1 promotes LUAD by regulating HS3ST1-GPC4-mediated glycolysis via miR-200c-3p.

Facilitated Drug Repurposing with Artemisinin-Derived PROTACs: Unveiling PCLAF as a Therapeutic Target.

Artemisinin, a prominent anti-malaria drug, is being investigated for its potential as a repurposed cancer treatment. However, its effectiveness in tumor cell lines remains limited, and its mechanism of action is unclear. To make more progress, the PROteolysis-TArgeting chimera (PROTAC) technique has been applied to design and synthesize novel artemisinin derivatives in this study. Among them, AD4, the most potent compound, exhibited an IC50 value of 50.6 nM in RS4;11 cells, over 12-fold better than that of its parent compound, SM1044. This was supported by prolonged survival of RS4;11-transplanted NOD/SCID mice. Meanwhile, AD4 effectively degraded PCLAF in RS4;11 cells and thus activated the p21/Rb axis to exert antitumor activity by directly targeting PCLAF. The discovery of AD4 highlights the great potential of using PROTACs to improve the efficacy of natural products, identify therapeutic targets, and facilitate drug repurposing. This opens a promising avenue for transforming other natural products into effective therapies.

Near-Infrared-Activatable PROTAC Nanocages for Controllable Target Protein Degradation and On-Demand Antitumor Therapy.

As a novel protein knockdown tool, proteolysis targeting chimeras (PROTACs) can induce potent degradation of target proteins by hijacking E3 ubiquitin ligases. However, the uncontrollable protein disruption of PROTACs is prone to cause "off-target" toxicity after systemic administration. Herein, we designed a photocaged-PROTAC (phoBET1) and loaded it in UCNPs-based mesoporous silica nanoparticles (UMSNs) to construct a NIR light-activatable PROTAC nanocage (UMSNs@phoBET1) for controllable target protein degradation. Upon NIR light (980 nm) irradiation, UMSNs@phoBET1 nanocages could be activated to release active PROTAC via a controlled pattern for degrading bromodomain-containing protein 4 (BRD4) and inducing MV-4-11 cancer cell apoptosis. In vivo experiments demonstrated that UMSNs@phoBET1 nanocages were capable of responding to NIR light in tumor tissues to achieve BRD4 degradation and effectively suppress tumor growth. This NIR light-activatable PROTAC nanoplatform compensates for the current shortcomings of short-wavelength light-controlled PROTACs and presents a paradigm for the precise regulation of PROTACs in living tissues.

T1 rectal mucinous adenocarcinoma with bilateral enlarged lateral lymph nodes and unilateral metastasis: A case report.

BACKGROUND: There are a few cases of lateral lymph node (LLN) metastasis (LLNM) of T1 rectal cancer. Moreover, LLNM is easily missed, especially in patients with early-stage rectal cancer. To our knowledge, the possibility of bilateral LLNM before surgery has not been reported in previous studies. CASE SUMMARY: A 36-year-old woman underwent endoscopic submucosal dissection at a local hospital owing to a clinical diagnosis of a rectal polyp. The pathology report showed a diagnosis of T1 rectal mucinous adenocarcinoma. She was considered to have bilateral LLNM after the examination at our hospital. Laparoscopic total mesorectal excision plus bilateral LLN dissection was performed and the pathological outcomes indicated unilateral LLNM. The patient received long-course adjuvant chemoradiotherapy with no recurrence or metastasis observed during the 1-year follow-up period. CONCLUSION: T1 rectal cancer could lead to LLNM and possibly, bilateral LLNM. Therefore, adequate clinical evaluation is essential for these patients.

CDX2 as a Predictive Biomarker Involved in Immunotherapy Response Suppresses Metastasis through EMT in Colorectal Cancer.

Background: Studies have confirmed that Caudal Type Homeobox 2 (CDX2) plays a tumor suppressor role in colorectal cancer (CRC) and as a prognostic and predictive marker for colorectal cancer. The epithelial to mesenchymal transition (EMT) is a transdifferentiation process, providing migratory and invasive properties to cancer cells during tumor progression. However, the role of CDX2 during the activation of EMT in CRC maintains controversial. Aim: To investigate whether CDX2 is associated with EMT in CRC. Methods: Forty-six CRC patients were included in the study. Expressions of CDX2, E-cadherin, and N-cadherin in all CRC patients were detected by IHC. ROC assays were applied to detect cut-off points for IHC scores to distinguish high and low expressions of CDX2 in 46 CRC samples. The prognostic value of CDX2 was statistically analyzed. MTT, Western blot, invasion, and migration assays in vitro were employed to explore the function of CDX2. Results: We observed that high expressions of CDX2 and E-cadherin as well as low expressions of N-cadherin were significantly correlated with favorable prognosis. The levels of CDX2 protein exhibited a positive associated with E-cadherin while negative correlation with N-cadherin. Then, the low expression of CDX2 and high expression of CA199 in combination are positively related with poor prognosis. Overexpression of CDX2 reduced expression of MMP-2 and diminished cell proliferation, invasion, and migration, while knockdown CDX2 enhanced MMP-2 expression and increased cell proliferation, invasion, and migration in HCT-116 cells. CDX2 was correlated with expression of EMT markers. Overexpression of CDX2 suppressed the EMT markers indicating that CDX2 suppresses CRC cell viability, invasion, and metastasis through inhibiting EMT. Finally, we found that the expression of CDX2 was negatively associated with Th1 cells, macrophages, Th2 cells, cytotoxic cells, T cells, and T helper cells. Conclusions: These results indicated CDX2 as prognostic biomarkers involved in immunotherapy response for CRC. CDX2 loss promotes metastasis in CRC through a CDX2-dependent mechanism.

ROS-cleavable diselenide nanomedicine for NIR-controlled drug release and on-demand synergistic chemo-photodynamic therapy.

Many chemotherapeutic drugs and photosensitizers suffer from poor solubility, unspecific delivery and uncontrollable release, which severely impede their biomedical applications. Herein, we designed a type of ROS-cleavable hydrophilic diselenide nanoparticles through self-assembling of PEG-modified camptothecin (CPT, a hydrophobic drug) and meso­tetra (4-carboxyphenyl) porphine (TCPP, a hydrophobic photosensitizer). The TCPP@SeSe-CPT nanomedicine (particle size: 116.5 ± 1.9 nm) has stability for long-time blood circulation. Near-infrared (NIR) laser-triggered generation of ROS from TCPP can efficiently break the ROS-sensitive diselenide bond, which induces the decomposition of TCPP@SeSe-CPT nanomedicine for concurrent release of CPT and TCPP. Moreover, the released amounts of CPT and TCPP can be regulated by adjusting the NIR laser irradiation time. Such NIR-controlled release of CPT and TCPP can give rise to on-demand synergistic chemo-/photodynamic therapeutic effects for maximized tumor growth suppression with minimized side effects. STATEMENT OF SIGNIFICANCE: In this work, a ROS-cleavable diselenide nanoparticle was designed and successfully self-assembled with the hydrophobic drug camptothecin and photosensitizer TCPP into a hydrophilic TCPP@SeSe-CPT nanomedicine. Compared with traditional drug delivery systems, TCPP@SeSe-CPT nanomicelles could reduce premature drug release and co-deliver hydrophobic chemotherapeutic drugs/photosensitizers to tumors, which yielded a NIR-controlled synergistic chemo-/photodynamic therapeutic effect. Since diselenide bond is more sensitive than the traditional disulfide bond, under the 660 nm laser irradiation (300 mW/cm2), ROS generated from laser-excited TCPP in TCPP@SeSe-CPT nanomicelles could break the diselenium bonds to achieve the light-controlled release of CPT. In addition, the photosensitizer TCPP could also be imaged at the tumor site. Due to the photodynamic therapy from laser-excited TCPP and chemotherapy from photocontrolled release of CPT in TCPP@SeSe-CPT, our designed nanomicelles yielded potent antitumor effects both in vitro and in vivo.

Analysis of nosocomial infection and risk factors in lung transplant patients: a case-control study.

Background: Infection is the leading cause of short-term mortality after lung transplantation. This study aimed to investigate the epidemiology and risk factors of infection in Chinese lung transplant recipients. Methods: A total of 107 lung transplant patients from 2016 to 2020 were included in this study. The basic data of patients were collected, combined with clinically relevant physiological and biochemical indicators and laboratory test results. Transplant patients with new infections 48 hours after surgery were included in the infected group, and the rest were in the Uninfected group. The risk factors of postoperative infection were analyzed between the two groups. Results: A total of 107 patients were included in the study, including 89 males and 18 females. All patients underwent lung transplantation. A total of 80 patients (74.8%) experienced a postoperative infection. Pathogenic microorganisms were found in 136 samples, predominantly in the sputum (n=120 samples; 88.2%). We detected 107 strains of Gram-negative bacteria (78.7%), including 30 strains of Acinetobacter baumannii (22.1%) and 27 strains of Klebsiella pneumoniae (19.9%); 18 strains of Gram-positive bacteria (13.2%), including 11 strains of Staphylococcus haemolyticus (8.1%) and 2 strains of Enterococcus faecium (1.5%); and 11 strains (8.1%) were infected by fungi. There were 87 strains of multidrug-resistant bacteria. The main multidrug-resistant bacteria included 28 strains of Acinetobacter baumannii (32.2%) and 25 strains of Klebsiella pneumoniae (28.7%). Multivariate analysis showed that ventilator use over 3 days was an independent risk factor for postoperative infection [odds ratio (OR): 4.94, 95% confidence interval (CI): 1.31 to 18.66, P=0.019]. Conclusions: The infection rate after lung transplantation in our hospital is similar to that of other lung transplantation studies, but higher than that following transplantation of other organs. The pathogens of postoperative infection were similar to those identified in other lung transplantation studies. Using a ventilator for more than 3 days is a risk factor for postoperative infection, suggesting that preventive measures for postoperative infection should be taken in such patients, and early postoperative discontinuation of the ventilator may reduce postoperative infection.

HS3ST1 Promotes Non-Small-Cell Lung Cancer Progression by Targeting the SPOP/FADD/NF-κB Pathway.

Heparan sulfate proteoglycan is a key component of cell microenvironment and plays an important role in cell-cell interaction, adhesion, migration, and signal transduction. Heparan sulfate 3-O-sulfotransferase 1 (HS3ST1) is a metabolic-related gene of HS. The present study was aimed at exploring the role of HS3ST1 in the progress of non-small-cell lung cancer (NSCLC). Our results illustrated that HS3ST1 promoted the malignant behaviors of NSCLC cells both in vitro and in vivo. HS3ST1 was found to inhibit spot-type zinc finger protein (SPOP) expression, which might inhibit the NF-κB pathway activation through mediating the degradation of Fas-associated death domain protein (FADD). By analyzing NSCLC patient samples, we also found increased HS3ST1 expression and decreased SPOP expression in tumor tissues in contrast with those in adjoining normal tissues. In conclusion, HS3ST1 promotes NSCLC tumorigenesis by regulating SPOP/FADD/NF-κB pathway.

Effects of psychological nursing care on anxiety and depression in perioperative patients with lung cancer: A systematic review and meta-analysis.

BACKGROUND: This study aimed to investigate the effects of psychological nursing care (PNC) on anxiety relief in perioperative lung cancer (LC) patients. METHODS: We searched the Cochrane Library, PubMed, Embase, CNKI, CBM, and Wangfang electronic databases from inception to May 1, 2022. Eligible randomized controlled trials (RCTs) investigating the effects and safety of PNC on anxiety relief in perioperative LC patients. Anxiety was the primary outcome measure. The secondary outcomes were depression, length of hospital stay, and the occurrence of adverse events. RESULTS: Six eligible RCTs with 494 patients were included in this study. Compared with routine nursing care, PNC showed better outcomes in terms of anxiety relief (mean difference [MD] = -13.24; random 95% confidence interval (CI), -18.28 to -8.20; P<.001), depression decrease (MD = -11.84; random 95% CI, -18.67 to -5.01; P < .001), and length of hospital stay (MD = -2.6; fixed 95% CI, -3.13 to -2.07; P < .001). No data on adverse events were pooled because only 1 trial reported this outcome. CONCLUSIONS: This study showed that PNC may benefit more than routine nursing care for patients with LC in anxiety, depression, and length of hospital stay. High-quality RCTs are needed to validate the current findings in the future.

Targeting TLR9 agonists to secondary lymphoid organs induces potent immune responses against HBV infection.

Despite the existence of a prophylactic vaccine against hepatitis B virus (HBV), chronic hepatitis B virus (CHB) infection remains the leading cause of cirrhosis and liver cancer in developing countries. Because HBV persistence is associated with insufficient host immune responses to the infection, development of an immunomodulator as a component of therapeutic vaccination may become an important strategy for treatment CHB. In the present study, we aimed to design a novel immunomodulator with the capacity to subvert immune tolerance to HBV. We developed a lymphoid organ-targeting immunomodulator by conjugating a naturally occurring, lipophilic molecule, α-tocopherol, to a potent CpG oligonucleotide adjuvant pharmacophore. This approach resulted in preferential trafficking of the α-tocopherol-conjugated oligonucleotide to lymphoid organs where it was internalized by antigen-presenting cells (APCs). Moreover, we show that conjugation of the oligonucleotides to α-tocopherol results in micelle-like structure formation, which improved cellular internalization and enhanced immunomodulatory properties of the conjugates. In a mouse model of chronic HBV infection, targeting CpG oligonucleotide to lymphoid organs induced strong cellular and humoral immune responses that resulted in sustained control of the virus. Given the potency and tolerability of an α-tocopherol-conjugated CpG oligonucleotide, this modality could potentially be broadly applied for therapeutic vaccine development.

JNJ-64794964 (AL-034/TQ-A3334), a TLR7 agonist, induces sustained anti-HBV activity in AAV/HBV mice via non-cytolytic mechanisms.

JNJ-64794964 (JNJ-4964/AL-034/TQ-A3334), an oral toll-like receptor 7 agonist, is being investigated for the treatment of chronic hepatitis B (CHB), a condition with a high unmet medical need. The anti-hepatitis B (HBV) activity of JNJ-4964 was assessed preclinically in an adeno-associated virus vector expressing HBV (AAV/HBV) mouse model. Mice were treated orally with 2, 6 or 20 mg/kg of JNJ-4964 once-per-week for 12 weeks and then followed up for 4 weeks. At 6 mg/kg, a partial decrease in plasma HBV-DNA and plasma hepatitis B surface antigen (HBsAg) was observed, and anti-HBs antibodies and HBsAg-specific T cells were observed in 1/8 animals. At 20 mg/kg, plasma HBV-DNA and HBsAg levels were undetectable for all animals 3 weeks after start of treatment, with no rebound observed 4 weeks after JNJ-4964 treatment was stopped. High anti-HBs antibody levels were observed until 4 weeks after JNJ-4964 treatment was stopped. In parallel, HBsAg-specific immunoglobulin G-producing B cells and interferon-γ-producing CD4+ T cells were detected in the spleen. In 2/4 animals, liver HBV-DNA and HBV-RNA levels and liver hepatitis B core antigen expression dropped 4 weeks after JNJ-4964 treatment-stop. In these animals, HBsAg-specific CD8+ T cells were detectable. Throughout the study, normal levels of alanine aminotransferase were observed, with no hepatocyte cell death (end of treatment and 4 weeks later) and minimal infiltrations of B and T cells into the liver, suggesting induction of cytokine-mediated, non-cytolytic mechanisms.

Rosai-Dorfman disease with lung involvement in a 10-year-old patient: A case report.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare benign proliferative disease whose etiology is not clear and may be related to infection or unexplained immune dysfunction. The authors present a case of RDD with lung involvement in a 10-year-old patient. CASE SUMMARY: A 10-year-old girl found that her left cervical lymph nodes were enlarged for more than 7 mo, and the largest range was about 6.5 cm × 5.9 cm × 8.1 cm. Cervical magnetic resonance imaging showed multiple masses in the left neck, with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. A malignant tumor, with a high possibility of lymph node metastasis, was initially considered. At the same time, lung computed tomography showed multiple nodules of different sizes scattered on both sides of the lung, with uniform internal density. Thus, a possible metastatic tumor was considered. Finally, RDD was diagnosed by pathology and immunohistochemistry. According to the antibiogram, clindamycin was administered for 2 wk, and prednisone acetate was administered for 7 wk. Nine months later, the ulcer in the left neck was better than before, but the imaging showed that the lesion was not controlled. CONCLUSION: The diagnosis of RDD cannot be made by a single tool and its treatment is a long-term exploratory process. Follow-up is necessary.

Discovery of STAT3 and Histone Deacetylase (HDAC) Dual-Pathway Inhibitors for the Treatment of Solid Cancer.

Nowadays, simultaneous inhibition of multiple targets through drug combination is an important anticancer strategy owing to the complex mechanism behind tumorigenesis. Recent studies have demonstrated that the inhibition of histone deacetylases (HDACs) will lead to compensated activation of a notorious cancer-related drug target, signal transducer and activator of transcription 3 (STAT3), in breast cancer through a cascade, which probably limits the anti-proliferation effect of HDAC inhibitors in solid tumors. By incorporating the pharmacophore of the HDAC inhibitor SAHA (vorinostat) into the STAT3 inhibitor pterostilbene, a series of potent pterostilbene hydroxamic acid derivatives with dual-target inhibition activity were synthesized. An excellent hydroxamate derivate, compound 14, inhibited STAT3 (KD = 33 nM) and HDAC (IC50 = 23.15 nM) with robust potency in vitro. Compound 14 also showed potent anti-proliferation ability in vivo and in vitro. Our study provides the first STAT3 and HDAC dual-target inhibitor for further exploration.

Different clinical features between patients with ROS1-positive and ALK-positive advanced non-small cell lung cancer.

OBJECTIVE: To compare the baseline clinical characteristics between patients with ROS1-positive and ALK-positive advanced non-small cell lung cancer (NSCLC), and the correlations of these subtypes with the distribution of metastases. METHODS: We compared the clinical characteristics and imaging features of patients with ROS1-positive and ALK-positive NSCLC using statistical methods. RESULTS: Data for 232 patients were analyzed. Compared with ALK-positive NSCLC, ROS1-positive NSCLC was more likely to occur in women (71% vs 53%), and primary lesions ≤3 cm were more common in patients with ROS1-positive compared with ALK-positive NSCLC (58% vs 37%). There was no significant difference in the distribution of metastases between the two groups. Subgroup analysis within the ROS1-positive group showed that, compared with primary lesions >3 cm, primary lesions ≤3 cm were more likely to present as peripheral tumors (72% vs 43%) and more likely to exhibit non-solid density (44% vs 4%). CONCLUSIONS: Although ROS1-positive and ALK-positive NSCLCs show similar clinical features, the differences may help clinicians to identify patients requiring further genotyping at initial diagnosis.

miR-338-5p inhibits cell growth and migration via inhibition of the METTL3/m6A/c-Myc pathway in lung cancer.

Lung cancer is a common type of cancer that causes a very large public health burden worldwide. Achieving a better understanding of the molecular mechanism underlying the progression of lung cancer is of benefit for the diagnosis, prognosis, and treatment of lung cancer. Here, we first identified dramatically decreased expression of miR-338-5p in lung cancer tissues and cells using quantitative polymerase chain reaction (qPCR) analysis. We then revealed that miR-338-5p inhibited the cell growth and migration of lung cancer cells using cell counting kit 8 (CCK8), EdU, and Transwell analysis. Furthermore, we demonstrated that miR-338-5p inhibited METTL3 expression by qPCR, western blot analysis, and luciferase reporter assay, while upregulation of METTL3 alleviated the role of miR-338-5p in lung cancer cells. We also showed that METTL3 promoted c-Myc expression by increasing the m6A modification of c-Myc, and overexpression of c-Myc restored the inhibition of cell growth and migration of lung cancer cells induced by METTL3 silencing. Ultimately, this research illustrated that modification of the miR-338-5p/METTL3/c-Myc pathway affected cellular progression in lung cancer cells. Collectively, our study revealed the underlying mechanism of miR-338-5p in lung cancer, providing a novel regulatory pathway in lung cancer. There is potential for this pathway to serve as a diagnostic, prognostic, and therapeutic biomarker for lung cancer.

Proton radiation effects on carrier transport in diamond radiation detectors.

Diamond, a highly radiation-resistant material, is considered a nearly ideal material for radiation detection, particularly in high-energy physics. In this study, radiation damage from high-energy proton beams was induced in diamond crystals to determine exposure lifetime in detectors made from this material; the effects were investigated using non-destructive x-ray techniques and through the FLUKA simulation package. Two diamond detectors were irradiated by an 800 MeV proton beam at different fluence rates, and the real-time current response was recorded to observe degradation in the signal over time. It was determined that the proton fluence rate had a significant effect on the device degradation. The detector performance from the irradiated detectors was characterized using x-ray beam-induced current measurements, and the mechanism of proton radiation damage to diamond sensors, especially the radiation effects on carrier transport, was studied. The vacancies generated from proton irradiation were considered the major source of detector degradation by trapping holes and inducing an internal electric field. Simulation results from the FLUKA package revealed an uneven distribution of the radiation-induced vacancies along the beam path, and the corresponding detector signals calculated from the simulation results displayed a good match to the experimental results.

Helicobacter pylori infection and the risk of colorectal carcinoma: a systematic review and meta-analysis.

INTRODUCTION: Helicobacter pylori is a gram-negative bacterium that is colonized in the stomach. H. pylori infection can lead to a series of stomach diseases. However, the relationship between H. pylori infection and colorectal cancer is currently controversial. Therefore, we performed this meta-analysis to further understand the relationship between H. pylori infection and colorectal cancer. EVIDENCE ACQUISITION: We conducted a comprehensive retrieval from electronic databases, included the PubMed, Medline, China National Knowledge Infrastructure (CNKI), and China Wanfang Data Knowledge Service Platform databases (Wanfang Databases) through May 1st, 2018. We used the search terms H. pylori and colorectal cancer or colorectal carcinoma and collected all relevant studies to explore the association between H. pylori infection and colorectal cancer. EVIDENCE SYNTHESIS: Twenty-seven studies including 14357 cases were included. H. pylori infection was associated with an increased risk of colorectal cancer. A pooled odds ratio (OR) of 1.27 with a 95% CI of 1.17-1.37 (P<0.001) was calculated by using a fixed-effects model (I2=45.5%, P=0.006). The subgroup analysis revealed that H. pylori infection was associated with an increased risk of colorectal cancer in the subgroups of Western countries (OR=1.34, 95% CI: 1.14-1.57) (P<0.001), serological testing (OR=1.20, 95% CI: 1.08-1.34) (P=0.001), multiple methods of testing (OR=2.63, 95% CI: 1.09-6.31) (P=0.031), cross-sectional studies (OR=1.92, 95% CI: 1.17-3.16) (P=0.010) and case-control studies (OR 1.26, 95% CI: 1.16-1.36) (P<0.001). CONCLUSIONS: The present meta-analysis provides evidence suggests that a positive association between H. pylori infection and the risk of colorectal cancer.

Physiological significance of R-fMRI indices: Can functional metrics differentiate structural lesions (brain tumors)?

Resting-state functional MRI (R-fMRI) research has recently entered the era of "big data", however, few studies have provided a rigorous validation of the physiological underpinnings of R-fMRI indices. Although studies have reported that various neuropsychiatric disorders exhibit abnormalities in R-fMRI measures, these "biomarkers" have not been validated in differentiating structural lesions (brain tumors) as a concept proof. We enrolled 60 patients with intracranial tumors located in the unilateral cranialcavity and 60 matched normal controls to test whether R-fMRI indices can differentiate tumors, which represents a prerequisite for adapting such indices as biomarkers for neuropsychiatric disorders. Common R-fMRI indices of tumors and their counterpart control regions, which were defined as the contralateral normal areas (for amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo) and degree centrality (DC)) and ipsilateral regions surrounding the tumors (for voxel-mirrored homotopic connectivity (VMHC)), were comprehensively assessed. According to robust paired t-tests with a Bonferroni correction, only VMHC (Fisher's r-to-z transformed) could successfully differentiate substantial tumors from their counterpart normal regions in patients. Furthermore, ALFF and DC were not able to differentiate tumor from normal unless Z-standardization was employed. To validate the lower power of the between-subject design compared to the within-subject design, each metric was calculated in a matched control group, and robust two-sample t-tests were used to compare the patient tumors and the normal controls at the same place. Similarly, only VMHC succeeded in differentiating significant differences between tumors and the sham tumor areas of normal controls. This study tested the premise of R-fMRI biomarkers for differentiating lesions, and brings a new understanding to physical significance of the Z-standardization.

Ascorbic Acid Attenuates Multifidus Muscles Injury and Atrophy After Posterior Lumbar Spine Surgery by Suppressing Inflammation and Oxidative Stress in a Rat Model.

STUDY DESIGN: A rat model of multifidus muscles injury and atrophy after posterior lumbar spine surgery. OBJECTIVE: We determined the effect of ascorbic acid (AA) on the postoperative multifidus muscles in rat model. SUMMARY OF BACKGROUND DATA: Previous studies show oxidative stress and inflammation are two main molecular mechanisms in multifidus muscle injury and atrophy after posterior lumbar surgery. AA may have a protective effect in postoperative multifidus muscles. METHODS: Rats were divided into sham surgery, control surgery, and surgery plus AA groups. Multifidus muscles of the control and AA groups were excised from the osseous structures. The muscles were retracted continuously for 2 hours. In the sham and AA groups, AA was administered via oral gavage daily in the first week. In each group, the oxidative stress was evaluated by measuring malondialdehyde (MDA) and Total superoxide dismutase (T-SOD). The inflammation, fat degeneration, or fibrosis of multifidus muscle were evaluated by quantitative real-time polymerase chain reaction (q-PCR), histology, or immunohistochemical analysis. RESULTS: T-SOD activity was significantly lower in the control group than that in the AA group in the first week. MDA levels were significantly higher in the AA group. Interleukin-6 and tumor necrosis factor-α in multifidus muscles also showed significant differences when treated with AA. The inflammation score on histology was significantly lower in the AA group postoperatively in the first week. In the long run, marker genes for fibrosis and fat degeneration, and fibrosis and fat degeneration scores, were significantly lower in the AA than the control group on days 14 and 28 postoperatively. CONCLUSION: In conclusion, AA attenuated the oxidative stress and inflammation response in the postoperative multifidus muscles, and remarkable differences were observed from the histological assessment and related marker genes expression. Our results provided important insight into the anti-inflammatory and anti-oxidative effects of AA in the postoperative multifidus muscles. LEVEL OF EVIDENCE: N/A.