Factors influencing pathological changes in the liver tissue in hepatitis B virus carriers with low-level viremia.

OBJECTIVES: To investigate the optimal timing for initiating antiviral therapy in hepatitis B virus (HBV) carriers with low-level viremia (LLV). METHODS: We retrospectively enrolled 126 HBV carriers with LLV who underwent liver biopsy. Patients' clinical data, routine blood test results, portal vein diameter, splenic vein diameter and thickness, and measurements (LSM) within 1 week before liver biopsy were obtained. Single-factor and multifactor statistical methods were used to analyze factors that affected inflammation and fibrosis in pathological liver tissues. The receiver operating characteristic curve was used to analyze liver stiffness and HBV DNA levels to determine liver tissue inflammation and fibrosis. R -Studio software was used to draw nomograms, calibration plots, and model decision curves. RESULTS: Infection duration and HBV DNA levels affected liver tissue inflammation. Albumin(ALB), aspartate aminotransferase (AST), HBV DNA, liver stiffness, age, and splenic thickness affected liver fibrosis. The best cutoff value of the LSM for diagnosing liver inflammation and fibrosis was 7.45 (specificity, 92%). The best cutoff value of HBV DNA for diagnosing liver inflammation and fibrosis was 39.5 (specificity, 96%). HBV DNA,and splenic thickness affected the treatment decision in naive chronic hepatitis Bpatients with LLV CONCLUSIONS: HBV carriers with LLV have high incidences of liver tissue inflammation and fibrosis. The infection duration and HBV DNA levels affected liver inflammation whereas the ALB, AST levels, HBV DNA, LSM, age, and splenic thickness affected liver fibrosis. Eligible expansion of antiviral treatment indications is necessary, however, a universal treatment approach may be inefficient. HBV DNA can be a reference for initiating antiviral therapy.

Deficiency of P2RY11 causes narcolepsy and attenuates the recruitment of neutrophils and macrophages in the inflammatory response in zebrafish.

Purinergic receptor P2Y11, a G protein-coupled receptor that is stimulated by extracellular ATP, has been demonstrated to be related to the chemotaxis of granulocytes, apoptosis of neutrophils, and secretion of cytokines in vitro. P2Y11 mutations were associated with narcolepsy. However, little is known about the roles of P2RY11 in the occurrence of narcolepsy and inflammatory response in vivo. In this study, we generated a zebrafish P2Y11 mutant using CRISPR/Cas9 genome editing and demonstrated that the P2Y11 mutant replicated the narcolepsy-like features including reduced HCRT expression and excessive daytime sleepiness, suggesting that P2Y11 is essential for HCRT expression. Furthermore, we accessed the cytokine expression in the mutant and revealed that the P2RY11 mutation disrupted the systemic inflammatory balance by reducing il4, il10 and tgfb, and increasing il6, tnfa, and il1b. In addition, the P2RY11-deficient larvae with caudal fin injuries exhibited significantly slower migration and less recruitment of neutrophils and macrophages at damaged site, and lower expression of anti-inflammatory cytokines during tissue damage. All these findings highlight the vital roles of P2RY11 in maintaining HCRT production and secreting anti-inflammatory cytokines in the native environment, and suggested that P2RY11-deficient zebrafish can serve as a reliable and unique model to further explore narcolepsy and inflammatory-related diseases with impaired neutrophil and macrophage responses.

Observation on the Analgesic Effect of Different Doses of a Combination of Esketamine and Dexmedetomidine Administered for Percutaneous Endoscopic Transforaminal Discectomy: A Randomized, Double-Blind Controlled Trial.

BACKGROUND: Percutaneous endoscopic transforaminal discectomy (PETD) is an effective method for treating lumbar disc herniation, and is typically performed under local anesthesia. However, inadequate analgesia during the procedure remains a concern, prompting the search for a medication that can provide optimal pain control with minimal impact on the respiratory and circulatory systems. OBJECTIVES: The aim of this study was to observe the effects of different doses of esketamine combined with dexmedetomidine on reducing visual analog scale (VAS) scores during surgical interventions. METHODS: One hundred two patients who underwent PETD were randomly divided into a control group (group C: normal saline + dexmedetomidine), an E1 group (0.1 mg kg-1 esketamine + dexmedetomidine), and an E2 group (0.2 mg kg-1 esketamine + dexmedetomidine). The primary outcome was the maximum visual analogue scale (VAS) (score: 0 = no pain and 10 = worst pain) at six time points. The secondary outcomes included the Assessment of Alertness/Sedation Scale (OAA/S) score and mean arterial pressure (BP), heart rate (HR), respiratory rate (RR), and oxygen saturation (SpO2) at 11 time points. The incidence of adverse reactions during and 24 h after the operation and patient satisfaction with the anesthesia were also recorded. RESULTS: Compared with those in group C, the VAS scores of patients in groups E1 and E2 were lower at T6, T7, and T9 (P < 0.05). From T4 to T10, the OAA/S scores of the E1 and E2 groups were both lower than those of group C (P < 0.05), and at the T4-T6 time points, the OAA/S score of the E2 group was lower than that of group E1 (P < 0.05). At T4 and T5, the HR and BP of patients in groups E1 and E2 were greater than those in group C (P < 0.05). Compared with those in group C, the incidences of intraoperative illusion, floating sensation, postoperative dizziness, and hyperalgesia in groups E1 and E2 were significantly greater (P < 0.01). There was no significant difference in patient RR, SpO2, or postoperative satisfaction with anesthesia among the three groups (P > 0.05). CONCLUSION: The combination of esketamine and dexmedetomidine can reduce VAS scores during certain stages of this type of surgery; it has minimal impact on respiration and circulation. However, this approach is associated with increased incidences of postoperative dizziness and psychiatric side effects, which may also affect patients' compliance with surgical instructions from medical staff. Patient satisfaction was not greater with dexmedetomidine combined with esketamine than with dexmedetomidine alone. TRIAL REGISTRATION: http://www.chictr.org.cn . Identifier: ChiCTR2300068206. Date of registration: 10 February 2023.

Acquired heat acclimation in rats subjected to physical exercise under environmental heat stress alleviates brain injury caused by exertional heat stroke.

BACKGROUND: Exertional heatstroke (EHS) is an emergency with a high mortality rate, characterized by central nervous system dysfunctions. This study aims to establish a Heat acclimation/acclimatization (HA) rat model in locomotion to recapitulate the physical state of human in severe environment of high temperature and humidity, and investigate the mechanism of organism protection in HA. (2) Methods: Wistar rats were exposed to 36 °C and ran 2 h/d for 21 days, acquired thermal tolerance test was conducted to assess the thermotolerance and exercise ability. Core temperature and consumption of water and food were observed. Expression of HSP70 and HSP90 of different tissues were determined by WB. Pathological structure of brain tissue was detected with HE staining. Proteomics was used to identify the differently expressed proteins in cerebral cortex of different groups. And key molecules were identified by RT-PCR and WB. (3) Results: HA rats displayed stronger thermotolerance and exercised ability on acquired thermal tolerance test. Brain water content of HA + EHS group reduced compared with EHS group. HE staining revealed slighter brain injuries of HA + EHS group than that of EHS. Proteomics focused on cell death-related pathways and key molecules Aquaporin 4 (AQP4) related to cell edema. Identification results showed HA increased AQP4, Bcl-xl, ratio of p-Akt/AKT and Bcl-xl/Bax, down-regulated Cleaved Caspase-3. (4) Conclusions: This HA model can ameliorate brain injury of EHS by reducing cerebral edema and cell apoptosis, offering experimental evidence for EHS prophylaxis.

Epidemiological characteristics, virulence potential, antimicrobial resistance profiles, and phylogenetic analysis of Aeromonas caviae isolated from extra-intestinal infections.

Objective: Aeromonas caviae (A. caviae) is one of the major etiological agents in human intestinal infections reported to be associated with a broad spectrum of extra-intestinal infections with increasing incidence over recent years. Although previous studies have established its significance as a causative agent of both bloodstream and gastrointestinal infections, the characteristics of A. caviae that cause extra-intestinal infections remain unilluminated.In this single-center retrospective study, we investigated epidemiological characteristics, antimicrobial resistance genes and phenotypes, virulence genes, and phyloevolution of 47 clinical A. caviae isolated from patients with extra-intestinal infections from 2017 to 2020. Methods: A. caviae strains were identified by biochemical tests and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF/MS), ultimately confirmed to species level by whole-genome sequencing (WGS). Antimicrobial resistance and virulence genes were identified using the Comprehensive Antibiotic Resistance Database (CARD) and the virulence factor database (VFDB), respectively. Phylogenetic analysis of 47 clinical strains was performed by combining with 521 A. caviae strains from NCBI database. Results: A. caviae was an opportunistic pathogen in immunocompromised patients, especially those with underlying hepatobiliary diseases and malignancies. 19 out of 47 isolates were identified as multidrug resistance (MDR) strains. Piperacillin-tazobactam, levofloxacin, gentamicin, amikacin with a resistance rate of less than 10% remained as options to treat extra-intestinal infections. 24 out of 47 isolates exhibited non-susceptibility to cephalosporins and cephamycins, all of which carried ß-lactamase gene, including bla MOX, bla PER-3, bla OXA, bla NDM, and bla CphA. Most stains (98%, 46/47) carried at least one of the virulence genes, but extra-intestinal infections had a low mortality rate. Phylogenetic analysis indicated the risk of nosocomial transmission but revealed no outbreak. However, the emergence of MDR and ß-lactamase resistance genes in extra-intestinal isolates of A. caviae is becoming an increasing risk to public health and requires attention. Conclusions: This study strengthen our understanding of A.caviae isolated from extra-intestinal infections. It may contribute to the management of extra-intestinal infections as well as the prevention and control of drug resistance.

Transcutaneous electrical acupoint stimulation for reducing cognitive dysfunction in lumbar spine surgery: A randomized, controlled trail.

Objective: This study aimed to evaluate the effect of perioperative transcutaneous electrical acupoint stimulation (TEAS) on postoperative cognitive dysfunction (POCD) in older patients with lumbar spine surgery. Methods: Older patients (aged 60-80 years old) receiving lumbar spine surgery under general anesthesia were randomly divided into group A, 3-day intervention group; group B, 7-day intervention group; control group C, sham TEAS group, selected "Baihui" (GV 20) and "Dazhui" (GV 14) point was intervened once 30 min before operation with "HANS" transcutaneous electrical stimulation device, and then once a day after operation for 30 min each time. The primary outcome was the incidence of postoperative cognitive impairment assessed by the use of the Mini Mental Rating Scale (MMSE), patients developed POCD according to the Z score method. The secondary outcome was serum interleukin-6 (IL-6), tumor Necrosis factor α (TNF-α), neuron-specific enolase (NSE), and S100ß protein levels. Results: Three days after surgery, the incidence of POCD in groups A((22.4%)) and B ((18.3%)) were lower than those in group C ((42.9%)) (P < 0.05). There was no significant difference between groups A and B (P > 0.05). Seven days after surgery, the incidence of POCD in group B (18.3%) was lower than that in groups A (26.5%) and B (42.9%), and the comparison between groups B and C was statistically significant (P < 0.05). On the 3rd and 7th days after surgery, the levels of IL-6, TNF-α, NSE, and S100ß in the two TEAS groups were lower than those in the sham TEAS group (P < 0.01), but higher than the preoperative levels in the three groups (P < 0.01). Conclusion: It seems that Perioperative TEAS intervention could reduce the level of inflammatory factors IL-6, TNF-α in the blood of older patients with lumbar spine surgery, and reduce the incidence of POCD. Clinical trial registration: www.chictr.org.cn, identifier ChiCTR2200063030.

Cancer-associated fibroblasts subtypes and role in invasion and metastasis of gastric cancer.

Gastric cancer (GC) is the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide. Cancer-associated fibroblasts (CAFs), an important cell type in the tumor microenvironment, play an important role in GC development. In this review, we describe the current knowledge of CAFs' heterogeneity and their role in GC invasion and metastasis. Currently, CAF-targeted cancer therapies are being rapidly explored and developed. However, the heterogeneity of CAFs limits the application of this therapy, so it is urgent to find specific markers and divide them into different subpopulations. With the development of single-cell RNA sequencing technology, researchers have used this technology to classify CAFs in many tumors, but whether it is applicable to GC and other tumors needs further study. And we believe that this technology will be in the near future utilized to sort CAFs on the basis of different cell markers and functions, so as to target tumor-promoting CAFs and inhibit tumor progression. Targeting CAFs by cell surface markers or normalizing the activated CAFs subsets may be an effective therapy, alone or in combination with other therapeutic approaches for GC treatment. Therefore, in the coming decades, the interaction between CAFs and GC cells will be still the focus of our research.

Soluble Receptor for Advanced Glycation End Product Is Involved in the Inflammatory Response of Human Adenovirus-Infected Patients.

Human adenovirus (HAdV) infection causes excessive inflammation associated with severe tissue injury, such as pneumonia. The molecules involved in the underlying inflammatory mechanisms remain to be elucidated. Receptor for advanced glycation end product (RAGE) is mainly expressed on immune cells and lung tissues, and it is a key factor in the initiation and development of inflammation. RAGE can be cleaved by metalloprotease 9 (MMP9) to release the extracellular segment, which is named soluble RAGE (sRAGE), into the intercellular space, where it can bind to RAGE ligands and block RAGE activation and subsequent inflammation. In our study, we enrolled HAdV-infected patients and their contacts to examine the relationship between sRAGE and inflammation induced by HAdV infection. The results showed that HAdV infection stimulated inflammatory cytokine secretion, increased such as high mobility group box 1 (HMGB1) levels, and suppressed sRAGE expression. sRAGE levels were significantly different between patients with or without pneumonia. We also found that MMP9 was significantly lower in patients with pneumonia, and it was positively correlated with sRAGE levels over 7 days after disease onset. The mitogen-activated protein kinase (MAPK) pathway is an important immune activation signaling pathway that is regulated by RAGE. We observed the activation of the MAPK pathway in the peripheral blood mononuclear cells (PBMCs) of patients. Negative correlations between sRAGE and phosphorylated JNK and p38 were observed. These results suggest that sRAGE is involved in HAdV-induced inflammatory responses, and might be a potential therapeutic target to alleviate the HAdV-induced excessive inflammation.

Common mtDNA variations at C5178a and A249d/T6392C/G10310A decrease the risk of severe COVID-19 in a Han Chinese population from Central China.

BACKGROUND: Mitochondria have been shown to play vital roles during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) development. Currently, it is unclear whether mitochondrial DNA (mtDNA) variants, which define mtDNA haplogroups and determine oxidative phosphorylation performance and reactive oxygen species production, are associated with COVID-19 risk. METHODS: A population-based case-control study was conducted to compare the distribution of mtDNA variations defining mtDNA haplogroups between healthy controls (n = 615) and COVID-19 patients (n = 536). COVID-19 patients were diagnosed based on molecular diagnostics of the viral genome by qPCR and chest X-ray or computed tomography scanning. The exclusion criteria for the healthy controls were any history of disease in the month preceding the study assessment. MtDNA variants defining mtDNA haplogroups were identified by PCR-RFLPs and HVS-I sequencing and determined based on mtDNA phylogenetic analysis using Mitomap Phylogeny. Student's t-test was used for continuous variables, and Pearson's chi-squared test or Fisher's exact test was used for categorical variables. To assess the independent effect of each mtDNA variant defining mtDNA haplogroups, multivariate logistic regression analyses were performed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) with adjustments for possible confounding factors of age, sex, smoking and diseases (including cardiopulmonary diseases, diabetes, obesity and hypertension) as determined through clinical and radiographic examinations. RESULTS: Multivariate logistic regression analyses revealed that the most common investigated mtDNA variations (> 10% in the control population) at C5178a (in NADH dehydrogenase subunit 2 gene, ND2) and A249d (in the displacement loop region, D-loop)/T6392C (in cytochrome c oxidase I gene, CO1)/G10310A (in ND3) were associated with a reduced risk of severe COVID-19 (OR = 0.590, 95% CI 0.428-0.814, P = 0.001; and OR = 0.654, 95% CI 0.457-0.936, P = 0.020, respectively), while A4833G (ND2), A4715G (ND2), T3394C (ND1) and G5417A (ND2)/C16257a (D-loop)/C16261T (D-loop) were related to an increased risk of severe COVID-19 (OR = 2.336, 95% CI 1.179-4.608, P = 0.015; OR = 2.033, 95% CI 1.242-3.322, P = 0.005; OR = 3.040, 95% CI 1.522-6.061, P = 0.002; and OR = 2.890, 95% CI 1.199-6.993, P = 0.018, respectively). CONCLUSIONS: This is the first study to explore the association of mtDNA variants with individual's risk of developing severe COVID-19. Based on the case-control study, we concluded that the common mtDNA variants at C5178a and A249d/T6392C/G10310A might contribute to an individual's resistance to developing severe COVID-19, whereas A4833G, A4715G, T3394C and G5417A/C16257a/C16261T might increase an individual's risk of developing severe COVID-19.

Mesenchymal stem cell therapy in decompensated liver cirrhosis: a long-term follow-up analysis of the randomized controlled clinical trial.

BACKGROUND: Mesenchymal stem cell (MSC) infusion was reported to improve liver function in patients with decompensated liver cirrhosis (DLC); however, whether the medication can improve outcome of these patients is poorly understood. METHODS: This prospective, open-labeled, randomized controlled study enrolled 219 patients with HBV-related DLC who were divided into control group (n = 111) and umbilical cord-derived MSC (UC-MSC)-treated group (n = 108), then all of them received a follow-up check from October 2010 to October 2017. The treated patients received three times of UC-MSC infusions at 4-week intervals plus conventional treatment that was only used for control group. The overall survival rate and HCC-free survival rate were calculated as primary endpoints and the liver function and adverse events associated with the medication were also evaluated. RESULTS: During the follow-up check period from 13 to 75th months, there was a significantly higher overall survival rate in the treated group than the control group, while the difference of the hepatocellular carcinoma event-free survival rate between the treated and control groups was not observed during the 75-month follow-up. UC-MSC treatment markedly improved liver function, as indicated by the levels of serum albumin, prothrombin activity, cholinesterase, and total bilirubin during 48 weeks of follow-up. No significant side effects or treatment-related complications were observed in the UC-MSC group. CONCLUSIONS: Therapy of UC-MSC is not only well tolerated, but also significantly improves long-term survival rate, as well as the liver function in patients with HBV-related DLC. UC-MSC medication, therefore, might present a novel therapeutic approach for the disease.

Nasal metastases from neuroblastoma-a rare entity: Two case reports.

BACKGROUND: Neuroblastoma (NB) is one of the most common malignancies in children. Metastasis in NB is not uncommon. However, nasal metastases are rare. Here, we reported two pediatric cases of nasal metastases. CASE SUMMARY: Case 1 was a 3-year-old boy without a history of NB. Case 2 was a 10-year-old girl who had a history of NB for 6 years. Both of them presented with symptoms of nasal and sinus masses such as epistaxis or discharge from the nose. The radiologic imaging results revealed masses in the nasal cavity or nasopharynx in both cases and a mass in the right adrenal gland of case 1. The pathologic examination of biopsy samples of their nasal masses revealed "small round blue-cell tumor" along with abundant vascular fibrous septa. The tumor cells expressed synaptophysin, cluster of differentiation 56, chromogranin A, paired like homeobox protein 2B and a very high Ki67 index in both case but were negative for vimentin, desmin, leucocyte common antigen and cytokeratin. Myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN) amplification was detected in both cases. Finally, the two cases were diagnosed as nasal metastases from NB based on the clinical and pathologic findings. The two patients affected by NB were > 18 mo old, the primary tumor location was adrenal gland, and they presented with multiple metastases. CONCLUSION: It is difficult to differentiate between metastatic NB in the nose and olfactory neuroblastoma in the absence of a history of NB. Paired like homeobox protein 2B can play an important role in the diagnosis and differential diagnosis of this disease.

Survival Outcomes of Lobectomy Versus Segmentectomy in Clinical Stage I Non-Small Cell Lung Cancer: A Meta-Analysis.

INTRODUCTION: The gold standard surgical therapy for patients with clinical stage I non-small cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection. Meanwhile, segmentectomy has emerged as an alternative choice with the advantage of fewer postoperative complications. The acceptance of this procedure remains controversial, and conflicting results exist in the retrospective trials. OBJECTIVES: The aim of this meta-analysis was to analyze the survival outcomes of lobectomy versus segmentectomy in clinical stage I NSCLC. METHODS: A computerized literature search was done on published trials in PubMed, Embase, and the Cochrane Library to June 2019 to identify clinical trials. Lung cancer-specific survival (LCSS) and overall survival (OS) were measured as outcomes. Statistical analysis was performed in the Meta-analysis Revman 5.3 software. RESULTS: A systematic literature search was conducted including seven studies. In this meta-analysis, the LCSS and OS in the lobectomy group were linked to a markedly lower trend in comparison to the segmentectomy group without significant statistical difference (P > 0.05), indicating that lobectomy confers an equivalent survival outcome compared with segmentectomy. CONCLUSION: No significant differences were found in survival outcomes between lobectomy and segmentectomy. Further large-scale, prospective, randomized trials are needed to explore reasonable surgical treatments for early-stage lung cancer.

Dynamics of HIV reservoir decay and naïve CD4 T-cell recovery between immune non-responders and complete responders on long-term antiretroviral treatment.

BACKGROUND: The dynamics of viral reservoir decay and naïve CD4 T-cell recovery between immunological non-responders (INR) and complete responders (CR) during long-term antiretroviral treatment (ART) are not fully known. METHODS: Twenty-eight chronic HIV-infected individuals on 5-year ART were divided into two groups: INR (CD4 counts ≤350 cells/µL, n = 13) and CR (CD4 counts ≥500 cells/µL, n = 15). The levels of HIV DNA and cell-associated HIV RNA (CA-RNA), CD4 counts, naïve CD4 counts and their correlations were analyzed at baseline, years 1, 3 and 5 of ART between the two groups. Expression of PD-1 on CD4 T-cells was quantified by flow cytometry. Linear mixed effect models were used to estimate the change procession in repeated measurements over 5 years. Slopes of the above-mentioned indicators were estimated using participant-specific linear regressions, respectively. RESULTS: INR maintained higher levels of HIV DNA and CA-RNA with higher percentages of PD-1+CD4 T-cells compared with CR during 5-year ART, concurrent with lower naïve CD4 T-cells. However, the rates of HIV DNA and CA-RNA decay in INR were not different from that in CR over time, and INR had higher rates of naïve CD4 T-cell percentage recovery. The baseline levels of HIV DNA were positively associated with the 5-year levels of HIV DNA, but negatively associated with the 5-year naïve CD4 counts. CONCLUSIONS: INR maintained significantly higher viral reservoir and lower naïve CD4 T-cells compared with CR during 5-year ART, however, the rates of reservoir decay and naïve CD4 T-cell percentage growth within INR were not lower than that in CR over time.

LysR Family Regulator LttR Controls Production of Conjugated Linoleic Acid in Lactobacillus plantarum by Directly Activating the cla Operon.

Conjugated linoleic acids (CLAs) have attracted more attention as functional lipids due to their potential physiological activities, including anticancer, anti-inflammatory, anti-cardiovascular disease, and antidiabetes activities. Microbiological synthesis of CLA has become a compelling method due to its high isomer selectivity and convenient separation and purification processes. In Lactobacillus plantarum, the generation of CLA from linoleic acids (LAs) requires the combination of CLA oleate hydratase (CLA-HY), CLA short-chain dehydrogenase (CLA-DH), and CLA acetoacetate decarboxylase (CLA-DC), which are separately encoded by cla-hy, cla-dh, and cla-dc. However, the regulatory mechanisms of CLA synthesis remain unknown. In this study, we found that a LysR family transcriptional regulator, LTTR, directly bound to the promoter region of the cla operon and activated the transcription of cla-dh and cla-dc. The binding motif was also predicted by bioinformatics analysis and verified by electrophoretic mobility shift assays (EMSAs) and DNase I footprinting assays. The lttR overexpression strain showed a 5-fold increase in CLA production. Moreover, we uncovered that the transcription of lttR is activated by LA. These results indicate that LttR senses LA and promotes CLA production by activating the transcription of cla-dh and cla-dc. This study reveals a new regulatory mechanism in CLA biotransformation and provides a new potential metabolic engineering strategy to increase the yield of CLA.IMPORTANCE Our work has identified a novel transcriptional regulator, LTTR, that regulates the production of CLA by activating the transcription of cla-dh and cla-dc, essential genes participating in CLA synthesis in Lactobacillus plantarum This study provides insight into the regulatory mechanism of CLA synthesis and broadens our understanding of the synthesis and regulatory mechanisms of the biosynthesis of CLA.

Targeting MUC1-C reverses the cisplatin resistance of esophageal squamous cell carcinoma in vitro and in vivo.

BACKGROUND: The efficacy of chemotherapeutic treatment of esophageal squamous cell carcinoma (ESCC) is limited by drug resistance during. This severely compromises the long-term survival rate of patients. Therefore, reversing chemotherapy resistance in ESCC may improve the therapeutic outcome. Here, we investigated the molecular mechanism of MUC1-C, the C-terminal transmembrane subunit of MUC1 (a transmembrane heterodimer protein), and its role in the reversal of cisplatin sensitivity in ESCC cells. METHODS: We assessed the efficacy of GO-203, a cell-penetrating peptide, as a chemotherapeutic target of MUC1-C using cell proliferation, colony-forming, and transwell assays. Apoptosis was analyzed in GO-203-treated cells by flow cytometry. Tumor xenograft assay was performed in nude mice to corroborate our in vitro findings. RESULTS: GO-203 treatment inhibited cell proliferation and restrained the migration and invasion of cisplatin-resistant ESCC. Moreover, targeting MUC1 resulted in enhanced apoptosis in GO-203-treated cells. These in vitro pro-apoptotic and anti-proliferative effects of GO-203 in combination with cisplatin were validated by in vivo models. Significantly smaller tumor volumes were observed in ESCCs-xenografted nude mice treated with GO-203 in combination with cisplatin compared with mice treated with monotherapy or their control counterparts. We found that blocking MUC1-C with GO-203 significantly reversed the cisplatin resistance in ESCC via modulating Akt and ERK pathways. CONCLUSIONS: Our findings suggest that GO-203 may hold potential as an ancillary therapeutic molecule and a chemosensitizer to improve the outcomes of cisplatin-based chemotherapy especially in patients with cisplatin-resistant ESCC.

Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients With Advanced Lung Adenocarcinoma.

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy. Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. Results: The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set. Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

HIV Reservoir Decay and CD4 Recovery Associated With High CD8 Counts in Immune Restored Patients on Long-Term ART.

Background: Whether varying CD8 counts influence the human immunodeficiency virus (HIV) reservoir and CD4 restoration in patients with CD4 counts ≥ 500 cells/µL after long-term antiretroviral therapy (ART) remains unknown. In this study, we analyzed relationships between CD8 levels and viral reservoir decay or CD4 recovery in immune restored patients on long-term ART. Methods: Chronic HIV-infected patients who received 5 years of ART with CD4 counts ≥ 500 cells/µL were grouped according to CD8 counts: CD8 <500 (Group 1), 500-1,000 (Group 2), and ≥1,000 cells/µL (Group 3). CD4 recovery, viral decay, CD8 T-cell function, and their correlations were analyzed during ART among the three groups. Results: Dynamics of viral decay and CD4 recovery were different among the three groups. Both viral decay and CD4 recovery were higher in Group 3 than the other two groups after 5 years of ART, mainly during years 3-5 of ART. Higher expression levels of Ki67 while PD-1 levels were lower on CD8 T-cells in Group 3 compared with the other groups, and Group 3 showed stronger CD8 T-cells functional capacity after 3 years of ART. Reduced HIV DNA levels and increased CD4 counts between years 3 and 5 of ART were positively correlated with CD8 counts and function. Conclusions: High CD8 counts are beneficial for persistent viral decay and CD4 recovery in immune restored patients during long-term ART.

The Latest Battles Between EGFR Monoclonal Antibodies and Resistant Tumor Cells.

Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor involved in homeostatic regulation of normal cells and carcinogenesis of epithelial malignancies. With rapid development of the precision medicine era, a series of new therapies targeting EGFR are underway. Four EGFR monoclonal antibody drugs (cetuximab, panitumumab, nimotuzumab, and necitumumab) are already on the market, and a dozen other EGFR monoclonal antibodies are in clinical trials. Here, we comprehensively review the newly identified biological properties and anti-tumor mechanisms of EGFR monoclonal antibodies. We summarize recently completed and ongoing clinical trials of the classic and new EGFR monoclonal antibodies. More importantly, according to our new standard, we re-classify the complex evolving tumor cell resistance mechanisms, including those involving exosomes, non-coding RNA and the tumor microenvironment, against EGFR monoclonal antibodies. Finally, we analyzed the limitations of EGFR monoclonal antibody therapy, and discussed the current strategies overcoming EGFR related drug resistance. This review will help us better understand the latest battles between EGFR monoclonal antibodies and resistant tumor cells, and the future directions to develop anti-tumor EGFR monoclonal antibodies with durable effects.

[Clinical effect and safety of different maintenance doses of caffeine citrate in treatment of apnea in very low birth weight preterm infants: a prospective randomized controlled trial].

OBJECTIVE: To study the clinical effect and safety of different maintenance doses of caffeine citrate in the treatment of apnea in very low birth weight preterm infants. METHODS: A total of 78 very low birth weight preterm infants with primary apnea were enrolled who were admitted from January 2016 to January 2018. They were randomly divided into high-dose caffeine group with 38 children and low-dose caffeine group with 40 children. Both groups received a loading dose of 20 mg/kg caffeine citrate, and 24 hours later, the children in the high-dose caffeine group were given a maintenance dose of 10 mg/kg, and those in the low-dose caffeine group were given a maintenance dose of 5 mg/kg. The two groups were compared in terms of response rate and incidence rate of adverse events. RESULTS: The high-dose caffeine group had a significantly higher response rate than the low-dose caffeine group (71% vs 48%; P<0.05). Compared with the low-dose caffeine group, the high-dose caffeine group had significantly shorter duration of apnea and time of caffeine treatment (P<0.05). There were no significant differences between the two groups in length of hospital stay and incidence rates of tachycardia, feeding intolerance, bronchopulmonary dysplasia, necrotizing enterocolitis, and intracranial hemorrhage (P>0.05). There was no significant difference in the mortality rate between the two groups (P>0.05). CONCLUSIONS: Higher maintenance dose of caffeine citrate has a better clinical effect than lower maintenance dose of caffeine citrate in the treatment of apnea in very low birth weight preterm infants, without increasing the incidence rates of adverse drug reactions and serious complications in preterm infants.