Search

Arctium lappa L. is one of the medicinal and food homologous plants in China, which is rich in nutrients and medicinal ingredients. The use of plant growth-promoting (PGP) endophytic bacteria is an alternative to reducing chemical fertilizers in agricultural production. The aim of this study was to analyze the diversity of endophytic bacteria in different cultivars of A. lappa L. collected from two geographical locations in China and evaluate PGP traits of the isolates and their potential PGP ability in greenhouse condition. Endophytic bacterial community was investigated by culture-dependent and culture-independent methods. Isolates were screened and investigated for multiple PGP traits, and representative strains were inoculated host seedlings to evaluate the growth promoting effect. A total of 348 endophytic bacteria were obtained and they were distributed into 4 phyla and 30 genera. In addition, high throughput sequencing revealed more abundant bacterial community, including 17 bacterial phyla and 207 genera. A high proportion of PGP traits were detected, including production of indole acetic acid, siderophore, ammonia and phosphate solubilization. Four representative strains with multiple PGP traits of the most dominant genera (Bacillus, Pantoea, Microbacterium and Pseudomonas) were further selected for host inoculation and growth promoting evaluation, and they significantly increase seedlings length, root length and fresh weight. This study demonstrated that A. lappa L. harbors abundant endophytic bacteria, and some endophytic bacteria showed good potential for the development of microbial fertilizer in the future., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Implementing effective antimicrobial therapy close to the onset of infection lowers morbidity and mortality and attenuates the spread of antimicrobial resistance. Current antimicrobial susceptibility testing (AST) methods, however, require several days to determine optimal therapies. We present technology and an automated platform that identify (ID) Urinary Tract Infection pathogens in 45 min and provide phenotypic AST results in less than 5 h from urine specimens without colony isolation. The ID and AST tests count cells fluorescently labeled with specific rRNA probes using non-magnified digital imaging. The ID test detected five pathogens at ≤ 7,000 CFU/mL and had a linear range of ~ 4 orders of magnitude. For contrived specimens, AST tests gave 93.1% categorical agreement with 1.3% Very Major Errors (VME), 0.3% Major Errors (ME), and 6.3% minor Errors (mE) compared to the broth microdilution (BMD) reference method. For clinical specimens, the ID test had 98.6% agreement and the AST test had 92.3% categorical agreement with 4.2% mE, 3.4% ME and 4.0% VME compared to BMD. Data presented demonstrates that direct-from-specimen AST tests can accurately determine antimicrobial susceptibility/resistance for each pathogen in a specimen containing two pathogens. The method is robust to urine matrix effects and off-target commensal and contaminating bacteria., (© 2022. The Author(s).)

Background: Developing adequate regional anaesthesia for knee surgeries without affecting lower limb mobilization is crucial to perioperative analgesia. However, reports in this regard are limited. We proposed a technique for ultrasound-guided peripatellar plexus (PP) block. Compared with the femoral nerve (FN) block, we hypothesized that this technique would provide a noninferior block duration and a complete cutaneous sensory block in the peripatellar region without affecting lower limb mobilization. An investigation was conducted to verify our hypothesis in cadavers and volunteers., Methods: The study was designed in two parts. First, eight cadaveric lower limbs were dissected to verify the feasibility of PP block after methylene blue injection under ultrasound. Second, using a noninferiority study design, 50 healthy volunteers were randomized to receive either a PP block (PP group) or an FN block (FN group). The primary outcome was the duration of peripatellar cutaneous sensory block, with the prespecified noninferiority margin of -3.08 h; the secondary outcome was the area of peripatellar cutaneous sensory block; in addition, the number of complete anaesthesias of the incision line for total knee arthroplasty and the Bromage score 30 min after block were recorded., Results: The PP was successfully dyed, whereas the FN and saphenous nerve were unstained in all cadaveric limbs. The mean difference of the block duration between the two groups was - 1.24 (95% CI, -2.81 - 0.33) h, and the lower boundary of the two-sided 95% CI was higher than the prespecified noninferiority margin (P noninferiority = 0.023), confirming the noninferiority of our technique over FN block. The cutaneous sensory loss covered the entire peripatellar region in the PP group. PP block achieved complete anaesthesia of the incision line used for total knee arthroplasty and a Bromage score of 0 in 25 volunteers, which differed significantly from that of volunteers who underwent FN block., Conclusion: Ultrasound-guided PP block is a feasible technique. Compared with FN block, PP block provides noninferior block duration and complete blocking of the peripatellar region without affecting lower limb mobilization., Trial Registration: This study was registered in the Chinese Clinical Trial Register (registration no. ChiCTR2000041547, registration date 28/12/2020)., (© 2022. The Author(s).)

Background: Robotic liver resection (RLR) has increasingly been accepted as it has overcome some of the limitations of open liver resection (OLR), while the outcomes following RLR in elderly patients with hepatocellular carcinoma (HCC) are still uncertain. This study aimed to evaluate the short and long-term outcomes of RLR vs. OLR in elderly HCC patients., Methods: Perioperative data of elderly patients (≥ 65 years) with HCC who underwent RLR or OLR between January 2010 and December 2020 were retrospectively analyzed. A 1:2 propensity score-matched (PSM) analysis was performed to minimize the differences between RLR and OLR groups. Univariable and multivariable Cox regression analyses were used to identify independent prognosis factors for overall survival (OS) and recurrence-free survival (RFS) of these patients., Results: Of the 427 elderly HCC patients included in this study, 113 underwent RLR and 314 underwent OLR. After the 1:2 PSM, there were 100 and 178 patients in the RLR and the OLR groups, respectively. The RLR group had a less estimated blood loss (EBL), a shorter postoperative length of stay (LOS), and a lower complications rate (all P < 0.05), compared with the OLR group before and after PSM. Univariable and multivariable analyses showed that advanced age and surgical approaches were not independent risk factors for long-term prognosis. The two groups of elderly patients who were performed RLR or OLR had similar OS (median OS 52.8 vs. 57.6 months) and RFS (median RFS 20.4 vs. 24.6 months) rates after PSM., Conclusions: RLR was comparable to OLR in feasibility and safety. For elderly patients with HCC, RLR resulted in similar oncologic and survival outcomes as OLR., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an affinity-enhanced mutant sBCMA-Fc fusion molecule (sBCMA-Fc V3) 4- and 500-fold stronger in binding to APRIL and BAFF, respectively. The mutant sBCMA-Fc V3 clone significantly enhanced antitumor activity against both MM and DLBCL. Importantly, we also demonstrated an adequate toxicity profile and on-target mechanism of action in nonhuman primate studies., (© 2022 Miao et al.)

Interleukin 4 (IL-4) plays a major role in T-lymphocyte development and is thought to be a central regulator as a cofactor in resting B-lymphocyte proliferation. Primary infection with porcine reproductive and respiratory syndrome virus (PRRSV) induces minimal IL-4 production, whereas an IL-4 response occurs in the peripheral blood of piglets reinfected by PRRSV. The locations and interaction partners for the massive volume of IL-4 triggered by PRRSV reinfection remain unclear. This study aimed to investigate the characteristics of IL-4 secretion and location changes in peripheral immune organs induced by PRRSV infection and reinfection. Our results show that PRRSV reinfection induced higher levels of IL-4 mRNA and protein expression in the peripheral immune organs (e.g., lymph node and spleen) and peripheral blood compared with PRRSV primary infection. Importantly, we found that, following PRRSV reinfection, an obvious large-scale migration of IL-4 occurred in the lymph nodes. During PRRSV primary infection, IL-4 was mainly concentrated around the lymphoid follicles and paracortical regions of the lymph node and also located in the marginal area and periarterial lymphatic sheath region of the spleen. During PRRSV reinfection, the now abundant IL-4 gathered into the lymphoid follicles of the lymph node and spleen. Notably, IL-4 changed its location state from scattered and sparse during primary infection to clinging to B lymphocytes in the lymphoid follicles during reinfection. During reinfection, IL-4 was often co-localized with T and B lymphocytes; furthermore, the percentages of several T lymphocyte subsets, N protein-specific antibody levels, and viral load in the peripheral blood or lymph tissues underwent remarkable variation. Another important finding of this study was that the numbers of B lymphocytes and T lymphocytes in the lymphoid nodes were significantly reduced after PRRSV infection or reinfection, presumably due to PRRSV-induced acute bone marrow failure and autophagy in thymic epithelial cells. This study revealed the characteristics of IL-4 migration and distribution in the peripheral lymph organs induced by PRRSV reinfection and provides valuable clues for further exploration of the interactions between IL-4, B lymphocytes, and T lymphocytes during PRRSV infection and reinfection., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC). However, the potential anti-SCLC mechanisms of pazopanib remain unclear., Methods: Cell viability was evaluated by CCK-8, apoptotic cell detection was conducted using annexin V/PI staining followed by flow cytometry, and Western blot analysis was used to detect the apoptotic-related molecules and ER-stress pathway effectors. The intracellular reactive oxygen species (ROS) level was determined by DCFH-HA staining followed by flow cytometry. An NCI-H446 xenograft model was established to evaluate pazopanib on tumor suppression in vivo. Immunohistochemistry (IHC) was used to assess the proliferative activity of xenograft in NCI-H446 cell-bearing NOD-SCID mice., Results: Pazopanib dose- and time-dependently inhibited SCLC cell proliferation induced significant apoptosis in SCLC cell lines, increased cleaved-caspase3 and Bax, and decreased Bcl-2. Moreover, the PERK-related ER-stress pathway was potently activated by pazopanib treatment, inhibiting ER-stress by salubrinal significantly reversing pazopanib-mediated apoptosis in SCLC cell lines. Furthermore, pazopanib-induced intracellular ROS levels increased, while inhibiting ROS by NAC significantly reversed pazopanib-induced apoptosis in SCLC cells. In addition, pazopanib significantly suppressed NCI-H446 xenograft growth and decreased Ki67 positive cells in the tumor., Conclusion: Our findings indicate that pazopanib induces SCLC cell apoptosis through the ER-stress process via upregulation of ROS levels. Further investigation of relevant biomarkers to accurately select patients for benefit from pazopanib should be further investigated., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objective: To investigate the short-term clinical effect of the cervical anterior Hybrid surgery in the treatment of two-segment and three-segment cervical spondylosis., Methods: From January 2018 to January 2019, 108 patients who were performed anterior Hybrid surgery with cervical degenerative diseases were collected. The patients were divided into a two-segment group with 52 patients and a three-segment group with 56 patients according to surgical segments. In two-segment group, there were 24 males and 28 females, aged from 35 to 67 years old with an average of(45.94±14.67) years old. In three-segment group, there were 23 males and 33 females, aged from 32 to 65 years old with an average of (47.54±15.34) years old. The outcome indicators of the two groups were compared. Clinical indicators:neck disability index(NDI) was used to evaluate daily life ability, Japanese Orthopedic Association(JOA) score was used to evaluate neurological function improvement, visual analogue scale(VAS) was used to evaluate pain intensity, and general clinical results were graded according to Odom's score. Cervical range of motion (ROM), fusion and complications were measured by X-ray, CT and MRI., Results: All operations were successfully completed and all patients were followed up for more than 12 months. The operation time of two-segment group and three-segment group were 95 to 180 min with an average of(152.30±44.74) min and 110 to 210 min with an average of (165.18±45.86) mins, the blood loss were 20 to 100 ml with an average of (32.88±8.75) ml and 20 to 150 ml with an average of(34.64±10.63) ml respectively which has no statistical differences between the two groups ( P >0.05). Compared with those before surgery, NDI, JOA, VAS and Odom's scores between two groups were significantly improved at 12 months after operation( P <0.05). However, there was no significant difference in the NDI, JOA and Odom's scores between two groups ( P >0.05), and VAS in three-segment group was higher than that in two-segment group. There was no significant difference in C 3 -C 7 cervical mobility between two groups. Surgical incisions healed smoothly in all patients without complication such as spinal cord injury and cerebrospinal fluid leakage. The bone fusion of the two groups were 43 cases (82.69%) and 45 cases(80.35%) respectively. In two-segment group, there were 2 cases of adjacent segmental hyperosteogeny, and there were 3 cases of adjacent segmental hyperosteogeny and 1 case of adjacent posterior longitudinal ligament ossification in the three-segment group. In addition, in three-segment group, there was 1 case of looseness of implants with no obvious clinical symptoms., Conclusion: The anterior Hybrid surgery in treating multi-level cervical spondylosis could not only improve clinical symptoms of patients but also preserve mobility. Meanwhile, the efficacy and safety of Hybrid surgery in different multi-level cervical disc diseases are confirmed, proving its value in clinical practice.

The complex association between the gut microbiome and cancer development has been an emerging field of study in recent years. The gut microbiome plays a crucial role in the overall maintenance of human health and interacts closely with the host immune system to prevent and fight infection. This review was designed to draw a comprehensive assessment and summary of recent research assessing the anticancer activity of the metabolites (produced by the gut microbiota) specifically against breast cancer. In this review, a total of 2701 articles were screened from different scientific databases (PubMed, Scopus, Embase and Web of Science) with 72 relevant articles included based on the predetermined inclusion and exclusion criteria. Metabolites produced by the gut microbial communities have been researched for their health benefits and potential anticancer activity. For instance, the short-chain fatty acid, butyrate, has been evaluated against multiple cancer types, including breast cancer, and has demonstrated anticancer potential via various molecular pathways. Similarly, nisin, a bacteriocin, has presented with a range of anticancer properties primarily against gastrointestinal cancers, with nominal evidence supporting its use against breast cancer. Comparatively, a natural purine nucleoside, inosine, though it has not been thoroughly investigated as a natural anticancer agent, has shown promise in recent studies. Additionally, recent studies demonstrated that gut microbial metabolites influence the efficacy of standard chemotherapeutics and potentially be implemented as a combination therapy. Despite the promising evidence supporting the anticancer action of gut metabolites on different cancer types, the molecular mechanisms of action of this activity are not well established, especially against breast cancer and warrant further investigation. As such, future research must prioritise determining the dose-response relationship, molecular mechanisms, and conducting animal and clinical studies to validate in vitro findings. This review also highlights the potential future directions of this field.

Endothelial dysfunction is an early pathological event in diabetic angiopathy which is the most common complication of diabetes. This study aims to investigate individual and combined actions of Curcumin (Cur) and Baicalein (Bai) in protecting vascular function. The cellular protective effects of Cur, Bai and Cur+Bai (1:1, w/w ) were tested in H 2 O 2 (2.5 mM) impaired EA. hy926 cells. Wistar rats were treated with vehicle control as the control group, Goto-Kakizaki rats (n=5 each group) were treated with vehicle control (model group), Cur (150 mg/kg), Bai (150 mg/kg), or Cur+Bai (75 mg/kg Cur + 75 mg/kg Bai, OG) for 4 weeks after a four-week high-fat diet to investigate the changes on blood vessel against diabetic angiopathy. Our results showed that Cur+Bai synergistically restored the endothelial cell survival and exhibited greater effects on lowering the fasting blood glucose and blood lipids in rats comparing to individual compounds. Cur+Bai repaired the blood vessel structure in the aortic arch and mid thoracic aorta. The network pharmacology analysis showed that Nrf2 and MAPK/JNK kinase were highly relevant to the multi-targeted action of Cur+Bai which has been confirmed in the in vitro and in vivo studies. In conclusion, Cur+Bai demonstrated an enhanced activity in attenuating endothelial dysfunction against oxidative damage and effectively protected vascular function in diabetic angiopathy rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. As a medical research institute, NICM Health Research Institute receives re-search grants and donations from foundations, universities, government agencies, individuals and industry. Sponsors and donors also provide untied funding for work to advance the vision and mission of the Institute., (Copyright © 2022 Wang, Sun, Liu, Liu, Afzal, Grover, Chang, Münch, Li, Lin, Chen, Zhang, Cheng, Lin, Zheng, Huang and Zhou.)

The scaling problem in the water supply pipeline will increase the resistance coefficient of the pipeline and the pressure of the water supply pipeline, which will not only affect the operation safety of the water supply pipeline, but also cause energy waste. The scale in the pipeline will also enrich heavy metal ions and pathogenic microorganisms, affecting the safety of water supply water quality and causing secondary pollution of water quality. At present, a lot of research has been done on the composition structure and crystallization process of the scale. The study found that calcite is the main component of the scale; the scale process is a heterogeneous nucleation process induced by heavy metal particles and their corrosion products in the pipeline. The introduction of electrochemical detection technology, density functional theory and molecular dynamics simulation has greatly improved the accuracy and timeliness of water scaling conditions detection and realized the visualization of scaling mechanism. In this paper, the measurement methods of the scale in the water supply pipeline and the corresponding material composition and crystal structure characteristics are reviewed, and the mechanism of the scale and the water quality conditions are summarized. At the end of this paper, based on summarizing the existing water quality scaling tendency evaluation methods, it is proposed to establish a water quality potential scaling risk assessment framework based on Puckorius scaling index (PSI) and electrochemical impedance spectroscopy (EIS) in the future., (Copyright © 2022. Published by Elsevier Ltd.)

Crocins (CRs) and the related active constituents derived from Crocus sativus L. (Saffron) have demonstrated protective effects against cerebral ischemia and ischemic stroke, with various bioactivities including neuroprotection, anti-neuroinflammation, antioxidant, and cardiovascular protection. Among CRs, crocin (CR) has been shown to act on multiple mechanisms and signaling pathways involved in ischemic stroke, including mitochondrial apoptosis, nuclear factor kappa light chain enhancer of B cells pathway, S100 calcium-binding protein B, interleukin-6 and vascular endothelial growth factor-A. CR is generally safe and well-tolerated. Pharmacokinetic studies indicate that CR has poor bioavailability and needs to convert to crocetin (CC) in order to cross the blood-brain barrier. Clinical studies have shown the efficacy of saffron and CR in treating various conditions, including metabolic syndrome, depression, Alzheimer's disease, and coronary artery disease. There is evidence supporting CR as a treatment for ischemic stroke, although further studies are needed to confirm their efficacy and safety in clinical settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shahbaz, Chang, Zhou, Low, Seto and Li.)

In order to investigate the pore properties and effect of storage time on the microstructure of CO 2 -dried aerogels, chitosan aerogel beads were obtained from chitosan hydrogels with an initial concentration in the range of 1.5-3.0 wt% through SCCO 2 drying and freeze-drying (as a comparison). The SCCO 2 -dried chitosan aerogels showed a three-dimensional network structure, and had higher BET surface area (200 m 2 g -1 ) and higher crystallinity (0.62/XRD, 0.80/ATR-FTIR) than the freeze-dried aerogels. The stability of the microstructure of the SCCO 2 -dried chitosan aerogel beads during 10 months was studied. The BET surface area of the aerogel beads at each concentration declined by 30.5% at 2 months, 56.7% at 6 months and 67.2% at 10 months. Accelerated aging tests of the chitosan aerogel beads were carried out to study the effect of humidity on the chitosan aerogel beads. The average diameter of the chitosan aerogel decreased from 2.3 mm to 0.9 mm when stored at 65 °C with 90% relative humidity (RH). In contrast, there was no obvious change during storage at 65 °C with 20% RH. The amount of adsorbed water increased from 4% to 12% at 65 °C with 90% RH for 96 h, and the bound water content of the aerogel beads gradually increased. This study demonstrates that SCCO 2 -dried chitosan aerogel beads could be better at maintaining their mesoporous structure, and the adsorption of water from the surrounding air had a significant effect on the microstructure and shrinkage of the chitosan aerogel beads., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: The neutrophil to lymphocyte ratio (NLR) has been reported as an indicator for poor prognosis in many cancers including esophageal cancer. However, the relationship between the NLR and postoperative complications after esophageal cancer resection remains unclear. At present, enhanced recovery after surgery (ERAS) lacks inclusion criteria. The aim of this study is to determine whether the preoperative NLR ( pre NLR) can predict complications after esophageal cancer resection, which could represent the criteria for ERAS., Methods: This was a retrospective study on 171 patients who underwent esophagectomy at Hospital between November 2020 and November 2021(68 patients from Changhai Hospital, 65 patients from Shanghai General Hospital and 38 patients from Affiliated Hospital of Qingdao University). Univariate and multivariate logistic regression analyses were performed to demonstrate that the pre NLR could predict complications after esophagectomy., Results: A pre NLR cutoff value of 2.30 was identified as having the greatest ability to predict complications with a sensitivity of 76% and specificity of 65%. Moreover, the Chi-squared test results showed that the pre NLR was significantly associated with complications (x 2  = 13.641, p  < 0.001), and multivariate logistic regression analysis showed that body mass index (BMI), p stage and pre NLR were independent variables associated with the development of postoperative complications ( p  < 0.05)., Conclusion: The pre NLR can predict complications after esophagectomy, and these predicted complications can represent the criteria for recruiting patients for ERAS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shi, Xu, Gong, Yang, Han, Chen and Li.)

Pancreatic cancer is one of the deadliest cancers, against which current immunotherapy strategies are not effective. Herein, we analyzed the immune cell composition of the tumor microenvironment of pancreatic cancer samples in The Cancer Genome Atlas and found that the presence of intratumoral NK cells correlates with survival. Subsequent analysis also indicated that NK cell exclusion from the microenvironment is found in a high percentage of clinical pancreatic cancers and in preclinical models of pancreatic cancer. Mechanistically, NK cell exclusion is regulated in part by complement C3a and its receptor signaling. Inhibition of the C3a receptor enhances NK cell infiltration in syngeneic mouse models of pancreatic cancer resulting in tumor growth delay. However, tumor growth inhibition mediated by NK cells is not sufficient alone for complete tumor regression, but is potentiated when combined with radiation therapy. Our findings indicate that although C3a inhibition is a promising approach to enhance NK cell-based immunotherapy against pancreatic cancer, its combination with radiation therapy hold greater therapeutic benefit.

This study aims to investigate the combined anti-inflammatory activity of ginger and turmeric extracts. By comparing the activities of individual and combined extracts in lipopolysaccharide and interferon-γ-induced murine RAW 264.7 cells, we demonstrated that ginger-turmeric combination was optimal at a specific ratio (5:2, w/w) in inhibiting nitric oxide, tumour necrosis factor and interleukin 6 with synergistic interaction (combination index < 1). The synergistic inhibitory effect on TNF was confirmed in human monocyte THP-1 cells. Ginger-turmeric combination (5:2, w/w) also upregulated nuclear factor erythroid 2−related factor 2 activity and heme oxygenase-1 protein expression. Additionally, 6-shogaol, 8-shogaol, 10-shogaol and curcumin were the leading compounds in reducing major proinflammatory mediators and cytokines, and a simplified compound combination of 6-s, 10-s and curcumin showed the greatest potency in reducing LPS-induced NO production. Our study provides scientific evidence in support of the combined use of ginger and turmeric to alleviate inflammatory processes.

Background: Effective biomarkers for early diagnosis of lung cancer are needed. Previous studies have indicated positive associations between abnormal circulating cytokines and the etiology of lung cancer., Methods: Blood samples were obtained from 286 patients with pretreatment lung cancer and 80 healthy volunteers. Circulating cytokine levels were detected with a Luminex assay and enzyme-linked immunosorbent assay (ELISA). Urine samples were obtained from 284 patients and 122 healthy volunteers. CXC chemokine ligand 14 (CXCL14) expression in tumors and nontumor regions of lung tissues from 133 lung cancer cases was detected by immunohistochemical (IHC) staining and immunofluorescence (IF) staining of formalin fixed paraffin-embedded (FFPE) tissues., Results: Compared with healthy volunteers, a 65.7-fold increase was observed in the level of CXCL14 in the plasma of lung cancer patients, and a 1.7-fold increase was observed in the level of CXCL14 in the urine of lung cancer patients, achieving a 0.9464 AUC (area under the curve) value and a 0.6476 AUC value for differentiating between lung cancer patients and healthy volunteers, respectively. Stromal CXCL14 expression was significantly associated with advanced pathologic stage ( P <0.001), pathologic N stage ( P <0.001), and recurrence and metastasis ( P =0.014). Moreover, multivariate analysis suggested stromal CXCL14 expression as an independent predictor of DFS and OS., Conclusions: Our study demonstrates that CXCL14 might serve as a potential diagnostic and prognostic biomarker in patients with lung cancer., Impact: CXCL14 might serve as a potential diagnostic and prognostic biomarker in patients with lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tian, Ma, Yue, Liang, Li, Chen, Zhang, Sun, Huang, Zhang, Zhou, Wang, Zhang and Wang.)

Introduction: Tamoxifen (TAM) is the most commonly used hormone therapeutic drug for the treatment of estrogen receptor-positive (ER+) breast cancer. 30%-70% of clinical breast cancer patients use natural products, which may increase the likelihood of drug interactions. Objective: To evaluate the evidence for the interactions between natural products and TAM in breast cancer. Methods: Electronic databases, including PubMed, CINAHL Plus ( via EbscoHost), European PMC, Medline, and Google Scholar, were searched for relevant publications. The search terms include complementary and alternative medicine, natural products, plant products, herbs, interactions, tamoxifen, breast cancer, and their combinations. Results: Various in vitro and in vivo studies demonstrated that the combined use of natural products with TAM produced synergistic anti-cancer effects, including improved inhibition of tumor cell growth and TAM sensitivity and reduced side effects or toxicity of TAM. In contrast, some natural products, including Angelica sinensis (Oliv.) Diels [Apiaceae] , Paeonia lactiflora Pall . , Rehmannia glutinosa (Gaertn.) DC. , Astragalus mongholicus Bunge, and Glycyrrhiza glabra L. [Fabaceae], showed estrogen-like activity, which may reduce the anti-cancer effect of TAM. Some natural products, including morin, silybin, epigallocatechin gallate (EGCG), myricetin, baicalein, curcumin, kaempferol, or quercetin, were found to increase the bioavailability of TAM and its metabolites in vivo . However, three are limited clinical studies on the combination of natural products and TAM. Conclusion: There is evidence for potential interactions of various natural products with TAM in pre-clinical studies, although the relevant clinical evidence is still lacking. Further studies are warranted to evaluate the potential interactions of natural products with TAM in clinical settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yen, Zhao, Yu, Zhu and Li.)

Synergy plays a prominent role in herbal medicines to increase potency and widen the therapeutic windows. The mechanism of synergy in herbal medicines is often associated with multi-targeted behavior and complex signaling pathways which are challenging to elucidate. This study aims to investigate the synergistic mechanism of a combination (GT) of ginger (G) and turmeric (T) extracts by exploring the modulatory activity in lipopolysaccharides (LPS)-induced inflammatory pathways and key molecular targets. A Bioplex ProTM mouse cytokine 23-plex assay was utilized to assess the broad anti-cytokine activity of GT in LPS and interferon (IFN)-ɣ (both at 50 ng/mL)-activated RAW 264.7 cells. The inhibitory effects of individual and combined G and T on major proinflammatory mediators including nitric oxide (NO), tumor necrosis factor (TNF) and interleukin (IL)-6 were tested using Griess reagents and ELISA assays, respectively. Immunofluorescent staining and Western blot were used to investigate the modulatory effect of GT on key proteins in the LPS/TLR4 signaling transduction. The regulation of murine microRNA miR-155-5p was tested using real-time PCR. The IC 50 value and combination index (CI) values were used to demonstrate potency and synergistic interaction, respectively. GT synergistically attenuated a range of pro-inflammatory mediators including inducible NO, major cytokines (TNF and IL-6) and secondary inflammatory cytokines (GM-CSF and MCP-1). GT significantly inhibited LPS-induced NF-kB p65 translocation, the activation of TLR4, TRAF6, and phosphorylation of JNK and c-JUN. Moreover, the suppressive effect of GT on each of the protein targets in this axis was stronger than that of the individual components. Real-time PCR analysis showed that GT suppressed miR-155-5p to a greater extent than G or T alone in LPS-stimulated cells. Our study demonstrates the synergistic mechanism of GT in downregulating LPS-induced proinflammatory pathways at the miRNA and protein levels. Our results establish a scientific basis for the combined application of G and T as an advanced therapeutic candidate in inflammatory diseases with broad and synergistic anti-inflammatory activity and multi-targeted mechanisms., Competing Interests: DL and HW are employees of Integria Healthcare (Australia) Pty Ltd which provided funding and in-kind support for the work as an Australian Research Council Linkage Project industry partner. A patent application (Australian Patent Application No. 2021902926) based in part on these results has been filed by Integria Healthcare (Australia) Pty Ltd naming XZ, GM, ML, DL HW, CGL and others as inventors. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Münch, Wohlmuth, Afzal, Kao, Al-Khazaleh, Low, Leach and Li.)

Background: Metabolic reprogramming has been identified as a core hallmark of cancer. Solute carrier family 2 is a major glucose carrier family. It consists of 14 members, and we mainly study solute carrier family 2 member 1 (SLC2A1) and solute carrier family 2 member 2 (SLC2A2) here. SLC2A1, mainly existing in human erythrocytes, brain endothelial cells, and normal placenta, was found to be increased in hepatocellular carcinoma (HCC), while SLC2A2, the major transporter of the normal liver, was decreased in HCC., Aim: To identify if SLC2A1 and SLC2A2 were associated with immune infiltration in addition to participating in the metabolic reprogramming in HCC., Methods: The expression levels of SLC2A1 and SLC2A2 were tested in HepG2 cells, HepG215 cells, and multiple databases. The clinical characteristics and survival data of SLC2A1 and SLC2A2 were examined by multiple databases. The correlation between SLC2A1 and SLC2A2 was analyzed by multiple databases. The functions and pathways in which SLC2A1, SLC2A2, and frequently altered neighbor genes were involved were discussed in String. Immune infiltration levels and immune marker genes associated with SLC2A1 and SLC2A2 were discussed from multiple databases., Results: The expression level of SLC2A1 was up-regulated, but the expression level of SLC2A2 was down-regulated in HepG2 cells, HepG215 cells, and liver cancer patients. The expression levels of SLC2A1 and SLC2A2 were related to tumor volume, grade, and stage in HCC. Interestingly, the expression levels of SLC2A1 and SLC2A2 were negatively correlated. Further, high SLC2A1 expression and low SLC2A2 expression were linked to poor overall survival and relapse-free survival. SLC2A1, SLC2A2, and frequently altered neighbor genes played a major role in the occurrence and development of tumors. Notably, SLC2A1 was positively correlated with tumor immune infiltration, while SLC2A2 was negatively correlated with tumor immune infiltration. Particularly, SLC2A2 methylation was positively correlated with lymphocytes., Conclusion: SLC2A1 and SLC2A2 are independent therapeutic targets for HCC, and they are quintessential marker molecules for predicting and regulating the number and status of immune cells in HCC., Competing Interests: Conflict-of-interest statement: The authors declare no competing interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Previous studies reported inconsistent findings on autophagy activation in skeletal muscles after acute exercise. In this study, we investigated the effect of a single bout of exhaustive treadmill exercise on AMPK and autophagy activations in mice gastrocnemius muscle in vivo. Male ICR/CD-1 mice were randomly divided into the control and exercise groups. The later was subjected to a single bout of exhaustive treadmill exercise. Changes of AMPK, phosphorylation of AMPK Thr172 (pAMPK Thr172 ), and autophagy markers including Beclin1, LC3II/LC3I and p62 mRNA and protein expressions in gastrocnemius muscle at different times (0, 6, 12, 24 h) after the exercise were analysed by quantitative real-time PCR and western blot. Our results demonstrated that a single bout of exhaustive treadmill exercise significantly induced AMPK content and AMPK activity at 0, 6 and 12 h after the exercise, and changed the expressions of autophagy markers at different time points in the recovery period, respectively. Moreover, we observed positive correlations between expressions of LC3II/LC3I ratio and pAMPK Thr172 or AMPK, and a negative correlation between expressions of p62 and AMPK or pAMPK Thr172 . In conclusion, a single bout of exhaustive treadmill exercise in mice caused a prolonged activation of AMPK and improved autophagy in the gastrocnemius muscle. The regulation of autophagic markers were related to enhanced AMPK activity. The findings indicate that acute exercise enhanced AMPK-related autophagy activation may be the underlying molecular mechanism that regulates cellular energy metabolism during exercise., (© 2022 John Wiley & Sons Australia, Ltd.)

Volatile organic compounds (VOCs) produced by microorganisms are considered promising environmental-safety fumigants for controlling postharvest diseases. Ceratocystis fimbriata, the pathogen of black spot disease, seriously affects the quality and yield of sweet potato in the field and postharvest. This study tested the effects of VOCs produced by Streptomyces setonii WY228 on the control of C. fimbriata in vitro and in vivo . The VOCs exhibited strong antifungal activity and significantly inhibited the growth of C. fimbriata. During the 20-day storage, VOC fumigation significantly controlled the occurrence of the pathogen, increased the content of antioxidants and defense-related enzymes and flavonoids, and boosted the starch content so as to maintain the quality of the sweet potatoes. Headspace analysis showed that the volatiles 2-ethyl-5-methylpyrazine and dimethyl disulfide significantly inhibited the mycelial growth and spore germination of C. fimbriata in a dose-dependent manner. Fumigation with 100 μL/L 2-ethyl-5-methylpyrazine completely controlled the pathogen in vivo after 10 days of storage. Transcriptome analysis showed that volatiles mainly downregulated the ribosomal synthesis genes and activated the proteasome system of the pathogen in response to VOC stress, while the genes related to spore development, cell membrane synthesis, mitochondrial function, and hydrolase and toxin synthesis were also downregulated, indicating that WY228-produced VOCs have diverse modes of action for pathogen control. Our study demonstrates that fumigation of sweet potato tuberous roots with S. setonii WY228 or use of formulations based on the VOCs is a promising new strategy to control sweet potato and other food and fruit pathogens during storage and shipment. IMPORTANCE Black spot disease caused by Ceratocystis fimbriata has caused huge economic losses to worldwide sweet potato production. At present, the control of C. fimbriata mainly depends on toxic fungicides, and there is a lack of effective alternative strategies. The research on biological control of sweet potato black spot disease is also very limited. An efficient biocontrol technique against pathogens using microbial volatile organic compounds could be an alternative method to control this disease. Our study revealed the significant biological control effect of volatile organic compounds of Streptomyces setonii WY228 on black spot disease of postharvest sweet potato and the complex antifungal mechanism against C. fimbriata. Our data demonstrated that Streptomyces setonii WY228 and its volatile 2-ethyl-5-methylpyrazine could be a candidate strain and compound for the creation of fumigants and showed the important potential of biotechnology applications in the field of food and agriculture.

Aiming at the problems of low accuracy and large prediction errors caused by the serious overlap of multi-metal spectral signals in zinc smelting industrial wastewater, a characteristic interval modeling method is proposed. First, according to the absorption spectra of mixed solution, the characteristic intervals of copper and nickel are preliminarily screened by using different partition lengths. Second, take the smallest root mean squares error of cross validation and the largest correlation coefficient as the evaluation indicators, compare the full-spectral model and each local model, and select the optimal feature sub-intervals of copper and nickel. Last, the partial least squares method is used to model the combined wavelengths of the optimal sub-intervals to realize the simultaneous detection of copper and nickel. The linear determination ranges are 0.3-3.0 mg/L for copper and nickel. the correlation coefficients of copper and nickel are 0.9974 and 0.9966, respectively. The results show that the method reduces the complexity of the wavelength variable screening process, improves the accuracy of the model, and lays the foundation for the accurate analysis of polymetallic ions in zinc smelting industrial wastewater., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Li and Zhu.)

Many solid tumors have low levels of cytotoxic CD56 dim natural killer (NK) cells, suggesting that CD56 dim NK-cell exclusion from the tumor microenvironment (TME) contributes to the decreased response rate of immunotherapy. Complement component 3a (C3a) is known for its tumor-promoting and immunosuppressive roles in solid tumors. Previous reports have implicated the involvement of the C3a receptor (C3aR) in immune cell trafficking into the TME. C3aR is predominantly expressed on the surface of activated cytotoxic NK cells, but a specific role for C3aR in NK-cell biology has not been investigated. Because solid tumors generate elevated C3a and have decreased NK-cell infiltration, we hypothesized that C3aR might play a role in cytotoxic NK-cell recruitment into the TME. Our results indicate that blocking C3aR signaling in NK cells increased NK-cell infiltration into the TME in mouse models and led to tumor regression. Because the critical lymphocyte trafficking integrin LFA-1 orchestrates the migration of activated NK cells, we wanted to gain insight into the interaction between C3aR signaling and LFA-1. Our results demonstrated that direct interaction between C3aR and LFA-1, which led to a high-affinity LFA-1 conformation, decreased NK-cell infiltration into the TME. We propose that approaches to enhance cytotoxic NK-cell infiltration into the TME, through either disrupting C3a and C3aR interaction or inhibiting the formation of high-affinity LFA-1, represent a new strategy to improve the efficiency of immunotherapy for cancer treatment., (©2021 American Association for Cancer Research.)

This study aimed to elucidate the role of transcription factor EB (TFEB) in protecting C2C12 myotubes against palmitate (PA)-induced insulin resistance (IR) and explored its mechanism associated with autophagy. PA treatment significantly decreased insulin sensitivity in myotubes and downregulated TFEB protein expression. TFEB overexpression significantly reversed the PA-suppressed glucose transporter 4 (GLUT4) protein expression and improved intracellular glucose uptake and consumption, and also alleviated the decrease of autophagy markers induced by PA. The effect of TFEB overexpression on GLUT4 was also abolished by the autophagy inhibitor 3-MA. In addition, AMPKɑ2-DN inhibited or abolished the effects of TFEB overexpression on upregulation of GLUT4 and PA-induced decrease of autophagy marker expressions. Taken together, our data demonstrated that upregulation of TFEB improved PA-induced IR in C2C12 myotubes by enhancing autophagy and upregulating AMPK activity. TFEB, as a critical regulator of glucose homeostasis in skeletal muscle cells, may be a potential therapeutic target for IR and Type 2 diabetes., (© 2021 John Wiley & Sons Australia, Ltd.)

Background: Medicinal dendrobiums are used popularly in traditional Chinese medicine for the treatment of diabetes, while their active compounds and mechanism remain unclear. This review aimed to evaluate the mechanism and active compounds of medicinal dendrobiums in diabetes management through a systematic approach., Methods: A systematic approach was conducted to search for the mechanism and active phytochemicals in Dendrobium responsible for anti-diabetic actions using databases PubMed, Embase, and SciFinder., Results: Current literature indicates polysaccharides, bibenzyls, phenanthrene, and alkaloids are commonly isolated in Dendrobium genusin which polysaccharides and bibenzyls are most aboundant. Many animal studies have shown that polysaccharides from the species of Dendrobium provide with antidiabetic effects by lowering glucose level and reversing chronic inflammation of T2DM taken orally at 200 mg/kg. Dendrobium polysaccharides protect pancreatic β-cell dysfunction and insulin resistance in liver. Dendrobium polysaccharides up-regulate the abundance of short-chain fatty acid to stimulate GLP-1 secretion through gut microbiota. Bibenzyls also have great potency to inhibit the progression of the chronic inflammation in cellular studies., Conclusion: Polysaccharides and bibenzyls are the major active compounds in medicinal dendrobiums for diabetic management through the mechanisms of lowering glucose level and reversing chronic inflammation of T2DM by modulating pancreatic β-cell dysfunction and insulin resistance in liver as a result from gut microbita regulation., Competing Interests: DX, SC, and YH was employed by the company Chengdu Tepu Biotech Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Sichuan Science and Technology Program. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2022 Li, Trapika, Tang, Cho, Qi, Li, Li, Yao, Yang, Liu, Li, Yang, Ma, Ren, Huang, Xie, Chen, Li, Yang, Leng, Huang and Li.)

The non-classical Major Histocompatibility Complex class II (MHCII) protein, H2-M, edits peptides bound to conventional MHCII in favor of stable peptide/MHCII (p/MHCII) complexes. Here, we show that H2-M deficiency affects B-1 cell survival, reduces cell renewal capacity, and alters immunoglobulin repertoire, allowing for the selection of cells specific for highly abundant epitopes, but not low-frequency epitopes. H2-M-deficient B-1 cells have shorter CDR3 length, higher content of positively charged amino acids, shorter junctional regions, less mutation frequency, and a skewed clonal distribution. Mechanistically, H2-M loss reduces plasma membrane p/MHCII association with B cell receptors (BCR) on B-1 cells and diminishes integrated BCR signal strength, a key determinant of B-1 cell selection, maturation, and maintenance. Thus, H2-M:MHCII interaction serves as a cell-intrinsic regulator of BCR signaling and influences the selection of the B-1 cell clonal repertoire., Competing Interests: Declaration of interests The authors declare no competing financial interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In recent years, the role of gut microbial metabolites on the inhibition and progression of cancer has gained significant interest in anticancer research. It has been established that the gut microbiome plays a pivotal role in the development, treatment and prognosis of different cancer types which is often mediated through the gut microbial metabolites. For instance, gut microbial metabolites including bacteriocins, short-chain fatty acids and phenylpropanoid-derived metabolites have displayed direct and indirect anticancer activities through different molecular mechanisms. Despite the reported anticancer activity, some gut microbial metabolites including secondary bile acids have exhibited pro-carcinogenic properties. This review draws a critical summary and assessment of the current studies demonstrating the carcinogenic and anticancer activity of gut microbial metabolites and emphasises the need to further investigate the interactions of these metabolites with the immune system as well as the tumour microenvironment in molecular mechanistic and clinical studies.

Unsupervised person re-identification (Re-ID) aims to match pedestrian images from different camera views in an unsupervised setting. Existing methods for unsupervised person Re-ID are usually built upon the pseudo labels from clustering. However, the result of clustering depends heavily on the quality of the learned features, which are overwhelmingly dominated by colors in images. In this paper, we attempt to suppress the negative dominating influence of colors to learn more effective features for unsupervised person Re-ID. Specifically, we propose a Cluster-guided Asymmetric Contrastive Learning (CACL) approach for unsupervised person Re-ID, in which clustering result is leveraged to guide the feature learning in a properly designed asymmetric contrastive learning framework. In CACL, both instance-level and cluster-level contrastive learning are employed to help the siamese network learn discriminant features with respect to the clustering result within and between different data augmentation views, respectively. In addition, we also present a cluster refinement method, and validate that the cluster refinement step helps CACL significantly. Extensive experiments conducted on three benchmark datasets demonstrate the superior performance of our proposal.

Purpose: To analyzed the outcome of ETV6/RUNX1-positive pediatric acute B lymphoblastic leukemia (B-ALL) with the aim of identifying prognostic value., Method: A total of 2,530 pediatric patients who were diagnosed with B-ALL were classified into two groups based on the ETV6/RUNX1 status by using a retrospective cohort study method from February 28, 2008, to June 30, 2020, at 22 participating ALL centers., Results: In total, 461 (18.2%) cases were ETV6/RUNX1-positive. The proportion of patients with risk factors (age <1 year or ≥10 years, WB≥50×10 9 /L) in ETV6/RUNX1-positive group was significantly lower than that in negative group ( P <0.001), while the proportion of patients with good early response (good response to prednisone, D15 MRD < 0.1%, and D33 MRD < 0.01%) in ETV6/RUNX1-positive group was higher than that in the negative group ( P <0.001, 0.788 and 0.004, respectively). Multivariate analysis of 2,530 patients found that age <1 or ≥10 years, SCCLG-ALL-2016 protocol, and MLL were independent predictor of outcome but not ETV6/RUNX1. The EFS and OS of the ETV6/RUNX1-positive group were significantly higher than those of the negative group (3-year EFS: 90.11 ± 4.21% vs 82 ± 2.36%, P <0.0001, 3-year OS: 91.99 ± 3.92% vs 88.79 ± 1.87%, P =0.017). Subgroup analysis showed that chemotherapy protocol, age, prednisone response, and D15 MRD were important factors affecting the prognosis of ETV6/RUNX1-positive children., Conclusions: ETV6/RUNX1-positive pediatric ALL showed an excellent outcome but lack of independent prognostic significance in South China. However, for older patients who have the ETV6/RUNX1 fusion and slow response to therapy, to opt for more intensive treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Qiu, Xu, Luo, Mai, Liao, Yang, Zheng, Wan, Wu, Liu, Chen, Chen, Sun, Jiang, Long, Chen, Li, Li, Huang, Ling, Lin, Wen, Kuang, Feng, Ye, Wu, He, Li, Wang, Kong, Xu, Li and Fang.)

Aim: Duodenal gastrointestinal stromal tumors (GISTs) constitute a small rare subset. This study aims to analyze the prognostic differences between duodenal and jejunoileal GISTs and evaluate the clinical treatment and prognostic characteristics of patients with duodenal GISTs., Methods: Data of patients with primary duodenal or jejunoileal GISTs were collected. Patients were matched through propensity score matching (PSM). Perioperative and long-term outcomes of patients with duodenal GISTs were compared based on surgical approach., Results: Altogether, 101 duodenal and 219 jejunoileal GISTs were identified. In patients with duodenal GISTs, 79 (78%) underwent local resection (LR) and 22 (22%) underwent pancreaticoduodenectomy (PD). Patients undergoing PD had a longer postoperation stay (18.5 vs 13 days, P = 0.001) and more complications (Clavien-Dindo I-II complications for PD vs LR, 31.8 vs 15.2%; Clavien-Dindo III-V complications for PD vs LR, 22.7 vs. 2.5%; P < 0.001). There was no difference in recurrence-free survival (RFS) (P = 0.8) or overall survival (OS) (P = 0.9) when comparing patients who underwent LR versus PD. Multivariable analysis showed that tumor size >5 cm was the only independent predictor of shorter RFS (P = 0.004) and OS (P = 0.012). After matching, there was no significant difference in RFS and OS between patients with duodenal versus jejunoileal GISTs (both P > 0.05)., Conclusion: The prognosis of duodenal and jejunoileal GISTs are similar. Recurrence and OS of duodenal GISTs primarily depend on tumor size. For duodenal GISTs, LR is associated with comparable long-term survival when compared to PD, but with superior short-term outcomes., (© 2021 John Wiley & Sons Australia, Ltd.)

We developed an electrochemical trifluoromethylation of thiophenols without the use of metal catalysts and oxidants. This reaction features mild reaction conditions, readily available substrate, as well as moderate to good yields. In addition, this protocol can be easily scaled up with moderate efficiency.

Objective: To identify gene variants and investigate clinical features of nonmuscle myosin heavy chain 9-related disease (MYH9-RD). Methods: In this retrospective study, the data of patients with MYH9-RD admitted to Shenzhen Children's Hospital from July 2017 to September 2020 were extracted. The gene variants, clinical features and laboratory tests results were summarized. Results: Among the 6 children, 4 were males and 2 were females, aged 4.0 (0.5-7.6) years. Main clinical manifestations included thrombocytopenia (6 cases), epistaxis (3 cases), petechias (2 cases), traumatic hematoma (1 case), and abnormal liver enzymes (1 case). One patient had no family history, and the other 5 cases were pedigrees. Two pedigrees (2 cases) had long-term microscopic hematuria, one pedigree (2 cases) had history of early cataract, and three pedigrees (5 cases) had chronic mild elevation of liver enzymes. Four MYH9 gene variants were found in 12 patients, including c.2104C>T(p.R702C) in exon 17, c.4270G>A(p.D1424N) in exon 31, c.5521G>A (p.E1841K) in exon 39, and c.5797C>T (p.R1933X) in exon 41. According to the family pedigrees analysis, except for the case of variant in exon 17 which was spontaneous mutation with no family history, the other variants were from their father or mother. The complete blood count results showed a decreased platelet number in these patients, and the counting results of the automated hematology analyzer were significantly lower than that of manual counting method ((33.4±17.2) × 10⁹ vs. (60.4±21.0) × 10 9 /L, t =-5.83, P< 0.05). The examination of the peripheral blood smear revealed the presence of thrombocytopenia with giant platelets and granulocyte inclusion bodies. The MYH9 gene variant (R702C) located at the N-terminus head domain of non-muscle myosin heavy chain ⅡA (NMMHC-ⅡA), which has ATPase activity, led to severe reduction of platelet number (<20×10 9 /L) and obscure granulocyte inclusion bodies. However, higher platelet numbers (40×10 9 -80×10 9 /L) and obvious granulocyte inclusion bodies were observed in patients with tail-position mutations at C-terminus. Conclusions: The clinical phenotypes of MYH9-RD were variable. The mutations in certain regions of MYH9 gene were related to platelet count and granulocyte inclusion bodies. MYH9-RD should be considered in individuals with unknown etiology and persistent thrombocytopenia which is non-responsive to conventional treatment, regardless of family history. Complete blood count and blood smear morphology examinations are the first steps to screen and diagnose the disease. The laboratory should pay attention to the morphological review rules and standardized reports.

Objective: To investigate the clinicopathological characteristics and prognosis of sporadic multiple primary gastrointestinal stromal tumor (GIST). Methods: A retrospective cohort study was conducted. Case inclusion criteria: (1) postoperative pathological diagnosis of GIST; (2) primary GIST with single lesion or sporadic multiple primary GIST (sporadic GIST was defined as primary GIST other than familial and syndrome-related GIST, and multiple primary GIST was defined as the number of primary GISTs in the same patient ≥ 2); (3) patients with complete clinicopathological data. Those with tumor recurrence or distant metastasis, and with other malignancies were excluded. Medical records of patients with primary GIST who underwent surgical resection in the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 2010 to December 2020 were collected. Patients were divided into sporadic multiple primary GIST group and single primary GIST group according to the number of primary GIST lesions. The clinicopathological data and prognosis of the two groups were observed and compared. Results: A total of 1200 patients with primary GIST were enrolled in this study, including 628 males (52.3%) and 572 females (47.7%), with a median onset age of 58 (19-93) years. Among them, 1165 cases (97.1%) were sporadic primary GIST with single lesion; 35 cases (2.9%) were sporadic multiple primary GIST. Among 35 cases of sporadic multiple primary GIST, 3 cases (8.6%) had acid reflux as the first symptom, which was higher than the single primary GIST group (22/1165, 1.9%) (χ(2)=7.437, P =0.006). There were no significant differences in other clinical characteristics between the two groups (all P >0.05). Patients in the sporadic multiple primary GIST group contained a total of 80 primary tumors. Compared with the single primary GIST group, the sporadic multiple primary GIST group had a higher proportion of tumors originating in the stomach [87.5% (70/80) vs. 59.1% (689/1165)], lower proportion of spindle cell in histology [85.0% (68/80) vs. 93.7% (1092/1165)], higher proportion of positive CD34 [97.5% (78/80) vs. 87.6% (1021/1165)], smaller maximum diameter [maximum diameter ≤2.0 cm: 61.2% (49/80) vs. 28.8% (335/1165)], lower mitotic rate [≤5/50 high-power fields (HPF): 93.8% (75/80) vs. 74.5% (868/1165)], lower risk of recurrence [60.0% (48/80) vs. 23.3% (271/1165)], and the differences were all statistically significant (all P <0.05). The 3-year recurrence-free survival rate in the sporadic multiple primary group and the single primary GIST group was 96.6% and 89.3% respectively ( P =0.160), and the 3-year overall survival rate was 100.0% and 92.8%, respectively ( P =0.088). Conclusions: The most common type of sporadic multiple primary GIST is multiple tumors originating in the stomach at the same time. Compared with primary GIST with single lesion, sporadic multiple primary GIST presents smaller maximum diameter and lower mitotic rate. The prognosis of patients between two groups is not significantly different.

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has recently emerged as a potential cytotoxic agent in addition to its ameliorative activity in chemotherapy-associated side effects. In this work, the potential interactions of CBD with docetaxel (DOC), doxorubicin (DOX), paclitaxel (PTX), vinorelbine (VIN), and 7-ethyl-10-hydroxycamptothecin (SN-38) were explored in MCF7 breast adenocarcinoma cells using different synergy quantification models. The apoptotic profiles of MCF7 cells after the treatments were assessed via flow cytometry. The molecular mechanisms of CBD and the most promising combinations were investigated via label-free quantification proteomics. A strong synergy was observed across all synergy models at different molar ratios of CBD in combination with SN-38 and VIN. Intriguingly, synergy was observed for CBD with all chemotherapeutic drugs at a molar ratio of 636:1 in almost all synergy models. However, discording synergy trends warranted the validation of the selected combinations against different models. Enhanced apoptosis was observed for all synergistic CBD combinations compared to monotherapies or negative controls. A shotgun proteomics study highlighted 121 dysregulated proteins in CBD-treated MCF7 cells compared to the negative controls. We reported the inhibition of topoisomerase II β and α, cullin 1, V-type proton ATPase, and CDK-6 in CBD-treated MCF7 cells for the first time as additional cytotoxic mechanisms of CBD, alongside sabotaged energy production and reduced mitochondrial translation. We observed 91 significantly dysregulated proteins in MCF7 cells treated with the synergistic combination of CBD with SN-38 (CSN-38), compared to the monotherapies. Regulation of telomerase, cell cycle, topoisomerase I, EGFR1, protein metabolism, TP53 regulation of DNA repair, death receptor signalling, and RHO GTPase signalling pathways contributed to the proteome-wide synergistic molecular mechanisms of CSN-38. In conclusion, we identified significant synergistic interactions between CBD and the five important chemotherapeutic drugs and the key molecular pathways of CBD and its synergistic combination with SN-38 in MCF7 cells. Further in vivo and clinical studies are warranted to evaluate the implementation of CBD-based synergistic adjuvant therapies for breast cancer.

Objective: To explore the incidence, clinical and microbiological characteristics and risk factors of infection in patients with acute lymphoblastic (ALL) , non-Hodgkin lymphoma (NHL) , and multiple myeloma (MM) within 28 days after CAR-T cell infusion. It provides data support for early identification of infection and the rational use of antibacterial drugs in these patients. Methods: We retrospectively analyzed the baseline data of 170 patients with ALL, NHL and MM who received chimeric antigen receptor-modified T (CAR-T) -cell treatment in the Department of Hematology of Wuhan Union Hospital from January 2016 to December 2020, and the clinical characteristics of infection within 28 days after infusion, including 72 patients with ALL, 56 patients with NHL, and 42 patients with MM; we used Poisson regression and Cox proportional hazard regression models to assess high-risk factors for infection before and after infusion, respectively. Results: Among 170 patients, 119 infections occurred in 99 patients within 28 days, with a cumulative infection rate of 58.2%. Seventy-eight patients had 98 bacterial infections and the cumulative incidence of bacterial infection was 45.9%. The infection density was 2.01, and the median time for the first infection was about 12 days after infusion. The adjusted baseline characteristic model showed that ALL patients, previous 30 days of infection history, refractory disease, absolute neutrophil count (ANC) <0.5×10(9)/L before infusion and ≥4 prior antitumor treatment regimens had a higher infection density within 28 days; grade 3 or 4 CRS was the only high-risk factor related to infection after infusion in the multivariate analysis. Conclusion: Infection is a common complication of CAR-T cell therapy in patients with hematologic malignancy. Bacterial infections occur in most patients regardless of the type of disease. ALL patients, previous 30 days of infection history, refractory disease, ANC<0.5×10(9)/L before infusion and grade 3 or 4 CRS are risk factors for infection. Chinese Clinical Trial Register:: ChiCTR-OIC-17011180, ChiCTR1800018143.

Curcumin (C) and resveratrol (R) are two well-known nutraceuticals with strong antioxidant activity that can protect cells from oxidative stress. This study aims to investigate the synergy of CR combinations in protecting human endothelial EAhy926 cells against H 2 O 2 -induced oxidative stress and its related mechanisms. C and R as individual compounds as well as CR combinations at different ratios were screened for their protective effects against H 2 O 2 (2.5 mM) induced cell death assessed by cell viability assays. The synergistic interaction was analysed using the combination index model. The effects of optimal CR combinations on caspase-3 activity, ROS level, SOD activity, NAD cellular production, expression of Nrf2 and HO-1, and Nrf2 translocation were determined. CR combinations produced a synergistic protection against that of H 2 O 2 -induced changes in cell viability, caspase-3 activity, and ROS production. The strongest effect was observed for CR with the ratio of 8 : 2. Further experiments showed that CR 8 : 2 exhibited significantly greater effects in increasing Nrf2 translocation and expressions of Nrf2 and HO-1 proteins, as well as SOD activity and total cellular NAD production, than that of C or R alone. The findings demonstrate that combination of C and R produced a strong synergy in activity against H 2 O 2 -induced oxidative stress in EAhy926 cells. The mechanism of this synergy involves the activation of Nrf2-HO-1 signaling pathway and promotion of antioxidant enzymes. Further studies on CR synergy may help develop a new combination therapy for endothelial dysfunction and other conditions related to oxidative stress., Competing Interests: The authors declare no conflicts of interest. As a medical research institute, NICM Health Research Institute receives research grants and donations from foundations, universities, government agencies, individuals, and industry. Sponsors and donors also provide united funding for work to advance the vision and mission of the institute., (Copyright © 2021 Xian Zhou et al.)

The association between human gut microbiota and cancers has been an evolving field of biomedical research in recent years. The gut microbiota is composed of the microorganisms residing in the gastrointestinal system that interact with the host to regulate behaviours and biochemical processes within the gut. This symbiotic physiological interaction between the gut and the microbiota plays a significant role in the modulation of gut homeostasis, in which perturbations to the microbiota, also known as dysbiosis can lead to the onset of diseases, including cancer. In this review, we analysed the current literature to understand the role of gut microbiota in the five most prevalent cancer types, namely colon (colorectal), lung, breast, prostate, and stomach cancers. Recent studies have observed the immunomodulatory and anti-tumoural effects of gut microbiota in cancers. Furthermore, gut microbial dysbiosis can induce the release of toxic metabolites and exhibit pro-tumoural effects in the host. The gut microbiota was observed to have clinical implications in each cancer type in addition to regulating the efficacy of standard chemotherapy and natural anticancer agents. However, further research is warranted to understand the complex role of gut microbiota in the prevention, diagnosis, treatment, and prognoses of cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

NLRP3 inflammasome is a key mediator in ischemic stroke-induced neuroinflammation and subsequent brain injury. Our previous study demonstrated the potent activity of Pien-Tze-Huang (PTH), a well-known Chinese patent formula, in reducing mitochondria-mediated neuronal apoptosis in cerebral ischemia/reperfusion impaired rats. This study aims to elucidate the mechanistic action of PTH related to neuroinflammation in LPS-induced BV2 microglial cells and cerebral ischemia/reperfusion impaired rats. BV2 cells were stimulated with LPS for 12 h and treated with PTH with various concentrations. Modulation by PTH of relevant genes (IL-6, IL-1β, IL-18, TNF-α, COX-2 and iNOS mRNA) and proteins (NLRP3 inflammasome, autophagy and AMPK/mTOR/ULK signaling) was analyzed by real-time PCR and western blot, respectively. Similar analyses were conducted in middle cerebral artery occlusion rat model including neurological deficit, infarct volume, microglial activation, and key genes and proteins in modulating autophagy and NLRP3. Our results showed that PTH significantly inhibited the production of key proinflammatory mediators and protein expressions of NLRP3 and caspase-1 p20 in LPS induced BV2 cells. It also enhanced the autophagy response by modulating the key autophagy proteins via AMPK/mTOR/ULK related pathway. The reduced inflammatory responses and NLRP3 expressions by PTH were partially blocked by the autophagy inhibitor (3-MA) and AMPK blocker (compound C). In rats, PTH significantly reduced infarct size, suppressed microglial activation, and improved neuron deficit. It also promoted autophagy and reduced NLRP3 activity. Our study demonstrated that PTH inhibited NLRP3 inflammasome-mediated neuroinflammation, which was associated with enhanced autophagy via AMPK/mTOR/ULK1 pathway in vitro and in vivo., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To observe the change of cervical curvature and range of motion (ROM) on imaging at 6 months after Hybrid surgery., Methods: A total of 29 patients with cervical degenerative disease who underwent Hybrid surgery from January 2017 to July 2018 were retrospectively analyzed. Also, they all met the inclusion criteria and had complete preoperative and 6 months postoperative imaging data. There were 11 males and 18 females, aged from 34 to 76 (55.86±10.69) years, and the operation time was from 2 to 4(3.03±0.51) hours. The Cobb angle method was used to measure the changes of cervical curvature and ROM of C 2 -C 7 , replacement segments, fusion segments, and upper adjacent segments on cervical lateral X-rays before and 6 months after surgery., Results: There was no statistically significant difference in C 2 -C 7 curvature and ROM between 6 months after operation and before operation ( P >0.05). The degree of curvature and ROM of the replacement segment increased compared with that before operation ( P <0.05). The curvatureof the fusion segment was increased than that before operation ( P <0.05). There was no statistically significant difference in ROM of the fusion segment compared with that before operation ( P >0.05). There was no statistically significant difference in the curvature and ROM of the upper adjacent segments compared with those before operation ( P >0.05). There was no significant difference in the curvature between the replacement and fusion segments before and 6 months after operation ( P >0.05);the ROM of the replacement segment was higher than that of the fusion segment at 6 months after operation ( P <0.05)., Conclusion: Hybrid surgery reconstructs the lordotic curvature of the entire cervical spine and the responsible segment, retains the ROM of the cervical replacement segment, and restores the biomechanical function of cervical spine.

Exposure to prenatal maternal stress (PNMS) has been implicated as a risk factor for a range of psychiatric disorders in children. However, there have been a few studies showing inconsistent associations between PNMS and offspring autistic-like behaviours. We therefore aimed to examine whether trimester-specific PNMS exposure might be related to an increased risk of autistic-like behaviours among preschoolers. Using data from Longhua Children Cohort Study, mothers of 65,931 preschool children were asked to recall their level of PNMS in each of the three trimesters of pregnancy, while children's current autistic-like behaviours were assessed using the Autism Behaviour Checklist. A series of Cox regression models were fitted to assess the association between PNMS exposure and autistic-like behaviours. After adjusting for potential confounders, the Cox regression models showed that PNMS exposure, especially during the second pregnant trimester, was significantly and positively associated with the presence of children's autistic-like behaviours. The strength of these associations was enhanced with the increase of PNMS exposure level. Furthermore, based on different permutations of exposure versus no exposure in each trimester, the participants were divided into eight groups. A cross-over analysis confirmed the aforementioned finding that the second pregnant trimester might be the sensitive period for PNMS exposure increasing the risk of autistic-like behaviours. Our findings supported the hypothesis of an association between PNMS exposure and autistic-like behaviours among preschoolers. Preventive interventions should be trialled to examine whether minimizing maternal psychological stress during pregnancy, especially the second trimester, may reduce the risk of offspring autistic-like behaviours., (© 2020 John Wiley & Sons Ltd.)

In the zinc hydrometallurgical purification process, the concentration ratio of zinc ion to trace nickel ion is as high as 10 5 , so that the nickel spectral signal is completely covered by high concentration zinc signal, resulting in low sensitivity and nonlinear characteristics of nickel spectral signal. Aiming at the problem that it is difficult to detect nickel in zinc sulfate solution, this paper proposes a nonlinear integrated modeling method of extended Kalman filter based on Adaboost algorithm. First, a non-linear nickel model is established based on nickel standard solution. Second, an extended Kalman filter wavelength optimization method based on correlation coefficient is proposed to select wavelength variables with high signal sensitivity, large amount of information and strong nonlinear correlation. Finally, a nonlinear integrated modeling method based on Adaboost algorithm is proposed, which uses extended Kalman filter as a basic submodel, and realizes the stable detection of trace nickel through the weighted combination of multiple basic models. The results show that the average relative error of this method for detecting nickel is 4.56%, which achieves accurate detection of trace nickel in zinc sulfate solution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Li and Zhu.)

The combination of natural products with standard chemotherapeutic agents offers a promising strategy to enhance the efficacy or reduce the side effects of standard chemotherapy. Doxorubicin (DOX), a standard drug for breast cancer, has several disadvantages, including severe side effects and the development of drug resistance. Recently, we reported the potential bioactive markers of Australian propolis extract (AP-1) and their broad spectrum of pharmacological activities. In the present study, we explored the synergistic interactions between AP-1 and DOX in the MCF7 breast adenocarcinoma cells using different synergy quantitation models. Biochemometric and metabolomics-driven analysis was performed to identify the potential anticancer metabolites in AP-1. The molecular mechanisms of synergy were studied by analysing the apoptotic profile via flow cytometry, apoptotic proteome array and measuring the oxidative status of the MCF7 cells treated with the most synergistic combination. Furthermore, label-free quantification proteomics analysis was performed to decipher the underlying synergistic mechanisms. Five prenylated stilbenes were identified as the key metabolites in the most active AP-1 fraction. Strong synergy was observed when AP-1 was combined with DOX in the ratio of 100:0.29 ( w / w ) as validated by different synergy quantitation models implemented. AP-1 significantly enhanced the inhibitory effect of DOX against MCF7 cell proliferation in a dose-dependent manner with significant inhibition of the reactive oxygen species ( p < 0.0001) compared to DOX alone. AP-1 enabled the reversal of DOX-mediated necrosis to programmed cell death, which may be advantageous to decline DOX-related side effects. AP-1 also significantly enhanced the apoptotic effect of DOX after 24 h of treatment with significant upregulation of catalase, HTRA2/Omi, FADD together with DR5 and DR4 TRAIL-mediated apoptosis ( p < 0.05), contributing to the antiproliferative activity of AP-1. Significant upregulation of pro-apoptotic p27, PON2 and catalase with downregulated anti-apoptotic XIAP, HSP60 and HIF-1α, and increased antioxidant proteins (catalase and PON2) may be associated with the improved apoptosis and oxidative status of the synergistic combination-treated MCF7 cells compared to the mono treatments. Shotgun proteomics identified 21 significantly dysregulated proteins in the synergistic combination-treated cells versus the mono treatments. These proteins were involved in the TP53/ATM-regulated non-homologous end-joining pathway and double-strand breaks repairs, recruiting the overexpressed BRCA1 and suppressed RIF1 encoded proteins. The overexpression of UPF2 was noticed in the synergistic combination treatment, which could assist in overcoming doxorubicin resistance-associated long non-coding RNA and metastasis of the MCF7 cells. In conclusion, we identified the significant synergy and highlighted the key molecular pathways in the interaction between AP-1 and DOX in the MCF7 cells together with the AP-1 anticancer metabolites. Further in vivo and clinical studies are warranted on this synergistic combination.