Human amniotic mesenchymal stem cells inhibit immune rejection injury from allogeneic mouse heart transplantation: A preliminary study on the microRNA expression.

BACKGROUND: Mesenchymal stem cell therapy is a new treatment for immune rejection in heart transplantation. The aim of this paper is to investigate the effect of human amniotic mesenchymal stem cells (hAMSCs) on alleviating immune rejection of allogeneic heart transplantation in mice and its possible underlying mechanism. METHODS: We injected hAMSCs into cervical ectopic heart transplantation model mice via tail vein to observe the survival time, the pathological changes of donor myocardium, and the fluorescent distribution of hAMSCs after the transplantation. MicroRNAs (miRs) with significantly differential expression were obtained by RNA sequencing and bioinformatic analysis, and a dual luciferase reporter gene assay together with real-time quantitative PCR (qRT-PCR) was performed to verify the relationship between miRs and their targeting genes. RESULTS: The intervention of hAMSCs prolonged the graft survival time and alleviated the pathological damage of the donor heart. The injected hAMSCs were distributed mainly in the liver, spleen, and kidney, only a very small portion in the donor and recipient hearts. In the allogeneic transplantation models, the expression of miR-34b-5p significantly increased after hAMSC treatment. MiR-34b-5p showed a knockdown effect on gene Fc gamma receptor 2B (FCGR2B). CONCLUSIONS: hAMSCs can reduce the immune rejection injury after allogeneic heart transplantation. This effect may be associated with the upregulation of miR-34b-5p expression to knock down its targeting gene FCGR2B.

A Bibliometric Analysis of Comorbidity of COPD and Lung Cancer: Research Status and Future Directions.

Objective: Although studies on the association between COPD and lung cancer are of great significance, no bibliometric analysis has been conducted in the field of their comorbidity. This bibliometric analysis explores the current situation and frontier trends in the field of COPD and lung cancer comorbidity, and to lay a new direction for subsequent research. Methods: Articles in the field of COPD and cancer comorbidity were retrieved from Web of Science Core Collections (WoSCC) from 2004 to 2023, and analyzed by VOSviewer, CiteSpace, Biblimatrix and WPS Office. Results: In total, 3330 publications were included. The USA was the leading country with the most publications and great influence. The University of Groningen was the most productive institution. Edwin Kepner Silverman was the most influential scholar in this field. PLOS One was found to be the most prolific journal. Mechanisms and risk factors were of vital importance in this research field. Environmental pollution and pulmonary fibrosis may be future research prospects. Conclusion: This bibliometric analysis provided new guidance for the development of the field of COPD and lung cancer comorbidity by visualizing current research hotspots, and predicting possible hot research directions in the future.

LW-213 induces immunogenic tumor cell death via ER stress mediated by lysosomal TRPML1.

Dying tumor cells release biological signals that exhibit antigenicity, activate cytotoxic T lymphocytes, and induce immunogenic cell death (ICD), playing a key role in immune surveillance. We demonstrate that the flavonoid LW-213 activates endoplasmic reticulum stress (ERS) in different tumor cells and that the lysosomal calcium channel TRPML1 mediates the ERS process in human cellular lymphoma Hut-102 cells. Apoptotic tumor cells induced by ERS often possess immunogenicity. Tumor cells treated with LW-213 exhibit damage-associated molecular patterns (DAMPs), including calreticulin translocation to the plasma membrane and extracellular release of ATP and HMGB1. When co-cultured with antigen-presenting cells (APCs), LW-213-treated tumor cells activated APCs. Two groups of C57BL/6J mice were inoculated with Lewis cells: a "vaccine group", which demonstrated that LW-213-treated tumor cells promote the maturation of dendritic cells and increase CD8+ T cells infiltration in the tumor microenvironment and a "pharmacodynamic group", treated with a combination of LW-213 and PD1/PD-L1 inhibitor (BMS-1), which reduced tumor growth and significantly prolonged the survival time of mice in the "pharmacodynamic group". Therefore, LW-213 can be developed as a novel ICD inducer, providing a new concept for antitumor immunotherapy.

H2S Alleviates Neuropathic Pain in Mice by Nrf2 Signaling Pathway Activation.

Neuropathic pain is a chronic pain caused by direct damage to the peripheral or central nervous system, characterized by hyperalgesia, allodynia, and spontaneous pain. Hydrogen sulfide (H2S) therapy has been applied for neuropathic pain treatment, although the underlying mechanisms remain unknown. In this study, we sought to ascertain whether H2S therapy could alleviate neuropathic pain in a model of chronic constriction injury (CCI) and, if so, the potential mechanism. A CCI model was established in mice through a spinal nerve ligation method. Intrathecal injection of NaHS was used to treat CCI model mice. The thermal paw withdrawal latency (TPWL) and mechanical paw withdrawal threshold (MPWT) were used for pain threshold evaluation in mice. A series of experiments including immunofluorescence, enzyme-linked immunosorbent assay, electrophysiological test, mitochondrial DNA (mtDNA) quantification, measurement of ATP content, demethylase activity, and western blot were performed to investigate the specific mechanism of H2S treatment in neuropathic pain. Mice with CCI exposure exhibited a decrease in MPWT and TPWL, an increase in IL-1ß and TNF-α expressions, elevated eEPSP amplitude, an upregulation of mtDNA, and a reduction in ATP production, whereas H2S treatment significantly reversed these changes. Furthermore, CCI exposure induced a remarkable increase in vGlut2- and c-fos-positive as well as vGlut2- and Nrf2-positive cells, an increase in Nrf2 located in the nucleus, and an upregulation of H3K4 methylation, and H2S treatment further enhanced these changes. In addition, ML385, a selective Nrf2 inhibitor, reversed the neuroprotective effects of H2S. H2S treatment mitigates CCI-induced neuropathic pain in mice. This protective mechanism is possibly linked to the activation of the Nrf2 signaling pathway in vGlut2-positive cells.

Biosensor-based active ingredient recognition system for screening TNF-α inhibitors from lotus leaves.

Erhuangquzhi granules (EQG) have been clinically proven to be effective in nonalcoholic steatohepatitis (NASH) treatment. However, the active components and molecular mechanisms remain unknown. This study aimed to screen active components targeting tumor necrosis factor α (TNF-α) in EQG for the treatment of NASH by a surface plasmon resonance (SPR) biosensor-based active ingredient recognition system (SPR-AIRS). The amine-coupling method was used to immobilize recombinant TNF-α protein on an SPR chip, the specificity of the TNF-α-immobilized chip was validated, and nine medicinal herbs in EQG were prescreened. Nuciferine (NF), lirinidine (ID), and O-nornuciferine (NNF) from lotus leaves were found and identified as TNF-α ligands by UPLC‒MS/MS, and the affinity constants of NF, ID, and NNF to TNF-α were determined by SPR experiments (Kd = 61.19, 31.02, and 20.71 µM, respectively). NF, ID, and NNF inhibited TNF-α-induced apoptosis in L929 cells, the levels of secreted IL-6 and IL-1ß were reduced, and the phosphorylation of IKKß and IκB was inhibited in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. In conclusion, a class of new active small-molecule TNF-α inhibitors was discovered, which also provides a valuable reference for the material basis and mechanism of EQG action in NASH treatment.

Wright's Technique with the Addition of Visualized Axial Cortical Windows in Odontoid Fractures.

This study sought to investigate and evaluate a modified axial translaminar screw fixation for treating odontoid fractures. We performed a retrospective study at Wenzhou Medical University Affiliated Second Hospital between March 2016 and June 2018. We retrospectively collected and analyzed the medical records of 23 cases with odontoid fractures. All patients were identified as type II odontoid fractures without neurological deficiency and serious diseases following the classification of Anderson. The average age, gender ratio, and body mass index (BMI) were 54.3 ± 11.1 years, 12 men to 11 women, and 22.6 ± 2.4 kg/m2 , respectively. Patients in this study accepted screw fixation using our modified axial translaminar screw fixation combined with atlas pedicle or lateral mass screw fixation. Within the technique, a small cortical "window" was dug in the middle of the axial contralateral lamina, such that the screws in the lamina were visualized to prevent incorrectly implanting the posterior spinal canal through the visualized "window." A total of 46 bone screws were accurately inserted into the axial lamina without using fluoroscopy. The length of all translaminar screws ranged between 26 and 30 mm, while the diameter was 3.5 mm. During the follow-up survey, the visual analog scale (VAS) and neck disability index (NDI) were measured. We provide a simple modification of Wright's elegant technique with the addition of "visualized windows" at the middle of the axial lamina. In all patients, screws were inserted accurately without bony breach and the screw angle was 56.1 ± 3.0°. Mean operative time was 102 ± 28 min with an average blood loss of 50 ± 25 mL. Postoperative hemoglobin and mean length of hospital stay were 12.0 ± 1.4 g/dL and 10.4 ± 3.4 days, respectively. The average follow-up time of all cases was 14.7 months and no internal fixation displacement, loosening, or breakage was found. All patients with odontoid fractures reported being satisfied with the treatment during the recheck period and good clinical outcomes were observed. At 1, 6, and 12 months, NDI and VAS showed that the symptoms of neck pain and limitations of functional disability improved significantly during follow-up. Our results suggest that the modified translaminar screw fixation technique can efficiently treat Anderson type II odontoid fracture, followed by the benefits of less soft tissue dissection, simple operation, no fluoroscopy, and accurate placement of screws.

Total knee arthroplasty exhibits satisfactory long-term clinical efficacy in the treatment of hemophilia patients with stiff knees.

Objective: This study aimed to (1) determine the long-term clinical efficacy of total knee arthroplasty (TKA) in the treatment of hemophilia patients with stiff knessknees, (2) assess the 5- and 10-year prosthesis survival in hemophilia, and (3) determine whether the severity of preoperative stiffness would affect postoperative clinical outcomes and complication rates. Methods: The clinical data of 71 patients (78 knees) with hemophilia and concomitant knee stiffness who had undergone TKA between September 2007 and June 2018 were retrospectively analyzed. All patients were male, their mean age at the time of surgery was 38.4. ± 7.9 years (range: 21-63 years), and the mean follow-up time was 8.7 years. To determine the effect of stiffness severity on clinical outcomes, the participants were categorized into two groups: severe [preoperative range of motion (ROM): <50°, 34 knees] and moderate (preoperative ROM: 50-90°, 44 knees). At preoperative and final follow-up, patients' post-TKA clinical and radiological outcomes, quality of life, complications, and long-term survival were assessed. Results: Flexion contracture improved from 23.2 ± 10.8° before surgery to 5.9 ± 7.5° upon final follow-up, the Knee Society Score (KSS) increased from 31.4 ± 12.4 to 74.9 ± 11.5, and the KSS functional score increased from 37.6 ± 9.3 to 81.4 ± 12.8. The mean ROM improved from 54.6 ± 32.6° preoperatively to 80.9 ± 34.5° postoperatively. The 36-Item Short Form Survey physical and mental scores also improved significantly. All these differences were statistically significant before and after surgery (P < 0.001). The following postoperative complications occurred in 10 knees (12.8%): hemarthrosis (n = 3), stiffness (n = 4), superficial infection (n = 1), skin necrosis (n = 1), and periprosthetic infection (n = 2), and revision TKA was performed on two knees. The 5- and 10-year survival rates of the prostheses were 98.5% and 93.7%, respectively. The mean ROM in the severe group increased from 30.7 ± 18.7° preoperatively to 70.5 ± 28.3° postoperatively (p < 0.001). The mean flexion contracture decreased from 27.3 ± 10.8° to 6.4 ± 12.0° (p < 0.001). The mean KSS improved from 27.0 ± 7.8 to 68.3 ± 9.6 (p < 0.001). The mean ROM in the moderate group improved from 84.3 ± 22.7 to 92.9 ± 28.8 (p < 0.001), while the mean flexion contracture decreased from 12.8 ± 11.0° to 4.8 ± 5.0° (p < 0.001) and the mean KSS improved from 41.3 ± 11.5 to 81.3 ± 12.2 (p < 0.001). The severe group had worse postoperative ROM and functional scores than the moderate group. Furthermore, the severe group used varus-valgus constrained or hinged prostheses more frequently (52.8% vs. 18.1%) and had more complications (18.9% vs. 9.0%) than the moderate group. Conclusion: TKA exhibits satisfactory long-term efficacy in patients with hemophilic knee joint disease involving preoperative stiffness, thus potentially providing a significant improvement in function and reducing pain. Furthermore, severely stiff knee joints have worse clinical outcomes and more complications than moderately stiff knee joints.

Repellent, larvicidal and adulticidal activities of essential oil from Dai medicinal plant Zingiber cassumunar against Aedes albopictus.

Zingiber cassumunar is an important plant used in traditional medicine and as a natural mosquito repellent. However, the compounds responsible for the repellent activity of the plant are still unknown. The aim of the study is to identify the components of Z. cassumunar essential oil that show repellent activity against Aedes albopictus. We also evaluated the larvicidal and adulticidal activities of Z. cassumunar essential oil against Ae. albopictus. In-cage mosquito repellent experiments showed that Z. cassumunar essential oil possessed moderate repellent activity with a minimum effective dose (MED) of 0.16 ± 0.01 mg/cm2, compared to reference standard N,N-diethyl-3-methylbenzamide (DEET, 0.03 ± 0.01 mg/cm2). Bioassay-guided fractionation identified the major active compound of Z. cassumunar essential oil as (-)-terpinen-4-ol (1) (MED: 0.19 ± 0 mg/cm2). We also found that Z. cassumunar essential oil showed moderate larvicidal activity against first instar larvae of Ae. albopictus with a LC50 (50% lethal concentration) of 44.9 µg/L after 24 h. Fumigation bioassays showed that Z. cassumunar essential oil exhibits moderate adulticidal activity against Ae. albopictus with a LC50 of 5.44%, while (-)-terpinen-4-ol showed significant adulticidal activity with a LC50 of 2.10% after 24 h. This study verifies that the Z. cassumunar essential oil has mosquito repellent activity, and that (-)-terpinen-4-ol is mainly responsible for this activity. Furthermore, this study provides scientific support for the folk usage of Z. cassumunar essential oil as mosquito repellent and indicates that Z. cassumunar essential oil and (-)-terpinen-4-ol can be used as plant-derived repellents and insecticides for mosquito control.

TIPE2-modified human amnion-derived mesenchymal stem cells promote the efficacy of allogeneic heart transplantation through inducing immune tolerance.

BACKGROUND: Immune rejection of heart transplantation has been regarded as the biggest challenge encountered by a patient suffering from end-stage heart disease. The transplantation of human amnion-derived mesenchymal stem cells (hAD-MSCs) has exhibited promising application prospects in organ transplantation. However, its persistent unsatisfactory tolerance has limited the widespread application of this technology. We aim to investigate the role of tumor necrosis factor-α-induced protein-8 like-2 (TIPE2)-mediated hAD-MSCs in immune tolerance in heart transplantation and its molecular regulatory mechanisms. METHODS: This project detected the effect of TIPE2 on immune tolerance by constructing an allogeneic heart transplantation mouse model through which TIPE2-overexpressed hAD-MSCs were injected into recipients. The fluorescence distribution of TIPE2-hAD-MSCs in mice was observed by a small animal in vivo imaging system. Pathological changes of the transplanted heart were detected by hematoxylin and eosin (HE) staining. Flow cytometry was performed to detect the content of cardiac lymphocytes. The expression of immune-induced related factors was measured by quantitative real-time PCR (qRT-PCR) and western blot assays. RESULTS: TIPE2-hAD-MSCs protected myocardial tissue structures, reduced the spleen and thymus indexes in recipient mice, minimized the content of cardiac lymphocytes, reduced expressions of ERK, p38, and IFN-γ, and elevated expressions of both IL-10 and TGF-ß, markedly improving the survival time and survival rates of recipient mice. CONCLUSIONS: TIPE2-hAD-MSCs induce immune tolerance and improve the survival rates of allogeneic heart transplantation in mice. This study is expected to offer an ideal source and target of cells for organ transplantation.

Clinical therapeutic effects of acupuncture in treating patients with dysphagia after radiotherapy in nasopharyngeal carcinoma: A protocol for systematic review and meta-analysis.

BACKGROUND: Dysphagia is a commonly occurring condition in nasopharyngeal carcinoma (NPC) patients after radiotherapy. There has been an increasing number of studies focused on assessing the use of acupuncture to manage dysphagia. Moreover, the quality of the research has gradually increased. The present research will be conducted to systematically evaluate the efficiency and safety of using acupuncture to treat cases of dysphagia after radiation therapy in NPC patients. METHODS: Literature search will include all potential randomized controlled trials using MEDLINE, Cochrane Library, Web of Science, EMBASE, Chinese National Knowledge Infrastructure, Chinese BioMedical Literature, and WanFang database from their inception to May, 2021 without language or publication status restrictions, to evaluate the efficiency and safety of using acupuncture to treat dysphagia cases following radiation therapy in NPC patients. A couple of independent authors will select related literature, extract data from studies, and estimate this risk in the bias of the selected study articles. In the instance of contrasting opinions, the outcome is mediated through discussion with a different independent author. The data synthesis and statistical analysis will be completed with the RevMan software (version 5.3). RESULTS: This study will evaluate the efficiency and safety of using acupuncture to treat dysphagia cases after radiation therapy in NPC patients. CONCLUSION: This study will determine the suitability of acupuncture as an effective and safe intervention for dysphagia in NPC patients after radiotherapy. ETHICS AND DISSEMINATION: The present study does not need ethical approval. REGISTRATION NUMBER: May 19, 2021.osf.io/f2cvt. (https://osf.io/f2cvt/).

Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b.

Cholesterol is essential for cell physiology. Transport of the "accessible" pool of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER) by ER-localized GRAMD1 proteins (GRAMD1a/1b/1c) contributes to cholesterol homeostasis. However, how cells detect accessible cholesterol within the PM remains unclear. We show that the GRAM domain of GRAMD1b, a coincidence detector for anionic lipids, including phosphatidylserine (PS), and cholesterol, possesses distinct but synergistic sites for sensing accessible cholesterol and anionic lipids. We find that a mutation within the GRAM domain of GRAMD1b that is associated with intellectual disability in humans specifically impairs cholesterol sensing. In addition, we identified another point mutation within this domain that enhances cholesterol sensitivity without altering its PS sensitivity. Cell-free reconstitution and cell-based assays revealed that the ability of the GRAM domain to sense accessible cholesterol regulates membrane tethering and determines the rate of cholesterol transport by GRAMD1b. Thus, cells detect the codistribution of accessible cholesterol and anionic lipids in the PM and fine-tune the non-vesicular transport of PM cholesterol to the ER via GRAMD1s.

LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK-eIF2α-ATF4-CHOP axis.

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1-25 µM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC50 values of around 10 µM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP3R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK-eIF2α-ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP3R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.

Panax Notoginseng Saponins Inhibits Ventricular Remodeling after Myocardial Infarction in Rats Through Regulating ATF3/MAP2K3/p38 MAPK and NF κ B Pathway.

OBJECTIVE: To explore whether Panax notoginseng saponins (PNS) exhibits heart protective effect in myocardial infarction (MI) rats and to identify the potential signaling pathways involved. METHODS: MI rats induced by ligating the left anterior descending (LAD) coronary artery were assigned to sham coronary artery ligation or coronary artery ligation. Totally 36 Sprague-Dawley rats were randomly divided into sham group (distilled water, n=9), MI group (distilled water, n=9), PNS group (PNS, 40 mg/kg daily, n=9) and fosinopril group (FIP, 1.2 mg/kg daily, n=9) according to a random number table. The left ventricular morphology and function were conducted by echocardiography. Histological alterations were evaluated by the stainings of HE and Masson. The serum levels of C reactive protein (CRP), tumor necrosis factor α (TNF-α), growth differentiation factor-15 (GDF-15) and the ratio of metalloproteinase-9 (MMP-9) and tissue inhibitor of MMP-9 (TIMP-1) were determined by ELISA. The levels of activating transcription factor 3 (ATF3), mitogen-activated protein kinase kinase 3 (MAP2K3), p38 mitogen-activated protein kinase (p38 MAPK), phosphorylation of p38 MAPK (p-p38 MAPK), transforming growth factor-ß (TGF-ß1), collagen I, nuclear factor kappa B p65 (NFκB p65), phosphorylation of NFκB p65 (p-NFκB p65), and phosphorylation of inhibitory kappa Bα (p-Iκ Bα) in hearts were measured by Western blot and immunohistochemical staining, respectively. RESULTS: PNS improved cardiac function and fibrosis in MI rats (P<0.05). The serum levels of CRP, TNF-α, GDF-15 and the ratio of MMP9/TIMP1 were reversed by PNS in MI rats. The expressions of TGF-ß1, collagen I, MAP2K3, p38 MAPK, p-p38 MAPK, NFκB p65, p-NFκB p65, and p-IκBα were down-regulated, while ATF3 increased with the treatment of PNS (P<0.05). CONCLUSIONS: PNS may improve cardiac function and fibrosis in MI rats via regulating ATF3/MAP2K3/p38 MAPK and NFκB signaling pathways. These results suggest the potential of PNS in preventing the development of ventricular remodeling in MI rats.

Psoas hematoma as a rare complication of posterior lumbar interbody fusion: a case report.

BACKGROUND: Psoas hematoma rarely occurs in patients with spondylolisthesis who undergo posterior lumbar interbody fusion (PLIF) surgery. CASE PRESENTATION: Here we reported a case of a 57-year-old male patient diagnosed with spondylolisthesis who underwent PLIF at the local hospital. Seven days post-surgery, abdominal pain occurred, and the pain in the right lower limb gradually increased. The computerized tomography (CT) indicated a formation of hematoma around the psoas muscle. Digital-subtraction angiography (DSA) suggested a vascular injury, a rupture of the right segmental artery of the lumbar vertebral level 4. The patient then received DSA vascular embolization, after which the lower lumbar segmental artery active bleeding was stopped. One month after discharge, the abdominal hematoma was gradually absorbed, and the pain in the waist, leg, and abdomen disappeared. CONCLUSION: Symptoms such as abdominal pain, abdominal distension, and exacerbation of lower limb pain, may suggest the occurrence of psoas hematoma after PLIF. DSA vascular embolization is suggested as the first treatment approach for this type of complication.

Efficacy and safety of Kanglaite injection combined with first-line platinum-based chemotherapy in patients with advanced NSCLC: a systematic review and meta-analysis of 32 RCTs.

BACKGROUND: As a Chinese medicine injections, Kanglaite injection (KLT) is a complementary or alternative therapy for first-line platinum-based chemotherapy. However, the effect that certain factors, including the dose of KLT, chemotherapy cycles, evaluation criteria, or supportive treatment, have on the efficacy of the objective response rate (ORR), median survival time (MST), and adverse reactions is still unknown. METHODS: Eight databases were systematically searched from the inception dates to December 1, 2019, using the keywords Kanglaite, chemotherapy, and non small cell lung carcinoma to identify randomized clinical trials (RCTs). Analyses were performed using Review Manager 5.3 and Stata 15.1. RESULTS: There were 32 randomized controlled trials, involving 2,577 participants, that fulfilled the inclusion criteria. Compared with first-line platinum-based chemotherapy alone, KLT combined with chemotherapy could increase the ORR [risk ratio (RR), 1.41 (95% CI: 1.28 to 1.56); absolute risk difference (ARD), 0.13 (95% CI: 0.1 to 0.17)], decrease the risk ratio of adverse reactions [nausea and vomiting: RR, 0.58 (95% CI: 0.42 to 0.81); ARD, -0.17 (95% CI: -0.26 to -0.08); leukopenia: RR, 0.61 (95% CI: 0.44 to 0.86); ARD, -0.16 (95% CI: -0.24 to -0.08)], prolong MST, and increase disease control rate and Karnofsky performance status. According to the subgroup analyses, KLT combined with cisplatin or paraplatin plus paclitaxel (TP) failed to demonstrate a significant association with the ORR. And when lacking the use of supportive treatment, this combination would not decrease the RR of both adverse reactions compared with chemotherapy alone. CONCLUSIONS: KLT plus first-line platinum-based chemotherapy, except when chemotherapy regimens were TP, increased efficacy and quality of life in patients with advanced NSCLC. We are unsure whether this combination offers a low risk of adverse reactions. Additional high-quality RCTs are warranted to assess the effects of the combined therapy further.

Unexpected Short-Tandem-Repeat Patterns in Posttransplant Chimerism Testing: Investigation of 3 Cases with Help from Forensic Science.

Chimerism testing by short tandem repeats (STRs) is used to monitor engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). Generally, STR alleles are stable and transferred from parent to child or from donor to recipient. However, 3 cases did not follow this norm. Additional work-up with help from forensic literature solved these mysteries. In case 1, the patient received HSCT from his son. The son shared STR alleles in 22/23 loci except Penta E, which was explained by repeat expansion in the son. In case 2, the patient had been in remission for 14 years after HSCT for lymphoma and developed repeat expansion in CSF1PO in granulocytes. In case 3, a pre-HSCT patient demonstrated 3 alleles, with 2 peaks taller than the third, in the FGA locus (chromosome 4). A combination of a triallelic variant and leukemia-associated trisomy 4 explained the finding. STR number variants are rare and clinically inconsequential but can overlap malignancy-associated, clinically significant changes.

Melanin-based nanomaterials: The promising nanoplatforms for cancer diagnosis and therapy.

Melanin-based nanoplatforms are biocompatible nanomaterials with a variety of unique physicochemical properties such as strong photothermal conversion ability, excellent drug binding capacity, strong metal chelation capacity, high chemical reactivity and versatile adhesion ability. These innate talents not only make melanin-based nanoplatforms be an inborn theranostic nanoagent for photoacoustic imaging-guided photothermal therapy of cancers, but also enable them to be conveniently transferred into cancer-targeting drug delivery systems and multimodality imaging nanoprobes. Due to the intriguing properties, melanin-based nanoplatforms have attracted much attention in investigations of cancer diagnosis and therapy. This review provides an overview of recent research advances in applications of melanin-based nanoplatforms in the fields of cancer diagnosis and therapy including cancer photothermal therapy, anticancer drug delivery, cancer-specific multimodal imaging and theranostics, etc. The remaining challenges and prospects of melanin-based nanoplatforms in biomedical applications are discussed at the end of this review.

Phosphatase POPX2 interferes with cell cycle by interacting with Chk1.

Protein-protein interaction network analysis plays critical roles in predicting the functions of target proteins. In this study, we used a combination of SILAC-MS proteomics and bioinformatic approaches to identify Checkpoint Kinase 1 (Chk1) as a possible POPX2 phosphatase interacting protein. POPX2 is a PP2C phosphatase that has been implicated in cancer cell invasion and migration. From the Domain-Domain Interaction (DDI) database, we first determined that the PP2C phosphatase domain interacts with Pkinase domain. Subsequently, 46 proteins with Pkinase domain were identified from POPX2 SILAC-MS data. We then narrowed down the leads and confirmed the biological interaction between Chk1 and POPX2. We also found that Chk1 is a substrate of POPX2. Chk1 is a key regulator of the cell cycle and is activated when the cell suffers DNA damage. Our approach has led us to identify POPX2 as a regulator of Chk1 and can interfere with the normal function of Chk1 at G1-S transition of the cell cycle in response to DNA damage.

Long Non-coding RNA BTG3-7:1 and JUND Co-regulate C21ORF91 to Promote Triple-Negative Breast Cancer Progress.

BACKGROUND: Triple-negative breast cancer (TNBC) is a type of highly invasive breast cancer with poor prognosis. Recently, massive data reveal that long non-coding RNAs (lncRNAs) play important roles in cancer progress. Recently, although the role of lncRNAs in breast cancer has been well documented, few focused on TNBC. In this study, we aimed to systematically identify functional lncRNAs and to explore its molecular mechanism on TNBC progress. METHODS: The recurrence of lncRNAs and their target genes were validated with TNBC biopsies and cell lines. Total one hundred and thirteen TNBC biopsies, including nineteen patient-matched samples, were collected. The profile of TNBC-related lncRNAs and their target genes were characterized by RNA sequencing (RNA-seq) and bioinformatic analysis. Tumor specific lncRNAs, which also showed biological function correlated with TNBC, were identified as potential candidates; and the target genes, which regulated by the identified lncRNAs, were predicted by the analysis of expression correlation and chromosome colocalization. Cross bioinformatic validation was performed with TNBC independent datasets from the cancer genome atlas (TCGA). The biological functions and molecular mechanism were investigated in TNBC model cell lines by cell colony forming assay, flow cytometry assay, western-blot, RNA Fluorescence in situ Hybridization assay (RNA FISH) and chromatin immunoprecipitation-qPCR (ChIP-qPCR). RESULTS: Abundant Lnc-BTG3-7:1, which targets gene C21ORF91, was specifically observed in TNBC biopsies and cell lines. Knockdown of Lnc-BTG3-7:1 or C21ORF91 strongly inhibited cell proliferation, promoted cell apoptosis and cell cycle G1-arrested. Meanwhile, investigation of molecular mechanism indicated that Lnc-BTG3-7:1, cooperated with transcription factor JUND, cis-regulated the transcription of C21ORF91 gene, and down-regulation of Lnc-BTG3-7:1/C21ORF91 suppressed GRB2-RAS-RAF-MEK-ERK and GRB2-PI3K-AKT-GSK3ß-ß-catenin pathways. CONCLUSIONS: In this study, we identified a TNBC specific lncRNA Lnc-BTG3-7:1, which sustained tumor progress. Up-regulation of Lnc-BTG3-7:1 promoted the transcription of oncogene C21ORF91 and activated PI3K-AKT-GSK3ß-ß-catenin and MAPK pathways. Taken together, our results not only identified a biomarker for diagnosis but also provided a potential therapeutic target against TNBC.

Epigenetic Therapy Promotes the Ratio of Th1/Th17 Lineage to Reverse Immune Evasion and Treat Leukemia Relapse Post-allogeneic Stem Cell Transplantation in Non-APL AML Patients.

To reverse the early-stage relapse post-hematopoietic stem cell transplantation, we investigated the safety and efficacy of a new epigenetic regimen (chidamide and decitabine plus thymalfasin simultaneously) on acute myeloid leukemia patients (excluding acute promyelocytic leukemia). Twenty-four patients were enrolled in this observational study during April 2015 to May 2018. The most common adverse event was reversible CTCAE grade 2 thrombocytopenia (20/24). Strikingly, all 24 patients had response to this epigenetic regimen accompanied with decreased measurable residual disease. The overall survival rate is 79.2% (19/24), with a relapse-free survival rate of 79.2% (19/24). During this regimen treatment, Th1 cells and CD3+CD4-CD8+T cells increased, and Th17 cells decreased gradually. The status of high Th1 and low Th17 cells was still observed on the 3rd month after discontinuation of this regimen. Interestingly, the significantly elevated ratio of Th1/Th17 seemed to reflect the treatment-related immune effect, which may be a valuable marker to be monitored in the early-relapse stage for evaluating the efficacy and prognosis.