Associations between polychlorinated biphenyls and cancer risk among type 2 diabetes: The modifying effects of lifestyle.

A growing percentage of diabetes-related deaths has been attributed to cancer, with environmental factors playing important contributions. Thus, we studied the potential relationship between endocrine disruptors polychlorinated biphenyls (PCBs) and cancer risk in diabetes. We aimed to evaluate the association between serum seven indicator-PCB (PCB-28/52/101/118/138/153/180) levels and incident cancer, and further explore the possible modifying role of lifestyle. A total of 2806 type 2 diabetes mellitus (T2DM) cases were included from the Dongfeng-Tongji cohort at the baseline in 2008 and tracked until December 2018, and 320 incident cancers were identified during about 10-year follow-up. Cox proportional hazards models and competing risk regression models were used to reveal associations of baseline concentrations of PCBs with total cancer and specific cancer, respectively. Lifestyle score was determined by body mass index, waist circumference, physical activity, smoking, alcohol drinking, and diet. Each interquartile range (IQR) increment of non-dioxin-like PCBs (NDL-PCBs) generated an 8%-30% increase in cancer incidence. Individuals in the highest quartile for PCB-52, PCB-101, PCB-138, and lowly chlorinated PCBs had 1.44- to 1.68-fold higher cancer risk compared to those in the lowest quartile. Restricted cubic spline analyses and the quantile g-computation model showed similar results. Significant interactions were found between PCBs and fasting blood glucose or simplified insulin resistance assessment indicators. NDL-PCBs were positively and significantly associated with gastrointestinal cancer and respiratory cancer, especially with liver cancer, colorectal cancer, and lung cancer. Higher PCBs showed a significant increase in total cancer risk among participants with an unhealthy lifestyle, however, no associations were observed in those with a relatively healthy lifestyle (Pinteraction < 0.05). Our findings indicated an increased cancer risk associated with NDL-PCBs, highlighted the role of a healthy lifestyle in potentially reducing adverse impact, and provided preliminary data for environmental and public health interventions to alleviate the risk of cancer among diabetes.

Dynamic molecular architecture and substrate recruitment of cullin3-RING E3 ligase CRL3KBTBD2.

Phosphatidylinositol 3-kinase α, a heterodimer of catalytic p110α and one of five regulatory subunits, mediates insulin- and insulin like growth factor-signaling and, frequently, oncogenesis. Cellular levels of the regulatory p85α subunit are tightly controlled by regulated proteasomal degradation. In adipose tissue and growth plates, failure of K48-linked p85α ubiquitination causes diabetes, lipodystrophy and dwarfism in mice, as in humans with SHORT syndrome. Here we elucidated the structures of the key ubiquitin ligase complexes regulating p85α availability. Specificity is provided by the substrate receptor KBTBD2, which recruits p85α to the cullin3-RING E3 ubiquitin ligase (CRL3). CRL3KBTBD2 forms multimers, which disassemble into dimers upon substrate binding (CRL3KBTBD2-p85α) and/or neddylation by the activator NEDD8 (CRL3KBTBD2~N8), leading to p85α ubiquitination and degradation. Deactivation involves dissociation of NEDD8 mediated by the COP9 signalosome and displacement of KBTBD2 by the inhibitor CAND1. The hereby identified structural basis of p85α regulation opens the way to better understanding disturbances of glucose regulation, growth and cancer.

The Role of microRNAs in Arsenic-Induced Human Diseases: A Review.

MicroRNAs (miRNAs) are noncoding RNAs with 20-22 nucleotides, which are encoded by endogenous genes and are capable of targeting the majority of human mRNAs. Arsenic is regarded as a human carcinogen, which can lead to many adverse health effects including diabetes, skin lesions, kidney disease, neurological impairment, male reproductive injury, and cardiovascular disease (CVD) such as cardiac arrhythmias, ischemic heart failure, and endothelial dysfunction. miRNAs can act as tumor suppressors and oncogenes via directly targeting oncogenes or tumor suppressors. Recently, miRNA dysregulation was considered to be an important mechanism of arsenic-induced human diseases and a potential biomarker to predict the diseases caused by arsenic exposure. Endogenic miRNAs such as miR-21, the miR-200 family, miR-155, and the let-7 family are involved in arsenic-induced human disease by inducing translational repression or RNA degradation and influencing multiple pathways, including mTOR/Arg 1, HIF-1α/VEGF, AKT, c-Myc, MAPK, Wnt, and PI3K pathways. Additionally, exogenous miRNAs derived from plants, such as miR-34a, miR-159, miR-2911, miR-159a, miR-156c, miR-168, etc., among others, can be transported from blood to specific tissue/organ systems in vivo. These exogenous miRNAs might be critical players in the treatment of human diseases by regulating host gene expression. This review summarizes the regulatory mechanisms of miRNAs in arsenic-induced human diseases, including cancers, CVD, and other human diseases. These special miRNAs could serve as potential biomarkers in the management and treatment of human diseases linked to arsenic exposure. Finally, the protective action of exogenous miRNAs, including antitumor, anti-inflammatory, anti-CVD, antioxidant stress, and antivirus are described.

A novel mutation of the RPGRIP1L gene in a Chinese boy with Joubert syndrome with oculorenal involvement.

BACKGROUND: Joubert syndrome (JS) is a rare genetically heterogeneous primary ciliopathy characterized by a pathognomonic cerebellar and brainstem malformation, the "molar tooth sign", and variable organ involvement (such as eye, kidney, liver, and skeleton). Here, we present a case of JS in a Chinese boy. CASE PRESENTATION: An 11-year-old Chinese boy presented with neonatal asphyxiation and hypoxia, strabismus, subsequent developmental delay, ataxia and end-stage kidney disease (ESKD). Routine blood tests showed severe anemia, increasing blood urea nitrogen and creatinine, elevated parathyroid hormone, hypocalcemia, hypokalemia and metabolic acidosis. Urine tests showed mild proteinuria. Ultrasound showed two small kidneys. Brain magnetic resonance imaging (MRI) showed dysplasia of the cerebellar vermis and extension of the upper cerebellar feet with the "molar tooth sign". Genetic analysis showed novel compound heterozygous mutations in the RPGRIP1L gene [p.L447fs*7(p.Leu447fsTer7) and p.G908V (p.Gly908Val)]. CONCLUSION: In the present study, we identified novel compound heterozygous mutations in the RPGRIP1L gene in a Chinese boy. The clinical and genetic findings of this study will expand the understanding of JS.

Development and challenges of antimicrobial peptide delivery strategies in bacterial therapy: A review.

The escalating global prevalence of antimicrobial resistance poses a critical threat, prompting concerns about its impact on public health. This predicament is exacerbated by the acute shortage of novel antimicrobial agents, a scarcity attributed to the rapid surge in bacterial resistance. This review delves into the realm of antimicrobial peptides, a diverse class of compounds ubiquitously present in plants and animals across various natural organisms. Renowned for their intrinsic antibacterial activity, these peptides provide a promising avenue to tackle the intricate challenge of bacterial resistance. However, the clinical utility of peptide-based drugs is hindered by limited bioavailability and susceptibility to rapid degradation, constraining efforts to enhance the efficacy of bacterial infection treatments. The emergence of nanocarriers marks a transformative approach poised to revolutionize peptide delivery strategies. This review elucidates a promising framework involving nanocarriers within the realm of antimicrobial peptides. This paradigm enables meticulous and controlled peptide release at infection sites by detecting dynamic shifts in microenvironmental factors, including pH, ROS, GSH, and reactive enzymes. Furthermore, a glimpse into the future reveals the potential of targeted delivery mechanisms, harnessing inflammatory responses and intricate signaling pathways, including adenosine triphosphate, macrophage receptors, and pathogenic nucleic acid entities. This approach holds promise in fortifying immunity, thereby amplifying the potency of peptide-based treatments. In summary, this review spotlights peptide nanosystems as prospective solutions for combating bacterial infections. By bridging antimicrobial peptides with advanced nanomedicine, a new therapeutic era emerges, poised to confront the formidable challenge of antimicrobial resistance head-on.

AMEERA-3: Randomized Phase II Study of Amcenestrant (Oral Selective Estrogen Receptor Degrader) Versus Standard Endocrine Monotherapy in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer.

PURPOSE: Amcenestrant (oral selective estrogen receptor degrader) demonstrated promising safety and efficacy in earlier clinical studies for endocrine-resistant, estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (aBC). PATIENTS AND METHODS: In AMEERA-3 (ClinicalTrials.gov identifier: NCT04059484), an open-label, worldwide phase II trial, patients with ER+/HER2- aBC who progressed in the (neo)adjuvant or advanced settings after not more than two previous lines of endocrine therapy (ET) were randomly assigned 1:1 to amcenestrant or single-agent endocrine treatment of physician's choice (TPC), stratified by the presence/absence of visceral metastases, previous/no treatment with cyclin-dependent kinase 4/6 inhibitor, and Eastern Cooperative Oncology Group performance status (0/1). The primary end point was progression-free survival (PFS) by independent central review, compared using a stratified log-rank test (one-sided type I error rate of 2.5%). RESULTS: Between October 22, 2019, and February 15, 2021, 290 patients were randomly assigned to amcenestrant (n = 143) or TPC (n = 147). PFS was numerically similar between amcenestrant and TPC (median PFS [mPFS], 3.6 v 3.7 months; stratified hazard ratio [HR], 1.051 [95% CI, 0.789 to 1.4]; one-sided P = .643). Among patients with baseline mutated ESR1; (n = 120 of 280), amcenestrant numerically prolonged PFS versus TPC (mPFS, 3.7 v 2.0 months; stratified HR, 0.9 [95% CI, 0.565 to 1.435]). Overall survival data were immature but numerically similar between groups (HR, 0.913; 95% CI, 0.595 to 1.403). In amcenestrant versus TPC groups, treatment-emergent adverse events (any grade) occurred in 82.5% versus 76.2% of patients and grade ≥3 events occurred in 21.7% versus 15.6%. CONCLUSION: AMEERA-3 did not meet its primary objective of improved PFS with amcenestrant versus TPC although a numerical improvement in PFS was observed in patients with baseline ESR1 mutation. Efficacy and safety with amcenestrant were consistent with the standard of care for second-/third-line ET for ER+/HER2- aBC.

AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclib versus letrozole plus palbociclib for previously untreated ER+/HER2- advanced breast cancer.

Background: For estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), the current standard first-line treatment includes an aromatase inhibitor in combination with a cyclin-dependent kinase 4/6 inhibitor. When resistance occurs, often related to the occurrence of ESR1 mutations, selective estrogen receptor modulators or degraders (SERDs) may be used, alone or in combination regimens. Amcenestrant (SAR439859), an optimized oral SERD, has shown clinical antitumor activity in combination with palbociclib in patients with ER+/HER2- ABC and, as monotherapy, in patients with and without ESR1 mutations. Here, we describe the study design of AMEERA-5, an ongoing, prospective, phase 3, randomized, double-blind, multinational study comparing the efficacy and safety of amcenestrant plus palbociclib versus letrozole plus palbociclib in patients with advanced (locoregional recurrent or metastatic) ER+/HER2- breast cancer. Methods: Patients are pre-/postmenopausal women and men with no prior systemic therapy for ABC. The planned enrollment is 1066 patients. Patients are randomized 1:1 to either amcenestrant 200 mg plus palbociclib 125 mg or letrozole 2.5 mg plus palbociclib 125 mg. Amcenestrant, letrozole, and their matching placebos are taken once daily continuously; palbociclib is taken once daily for 21 days, followed by 7 days off-treatment for a 28-day cycle. Treatment continues until disease progression, unacceptable toxicity, or decision to stop treatment. Pre-/perimenopausal women and men receive goserelin subcutaneously. Randomization is stratified by de novo metastatic disease, menopausal status, and visceral metastases. The primary endpoint is progression-free survival. The key secondary endpoint is overall survival; others are safety, pharmacokinetics, and quality of life. Conclusions: AMEERA-5 is evaluating the efficacy and safety of amcenestrant in combination with palbociclib as first-line therapy in pre-/postmenopausal women and men with ER+/HER2- ABC. ClinicalTrials Identifier: NCT04478266.

High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors.

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 µmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

Boosted EfficientNet: Detection of Lymph Node Metastases in Breast Cancer Using Convolutional Neural Networks.

(1) Purpose: To improve the capability of EfficientNet, including developing a cropping method called Random Center Cropping (RCC) to retain the original image resolution and significant features on the images' center area, reducing the downsampling scale of EfficientNet to facilitate the small resolution images of RPCam datasets, and integrating attention and Feature Fusion (FF) mechanisms with EfficientNet to obtain features containing rich semantic information. (2) Methods: We adopt the Convolutional Neural Network (CNN) to detect and classify lymph node metastasis in breast cancer. (3) Results: Experiments illustrate that our methods significantly boost performance of basic CNN architectures, where the best-performed method achieves an accuracy of 97.96% ± 0.03% and an Area Under the Curve (AUC) of 99.68% ± 0.01% on RPCam datasets, respectively. (4) Conclusions: (1) To our limited knowledge, we are the only study to explore the power of EfficientNet on Metastatic Breast Cancer (MBC) classification, and elaborate experiments are conducted to compare the performance of EfficientNet with other state-of-the-art CNN models. It might provide inspiration for researchers who are interested in image-based diagnosis using Deep Learning (DL). (2) We design a novel data augmentation method named RCC to promote the data enrichment of small resolution datasets. (3) All of our four technological improvements boost the performance of the original EfficientNet.

Plerixafor combined with standard regimens for hematopoietic stem cell mobilization in pediatric patients with solid tumors eligible for autologous transplants: two-arm phase I/II study (MOZAIC).

This study (NCT01288573) investigated plerixafor's safety and efficacy in children with cancer. Stage 1 investigated the dosage, pharmacokinetics (PK), pharmacodynamics (PD), and safety of plerixafor + standard mobilization (G-CSF ± chemotherapy). The stage 2 primary endpoint was successful mobilization (doubling of peripheral blood CD34+ cell count in the 24 h prior to first apheresis) in patients treated with plerixafor + standard mobilization vs. standard mobilization alone. In stage 1, three patients per age group (2-<6, 6-<12, and 12-<18 years) were treated at each dose level (160, 240, and 320 µg/kg). Based on PK and PD data, the dose proposed for stage 2 was 240 µg/kg (patients 1-<18 years), in which 45 patients were enrolled (30 plerixafor arm, 15 standard arm). Patient demographics and characteristics were well balanced across treatment arms. More patients in the plerixafor arm (24/30, 80%) met the primary endpoint of successful mobilization than in the standard arm (4/14, 28.6%, p = 0.0019). Adverse events reported as related to study treatment were mild, and no new safety concerns were identified. Plerixafor + standard G-CSF ± chemotherapy mobilization was generally well tolerated and efficacious when used to mobilize CD34+ cells in pediatric cancer patients.

Results from a multicenter, noninterventional registry study for multiple myeloma patients who received stem cell mobilization regimens with and without plerixafor.

Plerixafor plus granulocyte-colony stimulating factor (G-CSF) enhances the mobilization of hematopoietic stem cells (HSCs) for collection and subsequent autologous hematopoietic stem cell transplantation (HSCT) in patients with multiple myeloma (MM). This international, multicenter, noninterventional registry study (NCT01362972), evaluated long-term outcomes for MM patients who received plerixafor versus other mobilization regimens. The comparisons were: G-CSF + plerixafor (G-CSF + P) versus G-CSF-; G-CSF + P versus G-CSF + chemotherapy (G-CSF + C); and G-CSF + P + C versus G-CSF + C. Propensity score matching was used to balance groups. Primary outcome measures were progression free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR) after transplantation. After propensity matching, 77 versus 41 patients in the G-CSF + P versus G-CSF cohorts, 129 versus 129 in the G-CSF + P versus G-CSF + C cohorts, and 117 versus 117 in the G-CSF + P + C versus G-CSF + C cohorts were matched, respectively. Propensity score matching resulted in a smaller sample size and imbalances were not completely overcome. For both PFS and OS, the upper limits of the hazard ratio 95% confidence intervals exceeded prespecified boundaries; noninferiority was not demonstrated. CIR rates were higher in the plerixafor cohorts. G-CSF + P remains an option for the mobilization of HSCs in poor mobilizers with MM with no substantial differences in PFS, OS, and CIR in comparison with other regimens.

Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry on a cohort of lymphoma patients receiving plerixafor.

Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups.

A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma.

This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 [n = 8], 10 [n = 31], or 20 [n = 6] mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at www.clinicaltrials.gov as #NCT02283775.

Mequindox induces apoptosis, DNA damage, and carcinogenicity in Wistar rats.

Mequindox (MEQ) is a synthetic antibacterial agent. Recent studies showed that MEQ and its primary metabolites exhibit strong genotoxicity to mammalian cells, and MEQ induced carcinogenicity in mice. These findings suggest that chronic exposure to MEQ could lead to an increased risk of cancer later in life. In the present study, four groups of Wistar rats (55 rats/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for 2 years. The results showed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive systems, were the main targets for MEQ. Liver toxicity mediated by MEQ was associated with apoptosis and the nuclear factor κB (NF-κB) signaling pathway. In addition, MEQ increased the incidence of tumors in rats. Phosphorylated histone H2AX (γ-H2AX) is identified as a biomarker of cellular response to DNA double-strand breaks (DSB). Our data demonstrated that γ-H2AX expression was significantly increased in tumors. Thus, high levels of DSB might be responsible for carcinogenesis in rats, and further investigation is absolutely required to clarify the exact molecular mechanisms for carcinogenicity caused by MEQ in vivo.

Astrocyte activation in the periaqueductal gray promotes descending facilitation to cancer-induced bone pain through the JNK MAPK signaling pathway.

Descending nociceptive modulation from the supraspinal structures has an important role in cancer-induced bone pain (CIBP). Midbrain ventrolateral periaqueductal gray (vlPAG) is a critical component of descending nociceptive circuits; nevertheless, its precise cellular and molecular mechanisms involved in descending facilitation remain elusive. Our previous study has shown that the activation of p38 MAPK in vlPAG microglia is essential for the neuropathic pain sensitization. However, the existence of potential connection between astrocytes and c-Jun N-terminal kinase (JNK) pathway in CIBP has not yet been elucidated. The following study examines the involvement of astrocyte activation and upregulation of p-JNK in vlPAG, using a CIBP rat model. Briefly, CIBP was mimicked by an intramedullary injection of Walker 256 mammary gland carcinoma cells into the animal tibia. A significant increase in expression levels of astrocytes in the vlPAG of CIBP rats was observed. Furthermore, stereotaxic microinjection of the astrocytic cytotoxin L-α-aminoadipic acid decreased the mechanical allodynia as well as established and reversed the astrocyte activation in CIBP rats. A significant increase in expression levels of p-JNK in astrocytes in vlPAG of CIBP rats was also observed. Moreover, the intrathecal administration of JNK inhibitors SP600125 reduced the expression of glial fibrillary acidic protein, while microinjection of the SP600125 decreased the mechanical allodynia of CIBP rats. These results suggested that CIBP is associated with astrocyte activation in the vlPAG that probably participates in driving descending pain facilitation through the JNK MAPK signaling pathway. To sum up, these findings reveal a novel site of astrocytes modulation of CIBP.

Crosstalk between NFκB-dependent astrocytic CXCL1 and neuron CXCR2 plays a role in descending pain facilitation.

BACKGROUND: Despite accumulating evidence on the role of glial cells and their associated chemicals in mechanisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of chronic pain. We aimed to study the hypothesis that CXCL1/CXCR2 axis in the periaqueductal gray (PAG), a co-restructure of the descending nociceptive system, is involved in descending pain facilitation. METHODS: Intramedullary injection of Walker 256 mammary gland carcinoma cells of adult female Sprague Dawley rats was used to establish a bone cancer pain (BCP) model. RT-PCR, Western blot, and immunohistochemistry were performed to detect pNfkb, Cxcl1, and Cxcr2 and their protein expression in the ventrolateral PAG (vlPAG). Immunohistochemical co-staining with NeuN, GFAP, and CD11 were used to examine the cellular location of pNFκB, CXCL1, and CXCR2. The effects of NFκB and CXCR2 antagonists and CXCL1 neutralizing antibody on pain hypersensitivity were evaluated by behavioral testing. RESULTS: BCP induced cortical bone damage and persistent mechanical allodynia and increased the expression of pNFκB, CXCL1, and CXCR2 in vlPAG. The induced phosphorylation of NFκB was co-localized with GFAP and NeuN, but not with CD11. Micro-injection of BAY11-7082 attenuated BCP and reduced CXCL1 increase in the spinal cord. The expression level of CXCL1 in vlPAG showed co-localization with GFAP, but not with CD11 and NeuN. Micro-administration of CXCL1 neutralizing antibody from 6 to 9 days after inoculation attenuated mechanical allodynia. Furthermore, vlPAG application of CXCL1 elicited pain hypersensitivity in normal rats. Interestingly, CXCR2 was upregulated in vlPAG neurons (not with CD11 and GFAP) after BCP. CXCR2 antagonist SB225002 completely blocked the CXCL1-induced mechanical allodynia and attenuated BCP-induced pain hypersensitivity. CONCLUSION: The NFκB-dependent CXCL1-CXCR2 signaling cascade played a role in glial-neuron interactions and in descending facilitation of BCP.

A Pilot, Exploratory, Randomized, Phase II Safety Study Evaluating Tumor Cell Mobilization and Apheresis Product Contamination in Patients Treated with Granulocyte Colony-Stimulating Factor Alone or Plus Plerixafor.

Because of the potential risk of tumor cell mobilization with granulocyte colony-stimulating factor (G-CSF), it is crucial to evaluate any potential effect of plerixafor treatment in the presence of G-CSF on multiple myeloma (MM) cell mobilization. This was an open-label, multicenter, randomized, exploratory, safety study (NCT01753453) that investigated the extent of MM cell mobilization after treatment with G-CSF + plerixafor in patients who were deemed poor mobilizers of hematopoietic stem cells. The primary efficacy outcome was the number of MM cells in peripheral blood and apheresis product after G-CSF + plerixafor treatment versus G-CSF alone. Key secondary efficacy outcomes included overall survival and disease status up to 2 years after the first G-CSF dose. Twenty patients were randomized and received at least 1 dose of study treatment. There were no patients with MM cells in peripheral blood up to day 8 G-CSF administration in either treatment group. Up to day 8 no patient in the G-CSF + plerixafor arm and only 1 patient in the G-CSF arm mobilized at least 4.5 × 105 MM cells in the apheresis product. Nine of 10 patients from each treatment arm proceeded to transplantation. MM cells were detected in 5 patients from each treatment arm before and after transplantation. Adverse events observed in the G-CSF + plerixafor arm were consistent with the known safety profile of plerixafor. No MM cells were detected in peripheral blood of either treatment group up to day 8 of mobilization. Only 1 patient in the G-CSF alone group mobilized at least 4.5 × 105 MM tumor cells in apheresis product up to day 8. However, 50% of patients in both treatment arms had detectable amounts of MM cells in their peripheral blood pre- and post-transplantation. There were no new safety concerns with plerixafor.

Corrigendum: Mequindox Induced Genotoxicity and Carcinogenicity in Mice.

[This corrects the article DOI: 10.3389/fphar.2018.00361.].

N-O Reduction and ROS-Mediated AKT/FOXO1 and AKT/P53 Pathways Are Involved in Growth Promotion and Cytotoxicity of Cyadox.

Cyadox is a novel derivative of quinoxaline-1,4-dioxides (QdNOs) with the potential to be developed as a feed additive. However, the pharmacological and toxicological bioactive molecules of cyadox and the molecular mechanism of its pharmacological and toxic actions remain unclear. In the present study, cyadox and its main metabolites of cy1, cy4, cy6, and cy12 were selected; the growth promotion characteristic was indicated by the mRNA level of EGF; and the cytotoxicity of cyadox was determined by methylthiazol tetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release, and Annexin V-FITC/PI apoptosis detection kit with flow cytometry. The intracellular ROS, cyclin D1, and Akt/P53/FOXO1 signaling pathway were also investigated. Our data suggested that cyadox showed relatively higher activity than its metabolites, and the ROS was generated from N-O reduction of cyadox. Moreover, cyadox (2 µM) activated the Akt and increased the EGF, cyclin D1, and FOXO1 expression levels. Cyadox (100 µM) induced cytotoxicity in L02 cells in a concentration- and time-dependent manner. Additionally, the activated P53 pathway, hyperactivated Akt, and apoptosis were found in L02 cells after incubation with 100 µM cyadox. Our data demonstrated that Akt promoted cell survival when it was mildly activated by cyadox at 2 µM, and Akt leads to apoptosis when it was severely activated by cyadox at 100 µM. Thus, the present study revealed that N-O reduction of cyadox and ROS-mediated AKT/FOXO1 and AKT/P53 pathways were involved in growth promotion and cytotoxicity of cyadox.