Melatonin protects against developmental PBDE-47 neurotoxicity by targeting the AMPK/mitophagy axis.

The neurotoxicity of 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is closely linked to mitochondrial abnormalities while mitophagy is vital for mitochondrial homeostasis. However, whether PBDE-47 disrupts mitophagy contributing to impaired neurodevelopment remain elusive. Here, this study showed that neonatal PBDE-47 exposure caused learning and memory deficits in adult rats, accompanied with striatal mitochondrial abnormalities, neuronal apoptosis and the resultant neuronal loss. Mechanistically, PBDE-47 suppressed PINK1/Parkin-mediated mitophagy induction and degradation, inducing mitophagosome accumulation and mitochondrial dysfunction in vivo and in vitro. Additionally, stimulation of mitophagy by adenovirus-mediated Parkin or Autophagy-related protein 7 (Atg7) overexpression aggravated PBDE-47-induced mitophagosome accumulation, mitochondrial dysfunction, neuronal apoptosis and death. Conversely, suppression of mitophagy by the siRNA knockdown of Atg7 rescued PBDE-47-induced detrimental consequences. Importantly, melatonin, a hormone secreted rhythmically by the pineal, improved PBDE-47-caused neurotoxicity via preventing neuronal apoptosis and loss by restoring mitophagic activity and mitochondrial function. These neuroprotective effects of melatonin depended on activation of the AMP-activated protein kinase (AMPK)/Unc-51-like kinase 1 (ULK1) signaling. Collectively, these data indicate that PBDE-47 impairs mitophagy to perturb mitochondrial homeostasis, thus triggering apoptosis, leading to neuronal loss and consequent neurobehavioral deficits. Manipulation of the AMPK-mitophagy axis via melatonin could be a novel therapeutic strategy against developmental PBDE-47 neurotoxicity.

The efficacy and safety of cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma: A comparative analysis of retrospective studies versus prospective studies.

Cemiplimab has been widely recommended by international guidelines to treat patients with locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). In this study, we conducted a comparative analysis to integrate the efficacy and safety data in the published prospective and retrospective studies for better understanding the application of cemiplimab. The online databases (PubMed, Cochrane CENTRAL, Web of Science, and EMBASE) were searched to find out eligible studies from inception to November 4, 2021. The "R" software and the "meta" package were used to synthesize the objective response rates (ORRs), disease control rates (DCRs), and the incidences of treatment-related adverse events (TRAEs). Overall, three retrospective studies with 398 patients and three prospective studies with 219 patients were enrolled. The pooled ORR and DCR were 53% (95% confidence interval [CI] 46-59) and 70% (95% CI 57-82) for retrospective studies versus 45% (95% CI 39-52) and 68% (95% CI 56-79) for prospective studies. In regard of toxicities, prospective studies reported much higher incidences of any grade (99% vs. 47%) and grade 3-4 TRAEs (43% vs. 15%) against retrospective studies. The most reported TRAE was fatigue, followed by diarrhea and pruritus. In addition, nine treatment-related deaths (four in retrospective studies vs. five in prospective studies) were documented. In both retrospective and prospective clinical practices, cemiplimab could be an effective regimen for locally advanced or metastatic CSCC patients, but toxicities during the treatment deserve further attention.

Irinotecan plus temozolomide in relapsed Ewing sarcoma: an integrated analysis of retrospective studies.

BACKGROUND: The prognosis of patients with relapsed Ewing sarcoma is poor. In this study, we aimed to pooled-analyze the efficacy and safety of the combination of irinotecan and temozolomide in treating patients with relapsed Ewing sarcoma. METHODS: PubMed, Cochrane CENTRAL, Web of Science, and EMBASE were systematically searched on September 27, 2021. The primary outcomes were rates of objective response and disease control, and the secondary outcomes were toxicities. RESULTS: Six retrospective studies with 184 patients were enrolled in the analysis. The median age ranged from 14 to 21. The integrated rates were 44% (95% confidence interval [CI] 31-58) for objective response and 66% (55-77) for disease control. Grade 3-4 neutropenia, thrombocytopenia, and diarrhea occurred in 8% (3-16), 7% (3-11), and 8% (5-10) of chemotherapeutic cycles, respectively. 18% (7-32) and 6% (2-11) of patients suffered grade 3-4 neutropenia and thrombocytopenia after irinotecan plus temozolomide treatment. CONCLUSION: Irinotecan plus temozolomide combination chemotherapy showed antitumor activity and an acceptable safety profile in patients with relapsed Ewing sarcoma. More future prospective studies are needed to confirm the retrospective results.

A Bayesian network meta-analysis of the primary definitive therapies for locoregionally advanced nasopharyngeal carcinoma: IC+CCRT, CCRT+AC, and CCRT alone.

BACKGROUND: The major aim of this Bayesian network analysis was to determine the optimal treatment strategy for locoregionally advanced nasopharyngeal carcinoma (LANPC). METHOD: We systematically searched databases and extracted data from randomized clinical trials involving LANPC patients randomly assigned to receive induction chemotherapy followed by concurrent chemoradiotherapy (IC+CCRT), CCRT followed by adjuvant chemotherapy (CCRT+AC), or CCRT. RESULTS: In the network analysis, IC+CCRT was significantly better than CCRT alone for 5-year FFS (odds ratio [OR]: 1.63, 95% credible interval [CrI] 1.16-2.29), DMFS (OR: 1.56, 95% CrI 1.08-2.22), and LFRS (OR: 1.62, 95% CrI 1.02-2.59), but not OS (OR: 1.35, 95% CrI 0.92-2.00). Rank probabilities showed that IC+CCRT was ranked the best followed by CCRT+AC and CCRT for all 5-year outcomes. Although compared to IC+CCRT and CCRT, CCRT+AC did not significantly improve survival but had the highest 5-year survival rates. CONCLUSIONS: IC+CCRT could be recommended as a front-preferred primary definitive therapy for patients with LANPC.

Perinatal exposure to low-level PBDE-47 programs gut microbiota, host metabolism and neurobehavior in adult rats: An integrated analysis.

Polybrominated diphenyl ethers (PBDEs), a major class of flame retardants, have been extensively applied in plastics, electrical equipment, textile fabrics, and so on. Early-life exposure to PBDEs is correlated to neurobehavioral deficits in adulthood, yet the underlying mechanism has not been fully understood. Increasing evidence has demonstrated that gut microbiota dysbiosis and serum metabolites alterations play a role in behavioral abnormalities. However, whether their perturbation is implicated in PBDEs-induced neurotoxicity remains unclear. Here, we sought to explore the effects of developmental exposure to environmentally relevant levels of 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47), a major congener in human samples, on gut microbiota and serum metabolic profile as well as their link to neurobehavioral parameters in adult rats. The open field test showed that gestational and lactational exposure to PBDE-47 caused hyperactivity and anxiety-like behavior. Moreover, 16S rRNA sequencing of fecal samples identified a distinct community composition in gut microbiota following PBDE-47 exposure, manifested as decreased genera Ruminococcaceae and Moraxella, increased families Streptococcaceae and Deferribacteraceae as well as genera Escherichia-Shigella, Pseudomonas and Peptococcus. Additionally, the metabolomics of the blood samples based on liquid chromatography-mass spectrometry revealed a significant shift after PBDE-47 treatment. Notably, these differential serum metabolites were mainly involved in amino acid, carbohydrate, nucleotide, xenobiotics, and lipid metabolisms, which were further validated by pathway analysis. Importantly, the disturbed gut microbiota and the altered serum metabolites were associated with each other and with neurobehavioral disorders, respectively. Collectively, these results suggest that gut microbiota dysbiosis and serum metabolites alterations potentially mediated early-life low-dose PBDE-47 exposure-induced neurobehavioral impairments, which provides a novel perspective on understanding the mechanisms of PBDE-47 neurotoxicity.

A pooled analysis of adding olanzapine to guideline-recommended antiemetic therapy for breast cancer patients treated with an anthracycline and cyclophosphamide in prospective and retrospective studies.

PURPOSE: As an antipsychotic agent that targets multiple neurotransmitter receptors, olanzapine has been added to antiemetic therapies. For better understanding the application of olanzapine in antiemetic strategies for breast cancer patients who suffered anthracycline plus cyclophosphamide-induced nausea and vomiting, we comprehensively reviewed the antiemetic researches related to olanzapine and pooled-analyzed the results to confirm the efficacy and safety of olanzapine in breast cancer. METHODS: PubMed, Web of Science, EMBASE, and Cochrane CENTRAL databases were searched from inception through Sep 15, 2021. Both prospective and retrospective studies were eligible. The primary outcomes were complete response (defined as no vomiting and no use of rescue medications) and no nausea rate, and the secondary outcome was treatment-related adverse events. RESULTS: Four studies with 466 breast cancer patients were identified in the pooled analysis. In the acute period (0-24 h), the olanzapine group had significantly higher rates of complete response (71.3% vs 48.1%, odds ratio [OR]: 2.66, 95% confidence interval [CI] 1.39-5.11, p = 0.003) and no nausea (70.0% vs 43.0%, OR: 3.55, 95% CI 1.76-7.18, p = 0.04) than the placebo group, while in the delayed period, the olanzapine group was also superior to the placebo group in terms of the complete response (82.5% vs 63.3%, OR: 3.81, 95% CI 1.58-9.15, p = 0.003) and no nausea (66.3% vs 51.9%, OR: 2.08, 95% CI 1.03-4.21, p = 0.04) rates. During the overall period in prospective studies, the proportions of complete response (50.0% vs 34.2%, OR: 1.93, p = 0.04) and no nausea (51.3% vs 25.3%, OR: 3.40, p = 0.0006) in the olanzapine group were higher than those in the placebo group. CONCLUSION: Highly emetogenic chemotherapy breast patients could benefit from olanzapine-contained antiemetic therapy. Furthermore, since the cost is low, olanzapine is worth further clinical application and promotion.

Doxorubicin/Adriamycin Monotherapy or Plus Ifosfamide in First-Line Treatment for Advanced Soft Tissue Sarcoma: A Pooled Analysis of Randomized Trials.

BACKGROUND: Doxorubicin/Adriamycin (ADM) alone or combined with ifosfamide (IFO) (AI) is available for previously untreated advanced soft tissue sarcoma (ASTS). However, the clinical choice between them remains controversial. In this pooled analysis, we comprehensively compared the efficacy and tolerability of AI versus ADM in patients with ASTS. METHODS: PubMed, Web of Science, EMBASE, and Cochrane Library were systematically searched from inception to April 14, 2021. Eligible studies were randomized clinical trials comparing AI to ADM. The primary outcomes were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Discontinuation rate (DR) and toxic death (TD) were explored as secondary outcomes. RESULTS: Overall, three open-label randomized phase 2/3 clinical trials with a total of 1108 newly diagnosed ASTS patients were enrolled. Between AI and ADM, pooled hazard ratios were 0.93 (95% confidence interval 0.58-1.50, p = 0.78) for OS and 0.85 (0.57-1.25, p = 0.41) for PFS. While pooled risk ratios for ORR, DR, and TD were 1.37 (0.94-1.99, p = 0.10), 1.04 (0.74-1.46, p = 0.82), and 0.68 (0.19-2.36, p = 0.54) respectively. No publication bias was observed across the studies. CONCLUSION: In the first-line setting, adding IFO to ADM failed to benefit ASTS patients against ADM alone, even with comparable tolerability.

Impacts of PBDE-47 exposure before, during and after pregnancy on the maternal gut microbiome and its association with host metabolism.

Maternal gut microbiota play an important role in the modulation of offspring disease susceptibility and gut microbiota dysbiosis has been proposed as a mechanism through which toxic environmental chemicals exert their adverse impacts on health. The brominated flame retardants polybrominated diphenyl ethers (PBDEs) are developmental toxicants and induce dysbiotic gut microbiota in offspring. Yet, whether and how PBDEs impact the maternal gut microbiota remain unclear. Here, we sought to investigate the effect of 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) exposure from preconception through lactation cessation on maternal gut microbiota and its link to host serum metabolic consequences. Female Sprague-Dawley rats were daily exposed to 10 mg/kg PBDE-47 via oral gavage from ten days before conception until offspring were weaned on postnatal day 21, then maternal fecal and blood samples were collected for microbiome and metabolome analyses by using 16S ribosomal RNA gene sequencing and gas chromatography-mass spectrometry, respectively. Maternal exposure to PBDE-47 showed a distinct profile in gut microbiota compared to control dams, as evidenced by increased Actinobacteria phylum and genera Blautia, Gemella and Phascolarctobacterium, and decreased genera AF12 and Oscillospira. Additionally, global metabolomics analysis identified 26 differential serum metabolites to distinguish PBDE-47 from controls, which were mainly involved in amino acid, lipid, carbohydrate and energy metabolism, further confirmed by pathway analysis. Importantly, the differential serum metabolites are closely correlated with the disturbed gut microbiota in response to PBDE-47. Collectively, our results suggest that maternal gut microbial dysbiosis may serve as a potential mechanism underlying PBDE-47-elicited health hazards to mothers or even offspring.

A tolerability and safety analysis of adding granulocyte-macrophage colony-stimulating factor to local radiotherapy in a case series of seven patients with thoracic cancer.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to improve the anti-cancer effects in combination with radiotherapy. However, the tolerability and safety of adding GM-CSF to radiotherapy in thoracic cancer patients need to be further explored. METHODS: Between June 2020 and Sep 2020, seven patients with thoracic cancer were treated with concurrent radiotherapy and GM-CSF (200 µg subcutaneously injected q.o.d during the radiotherapy). The primary endpoint was adverse event. RESULTS: Of seven enrolled patients, four were non-small cell lung cancer, two were small cell lung cancer, and the other one patient was thymic carcinoma. The total dose of GM-CSF that each patient received was at least 3000 µg. All patients had finished the radiotherapy and GM-CSF injection and suffered one or more any grade adverse events. Only one patient had a grade ≥3 hematological adverse event (lymphocytopenia). Grade ≥3 non-hematological toxicities were not observed during the combination treatment. The highest cell counts of white blood cell, neutrophile granulocyte, and monocyte across the treatment were 22.38×109/L,18.65×109/L, and 1.28×109/L respectively. CONCLUSIONS: The combination therapy of radiotherapy and GM-CSF (200 µg subcutaneously q.o.d) is tolerable and safe. Further studies are warranted to confirm the effects and optimal total GM-CSF injection doses in the combination of radiotherapy in thoracic cancer patients.

6 versus 12 months of adjuvant trastuzumab in HER2+ early breast cancer: A systematic review and meta-analysis.

BACKGROUND: Adjuvant trastuzumab improves survival outcomes of human epidermal receptor 2 positive early breast cancer patients. Currently, administration of 12 months adjuvant trastuzumab is the standard therapy. However, whether 6 months treatment is non-inferior to the standard 12 months treatment remains controversial. METHODS: Relevant records were searched in PubMed, Cochrane Library, Web of Science, and EMBASE through Jan 14, 2020. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were meta-analyzed. The primary endpoint was DFS with a non-inferiority hazard margin of 1.2 and the second was OS with 1.43. RESULTS: Three randomized clinical studies met the inclusion criteria, including 3974 patients in 6 months group and 3976 in 12 months group. HR for DFS was 1.18 (95% CI 0.97-1.44, P = .09), with the non-inferiority margin comprised in the 95% CI. HR for OS was 1.14 (95% CI 0.98-1.32, P= .08), whereas the upper limit of 95% CI did not exceed the non-inferiority hazard margin. CONCLUSION: Our analysis failed to show that 6 months treatment was non-inferior to 12 months treatment in improving the DFS. Although the non-inferiority of the 6-month adjuvant trastuzumab treatment was found for OS, considering that breast cancer patients should receive additional systematic therapies when disease progression or relapse happens, we suggest that 12 months adjuvant trastuzumab treatment should remain the standard therapeutic strategy for patients with early human epidermal receptor 2 positive breast cancer.

Corrigendum to "Efficacy and Safety of First-Line Immunotherapy in Combination with Chemotherapy for Patients with Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis".

[This corrects the article DOI: 10.1155/2020/2368164.].

Efficacy and Safety of First-Line Immunotherapy in Combination with Chemotherapy for Patients with Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis.

BACKGROUND: The prognosis of patients with extensive-stage small cell lung cancer (SCLC) is poor. Adding an immune checkpoint inhibitor (ICI) to chemotherapy may exert a synergistic effect and improve survival outcomes. However, for treatment-naive extensive-stage SCLC patients, the efficacy of immunotherapy in combination with cytotoxic chemotherapy remains controversial. OBJECTIVE: To evaluate the benefits and risks of the combination of immunotherapy and chemotherapy and to assess the comparative effectiveness of different first-line treatment strategies for extensive-stage SCLC. METHODS: PubMed, Web of Science, EMBASE, and Cochrane Library were searched for randomized clinical trials studying different immunotherapeutics for patients with previously untreated extensive-stage SCLC up to Feb 16, 2020. The primary outcomes were overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were objective response rate (ORR), disease control rate (DCR), and adverse events. RESULTS: We identified 141 published records, and 4 studies (comprising 2202 patients) were included in the analysis. Immunotherapy (including ipilimumab, atezolizumab, and durvalumab) plus chemotherapy was associated with better OS (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.75-0.93; risk ratio (RR) 0.90, 95% CI 0.81-1.00) and PFS (HR: 0.81, 95% CI 0.74-0.88; RR 0.96, 95% CI 0.93-0.99) than placebo plus chemotherapy. The addition of immunotherapy to chemotherapy showed similar improvement in ORR, DCR, and adverse events versus placebo plus chemotherapy. On the surface under the cumulative ranking (SUCRA) analysis, the anti-PD-L1 agent, atezolizumab, had the highest likelihood of achieving improved OS (93.4%) and PFS (95.0%). CONCLUSION: In the first-line setting, combining immunotherapy with chemotherapy is better than standard chemotherapy in terms of OS and PFS. Across the eligible studies, PD-L1 inhibitors might be preferred. Further explorations of more ICIs in the first-line treatment for extensive-stage SCLC patients should be needed.

Efficacy and safety of gemcitabine plus capecitabine in the treatment of advanced or metastatic pancreatic cancer: a systematic review and meta-analysis.

BACKGROUND: Gemcitabine combined the oral fluoropyrimidine capecitabine (GemCap) is an active antitumor therapy in the treatment of advanced or metastatic pancreatic cancer, and has been shown potential synergistic activity in previous clinical trials. In this study, we sought to systematically review and synthesize the efficacy and safety of GemCap in the treatment of advanced or metastatic pancreatic cancer. METHODS: A systematic review was performed through PubMed, Cochrane Library, EMBASE, and Web of Science databases up to Jul 10, 2019 to identify clinical trials that included advanced or metastatic pancreatic cancer patients treated with GemCap. Data of overall survival (OS), progression-free survival (PFS), 1-year survival rate, objective response rate (ORR), disease control rate (DCR) and adverse events were extracted and meta-analyzed. RESULTS: Fifteen studies were identified for systematic review, of which 13 were included in the metaanalysis. In comparison with Gem monotherapy, the pooled hazard ratios (HR) of GemCap treatment for OS and PFS were 0.85 (95% CI: 0.75-0.95, P=0.007) and 0.80 (95% CI: 0.72-1.04, P=0.0002). The pooled 1-year survival rate, ORR and DCR of GemCap were, respectively, 33.1% (95% CI: 28.7-37.5), 22.9% (95% CI: 17.6-28.3) and 65.7% (95% CI: 56.7-74.8). GemCap combination therapy showed significantly higher ORR (OR: 1.98, 95% CI: 1.34-2.67, P=0.0003) and DCR (OR: 1.41, 95% CI: 1.05- 1.88, P=0.02) compared to Gem monotherapy. The most common grade ≥3 hematological toxicities in patients treated with GemCap combination therapy were neutropenia (19.7%), leucocytopenia (7.9%) and anemia (4.9%). The most common grade ≥3 non-hematological toxicities were hand-foot syndrome (6.3%), fatigue (5.7%) and nausea (4.8%). CONCLUSIONS: GemCap combination therapy had an encouraging activity and might be a better treatment strategy compared with Gem alone in the first-line treatment for patients with advanced or metastatic pancreatic cancer.

The efficacy and safety of induction chemotherapy combined with concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in nasopharyngeal carcinoma patients: a systematic review and meta-analysis.

BACKGROUND: Induction chemotherapy (IC) combined with concurrent chemoradiotherapy (CCRT) has been recommended as the first-line therapy for locoregional nasopharyngeal carcinoma (NPC). Due to the different chemotherapeutic drugs used in the IC and CCRT, the results remain controversial. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically retrieved to search potentially eligible clinical trials up to Sep 11, 2019. Eligible studies were registered and prospective randomized controlled clinical trials. RESULTS: From 526 records, nine articles including seven randomized controlled clinical trials were eligible, with a total of 2311 locoregional advanced NPC patients. IC + CCRT had significantly lower risks of death (3-year hazard ratio [HR]: 0.70, 95% confidence interval [CI] 0.55-0.89, p = 0.003; 5-year HR: 0.77, 95% CI 0.62-0.94, p = 0.01), disease progression (3-year HR: 0.67, 95% CI 0.55-0.80, p < 0.001; 5-year HR: 0.70, 95% CI 0.58-0.83, p < 0.0001), distant metastasis (3-year HR: 0.58, 95% CI 0.45-0.74, p < 0.0001; 5-year HR: 0.69, 95% CI 0.55-0.87, p = 0.001) and locoregional relapse (3-year HR: 0.69, 95% CI 0.50-0.95, p = 0.02; 5-year HR: 0.66, 95% CI 0.51-0.86, p = 0.002) than CCRT. Compared with CCRT, IC + CCRT showed higher relative risks of grade 3 or more neutropenia, thrombocytopenia, nausea, vomiting and hepatotoxicity throughout the course of treatment, and higher relative risks of grade ≥ 3 thrombocytopenia and vomiting during CCRT. CONCLUSION: IC combined with CCRT significantly improved the survival in locoregional advanced NPC patients. Moreover, toxicities were well tolerated during IC and CCRT. Further clinical trials are warranted to confirm the optimal induction chemotherapeutic regimen in the future.

The efficacy and safety of PD-1/PD-L1 inhibitors in breast cancer: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibition has been increasingly used in breast cancer therapy. Understanding the benefit and risk of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors is critical for clinical practice. This study aims to determine the objective response, disease control and adverse events of breast cancer patients treated with PD-1/PD-L1 inhibitors. METHODS: PubMed, Cochrane Library, Web of Science and EMBASE databases were searched up to Aug 1, 2019. Both nonrandomized and randomized studies were included. Pooled objective response rate (ORR), disease control rate (DCR) and adverse events were pooled analyzed. RESULTS: A total of nine clinical studies were identified. Triple-negative breast cancer (TNBC) showed the highest estimates of ORR [overall population: 49.7%, 95% confidence interval (CI): 33.9-65.5%; PD-L1 positive population: 55.8%, 95% CI: 42.9-68.8%] and DCR (overall population: 67.5%, 95% CI: 38.6-96.4%; PD-L1 positive population: 83.4%, 95% CI: 72.2-94.5%) post-anti-PD-L1 plus nab-paclitaxel treatment. With respect to grade ≥3 treatment related adverse events, the pooled estimates ranged from 12.0% to 50.9% for anti-PD-1/PD-L1 monotherapy. The pooled estimates percentages of grade ≥3 treatment related adverse events in TNBC patients treated with anti-PD-L1 plus nab-paclitaxel were 59.6% (95% CI: 36.1-83.0). CONCLUSIONS: We presented the aggregate estimates of ORR, DCR, and treatment related adverse events for breast cancer patients receiving anti-PD-1/PD-L1 treatment. However, these results were largely derived from single-arm studies, and randomized studies with head-to-head comparison of PD-1/PD-L1 inhibitors and chemotherapy are lacking. Additionally, the incidence of varying treatment related adverse events should be also carefully monitored.

Perigestational low-dose BDE-47 exposure alters maternal serum metabolome and results in sex-specific weight gain in adult offspring.

Emerging evidence suggests environmental contaminant exposures during critical windows of development may contribute to the increasing prevalence of obesity. It has been shown that early life polybrominated diphenyl ethers exposures have critical impacts on child weight trajectories, however, little is known about their maternal mechanisms responsible for offspring obesity development. In this study, we investigated the effects of perigestational low-dose 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) exposure on maternal metabolome, and its possible link to adult offspring bodyweight changes. Female Sprague-Dawley rats were exposed to daily doses of 0.1, or 1 mg/kg BDE-47 from 10 days prior to conception until offspring were weaned on postnatal day 21, and then a gas chromatography-mass spectrometry based metabolomics analysis was used to uncover the global metabolic response in dams. The pups continued to grow into adulthood for measurements of bodyweight. Perigestational BDE-47 exposure caused increased adult bodyweight in male but not in female offspring and dams. Metabolomics revealed significant changes in maternal serum metabolites that clearly distinguish BDE-47 from control rats. These differentially expressed metabolites were primarily implicated in amino acid, lipid, carbohydrate, and energy metabolisms, which was confirmed by pathway analysis. Importantly, most of these identified metabolites were decreased, a state similar to maternal malnutrition that can predispose adult male offspring to weight increase and adiposity in a postnatal environment with abundant calories. Collectively, our data suggest that perigestational exposure to low-dose BDE-47 produces altered maternal serum metabolome, which may be an additional contributing factor to weight gain in adult male offspring.