Narrative review on advancing breast cancer treatment: harnessing the power of PD-1/PD-L1 inhibitors for improved patient outcomes.

Background and Objective: Cancer immunotherapy has significantly advanced the field of oncology, providing novel therapeutic strategies for various malignancies, including breast cancer. The programmed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway is pivotal in immune regulation, and its inhibitors have demonstrated therapeutic benefits in diverse tumors. This review aims to critically examine the role, clinical efficacy, safety, and future directions of PD-1/PD-L1 inhibitors in breast cancer treatment, with a focus on pembrolizumab, nivolumab, and tislelizumab, and to elucidate the challenges and prospects in this dynamic field. Methods: A comprehensive literature search was conducted, adhering to Narrative Review reporting checklist for transparent reporting. Data from selected studies were qualitatively analyzed to synthesize key findings related to the mechanisms of action, clinical applications, and challenges of PD-1/PD-L1 inhibitors in breast cancer. Key Content and Findings: PD-1 inhibitors have shown remarkable efficacy in various malignancies, including advanced triple-negative breast cancer (TNBC), where they have been investigated both in combination with chemotherapy and as neoadjuvant/adjuvant treatment. The exploration of these inhibitors in other breast cancer subtypes, such as human epidermal growth factor receptor-positive and hormone receptor-positive breast cancer, is ongoing. The review highlights the challenges in patient selection, management of immune-related adverse events (irAEs), and the emergence of resistance mechanisms. It underscores the need for ongoing research focusing on identifying reliable predictive biomarkers, elucidating mechanisms of resistance, and optimizing treatment strategies. Conclusions: PD-1/PD-L1 inhibitors hold substantial promise in advancing breast cancer treatment. This review provides critical insights and emphasizes the clinical importance of continued scientific exploration to refine patient selection criteria, improve treatment outcomes, and expand the applications of immunotherapy in breast cancer. Further research is imperative to overcome the existing challenges and realize the full therapeutic potential of these inhibitors in breast cancer and other malignancies.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Molecular subtypes predict the preferential site of distant metastasis in advanced breast cancer: a nationwide retrospective study.

Objective: This study aimed to explore possible associations between molecular subtypes and site of distant metastasis in advanced breast cancer (ABC). Methods: 3577 ABC patients were selected from 21 hospitals of seven geographic regions in China from 2012-2014. A questionnaire was designed to collect medical information regarding demographic characteristics, risk factors, molecular subtype, recurrence/metastasis information, and disease-free survival (DFS). The cancers were classified into Luminal A, Luminal B, HER2-enriched and Triple Negative subtypes. Chi-square test and multivariate Cox proportional hazard models were performed to explore the associations between molecular subtypes and distant metastasis sites. Results: A total of 2393 cases with molecular subtypes information were finally examined. Patients with Luminal A (51.1%) and Luminal B (44.7%) were most prone to bone metastasis, whereas liver metastasis was more frequently observed in HER2-enriched ABC patients (29.1%).The cumulative recurrence and metastasis rates of ABC patients at 36 months of DFS were the most significant within molecular types, of which Triple Negative was the highest (82.7%), while that of Luminal A was the lowest (58.4%). In the adjusted Cox regression analysis, Luminal B, HER2-enriched and Triple Negative subtypes increased the risk of visceral metastasis by 23%, 46% and 87% respectively. In addition, Triple Negative patients had a higher probability of brain metastasis (HR 3.07, 95% CI: 1.04-9.07). Conclusion: Molecular subtypes can predict the preferential sites of distant metastasis, emphasizing that these associations were of great help in choices for surveillance, developing appropriate screening and cancer management strategies for follow-up and personalized therapy in ABC patients.

Age at initial diagnosis and prognosis of breast cancer: a nationwide multicenter retrospective study in China.

Background: Several studies have indicated possible associations between age and the prognosis of breast cancer (BC), but limited data are available from hospital-based multicenter studies in China. This study aimed to explore the associations between age at initial diagnosis of BC and the risk of recurrence or metastasis among Chinese women with newly diagnosed advanced breast cancer (ABC) and provide treatment decision support for BC patients of different ages to medical workers. Methods: The medical records of patients newly diagnosed with ABC were obtained from 21 hospitals in seven geographic regions in China from 2012 to 2014. Patients' general information, clinicopathological features at first diagnosis, treatment information, and prognosis were retrospectively collected based on the self-designed case report form (CRF). Cox proportional hazards regression models were used to determine hazard ratios (HR) and 95% confidence intervals (CI) for the associations between age groups and the risk of recurrence and metastasis. Results: A total of 1,852 cases were included in the final analysis. Age at initial diagnosis was shown to be significantly related to hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, molecular subtypes, and the number of lymph node metastasis (all P<0.05). Patients aged <35 years were more likely to have bone metastasis (45.6%). Patients aged ≥65 years had a lower percentage of receiving surgery (87.1%), adjuvant chemotherapy (61.3%), adjuvant radiotherapy (35.5%), and adjuvant endocrine therapy (30.6%) than the other groups (all P<0.05). Compared with patients aged <35 years, the risk of recurrence or metastasis in those aged 55-64 years was significantly higher (HRage 55-64 =1.24, 95% CI: 1.04-1.47), and the risk of bone metastasis and lung metastasis in those aged 35-44 years was lower (HRbone metastasis =0.74, 95% CI: 0.59-0.93; HRlung metastasis =0.70, 95% CI: 0.53-0.93). After adjusting for stage, grade, and molecular subtype, surgery, neoadjuvant chemotherapy, adjuvant chemotherapy, adjuvant radiotherapy, adjuvant endocrine therapy, and family history of BC, patients aged 35-44 years still had a significantly reduced risk of bone metastasis and lung metastasis by 31% and 52%, respectively (HRbone metastasis =0.69, 95% CI: 0.48-0.98; HRlung metastasis =0.48, 95% CI: 0.31-0.74). Conclusions: Age at initial diagnosis is related to the clinicopathological characteristics and treatment pattern. Although the risk of site-specific metastasis varies by age, age is not an independent factor influencing the risk of total recurrence and metastasis. In accordance with current clinical practice guidelines for BC, however, precise treatment shall be chosen personally for patients whose ages at initial diagnosis are different.

Perceived Importance of Breast Cancer Risk Factors: A Survey on 386 Physicians in China.

There are varying definitions of women at high risk of breast cancer across different institutions, and there are reports suggesting that the breast cancer risk assessment tools have not been well integrated into clinical practice. In this study, we tried to investigate the perceived importance of different breast cancer risk factors by physicians in China. A cross-sectional survey involving 386 anonymous physicians was conducted using a 20-item, 5-point Likert scale questionnaire. The Kruskal-Wallis test and post-hoc pairwise comparisons were used to compare the differences in response. Most of the respondents were either breast surgeons/specialists (n=161; 41.7%) or medical oncologists (n=151; 39.1%), and the results showed that the breast cancer risk factors were not perceived as equally important. The weighting of each risk factor also varied depending on the physician's medical specialty, location of practice, and the number of years of clinical experience.  This study provides a more updated insight into the perceptions of physicians in China toward the breast cancer risk factors, as well as underlines the potential improvements in breast cancer risk assessment strategies that can be done.

Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002).

PURPOSE: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy. PATIENTS AND METHODS: We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses. RESULTS: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0-44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7-21.7)] in the ET group and 14.8 months (12.8-16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71-1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group. CONCLUSIONS: Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.

Comparisons of Treatment for HER2-Positive Breast Cancer between Chinese and International Practice: A Nationwide Multicenter Epidemiological Study from China.

OBJECTIVE: To better understand the status of medical treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer and the differences between the Chinese and the international clinical practice. METHODS: This was a retrospective, nationwide, multicenter, epidemiological study of advanced breast cancer patients from China. Between January 01, 2012, and December 31, 2014, a total of 3649 patients, covering 7 geographic regions and 21 institutions, participated in this series of studies. HER2-positive breast cancer was selected among the group and adopted into this study. In comparison, we summarized the demographics and clinical characteristics of HER2-positive breast cancer from the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: A total of 918 patients diagnosed as HER2-positive breast cancer patients were included. The median age at diagnosis was 46 years (ranging, 23 to 78) with a single-peak incidence. The proportions of stages II-IV at diagnosis and distance metastasis in viscera were more than half of the participants. In comparison, the prevalence of estrogen or progesterone receptor-positive expression and luminalB subtype was relatively lower than that of the United States. The receipt of chemotherapy was fairly higher, while the usage of targeted therapy was seriously insufficient. Tumor size was in significantly positive associations with the duration of targeted therapy (Kendall's correlation coefficient = 0.3, P < 0.0001), while no prohibitive variables among clinical characteristics were detected. CONCLUSION: Our study suggested that HER2-positive breast cancer patients were characterized as a younger trend, a lower prevalence of hormonal receptor (HR)-positive expression, and less accessible to anti-HER2 targeted therapy with insufficient duration over the past few years in China. Concerted efforts should be exerted for promising survival benefits in the future. The trial registration number is https://clinicaltrials.gov/ct2/show/NCT03047889.

[Supergenes:Generalists in Gene Expression].

In eukaryote cells,transcription from genome DNA is a key process of gene expression.The transcription products contain not only messenger RNAs that code proteins,but also various types of non-coding RNAs.During transcription,some of the gene loci produce more than one kind of RNA molecule,including coding RNAs and more often non-coding RNAs.These gene loci that generate several kinds of RNA molecules are named supergenes.According to the transcription pattern,supergenes are divided into three types,known as types Ⅰ,Ⅱ and Ⅲ.In this review,we summarize the transcription pattern of each type of supergene,and exposit the role of these genes in cells.

Cyclin G2 promotes the formation of smooth muscle cells derived foam cells in atherosclerosis via PP2A/NF-κB/LOX-1 pathway.

BACKGROUND: To investigate the role and underlying mechanism of cyclin G2 (G2-type cyclin) in the formation of vascular smooth muscle cells (VSMCs) derived foam cells. METHODS: The levels of α-SMA (alpha-SM-actin), p-NF-κB (phosphorylation nuclear transcription factors kappa B), and LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) were measured by immunohistochemistry and western blotting. The mouse aortic root smooth muscle cell line MOVAS was transfected to over-express cyclin G2, which were then stimulated with 80 µg/mL ox-LDL (oxidized low-density lipoprotein) to induce foam cell formation. DT-061 an activator of PP2A (protein phosphatase 2A) agonist was used to verify the role of PP2A in the process. RESULTS: Knocking out the Ccng2 gene in Apoe-/- mice alleviated aortic lipid plaque, foam cell formulation, ameliorative body weight, and LDL-cholesterol. We observed that the number of α-SMA positive cells was significantly decreased in Apoe-/-Ccng2-/- mice compared to Apoe-/- mice. Also, the protein levels of p-NF-κB and LOX-1 were markedly reduced in the aortic root of Apoe-/-Ccng2-/- mice. Upon stimulation with ox-LDL, upregulated cyclin G2 increased the intracellular lipid accumulation in MOVAS cells. Also, it suppressed the activity of PP2A but up-regulated LOX-1. Additionally, the cell nuclear translocation of p-NF-κB was increased. Interestingly, DT-061 intervention, re-activating the activity of PP2A, reduced the levels of nuclear p-NF-κB and LOX-1. This led to decreased lipid endocytosis reducing the formation of VSMCs- derived foam cells. CONCLUSIONS: Cyclin G2 increases the nuclear translocation of p-NF-κB by reducing the enzymatic activity of PP2A and upregulating LOX-1, thereby promotes the formation of VSMCs -derived foam cells in atherosclerosis.

Sulfur autotrophic denitrification filter and heterotrophic denitrification filter: Comparison on denitrification performance, hydrodynamic characteristics and operating cost.

Sulfur autotrophic denitrification (SAD) process, as an alternative to heterotrophic denitrification (HD) filter, receives growing interest in polishing the effluent from secondary sewage treatment. Although individual studies have indicated several advantages of SAD over HD, rare study has compared these two systems under identical condition and by using real secondary effluent. In this study, two small pilot scale filters (SAD and HD) were designed with identical configuration and operated parallelly by feeding the real secondary effluent from a WWTP. The results showed SAD filter can be started up without the addition of soluble electron donor, although the time (14 days) was about 3 times longer than that of HD filter. The nitrate removal rate of SAD filter at HRT of 1.4 h was measured as 0.268 ± 0.047 kg N/(m3∙d). Similar value was observed in HD filter with supplementing 90 mg/L COD. The COD concentration of effluent always kept lower than that of influent in SAD filter but not in HD filter. In addition, SAD filter could maintain a stable denitrification performance without backwash for 15 days, while decline of nitrate removal rate was observed in HD filter just 2 days after stopping the backwash. This different behavior was further confirmed as the SAD filter had a better hydraulic flow pattern. Analysis according to high-throughput 16S rRNA gene-based Illumina MiSeq sequencing clearly showed the microbial community evolution and differentiation among the samples of seed sludge, SAD and HD filters. Finally, the economic assessment was carried out, showing the operation cost of SAD filter was over 50% lower than that of HD filter.

Profile and outcome of receptor conversion in breast cancer metastases: a nation-wide multicenter epidemiological study.

Although receptor status including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) of the primary breast tumors was related to the prognosis of breast cancer patients, little information is yet available on whether patient management and survival are impacted by receptor conversion in breast cancer metastases. Using data from the nation-wide multicenter clinical epidemiology study of advanced breast cancer in China (NCT03047889), we report the situation of retesting ER, PR and HER2 status for breast cancer metastases and evaluate the patient management and prognostic value of receptor conversion. In total, 3295 patients were analyzed and 1583 (48.0%) patients retesting receptor status for metastasis. Discordance in one or more receptors between the primary and the metastatic biopsy was found in 37.7% of women. Patients who remained hormone receptor (HR) positive in their metastases had similar progression-free survival of first-line and second-line treatment compared to patients with HR conversion (P > .05). In multivariate analysis, patients who showed ER conversion from negative to positive had longer disease-free survival (DFS) than patients who remained negative in their metastases (hazard ratio, 2.05; 95% confidence interval [CI], 1.45-2.90; P < .001). Patients with PR remained positive and had longer DFS than patients with PR conversion from negative to positive (hazard ratio, 0.56; 95% CI, 0.38-0.83; P = .004). Patients with PR conversion have shorter overall survival than patients with PR remained positive or negative (P = .016 and P = .041, respectively). Our findings showed that the receptors' conversions were common in metastatic breast cancer, and the conversion impacted the survival.

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.

Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.

CORM-2 Pretreatment Attenuates Inflammation-mediated Islet Dysfunction.

During the process of human islet isolation a cascade of stressful events are triggered and negatively influence islet yield, viability, and function, including the production of proinflammatory cytokines and activation of apoptosis. Carbon monoxide-releasing molecule 2 (CORM-2) is a donor of carbon monoxide (CO) and can release CO spontaneously. Accumulating studies suggest that CORM-2 exerts cytoprotective and anti-inflammatory properties. However, the effect of CORM-2 on islet isolation is still unclear. In this study, we found that CORM-2 pretreatment significantly decreased the expression of critical inflammatory genes, including tissue factor, intercellular adhesion molecule-1, chemokine (C-C motif) ligand 2, C-X-C motif chemokine 10, Toll-like receptor 4, interleukin-1ß, interleukin-6, and tumor necrosis factor-α (TNF-α). The isolated islets of the CORM-2 pretreatment group showed reduced apoptotic rate, improved viability, and higher glucose-stimulated insulin secretion, and functional gene expression in comparison to control group. Importantly, CORM-2 pretreatment prevented the impairment caused by TNF-α, evidenced by the improved glucose-stimulated index and transplantation outcomes. The present study demonstrated the anti-inflammatory property of CORM-2 during human islet isolation, and we suggest that CORM-2 pretreatment is an appealing treatment to mitigate inflammation-mediated islet dysfunction during isolation and culture ex vivo and to preserve long-term islet survival and function.

Electrochemistry-stimulated environmental bioremediation: Development of applicable modular electrode and system scale-up.

Bioelectrochemical systems (BESs) have been studied extensively during the past decades owing primarily to their versatility and potential in addressing the water-energy-resource nexus. In stark contrast to the significant advancements that have been made in developing innovative processes for pollution control and bioresource/bioenergy recovery, minimal progress has been achieved in demonstrating the feasibility of BESs in scaled-up applications. This lack of scaled-up demonstration could be ascribed to the absence of suitable electrode modules (EMs) engineered for large-scale application. In this study, we report a scalable composite-engineered EM (total volume of 1 m3), fabricated using graphite-coated stainless steel and carbon felt, that allows integrating BESs into mainstream wastewater treatment technologies. The cost-effectiveness and easy scalability of this EM provides a viable and clear path to facilitate the transition between the success of the lab studies and applications of BESs to solve multiple pressing environmental issues at full-scale.

Coupled Sulfur and Iron(II) Carbonate-Driven Autotrophic Denitrification for Significantly Enhanced Nitrate Removal.

Sulfur-based denitrification process has attracted increasing attentions because it does not rely on the external addition of organics and avoids the risk of COD exceeding the limit. Traditionally, limestone is commonly employed to maintain a neutral condition (SLAD process), but it may reduce the efficiency as the occupied zone by limestone cannot directly contribute to the denitrification. In this study, we propose a novel sulfur-based denitrification process by coupling with iron(II) carbonate ore (SICAD system). The ore was demonstrated to play roles as the buffer agent and additional electron donor. Moreover, the acid produced through sulfur driven denitrification was found to promote the Fe(II) leaching from the ore and likely extend the reaction zone from the surface to the liquid. As a result, more biomass was accumulated in the SICAD system compared with the controls (sulfur, iron(II) carbonate ore and SLAD systems). Owing to these synergistic effects of sulfur and iron(II) carbonate on denitrification, SICAD system showed much higher denitrification rate (up to 720.35 g·N/m3·d) and less accumulation of intermediates (NO2- and N2O) than the controls. Additionally, sulfate production in SICAD system was reduced. These findings offer great potential of SICAD system for practical use as a highly efficient postdenitrification process.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

Microbial Photoelectrotrophic Denitrification as a Sustainable and Efficient Way for Reducing Nitrate to Nitrogen.

Biological removal of nitrate, a highly concerning contaminant, is limited when the aqueous environment lacks bioavailable electron donors. In this study, we demonstrated, for the first time, that bacteria can directly use the electrons originated from the photoelectrochemical process to carry out the denitrification. In such photoelectrotrophic denitrification (PEDeN) systems (denitrification biocathode coupling with TiO2 photoanode), nitrogen removal was verified solely relying on the illumination dosing without consuming additional chemical reductant or electric power. Under the UV illumination (30 mW·cm-2, wavelength at 380 ± 20 nm), nitrate reduction in PEDeN apparently followed the first-order kinetics with a constant of 0.13 ± 0.023 h-1. Nitrate was found to be almost completely converted to nitrogen gas at the end of batch test. Compared to the electrotrophic denitrification systems driven by organics (OEDeN, biocathode/acetate consuming bioanode) or electricity (EEDeN, biocathode/abiotic anode), the denitrification rate in PEDeN equaled that in OEDeN with a COD/N ratio of 9.0 or that in EEDeN with an applied voltage at 2.0 V. This study provides a sustainable technical approach for eliminating nitrate from water. PEDeN as a novel microbial metabolism may shed further light onto the role of sunlight played in the nitrogen cycling in certain semiconductive and conductive minerals-enriched aqueous environment.

Corrugated stainless-steel mesh as a simple engineerable electrode module in bio-electrochemical system: Hydrodynamics and the effects on decolorization performance.

The application of bio-electrochemical system (BESs) is strongly depended on the development of the engineering applicable electrode. Here we described an economical and readily processable electrode module with three-dimensional structure, the corrugated stainless-steel mesh electrode module (c-SMEM). This novel developed electrode module was demonstrated to provide a good hydrodynamic characteristic and significantly enhanced the decolorization performance of the BES when serving for treating azo dye (acid orange 7, AO7) containing wastewater. Compared to the conventional planar electrodes module (p-SMEM), c-SMEM was found to prolong the mean residence time (MRTθ) of AO7 and change the flow pattern closer to the plug flow. As a result, the maximum enhancement of the volumetric decolorization rate (vDR) can reach to 255%, even when the c-SMEM and p-SMEM have the same electrode surface area. In addition, a techno-economic analysis model was established to elucidated the effects of the decolorization performance and the material cost on the initial capital cost, which revealed the BES with c-SMEM could be economically comparable to or even better than the traditional bio-decolorization technologies. These results suggest c-SMEM holds great potential for engineering application, which may help paving the way of applying BES at large-scale.

LAMC1 mRNA promotes malignancy of hepatocellular carcinoma cells by competing for MicroRNA-124 binding with CD151.

Specific RNAs can function as sinks for endogenous miRNAs, known as competing endogenous RNAs (ceRNAs). Here, we confirm a miR-124 mediated ceRNA crosstalk between LAMC1 and CD151 in hepatocellular carcinoma (HCC). miR-124 negatively regulates LAMC1 expression through two miRNA binding sites within its 3' untranslated region (3'UTR) and suppresses migration and invasion of HCC cells through regulating LAMC1. The wild type LAMC1 miRNA response elements (MREs) facilitate expression of CD151, and this regulation is miR-124 dependent. In clinical hepatic tissues, LAMC1 and CD151 mRNAs exhibit positive correlation. Importantly, LAMC1 MREs promote HCC malignancy by absorbing miR-124 and by assisting CD151 expression. We conclude that LAMC1 mRNA acts as a trans regulator to stimulate CD151 expression by competing for miR-124 binding in HCC cells. © 2017 IUBMB Life, 69(8):595-605, 2017.

Gastric submucosa is inferior to the liver as transplant site for autologous islet transplantation in pancreatectomized diabetic Beagles.

Intraportal transplantation of islets is no longer considered to be an ideal procedure and finding the extrahepatic alternative site is becoming a subject of high priority. Herein, in this study, we would introduce our initial outcomes of using gastric submucosa (GS) and liver as sites of islet autotransplantation in pancreatectomized diabetic Beagles. Total pancreatectomy was performed in Beagles and then their own islets extracted from the excised pancreas were transplanted into GS (GS group, n=8) or intrahepatic via portal vein (PV group, n=5). Forty-eight hours post transplantation, graft containing tissue harvested from the recipients revealed the presence of insulin-positive cells. All recipients in GS group achieved euglycemia within 1 day, but returned to a diabetic state at 6 to 8 days post-transplantation (mean survival time, 7.16±0.69 days). However, all of the animals kept normoglycemic until 85 to 155 days post-transplantation in PV group (mean survival time, 120±28.58 days; P<0.01 vs. GS group). The results of intravenous glucose tolerance test (IVGTT) confirmed that the marked improvement in glycometabolism was obtained in intrahepatic islet autotransplantation. Thus, our findings indicate that the liver is still superior to the GS as the site of islet transplantation, at least in our islet autotransplant model in pancreatectomized diabetic Beagles.