Effectiveness of gonadotropin-releasing hormone agonists for ovarian function suppression in premenopausal patients with hormone receptor-positive breast cancer: a retrospective single-center real-world study.

PURPOSE: This study evaluated the effectiveness of ovarian function suppression (OFS) of various gonadotropin-releasing hormone agonists (GnRHa) combined with aromatase inhibitors (AI) in premenopausal patients with hormone receptor-positive (HR-positive) breast cancer. Potential risk factors associated with insufficient OFS were analyzed. PATIENTS AND METHODS: Premenopausal HR-positive breast cancer patients who had received AI with GnRHa were studied retrospectively. Patients were divided into different groups according to monthly or trimonthly GnRHa schedules they received, and the effectiveness of OFS was compared between groups. Insufficient OFS was defined as at least one instance of estradiol ≥ 30 pg/ml. Patient data was gathered from medical records for this comparison. RESULTS: Of the 264 patients enrolled in this study, 117 were administered 3.6 mg of goserelin monthly (goserelin 1 M group), 63 received 3.75 mg of leuprorelin monthly (leuprorelin 1 M group) and 84 were given 11.25 mg of leuprorelin every three months (leuprorelin 3 M group). Overall, 7.20% experienced insufficient OFS. The incidence rates in the three GnRHa depot groups were 7.69%, 6.35%, and 7.14%, respectively, without a significant statistical difference (P = 0.900). Notably, younger patients exhibited a higher likelihood of insufficient OFS [OR = 0.900, 95%CI (0.824-0.982), P = 0.018]. CONCLUSION: Insufficient OFS remains a concern during GnRHa and AI treatment. The effectiveness of the three GnRHa depots commonly used in China seems comparable. Younger patients face a heightened risk of insufficient OFS.

Rolling Circle Amplification-Based Self-Assembly to Form a "GPS-Nanoconveyor" for In Vitro Targeted Imaging and Enhanced Gene/Chemo (CRISPR/DOX) Synergistic Therapy.

The GPS-Nanoconveyor (MA-NV@DOX-Cas13a) is a targeted nanoplatform designed for the imaging and gene/chemotherapy synergistic treatment of melanoma. It utilizes rolling circle amplification (RCA) products as a scaffold to construct a DNA "Nanoconveyor" (NV), which incorporates a multivalent aptamer (MA) as a "GPS", encapsulates doxorubicin (DOX) in the transporter, and equips it with CRISPR/Cas13a ribonucleoproteins (Cas13a RNP). Carrying MA enhances the ability to recognize the overexpressed receptor nucleolin on B16 cells, enabling targeted imaging and precise delivery of MA-NV@DOX-Cas13a through receptor-mediated endocytosis. The activation of signal transducer and activator of transcription 3 (STAT3) in cancer cells triggers cis-cleavage of CRISPR/Cas13a, initiating its trans-cleavage function. Additionally, deoxyribonuclease I (DNase I) degrades MA-NV, releasing DOX for intracellular imaging and as a chemotherapeutic agent. Experiments demonstrate the superior capabilities of this versatile nanoplatform for cellular imaging and co-treatment while highlighting the advantages of these nanodrug delivery systems in mitigating DOX side effects.

Three-Week Versus 4-Week Schedule of nab-Paclitaxel in Patients With Metastatic Breast Cancer: A Randomized Phase II Study.

BACKGROUND: This head-to-head study compared a 3-week versus 4-week schedule of nab-paclitaxel in patients with metastatic breast cancer (mBC). METHODS: Patients with HER2-negative mBC were enrolled and randomly assigned (1:1) to receive nab-paclitaxel for a 3-week schedule (125 mg/m2 on days 1 and 8) or a 4-week schedule (same dose on days 1, 8, and 15) until disease progression or treatment intolerance. Patients with intolerable toxicities were allowed to receive a maintenance regimen after benefiting from nab-paclitaxel. The primary endpoint was progression-free survival (PFS). RESULTS: Ninety-four patients were included in the analysis (n = 47 in each arm). A longer median PFS (mPFS) was observed in the 3-week versus the 4-week schedule in the overall population (not reached vs. 6.8 months; hazard ratio [HR] = 0.44; P = .029). Patients in the 2 arms had a similar overall survival (28.0 vs. 25.8 months), objective response rate (51.1% vs. 48.9%), and disease control rate (93.6% vs. 80.9%). The 3-week schedule was associated with a lower rate of toxicity-related treatment discontinuation (8.5% vs. 29.8%) and dose delays (6.4% vs. 23.4%). CONCLUSION: This study demonstrated the better antitumor activity and safety profile of a 3-week over 4-week nab-paclitaxel schedule in HER2-negative mBC, suggesting that a 3-week schedule may be a better treatment regimen in clinical practice (ClinicalTrials.gov Identifier: NCT04192331).

Pegylated liposomal doxorubicin (Duomeisu®) monotherapy in patients with HER2-negative metastatic breast cancer heavily pretreated with anthracycline and taxanes: a single-arm, phase II study.

PURPOSE: To evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) heavily pretreated with anthracycline and taxanes. METHODS: In this single-arm, phase II study, patients with HER2-negative MBC previously treated with anthracycline and taxanes as second- to fifth chemotherapy received PLD (Duomeisu®, generic doxorubicin hydrochloride liposome) 40 mg/m2 every 4 weeks until disease progression, unacceptable toxicity, or completion of six cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety. RESULTS: Of 44 enrolled patients (median age, 53.5 years; range, 34-69), 41 and 36 were evaluable for safety and efficacy, respectively. In total, 59.1% (26/44) of patients had ≥ 3 metastatic sites, 86.4% (38/44) had visceral disease, and 63.6% (28/44) had liver metastases. Median PFS was 3.7 months (95% confidence interval [CI] 3.3-4.1) and median OS was 15.0 months (95% CI 12.1-17.9). ORR, DCR, and CBR were 16.7%, 63.9%, and 36.1%, respectively. The most common adverse events (AEs) were leukopenia (53.7%), fatigue (46.3%), and neutropenia (41.5%), with no grade 4/5 AEs. The most common grade 3 AEs were neutropenia (7.3%) and fatigue (4.9%). Patients experienced palmar-plantar-erythrodysesthesia (24.4%, 2.4% grade 3), stomatitis (19.5%, 7.3% grade 2), and alopecia (7.3%). One patient displayed a left ventricular ejection fraction decline of 11.4% from baseline after five cycles of PLD therapy. CONCLUSION: PLD (Duomeisu®) 40 mg/m2 every 4 weeks was effective and well-tolerated in patients with HER2-negative MBC heavily pretreated with anthracycline and taxanes, revealing a potentially viable treatment option for this population. Trial registration Chinese Clinical Trial Registry: ChiCTR1900022568.

A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis.

BACKGROUND: The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC). METHODS: This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCAmut). RESULTS: Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6-51.0) and 65.4% (95% CI 50.9-78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7-84.3); this dose was determined to be the RP2D. Patients with gBRCAmut had higher ORR and longer median progression-free survival (PFS) than those with gBRCAwt, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg. CONCLUSIONS: Fuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03075462 (Mar. 9, 2017).

Rolling Circle Amplification-Based DNA Nano-Assembly for Targeted Drug Delivery and Gene Therapy.

Combining the killing ability of chemotherapy drugs on tumor cells with the inhibiting ability of genetic drugs on tumor cell growth, a dual drug delivery system loaded with therapy drugs and siRNA has gradually received more and more research and extensive attention. In this paper, we designed a DNA nano-assembly based on rolling circle amplification that can co-deliver doxorubicin (Dox) and siRNA simultaneously. In order to fully exploit the potential of the dual loading system in cancer treatment, we selected STAT3 gene as a target and used siRNA to target STAT3 of mRNA and reduce the STAT3 expression in mouse melanoma cell line (B16); meanwhile, Dox as a chemotherapy drug was combined with multivalent aptamers specifically targeting B16 to achieve efficient delivery of siRNA and Dox. The results showed that the synergistic delivery system could achieve high efficiency in targeting and inhibiting proliferation in mouse melanoma cells. In addition, the synergistic effect of the dual delivery system on apoptosis of cancer cells was significantly better than that of single drug delivery systems.

A nucleolin-activated polyvalent aptamer nanoprobe for the detection of cancer cells.

Sensitive detection of cancer cells plays a critical role in early cancer diagnosis. Nucleolin, overexpressed on the surface of cancer cells, is regarded as a candidate biomarker for cancer diagnosis. Thus, cancer cells can be detected through the detection of membrane nucleolin. Herein, we designed a nucleolin-activated polyvalent aptamer nanoprobe (PAN) to detect cancer cells. In brief, a long single-stranded DNA with many repeated sequences was synthesized through rolling circle amplification (RCA). Then the RCA product acted as a scaffold chain to combine with multiple AS1411 sequences, which was doubly modified with fluorophore and quenching group, respectively. The fluorescence of PAN was initially quenched. Upon binding to target protein, the conformation of PAN changed, leading to the recovery of fluorescence. The fluorescence signal of cancer cells treated with PAN was much brighter compared with that of monovalent aptamer nanoprobes (MAN) at the same concentration. Furthermore, the binding affinity of PAN to B16 cells was proved to be 30 times higher than that of MAN by calculating the dissociation constants. The results indicated that PAN could specifically detect target cells, and this design concept has potential to become promising in cancer diagnosis.

Elucidating the effects of B/Al doping on the structure stability and electrochemical properties of silicene using DFT.

Using first-principles calculation based on density functional theory, the effects of B, Al and B-Al doping on the structural stability and electrochemical properties of silicene were systematically studied, and their potential as anode materials for lithium ion batteries was evaluated. The calculated results of formation energy indicate that the doped system has good stability. The charge density difference and density of states show that doping can improve the conductivity of silicene, and enhance the interaction with Li. Moreover, on the surface of B, Al and B-Al doped silicene, the diffusion barriers of the most easily migrated path for Li ions are 0.22 eV, 0.19 eV, and 0.21 eV, respectively, suggesting that all doped systems have good Li ion migration rates. And the open circuit voltage is between 0.40 V and 0.54 V, which is relatively stable and low. Therefore, B, Al and B-Al doping can effectively regulate the structural stability and electrochemical performance of silicene, which provides a theoretical basis for the experimental preparation of excellent silicene anode materials.

Exploring the structural stability and electrochemical performance of B doped T-graphene nanotubes from first-principles calculations.

The structural stability and electrochemical performance of intrinsic and B doped T-graphene nanotubes with different tube lengths are systematically studied by using first-principles calculations within the framework of density functional theory (DFT). The results show that with the increase of tube length, the adsorption energy of both intrinsic and B doped T-graphene nanotubes exhibits regular oscillations, and B doping is beneficial for elevating the adsorption ability of T-graphene nanotubes. The density of states show that intrinsic T-graphene nanotubes are zero band gap semiconductors, and the orbitals' electronic states cross the Fermi level to form a p-type semiconductor, indicating that B doping greatly improves the conductivity of the system. The results of migration behavior demonstrate that B doping can effectively reduce the diffusion barrier of lithium ions on their surface, especially in B doped T-graphene nanotubes with a tube length of N = 1, resulting in more effective migration behavior and excellent rate performance. These findings provide a theoretical basis for the development and application of negative electrode materials for lithium-ion batteries.

Translation information processing is regulated by protein kinase C-dependent mechanism in Purkinje cells in murine posterior vermis.

The cerebellar posterior vermis generates an estimation of our motion (translation) and orientation (tilt) in space using cues originating from semicircular canals and otolith organs. Theoretical work has laid out the basic computations necessary for this signal transformation, but details on the cellular loci and mechanisms responsible are lacking. Using a multicomponent modeling approach, we show that canal and otolith information are spatially and temporally matched in mouse posterior vermis Purkinje cells and that Purkinje cell responses combine translation and tilt information. Purkinje cell-specific inhibition of protein kinase C decreased and phase-shifted the translation component of Purkinje cell responses, but did not affect the tilt component. Our findings suggest that translation and tilt signals reach Purkinje cells via separate information pathways and that protein kinase C-dependent mechanisms regulate translation information processing in cerebellar cortex output neurons.

"Willow Branch" DNA Self-Assembly for Cancer Dual-Target and Proliferation Inhibition.

DNA nanotechnology is beginning to yield unique advantages in the area of drug delivery. For the dual-targeting and proliferation suppression of cancer cells, a "willow branch" DNA assembly based on rolling circle amplification (RCA) was built. Three single-stranded DNAs, including antibody modified cDNAs, aptamer cDNAs, and simple cDNAs, were employed in the DNA self-assembly, along with the RCA scaffolds (every 63 bases is a repeat unit). "Willow branch" DNA (WB DNA) assembly successfully linked multiple antibodies and aptamers together to achieve dual targeting of cancer cells. Binding of CD44 antibodies and S2.2 aptamers to receptors on the cell membrane inhibits both pathways, ß-catenin signaling and nuclear factor-kappa B-specific transcription activity, through feedback regulation. Results demonstrated that WB DNA assembly could effectively exert multivalency clustering cell-surface receptors, modulating signal pathways and inhibiting proliferation. This study proposes a new approach for cancer dual-target and proliferation inhibition by clustering multivalent receptors.

Tuning the structural stability and electrochemical properties in graphene anode materials by B doping: a first-principles study.

The first-principles method of density functional theory (DFT) is used to study the structural stability and electrochemical properties of B doped graphene with concentrations of 3.125%, 6.25% and 18.75% respectively, and their lithium storage mechanism and characteristics are further studied. The results show that the doped systems all have negative adsorption energy, indicating that the structures can exist stably, and the adsorption energy of lithium ions on graphene decreases with the increase of B doping concentration. Among them, the B6C26 structure has the lowest adsorption energy and can adsorb more lithium ions. The density of states indicates that doping with B can increase the conductivity of graphene greatly. Subsequently, the CI-NEB method to search for the transition state of the doped structure is used, showing that the B6C26 structure has the lowest diffusion barrier and good rate performance. Therefore, these findings provide a certain research foundation for the development and application of lithium-ion battery anode materials.

A Case for the Use of the 5-Item Modified Frailty Index in Preoperative Risk Assessment for Tissue Expander Placement in Breast Reconstruction.

BACKGROUND: Preoperative risk assessment is essential in determining which surgical candidates will have the most to gain from an operation. The 5-item modified frailty index (mFI-5) has been validated as an effective way to determine this risk. This study sought to evaluate the performance of the mFI-5 as a predictor of postoperative complications after tissue expander placement. METHODS: Patients who underwent placement of a tissue expander were identified using the 2012 to 2018 American College of Surgeons National Surgical Quality Improvement Project database. Univariate and multivariate regression analysis models were used to assess how mFI-5, the components of the mFI-5 (functional status, diabetes, chronic obstructive pulmonary disease, chronic heart failure, and hypertension), and other factors commonly used to risk stratify (age, body mass index [BMI], American Society of Anesthesiologists (ASA) classification, and history of smoking) were associated with complications. RESULTS: In 44,728 tissue expander placement cases, the overall complication rate was 10.5% (n = 4674). The mFI-5 score was significantly higher in the group that experienced complications (0.08 vs 0.06, P < 0.001). Compared with the mFI-5 individual components and other common variables used preoperatively to risk stratify patients, univariate analysis demonstrated that mFI-5 had the largest effect size (odds ratio [OR], 5.46; confidence interval [CI], 4.29-6.94; P < 0.001). After controlling for age, BMI, ASA classification, and history of smoking, the mFI-5 still remained the predictor of complications with the largest effect size (OR, 2.25; CI, 1.70-2.97; P < 0.001). In assessing specific complications, the mFI-5 is the independent predictor with the largest significant effect size for surgical dehiscence (OR, 12.76; CI, 5.58-28.18; P < 0.001), surgical site infection (OR, 6.68; CI, 4.53-9.78; P < 0.001), reoperation (OR, 5.23; CI, 3.90-6.99; P < 0.001), and readmission (OR, 4.59; CI, 3.25-6.45; P < 0.001) when compared with age, BMI, ASA class, and/or history of smoking alone. CONCLUSIONS: The mFI-5 can be used as an effective preoperative predictor of postoperative complications in patients undergoing tissue expander placement. Not only does it have the largest effect size compared with other historical perioperative risk factors, it is more predictive than each of its individual components.

Activity of preclinical and phase I clinical trial of a novel androgen receptor antagonist GT0918 in metastatic breast cancer.

PURPOSE: To evaluate GT0918, a 2nd-generation AR antagonist, for its AR down-regulation activity among breast cancer patients. METHODS: The effect of GT0918 on AR protein expression was evaluated in AR expression breast cancer cells and in breast cancer xenograft model. A 3 + 3 phase I dose-escalation study was launched in Peking University Cancer Hospital. The endpoints included dose finding, safety, pharmacokinetics, and antitumor activity. RESULTS: GT0918 was demonstrated to effectively suppress the expression of AR protein and the growth of AR-positive breast cancer tumors in mouse xenograft tumor models. All patients treated with GT0918 were at a QD dose-escalation of five dose levels from 100 to 500 mg. The most common treatment-related AEs of any grade were asthenia, anemia, decreased appetite, increased blood cholesterol, increased blood triglycerides, decreased white blood cell count, and increased low-density lipoprotein. Grade 3 AEs were fatigue (2 of 18, 11.1%), aspartate aminotransferase increase (1 of 18, 5.6%), alanine aminotransferase increase (1 of 18, 5.6%), and neutrophil count decrease (1 of 18, 5.6%). Clinical benefit rate (CBR) in 16 weeks was 23.1% (3/13). Among 7 AR-positive patients, 6 can evaluate efficacy, and 2 completed 23.5- and 25-cycle treatment, respectively (as of 2020/1/20). PK parameters showed a fast absorption profile of GT0918 in the single-dose study. GT0918 and its major metabolite reached steady-state serum concentration levels at day 21 after multiple dosing. CONCLUSION: GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC.

Large-Scale DNA Nanoarrays with a Controllable Fluorescence Switch Constructed by RCA Simplified Origami.

The manufacture of large-scale and highly ordered fluorescent assemblies has received more and more scientific attention in recent years. An ingenious and low-cost strategy for constructing large-scale DNA nanoarrays by rolling circle amplification (RCA) and a simplified DNA origami technique is proposed in this study. Thrombins are used to trigger the excitation of the fluorescent groups modified on the aptamer staple strands of nanoladders, which leads to the delicate construction of millimeter large-scale fluorescent nanoarrays, whose fluorescence intensity could be effectively regulated by the concentration of thrombin. The above fluorescent nanoarrays will generate a potential application value in the fields of biosensors, super-resolution imaging, and novel light-emitting devices.

Peptide-free Synthetic Nicotine Vaccine Candidates with α-Galactosylceramide as Adjuvant.

Peptides are generally needed as T-helper epitopes in nicotine vaccines to induce effective antibody responses, but the highly polymorphic property of major histocompatibility complex (MHC) molecules may limit opportunities of B cell to receive CD4+ T-cell help. Invariant natural killer T (iNKT) cells recognize lipid antigens presented by the nonpolymorphic CD1d molecule that is conserved in mammals to a great extent. iNKT cells also display some similar functions to conventional CD4+ T-helper cells, especially they license dendritic cells stimulate antibody isotype switching by B cells. Herein, α-galactosylceramide (αGalCer), a classical iNKT cell agonist, serves as an adjuvant in synthetic nicotine vaccine candidates absent of peptide or protein. Our study reveals that αGalCer displays better adjuvant activity than Pam3CSK4 (a commonly used lipopeptide TLR agonist). Remarkably, the covalent linker between the nicotine hapten and αGalCer is not critical. Self-assembly of the lipid-tailed nicotine and αGalCer into the liposome represents a structurally simple but immunologically effective way to develop nicotine vaccines. This is the first time to introduce the iNKT cell agonist as an adjuvant to an antidrug vaccine. This discovery may contribute to improving the efficacy of clinical candidate nicotine vaccines in the future.

Combination versus sequential paclitaxel plus gemcitabine as first-line chemotherapy for women with metastatic breast cancer: a prospective randomized phase II study.

PURPOSE: Paclitaxel (T) plus gemcitabine (G) is an active concomitant combination for the treatment of metastatic breast cancer (MBC). However, the efficacy of sequential administration of these two drugs is unclear. This randomized phase II study was conducted to evaluate the efficacy of T and G administered either as a concomitant or as a sequential regimen in patients with MBC. METHODS: Patients with MBC (n=66) were randomized to either receive 6 cycles of concomitant T and G or 4 cycles of T followed by 4 cycles of G, as first line chemotherapy. With no progression, the arms would switch to maintenance with paclitaxel. Progression free survival (PFS) was defined as the primary endpoint; secondary endpoints were the overall response rate (ORR), overall survival (OS), and toxicity. In total, 33 patients were randomized to the concomitant or sequential arms. Patient characteristics were well balanced. The median number of chemotherapy cycles was 6 for the concomitant arm and 8 for the sequential arm. RESULTS: No significant difference was observed in terms of PFS, ORR, and OS. Only 13 (39.4%) patients progressed in the sequential arm. Although there was no significant difference between the two arms (p=0.056),the sequential arm had a remarkable trend of longer PFS than the concomitant arm. Toxicities were manageable and similar in both arms.The incidence of neutropenia was significantly higher in the concomitant arm (90.9%) than in the sequential arm (60.6%). Grade 3 or 4 neutropenia was not significantly different between the two arms. CONCLUSIONS: Concomitant and sequential treatment with paclitaxel and gemcitabine had no significant difference in terms of PFS.

Combined peripheral natural killer cell and circulating tumor cell enumeration enhance prognostic efficiency in patients with metastatic triple-negative breast cancer.

OBJECTIVE: Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis. Circulating tumor cells (CTCs) are a promising predictor for breast cancer prognoses but their reliability regarding progression-free survival (PFS) is controversial. We aim to verify their predictive value in TNBC. METHODS: In present prospective cohort study, we used the Pep@MNPs method to enumerate CTCs in baseline blood samples from 75 patients with TNBC (taken at inclusion in this study) and analyzed correlations between CTC numbers and outcomes and other clinical parameters. RESULTS: Median PFS was 6.0 (range: 1.0-25.0) months for the entire cohort, in whom we found no correlations between baseline CTC status and initial tumor stage (P=0.167), tumor grade (P=0.783) or histological type (P=0.084). However, among those getting first-line treatment, baseline CTC status was positively correlated with ratio of peripheral natural killer (NK) cells (P=0.032), presence of lung metastasis (P=0.034) and number of visceral metastatic site (P=0.037). Baseline CTC status was predictive for PFS in first-line TNBC (P=0.033), but not for the cohort as a whole (P=0.118). This prognostic limitation of CTC could be ameliorated by combining CTC and NK cell enumeration (P=0.049). CONCLUSIONS: Baseline CTC status was predictive of lung metastasis, peripheral NK cell ratio and PFS in TNBC patients undergoing first-line treatment. We have developed a combined CTC-NK enumeration strategy that allows us to predict PFS in TNBC without any preconditions.

The Impacts of Cellulose on Volatile Fatty Acid Production and the Microbial Community in Anaerobic Fermentation of Sludge at High and Medium Temperatures.

During large-scale sewage treatment, a large amount of excessive sludge is produced, which will cause serious pollution in the environment. In recent years, anaerobic digestion technology has been widely promoted because it can achieve better sludge reduction, and the products and byproducts after anaerobic digestion can be fully utilized as resources. In this study, cellulose was added as the co-fermentation substrate during the fermentation process at 30 ℃ and 50 ℃ to enhance the production of VFAs. The result indicated that cellulose could significantly increase the yield of VFAs in both 30 ℃ and 50 ℃. Meanwhile, COD and reducing sugar generation in the fermentation process were also measure. Analysis of the microbial community structure at the class and genus levels revealed that the proportion of several genus closely related with cellulose degradation such as Cellvibrio, Fibrobacter, and Sporocytophaga were significantly increased with the addition of cellulose. Co-fermentation was recognized as an economic and environmental friendly strategy for sludge and other solid waste treatment. The analysis of the effect of cellulose as a substrate on the production of VFAs at high and medium temperatures is highly important for exploring ways to increase the production of VFAs in anaerobic fermentation.

Trastuzumab Biosimilar (HLX02), Pertuzumab Plus Chemotherapy in Patients with HER2-Positive Metastatic Breast Cancer after Progression of Trastuzumab: A Prospective, Phase II Study.

PURPOSE: This study aims to evaluate the efficacy and safety of trastuzumab biosimilar (HLX02) in combination with pertuzumab and chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) after progression of trastuzumab. MATERIALS AND METHODS: In this prospective, single-arm, phase II study, patients with HER2-positive MBC after progression of trastuzumab received pertuzuamb, HLX02, and chemotherapy in Beijing Cancer Hospital from March 2020 to December 2022. The primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov (NCT05188495). RESULTS: A total of 45 patients were included in this study. Twelve patients (26.7%) were treated in second-line and 33 patients (73.3%) were in third-line and later setting. Eighty percent and 15.5% patients had previously received pyrotinib/lapatinib and T-DM1, respectively. With a median follow-up of 24.4 months (range, 1.2 to 43.9 months), the median PFS was 7.6 months (95% confidence interval, 4.3 to 10.9), OS was not reached, the ORR was 31.1%, and DCR was 91.1%. The treatment was well tolerated. CONCLUSION: The combination of trastuzumab biosimilar HLX02, pertuzumab, and chemotherapy exhibited promising efficacy and a favorable safety profile as second- and beyond-line treatment in HER2-positive MBC.