Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and ...select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients.
We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes.
CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival.
This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments.
ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.
Membrane fouling especially organic fouling of nanofiltration (NF) membranes is notorious but yet remains not fully understood. This study was conducted to identify the key organic substances ...responsible for organic fouling and quantify the individual and interactive effects of these key foulants on organic fouling, primarily by using statistical methods. A total of ten different water, covering lake water and water collected from water and wastewater treatment plants, were filtered to obtain the fouling potential and determined for organic and inorganic components. Pearson correlation showed that fouling potential could correlate with TOC with a moderate significance. Partial correlation revealed that, in addition to polysaccharides and protein-like substances, fulvic acid-like substances could act as key foulants to organic fouling of NF membranes, though protein-like and fulvic-like substances were mutually highly correlated. Generally, most polysaccharides were macromolecules (>10 kDa) while protein-like and fulvic acid-like substances were more of low molecular weight. A regression equation was established between fouling potential and the three types of key foulants; the calculated value by this equation matched well with the experimental result especially when the fouling potential was relatively high. Variance partitioning analysis showed that individual contributions to organic fouling by polysaccharides, protein-like and fulvic acid-like substances were all lower than 30%, while the interactive effect among these three components was as high as 66% ± 7%. This suggested that organic fouling was a complex process with the three key types of foulants involved simultaneously. Spearman correlation showed that higher contents of polysaccharides and protein-like substances in feed water generally led to a faster accumulation of these two types of foulants (determined from FTIR results) onto membrane, respectively, but not necessarily resulted in a heavier organic fouling.
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•Research highlights:•Statistical methods were adopted to elucidate organic fouling of nanofiltration membranes.•Polysaccharides, protein-like and fulvic acid-like substances were the key foulants.•Interactive contribution to organic fouling among the key foulants was predominant.•A higher foulant concentration in feed water generally led to a more accumulation on membrane.
Abstract Purpose To perform a systematic review and meta-analysis to compare the clinical outcomes and toxicity of hepatocellular carcinoma (HCC) patients treated with charged particle therapy (CPT) ...with those of individuals receiving photon therapy. Methods We identified relevant clinical studies through searching databases. Primary outcomes of interest were overall survival (OS) at 1, 3, 5 years, progression-free survival (PFS), and locoregional control (LC) at longest follow-up. Results 73 cohorts from 70 non-comparative observational studies were included. Pooled OS was significantly higher at 1, 3, 5 years for CPT than for conventional radiotherapy (CRT) relative risk (RR) 1·68, 95% CI 1·22–2·31; p < 0·001; RR 3.46, 95% CI: 1.72–3.51, p < 0.001; RR 25.9, 95% CI: 1.64–408.5, p = 0.02; respectively. PFS and LC at longest follow-up was also significantly higher for CPT than for CRT ( p = 0·013 and p < 0.001, respectively), while comparable efficacy was found between CPT and SBRT in terms of OS, PFS and LC at longest follow-up. Additionally, high-grade acute and late toxicity associated with CPT was lower than that of CRT and SBRT. Conclusion Survival rates for CPT are higher than those for CRT, but similar to SBRT in patients with HCC. Toxicity tends to be lower for CPT compared to photon radiotherapy.
Exosomal microRNAs (miRNAs) have been suggested to participate in the pathogenesis of neuropsychiatric diseases, but their role in major depressive disorder (MDD) is unknown. We performed a ...genome-wide miRNA expression profiling of blood-derived exosomes from MDD patients and control subjects and revealed the top differentially expressed exosomal miRNA, i.e. hsa-miR-139-5p (upregulation), had good performance to differentiate between MDD patients and controls. Tail vein injection of blood exosomes isolated from MDD patients into normal mice caused their depressive-like behaviors as determined by the forced swimming, tail suspension, and novelty suppressed feeding tests, and injection of blood exosomes isolated from healthy volunteers into unpredictable mild stress (CUMS)-treated mice alleviated their depressive-like behaviors. CUMS mice also showed significantly increased blood and brain levels of exosomal miR-139-5p. Furthermore, the depressive-like behaviors in CUMS-treated mice were rescued by intranasal injection of miR-139-5p antagomir, suggesting that increased exosomal miR-139-5p levels may mediate stress-induced depression-like behavior in mice. Both exosome treatment and miR-139-5p antagomir treatment increased hippocampal neurogenesis in the CUMS-treated mice, and treatment of exosome from MDD patients decreased hippocampal neurogenesis in the normal mice. The role of miR-139-5p in neurogenesis was validated by in vitro experiments, demonstrating that miR-139-5p is a negative regulator for neural stem cell proliferation and neuronal differentiation. Our findings together suggest that exosomes from patients with major depression caused depressive-like behaviors in mice with involvement of miR-139-5p-regulated neurogenesis. Therefore, exosomal miRNAs are promising targets for the diagnosis and treatment of MDD.
Aims
To evaluate the association between glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and the risk of bone fracture in patients with type 2 diabetes mellitus (T2DM).
Materials and methods
We ...conducted a systematic literature search in PubMed, Embase, the Cochrane Library, and Web of Science from inception to 28 February 2018 and identified eligible randomized controlled trials. The following data were extracted from each study: first author, year of publication, sample size, patient characteristics, study design, intervention drug, control drug, follow‐up time, and incident bone fracture events. A meta‐analysis was conducted using Review Manager 5.3 software to calculate the odds ratio (OR) and 95% confidence intervals (CI) for dichotomous variables.
Results
A total of 38 studies with 39 795 patients with T2DM were included. There were 241 incident bone fracture cases (107 in the GLP‐1 RAs group and 134 in the control group). Compared with patients who received placebo and other anti‐diabetic drugs, those who received GLP‐1 RAs treatment showed a pooled OR of 0.71 (95% CI, 0.56‐0.91) for bone fracture. Subgroup analysis showed that treatments with liraglutide and lixisenatide were associated with significantly reduced risk of bone fractures (ORs, 0.56; 95% CI, 0.38‐0.81 and 0.55; 95% CI, 0.31‐0.97, respectively). However, other GLP‐1 RAs did not show superiority to placebo or other anti‐diabetic drugs. Moreover, these beneficial effects were dependent on the duration of GLP‐1 RAs treatment, only a GLP‐1 RAs treatment period of more than 52 weeks could significantly lower the risk of bone fracture in patients with T2DM (OR, 0.71; 95% CI, 0.56‐0.91).
Conclusions
Compared with placebo and other anti‐diabetic drugs, liraglutide and lixisenatide were associated with a significant reduction in the risk of bone fractures, and the beneficial effects were dependent on the duration of treatment.
Activated B cells contribute to heart diseases, and inhibition of B‐cell activating factor (BAFF) expression is an effective therapeutic target for heart diseases. Whether activated B cells ...participate in the development and progression of hyperthyroid heart disease, and what induces B cells activation in hyperthyroidism are unknown. The present study aimed to determine the roles of BAFF overexpression induced by high concentrations of triiodothyronine (T3) in the pathogenesis of hyperthyroid heart disease. Female C57BL/6J mice were subcutaneously injected with T3 for 6 weeks, and BAFF expression was inhibited using shRNA. Protein and mRNA expression of BAFF in mouse heart tissues evaluated via immunohistochemistry, western blotting and polymerase chain reaction (PCR). Proportions of B cells in mouse cardiac tissue lymphocytes were quantified via flow cytometry. Morphology and left ventricle function were assessed using pathological sections and echocardiography, respectively. Here, we demonstrate that compared with the control group, the proportion of myocardial B cells was larger in the T3 group; immunohistochemistry, western blotting and PCR analyses revealed increased protein and mRNA expression levels of TNF‐α and BAFF in heart tissues of the T3 group. Compared with the normal controls group, in the T3 group, the diameter of myocardial cells and some echocardiographic values significantly increased and hypertrophy and structural disorder were noticeable. Our results revealed that elevated levels of circulating T3 can promote the expression of BAFF in myocardial cells and can lead to B‐cell activation, an elevated inflammatory response and ventricular remodelling.
Abstract
Context
Regulatory T cell (Treg) dysfunction plays an important role in the development and progression of Graves’ disease (GD). Programmed cell death 1 (PD-1) prompts FoxP3 in Treg ...expression and enhances the suppressive activity of Tregs. Whether abnormal expression of PD-1 contributes to the breakdown of Tregs and the role of thyroid hormone in the PD-1 expression of Tregs in GD remain substantially undefined.
Objective
To evaluate the role of PD-1 in Treg function and triiodothyronine (T3) in PD-1 expression in patients with GD and mice treated with T3.
Methods
We recruited 30 patients with GD and 30 healthy donors. PD-1 expression in Tregs and Treg function were determined. To evaluate the effects of thyroid hormone on PD-1 expression in Tregs, we used T3 for the treatment of human peripheral blood mononuclear cells (PBMCs). We then treated mice with T3 to confirm the effect of thyroid hormone on PD-1 expression in Tregs and Tregs function in vivo.
Results
PD-1 expression in Tregs and the suppressive function of Tregs significantly decreased in patients with GD. T3 reduced PD-1 expression in human Tregs in a concentration- and time-dependent manner in vitro. High levels of circulating T3 reduced PD-1 expression in Tregs, impaired Treg function, and disrupted T-helper cell (Th1 and Th2) balance in mice treated with T3.
Conclusion
Treg dysfunction in GD patients might be due to downregulation of PD-1 expression in Tregs induced by high levels of serum T3.
ObjectiveCurrently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with ...acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice.DesignA capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models).ResultsThe constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process.ConclusionOne-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.
MK-8776 is a recently described inhibitor that is highly selective for checkpoint kinase 1 (Chk1), which can weaken the DNA repair capacity in cancer cells to achieve chemo-sensitization. A number of ...studies show that MK-8776 enhances the cytotoxicity of hydroxyurea and gemcitabine without increasing normal tissue toxicities. Thus far, there is no evidence that MK-8776 can be used as a radiotherapy sensitization agent. In this study, we investigated the effects of MK-8776 on the radiosensitivity of 3 human triple-negative breast cancer (TNBC) cell lines MDA-MB-231, BT-549 and CAL-51. MK-8776 dose-dependently inhibited the proliferation of MDA-MB-231, BT-549 and CAL-51 cells with IC
values of 9.4, 17.6 and 2.1 μmol/L, respectively. Compared with irradiation-alone treatment, pretreatment with a low dose of MK-8776 (100-400 nmol/L) significantly increased irradiation-induced γH2A.X foci in the 3 TNBC cell lines, suggesting enhanced DNA damage by MK-8776, inhibited the cell proliferation and increased the radiosensitivity of the 3 TNBC cell lines. Similar results were obtained in MDA-MB-231 xenograft tumors in nude mice that received MK-8776 (15 or 40 mg/kg, ip) 26 d after irradiation. To explore the mechanisms underlying the radio-sensitization by MK-8776, we used TEM and found that irradiation significantly increased the numbers of autophagosomes in the 3 TNBC cell lines. Moreover, irradiation markedly elevated the levels of Atg5, and promoted the transformation of LC3-I to LC3-II in the cells. Pretreatment with the low dose of MK-8776 suppressed these effects. The above results suggest that MK-8776 increases human TNBC radiosensitivity by inhibiting irradiation-induced autophagy and that MK-8776 may be a potential agent in the radiosensitization of human TNBC.
Fifteen constituents, including one new lignan (schisandroside E) and one new terpenoid (schisandenoid A) as well as nine known lignans and four known terpenoids, were isolated from Schisandra ...chinensis leaves. The structures of schisandroside E and schisandenoid A were established by entirely meticulous spectroscopic analysis (NMR, MS, CD, IR and UV). All compounds were tested for cytotoxicity against MGC‐803, Caco‐2 and Ishikawa cell lines. Some compounds showed strong cytotoxicity against these three cancer cell lines with IC50<1 μm.
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