Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling ...of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.
High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and ...2 inhibitor, would be active in BRCA wild-type disease.
In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0–2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA-mutated ovarian cancer cohort.
Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0–69·5) who had previously received a median of 5·0 (IQR 2·5–5·0) systemic therapies. Most patients (22 79%) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16–55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13–49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days IQR 4–8) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression.
Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease.
Intramural Research Program of the National Institutes of Health and National Cancer Institute.
Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 treatment has yielded clinical benefits in several ...types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that exosomes derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T-cell activity and promoting tumor growth. The abundance of PD-L1 on exosomes represented the quantity of PD-L1 expression on cell surfaces. Exosomes containing PD-L1 inhibited interferon-gamma (IFN-γ) secretion by Jurkat T cells. IFN-γ secretion was restored by PD-L1 knockout or masking on the exosomes. Both forced expression of PD-L1 on cells without PD-L1 and treatment with exosomes containing PD-L1 enhanced tumor growth in vivo. PD-L1 was present on exosomes isolated from the plasma of patients with non-small cell lung cancer, and its abundance in exosomes was correlated with PD-L1 positivity in tumor tissues. Exosomes can impair immune functions by reducing cytokine production and inducing apoptosis in CD8
T cells. Our findings indicate that tumor-derived exosomes expressing PD-L1 may be an important mediator of tumor immune escape.
Mesenchymal stem cells (MSCs) can protect against cartilage breakdown in osteoarthritis (OA) via their immunomodulatory capacities. However, the optimization strategy for using MSCs remains ...challenging. This study's objective was to identify the in vivo effects of metformin-stimulated adipose tissue-derived human MSCs (Ad-hMSCs) in OA. An animal model of OA was established by intra-articular injection of monosodium iodoacetate into rats. OA rats were divided into a control group and two therapy groups (treated with Ad-hMSCs or metformin-stimulated Ad-hMSCs). Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Our data show that metformin increased IL-10 and IDO expression in Ad-hMSCs and decreased high-mobility group box 1 protein, IL-1β, and IL-6 expression. Metformin increased the migration capacity of Ad-hMSCs with upregulation of chemokine expression. In cocultures, metformin-stimulated Ad-hMSCs inhibited the mRNA expression of RUNX2, COL X, VEGF, MMP1, MMP3, and MMP13 in IL-1β-stimulated OA chondrocytes and increased the expression of TIMP1 and TIMP3. The antinociceptive activity and chondroprotective effects were greater in OA rats treated with metformin-stimulated Ad-hMSCs than in those treated with unstimulated Ad-hMSCs. TGF-β expression in subchondral bone of OA joints was attenuated more in OA rats treated with metformin-stimulated Ad-hMSCs. Our findings suggest that metformin offers a promising option for the clinical application of Ad-hMSCs as a cell therapy for OA.
Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. ...Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations.
Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations.
Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5-16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7-72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8-18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response.
Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities.
ClinicalTrials.gov identifier: NCT02484404 .
Exceptional power conversion efficiency (PCE) of 25.7% in perovskite solar cells (PSCs) has been achieved, which is comparable with their traditional rivals (Si‐based solar cells). However, ...commercialization‐worthy efficiency and long‐term stability remain a challenge. In this regard, there are increasing studies focusing on the interface engineering in PSC devices to overcome their poor technical readiness. Herein, the roles of electrode materials and interfaces in PSCs are discussed in terms of their PCEs and perovskite stability. All the current knowledge on the factors responsible for the rapid intrinsic and external degradation of PSCs is presented. Then, the roles of carbonaceous materials as substitutes for noble metals are focused on, along with the recent research progress in carbon‐based PSCs. Furthermore, a sub‐category of PSCs, that is, flexible PSCs, is considered as a type of exceptional power source due to their high power‐to‐weight ratios and figures of merit for next‐generation wearable electronics. Last, the future perspectives and directions for research in PSCs are discussed, with an emphasis on their commercialization.
The roles of electrode materials and interfaces in perovskite solar cell (PSC) devices are discussed in terms of perovskite stability. The various factors responsible for rapid degradation in PSCs are provided. Then, the roles of carbonaceous materials for carbon‐based PSC as a substitute for noble metals are addressed, along with the recent progress.
Recent advances of plasmonic nanoparticles include fascinating developments in the fields of energy, catalyst chemistry, optics, biotechnology, and medicine. The plasmonic photothermal properties of ...metallic nanoparticles are of enormous interest in biomedical fields because of their strong and tunable optical response and the capability to manipulate the photothermal effect by an external light source. To date, most biomedical applications using photothermal nanoparticles have focused on photothermal therapy; however, to fully realize the potential of these particles for clinical and other applications, the fundamental properties of photothermal nanoparticles need to be better understood and controlled, and the photothermal effect‐based diagnosis, treatment, and theranostics should be thoroughly explored. This Progress Report summarizes recent advances in the understanding and applications of plasmonic photothermal nanoparticles, particularly for sensing, imaging, therapy, and drug delivery, and discusses the future directions of these fields.
Photothermally active plasmonic nanoparticles are of great interest in biomedical science due to their tunable resonance wavelength, high spatiotemporal resolution, photothermal therapeutic potential, and remote‐controllability by an external light source. Fundamentals in the design, synthesis, and properties of photothermal nanomaterials and the recent key advances in their biomedical applications, including in biosensors, imaging, therapy, drug delivery, and theranostics, are summarized and discussed.
The effect of combining various reinforcement materials, such as potassium titanate, Cu fiber, and steel fiber on the frictional and morphological properties of brake pads was investigated. The pad ...types were denoted as PT (with only potassium titanate), PC (with potassium titanate and Cu fiber), and PF (with potassium titanate and steel fiber). The PC pad exhibited the most stable coefficient of friction during repetitive braking across all the test temperatures. The PF pad exhibited a stable coefficient of friction below 250 °C, with unstable behavior at 300 °C. The surfaces of all three pads contained contact plateaus. The PC and PF pads showed primary and secondary contact plateaus, while the PT pad showed only primary contact plateaus.
•Potassium titanate, copper fiber, and steel fiber were used as reinforcements to prepare brake pads.•The brake pad with potassium titanate and Cu fiber (PC pad) showed the most stable coefficient of friction.•Brake pads with metal fibers exhibited primary and secondary contact plateaus.
Lessons Learned
Monotherapy with prexasertib demonstrated modest activity in BRCA wild‐type, recurrent triple‐negative breast cancer, highlighting the unmet need for combination treatment strategies.
...Neutropenia, anemia, and thrombocytopenia are common with the use of prexasertib but are manageable with supportive care measures. Prophylactic use of granulocyte colony stimulating factor should be considered to avoid dose reductions or treatment delays.
Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells.
Background
Cell cycle checkpoint kinase 1 (CHK1) is a major G2/M cell cycle regulator in tumors with p53 dysfunction, such as triple‐negative breast cancer (TNBC). We hypothesized the second‐generation CHK1 inhibitor, prexasertib, would yield clinical activity in sporadic TNBC.
Methods
This single arm, phase II trial evaluated prexasertib at 105 mg/m2 IV every 2 weeks in patients with metastatic/recurrent TNBC. The primary endpoint was overall response rate (ORR).
Results
All nine patients enrolled were germline BRCA wild‐type (BRCAwt) and had at least one prior treatment. One partial response (PR) was observed (ORR of 11.1%). Four patients experienced stable disease. The median progression‐free survival (PFS) was 86 days (range 17 to 159 days). Grade 3/4 treatment‐related adverse events included afebrile neutropenia (n = 8; 88.9%), anemia (n = 3; 33.3%), and thrombocytopenia (n = 1; 11.1%). Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells and demonstrated a decrease in activated/reinvigorated CD8 T cells; however, the one patient with a PR showed evidence of T‐cell recovery.
Conclusion
Prexasertib monotherapy had modest clinical efficacy in BRCAwt TNBC. Further studies of prexasertib in combination with other agents are needed.
Advanced Zn–air batteries (ZABs) with ultrahigh cycle life, which also harness energy with bifunctional electrochemical reactions, are significantly challenging for the commercialization of ...hybrid/electric vehicles and wearable electronics. Herein, we demonstrated robust aqueous and flexible ZABs with novel three-dimensional dual-linked hexaiminobenzene metal–organic framework (Mn/Fe-HIB-MOF)-based bifunctional oxygen electrocatalysts and superionic functionalized bio-cellulose electrolytes (64 mS cm −1 ). The well-defined quintet-shelled hollow sphere MOFs possess a hierarchical porous structure, excellent packing density with a surface area of 2298 m 2 g −1 , and chemical stability as compared to conventional MOFs. Mn/Fe-HIB-MOF exhibited superior bifunctional oxygen electrocatalytic activity (0.627 V) with half-wave potential (0.883 V) for oxygen reduction and overpotential (280 mV@10 mA cm −2 ) for oxygen evolution reactions, outperforming commercial Pt/C and RuO 2 . Their favorable oxygen reactions and surface electronic structures were confirmed by density functional theory. Significantly, the Mn/Fe-HIB-MOF cathode demonstrated the highest lifetimes reported to date for rechargeable ZABs, namely 1000 h (0.75 V voltage gap@10 mA cm −2 ) over 6000 cycles and 600 h (efficiency ∼65.24%@25 mA cm −2 ) over 3600 cycles with excellent flexibility for liquid and all-solid-state flexible ZABs, respectively. These promising results illustrate the great potential of these novel hexaiminobenzene MOFs and superionic bio-cellulose membranes for the commercial implementation of rechargeable ZABs.
PDF
