Case report: The effective response to pembrolizumab in combination with bevacizumab in the treatment of a recurrent glioblastoma with multiple extracranial metastases.

Multiple extracranial metastases of recurrent glioblastoma are rare and often indicate a very poor prognosis. The main conventional treatments are chemotherapy, radiotherapy, chemoradiotherapy or antiangiogenic therapy. Median overall survival is 2.3 to 6 months after the detection of extracranial metastases, and to date, there is no effective treatment for these patients. Herein, we report a recurrent glioblastoma patient with lung metastasis treated with a combination therapy containing bevacizumab and pembrolizumab due to overexpression of PD-L1 and the absence of driver mutations. The progression-free survival was 11 months from lung metastases to bone metastases. This combination treatment was further used as maintenance therapy for another 11 months after bone metastasis and secondary dorsal metastasis because there was no suitable treatment alternative. The overall survival was 27 months after lung metastases, which is much longer than previously reported cases. To our knowledge, this was the first effective use of bevacizumab plus pembrolizumab in a glioblastoma patient with extracranial metastases. Furthermore, this was the first time that bevacizumab plus pembrolizumab was used as a maintenance treatment in glioblastoma, with 11 months of response. Importantly, we showed that such combination therapy may be a novel and effective therapy for glioblastoma patients with extracranial metastases.

Rapid subcutaneous progression after immunotherapy in pretreated patients with metastatic carcinoma: two case reports.

There is heterogeneity in cancer patients' responses to immune checkpoint inhibitors (ICIs), including hyperprogression, which is very rapid tumor progression following immunotherapy, and pseudoprogression, which is an initial increase followed by a decrease in tumor burden or in the number of tumor lesions. This heterogeneity complicates clinical decisions because either premature withdrawal of the treatment or prolonged ineffective treatment harms patients. We presented two patients treated with ICIs with heterogeneous responses. One patient had Merkel cell carcinoma in the right thigh, and the other had nasopharyngeal squamous carcinoma. The first patient was treated with sintilimab and the second with sintilimab combined with abraxane. In the first patient, subcutaneous lesions grew substantially after the first cycle of treatment with sintilimab. In the second patient, subcutaneous lesions grew gradually after the second cycle of treatment with sintilimab combined with abraxane. In both cases, biopsy examination confirmed that newly emerged lesions were metastases of the primary tumor. These two cases remind clinicians that when subcutaneous nodules appear after treatment with ICIs, pathological biopsy is needed to determine the nature-pseudoprogression or rapid progression-of the disease course.

An Integrated Pan-Cancer Analysis of ADAMTS12 and Its Potential Implications in Pancreatic Adenocarcinoma.

Background: A Disintegrin and Metallopeptidase with Thrombospondin Type 1 Motif 12 (ADAMTS12), a member of the ADAMTS family of multidomain extracellular protease enzymes, is involved in the progression of many tumors. However, a pan-cancer analysis of this gene has not yet been performed. Its role in pancreatic adenocarcinoma (PAAD) also remains unclear. Methods: The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression data (GTEx) databases were used to analyze ADAMTS12 expression in pan-cancer. We assessed the expression, clinical characteristics, prognostic significance, copy number alteration, methylation, and mutation of ADAMTS12 and its correlation with the tumor immune microenvironment. qRT-PCR and immunohistochemistry assays were also performed to validate the expression of ADAMTS12 in PAAD. Results: Through bioinformatics analysis and preliminary experimental verification, ADAMTS12 was found to be substantially overexpressed in PAAD. High expression level of ADAMTS12 was correlated with worse survival rates in patients with PAAD and high infiltration levels of tumor-associated macrophages, cancer-associated fibroblasts, immune checkpoint proteins, and immunosuppressive genes. Conclusion: Our findings suggest ADAMTS12 as a potential prognostic biomarker in PAAD. Elevated ADAMTS12 expression may also indicate an immunosuppressive microenvironment.

Smartphone Sensing of Road Surface Condition and Defect Detection.

Road surface condition is vitally important for road safety and transportation efficiency. Conventionally, road surface monitoring relies on specialised vehicles equipped with professional devices, but such dedicated large-scale road surveying is usually costly, time-consuming, and prohibitively difficult for frequent pavement condition monitoring-for example, on an hourly or daily basis. Current advances in technologies such as smartphones, machine learning, big data, and cloud analytics have enabled the collection and analysis of a great amount of field data from numerous users (e.g., drivers) whilst driving on roads. In this regard, we envisage that a smartphone equipped with an accelerometer and GPS sensors could be used to collect road surface condition information much more frequently than specialised equipment. In this study, accelerometer data were collected at low rate from a smartphone via an Android-based application over multiple test-runs on a local road in Ireland. These data were successfully processed using power spectral density analysis, and defects were later identified using a k-means unsupervised machine learning algorithm, resulting in an average accuracy of 84%. Results demonstrated the potential of collecting crowdsourced data from a large population of road users for road surface defect detection on a quasi-real-time basis. This frequent reporting on a daily/hourly basis can be used to inform the relevant stakeholders for timely road maintenance, aiming to ensure the road's serviceability at a lower inspection and maintenance cost.

Uniform decoration of UiO-66-NH2 nanooctahedra on TiO2 electrospun nanofibers for enhancing photocatalytic H2 production based on multi-step interfacial charge transfer.

Metal-organic framework (MOF) materials have been extensively incorporated with inorganic semiconductor photocatalysts to improve their photocatalytic activity through an efficient charge transfer process across their heterointerface. In this work, octahedral UiO-66-NH2 MOFs with edge-lengths of 110-330 nm are uniformly decorated on the surface of TiO2 electrospun nanofibers by a traditional solvothermal method combined with activation pretreatment. Before the solvothermal growth of UiO-66-NH2, the TiO2 electrospun nanofibers were activated in NaOH solution to etch the TiO2 surface for allowing the exposure of lattice oxygen. The exposed lattice oxygen on the TiO2 surface could interact with the MOF precursor of Zr4+ ions, thus enabling octahedral UiO-66-NH2 to grow uniformly on the surface of TiO2 nanofibers with an intimate Ti-O-Zr hetero-interface. Such an intimate hetero-interface provides an effective channel for boosting the electron transfer between UiO-66-NH2 and TiO2 in their heterostructure. Thus, the UiO-66-NH2/TiO2(anatase) heterostructures exhibited enhanced photocatalytic activity for H2 production as compared to either TiO2(anatase) nanofibers or UiO-66-NH2 nanooctahedra in the presence of Rhodamine B (RhB) as a sensitizer under visible light irradiation. In particular, the decoration of UiO-66-NH2 nanooctahedra on anatase/rutile mixed TiO2 nanofibers could induce further enhancement of the photocatalytic H2 production. The enhanced photocatalytic activity is attributed to the multi-step continuous interfacial transfer of photoinduced electrons with the way of RhB → UiO-66-NH2 → TiO2(anatase) → TiO2(rutile).

Prognostic Significance of Red Cell Distribution Width in Advanced Non-Small Cell Lung Cancer Patients.

BACKGROUND: Red blood cell distribution width (RDW) is a parameter reported in blood routine examination, and has been reported as an inflammatory biomarker. The objective of this study was to investigate the significance of RDW in NSCLC patients with EGFR mutations. METHODS: The clinical data of 102 patients with NSCLC who underwent radical resection surgery in the First Affiliated Hospital of Wenzhou Medical University from December 2012 to November 2017 were collected. Kaplan-Meier survival analysis and Cox proportional hazard models were used to examine the effect of RDW on survival. RESULTS: The RDW levels were divided into two groups: high RDW (≥ 13.1%), n = 47 vs. low RDW, n = 55 (< 13.1%). Univariate analysis showed that there were significant associations of high RDW values with smoking history and brain metastasis. Forty-seven patients with elevated RDW levels had shorter progression-free survival (PFS) than 55 patients with normal RDW levels (264 vs. 310 days, p = 0.039). CONCLUSIONS: RDW is associated with several factors that reflect inflammation and malnutrition in lung cancer patients. Moreover, high levels of RDW are associated with poor survival.

Nivolumab plus regorafenib in patients with small bowel adenocarcinoma: A case report.

INTRODUCTION: Small bowel adenocarcinomas (SBAs) are rare cancers that have a distinct clinical characteristic and genetic profile. The only potentially curative treatment for localized SBAs is surgery, and treatment options are limited for patients in the advanced stage of disease. PATIENT CONCERNS: A 39-year-old woman presented in October 2015 with a complaint of persistent vomiting for 8 months. DIAGNOSIS: The patient had obstruction caused by a 3 × 2 cm mass at the ascending part of the duodenum and suspected metastasis in the right adnexal region. Postoperative pathology showed a moderately differentiated adenocarcinoma with serosal invasion. The diagnosis was stage IV duodenum adenocarcinoma with right adnexal metastasis. INTERVENTIONS: After the failure of multi-line treatment with chemotherapy and targeted therapy, she was treated with the immune checkpoint inhibitor nivolumab plus regorafenib. OUTCOMES: Disease control lasted for 15 months with markedly improved symptoms. CONCLUSION: To the best of our knowledge, this is the first case of small bowel adenocarcinoma that has been treated with nivolumab combined with regorafenib. This case highlights the potential efficacy of combining nivolumab and regorafenib in the treatment of SBAs.

Successful Treatment of Patients with Refractory High-Grade Serous Ovarian Cancer with GOPC-ROS1 Fusion Using Crizotinib: A Case Report.

BACKGROUND: Recently, multiple poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated excellent efficacy among patients with ovarian cancer with or without BRCA mutations. However, alternative therapeutic options are urgently required for patients who cannot benefit from conventional chemotherapy or PARP inhibitors. CASE PRESENTATION: A patient with high-grade serous ovarian carcinoma presented to our clinic after developing resistance to chemotherapy. Paired tumor-normal next-generation sequencing (NGS) was performed using peripheral blood to identify potential actionable mutations. NGS revealed the patient harboring a GOPC-ROS1 fusion, which was subsequently verified using a reverse transcription polymerase chain reaction assay. No germline or somatic mutation in BRCA1/2 or mismatch repair genes was detected. Therefore, the patient received crizotinib treatment. A rapid, favorable clinical response (partial response at 1 month) was observed, with further pathological response monitored and evaluated in follow-up interrogation. CONCLUSION: This study suggested that crizotinib was an off-the-shelf, practical, and ostensibly effective treatment option for patients with ovarian cancer with ROS1 rearrangement. NGS-based genetic testing may guide to plan therapeutic paradigms, and render precision medicine promising in ovarian cancer treatment. IMPLICATIONS FOR PRACTICE: Despite the previous report of ROS1 fusion in patients with ovarian cancer, it remains unknown whether patients can benefit from targeted therapeutic drugs. This study reports a GOPC-ROS1 fusion identified by next-generation sequencing in a patient with chemotherapy-resistant ovarian cancer. The patient was administered crizotinib and showed rapid, remarkable response. This study suggests that comprehensive sequencing should be offered for patients with ovarian cancer without effective therapeutic strategies, and crizotinib can be used to treat ROS1-rearranged ovarian carcinomas.

Synthesis and high pressure studies of white luminescence host-guest complex nanocrystals based on C60 and p-But-calix[8]arene.

Host-guest structured nanocrystals consisting of p-But-calix[8]arene and fullerene C60 were fabricated with the facial solution deposition method. The as-prepared host-guest complex nanocrystals are well crystallized in a tetragonal structure, in which the guest C60 and host p-But-calix[8]arene molecules interact with each other via the van der Waals force. The host-guest crystal has a wider band gap compared to that of C60 crystals. The luminescence range of the host-guest structured nanocrystals was widely extended, and its photoluminescence (PL) intensity was highly enhanced by one order of magnitude. High pressure studies on such host-guest nanocrystals were carried out using the diamond anvil cell technique with the associated spectroscopic measurements. Raman and PL spectra show a phase transition occurred on the samples owing to the deformation of fullerene molecules. A PL behavior change was also observed synchronously with the phase transition. The host-guest structure strongly influences the structure and optical behaviors of C60 under pressure.

Endoplasmic reticulum Ca2+ release causes Rieske iron-sulfur protein-mediated mitochondrial ROS generation in pulmonary artery smooth muscle cells.

Mitochondrial reactive oxygen species (ROS) cause Ca2+ release from the endoplasmic reticulum (ER) via ryanodine receptors (RyRs) in pulmonary artery smooth muscle cells (PASMCs), playing an essential role in hypoxic pulmonary vasoconstriction (HPV). Here we tested a novel hypothesis that hypoxia-induced RyR-mediated Ca2+ release may, in turn, promote mitochondrial ROS generation contributing to hypoxic cellular responses in PASMCs. Our data reveal that application of caffeine to elevate intracellular Ca2+ concentration ([Ca2+]i) by activating RyRs results in a significant increase in ROS production in cytosol and mitochondria of PASMCs. Norepinephrine to increase [Ca2+]i due to the opening of inositol 1,4,5-triphosphate receptors (IP3Rs) produces similar effects. Exogenous Ca2+ significantly increases mitochondrial-derived ROS generation as well. Ru360 also inhibits the hypoxic ROS production. The RyR antagonist tetracaine or RyR2 gene knockout (KO) suppresses hypoxia-induced responses as well. Inhibition of mitochondrial Ca2+ uptake with Ru360 eliminates N- and Ca2+-induced responses. RISP KD abolishes the hypoxia-induced ROS production in mitochondria of PASMCs. Rieske iron-sulfur protein (RISP) gene knockdown (KD) blocks caffeine- or NE-induced ROS production. Taken together, these findings have further demonstrated that ER Ca2+ release causes mitochondrial Ca2+ uptake and RISP-mediated ROS production; this novel local ER/mitochondrion communication-elicited, Ca2+-mediated, RISP-dependent ROS production may play a significant role in hypoxic cellular responses in PASMCs.

P27 Promotes TGF-ß-Mediated Pulmonary Fibrosis via Interacting with MTORC2.

Pulmonary fibrosis (PF), a progressive and life-threatening pulmonary disease, is the main pathological basis of interstitial lung disease (ILD) which includes the idiopathic pulmonary fibrosis (IPF). No effective therapeutic strategy for pulmonary fibrosis has been established. TGF-ß signaling has emerged as the vital regulator of PF; however, the detailed molecular mechanisms of TGF-ß in PF were uncertain. In the present study, we proved that inhibition of MTORC2 suppresses the expression of P27 in MRC5 and HLF cells. And in bleomycin-induced PF model, the expression of α-SMA and P27 was upregulated. Moreover, TGF-ß application increased the level of α-SMA, vimentin, and P27 in MRC5 and HLF cells. Furthermore, P27 overexpression advanced the cell cycle process and promoted the proliferation of MRC5 and HLF cells. Finally, the rescue experiment showed that MTORC2 knockdown reversed P27 overexpression-induced cell cycle acceleration and proliferation. Thus, our results suggest that P27 is involved in TGF-ß-mediated PF, which was regulated by MTORC2, providing a novel insight into the development of PF.

High-Efficiency Cryo-Thermocells Assembled with Anisotropic Holey Graphene Aerogel Electrodes and a Eutectic Redox Electrolyte.

Thermocells, capable of converting temperature-dependent electrochemical redox potentials into electrical power, can harvest waste or low-grade heat in an economical and continuous approach with zero carbon emission. However, the power density and conversion efficiency of thermocells are hindered by a narrow operation window and low ion conductivity of the electrodes, especially in freezing weather conditions. Herein, highly efficient cylindrical thermocells, working in a wide operation window of cold temperatures, are developed. A eutectic electrolyte consisting of formamide and water is formulated with a high ion conductivity, which is retained at a significantly extended lower limit of the operation window from conventional 0 to -40 °C. In parallel, an electrode material based on anisotropic holey graphene aerogel is synthesized with improved ion conductivity, especially at temperatures below 0 °C, due to its aligned graphene sheets and pores. By taking the advantages of both components, the power density and the Seebeck coefficient of a single-cylinder thermocell reaches an exceptionally high value, i.e., 3.6 W m-2 and 1.3 mV K-1 , respectively. Moreover, assembled thermocells in series packaging substantially enhance the voltage of the open-circuit, i.e., from 140 mV (1-cylinder thermocell) to 2.1 V (15-cylinder thermocells).

Multiresponsive Graphene-Aerogel-Directed Phase-Change Smart Fibers.

Wearable devices and systems demand multifunctional units with intelligent and integrative functions. Smart fibers with response to external stimuli, such as electrical, thermal, and photonic signals, etc., as well as offering energy storage/conversion are essential units for wearable electronics, but still remain great challenges. Herein, flexible, strong, and self-cleaning graphene-aerogel composite fibers, with tunable functions of thermal conversion and storage under multistimuli, are fabricated. The fibers made from porous graphene aerogel/organic phase-change materials coated with hydrophobic fluorocarbon resin render a wide range of phase transition temperature and enthalpy (0-186 J g-1 ). The strong and compliant fibers are twisted into yarn and woven into fabrics, showing a self-clean superhydrophobic surface and excellent multiple responsive properties to external stimuli (electron/photon/thermal) together with reversible energy storage and conversion. Such aerogel-directed smart fibers promise for broad applications in the next-generation of wearable systems.

Investigate on Structure and Optical Properties of ZnO Nanostructures Grown on a-GaN/r-Sapphire.

ZnO nanostructures were directly grown on a-GaN/r-sapphire with different growth time via aqueous method. Structural and optical properties of the nanostructures were investigated by using a variety of techniques including X-ray diffraction (XRD), scan electron microscope (SEM), room-temperature photoluminescence (PL), and Raman scattering. The results showed the growth mechanism of ZnO nanostructures grown on a-GaN is Volmer-Weber (VW) mode, which is due to the high interfacial free-energy between a-plane ZnO and GaN. Meanwhile, compressive strains were revealed to exist by the optical characterizations. And the strengths were found to reduce with increasing growth time.

Two Highly Stable Luminescent Lead Phosphonates Based on Mixed Ligands: Highly Selective and Sensitive Sensing for Thymine Molecule and VO3 - Anion.

Two luminescent lead phosphonates with two-dimensional (2D) layer and three-dimensional (3D) framework structure, namely, Pb3[(L1)2(Hssc)(H2O)2] (1) and [Pb2(L2)0.5(bts)(H2O)2]·H2O (2) (H2L1 = O(CH2CH2)2NCH2PO3H2, H4L2 = H2PO3CH2NH(C2H4)2NHCH2PO3H2, H3ssc = 5-sulfosalicylic acid, NaH2bts = 5-sulfoisophthalic acid sodium) have been prepared via hydrothermal techniques. The two compounds not only show excellent thermal stability but also remain intact in aqueous solution within an extensive pH range. Moreover, the atomic absorption spectroscopy analysis experiment indicates that there does not exist the leaching of Pb2+ ions from the lead phosphonates, which show they are nontoxic in aqueous solution. In compound 1, the Pb(1)O4, Pb(2)O7, Pb(3)O4, and CPO3 polyhedra are interlinked into a one-dimensional chain, which is further connected to adjacent chain by sharing the Hssc2- to form a 2D layer. Interestingly, compound 1 as a highly selective and sensitive luminescent material can be used to detect the thymine molecule with a very low detection limit of 8.26 × 10-7 M. In compound 2, the Pb(1)O6 and Pb(2)O5 polyhedra are interlinked into a dimer via edge sharing, which is further connected to adjacent dimer to form a tetramer via corner sharing, and such a tetramer is then interlinked into a 2D layer through bts3- ligands; the adjacent 2D layers are finally constructed to a 3D structure by sharing the L2 4- ligand. Compound 2 can be applied as an excellent luminescent sensor for sensing of VO3 - anion. Furthermore, the probable fluorescent quenching mechanisms of the two compounds have also been studied.

Terbium Oxalatophosphonate as Efficient Multiresponsive Luminescent Sensors for Chromate Anions and Tryptophan Molecules.

A stable 2D terbium oxalatophosphonate with green luminescence, namely, [Tb2(H3L)(C2O4)3(H2O)4]·2H2O (1), has been hydrothermally obtained by using (4-carboxypiperidyl)-N-methylenephosphonic acid (H3L) and oxalate ligand. The luminescent investigation indicates that the emission behavior of compound 1 shows high water and pH stabilities. It can be applied as a multiresponsive luminescent probe with high selectivity, high sensitivity, recycling capability, and fast sensing of CrO4 2-, Cr2O7 2- anions and tryptophan (Trp) molecules in aqueous solution through the luminescence quenching effect. Moreover, the sensing results can be distinguished by the naked eye under the irradiation of UV light of 254 nm. In addition, the probable mechanisms for the quenching behavior are also discussed, which can be mainly attributed to the competitive absorption of excitation energy between compound 1 and the analytes.

Efficacy and safety of bevacizumab treatment for refractory brain edema: Case report.

OBJECTIVE: This retrospective study investigated the efficacy and safety of bevacizumab treatment for refractory brain edema. METHODS: Between March 2009 and December 2015, bevacizumab was used to treat 59 cases of brain metastatic patients with refractory brain edema. The median dose of bevacizumab was 4.68 mg/kg (range 2.8-6.52 mg/kg). The clinical-pathological data, the efficacy, and the side effects of bevacizumab were recorded. Magnetic resonance imaging (MRI) was performed before and after bevacizumab treatment. Tumor and edema volumes were measured separately. RESULTS: The clinical symptoms of 50 out of 59 cases (84.74%) improved the day after the bevacizumab treatment, and the edema volumes of 55 (93.22%) cases were reduced after the bevacizumab treatment. The average edema volume was significantly reduced after bevacizumab treatment from 125,583.43 ±â€Š14,093.27 to 71,613.42 ±â€Š9473.42 mm (Mann-Whitney rank test, P < .01), and the average edema index was significantly reduced from 25.66 ±â€Š11.54 to 17.87 ±â€Š6.87 (Mann-Whitney rank test, P < .01). One patient died from a hemorrhage due to a cancerous-ulcer of the maxillary sinus. The main complication observed was hypertension, which was observed in 11 cases (18.6%). CONCLUSION: The effective rate of bevacizumab for refractory brain edema is 84.74%. Hypertension was the main side effect of the bevacizumab treatment. Bevacizumab is an effective and relatively safe treatment for brain edema.

Growth of Indium Hydroxide Nanocubes Film by Hydrothermal Method.

A new strategy has been successfully designed for the first time to synthesize indium hydroxide (In(OH)3) nanocube film by employing a novel hydroxyl (OH−) solution corrosion-base approach. The structure and optical properties of the In(OH)3 structures were investigated. It showed that In(OH)3 cube film structure was formed. Meanwhile, the In(OH)3 obtained exhibits a strong blue PL emission which allows it to be considered as a promising material for electronic and optical properties. The results show that this preparation strategy of In(OH)3 nanocube film is proved to be a simple and effective synthesis method.

Photoluminescence changes of C70 nano/submicro-crystals induced by high pressure and high temperature.

Hollow C70 nano/submicro-crystals with a fcc lattice structure were treated under various high pressure and high temperature conditions. The energy band structure was visibly changed by the high pressure and high temperature treatment, and the luminescence of the treated C70 nano/submicro-crystals were tuned from the visible to the near infrared range. In-situ high pressure experiments at room temperature indicate that pressure plays a key role in the tuning of the band gap and PL properties in C70 nanocrystals, and temperature plays an important role in the formation of stable intermolecular bonds and thus to define the final red-shift of the PL peaks. The polymeric phases of C70 nanocrystals treated at high pressure and high temperature were identified from their Raman spectra, which showed a change from monomers to a dimer-rich phase and finally to a phase containing larger, disordered C70 oligomers.

Direct observation of magnetic vortex behavior in an ordered La0.7Sr0.3MnO3 dot arrays.

Directly observing the magnetic domain behavior in patterned nanostructures is crucial to the investigation into advanced spin-based devices. Herein, we show that the magnetic vortex behavior can be deterministically observed and controlled in highly spin polarized La0.7Sr0.3MnO3 (LSMO) triangular dots by successive in-field magnetic force microscopy (MFM). Imaging the magnetic domains with MFM shows that most of the LSMO dots exhibit magnetic vortex states with a clockwise or anticlockwise "pinwheel" structure for decreasing the demagnetization energy. Probing the vortex chirality using in-field MFM indicates that the selective spin circulation of the triangular dots depends on the magnetic orientation of the bias nanomagnet with specially designed geometries. Comparison between measurement and simulation reveals that the vortex behavior should be governed by an interface involved pinning strength at the boundaries, as well as a geometrically induced shape anisotropy of the triangular dot, both of which result in shape-dominated magnetic domain reversals.