Background
Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy has been established as a novel treatment approach for peritoneal sarcomatosis. Despite promising ...clinical reports, there is still a lack of knowledge regarding optimal drug usage and local effects. Therefore, we intended to establish a murine animal model for further evaluation.
Procedure
Alveolar rhabdomyosarcoma cells were xenotransplanted into NOD/LtSz‐scid IL2Rγnullmice (n = 100). The mice received a continuous intraperitoneal lavage with isotonic saline solution as control or with cisplatin (30 or 60 mg/m2) as treatment group for 60 minutes at 37°C or 42°C (6 subgroups, each n = 16). Tumor spread was documented by an adapted peritoneal cancer index and MRI (n = 4). Tumor and tissue samples, harvested at the end of the perfusion, were evaluated regarding morphology, proliferation, and apoptosis (H&E‐, Ki‐67‐, cleaved caspase 3–staining, TUNEL assay).
Results
Extensive peritoneal sarcomatosis in over 91% of the cases was observed. HIPEC was feasible without acute side effects. Ki‐67 staining revealed concentration‐ or temperature‐dependent effects of cisplatin‐based HIPEC on the tumors. Although cleaved caspase‐3 showed only sporadic apoptotic effects. TUNEL assay detected concentration‐ or temperature‐dependent apoptotic effects at the outer tumor surface. MRI scans confirmed the observed tumor dissemination.
Conclusion
This is the first animal model for evaluation of HIPEC in pediatric RMS in mice. Cisplatin‐based HIPEC had early effects on the proliferation whereas circumscribed apoptotic effects could be detected at the tumor surface. This model allows further insights on the possible efficiency of HIPEC in RMS. Further studies using other drug combinations and treatment will follow.
Permeability and physical properties of fine-grained clastic sediments show a wide range of variations. Despite rather intensive research, the impact of grain size distribution and mineralogical ...composition of individual rock constituents is not thoroughly investigated. We performed mechanical compaction of brine-statured reconstituted borehole cuttings and synthetic quartz-clay mixtures to study the evolution of properties in fine-grained clastic sediments during burial. The primary objective was to examine whether the hydraulic and physical properties of fine-grained sediments could be described and constrained by binary quartz-clay mixtures. The synthetic binary mixtures were prepared by mixing quartz with non-swelling (kaolinite) and strongly-swelling (smectite) clays, which can represent the endmember properties within the clay minerals. In addition to vertical permeability, physical and seismic properties, stress-dependence of permeability, and two-phase relative permeability of brine-oil system were investigated. Experimental results show that grain size distribution and mineralogical composition control the vertical permeability. A well-constrained porosity-permeability bound is defined, where the compaction trends of pure quartz and quartz-smectite 15:85 (wt %) mixtures describe the maximum and minimum boundaries, respectively. The quartz-clay mixtures, however, fail to provide bounds to constrain the broad range of variations in physical and seismic properties of reconstituted aggregates, and consequently natural mudstones. It is crucial to incorporate microstructure into the permeability prediction models because the experiments indicated that the microscale characteristics control the macroscale fluid flow properties.
•Reconstituted drill cuttings and quartz-clay mixtures were compacted in laboratory.•Binary quartz-kaolinite and quartz-smectite mixtures were tested as endmembers.•The evolution of hydraulic, physical, and seismic properties were investigated.•Grain size and mineralogical composition impose control on mudstone properties.•Pure quartz and quartz-smectite 15:85 define boundaries for porosity-permeability.
Memristive crossbar array suffers from severe sneak currents that incur reliability issues and extra energy waste. Complementary resistive switches (CRSs) provide a new concept to address the ...sneak-current problem. But the destructive read of CRS results in an additional recovery write operation, which strongly restricts its further promotion. Exploiting the dual CRS/memristor mode of CRS devices, we propose Aliens , a novel reconfigurable architecture that introduces one alien cell (memristor mode) for each bitline in the crossbar. Aliens draws advantages from both modes: restrained sneak currents of the CRS mode and nondestructive read of the memristor mode. The simple and regular cell mode organization one bitline one memristor (OBOM) of Aliens enables an energy-saving read method. Further, by exploiting memory access locality, an effective mode switching strategy called Lazy-Switch is proposed to delay and merge the recovery write operations of the CRS mode. Moreover, an 1TnR crossbar structure is adopted to enable larger crossbar arrays as well as a higher ratio of memristor mode cells without going against the OBOM rule. The effects of the memristor mode cell ratio on the energy consumption, endurance, and access performance are studied. Also, we show the bank architecture of Aliens and analyze how to extend our designs to 3-D arrays. Due to fewer recovery write operations and negligible sneak currents, Aliens achieves improvements in energy, overall endurance, and access performance. The experimental results show that our design offers average energy savings of <inline-formula> <tex-math notation="LaTeX">19.1\times </tex-math></inline-formula> compared with memristor-only memory, a memory lifetime <inline-formula> <tex-math notation="LaTeX">10.7\times </tex-math></inline-formula> longer than CRS-only memory, and a competitive performance compared with memristor-only memory.
The present paper introduces a practical and convenient artificial intelligence-based design approach for doubly reinforced concrete (RC) beams. Completed designs are automatically obtained from ...regression models and back-substitution (BS) procedures, which satisfy the preassigned flexural strength, curvature ductility, and calculate serviceability parameters. In addition, regression algorithms are developed by training multiple Gaussian Process Regression models on structural data. Furthermore, feature selections and Chained training scheme with Revised Sequence (CRS) techniques are implemented to enhance the training accuracy, providing acceptable accuracies (less than 0.7% errors) in 91 interpolation designs. First, CRS procedures are employed, improving the regression accuracy by sequentially predicting outputs, using predictions of predecessor steps as inputs for the successor ones. In doing so, the preciseness of models is improved as training continues. Appropriate inputs and reasonable output sequences for CRS are determined using a feature selection-based procedure for obtaining optimal training. This procedure implemented three feature selection methods (F-test, Neighborhood Component Analysis (NCA), and RReliefF) in a greedy algorithm, evaluating relations among design parameters. In summary, a direct design approach of a doubly reinforced concrete beam is presented, which enables engineers to control moment capacities and curvature ductility easily, replacing ineffective iteration-based conventional design procedures.
CAR T in adult ALL: When and for whom? Connor, Matthew P.; Frey, Noelle V.
Best practice & research. Clinical haematology,
March 2021, 2021-03-00, 20210301, Letnik:
34, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Chimeric antigen receptor T cell therapy targeting CD19 (CART19) has shown remarkable results in patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (ALL). In patients 25 ...years of age or younger CART19 therapy is an accepted standard of care, while the treatment of older adults is less straight forward and possible only in the context of a clinical trial. Treatment of older patients with CAR T cells requires careful consideration of overall treatment goals, suitability of a consolidative hematopoietic stem cell transplant (HSCT), alternative treatment options, patient risk profile, and anticipated responses and toxicities of the specific CAR T cell products available. Here we use patient guided examples to inform approaches to care.
Background
Endotypic and prognosticating features of chronic rhinosinusitis without nasal polyposis (CRSsNP) are poorly understood. Our objectives were to use an unbiased symptom‐based approach to: ...(1) study symptoms, clinical and endotypic features; and (2) identify features predicating outcomes from endoscopic sinus surgery (ESS).
Methods
Clinical, computed tomography (CT), histopathology, and 22‐item Sino‐Nasal Outcome Test (SNOT‐22) data was collected on 146 adult CRSsNP patients who underwent ESS. Unsupervised network modeling of presurgical SNOT‐22 scores was performed to classify symptom‐based clusters. Subject characteristics and post‐ESS SNOT‐22 scores were compared between clusters.
Results
Baseline characteristics of the subject population were as follows: females, 56.2%; revision ESS status in 35%; asthma prevalence, 32.6%; median Lund‐Mackay CT score, 8; and median SNOT‐22 total score, 43. Network mapping and unsupervised clustering of preoperative SNOT‐22 scores revealed 4 clusters: (A) severely burdened with high scores in all 4 subdomains; (B) moderately burdened with high scores in the rhinologic subdomain; (C) moderately burdened with high scores in psychological‐sleep subdomains; and (D) mildly burdened. The number of previous ESS and asthma prevalence differed significantly between clusters; CT scores were similar. Asthma burden and tissue eosinophilia were greatest in cluster A (p = 0.03). All groups showed significant improvement at 3 months post‐ESS (p < 0.0001). At 6 months, patients in cluster C tended to worsen.
Conclusion
SNOT‐22–based network modeling of CRSsNP patients yielded 4 clusters with distinct features. Asthma prevalence and tissue eosinophilia were highest in the cluster with highest SNOT‐22 scores. All patients showed significant improvement from ESS at 3 months; those with high sleep‐psychosocial symptoms tended to show worsening at 6 months.
Epithelial-mesenchymal transition (EMT) is thought to be involved in the tissue remodeling and long-term inflammatory process of chronic sinusitis (CRS), but the driving mechanism is still unclear. ...Using high-resolution mass spectrometry, we performed a proteomic screen of CRS nasal mucosal tissue to identify differentially expressed proteins. Data are available
ProteomeXchange with identifier PXD030884. Specifically, we identified S100 calcium binding protein A4 (S100A4), an effective factor in inflammation-related diseases, and its downstream protein closely related to tissue fibrosis collagen type I alpha 1 chain (COL1A1), which suggested its involvement in nasal mucosal tissue remodeling. In addition, stimulation of human nasal epithelial cells (HNEpCs) with lipopolysaccharide (LPS) mimicked the inflammatory environment of CRS and showed that S100A4 is involved in regulating EMT and thus accelerating tissue remodeling in the nasal mucosa, both in terms of increased cell motility and overexpression of mesenchymal-type proteins. Additionally, we further investigated the regulation mechanism of S100A4 involved in EMT in CRS. Our research results show that in the inflammatory environment of CRS nasal mucosal epithelial cells, TCF-4 will target to bind to S100A4 and regulate its transcription. The transcription of S100A4 in turn affects the execution of the important signaling pathway in EMT, the Wnt/GSK-3β/β-catenin pathway, through the TCF-4/β-catenin complex. In conclusion, this study confirmed that the expression of S100A4 was significantly increased during the progressive EMT process of CRS mucosal epithelial cells, and revealed that the transcriptional regulation of S100A4 plays an important role in the occurrence and development of EMT. This finding will help us to better understand the pathogenesis behind the remodeling in CRS patients, and identify target molecules for the treatment of CRS.
Objective - To determine whether national cultural dimensions influence a company's Corporate Social Responsibility (CRS) performance. Theoretical Framework - Hofstede's cultural dimensions and ...Stakeholder Theory were used as theoretical bases for the study. Methodology - The study uses the multiple linear regression method to analyze data from a sample of 4,598 companies from 41 countries. The data were collected from the CSRHub, Geert Hofstede, Transparency International, and Thomson Reuters websites. Results - The findings indicate a country's cultural dimensions influence business CRS activities. More specifically, companies based in countries with cultures that feature (i) a high power distance, (ii) high individualism, (iii) more femininity, (iv) low uncertainty avoidance, and (v) a long-term orientation exhibit higher CRS performance. Practical & Social Implications of the Research - Prior knowledge of expected CRS engagement according to the country's culture could contribute to formulating corporate strategies to expand a company's activities to countries other than the one of its origin. This would ensure stakeholders' expectations are met and improve competitiveness in the domestic market. Contributions - The culture of a country may determine whether stakeholders are interested in CRS practices.
For patients with colorectal cancer (CRC) peritoneal metastases (PM) who are eligible for cytoreductive surgery (CRS), the indication and timing of systemic chemotherapy (SC) are still under debate. ...This study aims to analyze the role of pre, post or perioperative SC on the survival and surgical complications of patients treated with CRS-HIPEC.
After a systematic search in MEDLINE, Cochrane Database of Systematic Reviews, Scopus, Web of Science and Embase, a meta-analysis was performed to compare postoperative complications, disease-free survival (DFS) and overall survival (OS) according to SC administration and timing.
CRD42023478977.
Of 1203 studies screened, 15 were included in the meta-analysis (4523 patients). Post-operative SC was associated with increased overall survival (post-SC vs. no post-SC: HR 0.81,
= 0.00001, I
= 0%; pre-SC vs. post-SC: HR 0.65,
= 0.01, I
= 28%), whereas SC (pre or post) or pre-SC compared to surgery alone was not (SC vs. no SC:
= 0.29, I
= 80%; pre-SC vs. no pre-SC:
= 0.59, I
= 58%). Similar results were seen for DFS. SC was not associated with an increased complication rate (
= 0.47, I
= 64%).
Systemic chemotherapy administration in patients undergoing radical surgery for colorectal peritoneal metastases is associated with increased survival only in the adjuvant/post-operative setting. Considering the limitations of the included studies, further trials are needed to answer this unresolved question.
A dynamic group signature (
DGS
) allows a user to generate a signature on behalf of a group, while preserving anonymity. Although many existing
DGS
schemes have been proposed in the random oracle ...model for achieving efficiency, their security proofs require knowledge extractors that cause loose security reductions. In this paper, we first propose a new practical
DGS
scheme whose security can be proven without knowledge extractors in the random oracle model. Moreover, our scheme can also be proven in the strong security model where an adversary is allowed to generate the group managers’ keys maliciously. The efficiency of our scheme is comparable to existing secure
DGS
schemes in the random oracle model using knowledge extractors. The security of our scheme is based on a new complexity assumption that is obtained by generalizing the Pointcheval–Sanders (PS) assumption. Although our generalized PS (GPS) assumption is interactive, we prove that, under the (2,1)-discrete logarithm assumption, the new GPS assumption holds in the algebraic group model.
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