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Objective Immune checkpoint inhibitors (ICI) that block the programmed cell death 1 (PD-1) pathway have shown promise with limited benefit. We and others have shown in small patient cohorts that an early proliferative CD8 T-cell response in the blood may be predictive of clinical response. However, these studies lack detailed analyses and comparisons between monotherapy and combination therapies.Methods and analysis We analysed longitudinal blood samples from 103 patients with cancer who received αPD-1 monotherapy or combined with anti-cytotoxic T lymphocyte-associated protein 4 (αCTLA-4) or chemotherapy. Transcriptional analysis of CD8 T cells after the first treatment cycle with effector cells generated following yellow fever virus (YFV-17D) vaccine-induced infection was also compared.Results An early proliferative (Ki-67+) CD8 T-cell response was observed after cycle 1 in 60 patients (58.3%). Patients with early-and-sustained proliferative responses (cycle 1 and beyond) had better clinical responses and survival than patients with an early-but-limited response (p=0.02). The proliferating cells had an effector-like phenotype. The transcriptional profiles of the effector-like CD8 T cells were similar irrespective of treatment type or clinical response but distinct from that of YFV-specific effector CD8 T cells.Conclusions Our data suggest that early proliferative CD8 T-cell response in the blood is predictive, and that an early-and-sustained proliferative response may further identify patients with prolonged survival. The ICI-induced effector-like CD8 T cells are transcriptionally distinct from highly functional YFV-specific cells, suggesting opportunities for improved T-cell effector function with combination therapies for better clinical outcome.

With the rapid advancement of technology, network security faces a significant challenge due to the proliferation of malicious software and its variants.These malicious software use various technical tactics to deceive or bypass traditional detection methods, rendering conventional non-visual detection techniques inadequate.In recent years, data visualization has gained considerable attention in the academic community as a powerful approach for detecting and classifying malicious software.By visually representing the key features of malicious software, these methods greatly enhance the accuracy of malware detection and classification, opening up extensive research opportunities in the field of cyber security.An overview of traditional non-visual detection techniques and visualization-based methods were provided in the realm of malicious software detection.Traditional non-visual approaches for malicious software detection, including static analysis, dynamic analysis, and hybrid techniques, were introduced.Subsequently, a comprehensive survey and evaluation of prominent contemporary visualization-based methods for detecting malicious software were undertaken.This primarily encompasses encompassed the integration of visualization with machine learning and visualization combined with deep learning, each of which exhibits distinct advantages and characteristics within the domain of malware detection and classification.Consequently, the holistic consideration of several factors, such as dataset size, computational resources, time constraints, model accuracy, and implementation complexity, is necessary for the selection of detection and classification methods.In conclusion, the challenges currently faced by detection technologies are summarized, and a forward-looking perspective on future research directions in the field is provided.

Aiming at the uncertaity of heat storage efficiency during the melting process of phase-change materials in the heat accumulator and the natural convection heat transfer process in the phase-change region, the influence of natural convection caused by gravity on the heat storage performance of the phase change heat storage was studied by numerical simulation with the tube-type solar phase change accumulator as the basic structure and the paraffin with 10% expanded graphite as the heat storage material. The results show that the natural convection caused by solid-liquid density difference has an obvious promoting effect on the phase change heat storage process. The heat storage time of the heat accumulator considering natural convection is nearly twice that of the heat accumulator without considering natural convection. The influence of natural convection on phase change materials in every region is different. In the early stage of melting of phase change materials, the melting rate above the innertube is faster due to the influence of natural convection of liquid phase. Based on the theoretical analysis and according to the characteristics of the melting rate and melting state of the heat accumulator, the melting process is segmented, which can further understand the heat storage process of the heat accumulator and provide certain theoretical guidance for optimizing the structure of the heat accumulator.

Abstract Background Targeted sequencing of cytologic samples has significantly increased in recent years. With increasing numbers of clinical trials for variant specific therapeutics, validating a comprehensive assay for cytologic samples has become clinically important. Aim For this study, a retrospective review of cytologic cell blocks from fine needle aspirations and fluid specimens was performed. Methods Two hundred twenty six total cases of solid tumor malignancies were identified, of which 120 cases and 20 lymph node negative controls were sequenced for the Oncomine Comprehensive Assay. Cytology and surgical specimen correlation was performed in a subset of cases. Statistical analysis to determine variant concordance was performed. Results Within the 117 cases sequenced, a total of 347 pathogenic variants were detected. Of the 117 cases, 32 cases (27.4%) would qualify for FDA approved targeted therapy according to the current guidelines, and an additional 23 cases (19.7%) would qualify for clinical trial based on pathogenic variants detected. Discussion With over 27% of cases in our cohort qualifying for some form of targeted therapy, our study shows the importance of providing comprehensive molecular diagnostic options. Despite only half of the cytology cases in the review period having enough material to be sequenced, overall approximately 27% of patients in this cohort would have benefitted from this service.

Background Periodontal disease is associated with systemic conditions such as diabetes, arthritis, and cardiovascular disease, all diseases with large inflammatory components. Some, but not all, reports show periopathogens Porphyromonas gingivialis and Tannerella forsythia at higher levels orally in people with one of these chronic diseases and in people with more severe cases. These oral pathogens are thought to be positively associated with systemic inflammatory diseases through induction of oral inflammation that works to distort systemic inflammation or by directly inducing inflammation at distal sites in the body. This study aimed to determine if, among patients with severe periodontal disease, those with multi-morbidity (or many chronic diseases) showed higher levels of periodontal pathogens. Methods A total of 201 adult subjects, including 84 with severe periodontal disease were recruited between 1/2017 and 6/2019 at a city dental clinic. Electronic charts supplied self-reported diseases and conditions which informed a morbidity index based on the number of chronic diseases and conditions present. Salivary composition was determined by 16S rRNA gene sequencing. Results As expected, patients with severe periodontal disease showed higher levels of periodontal pathogens in their saliva. Also, those with severe periodontal disease showed higher levels of multiple chronic diseases (multimorbidity). An examination of the 84 patients with severe periodontal disease revealed some subjects despite being of advanced age were free or nearly free of systemic disease. Surprisingly, the salivary microbiota of the least healthy of these 84 subjects, defined here as those with maximal multimorbidity, showed significantly lower relative numbers of periodontal pathogens, including Porphyromonas gingivalis and Tannerella Forsythia, after controlling for active caries, tobacco usage, age, and gender. Analysis of a control group with none to moderate periodontal disease revealed no association of multimorbidity or numbers of medications used and specific oral bacteria, indicating the importance of severe periodontal disease as a variable of interest. Conclusion The hypothesis that periodontal disease patients with higher levels of multimorbidity would have higher levels of oral periodontal pathogens is false. Multimorbidity is associated with a reduced relative number of periodontal pathogens Porphyromonas gingivalis and Tannerella forsythia.

Early-onset colorectal cancer (EOCRC) is defined as a diagnosis of colorectal cancer (CRC) in individuals younger than 50 years of age. While overall CRC rates in the United States (US) decreased between 2001 and 2018, EOCRC rates have increased. This research project aims to evaluate the feasibility and acceptability of Time-Restricted Eating (TRE), Mindfulness, or TRE combined with Mindfulness among young to middle-aged adults at risk of EOCRC. Forty-eight participants will be randomly assigned to one of four groups: TRE, Mindfulness, TRE and Mindfulness, or Control. Data on feasibility, adherence, and acceptability will be collected. Measures assessed at baseline and post-intervention will include body weight, body composition, dietary intake, physical activity, sleep behavior, circulating biomarkers, hair cortisol, and the gut microbiome. The effects of the intervention on the following will be examined: (1) acceptability and feasibility; (2) body weight, body composition, and adherence to TRE; (3) circulating metabolic, inflammation, and oxidative stress biomarkers; (4) intestinal inflammation; and (5) the gut microbiome. TRE, combined with Mindfulness, holds promise for stress reduction and weight management among individuals at risk of EOCRC. The results of this pilot study will inform the design and development of larger trials aimed at preventing risk factors associated with EOCRC.

This study aimed to enhance antitumor immune responses to pancreatic cancer via Ab-based blockade of IL-6 and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). Mice bearing s.c. or orthotopic pancreatic tumors were treated with blocking Abs to IL‑6 and/or CTLA-4. In both tumor models, dual IL-6 and CTLA-4 blockade significantly inhibited tumor growth. Additional investigations revealed that dual therapy induced an overwhelming infiltration of T cells into the tumor as well as changes in CD4+ T cell subsets. Dual blockade therapy elicited CD4+ T cells to secrete increased IFN-γ in vitro. Likewise, in vitro stimulation of pancreatic tumor cells with IFN-γ profoundly increased tumor cell production of CXCR3-specific chemokines, even in the presence of IL-6. In vivo blockade of CXCR3 prevented orthotopic tumor regression in the presence of the combination treatment, demonstrating a dependence on the CXCR3 axis for antitumor efficacy. Both CD4+ and CD8+ T cells were required for the antitumor activity of this combination therapy, as their in vivo depletion via Abs impaired outcomes. These data represent the first report to our knowledge of IL-6 and CTLA‑4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy.

Background/Aims Endoscopic resection has become the preferred treatment approach for select early esophageal adenocarcinoma (EAC); however, the epidemiology of early stage disease has not been well defined. Methods Surveillance Epidemiology and End Results (SEER) data were analyzed to determine age-adjusted incidence rates among major epithelial carcinomas, including EAC, from 1973 to 2017. The percent change in incidence over time was compared according to tumor subtype. Early T-stage, node-negative EAC without metastasis was examined from 2004 to 2017 when precise T-stage data were available. Results The percent change in annual incidence from 1973 to 2017 was 767% for EAC. Joinpoint analysis showed that the average annual percent change in EAC from 1973 to 2017 was 5.11% (95% confidence interval, 4.66%–5.56%). The annual percent change appeared to plateau between 2004 and 2017; however, early EAC decreased from 2010 to 2017, with an annual percent change of –5.78%. Conclusions There has been a 7-fold increase in the incidence of EAC, which was significantly greater than that of the other major epithelial malignancies examined. More recently, the incidence of early EAC has been decreasing. Approximately one in five patients has node negative, potentially resectable early stage disease.

Abstract The effect of oral microbial composition on periodontal health and on systemic health has been, and is being established. The oral microbiome, in turn, can be altered by local and systemic diseases and conditions. Gastroesophageal reflux disease (GERD), has been associated with increased acidity in the oral cavity resulting in dental erosion, and controversially a reduced risk of periodontal disease. We hypothesized that presence of GERD was linked to a modified microbial profile in untreated GERD patients and that the use of proton pump inhibitor (PPI) drugs: potent disruptors of gut microbiome, in GERD patients might result in a salivary microbiome that is further distinct. Untreated GERD patients showed multiple differences in salivary microbiome as compared to healthy controls. Taxa found at lower levels related to the presence of GERD not treated by PPI included: Prevotella melaninogenica, Prevotella pallens, Leptotrichia, and Solobacterium moorei and thirteen others. In contrast, GERD patients chronically using PPI showed minimal differences in salivary taxa compared to healthy controls not using PPI.

Background: Drug resistance is the major cause of increasing mortality in prostate cancer (PCa). Therefore, it an urgent to develop more effective therapeutic agents for PCa treatment. Xihuang pills (XHP) have been recorded as the efficient anti-tumor formula in ancient Chinese medical literature, which has been utilized in several types of cancers nowadays. However, the effect protective role of XHP on the PCa and its underlying mechanisms are still unclear.Methods: The active ingredients of XHP were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and BATMAN-TCM. The potential targets of PCa were acquired from the Gene Cards and OMIM databases. R language and Perl language program were utilized to clarify the interaction between the PCa-related targets and the potential targets of XHP. The potential targets of XHP for prostate cancer were gathered from the Gene ontology and KEGG pathway. Furthermore, cell proliferation assays were verified by PC3 and LNCaP cells. The efficacy and potential mechanism tests were confirmed by the PCa PC3 cells and mice subcutaneous transplantation. The effects of PI3K/Akt/mTOR-related proteins on proliferation, apoptosis, and cell cycle of PCa cells were measured by the Cell Counting Kit-8(CCK8), TUNEL assay, real-time quantitative reverse transcription PCR (QRT-PCR), and Western Blotting, respectively.Results: The active components of four traditional Chinese medicines in XHP were searched on the TCMSP and Batman TCM database. The biological active components of XHP were obtained as OB ≥30% and DL ≥0.18. The analysis of gene ontology and KEGG pathway identified the PI3K/Akt/mTOR signaling pathway as the XHP-associated pathway. Collectively, the results of in vitro and in vivo experiments showed that XHP had the effect of inhibiting on the proliferation of PC3 and LNCaP cells. XHP promoted the apoptosis and restrained the cell cycle and invasion of the PC3 cells and subcutaneous transplantation. Meanwhile, the suppression of XHP on the level of expression of PI3K, Akt, and mTOR-pathway-related pathway proteins has been identified in a dose-dependent manner.Conclusion: PI3K/Akt/mTOR pathway-related pathway proteins were confirmed as the potential XHP-associated targets for PCa. XHP can suppress the proliferation of prostate cancer via inhibitions of the PI3K/Akt/mTOR pathway.

Among various Phase I clinical trial designs, rule-based standard 3 + 3 designs are the most widely utilized for their simplicity and robustness. It is necessary to define crucial operating characteristics of a Phase I clinical trial before it starts. Based on the assumed probability of dose limiting toxicity (DLT) at each tested dose level, Lin and Shih elaborated formulas to calculate the five key operating characteristics of Phase I clinical trials using the two subtypes of standard 3 + 3 designs (with vs without dose de-escalation): probability of each dose level being chosen as the maximum tolerated dose (MTD); expected number of patients treated at each dose level; expected number of patients experiencing DLT at each dose level; target toxicity level (TTL) (expected probability of DLT at MTD); expected total number of patients experiencing DLT. Understanding these formulas requires advanced statistical knowledge and the formulas are too complicated to be used directly. To facilitate their application, we have developed stand-alone interactive software for convenient calculation of these key operating characteristics. The calculated results are presented in tables and plots that can be saved and easily edited for further use. Some examples of calculation using the software are presented and discussed. Keywords: Standard 3+3 design, Statistical software, Operating characteristics, Cancer phase I clinical trials, Maximum tolerated dose, Dose limiting toxicity

Fibroblast growth factor receptor 3 (FGFR3) is expressed in squamous cell carcinoma of the head and neck (SCCHN) including oropharyngeal squamous cell carcinoma (OPSCC) and is a potential therapeutic target. However, information on its correlation with other relevant cancer related proteins stratified by p16 status and its prognostic significance in OPSCC is limited. We examined FGFR3 expression and its correlation with clinical characteristics, p16 status, and mutant p53 (mp53) among 220 retrospectively collected OPSCC cases and 40 prospectively collected SCCHN cases, including a majority of OPSCC. Correlations of FGFR3 Weighted Index (WI) with p16 status and mp53 WI as well as its association with disease-free survival (DFS) and overall survival (OS) were evaluated. FGFR3 expression was detected in 61% and 70% of cases in cohorts 1 and 2, respectively. FGFR3 level was significantly higher in p16-negative tumors in both cohorts (p

Background Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 and cytotoxic T lymphocyte-associated protein 4 has achieved modest clinical activity as salvage therapy in relapsed small cell lung cancer (SCLC). We conducted this signal-finding study to assess the efficacy of ICB with or without radiation in relapsed SCLC.Methods Patients with relapsed SCLC and ≤2 previous lines of therapy were randomized to (1) arm A: durvalumab (D) 1500 mg/tremelimumab (T) 75 mg (intravenously every 4 weeks without stereotactic body radiation therapy (SBRT)) or (2) arm B: immune-sensitizing SBRT to one selected tumor site (9 Gy × 3 fractions) followed by D/T. Treatment continued until progression or a maximum of 12 months. The co-primary endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). We evaluated circulating lymphocyte repertoire in serial peripheral blood samples and tumor infiltrating lymphocytes (TILs) from on-treatment biopsies as pharmacodynamic markers.Results Eighteen patients were randomized to arms A and B (n=9 each): median age 70 years; 41.2% women. The median PFS and ORR were 2.1 months and 0% in arm A and 3.3 months and 28.6% in arm B. The median overall survival (OS) was 2.8 months in arm A and 5.7 months in arm B (p=0.3772). Pooled efficacy of D/T±SBRT in 15 Response evaluation criteria in solid tumors (RECIST) evaluable patients across both arms showed the best ORR in terms of partial response in 13.3%, stable disease in 26.6% and progressive disease in 60.0%; the overall median PFS and OS were 2.76 and 3.9 months. The most common adverse events were grade 1 fatigue (66%) and grade 1 elevated amylase (56%) in arm A, and grade 1 fatigue (56%) and pain (44%) in arm B. There was a significant increase in activated CD8(+)ICOS+ T cells (p=0.048) and a reduction in naïve T cells (p=0.0454) in peripheral blood following treatment, along with a significant amount of activated CD8+ICOS+ T cells in TILs from responders.Conclusions The D/T combination with and without SBRT was safe but did not show sufficient efficacy signal in relapsed SCLC. Changes in peripheral blood lymphocyte and TILs were consistent with an immunologic response.Trial registration number NCT02701400.

Background High epicardial adipose tissue (EAT) attenuation (Hounsfield units [HUs]) on computed tomography is considered a marker of inflammation and is associated with an increased risk of cardiovascular events. Statins reduce the volume of EAT, but it is unknown whether they affect EAT HUs. Methods and Results We reviewed the chest computed tomographic scans of 420 postmenopausal women randomized to either 80 mg of atorvastatin or 40 mg of pravastatin daily and rescanned after 1 year to measure change in coronary artery calcium score. EAT HUs were measured near the proximal right coronary artery and remote from any area of coronary artery calcium. Computed tomographic images were also queried for subcutaneous adipose tissue (SubQ) attenuation (HUs) change over time. The mean patients’ age was 65±6 years. The baseline EAT HU value was higher than the SubQ HU value (−89.4±24.0 HU versus −123.3±30.4 HU; P

BackgroundSignaling through mTOR and somatostatin pathway is implicated in thyroid cancer development.MethodWe evaluated everolimus, an mTOR inhibitor and pasireotide, a multi receptor somatostatin analogue as potential therapy of thyroid cancer focusing on the in vitro and in vivo efficacy, as well as possible mechanism to explain any observed interaction.ResultsBoth everolimus and pasireotide inhibit the growth of thyroid cancer cell lines in vitro with varied efficacy that correlates with tumor origin and somatostatin receptor (SSTR) expression profile of the cell lines. In vitro activity of everolimus show positive correlation with the expression of SSTR types 1, 4 and 5 (CC: 0.9; 0.85, 0.87) while pasireotide activity show negative correlation with SSTR2 (CC: -0.87). Although there is greater modulation of pS6 when pasireotide is combined with everolimus, there is no significant abrogation of the expected feedback upregulation of AKT induced by everolimus. Also, the combination is not significantly better than each agent alone in short and long term in vitro assays. Continuous administration of everolimus at a low dose as opposed to high intermittent dosing schedule has greater antitumor efficacy against thyroid cancer xenografts in vivo. Pasireotide LAR has modest in vivo efficacy and the combination of everolimus and pasireotide LAR achieve greater tumor growth inhibition than each agent alone in TPC-1 xenograft model of thyroid cancer (p = 0.048).ConclusionOur findings provide support for the clinical evaluation of everolimus and pasireotide in thyroid cancer and other neuroendocrine tumors.

Many biomarkers have been shown to be associated with the efficacy of cancer therapy. Estimation of personalized maximum tolerated doses (pMTDs) is a critical step toward personalized medicine, which aims to maximize the therapeutic effect of a treatment for individual patients. In this study, we have established a Bayesian adaptive Phase I design which can estimate pMTDs by utilizing patient biomarkers that can predict susceptibility to specific adverse events and response as covariates.Based on a cutting-edge cancer Phase I clinical trial design called escalation with overdose control using normalized equivalent toxicity score (EWOC-NETS), which fully utilizes all toxicities, we propose new models to incorporate patient biomarker information in the estimation of pMTDs for novel cancer therapeutic agents. The methodology is fully elaborated and the design operating characteristics are evaluated with extensive simulations.Simulation studies demonstrate that the utilization of biomarkers in EWOC-NETS can estimate pMTDs while maintaining the original merits of this Phase I trial design, such as ethical constraint of overdose control and full utilization of all toxicity information, to improve the accuracy and efficiency of the pMTD estimation.Our novel cancer Phase I designs with inclusion of covariate(s) in the EWOC-NETS model are useful to estimate a personalized MTD and have substantial potential to improve the therapeutic effect of drug treatment.

Objectives: ALK-EML4 translocation is an established driver aberration in non-small cell lung cancer (NSCLC), with reported predilection for cases with signet ring histology. We assessed the presence of anaplastic lymphoma kinase (ALK) gene rearrangements in signet ring cancers arising in the stomach and colon. Methods: Histologically confirmed cases of signet ring adenocarcinoma of the stomach or the colon were identified. The presence of the classic ALK and EML4 fusion gene was initially determined by fluorescence in-situ hybridization (FISH) technique. Immunohistochemistry (IHC) was performed using two previously validated antibodies, ALK1 clone (1:100; DAKO) and 5A4 (Novocastra, Leica Biosystems) along with positive controls of ALK-translocated lung cancer. Results: We employed 42 cases of signet ring carcinoma diagnosed between 2001 and 2011; 25 gastric and 17 colon cancer. Median age 63.3 years; male/female 17/25; race, black 47.5%, white 47.5%, others, 5%; stage I, 21.4%; stage II, 31%; stage III, 26.2%; stage IV, 21.4%. One of 42 cases (2.3%) was positive for ALK translocation by FISH using the standard criteria of at least 15% positive cells for the break-apart signal (50–70 cells enumerated per case). Using a less restrictive cut-off of 10% positive cells, 7 cases (16%) were considered possibly positive. None of the ‘possibly positive’ cases was found to harbor ALK translocation by another molecular testing approach (IHC). IHC with two previously validated monoclonal antibodies showed 0 of 42 (0%) cases positive. Conclusions: ALK gene rearrangement is very rare in gastrointestinal cancers and enrichment strategy focusing on signet ring cell histology did not significantly improve the detection rate.

We first review existing sequential methods for estimating a binomial proportion. Afterward, we propose a new family of group sequential sampling schemes for estimating a binomial proportion with prescribed margin of error and confidence level. In particular, we establish the uniform controllability of coverage probability and the asymptotic optimality for such a family of sampling schemes. Our theoretical results establish the possibility that the parameters of this family of sampling schemes can be determined so that the prescribed level of confidence is guaranteed with little waste of samples. Analytic bounds for the cumulative distribution functions and expectations of sample numbers are derived. Moreover, we discuss the inherent connection of various sampling schemes. Numerical issues are addressed for improving the accuracy and efficiency of computation. Computational experiments are conducted for comparing sampling schemes. Illustrative examples are given for applications in clinical trials.

The clinical trial, a prospective study to evaluate the effect of interventions in humans under prespecified conditions, is a standard and integral part of modern medicine. Many adaptive and sequential approaches have been proposed for use in clinical trials to allow adaptations or modifications to aspects of a trial after its initiation without undermining the validity and integrity of the trial. The application of adaptive and sequential methods in clinical trials has significantly improved the flexibility, efficiency, therapeutic effect, and validity of trials. To further advance the performance of clinical trials and convey the progress of research on adaptive and sequential methods in clinical trial design, we review significant research that has explored novel adaptive and sequential approaches and their applications in Phase I, II, and III clinical trials and discuss future directions in this field of research.