PX-478, an HIF-1α inhibitor, impairs mesoCAR T cell antitumor function in cervical cancer.

Introduction: Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated remarkable success in treating hematological malignancies. However, its efficacy against solid tumors, including cervical cancer, remains a challenge. Hypoxia, a common feature of the tumor microenvironment, profoundly impacts CAR T cell function, emphasizing the need to explore strategies targeting hypoxia-inducible factor-1α (HIF-1α). Methods: In this study, we evaluated the effects of the HIF-1α inhibitor PX-478 on mesoCAR T cell function through in-silico and in vitro experiments. We conducted comprehensive analyses of HIF-1α expression in cervical cancer patients and examined the impact of PX-478 on T cell proliferation, cytokine production, cytotoxicity, and exhaustion markers. Results: Our in-silico analyses revealed high expression of HIF-1α in cervical cancer patients, correlating with poor prognosis. PX-478 effectively reduced HIF-1α levels in T and HeLa cells. While PX-478 exhibited dose-dependent inhibition of antigen-nonspecific T and mesoCAR T cell proliferation, it had minimal impact on antigen-specific mesoCAR T cell proliferation. Notably, PX-478 significantly impaired the cytotoxic function of mesoCAR T cells and induced terminally exhausted T cells. Discussion: Our results underscore the significant potential and physiological relevance of the HIF-1α pathway in determining the fate and function of both T and CAR T cells. However, we recognize the imperative for further molecular investigations aimed at unraveling the intricate downstream targets associated with HIF-1α and its influence on antitumor immunity, particularly within the context of hypoxic tumors. These insights serve as a foundation for the careful development of combination therapies tailored to counter immunosuppressive pathways within hypoxic environments and fine-tune CAR T cell performance in the intricate tumor microenvironment.

A Comparative Analysis of the Full and Short Versions of the Social Responsiveness Scale in Estimating an Established Autism Risk Factor Association in ECHO: Do we Get the Same Estimates?

PURPOSE: Prior work developed a shortened 16-item version of the Social Responsiveness Scale (SRS), a quantitative measure of social communication and autism spectrum disorder (ASD)-related traits. However, its properties for use in risk factor estimation have not been fully tested compared to the full SRS. We compared the associations between gestational age (previously established risk factor for ASD) and the 65-item "full" and 16-item "short" versions of the SRS to test the shortened version's ability to capture associations in epidemiologic analyses of ASD risk factors. METHODS: We used data from participants in the Environmental influences on Child Health Outcomes (ECHO) Program (n = 2,760). SRS scores were collected via maternal/caregiver report when children were aged 2.5-18 years. We compared estimates of associations between gestational age and preterm birth between the full and short SRS using multivariable linear regression, quantile regression, and prediction methods. RESULTS: Overall, associations based on full and short SRS scores were highly comparable. For example, we observed positive associations between preterm birth with both full ([Formula: see text]=2.8; 95% CI [1.7, 4.0]) and short ([Formula: see text]=2.9; 95% CI [1.6, 4.3]) SRS scores. Quantile regression analyses indicated similar direction and magnitude of associations across the distribution of SRS scores between gestational age with both short and full SRS scores. CONCLUSION: The comparability in estimates obtained for full and short SRS scores with an "established" ASD risk factor suggests ability of the shortened SRS in assessing associations with potential ASD-related risk factors and has implications for large-scale research studies seeking to reduce participant burden.

Cancer Vaccines for Triple-Negative Breast Cancer: A Systematic Review.

Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the poorest outcomes, and is associated with a high risk of relapse and metastasis. The treatment choices for this malignancy have been confined to conventional chemotherapeutic agents, due to a lack of expression of the canonical molecular targets. Immunotherapy has been recently changing the treatment paradigm for many types of tumors, and the approach of evoking active immune responses in the milieu of breast tumors through cancer vaccines has been introduced as one of the most novel immunotherapeutic approaches. Accordingly, a number of vaccines for the treatment or prevention of recurrence have been developed and are currently being studied in TNBC patients, while none have yet received any approvals. To elucidate the efficacy and safety of these vaccines, we performed a systematic review of the available literature on the topic. After searching the PubMed, Scopus, Web of Science, Embase, Cochrane CENTRAL, and Google Scholar databases, a total of 5701 results were obtained, from which 42 clinical studies were eventually included based on the predefined criteria. The overall quality of the included studies was acceptable. However, due to a lack of reporting outcomes of survival or progression in some studies (which were presented as conference abstracts) as well as the heterogeneity of the reported outcomes and study designs, we were not able to carry out a meta-analysis. A total of 32 different vaccines have so far been evaluated in TNBC patients, with the majority belonging to the peptide-based vaccine type. The other vaccines were in the cell or nucleic acid (RNA/DNA)-based categories. Most vaccines proved to be safe with low-grade, local adverse events and could efficiently evoke cellular immune responses; however, most trials were not able to demonstrate significant improvements in clinical indices of efficacy. This is in part due to the limited number of randomized studies, as well as the limited TNBC population of each trial. However, due to the encouraging results of the currently published trials, we anticipate that this strategy could show its potential through larger, phase III randomized studies in the near future.

Iodine-catalyzed synthesis of benzoxazoles using catechols, ammonium acetate, and alkenes/alkynes/ketones via C-C and C-O bond cleavage.

An efficient metal-free synthesis strategy of benzoxazoles was developed via coupling catechols, ammonium acetate, and alkenes/alkynes/ketones. The developed methodology represents an operationally simple, one-pot and large-scale procedure for the preparation of benzoxazole derivatives using molecular iodine as the catalyst.

The Future of Artificial Intelligence in Monitoring Animal Identification, Health, and Behaviour.

With many advancements, technologies are now capable of recording non-human animals' location, heart rate, and movement, often using a device that is physically attached to the monitored animals. However, to our knowledge, there is currently no technology that is able to do this unobtrusively and non-invasively. Here, we review the history of technology for use with animals, recent technological advancements, current limitations, and a brief introduction to our proposed novel software. Canadian tech mogul EAIGLE Inc. has developed an artificial intelligence (AI) software solution capable of determining where people and assets are within public places or attractions for operational intelligence, security, and health and safety applications. The solution also monitors individual temperatures to reduce the potential spread of COVID-19. This technology has been adapted for use at the Toronto Zoo, initiated with a focus on Sumatran orangutans (Pongo abelii) given the close physical similarity between orangutans and humans as great ape species. This technology will be capable of mass data collection, individual identification, pose estimation, behaviour monitoring and tracking orangutans' locations, in real time on a 24/7 basis, benefitting both zookeepers and researchers looking to review this information.

Preclinical studies of chimeric antigen receptor-modified natural killer cells in cancer immunotherapy: a review.

INTRODUCTION: As one of the most efficacious methods of cancer immunotherapy, chimeric antigen receptor-modified immune cells have recently drawn enormous attention. After the great success achieved with CAR-T-cells in cancer treatment both in preclinical setting and in the clinic, other types of immune cells, including natural killer (NK)-cells and macrophages, have been evaluated for their anti-cancer effects along with their potential superiority against CAR-T-cells, especially in terms of safety. First introduced by Tran et al. almost 26 years ago, CAR-NK-cells are now being considered as efficient immunotherapeutic modalities in various types of cancers, not only in preclinical setting but also in numerous phase I and II clinical studies. AREAS COVERED: In this review, we aim to provide a comprehensive survey of the preclinical studies on CAR-NK-cells' development, with an evolutional approach on CAR structures and their associated signaling moieties. Current NK-cell sources and modes of gene transfer are also reviewed. EXPERT OPINION: CAR-NK-cells have appeared as safe and effective immunotherapeutic tools in preclinical settings; however, designing CAR structures with an eye on their specific biology, along with choosing the optimal cell source and gene transfer method require further investigation to support clinical studies.

Fabrication of Calcium Sulfate Coated Selenium Nanoparticles and Corresponding In-Vitro Cytotoxicity Effects Against 4T1 Breast Cancer Cell Line.

BACKGROUND: The inhibitory effect of selenium nanoparticles (SeNPs) on cancer cells has been reported in many studies. In this study, the purpose was to compare the in vitro effects of SeNPs and calcium sulfate coated selenium nanoparticles (CaSO4@SeNPs) on breast cancer cells. METHODS: CaSO4@SeNPs and SeNPs were chemically synthesized and characterized with Field Emission Scanning Electron Microscope (FESEM) and energy-dispersive X-ray spectroscopy (EDX). By applying MTT assay, the cytotoxicity effect of both nanomaterials on the 4T1 cancer cells was investigated. RESULTS: While LD50 of SeNPs on 4T1 cancer cells was 80 µg, the LD50 of CaSO4@SeNPs was reported to be only 15 µg. The difference between the inhibition rates obtained for SeNPs and CaSO4@SeNPs was statistically significant (p=0.05). In addition, at higher concentrations (50 µg) of CaSO4@SeNPs, the cytotoxicity was 100% more than SeNPs alone. CONCLUSION: According to the result of the present work, it can be concluded that decoration of SeNPs with calcium sulfate leads to an increase in potency by decreasing the effective dose. This effect can be attributed to activation of intrinsic apoptosis signaling and/or pH regulatory properties of CaSO4@SeNPs. However, further studies are still needed to determine the exact corresponding mechanisms of this synergistic effect.

Distributional Properties and Criterion Validity of a Shortened Version of the Social Responsiveness Scale: Results from the ECHO Program and Implications for Social Communication Research.

Prior work proposed a shortened version of the Social Responsiveness Scale (SRS), a commonly used quantitative measure of social communication traits. We used data from 3031 participants (including 190 ASD cases) from the Environmental Influences on Child Health Outcomes (ECHO) Program to compare distributional properties and criterion validity of 16-item "short" to 65-item "full" SRS scores. Results demonstrated highly overlapping distributions of short and full scores. Both scores separated case from non-case individuals by approximately two standard deviations. ASD prediction was nearly identical for short and full scores (area under the curve values of 0.87, 0.86 respectively). Findings support comparability of shortened and full scores, suggesting opportunities to increase efficiency. Future work should confirm additional psychometric properties of short scores.

Neuroblastoma-targeted nanoparticles and novel nanotechnology-based treatment methods.

Neuroblastoma is a complicated pediatric tumor, originating from the neural crest, which is the most prevalent in adrenal glands, but may rarely be seen in some other tissues as well. Studies are focused on developing new strategies through novel chemo- and immuno-therapeutic drug targets. Different types of oncogenes such as MYCN, tumor suppressor genes such as p53, and some structural genes such as vascular endothelial growth factor are considered as targets for neuroblastoma therapy. The individual expression patterns in NB cells make them appropriate for this purpose. The combined effect of nano-drug delivery systems and specific drug targets will result in lower systemic side effects, prolonged therapeutic effects, and improvements in the pharmacokinetic properties of the drugs. Some of these novel drug delivery systems with a focus on liposomes as carriers are also discussed. In this review, genes and protein products that are beneficial as drug targets in the treatment of neuroblastoma have been discussed.

Meso-architectured siliceous hollow quasi-capsule.

Reactive dyes have been identified to be highly hazardous pollutants because they were shown to be more toxic towards mammals than general organic compounds and organic dyes. Accordingly, for the first time, meso-architectured mercapto-modified siliceous hollow quasi-capsules (SH-SHQC) were prepared by a facile, ultrasonic-assisted, and one-step synthesis protocol. Adsorptive removal of rhodamine B (RhB) and methylene blue (MB) onto SH-SHQC in a batch system has been investigated. Isotherm results agreed very well with the Langmuir equation for both dyes. The maximum adsorption capacity of SH-SHQC for RhB and MB was determined with the Langmuir equation and was found to be 147.06 and 119.05 mg g-1 at 298 K, respectively (pH: 6.0 for RhB and 7.0 for MB; adsorbent dosage: 15.0 mg; the volume of the dye solution: 40.0 mL). Among different kinetic models, the pseudo-first-order equation was better fitted since experimental data agreed very well with theoretical data. SH-SHQC was shown to be a promising adsorbent for adsorptive removal of reactive dyes from aqueous solutions. To date, there has been no report on the adsorption of reactive dye cations by meso-architectured mercapto-modified siliceous hollow quasi-capsules prepared by an ultrasonic-assisted, one-pot, and sol-gel synthesis method.

Synthesis and characterization of novel N-methylimidazolium-functionalized KCC-1: A highly efficient anion exchanger of hexavalent chromium.

A key challenge in adsorption process of toxic organic and inorganic species is the design and development of adsorbent materials bearing an abundance of accessible adsorption sites with high affinity to achieve both fast adsorption kinetics and elevated adsorption capacity for toxic contaminants. Herein, a novel anion-exchange adsorbent based on fibrous silica nanospheres KCC-1 was synthesized by a facile hydrothermal-assisted post-grafting modification of KCC-1 with 1-methyl-3- (triethoxysilylpropyl)imidazolium chloride for the first time. Silica fibers with micro-mesoporous structure display the proper combination of features to serve as a potential scaffold for decorating adsorption sites to create desired ion-exchange adsorbent. The obtained N-methylimidazolium-functionalized KCC-1 (MI-Cl-KCC-1) with fibrous nanosphere morphology showed a high surface area (∼241 m2 g-1) and high pore volume (0.81 m2 g-1). The adsorption behaviors of toxic hexavalent chromium from aqueous media by the MI-Cl-KCC-1 were systematically studied using the batch method. The adsorption rate was relatively fast, and MI-Cl-KCC-1 possesses a high capacity for the adsorption of Cr(VI). The maximum Cr(VI) adsorption was obtained at pH 3.0-4.0. Different non-linear isotherm equations were tested for choosing an appropriate adorption isotherm behavior, and the adsorption data for MI-Cl-KCC-1 were consistent with the Langmuir model with a maximum adsorption capacity of 428 ±â€¯8 mg g-1.

High Frequency of Tc22 and Th22 Cells in Myasthenia Gravis Patients and Their Significant Reduction after Thymectomy.

OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease accompanied by a thymic pathology and in most patients thymectomy (TE) is used as the therapeutic approach. Both B and T cells play an important role in MG pathogenesis. METHODS: Twelve pre- and post-TE MG patients and 12 healthy controls (HCs) were enrolled. The mean percentages of Th22 and Tc22 cells were evaluated in MG patients (before and 6 months after TE) and HCs. RESULTS: The mean percentage of Tc22 cells in pre-TE patients was significantly higher than in HCs (p < 0.05), and after TE Tc22 cells significantly decreased compared to pre-TE (p < 0.05). The frequency of Th22 cells in pre-TE MG patients was not significantly different from HCs, but after TE Th22 cells were significantly decreased compared to pre-TE (p < 0.05). CONCLUSION: Our findings suggest a possible role of Th22 and Tc22 in MG pathogenesis.

Cognitive Differences between Men and Women who Fracture their Hip and Impact on Six-Month Survival.

OBJECTIVES: There is limited research in cognition and its relationship to mortality after hip fracture among men compared to women. Therefore, the goals of this study were to: (1) compare men and women who fractured their hip on cognition after hospital discharge, and (2) examine the impact of cognition on the differential risk of 6-month mortality between men and women post fracture. DESIGN: Prospective cohort study. SETTING: Eight hospitals in Baltimore, Maryland. PARTICIPANTS: Frequency matched 168 male and 171 female hip fracture patients, ages 65 or older, living in the community before fracture. MEASUREMENTS: Cognition assed by Modified Mini-Mental State Examination (3MS, and derived MMSE score), Hooper Visual Organization test (HVOT), and Trail-making test (Trails A & B) within 22 days of hospital admission, and 6-month mortality. RESULTS: Men had more impaired cognitive scores on 3MS, MMSE, HVOT, and Trails A (P < .05) at baseline. These statistically significant differences between men and women remained on MMSE and HVOT after controlling for pre-fracture dementia, in-hospital delirium, age, education, race, and comorbidity. Men had higher 6-month mortality rates (HR = 4.4, P < .001). Cognitive measures were also significantly associated with mortality, including 3MS, HVOT, and Trails B. Among the cognitive measures, higher 3MS was most protective for mortality (HR = 0.98, P < .001), both unadjusted and adjusted for other cognitive scales, comorbidity, delirium, and pre-existing dementia. The highest mortality was among men with 3MS<78, with 26.3% dying within 6 months. The effects of cognition on mortality did not differ by sex. CONCLUSION: Men display greater levels of cognitive impairment within the first 22 days of hip fracture than women, and cognitive limitations increase the risk of mortality in both men and women.

Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer.

The phosphoinositide 3 kinase AKT mammalian target of rapamycin (PI3K-AKTmTOR) signaling pathway is an important in the aetiology of pancreatic cancer (PC) and is frequently activated in PC. It is then associated with a poorer prognosis. Aberrant activation of this pathway is involved in cell metabolism and survival, cell cycle progression, regulation of apoptosis, protein synthesis, and genomic instability. Several agents have been developed to target the Akt/PI3K pathways, including PI3K inhibitors, (e.g. LY294002, Wortmannin), PI3K/mTOR inhibitors (e.g. BEZ235), or Akt inhibitors (e.g. perifosine, MK2206), which have been tested alone or in combinations with DNA-targeted agents (e.g., gemcitabine and fluorouracil) in pancreatic ductal adenocarcinoma (PDAC). However, due to their unfavorable pharmaceutical activities, toxicity, and crossover inhibition of other lipid and protein kinases, these compounds have not been used in clinical studies. In this review, we focus on the progress in the development of Akt, PI3K and mTOR inhibitors for clinical applications, together with the need for the development of in PDAC and the need for the identification of predictive biomarkers and combination strategies with less toxicity in counteracting the mechanisms of resistance to the therapy.

Therapeutic Potential of Curcumin in Treatment of Pancreatic Cancer: Current Status and Future Perspectives.

Pancreatic cancer is among the leading cause of deaths due to cancer with extremely poor prognosis. Gemcitabine is being used in the treatment of patient with pancreatic ductal adenocarcinoma (PDAC), although, the response rate is bellow 12%. A recent phase III trial revealed that FOLFIRINOX could be an option for the treatment of metastatic PDAC patients, although it is associated with increased toxicity. Therefore, identification of novel agents that either improves gemcitabine activity, within novel combinatorial approaches, or with a better efficacy than gemcitabine is warranted. The antitumor activity of curcumin in several tumors, including prostate, breast and colorectal cancers have investigated. A recent phase II trial explored the effects of curcumin in advanced pancreatic cancer patient. They found that oral curcumin was well tolerated. Another trial showed the activity of 8,000 mg of curcumin in combination with gemcitabine in patients with advanced pancreatic cancer. This review summarizes the current knowledge about possible molecular mechanisms of curcumin in PDAC with particular emphasis on preclinical/clinical studies in pancreatic cancer treatment. J. Cell. Biochem. 118: 1634-1638, 2017. © 2017 Wiley Periodicals, Inc.

Increased Proportion of Tc17 and Th17 Cells and Their Significant Reduction after Thymectomy May Be Related to Disease Progression in Myasthenia Gravis.

OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies against the neuromuscular junction. The thymus has an important role in the pathogenesis of MG because most patients have thymic pathology, and thymectomy (TE) can reduce the severity of the disease. METHODS: In this study, the frequency of Th17 and Tc17 cells was studied in 12 MG patients (pre-TE and 6 months post-TE) and in 12 healthy controls (HC). RESULTS: The frequency of Tc17 cells in the pre-TE patients was significantly higher than in the HC (p < 0.05), and after TE, these cells had significantly decreased compared to before TE (p < 0.05). The frequency of Th17 cells in pre-TE patients was significantly higher than in the HC (p < 0.05), and after TE, these cells had significantly decreased compared to before TE (p < 0.05). CONCLUSION: Our findings indicated a possible role of Tc17 and Th17 in MG pathogenesis.

Exosome-Encapsulated microRNAs as Potential Circulating Biomarkers in Colon Cancer.

Exosome-encapsulated microRNAs are being suggested as a new class novel biomarker as diagnostic and predictive markers in colorectal cancer. These particles are released from many cell types into the extracellular space upon fusion of multivesicular bodies (MVB) with the plasma membrane. They contain a wide variety of information, including proteins, lipids, RNAs, non-transcribed RNAs, microRNAs, which can be circulated in various body fluids (e.g., blood, salvia, ascites, urine). Exosomes can be taken up by neighboring or distant cells and thereby modulate the functional of recipient cells and play a key role in disease progression or facilitate metastasis in cancers. The aim of current review is to give an overview about origin and trafficking of exosomes between cells, techniques to isolate exosomal microRNAs as well as the potential applications of exosomeencapsulated microRNAs as diagnostic markers in clinical settings in colorectal cancer. There is growing body of evidence showing the prognostic and diagnostic value of some exosomal microRNAs in colon cancer (e.g., miR- 150, miR-21, miR-192, let-7a, miR-223, and miR-23a). These findings provide a new insight on novel application of these markers as being novel non-invasive biomarkers for early detection and risk assessment of patients with colorectal cancer, although further investigations in larger population are required to explore the clinical utility of exosomal microRNAs in colorectal cancer patients.

Circulating microRNAs as Potential Diagnostic, Prognostic and Therapeutic Targets in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a very poor prognosis, and excessive resistance to chemotherapy. MicroRNAs have been shown to play important roles in PDAC oncogenesis as they can act as both oncogenes and tumor suppressor molecules. Altered expression of specific microRNAs in PDAC has diagnostic and prognostic implications. There is growing body of evidence showing the important role of miR-486-5p and miR-938 for discrimination of PDAC patients from healthy subjects and those with chronic pancreatitis. Additionally the diagnostic features of miR-486-5p were comparable with CA 19-9 for the detection of PDAC patients, suggesting its diagnostic value as a blood-based miRNA in PDAC, although further investigations are warranted for validation of this marker. In addition to these applications, several studies have suggested therapeutic potential of some miRNAs in PDAC. In particular, modulations of let-7, miR-29a, miR-17-5p, miR-365, miR-181b, miR-21, miR-221 and miR-96 are reported to be associated with tumor response. Moreover, enforced expression of miR-17-92 inhibits tumourigenicity and increased chemoresistance in PDAC cancer stem cells via TGF-ß1 pathway, while overexpression of miR-96 suppresses cell proliferation, migration, and invasion in a manner associated with KRAS downregulation. In this review we attempt to give an overview about recent preclinical and clinical studies that have addressed the potential use of circulating microRNAs as diagnostic and prognostic biomarkers, their use as therapeutic targets and finally, we discuss the possible role of microRNAs in PDAC chemoresistance.